Update Endocrinology & Diabetology October 2022

Welcome new developments in obesity treatment

a special event ‘Overweight and Obesity... Lets Talk!’, where the HSE outlined some of its plans for the months ahead, and acknowledged the need to address the growing issue of childhood obesity.

research from around the world. So some very welcome, much-needed service developments in obesity care are on the way.

Welcome to the latest edition of Update Endocrinology and Diabetology.

The ever-growing pressure on endocrinology services in Ireland remains unmatched by resources and staffing, and it can seem like an insurmountable task to deal with the demand for care.

Currently, there are limited services available for the treatment of severe and complex obesity with adults, children, and young people travelling long distances and waiting many years for treatment.

Last year saw the publication of the HSE’s long-awaited Model of Care for the Management of Overweight and Obesity. Like most models of care published in Ireland, it outlines a service and pathway that would be a great improvement for patients and clinicians alike, but its implementation is where the biggest challenge lies. While there have been some welcome service additions, the main elements are yet to be realised.

In the UK, the prevalence of higher BMIs in primary school-aged children has increased since 2020, particularly among children living in areas where health risk factors are more concentrated, which is also likely the case in Ireland. Childhood obesity is treated most effectively by care delivered by a multidisciplinary team, but in Ireland there is limited availability of this type of care for children and young people who need it. But it seems like this is finally set to change.

Earlier this month the HSE collaborated with the Association for the Study of Obesity in Ireland (ASOI) and the Irish Coalition for people living with Obesity (ICPO) to host

Opening the event, Dr Ciara Martin, HSE National Clinical Advisor and Group Lead for Paediatrics, said: “2022 sees the continuation of implementation of the HSE Model of Care for the Management of Overweight and Obesity in Ireland. Specifically, two new multi-disciplinary communitybased services will be set up in South East Community Healthcare and Community Healthcare Dublin South, Kildare, and West Wicklow. These teams will provide specialist support for children and young people with overweight and obesity. The national specialist service in Children’s Health Ireland is also expanding to treat children and young people with severe and complex obesity.”

Also speaking at the event, Prof Donal O’Shea, HSE Obesity Clinical Lead, said: “We welcome the Government’s commitment to address obesity as a ministerial priority and allocate funding to the implementation of the model of care for adults and children’s services through initiatives including Sláintecare Healthy Communities and Scheduled Care Transformation.”

In addition, the publication of the 2022 Waiting List Action Plan earlier this year, the first year of a multi-annual reform programme to stabilise and reduce waiting lists and improve access to services, identified implementation of obesity care pathways as a priority. It is providing funding to increase access and capacity nationally to bariatric surgery.

Meanwhile, a new HIQA report published during the summer concluded that surgery is not only safe, but may be the most effective treatment for many patients with type 2 diabetes caused by obesity, based on a review of

On the medical front, there has also been much excitement this year about the ‘game changing’ weight-loss results of the newest obesity and type 2 diabetes agents, tirzepatide and semaglutide, with the latest data outlined in a number of articles in this edition of Update

This edition also features a detailed article on obesity by Dr Karl Neff, which aims to change how we view, diagnose, and treat the disease of obesity, with expert advice on the latest evidenced-based treatment approaches.

Beyond obesity, there are in-depth clinical articles on the diagnosis and management of type 2 diabetes, the latest and upcoming advances in diabetic kidney disease, new NICE guideline updates on managing type 1 diabetes, a detailed overview of the latest non-insulin therapies for type 1 diabetes, and a new CPD module on managing diabetes in children, as well as an overview of Cushing’s disease.

Conference-wise, there is a round-up of the most topical research presented at the recent 2022 European Association for the Study of Diabetes (EASD) Annual Meeting and the 24th European Congress of Endocrinology (ECE), both of which were held in person for the first time since the Covid-19 pandemic.

So all-in-all, a packed edition that should hopefully prove interesting and useful to all our readers.

Thank you to all our expert contributors for taking the time to share their knowledge and advice for the betterment of patient care. We always welcome new contributors and suggestions for future content, as well as any feedback on our content to date. Please contact me at priscilla@mindo.ie if you wish to comment or contribute an article. ■

Editor Priscilla Lynch priscilla@mindo.ie

Sub-editor

Emer Keogh emer@greenx.ie

Creative Director Laura Kenny laura@greenx.ie

Advertisements Graham Cooke graham@greenx.ie

Administration Daiva Maciunaite daiva@greenx.ie

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EASD 2022 round-up

Priscilla Lynch presents a round-up of some of the most topical research presented at this year’s European Association for the Study of Diabetes (EASD) Annual Meeting, which took place in in Stockholm, Sweden, from 19-23 September

Study shows ‘game-changing’ obesity drug more than halves risk of T2DM

The risk of type 2 diabetes mellitus (T2DM) is more than halved by weekly injections of the obesity drug semaglutide, according to new research presented at the 2022 Annual Meeting of the European Association for the Study of Diabetes (EASD) in Stockholm, Sweden (19-23 Sept).

Semaglutide was recently approved in the US and EU as an obesity treatment and has been provisionally approved to treat obesity in the UK.

“Semaglutide appears to be the most effective medication to date for treating obesity and is beginning to close the gap with the amount of weight loss following bariatric surgery,” said Dr W Timothy Garvey, of the Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, US, who led the research.

“Its approval was based on clinical trial results showing that it reduces weight by over 15 per cent on average, when used together with a healthy lifestyle programme.

“This amount of weight loss is sufficient to treat or prevent a broad array of obesity complications that impair health and quality-of-life and is a game changer in obesity medicine.”

Obesity is known to increase the risk of

T2DM at least six-fold and Dr Garvey and colleagues were interested in whether semaglutide could reduce this risk. To learn more, they carried out a new analysis of the data from two trials of semaglutide.

In STEP1, participants (1,961) with overweight or obesity received an injection of 2.4mg of semaglutide or a placebo weekly, for 68 weeks.

STEP4 involved 803 participants with overweight or obesity. All received weekly injections of 2.4mg semaglutide for 20 weeks. They then either remained on semaglutide or were switched to placebo for the next 48 weeks.

Participants in both trials received advice on diet and exercise.

The researchers used Cardiometabolic Disease Staging (CMDS) to predict the participants’ risk of developing T2DM in the next 10 years.

CDMS has been previously shown be a highly accurate measure of T2DM risk and is calculated using a formula which factors in a patient’s sex, age, race, BMI, and blood pressure, as well as blood glucose, HDL cholesterol and triglyceride levels.

In the STEP1 participants receiving semaglutide, 10-year risk scores for T2DM

decreased by 61 per cent (from 18.2 per cent at week 0 to 7.1 per cent at week 68).

This compares to a 13 per cent reduction in risk score for those given the placebo (17.8 per cent at week 0 to 15.6 per cent at week 68).

Risk scores mirrored weight loss, which was 17 per cent, on average, with semaglutide vs 3 per cent with placebo.

At the start of the trial, risk scores were higher in the participants with pre-diabetes than in those with normal blood sugar levels. However, semaglutide reduced the risk by a similar amount in both groups.

In the STEP 4 participants, the largest decreases in risk scores were seen in the first 20 weeks (from 20.6 per cent at week 0 to 11.4 per cent at week 20). In those who continued receiving semaglutide, the risk score decreased further to 7.7 per cent but, in those who were switched to placebo, it rose to 15.4 per cent. This indicates that sustained treatment with semaglutide is needed to maintain the reduction in T2DM risk

Dr Garvey said: “Semaglutide reduces the future risk of diabetes by over 60 per cent in patients with obesity – this figure is similar whether a patient has pre-diabetes or normal blood sugar levels.”

Young-onset T2DM diabetes linked to substantially higher relative risk of cardiovascular disease and death – study

Men and women who are diagnosed with type 2 diabetes (T2DM) aged 40 or younger are far more likely to develop cardiovascular disease (CVD) and die prematurely than those under 40 in the general population, according to new research presented at this year’s EASD Annual Meeting.

The observational population-based cohort study comparing over 634,000 people newly diagnosed with T2DM with over 1.2 million matched controls over an average of six years, indicates that individuals with early-onset diabetes (aged 40 or younger) were five times more likely to develop heart disease, seven times more likely to be hospitalised with heart failure, and at least five times as likely to die from CVD or from any cause compared with their diabetes-free counterparts.

“Our findings clearly highlight the serious health implications of developing type 2 diabetes at a young age and the importance of efforts to prevent diabetes in early life,” says lead author Dr Da Hea Seo from Inha University School of Medicine, South Korea.

While T2DM usually occurs in middleaged and older people, onset in young adults is becoming more common globally and is typically a more aggressive form that leads to earlier development of complications and higher rates of hospitalisations. As CVD is a major cause of death, it is important to ascertain its burden in people with early-onset T2DM, and to assess the age at which the risk of CVD begins to increase.

To find out more, researchers investigated the relationship between age at diagnosis with T2DM and CVD complications and death in 634,350 individuals with T2DM (average age at diagnosis 56 years) from the Korean National Health Insurance Service (NHIS) database between 2012 and 2014, compared to 1,268,700 gender-, age- and CVD-history matched controls from the general population.

Participants were followed for CVD outcomes (death from any cause, death from CVD, coronary heart disease, heart attack, stroke, hospitalisation for heart failure) or until 2019, and co-founders were adjusted for.

Over an average of six years of followup, 172,120 (40 per cent) of people with early-onset T2DM and 151,363 (23 per cent) controls had either a heart attack, stroke or died from CVD.

The researchers found that risk of CVD complications was strongly linked to age and adults diagnosed with T2DM aged 40 years or younger had the highest relative risk for most complications compared with the general population.

All risks reduced progressively with each increasing decade at age of diabetes diagnosis, but remained statistically significant.

Co-author Dr Seong Bin Hong from Inha University School of Medicine, South Korea, said: “Caring for young people with diabetes, which has traditionally focused on type 1 diabetes, should place more emphasis on type 2 diabetes. What’s more, effective healthcare policies around screening, early diagnosis, and treatment will help to combat the future rise of cardiovascular disease in this increasingly common young-onset, high-risk population.”

Latest type 2 diabetes drug achieves blood sugar and weight targets faster

The phase 3 SURPASS trials published in 2021 established that tirzepatide lowers blood sugar and supports weight loss better than other drugs for type 2 diabetes (T2DM). Now new research evaluating the time taken to reach

blood glucose targets indicates that tirzepatide also achieves blood sugar control and weight-loss goals faster than existing diabetes drugs.

The latest analyses of the SURPASS-2 and

SURPASS-3 trials, presented at this year’s EASD Annual Meeting in Stockholm, found that adults treated with various doses of injectable tirzepatide (5, 10, and 15mg) reached blood glucose targets about four weeks sooner than those taking

injectable semaglutide (1mg), and between four and 12 weeks sooner than those taking a once-daily insulin (degludec; iDeg), along with diet and exercise and oral glucose-lowering medications.

“Tirzepatide is unique because it mimics two natural insulin-releasing and appetite-suppressing hormones in one injection,” said lead author Dr Adie Viljoen, a Consultant Metabolic Physician and Chemical Pathologist from the East and North Hertfordshire NHS Trust, UK. “The speed we are seeing in glucose-lowering and weight loss is beyond anything else we have available right now and it may put adults with type 2 diabetes in a better position for preventing long-term complications. But it is important to remember that these medications should be used in addition to diet and exercise.”

Tirzepatide is a single molecule that belongs to a new class of diabetes drugs that mimics two hormones, glucagon like peptide-1 (GLP-1) and glucosedependent insulinotropic polypeptide (GIP), involved in blood sugar control and appetite suppression. It was approved for the treatment of T2DM by the US Food and Drug Administration (US FDA) in May 2022.

compared different doses of tirzepatide (5, 10, and 15mg) with a once-weekly injectable semaglutide 1mg (which is a single hormone, GLP-1 mimic agent) as an add-on therapy to metformin, or a long-acting insulin (iDeg), as an add-on therapy to metformin with or without a sodium-glucose cotransporter-2 inhibitor, respectively.

On average, participants treatedwith all doses of tirzepatide lowered their HbA1c more than those treated with semaglutide and iDeg, and a greater proportion achieved a HbA1c of less than 7 per cent (<53mmol/mol), less than or equal to 6.5 per cent (≤48mmol/mol), and less than 5.7 per cent (<39mmol/ mol) at 40-weeks (SURPASS-2) and 52-weeks (SURPASS-3), respectively.

In this latest analysis comparing the time to reach HbA1c targets from the start of the study, researchers found that participants taking tirzepatide reached HbA1c targets of less than 7 per cent and 6.5 per cent or less considerably faster than both semaglutide and iDeg.

The average (median) time to achieve a HbA1c level of less than 7 per cent was around eight weeks for all tirzepatide doses compared to 12 weeks for both semaglutide and iDeg; and to reach 6.5 per cent or less was 12 weeks versus about 16 weeks and 24 weeks, respectively.

Further analyses of SURPASS-2, found that participants treated with tirzepatide also reached weight-loss goals significantly faster than semaglutide. The average time to reach 5 per cent or more weight loss was around 12 weeks on the two higher doses of tirzepatide (10 and 15mg) compared to 24 weeks for semaglutide.

“Even a modest weight loss of 5 per cent of initial body weight is associated with clinically-significant improvements in weight-related health issues for many individuals,” said Dr Viljoen. “For people with type 2 diabetes to be able to achieve these improvements in health in around half the time is pretty incredible.”

Mild-to-moderate gastrointestinal adverse events, such as nausea, vomiting, and diarrhoea, were noted in participants taking tirzepatide and were most frequently reported during the dose escalation period and decreased over time.

The authors acknowledge several limitations of the study, including that the studies were not specifically designed to compare the rate of glycaemic control and weight loss and therefore these analyses should be interpreted with caution.

Reasons for hospital admissions in people with T2DM are changing

The most common reasons why people with type 2 diabetes (T2DM) are admitted to hospital with greater frequency than the general population are changing, with hospitalisation for traditional diabetes complications

now being accompanied by admissions for a diverse range of lesser-known complications including infections (ie, pneumonia, sepsis), mental health disorders, and gastrointestinal conditions, according to an analysis

of national data from Australia spanning seven years.

The findings presented at this year’s EASD Annual Meeting reveal that just four ‘traditional’ diabetes

complications (cellulitis, heart failure, urinary tract infections, and skin abscesses) were ranked in the top 10 leading causes of hospitalisation in men and women with T2DM.

While rates of traditional T2DM complications – including heart attack, stroke and amputations – have fallen substantially over the past 20 years in many high-income countries, driven by improvements in risk factors (eg, blood pressure, cholesterol, smoking, and blood sugar control) and better preventive care and management, leading causes of death and illness, such as cancer, liver disease, and mental disorders, are emerging among people with diabetes. In England, for example, classic complications accounted for more than half of hospitalisations in people with diabetes in 2003, but for less than a third in 2018.

To find out more, researchers analysed data from around 50 per cent of Australians diagnosed with T2DM from the Australian Diabetes Registry (the National Diabetes Services Scheme (NDSS)). In total, 456,265 individuals (aged 15 years and older) with T2DM registered on the NDSS between 2010 and 2017 were linked with hospital data and compared to over 19 million Australians aged 15 years and above.

Modelling was used to identify the leading individual diagnosis-level causes of hospitalisation among people with T2DM and to estimate the relative risk of hospitalisation compared to the general population, after adjusting for age and calendar-year effects. Admissions for T2DM itself (eg, glucose disturbances such as hypoglycaemia) were excluded from the analyses.

Diabetes complications were divided into three categories – traditional complications that included vascular diseases, kidney failure, retinopathy and cataracts, neuropathy, and obesity; infections traditionally linked to

diabetes (eg, urinary); and complications of procedures related to well-known diabetes complications (eg, amputation). Emerging complications included liver disease, mental health disorders, various cancers (eg, gastrointestinal, female sex organs), and infections less commonly associated with diabetes (eg, respiratory infections, sepsis). All other diagnoses were categorised as ‘not commonly acknowledged’ complications.

Overall, the analyses found that people with T2DM are at greater risk of being hospitalised with most medical conditions compared to the general population (exceptions include prostate cancer, aortic aneurysm, and wrist fractures).

were also noted for lesser-known complications including depression (256 per 100,000), gastrointestinal disorders (237 per 100,000) and asthma (192 per 100,000) – with hospitalisations for asthma more than twice as likely amongst women with T2DM compared to the general population.

Lead author Dr Dee Tomic from the Baker Heart and Diabetes Institute, Melbourne, Australia, noted that the emergence of non-traditional diabetes complications reflects improvements in diabetes management and people with diabetes living longer, making them susceptible to a broader range of complications.

The leading cause of excess hospitalisations in men with T2DM was cellulitis, responsible for 364 excess annual hospitalisations per 100,000 men with T2DM, followed by the lesser-recognised complications of stress disorders (241 per 100,000) and iron deficiency anaemia (228 per 100,000) – with diabetes doubling the risk of admission for these conditions compared to the general population.

In women with T2DM, iron deficiency anaemia was the leading cause of excess annual admissions (558 per 100,000), followed by the traditional complications of urinary tract infections (332 per 100,000) and cellulitis (267 per 100,000). High rates of excess hospitalisation

“The much greater risk for most mental health diagnoses in the diabetes population reinforces the evidence for mental health disorders as an emerging complication of T2DM,” added senior author Prof Dianna Magliano, Head of Diabetes and Population Health at Monash University, Melbourne, Australia. “The unexpected finding of a large burden of anaemia in both men and women with T2DM suggests the possibility of a biological link between diabetes and iron deficiency. To look at this and other novel findings in more detail, we must conduct further analyses as diabetes registries become more common to understand the effects of diabetes on all organs to guide prevention and management strategies.”

The authors acknowledge that their findings show observational associations rather than cause and effect. They also note some limitations, including that the study included people from one highincome country with a predominantly white Caucasian population, so the findings cannot be generalised to low- and middle-income countries. Additionally, they were unable to exclude people with diabetes from the general population, so the strength of the associations might be reduced compared to an analysis of people with versus without diabetes.

The unexpected finding of a large burden of anaemia in both men and women with T2DM suggests the possibility of a biological link between diabetes and iron deficiency

When a DPP-4 inhibitor is needed

Simplicity. Reinforced .

for a BROAD RANGE of adults with type 2 diabetes (T2D)

UNIQUE CONVENIENCE through always one dose, once daily 1 5mg once daily

Demonstrated CV AND KIDNEY SAFETY PROFILE 2,3

PROVEN EFFICACY VS PLACEBO

for adults with T2D 1,4

References:

1. TRAJENTA® (linagliptin) Summary of Product Characteristics. SmPC available at: https://www.medicines.ie/

2. Rosenstock J, et al. JAMA. 2019;321:69–79

3. Rosenstock J, et al. Cardiovasc Diabetol. 2018;17:39

4. McGill JB, et al. Diabetes Care. 2013;36:237–44

Prescribing Information (Ireland) TRAJENTA® (Linagliptin)

Film-coated tablets containing 5 mg linagliptin. Indication: Trajenta is indicated in adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycaemic control as: monotherapy when metformin is inappropriate due to intolerance, or contraindicated due to renal impairment; combination therapy in combination with other medicinal products for the treatment of diabetes, including insulin, when these do not provide adequate glycaemic control. Dose and Administration: 5 mg once daily. If added to metformin, the dose of metformin should be maintained and linagliptin administered concomitantly. When used in combination with a sulphonylurea or with insulin, a lower dose of the sulphonylurea or insulin, may be considered to reduce the risk of hypoglycaemia. Renal impairment: no dose adjustment required. Hepatic impairment: pharmacokinetic studies suggest that no dose adjustment is required for patients with hepatic impairment but clinical experience in such patients is lacking. Elderly: no dose adjustment is necessary based on age. Paediatric population: the safety and ef cacy of linagliptin in children and adolescents has not yet been established. No data are available. The tablets can be taken with or without a meal at any time of the day. If a dose is missed, it should be taken as soon as possible but a double dose should not be taken on the same day. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Warnings and Precautions: Linagliptin should not be used in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis. Hypoglycaemia: Caution is advised when linagliptin is used in combination with a sulphonylurea and/or insulin; a dose reduction of the sulphonylurea or insulin may be considered. Acute pancreatitis: Acute pancreatitis has been observed in patients taking linagliptin. Patients should be informed of the characteristic symptoms of acute pancreatitis. If pancreatitis is suspected, Trajenta should be discontinued. If acute pancreatitis is con rmed, Trajenta should not be restarted. Caution

should be exercised in patients with a history of pancreatitis. Bullous pemphigoid: Bullous pemphigoid has been observed in patients taking Linagliptin. If bullous pemphigoid is suspected, Trajenta should be discontinued. Interactions: Linagliptin is a weak competitive and a weak to moderate mechanism-based inhibitor of CYP isozyme CYP3A4, but does not inhibit other CYP isozymes. It is not an inducer of CYP isozymes. Linagliptin is a P-glycoprotein substrate and inhibits P-glycoprotein mediated transport of digoxin with low potency. Based on these results and in vivo interaction studies, linagliptin is considered unlikely to cause interactions with other P-glycoprotein substrates. Effects of other medicinal products on linagliptin: The risk for clinically meaningful interactions by other medicinal products on linagliptin is low. Rifampicin: Multiple co-administration of 5 mg linagliptin with rifampicin, a potent inductor of P-glycoprotein and CYP3A4, decreased linagliptin steady state AUC and Cmax. Thus, full ef cacy of linagliptin in combination with strong P-glycoprotein inducers might not be achieved, particularly if administered long term. Coadministration with other potent inducers of P-glycoprotein and CYP3A4, such as carbamazepine, phenobarbital and phenytoin has not been studied. Effects of linagliptin on other medicinal products: In clinical studies linagliptin had no clinically relevant effect on the pharmacokinetics of metformin, glibenclamide, simvastatin, warfarin, digoxin or oral contraceptives (please refer to Summary of Product Characteristics for a full list of interactions and clinical data). Fertility, pregnancy and lactation: The use of linagliptin has not been studied in pregnant women. As a precautionary measure, avoid use during pregnancy. A risk to the breast-fed child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from linagliptin therapy taking into account the bene t of breastfeeding for the child and the bene t of therapy for the woman. No studies on the effect on human fertility have been conducted

for linagliptin. Undesirable effects: Adverse reactions reported in patients who received linagliptin 5 mg daily as monotherapy or as add-on therapies in clinical trials and from post-marketing experience. Frequencies are de ned as very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or very rare (<1/10,000). Adverse reactions with linagliptin 5 mg daily as monotherapy: Common: lipase increased. Uncommon: nasopharyngitis; hypersensitivity; cough; rash; amylase increased. Rare: pancreatitis; angioedema; urticaria; bullous pemphigoid. Adverse reaction with linagliptin in combination with metformin plus sulphonylurea: Very common: hypoglycaemia. Adverse reaction with linagliptin in combination with insulin: Uncommon: constipation. Prescribers should consult the Summary of Product Characteristics for further information on side effects. Pack sizes: 28 tablets. Legal category: POM. MA number: EU/1/11/707/003. Marketing Authorisation Holder: Boehringer Ingelheim International GmbH, D-55216 Ingelheim am Rhein, Germany. Prescribers should consult the Summary of Product Characteristics for full prescribing information. Additional information is available on request from Boehringer Ingelheim Ireland Ltd, The Crescent Building, Northwood, Santry, Dublin 9. Prepared in September 2021.

Adverse events should be reported. Reporting forms and information can be found at https:// www.hpra.ie/homepage/about-us/report-an-issue. Adverse events should also be reported to Boehringer-Ingelheim Drug Safety on 01 2913960, Fax: +44 1344 742661, or by e-mail: PV_local_UK_Ireland@boehringer-ingelheim.com

Trial shows remission from T2DM possible even in people with lower body weight

Everyone has a ‘personal fat threshold’ which, if exceeded, will allow type 2 diabetes (T2DM) to develop, even if they are of a lower body weight, data presented at the 2022 Annual Meeting of the EASD showed.

Having a BMI over 30 is a risk factor for T2DM and landmark research from Newcastle University previously showed how and why an intensive weight loss programme can put T2DM into remission in people who are living with obesity or overweight.

But not everyone with T2DM is overweight. Around 15 per cent of T2DM diagnoses are in people with normal weight and it is generally assumed the condition has a different cause in such cases.

The ReTUNE Study (Reversal of Type 2 Diabetes upon Normalisation of Energy Intake in the Non-obese) looked at whether weight loss can also reverse the condition in people with a BMI at or only just above the ‘normal’ range (BMI below 27kg/m2).

This would support the idea that everyone has a ‘personal fat threshold’ – a level of body fat we can cope with – and if we go above it, we will develop T2DM, even if our weight seems unremarkable.

Twenty men and women with T2DM (average BMI 24.8kg/m2, average age 59.0 years) took part in the study, which was funded by Diabetes UK.

They followed a weight loss programme in which they consumed 800 calories a day (from low calorie soups and shakes and nonstarchy vegetables) for two weeks, followed by four-to-six weeks in which they kept their new weight steady. They completed up to three rounds of this diet/weight maintenance cycle until they had lost 10-to-15 per cent of their body weight.

Their results at the end of the study were

compared to those of a group of controls – 20 people without diabetes who were matched for age, sex, and BMI.

A total of 14 of the 20 participants (70 per cent) with T2DM went into remission – a similar proportion to previous studies involving participants living with T2DM and overweight and obesity. Remission was defined as an HbA1c of less than 48mmol/ mol for at least six months and off all medication. Participants had lost an average of 7.7kg at remission (10.7 per cent of initial weight). Weight remained stable between six and 12 months.

Average BMI fell from 24.8-to-22.4 and total body fat fell from 32.1-to-27.7 per cent. (Matched to the control group of people without diabetes who had an average BMI of 21.5 and 24.6 per cent total body fat.)

Participant MRI scans showed that levels of fat inside the liver and pancreas fell substantially.

Even though the average amount of fat in the liver of the study participants would be regarded as unremarkable at 4.1 per cent, this was around three times higher than in healthy controls of the same weight and it fell to 1.4 per cent, close to the healthy control level.

Fat in the pancreas fell from an average of 5.8-to-4.3 per cent and the activity of the insulin-producing cells returned towards normal.

The researchers say that their results clearly demonstrate that T2DM is caused by the same factors in normal-weight people as it is in those living with overweight or obesity.

This is important because doctors tend to assume that T2DM has a different cause in those with lower body weights and so they aren’t usually advised to lose weight before starting them on diabetes drugs and,

eventually, insulin.

“But if they lost around 10 per cent of their weight, they would have a very good chance of putting their type 2 diabetes into remission,” said Prof Roy Taylor, of Newcastle University, Newcastle, UK, the Principal Investigator on the trial.

The results should also help dispel the stigma that can be attached to a diagnosis of T2DM, said Prof Taylor. He explains:

“The results also support the personal fat threshold concept that anyone with type 2 diabetes has a little more fat on board than they individually can cope with. This is determined by your genes. Each of us has a threshold level under which they can store fat safely and that this has little to do with BMI.

“If you develop type 2 diabetes, you simply have more fat inside your body than you can cope with, even if apparently slim. This excess fat spills into your liver and pancreas stopping normal function and causing type 2 diabetes. You only need an extra half gram of fat in the pancreas to prevent normal insulin production.

“I’m often asked, ‘Why have I got type 2 diabetes when all my friends are larger than me and do not have diabetes?’ The present work answers this conundrum.

“This should help to remove some of the stigma that attaches to type 2 diabetes. It is clearly a condition which is not ‘caused’ by being over any level of BMI, but by storing a little too much fat inside the liver and pancreas, whatever your weight.”

The researchers recommend that anyone who has a family member with T2DM get their blood sugar checked each year, whatever their weight. Regular checks are also advised for anyone who has had diabetes in pregnancy or is not of white European ethnicity.

Common group of viruses strongly linked to T1DM

A common group of viruses is strongly associated with type 1 diabetes (T1DM), according to new research presented at the 2022 Annual Meeting of the EASD.

The Australian analysis found that individuals with T1DM were eight times more likely to have an enterovirus infection than those without T1DM. This very common group of viruses includes those that cause polio and hand, foot, and mouth disease (HFMD), as well as other types that cause milder, cold-like symptoms.

Vaccines that seek to reduce the incidence of T1DM by preventing enterovirus infection are already in clinical trials and confirmation of the role of enteroviruses would support this and other work towards the primary prevention of T1DM.

To explore the association more deeply, Sonia Isaacs, of the Department of Paediatrics and Child Health, School of Clinical Medicine, University of New South Wales, Australia, and colleagues carried out a systematic review and meta-analysis of existing research on the topic.

The meta-analysis – the largest in this field – included data on 12,077 participants (age 0-87 years) from 60 controlled observational studies found on the PubMed and Embase databases.

A total 5,981 of the participants had T1DM or islet autoimmunity (which typically progresses to T1DM). The remaining 6,096 participants had neither condition.

Enterovirus RNA or protein, a sign of a current or recent infection, was detected in blood, stool or tissue samples using a range of advanced, and highly sensitive, molecular techniques.

Those with islet autoimmunity had twice the odds of testing positive for enteroviruses as those without islet autoimmunity.

The odds of enterovirus infection were eight times greater in those with T1DM than those without T1DM.

Most importantly, individuals with T1DM were over 16 times more likely to have an enterovirus infection detected in the month after their T1DM diagnosis, than those without T1DM.

The researchers conclude that there is a clear association between enterovirus infection and both islet autoimmunity and T1DM.

pancreas, where a low-level, persistent infection and resulting inflammation can lead to an autoimmune response.

“Virus infections are also proposed to work in combination with other factors, such as diet, imbalances in the gut microbiome, and even chemical exposures, which may occur in utero (during pregnancy) or early childhood. There is still a lot to learn.”

Meanwhile, a number of separate studies on the link between Covid-19 and T1DM diagnosis were also presented at the meeting. A nationwide observational study from Norway found that young people who contracted Covid-19 were around 60 per cent more likely to develop T1DM 30 days or more after infection compared to those without a registered infection or who tested negative for the virus.

Ms Isaacs added: “These findings provide further support for ongoing work to develop vaccines to prevent the development of islet autoimmunity and therefore reduce the incidence of T1DM.”

There are several theories about how enteroviruses increase the risk of developing T1DM. It is thought, for example, that their interaction with particular genes may be important.

Ms Isaacs said: “Our study found that people with T1DM who had both genetic risk and a first-degree relative with T1DM were 29 times more likely to have an enterovirus infection.

“The number, timing and duration and even the site of enterovirus infections may also be important. The ‘leaky gut’ hypothesis suggests that viruses originating in the gut could travel along with activated immune cells to the

However, a Scottish study found that while testing positive for SARS-CoV-2 is associated with an increased incidence of new-onset T1DM in people aged younger than 35 years in the first month after infection, it is more likely explained by increased testing around the time of diabetes diagnosis and Covid-19 precipitating diabetes in those already developing it.

The analysis found no association between SARS-CoV-2 infection and new-onset T1DM 30 days or more after infection, or in those aged younger than 16 years, contrary to several previously reported studies.

However, the researchers did find that children and adults with a first positive SARS-CoV-2 test were 2.5 times as likely to be diagnosed with diabetes within 30 days of infection compared to those who did not have a previous registered infection; this risk was more than three times higher in those younger than 16 years. But the authors stressed strong arguments against a causal effect of Covid-19 underlying this association.

The number, timing and duration and even the site of enterovirus infections may also be important

Study reveals sex differences in care and outcomes of children and teens with T1DM

New research presented at the 2022 EASD Annual Meeting suggests that girls with type 1 diabetes (T1DM) have poorer metabolic control than boys and face more complications.

The systematic review synthesising all the available evidence on sex differences in the care and outcomes of children and adolescents (aged 18 or younger) was presented by Silvia de Vries from Amsterdam University Medical Centres in the Netherlands, and colleagues.

“Improving awareness of type 1 diabetes in young females is key to minimising disparities in care and reducing the likelihood of life-threatening complications later in life, such as heart disease and kidney failure,” says De Vries. “Our findings of troubling inequities call for urgent and targeted efforts, such as increased surveillance for sex disparities in daily clinical practice and cardiovascular risk prevention, sex-appropriate diabetic ketoacidosis awareness campaigns, and screening of quality-of-life tailored to adolescent girls.”

Sex differences have been found in cardiovascular care and outcomes among adult patients with T1DM. Women with T1DM have a roughly 40 per cent greater excess risk of death from any cause, and twice the excess risk of fatal and non-fatal vascular events, compared to men with T1DM. However, it is not known whether sex influences care and outcomes in children.

To find out more, De Vries and colleagues did a systematic review of observational studies worldwide investigating sex differences in patient and disease characteristics, treatment, comorbidities, and complications in children with T1DM (aged 18 or younger), up to June 2021. Of 8,640 articles identified, 90 studies reporting on important outcomes

relevant to the daily care process were included in the review.

Analysis of data from 89,700 children showed that in seven-out-of-10 studies, BMI was higher in girls. Similar results were observed for adolescent girls (seven studies, 33,153 children), with levels of overweight or obesity and dyslipidaemia higher in girls than boys.

Studies focusing on blood sugar control revealed a similar picture. Average blood sugar (HbA1c) levels were up to 6.4mmol/ mol higher in girls during treatment (21 studies including 144,613 young people). Similarly, this difference was present at diagnosis and in studies that reported increases in average blood sugar over time.

In addition, girls used insulin pump therapy (six studies, 211,324 young people) more often and needed higher insulin doses.

Diabetes-associated comorbidities like thyroid disease and Coeliac disease were also more common in young females.

The exact reasons behind this gap in metabolic control between girls and boys is not clear, but some evidence suggests that normal changes in girls’ bodies during puberty make it more difficult for them to get their diabetes under control. However, some differences seem to be present before puberty and may be caused by early differences in body composition and fat distribution. In addition, behavioural differences between boys and girls in childhood may play a role.

Eight studies (3,561 young people) looking at the serious complication of diabetic ketoacidosis (DKA) found similar results with DKA at diagnosis. DKA during treatment, as well as more severe DKA requiring hospitalisation, were more common in girls.

The authors speculate that the increased occurrence of DKA at diagnosis may be a sign that sex differences are already present in the very first stages of the disease. Disease progression and presentation of initial symptoms may vary between the sexes. A difference in interpretation of those initial signs by caregivers and the treatment team can also play a part and needs to be addressed.

On the other hand, some studies showed that hypoglycaemia and partial diabetes remission occurred more often in boys.

Analysis of data from 15 studies involving 8,722 children and teens found that all studies reported a lower overall quality-of-life in adolescent girls. Results also indicated that girls are particularly vulnerable to diabetes-related distress and fear of hypos.

“Improving disease-related coping mechanisms and quality-of-life during this vulnerable period may be an important strategy to improve glycaemic control and reduce the risk of complications,” says De Vries. “All young people with type 1 diabetes should be offered care that is tailored to their individual needs so they are able to manage their condition effectively. With the right care and support in place, there is no reason why both girls and boys with type 1 diabetes can’t live equally long and healthy lives.”

The authors acknowledge that the results are based on observational studies, so no direct conclusions on the causal relation between sex and the studied outcomes can be made. They also note that their aim was to identify sex differences in current paediatric diabetes care, potentially resulting in an under representation of studies with neutral outcomes, which may limit the conclusions that can be drawn.

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New treatment options to offer substantial control over diabetes and obesity

New third generation anti-obesity drugs, as well as expansion of metabolic surgery, are set to revolutionise the care of obesity and type 2 diabetes.

The results of a phase 3 trial on a new diabetes drug, tirzepatide, has found that it can help to reduce weight by up to four stone in 40 per cent of patients with obesity.

A symposium on the data to date on tirzepatide took place during the 2022 European Association for the Study of Diabetes (EASD) Annual Meeting in September.

Tirzepatide, a once-weekly subcutaneous injectable peptide for type 2 diabetes, is also known to enable patients to lose substantial amounts of weight. To quantify its impact on weight loss, Irish Society of Nutrition and Metabolism (IrSPEN) member and St Vincent’s University Hospital Obesity Specialist Prof Carel le Roux presented the findings of a trial of the medication in patients without diabetes during EASD 2022. SURMOUNT-1 was a phase 3 clinical trial of 2539 patients with overweight and obesity who had comorbidities related to weight, but did not have type 2 diabetes. Participants received either a placebo or once-weekly injections of tirzepatide (5mg, 10mg, or 15mg) for 18 months. Patients weighed 16 stone at the start of the study.

Those who received the placebo and lifestyle treatment lost on average half a stone. However, patients who received 10mg or 15mg doses of tirzepatide lost on average three stone, and 40 per cent lost more than four stone.

These outcomes also greatly improved patients’ risk factors for heart disease. Sideeffects were mild or moderate and included nausea, diarrhoea or constipation.

Prof le Roux said: “This 72-week trial in people with obesity showed that tirzepatide provides significant and sustained reductions in body weight and all indications are that the health gain is substantial.”

Tirzepatide has been approved by the US FDA to be used for patients with diabetes and has also received a favourable opinion from the European Medicines Agency. Final approval for use in patients in Ireland and other EU countries is awaited, but expected in the near future.

Speaking to Update, Prof le Roux said: “The third generation anti-obesity drugs such as semaglutide and tirzepatide appear to be as easy to prescribe and tolerate as antihypertensive agents such as ACE inhibitors.

“The benefit of the new anti-obesity medications are that you don’t have to ask a patient to lose weight, because by treating obesity effectively they naturally lose weight. What we now need to do is improve nutritional therapies to make sure we look after people as they lose 15-to-25 per cent bodyweight.”

Metabolic surgery for diabetes

Obesity is the major contributing factor to type 2 diabetes, which affects approximately 250,000 people in Ireland. Treatment for type 2 diabetes alone accounts for more than 10 per cent of the overall healthcare budget.

IrSPEN has welcomed the results of a HIQA health technology assessment, published during the summer, that recommended the introduction of a metabolic surgery programme as part of the clinical pathway for type 2 diabetes in Ireland.

While metabolic surgery is not currently offered as part of standard care for type

2 diabetes in Ireland, many diabetes and obesity organisations recommend it as an accepted treatment option for people with comorbid type 2 diabetes and obesity. HIQA’s review included evidence from 24 randomised controlled trials examining metabolic surgery with short- to mediumterm follow-up (maximum 10 years).

Dr Conor Teljeur, HIQA’s Chief Scientist, said: “When reviewing the evidence, we found that metabolic surgery is safe and very effective in patients with comorbid type 2 diabetes and obesity. It results in improved blood sugar control, weight loss, and reduced use of anti-hyperglycaemic medications. Overall, we found that providing metabolic surgery as part of the type 2 diabetes clinical care pathway would be an efficient and highly cost-effective use of healthcare resources.”

Commenting, Prof Le Roux said: “HIQA estimated that a new programme will cost €7.6 million over five years and be able to treat 200 patients per year. This can be done together with existing services and should provide end-to-end care, from referral, preoperative assessment, the surgical episode, and long-term follow-up.”

He added: “We often hear patients tell us that despite their using the best medical treatment, unfortunately their diabetes is slowly getting worse and affecting their liver, kidneys, or heart. Patients know if they can have diabetes surgery they can get rid of the diabetes and their organs will then improve.

“More than a thousand patients with diabetes are having this lifesaving operation in France each year. All patients need is for the HSE to follow the advice of the government experts and allow patients to be helped.” n

Type 1 diabetes: What do the new NICE guidelines say?

Type 1 diabetes is a chronic autoimmune disease that arises following the destruction of insulin-producing beta cells in the pancreas. As a result, people with type 1 diabetes require insulin therapy to adequately regulate blood glucose levels. In the short-term, people with type 1 diabetes may face significant challenges to daily living, such as hyperglycaemia, hypoglycaemia, and ketoacidosis, while longterm complications can occur in the form of both microvascular complications, such as diabetic retinopathy and neuropathy, and macrovascular complications, such as stroke and coronary artery disease.

The additional strain placed on healthcare resources when diabetes patients are hospitalised illustrates that diabetes-related complications impose not only a significant burden on patients and the healthcare system, but can also have a substantial societal impact due to productivity losses (such as days off work because of illness).

This year the UK’s National Institute for Health and Care Excellence (NICE) has updated a number of its diabetes-related clinical guidelines, including its one on type 1 diabetes care for adults (Type 1 diabetes in adults: Diagnosis and management (NG17)).

This guideline covers care and treatment for adults (aged 18 and over) with type 1 diabetes and includes advice on diagnosis, education and support, blood glucose management, cardiovascular risk, and identifying and managing long-term complications. It is presented here in an abridged format, highlighting the key elements.

In August 2022, NICE also amended its recommendations on blood pressure targets in people with diabetes to make them consistent with its recommendations on

blood pressure control in its guidelines on chronic kidney disease and hypertension.

1.1 Diagnosis and early care plan Initial diagnosis

1.1.1 Make an initial diagnosis of type 1 diabetes on clinical grounds in adults presenting with hyperglycaemia. Bear in mind that people with type 1 diabetes typically (but not always) have one or more of:

 Ketosis;

 Rapid weight loss;

 Age of onset under 50 years;

 Body mass index (BMI) below 25kg/m2;

 Personal and/or family history of autoimmune disease. [2015, amended 2022]

1.1.2 Do not use age or BMI alone to exclude or diagnose type 1 diabetes in adults. [2022]

1.1.3 Take into consideration the possibility of other diabetes subtypes and revisit the diagnosis at subsequent clinical reviews. Carry out further investigations if there is uncertainty (see recommendations 1.1.7 and 1.1.8). [2022]

1.1.4 Measure diabetes-specific autoantibodies in adults with an initial diagnosis of type 1 diabetes, taking into account that:

 The false negative rate of diabetesspecific autoantibody tests is lowest at the time of diagnosis.

 The false negative rate can be reduced by carrying out quantitative tests for two different diabetes-specific autoantibodies (with at least one being positive). [2022]

1.1.5 Do not routinely measure serum C peptide to confirm type 1 diabetes in adults. [2022]

1.1.6 In people with a negative diabetesspecific autoantibody result, and if diabetes

classification remains uncertain, consider measuring non-fasting serum C peptide (with a paired blood glucose). [2022]

Revisiting initial diagnosis

1.1.7 At subsequent clinical reviews, consider using serum C peptide to revisit the diabetes classification if there is doubt that type 1 diabetes is the correct diagnosis. [2022]

1.1.8 Take into account that the discriminative value of serum C peptide to diagnose type 1 diabetes increases the longer the test is done after initial diagnosis of diabetes. [2022]

1.1.9 For people aged 60 and over presenting with weight loss and newonset diabetes, follow recommendations on assessing for pancreatic cancer in the section on pancreatic cancer in the NICE guideline on suspected cancer: Recognition and referral. [2022]

Early care plan

1.1.10 At diagnosis (or, if necessary, after managing critically decompensated metabolism), the diabetes professional team should work with adults with type 1 diabetes to develop a plan for their early care. This will generally require:

 Medical assessment to:

• Ensure the diagnosis is accurate (see recommendations 1.1.1 to 1.1.5);

• Ensure appropriate acute care is given when needed;

• Review medicines and detect potentially associated disease;

• Detect adverse vascular risk factors.

 Environmental assessment to understand:

• The social, home, work, and recreational circumstances of the

person and their carers;

• Their lifestyle (including diet and physical activity);

• Other relevant factors, such as substance use.

 Cultural and educational assessment to:

• Find out what they know about diabetes;

• Help with tailoring advice, and with planning treatments, and diabetes education programmes.

 Assessment of their emotional wellbeing to decide how to pace diabetes education. [2004]

1.1.11 Use the results of the initial diabetes assessment to agree a future care plan. This assessment should include:

 Acute medical history.

 Social, cultural, and educational history, and lifestyle review.

 Complications history and symptoms.

 Diabetes history (recent and long-term).

 Other medical history.

 Family history of diabetes and cardiovascular disease.

 Medication history.

 Vascular risk factors.

 Smoking.

 General examination.

 Weight and BMI.

 Foot, eye, and vision examination.

 Urine albumin:creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR).

 Psychological wellbeing.

 Attitudes to medicine and self-care.

 Immediate family and social relationships, and availability of informal support. [2004, amended 2021]

1.1.12 Include the following in an individualised and culturally appropriate diabetes plan:

 When and where they will have their diabetes education, including their dietary advice (see the sections on education and information and dietary management).

 Initial treatment, including guidance on insulin injection and insulin regimens (see the sections on insulin therapy and insulin delivery in the full guideline).

 Self-monitoring and targets (see the section on blood glucose management).

 Symptoms, and the risk of hypoglycaemia and how it is treated.

 Management of special situations, such as driving.

 Communicating with the diabetes professional team (how often and how to contact them).

 Management of cardiovascular risk factors (see the section on control of cardiovascular risk).

 Implications for pregnancy and family planning advice (see NICE’s guideline on diabetes in pregnancy).

 How often they will have follow-up appointments, and what these will cover (including review of HbA1c levels, experience of hypoglycaemia, and annual reviews). [2004, amended 2015]

1.1.13 After the initial plan is agreed, implement it without inappropriate delay. Based on discussion with the adult with type 1 diabetes, modify the plan as needed over the following weeks. [2004]

1.3 Education and information

1.3.1 Offer all adults with type 1 diabetes a structured education programme of proven benefit, for example, the DAFNE (dose adjustment for normal eating) programme. [2015] Full details of this section are available at: www.nice.org.uk/ guidance/ng17/.

1.4 Dietary management Carbohydrate counting

1.4.1 Offer carbohydrate counting training to adults with type 1 diabetes as part of structured education programmes for selfmanagement (see the section on education and information). [2015]

1.4.2 Consider carbohydrate counting courses for adults with type 1 diabetes who are waiting for a more detailed structured education programme or who are unable to take part in a standalone structured education programme. [2015]

Glycaemic index diets

1.4.3 Do not advise adults with type 1 diabetes to follow a low glycaemic index diet for blood glucose control. [2015]

Dietary advice

1.4.4 Offer dietary advice to adults with type 1 diabetes about issues other than blood glucose control (such as managing weight and cardiovascular risk), as needed. [2015]

1.6 Blood glucose management HbA1c measurement and targets

Measurement

1.6.1 Measure HbA1c levels every three to six months in adults with type 1 diabetes. [2015]

1.6.2 Consider measuring HbA1c levels more often in adults with type 1 diabetes if their blood glucose control is suspected to be changing rapidly; for example, if their HbA1c level has risen unexpectedly above a previously sustained target. [2015]

1.6.3 Measure HbA1c using methods calibrated according to International Federation of Clinical Chemistry (IFCC) standardisation. [2015]

1.6.4 Tell adults with type 1 diabetes their HbA1c results after each measurement and have their most recent result available at consultations. Follow the principles on communication in NICE’s guideline on patient experience in adult NHS services. [2015]

1.6.5 If HbA1c monitoring is invalid because of disturbed erythrocyte turnover or abnormal haemoglobin type, estimate trends in blood glucose control using one of the following:

 Fructosamine estimation.

 Quality-controlled blood glucose profiles.

 Total glycated haemoglobin estimation (if abnormal haemoglobins). [2015]

Targets

1.6.6 Support adults with type 1 diabetes to aim for a target HbA1c level of 48mmol/mol (6.5 per cent) or lower, to minimise the risk of long-term vascular complications. [2015]

1.6.7 Agree an individualised HbA1c target with each adult with type 1 diabetes. Take into account factors, such as their daily activities, aspirations, likelihood of

complications, comorbidities, occupation, and history of hypoglycaemia. [2015]

1.6.8 Ensure that aiming for an HbA1c target is not accompanied by problematic hypoglycaemia in adults with type 1 diabetes. [2015]

1.6.9 Diabetes services should document the proportion of adults with type 1 diabetes who reach an HbA1c level of 53mmol/mol (7 per cent) or lower. [2015]

Blood glucose targets

1.6.22 Advise adults with type 1 diabetes to aim for:

 A fasting plasma glucose level of 5-to7mmol/litre on waking; and

 A plasma glucose level of 4-to-7mmol/litre before meals at other times of the day. [2015]

1.6.23 Advise adults with type 1 diabetes who choose to measure after meals to aim for a plasma glucose level of 5-to-9mmol/ litre at least 90 minutes after eating. (This timing may be different in pregnancy –for guidance on plasma glucose targets in pregnancy, see NICE’s guideline on diabetes in pregnancy.) [2015]

1.6.24 Agree bedtime target plasma glucose levels with each adult with type 1 diabetes. Take into account the timing of their last meal of the day and the related insulin dose, and ensure the target is consistent with the recommended fasting level on waking (see recommendation 1.6.22). [2015]

Preventing and managing hypoglycaemia

1.10.10 Explain to adults with type 1 diabetes that a fast acting form of glucose is needed for managing hypoglycaemic symptoms or signs in people who can swallow. [2004, amended 2015]

1.10.11 Adults with type 1 diabetes who have a decreased level of consciousness because of hypoglycaemia and so cannot safely take oral treatment should be:

 Given intramuscular glucagon by a family member or friend who has been shown how to use it (intravenous glucose

may be used by healthcare professionals skilled in getting intravenous access).

 Checked for response at 10 minutes, and then given intravenous glucose if their level of consciousness is not improving significantly.

 Then given oral carbohydrate when it is safe to administer it, and put under continued observation by someone who has been warned about the risk of relapse. [2004, amended 2015]

1.10.12 Explain to adults with type 1 diabetes that:

 It is very common to experience some hypoglycaemic episodes with any insulin regimen.

 They should use a regimen that avoids or reduces the frequency of hypoglycaemic episodes, while maintaining the most optimal blood glucose control possible. [2004]

1.10.13 Make hypoglycaemia advice available to all adults with type 1 diabetes, to help them find the best possible balance with any insulin regimen. (See the sections on insulin therapy and insulin delivery.) [2004]

1.10.14 If hypoglycaemia becomes unusually problematic or increases in frequency, review the following possible causes:

 Inappropriate insulin regimens (incorrect dose distributions and insulin types).

 Meal and activity patterns, including alcohol.

 Injection technique and skills, including insulin resuspension if necessary.

 Injection site problems.

 Possible organic causes, including gastroparesis.

 Changes in insulin sensitivity (including drugs affecting the renin–angiotensin system and renal failure).

 Mental health problems.

 Previous physical activity.

 Lack of appropriate knowledge and skills for self-management. [2004]

1.10.15 Manage nocturnal hypoglycaemia (symptomatic or detected on monitoring) by:

 Reviewing knowledge and selfmanagement skills.

 Reviewing current insulin regimen, evening eating habits, and previous physical activity.

 Choosing an insulin type and regimen that is less likely to cause low glucose levels at night. [2004, amended 2015]

1.10.16 If early cognitive decline occurs in adults on long-term insulin therapy, then in addition to normal investigations consider possible brain damage from overt or covert hypoglycaemia, and the need to manage this. [2004]

1.11 Ketone monitoring and managing diabetic ketoacidosis

Ketone self-monitoring to prevent diabetic ketoacidosis.

1.11.1 Consider ketone monitoring (blood or urine) as part of ‘sick day rules’ for adults with type 1 diabetes, to help with self-management of hyperglycaemia. [2015]

1.13 Control of cardiovascular risk

Aspirin

1.13.1 Do not offer aspirin for the primary prevention of cardiovascular disease in adults with type 1 diabetes. [2015]

Identifying cardiovascular risk

1.13.2 Assess cardiovascular risk factors annually, including:

 eGFR and urine ACR;

 Smoking;

 Blood glucose control;

 Blood pressure;

 Full lipid profile (including high-density lipoprotein [HDL] and low-density lipoprotein [LDL] cholesterol, and triglycerides);

 Age;

 Family history of cardiovascular disease;

 Abdominal adiposity. [2004, amended 2015 and 2021]

1.13.3 For guidance on tools for assessing risk of cardiovascular disease in adults with type 1 diabetes, see the recommendations on full formal risk-assessment in NICE’s guideline on lipid modification. [2015]

Interventions to reduce risk and manage cardiovascular disease

1.13.4 For guidance on the primary prevention of cardiovascular disease in adults with type 1 diabetes, see the section on primary prevention for people with type 1 diabetes in NICE’s guideline on lipid modification. [2015]

1.13.5 Give adults with type 1 diabetes who smoke advice on stopping smoking and stop smoking services, including NICE guidance recommended therapies (see the NICE topic page on smoking and tobacco). Reinforce these messages annually for people who currently do not plan to stop smoking, and at all clinical contacts if there is a prospect of the person stopping. [2004]

1.13.6 Advise adults who do not smoke never to start smoking. [2004, amended 2021]

1.13.7 Provide intensive management for adults who have had myocardial infarction or stroke, according to relevant non diabetes guidelines. For angina or other ischaemic heart disease, beta-blockers should be considered (for insulin use in these circumstances, see the section on caring for adults with type 1 diabetes in hospital). For guidance on secondary prevention of myocardial infarction, see NICE’s guideline on acute coronary syndromes. [2004, amended 2015]

Blood pressure management

1.13.8 In adults with type 1 diabetes aim for blood pressure targets as follows:

 For adults with a urine ACR less than 70mg/mmol, aim for a clinic systolic blood pressure less than 140mmHg (target range 120-to-139mmHg) and a clinic diastolic blood pressure less than 90mmHg.

 For adults with an ACR of 70mg/ mmol or more, aim for a clinic systolic blood pressure less than 130mmHg (target range 120-to-129mmHg) and a clinic diastolic blood pressure less than 80mmHg.

 In adults aged 80 or more, whatever the ACR, aim for a clinic systolic blood pressure less than 150mmHg (target range 140-to-149mmHg) and a clinic diastolic blood pressure less than 90mmHg.

 Use clinical judgement for adults with frailty, target organ damage (damage to organs because of diabetes, for example, to nerves or eyes) or multimorbidity. See the recommendations on pharmacotherapy in NICE’s guideline on chronic kidney disease, and NICE’s guidelines on hypertension in adults and multimorbidity. [2004, amended 2022]

1.13.9 Discuss the following with adults with type 1 diabetes who have hypertension to help them make an informed choice:

 Reasons for the choice of intervention level;

 The substantial potential gains from small improvements in blood pressure control;

 Any possible negative consequences of therapy. [2004, amended 2015]

1.13.10 Start a trial of a reninangiotensin system blocking drug as first-line therapy for hypertension in adults with type 1 diabetes. [2004, amended 2015]

1.13.11 Provide information to adults with type 1 diabetes on how lifestyle changes can improve their blood pressure control and associated outcomes, and offer help to achieve their aims in this area. [2004]

1.13.12 Do not allow concerns over potential side-effects to inhibit advising and offering the necessary use of any class of drugs, unless side-effects become symptomatic or otherwise clinically significant. In particular:

 Do not avoid selective beta-blockers for adults on insulin if these are indicated;

 Low-dose thiazides may be combined with beta blockers;

 When prescribing calcium channel antagonists, only use long-acting preparations;

 Ask adults directly about potential sideeffects of erectile dysfunction, lethargy and orthostatic hypotension with different drug classes. [2004, amended 2015]

1.13.13 This recommendation has been removed as the previous link to NICE’s guideline on chronic kidney disease no longer provides relevant information. n

Full Type 1 diabetes in adults: Diagnosis and management (NG17) guideline is available at: www.nice.org.uk/guidance/ng17/.

IRISH DIABETES CLINICAL GUIDELINES

There are a number of national guidelines for diabetes-related care published by the HSE’s National Clinical Programme for Diabetes, while the ICGP also published integrated care guidelines for the management of type 2 diabetes in general practice in 2016, which were developed in conjunction with the National Clinical Programme for Diabetes Working Group.

In relation to type 1 diabetes specifically, in 2018 the adult type 1 diabetes mellitus guideline was published ( Adult type 1 diabetes mellitus: National Clinical Guideline No. 17 ), which can be accessed here: www.hse.ie/eng/about/who/ cspd/ncps/diabetes/resources/ adult-type-1-diabetes-mellitus.pdf.

The document was put together by a Guideline Development Group, supported by the HSE National Clinical Programme for Diabetes, and developed through contextualisation of NICE’s 2015 Type 1 diabetes in adults: Diagnosis and management (NG17) guideline document.

Diabetes in the paediatric population

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T1DM currently accounts for greater than 95 per cent of cases of diabetes mellitus in paediatric populations in the UK and Ireland. Type 2 diabetes mellitus (T2DM) is most typically seen as a disorder of insulin resistance associated with a relative insulin deficiency. 4 While more common in adult populations, T2DM was traditionally uncommon in paediatric populations. However, with the growing problem of childhood obesity (particularly in the Western world), T2DM is becoming a more common paediatric diagnosis in late adolescence.

Presentation

Diabetes is one of the most common chronic diseases in the world, with an estimated one-in-11/12 people worldwide affected by it (more in some countries).1 The vast majority of cases are found in adults, but it remains a significant health burden for children worldwide, behind only asthma in prevalence among chronic diseases of childhood. It is important therefore that any medical professional working with children is comfortable with the diagnosis of diabetes, its day-to-day management, and the recognition and treatment of diabetic emergencies.

Traditionally diabetes was defined as either insulin-dependent or non-insulindependent, but the current approach sees diabetes defined by its mechanism of action. 2

Type 1 diabetes mellitus (T1DM) is an autoimmune condition characterised by destruction of beta cells of the pancreas, leading to an absolute insulin deficiency. 3 It occurs in individuals with a genetic susceptibility, typically following a trigger by an environmental agent such as a virus, and as the initial progression of beta cell destruction takes place the patient initially remains asymptomatic.

Secondary forms of diabetes mellitus also exist; cystic fibrosis-related diabetes (CFRD) is a complication of CF associated with a relative rather than absolute insulin deficiency following beta cell destruction, but with some elements of insulin resistance also noted. 5 It has been associated with increased morbidity and mortality in this patient cohort. Mature onset diabetes of the young (MODY) is an autosomal-dominant condition associated with ineffective insulin production or secretion and is caused by a single gene defect in one of a number of recognised genes.6 For this reason, it is also known as monogenic diabetes. There are other, rarer causes of diabetes mellitus in the paediatric population, including gestational diabetes in the case of pregnancy.

The typical presentation of diabetes mellitus is with a classic triad of symptoms (polydipsia, polyuria, and weight loss) and a raised blood glucose of >11.1mmol/L. Other symptoms that can also be features of presentation include nocturnal enuresis, lethargy, blurred vision, increased appetite, recurrent infections, slow-healing injuries, and constipation.7 Patients should have their blood glucose, blood ketones, and blood gases assessed at time of first presentation, and it is recommended to have blood tests sent to look for the presence of autoantibodies associated with T1DM (anti-GAD, anti-IA2 and anti-ZnT8 antibodies).

Diabetic ketoacidosis

It is also possible for patients to present in diabetic ketoacidosis (DKA) as a first presentation of diabetes mellitus; a recent study of an Irish paediatric population shows that 25 per cent of presentations with T1DM were in DKA, with a higher level in children aged under two years.7

DKA is a medical emergency and is the leading cause of morbidity and mortality among the paediatric T1DM population, 8 with the rare case of mortality occurring as a result of cerebral oedema.9 In DKA, high levels of glucose unchecked by insulin cause osmotic diuresis in the kidneys, leading to polyuria and dehydration; as well as causing beta oxidation of free fatty acids into ketones, which cause metabolic acidosis.10

The aims of managing DKA are to correct acidosis, reverse ketosis, correct dehydration, restore blood glucose to near-normal, monitor for complications of DKA, and treat any underlying

T1DM currently accounts for greater than 95 per cent of cases of diabetes mellitus in paediatric populations in the UK and Ireland

cause for DKA.9 Initial management is with assessment and resuscitation as required, including the use of boluses of 0.9 per cent NaCl to restore circulating volume. Following this initial stage, fluid requirements should be calculated to account for both maintenance requirements and the fluid deficit present in the patient and this should be administered over 48 hours. DKA is a naturally hypokalaemic state, with depletion of total body potassium through osmotic diuresis; however, initial serum potassium levels can appear normal. KCI should be added to IV fluids once urine output is confirmed or blood tests confirm the patient is not hyperkalaemic.

Insulin administration should be delayed until at least one hour after maintenance fluids have begun; this is associated with a lower risk of cerebral oedema.9 Despite being associated with acidosis, there is no role for bicarbonate in the management of DKA, and evidence suggests it being associated with a greater risk of worsening tissue hypoxia and cerebral acidosis.

Management

The long-term treatment and management of each variant of diabetes mellitus should be appropriate for the underlying pathophysiology behind each individual subtype. As T1DM is fundamentally caused by a lack of insulin, the treatment required for patients with T1DM is insulin.11 The decision regarding what particular insulin regime to commence in a well patient should be made following consultation with a consultant paediatric endocrinologist, but in general starting doses vary between 0.75-1.0 units/kg/day.

This total daily dose of insulin can then be divided between long-acting basal insulin (eg, Levemir, Lantus, Tresiba) and short-acting bolus insulin (eg, NovoRapid, Fiasp).

A typical starting ratio is to divide the total daily insulin dose into 50 per cent

basal and 50 per cent bolus insulin;12 basal insulin is designed to replace background endogenous insulin and is given once or twice a day, while bolus insulin is given prior to eating and is typically divided in three doses (prebreakfast, pre-lunch, and pre-dinner). These initial set doses for bolus insulin will ideally give way in time to more precise doses calculated, based on the amount of carbohydrate in the meal about to be eaten, following education.

Initial management for a new diagnosis of T1DM should focus on commencing insulin as outlined above, as well as education for the family around the essential skills required for living with diabetes.13 This includes information about what diabetes is, a basic management routine, developing the skills of blood glucose testing and insulin administration, and management of hypoglycaemia, hyperglycaemia, and intercurrent illness. Future education sessions should focus on strategies for optimising good glycaemic control.

Outpatient appointments should be offered every three months for clinical examination and assessment of glycaemic control through review of blood glucose diaries/blood glucose sensor data and monitoring of HbA1c.14 Annual review appointments should include screening for common autoimmune conditions (thyroid disease, Coeliac disease), screening for microalbuminuria, and a lipid profile. After the age of 12, referral should be made to the Diabetic Retinopathy Screening Programme (www. diabeticretinascreen.ie).

For both T1DM and T2DM, the role of the multidisciplinary team (MDT) is a central feature of patient management. Patients should have access to endocrinologists, diabetes clinical nurse specialists, dieticians, and psychologists. The most important initial function of the MDT is structured education for both day-today management and management of diabetes-related emergencies.11

Insulin pumps and CGM

Continuous subcutaneous insulin infusion (CSII) therapy, also known as ‘insulin pumps’, is rapidly becoming the standard of care for paediatric patients in health systems in the developed world.15 They work by continuously delivering a basal rate of rapid-acting insulin via a subcutaneous giving set, replacing the need for long-acting insulin – this delivery of insulin more closely resembles the physiological action of insulin in the body of a person without diabetes.

This move towards CSII therapy is occurring alongside developments in blood glucose monitoring.

Continuous glucose monitoring (CGM) uses a subcutaneous sensor to measure interstitial glucose levels and offer realtime feedback on blood glucose levels; it is considered to be the preferred option of blood glucose monitoring in the paediatric setting.16 CGM also offers a new therapeutic goal by providing information on how long a patient spends within a normal range for blood glucose; this ‘time in range’ value is considered more accurate than HbA1c as it is not confounded by episodes of hypoglycaemia.17

There is a new generation of CSII pumps which have the ability to communicate with CGM sensors to offer a number of functions, including suspending insulin delivery if blood glucose falls below a certain value, or real-time alteration of insulin delivery in response to blood glucose levels (the hybrid closed-loop system). As CSII and CGM technology improves, it continues to offer patients with T1DM more opportunities to maintain good glycaemic control, reduce the risk of adverse effects, and improve quality-of-life.

T2DM management

The management of T1DM contrasts with T2DM, which rather than being a failure of insulin production is instead caused by a problem with the action of insulin in the body. As such, the mainstay of

treatment is not insulin therapy, with first-line advice being management of diet and exercise to counter the risk of insulin resistance.14 Aside from these non-pharmacological interventions, there are several medications which have a role in T2DM management; metformin decreases glucose production in the liver and increases sensitivity to insulin in the body tissues;14 GLP1 agonists (eg, liraglutide, semaglutide) enhance glucose-mediated insulin secretion and reduce postprandial glucagon secretion;18

and insulin may be required by a small proportion of T2DM patients, but is recommended for any T2DM patient with evidence of ketosis or who have a significant raised blood glucose level (HbA1c >69mmol/mol).19

Future

The future of T1DM management is moving away from novel therapies and focusing on screening and immunotherapies for prevention. Recent studies taking place around

the world are investigating the role of autoantibodies as predictors of T1DM, both in families with a history of T1DM and in general populations. 20,21 Although at the early stages of development, the possibility of someday being able to prevent T1DM is an exciting one, and mirrors the innovation which has already transformed the management of diabetes since Banting and Best first isolated insulin just over 101 years ago. For patients and staff alike, the next century looks to be just as exciting as the last. n

NATIONAL CLINICAL GUIDELINES ON DIABETES IN CHILDREN

A Model of Care for all children and young people with type 1 diabetes was published in 2015. The primary aim of this model of care is to define excellent diabetes care, and improve access, quality, and value for all children with T1DM in Ireland. That document is available at: www.hse.ie/eng/about/Who/ clinical/natclinprog/paediatricsand neonatology/paedsmoc.pdf.

A Model of Care was developed in 2012 for the provision of continuous subcutaneous insulin infusion (CSII) therapy in children aged under five years of age and was updated in March 2015. That document is available at: www.lenus. ie/hse/bitstream/10147/275652/1/ ProvisionContinSubcutaInsuInfusiontreat Type1DiabetesUnderFives.pdf.

In March 2019 the HSE published a series of national clinical guidelines on diabetes care in children, with a number of updates and additions since then: Care of the child newly diagnosed with type 1 diabetes without DKA (updated April 2021); Identification and management of hypoglycaemia in children with type 1 diabetes (updated April 2021); Annual Review and comorbidity screening in type 1 paediatric diabetes (Version 1, November 2020);

Management of continuous glucose monitoring for children type 1 diabetes (Version 1, October 2020); Management of paediatric type 1 diabetes patient with a HbA1c >9 per cent (75mmol/ mol) (Version 3, March 2019); General principles in the management of children with diabetes requiring surgery (updated April 2021); Management of paediatric diabetic ketoacidosis (updated April 2021); Management of paediatric type 1 diabetes patient with an intercurrent illness (hospital) (updated April 2021); and Management of paediatric type 1 diabetes patient who did not attend (DNA), were not brought or repeatedly cancels their appointments (March 2019). All these clinical guidelines can be accessed at: www.hse.ie/eng/about/ who/cspd/ncps/paediatrics-neonatology/ resources/.

For parents and caregivers, there is also a Paediatric Type 1 Diabetes Resource Pack, which was developed jointly by paediatric clinical nurse specialists and dietitians working in Irish specialist services on behalf of the National Clinical Programme for Paediatric Diabetes. The aim is to give a clear, concise advice on common scenarios as the parent/child begins learning about diabetes. It is available at: www.hse.ie/eng/about/who/cspd/

ncps/paediatrics-neonatology/resources/ paediatric-type-1-diabetes-resourcepack.pdf.

The latest HSE document is the Meeting the care needs of primary school children with type 1 diabetes during school hours guideline, which is a useful resource for parents, carers, teachers, and school staff and was published in the summer of 2022. The document sets out clear guidelines that will help structure the conversation and preparations between the family, diabetes team, and school staff. It explains diabetes and diabetes management to teachers and school staff and sets out clear lines of responsibility for all partners. The document also includes a Personal Pupil Plan to agree on current diabetes management and the needs of a child, which includes information, such as personal hypoglycaemia symptoms, what to eat during hypoglycaemia, and when to check glucose levels and deliver insulin. The school can have a personalised ‘information pack’ for all their pupils with T1DM. This document can be accessed at: www.hse.ie/eng/ about/who/cspd/ncps/paediatricsneonatology/resources/meeting-careneeds-primary-school-children-withdiabetes1.pdf.

TRUE/FALSE QUESTIONS

Q1 T1DM is the only type of diabetes that can develop in children

True or false?

Q2 There is seasonal variation in diagnosis of T1DM

True or false?

Q3 A diagnosis of diabetes mellitus requires formal testing with an oral glucose tolerance test (OGTT)

True or false?

Q4 Any patient diagnosed with T1DM under the age of five years should be started on continuous subcutaneous

References

1. International Diabetes Federation. IDF Diabetes Atlas (2021). Available at: https://diabetesatlas.org/

2. World Health Organisation. Diabetes factsheet (2022). Available at: www.who.int/news-room/factsheets/detail/diabetes

3. Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. N Engl J Med. 1994 Nov 24;331(21):1428-36

4. Temneanu OR, Trandafir LM, Purcarea MR. Type 2 diabetes mellitus in children and adolescents: A relatively new clinical problem within paediatric practice. J Med Life. 2016 Jul-Sept;9(3):235

5. Moran A, Doherty L, Wang X, Thomas W. Abnormal glucose metabolism in cystic fibrosis. J Paediatr. 1998 Jul 1;133(1):10-7

6. Sanyoura M, Philipson LH, Naylor R. Monogenic diabetes in children and adolescents: Recognition and treatment options. Curr Diab Rep. 2018 Aug;18(8):1-3

7. Roche EF, Menon A, Gill D, Hoey H. Clinical presentation of type 1 diabetes. Paediatric Diabetes 2005 Jun;6(2):75-8

8. Edge JA, Ford-Adams ME, Dunger DB. Causes of death in children with insulin dependent diabetes 199096. Arch Dis Child. 1999 Oct 1;81(4):318-23

9. HSE. Management of paediatric diabetic ketoacidosis (2021). Available at: www.hse.ie/eng/about/ who/cspd/ncps/paediatrics-neonatology/resources/

insulin infusion (CSII) therapy as a priority once they have received all necessary education

True or false?

Q5 The first step in managing newly-diagnosed DKA in children is to start insulin infusion

True or false?

Q6 One-in-four patients with T1DM are diagnosed with another autoimmune condition in their lifetime

True or false?

Q7 Target HbA1c in a patient with diabetes mellitus is 20-42mmol/mol

True or false?

management-of-paediatric-diabetic-ketoacidosis1.pdf

10. Kitabchi AE, Umpierrez GE, Miles JM, Fisher JN. Hyperglycaemic crises in adult patients with diabetes. Diabetes Care. 2009 Jul 1;32(7):1335-43

11. HSE. Care of the child newly diagnosed with type 1 diabetes without DKA (2021). Available at: www.hse. ie/eng/about/who/cspd/ncps/paediatrics-neonatology/ resources/care-of-the-child-newly-diagnosed-with-type1-diabetes-without-dka.pdf

12. Levitsky LL, Misra M. Insulin therapy for children and adolescents with type 1 diabetes mellitus (2022). Available at: www.uptodate.com/contents/insulintherapy-for-children-and-adolescents-with-type-1diabetes-mellitus

13. Haller MJ, Atkinson MA, Schatz D. Type 1 diabetes mellitus: Etiology, presentation, and management. Paediatric Clinics. 2005 Dec 1;52(6):1553-78

14. American Diabetes Association. 13. Children and adolescents: Standards of medical care in diabetes – 2021. Diabetes Care. 2021 Jan 1;44(Supplement_1):S180-99

15. Phillip M, Battelino T, Rodriguez H, Danne T, Kaufman F. Consensus Forum Participants. Use of insulin pump therapy in the paediatric age-group: Consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Paediatric Endocrine Society, and the International Society for Paediatric and Adolescent Diabetes, endorsed by the American

Q8 The presenting symptom for T1DM can be nocturnal enuresis

True or false?

Q9 In a patient with diabetes, hypoglycaemia is defined as a blood sugar less than 4.0mmol/L if the patient is symptomatic, or any blood sugar less than 3.5mmol/L

True or false?

Q10 Incidence of new-onset T1DM increased during the Covid-19 pandemic

True or false?

To see the answers to these questions and to earn free CPD points, complete this module on www.doctorcpd.ie.

Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2007 Jun 1;30(6):1653-62

16. Chiang JL, Kirkman MS, Laffel LM, Peters AL. Type 1 Diabetes Sourcebook Authors. Type 1 diabetes through the life span: A position statement of the American Diabetes Association. Diabetes Care. 2014 Jul 1;37(7):2034-54

17. American Diabetes Association. Diabetes technology: Standards of medical care in diabetes – 2020. Diabetes Care. 2020 Jan 1;43(Supplement 1):S77-88

18. Lee YS, Jun HS. Anti-diabetic actions of glucagonlike peptide-1 on pancreatic beta-cells. Metabolism 2014 Jan;63(1): 9-19

19. Copeland KC, Silverstein J, Moore KR, Prazar GE, Raymer T, Shiffman RN, et al. Management of newly diagnosed type 2 diabetes mellitus (T2DM) in children and adolescents. Paediatrics. 2013 Feb;131(2):364-82

20. Mahon JL, Sosenko JM, Rafkin-Mervis L, KrauseSteinrauf H, Lachin JM, Thompson C, et al. The TrialNet Natural History Study of the development of type 1 diabetes: Objectives, design, and initial results. Paediatric diabetes. 2009 Mar;10(2):97-104

21. McCulloch DK, Palmer JP. The appropriate use of B-cell function testing in the preclinical period of type 1 diabetes. Diabetic Medicine. 1991 Nov;8(9):800-4

Type 2 diabetes mellitus

Diabetes is the most common chronic metabolic disease and a major source of morbidity and mortality. Type 2 diabetes mellitus (T2DM) is the most prevalent form, accounting for around 90 per cent of cases worldwide. Figures released by the International Diabetes Federation (IDF) in December 2021 show that more than half a billion adults globally are living with diabetes. This is a rise of 16 per cent (74 million) since the previous IDF estimates in 2019. Worldwide, 537 million adults aged 20-79 years are living with diabetes, and 541 million adults have pre-diabetes, which places them at high-risk of developing T2DM. The prevalence of diabetes worldwide is growing at an alarming rate, and is predicted to rise to 643 million by 2030, and 784 million by 2045. The diabetes epidemic is unfolding because of increasing obesity rates, sedentary lifestyles and an ageing population.1

There is still no National Diabetes Registry in Ireland, therefore national estimates are not fully accurate. The figures provided by Diabetes Ireland (Table 1, January 2022) use data modelled from the Scottish Diabetes Register. In Scotland, the prevalence of diabetes was 5.6 per cent of the total census population in 2020. Table 1 estimates the total diabetes prevalence in Ireland at approximately 266,664 people. The prevalence of T2DM is estimated at 234,398 people (87.9 per cent of the total diabetes population) and type 1 diabetes at 28,800 (10.8 per cent of the total diabetes population), based on the Scottish prevalence. The true prevalence of T2DM in Ireland, however, is likely to be higher, as hyperglycaemia develops gradually, and at the early stage many cases go undiagnosed.1

According to the 2015 Irish Longitudinal Study on Ageing (TILDA), 10 per cent of

adults aged 50 and over in Ireland have T2DM, rising to 16 per cent in those aged 80 and over. The TILDA study revealed that 1:10 people with diabetes in this population are undiagnosed, and that a further 5.5 per cent of the older population have pre-diabetes, which puts them at an increased risk of developing T2DM in the future. 2 The study also found that T2DM is more common in men (12 per cent) than women (7 per cent), and those with a self-reported history of hypertension, high cholesterol, and being centrally obese, while having low levels of physical activity also has a strong correlation with both diabetes and pre-diabetes. 2

The CODEIRE study (2006) stated that costs associated with diabetes in Ireland consume between 4-to-6 per cent of annual healthcare expenditure. If the same percentage (4-to-6 per cent) was to be applied to the Irish health service’s expenses in 2019, the costs associated with diabetes would have been as high as €1.2 billion to €1.4 billion, with approximately 50 per cent of the costs associated with hospitalisations and treatment of complications. With the growing prevalence of diabetes in Ireland, comprehensive economic data is required to ensure that appropriate resources are allocated to the management of the disease.4

Pathophysiology

T2DM is an insulin-resistance condition with associated beta-cell dysfunction. It occurs when blood glucose levels are too high (hyperglycaemia) due to insufficient insulin production, or when the insulin that is produced by the pancreas is not working effectively. T2DM results from an interaction between genetic and environmental factors, and ranks high on the international health agenda as a global pandemic, and as a threat to human health and global economies. 5

The IDF Atlas 2021 ranked Ireland seventh in the world for diabetes-related health expenditure per person. 3 The economic burden of diabetes on the Irish healthcare system is a major challenge for Government and the HSE. National estimates comparing health-service use between people over 50 years of age with and without diabetes (2009-2011) show that diabetes was associated with an 87 per cent increase in outpatient visits, a 52 per cent increase in hospital admissions, and a 33 per cent increase in emergency department attendances.1

In T2DM, the response to insulin is diminished, and this is defined as insulin resistance. During this state, insulin is ineffective and is initially countered by an increase in insulin production to maintain glucose homeostasis. However, as the disease progresses, beta cells change and insulin secretion is unable to maintain glucose homeostasis, producing hyperglycaemia, resulting in T2DM.6

T2DM is most commonly seen in people over the age of 40. However, it is also now increasingly seen in children, adolescents, and younger adults due to rising levels of obesity, physical inactivity, and energy-

The prevalence of T2DM is estimated at 234,398 people (87.9 per cent of the total diabetes population) and type 1 diabetes at 28,800 (10.8 per cent of the total diabetes population)

dense diets.6 Most patients with T2DM are obese or have a higher body fat percentage, distributed predominantly in the abdominal region. This adipose tissue promotes insulin resistance through various inflammatory mechanisms, including increased FFA release and adipokine dysregulation. Lack of physical activity in people with hypertension or dyslipidaemia also increases the risk of developing T2DM.6

Chronic hyperglycaemia can cause damage to various organ systems, leading to the development of disabling and lifethreatening health complications, most

prominent of which are microvascular (retinopathy, nephropathy, and neuropathy) and macrovascular complications, leading to a two-to-four-fold increased risk of cardiovascular disease.6

Risk factors

 Obesity: Obesity and T2DM are closely linked and are increasing in prevalence worldwide. Both chronic conditions have a multisystem impact and are associated with increased mortality and cardiovascular risk. The mechanisms linking obesity and T2DM are complex and still being understood. It is thought to involve a

combination of adipose tissue release of excess circulating fatty acids, glycerol, hormones and pro-inflammatory cytokines, impairing cellular insulin signalling and increasing insulin resistance; and chronically raised lipid levels leading to impaired islet beta-cell function and lower levels of insulin production.7

 Smoking, high alcohol consumption, and reduced physical activity: These are key factors that contribute to obesity and insulin resistance.

 Age: Although T2DM can occur at any age, older age from >40 years is associated with the progressive reduction in glucose tolerance, partly owing to the gradual decrease in responsiveness of beta-cells to carbohydrates.7

DIABETES TESTING IN ASYMPTOMATIC ADULTS

1. Testing for diabetes should be considered in all adults who are overweight (BMI ≥25kg/m2) and who have one or more additional risk factors:

 Physical inactivity

 First-degree relative with diabetes

 Are hypertensive (≥140/90mmhg) or on therapy for hypertension

 Dyslipidaemia – HDL<0.9 and/or triglycerides >2.82

 Have established arterial disease (IHD, CVA, PVD)

 High-risk ethnicity (eg, African, Asian, Hispanic, etc)

 Members of the Travelling Community

 Have delivered a baby weighing >4.1kgs or have a history of gestational diabetes mellitus (GDM)

 On previous testing had impaired glucose tolerance (IGT ) or impaired fasting glucose ( IFG)

 Have other clinical conditions associated with insulin resistance (eg, polycystic ovary syndrome (PCOS), acanthosis nigricans, long-term steroid use, or severe obesity

2. In the absence of the above additional risk factors, testing for diabetes should begin at age 45 years

3. If the results are normal, testing should be repeated at least at three-yearly intervals. Patients with IFG or IGT should be tested annually

 Genetics: Other risk factors include first-degree relatives of someone with diabetes, and women with gestational diabetes (GDM) or PCOS, which increases the risk of impaired glucose regulation. The risk of first-degree relatives of people with T2DM developing the condition is 40 per cent compared with just 6 per cent for the rest of the general population.7

 Ethnicity: T2DM is two-to-four times more likely in people of south-Asian, Afro-Caribbean or black-African descent than people of white-European origin. Migration of various ethnic subgroups has led to a change in dietary habits, with a higher consumption of calories and fat than in their countries of origin; hence the prevalence of diabetes is often higher in immigrant communities than in their country of origin.7

 Inflammation: Systemic inflammation also contributes to insulin resistance as an improvement in inflammatory markers, such as C-reactive protein and interleukin-6, are linked to an improvement in beta-cell function.7

Signs and symptoms

Symptoms of T2DM originate from persistent hyperglycaemia and the

impaired ability to use glucose as fuel, and include polyuria, nocturia, polydipsia, fatigue, and weight loss. A person with diabetes may also experience other symptoms, such as blurred vision, reduced sensations or pain in the hands and feet, along with recurrent genitourinary infections.7

Owing to insulin deficiency and altered energy metabolism, diabetes increases the risk of developing hyperosmolar hyperglycaemic states and ketoacidosis, both of which are life-threatening emergencies that require prompt hospital treatment. Diabetic ketoacidosis is less common in people with T2DM, because most people are insulin resistant rather than insulin deficient.7

Criteria for testing for diabetes in asymptomatic adult individuals

T2DM has a long pre-clinical phase and may be asymptomatic until well after long-term microvascular and macrovascular complications have occurred. T2DM can be detected before the onset of symptoms and clinical signs by identifying people who are at risk and performing diagnostic testing (see Table 2). The onset of T2DM is subtle and early detection in general practice requires clinical suspicion combined with systematic and opportunistic findings. Early identification of patients and initiation of treatment can reduce the development of complications, and therefore testing for diabetes in asymptomatic patients with risk factors associated with the development of diabetes is recommended.10

Diagnosis

A thorough medical history, physical examination and investigative tests are required to form a diagnosis for T2DM. The patient’s history will include an assessment for risk factors, such as a family history of diabetes, ethnicity, and increased age >40 years old. The patient’s vital signs and height, weight, and BMI should be recorded. The skin should be examined for wounds and signs of

ANNUAL

REVIEW

10

Along with the areas monitored at the regular review, surveillance of the following should also be carried out annually, according to the ICGP guidelines:

SYMPTOMS Ischaemic heart disease, peripheral vascular diseaseneuropathy, erectile dysfunction. All patients with symptoms that might reflect vascular disease, particularly ischaemic heart disease, should be investigated

FEET Footwear, deformity/joint rigidity, poor skin condition, ischaemia, ulceration, absent pulses, sensory impairment

EYES

Visual acuity and retinal review by ophthalmologist/ retinal screening programme

KIDNEY Renal damage, albumin excretion, serum creatinine and calculate EGFR

ARTERIAL RISK Blood glucose, blood pressure, blood lipids, and smoking status, ECG

ATTENDANCES

Podiatry/dietitian/other as indicated

TABLE 3: Annual diabetes review

infection. Pulses should be palpated to examine for peripheral arterial disease, and microfilament testing to determine the presence of peripheral neuropathy. The eyes should be examined with an ophthalmoscope and assessed for retinopathy. A series of blood tests will be carried out including a fasting blood glucose. Urinary glucose should not be used as a diagnostic test owing to its low sensitivity. Additional diagnostic tests are often required, such as ‘GAD’

autoantibody tests or C-peptide tests, to distinguish between T1DM and T2DM. Other types of DM must also be excluded, such as maturity-onset diabetes of the young, which is characterised by impaired insulin secretion with minimal or no defects in insulin action resulting from genetic defects in beta-cell function.7

Diagnosis can be made when fasting plasma glucose is ≥7.0mmol/L or random plasma glucose is ≥11.1mmol/L in the presence

DIABETES CARE

LET US HELP YOU MANAGE DIABETES

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Blood Glucose monitoring System (IDEAL FOR TYPE 1 & 2 PATIENTS).

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Blood Glucose & ß-Ketone monitoring System (IDEAL FOR TYPE 1 PATIENTS).

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99.33% of 4SURE SMART DUO test results are within ± 0.83 mmol/L (low glucose levels) or ± 15% (high glucose levels) of laboratory reference method test results.4

1. Haematocrit range 0-70% (blood glucose), 10-70% (ϐ-ketone). 2. For driving with diabetes, follow DVLA guidelines.

3. Follow NICE guidelines “Diabetes in pregnancy: management from preconception to the postnatal period”.

4. Assessment of System Accuracy, Intermediate Measurement Precision, and Measurement Repeatability of a Blood Glucose Monitoring System Based on ISO 15197. Jendrike N, et al., J Diabetes Sci Technol. 2018 Dec 14.

Clonmel Healthcare Ltd., Clonmel, Co. Tipperary. Always read the instructions before use. 2021/ADV/4SU/012H. Date prepared February 2021.

of symptoms, such as frequent urination, thirst, and unexplained weight loss.7,8

The oral glucose tolerance test (OGTT) can also be used as a diagnostic tool, where a diagnosis is made if a plasma glucose level of ≥11.1mmol/L is measured two hours after the ingestion of a 75g glucose solution. The OGTT has largely been replaced by the HbA1c test, and is now mainly used in the diagnosis of GDM. An HbA1c result of 48mmol/mol (6.5 per cent) is recommended as the threshold for diagnosing diabetes.7, 8

In an asymptomatic person, diagnosis should be confirmed with a repeat HbA1c or plasma glucose test, preferably using the same test. However, if both HbA1c or plasma glucose measurements are in diabetic range, a diagnosis can be made. If only one measurement is in range, a second abnormal result using the same test is required to confirm the diagnosis.7,8 There are patient groups in whom HbA1c is inappropriate for diagnosis, including:

 Children;

 Pregnant women;

 People who are taking medicines such as steroids or antipsychotics that can cause an acute glucose;

 People with acute pancreatic damage;

 People with haematological conditions that may influence HbA1c and its measurement, eg, haemoglobinopathies, decreased erythropoiesis/administration of erythropoietin, erythrocyte destruction, alcoholism, chronic kidney disease, and chronic opioid use.7

Treatment and management

The introduction of the HSE’s Cycle of Care for diabetes in October 2015 was the first step in the provision of reimbursement for structured diabetes care in general practice. To support the implementation of the Cycle of Care, A Practical Guide to Integrated Type 2 Diabetes Care was updated by GP Dr Velma Harkins on behalf of the ICGP with the support of the HSE’s National Clinical Programme for Diabetes (2016). The Programme then published its Model of Integrated Care for Patients with

Type 2 Diabetes18 document in 2018, which outlines the framework for the delivery of evidence-based practice guidelines to people with T2DM in Ireland.

Under the HSE’s National Integrated Model of Care, 18 patients with uncomplicated T2DM are seen three times a year in primary care in a structured fashion. Visits are every four months with an annual review. Patients who develop complications are referred from primary to secondary or tertiary care for an expert specialist opinion and their care will become shared between primary and secondary or tertiary care. These patients will be seen at least once a year in secondary care for their annual review or more frequently according to the severity of the diabetes-related complication and up to twice a year in primary care at fourmonthly intervals.10

Diabetes care should encompass patient education, dietary and lifestyle advice, management of cardiovascular risk, skin and foot care, as well as detection and management of long-term complications.

Patients with T2DM should be encouraged to eat high-fibre, low glycaemic index sources of carbohydrates, such as fruit, vegetables, wholegrains and pulses, as well as low-fat dairy products and oily fish. They should be advised to maintain a healthy weight to maintain a BMI of between 20 and 25kg/m 2 10,11 Patients should be taught how to measure and understand their blood glucose levels. Quality control of the glucose monitor should be checked four times a year and monitors should be changed or upgraded every two years. Patients should be advised to record home glucose readings in their patient record book and to bring the book to each of their diabetic reviews.10

The UK’s NICE guidelines12 recommend that all patients with T2DM should be referred to a diabetes structured education programme at or around the time of their diagnosis. Structured diabetes education is a group programme that provides patients with the knowledge, skill and ability to

manage their diabetes.

All patients with diabetes should receive the following checks at least once per year to reduce the risk of long-term complications: HbA1c level; blood pressure; cholesterol; retinal screening (depending on risk); foot examination; kidney function; urinary albumin; BMI; and smoking status. Reducing glucose levels lowers the risk of all long-term complications of diabetes, while reducing cholesterol levels lowers the risk of heart attacks and strokes.12

Blood glucose targets

Tight control of blood glucose with diet and/or medication reduces long-term diabetes-related complications and is central to the overall management of diabetes. Blood glucose targets should be individualised and discussed with the patient. A HbA1c ≤53mmol/l is appropriate for most people with T2DM and has been shown to reduce diabetesrelated complications.18

A HbA1c ≤58mmol/l or less stringent A1c goals may be appropriate for people with a history of:

 Severe hypoglycaemia;

 Limited life expectancy;

 Advanced microvascular or macrovascular complications;

 Extensive co-morbid conditions; or

 Where social circumstance may prevent tight glucose control.

A HbA1c ≤48mmol/l may be appropriate for newly-diagnosed people with T2DM and no significant co-morbidities.

Targets should be set in consultation with the individual and should be seen as a guide because a person’s individual circumstances need to be considered when setting and agreeing targets, according to the HSE’s Model of Care.18 The HbA1c should be checked more than twice a year in patients to maintain treatment targets.

Medications

Healthy eating and exercise are the

cornerstones of T2DM management, but frequently people need the addition of medications to help improve blood glucose control. When lifestyle modification fails to achieve the targeted blood glucose levels, the first-line medication prescribed is metformin,18 both for those who are overweight (BMI >25.0kg/m 2) and not overweight. Metformin is contraindicated in those with renal impairment and with endstage cardiac and hepatic failure. Metformin should be stopped in patients with eGFR <30mls/min and at possibly higher values in patients prone to dehydration.10

The HSE’s Model of Care contains an algorithm with a step-wise treatment approach, with second-line and other agents including DPP-4 inhibitors, sulphonylureas, GLP-1 receptor agonists, pioglitazone, acarbose, meglitinides, sodium glucose co-transporter 2 (SGLT2) inhibitors, and insulin.18

Since 2015, NICE has been advocating a patient-centred approach to glycaemic control and provides best practice advice on setting glycaemic targets and selecting hypoglycaemic agents for treatment intensification after metformin firstline treatment for T2DM in those with inadequate diabetes control.12

Most guidelines recommend the use of insulin alone or in combination with other GLDs when persons with T2DM are unstable, with sign and symptoms of acute decompensation including dehydration, acute weight loss, acute illness, very high glucose levels, and presence of ketones. Basal insulin should be preferred and it can be temporary. Most insulin algorithms start with 10 units or 0.2 units/kg and titrate once or twice weekly at one-to-two units each time to achieve a target fasting blood glucose between 3.9-and-7.2mmol/L (70-and-130mg/dL). 8

Diabetic Foot Model of Care 2021: T2DM

In 2021 the HSE published its Diabetic Foot Model of Care 13 document. The aim of diabetic foot screening and risk

classification is to establish the person’s risk of diabetic foot ulceration. All persons with diabetes are assigned a risk category and where appropriate referred for ongoing foot screening, a foot assessment, and a clinical care plan. The care plan ensures that all people with diabetes receive annual or more frequent foot

screening, foot care education and review according to their clinical needs and in the most appropriate setting.13

Exception: Those with very complicated T2DM should have annual foot screening and care provided by the endocrinologist and their team.

Based on the findings of this screening the person is categorised as being low-, moderate- or high-risk of future diabetic foot ulceration, or if known to have prior foot ulceration will be categorised as being in remission or categorised as active foot disease, if foot ulceration is present or active Charcot is suspected.13

Complications of T2DM

Long-term complications of T2DM include diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and macrovascular problems.

Diabetic retinopathy is one of the most common causes of blindness in the working age population in Ireland. Up to 10 per cent of people with diabetes are at risk of sight-threatening retinopathy. Diabetic retinopathy may have no obvious symptoms in its early stages, but when caught early, treatment is effective at reducing or preventing damage to sight.10 The national diabetic retinopathy screening programme, Diabetic RetinaScreen, has been providing free retinal screening to all diabetes patients in Ireland over the age of 12 years since

2013.18 Since the programme’s launch, prevalent, undiagnosed, and untreated diabetic retinopathy and maculopathy have been successfully identified and referred for evidence-based treatments at the programme’s seven treatment centres before any significant visual symptoms occur. Adding patients to the register to be screened is easy, and can be done by a patient’s GP, or allied health professionals using the free phone number: 1800 454 555 or email info@diabeticretinascreen.ie. Full screening information is available at www.diabeticretinascreen.ie.

Diabetic nephropathy is a significant cause of chronic kidney disease and endstage renal failure globally. If untreated, diabetic nephropathy can lead to impaired kidney function, dialysis, and/or kidney transplant. Diabetic nephropathy is identi fied when eGFR is <60mL/ min/1.73m² and albuminuria >30mg/g creatinine. 8,14 Annual assessment (at least) with urine ACR, serum creatinine and eGFR) is recommended.18

Diabetic neuropathy is the most common complication associated with diabetes

mellitus. Diabetes causes a broad spectrum of neuropathic complications, including peripheral, autonomic, proximal, and focal. Diabetic peripheral neuropathy (DPN) is the most common form of nerve damage, and it most often affects the nerves to the hands and feet. DPN leads to distressing and expensive clinical sequelae, such as foot ulceration, leg amputation, and neuropathic pain. DPN is often diagnosed late when irreversible nerve injury has occurred, and its first presentation may be with a diabetic foot DPN may be present at time of diagnosis in more than 10 per cent of patients and may affect up to 50 per cent of patients with long-standing diabetes. In 50 per cent of cases, DPN may be asymptomatic, but for 16-to-26 per cent of patients with diabetes the neuropathy is painful. Patients should be examined for DPN from time of diagnosis.18

T2DM can also affect the large blood vessels, causing plaque to build up, leading to a heart attack, stroke, and peripheral vascular disease. Cardiovascular disease (CVD) is the leading cause (∼70 per cent) of death in people with T2DM. People with diabetes have a four-fold greater risk for having a CVD event than people without diabetes after controlling for traditional risk factors for CVD, such as age, obesity, tobacco use, dyslipidaemia, and hypertension.16

Prevention and patient education

Patient education and effective lifestyle modifications including weight loss and adoption of a healthy diet together with increased physical activity are the cornerstones for the prevention of T2DM. Emphasis must be placed on promoting a healthier lifestyle and finding solutions for increased adherence and compliance, especially for high-risk individuals.

Diabetes SMART is a new free interactive online education course developed by Diabetes Ireland, for people diagnosed with T2DM. The Diabetes SMART programme contains six interactive modules, covering topics that explain what

diabetes is, understanding the key medical information, such as blood glucose levels, managing illness, and providing tips on healthy eating, and getting active. The programme was developed by diabetes healthcare professionals, and the resource will give people with T2DM the knowledge and accessible tools to learn how to manage their condition and protect their future health.1

The HSE also provides a number of free educational resources and support courses to diabetes patients, both online and in person. See www.hse.ie/services/diabetessupport-courses/diabetes-support-courses.html for more information.

Outlook

While there is still no cure for T2DM, several drugs are in the developmental stages. Perhaps, the most promising currently are the glucagon-like peptide-1 (GLP-1) receptor agonists, which induce insulin production while also suppressing the secretion of glucagon.7 Tirzepatide is the first dual GIP/GLP-1 receptor agonist licensed for the treatment of T2DM in the US and Europe, with very positive data on its impact on HbA1c levels, weight loss, and cholesterol published during EASD 2022.

Imeglimin, a drug being developed by the French company Poxel, has shown great promise in a phase 3 clinical trial

in Japan.17 Damage to the mitochondria, the structures that generate energy within cells, plays a key role in the progression of metabolic diseases, and imeglimin protects mitochondria from damage. With this unique method of action, imeglimin has the potential to treat T2DM by acting in three organs at once: The pancreas, the liver, and the muscles to reduce blood glucose levels.16

Adjustments to dietary nutrient composition, insulin-secreting cell implants, bariatric surgery, and agents primarily designed to suppress appetite and reduce adiposity, will also greatly contribute to the future management of T2DM. n

References

1. Diabetes Ireland (2022). Diabetes Prevalence in Ireland. Diabetes Ireland. Available at: www. diabetes.ie/about-us/diabetes-in-ireland/

2. Leahy S, O'Halloran AM, O'Leary N, Healy M, McCormack M, Kenny RA, O'Connell J. Prevalence and correlates of diagnosed and undiagnosed type 2 diabetes mellitus and pre-diabetes in older adults: Findings from the Irish Longitudinal Study on Ageing (TILDA). Diabetes Res Clin Pract. 2015 Dec;110(3):241-9. doi: 10.1016/j.diabres.2015.10.015

3. International Diabetes Federation Diabetes Atlas (2021), Available at: https:// diabetesatlas.org/

4. Nolan J, O’Halloran D, McKenna T, Firth R, Redmond S. (2006). CODEIRE. The cost of treating type 2 diabetes. Available at: http://archive.imj.ie/ViewArticleDetails. aspx?ArticleID=1508

5. Bellou V, Belbasis L, Tzoulaki I, Evangelo E. (2018). Risk factors for type 2 diabetes mellitus: An exposure-wide umbrella review of meta-analyses. PLoS One. 2018 Mar 20; 13(3):eo194127. doi: 10.1371/journal. pone.0194127

6. Goyal R, Jialal I. Diabetes Mellitus Type 2. In StatPearls Publishing; 2022 Jan. Available from: www.ncbi.nlm.nih.gov/books/NBK513253/

7. Lam M. (2019). Diagnosis and management of type 2 diabetes mellitus. The Pharmaceutical Journal. Vol 303; No 7929; 303. doi: 10.1211/ PJ.2019.20206770

8. International Diabetes Federation. (2017). IDF clinical practice recommendations for managing type 2 diabetes in primary care. Available at:  www.idf.org/e-library/ guidelines/128-idf-clinical-practicerecommendations-for-managing-type-2diabetes-in-primary-care.html

9. World Health Organisation. (2011). Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus: Abbreviated report of a WHO consultation. Available at: www.who.int/diabetes/publications/reporthba1c_2011.pdf?ua=1

10. ICGP (2016). A practical guide to integrated type 2 diabetes care. Irish College of General Practitioners, Ireland. Available at: www.ICGP.ie

11. Goyal R, Jialal I, Castano M. (2022). Diabetes Mellitus Type 2 (Nursing) In StatPearls Publishing; 2022 Jan. Available from: www.ncbi. nlm.nih.gov/books/NBK568737/

12. National Institute for Health and Care Excellence. Type 2 diabetes in adults: Management. NICE guideline [NG28]. 2019. Available at:  www.nice.org.uk/ guidance/NG28

13. HSE. (2021). Diabetic foot model of care. Health Service Executive. Available at: www. hse.ie/eng/about/who/cspd/ncps/diabetes/moc/ diabetic-foot-model-of-care-2021.pdf

14. Lim A. (2014). Diabetic nephropathy –complications and treatment. Int J Nephrol Renovasc Dis. 2014 Oct 15;7:361-81. doi: 10.2147/IJNRD.S40172

15. Yang H, Sloan G, Ye Y, et al (2020). New perspective in diabetic neuropathy: From the periphery to the brain, a call for early detection and precision medicine. Front Endocrinol, 17 January 2020. doi: 10.3389/fendo.2019.00929

16. Cade WT. (2018). Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Physical therapy, 88(11), 1322–1335. doi: 10.2522/ ptj.20180008

17. Smith J. (2019). French first-in-class diabetes drug Nails phase III trial. Labiotech.eu. Available at: www.labiotech.eu/trends-news/ poxel-type-2-diabetes-japan/

18. HSE. (2018). Model of Integrated Care for Patients with Type 2 Diabetes. A guide for healthcare professionals (Clinical Management Guidelines). Available at: www. hse.ie/eng/about/who/cspd/ncps/diabetes/ moc/model-of-integrated-care-type-2diabetes-2018.pdf

ADA/EASD consensus update on management of hyperglycaemia in type 2 diabetes

The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) have launched their new consensus update on management of hyperglycaemia in type 2 diabetes (T2DM).

The update, published in late September, has been prepared by an international committee of experts and updates the previous 2018 and 2019 consensus reports. At the ADA’s 82nd Scientific Sessions in June 2022, a draft version of the report was presented and the opportunity for feedback was provided. Among the suggested changes were more focus on person-centred care, equity of care, and managing weight loss, which have been incorporated into the final report. “We are excited to share an updated consensus report on the management of hyperglycaemia in type 2 diabetes,” said Dr Robert Gabbay, Chief Scientific and Medical Officer for the ADA. “This is a wide-ranging consensus report that has several new features. It not only speaks of what needs to be done, but it also has a section on how to implement those changes.”

Hyperglycaemia prevention

The document stresses the importance of averting symptomatic hyperglycaemia in people with T2DM, noting that doing so leads to a substantial and enduring reduction in microvascular complications.

Glycaemic control yields immediate benefits in reducing symptoms, such as thirst, polyuria, blurred vision, and fatigue; symptoms which are commonly associated with poor control. But beyond immediate symptom relief, substantial microvascular benefits emerge and increase over time. The evidence that the burden of microvascular complications of diabetes can be significantly reduced by early, rigorous, therapeutic intervention is unequivocal, states the document.

Risk reductions of 50-to-76 per cent were seen

in people with type 1 diabetes studied in the Diabetes Control and Complications Trial (DCCT), while the UK Prospective Diabetes Study (UKPDS) confirmed the importance of glycaemic control for microvascular risk reduction in T2DM.

Epidemiologic analysis of the UKPDS data showed that for every 1 per cent reduction in HbA1c, the relative risk for microvascular complications decreased by 37 per cent. The greatest benefit comes from improving control in those with the highest HbA1c who are at the highest risk of complications. Because macrovascular benefits emerged after the randomised intervention period, there is uncertainty regarding macrovascular benefit of blood glucose control in T2DM.

Main recommendations

The 2022 consensus document has a stronger focus on communication, patient education, shared decision making, and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management, and the use of evidence from randomised controlled trials on glucoselowering medications to support evidence on weight loss/weight gain. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including assessment of subgroups, inform broader recommendations for cardiorenal protection in people with diabetes at high risk of cardiorenal disease. The update also provides guidance on improving equity of care and reviews how social determinants of health affect the management of hyperglycaemia.

As is in other ADA-EASD joint consensus reports, significant attention is given to the person’s involvement in their own diabetes care, including their home and economic

circumstances, how they feel about the side-effects of different possible medications and helping to choose their medication(s), and playing a full part in forming a regularly monitored care-management lan with their doctor.

Various recommendations on physical activity are included, including light exercise/ resistance training every 30 minutes while sitting; an extra 500 daily steps; 150 minutes of moderate to vigorous physical activity each week; strength training two or three times per week; and getting between six and nine hours of sleep each night.

Updates on glucose-lowering therapies are provided. These include recommendations on the use of oral GLP-1 RAs, higher doses of dulaglutide and semaglutide, the GIP/GLP-1 RA class, and combination GLP-1 RA and insulin. Additionally, specific information on comorbid conditions (eg, atherosclerotic cardiovascular disease, heart failure, and chronic kidney disease) is described.

Finally, in the updated consensus report, many intersecting themes regarding personcentred care are covered. These include the language used discussing care with patients, shared decision-making, access to diabetes self-management education and support, considering the local care environment and the resources available, avoiding inertia in patient management plans, and the consideration of more aggressive and proactive treatment at initiation, such as the potential use of combination therapy immediately. 

Reference

Davies MJ, Aroda VR, Collins BS, et al. Management of hyperglycaemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia (2022). doi: 10.1007/s00125-022-05787-2

Managing diabetic kidney disease: What advances are next?

Just over 101 years ago, in July 1921, Banting and Best first isolated insulin, revolutionising the treatment of diabetes, changing the natural history of the disease from a short, swift, and brutal fatal illness to the chronic and manageable disease we have today. In the intervening century the strides in scientific discovery have been remarkable, with the development of continuous glucose monitoring, insulin pumps, and pancreatic transplants.

Concurrently, we have witnessed advances in understanding the aetiology of diabetes at the molecular level and we now see the promise of an artificial pancreas and targeted gene therapy on the horizon. As the medical world has reacclimatised to life in the postpandemic world, renewed focus on novel treatments for the more ‘mundane’ diseases has resulted in new hope for clinicians and patients alike. Diabetes is a perfect exemplar in this regard.

More than half a billion people worldwide live with diabetes, with prevalent cases having tripled since 2000. The acceleration of incidence is not a phenomenon isolated to highincome countries; it is quickly becoming a disease of low- and middle-income countries. In resource-restricted settings the substantial attendant cardiovascular and microvascular morbidity is likely to exact a high price physically, financially, and psychosocially. While in Ireland no national diabetes registry exists, accepted estimates for prevalent cases in the Republic are more than 250,000, with close to 90 per cent of these cases being type 2 diabetes (T2DM). Interestingly,

The Irish Longitudinal Study on Ageing (TILDA) 2015 showed that 10 per cent of adults aged 50 years and over in Ireland have T2DM, with one-in-10 people with diabetes being undiagnosed in this population. Given the magnitude of this visible and invisible disease burden both nationally and internationally, an understanding of recent developments

in the treatment of diabetes and associated complications is relevant to most clinicians.

The morbidity and mortality associated with T2DM is attributable to microvascular (nephropathy, retinopathy and neuropathy) and macrovascular disease (cardiovascular

disease). The onset of T2DM is often surreptitious and therefore these complications are frequently present at time of diagnosis of diabetes. In many cases the onset of these complications can be delayed through risk factor modification; namely addressing dyslipidaemia, hypertension, and satisfactory glycaemic control. Once these complications have become established their progression can be delayed through similar means.

With regard the rates of microvascular complications in Ireland, the most thorough estimate is from a systematic review and metanalysis in 2016, where prevalence of microvascular complications was varied, ranging from 6.5-to-25.2 per cent for retinopathy; 3.2to-32.0 per cent for neuropathy; and 2.5to-5.2 per cent for nephropathy. While these figures are similar to rates found internationally (apart from nephropathy, which is underrepresented), care must be exercised given the wide margin of variation, which is likely in part attributable to the varied study settings and heterogeneity in the diagnostic criteria for microvascular and macrovascular complications.

Current treatment options for diabetic kidney disease (DKD)

Diabetic nephropathy will complicate diabetes in 40 per cent of cases.

Separately, diabetes is the most common cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD), both worldwide and in Ireland. As already mentioned, prevention of diabetic complications can be achieved with good glycaemic control in both type 1 diabetes mellitus (T1DM) and T2DM. However, intensive glycaemic control in established microvascular disease has not been shown to improve cardiovascular outcomes or slow progression.

When considering treatment options for established DKD, several agents are effective in slowing progression

and reducing morbidity and mortality. In patients with albuminuria or proteinuria, the strong evidential basis for renin-angiotensin-aldosterone system (RAAS) inhibitor use has remained as a cornerstone in the treatment of DKD, regardless of the presence of hypertension. The dual use of both an angiotensin receptor blocker (ARB) and an angiotensin converting enzyme (ACE) inhibitor confer no clinical benefit across several trials, while increasing the risk of hyperkalaemia and acute kidney injury.

infections have been widely observed. While the incidence of euglycaemic diabetic ketoacidosis is increased with the use of SGLT2 inhibitors, the absolute risk remains relatively low.

Apart from SGLT2 inhibitors, the glucose-lowering agents with the greatest evidence of renal and cardiovascular protection are the glucagon-like peptide 1 (GLP1) receptor agonists. Great interest has arisen in the use of GLP1 mimetics due to the observation that significant weight loss has been associated with their use, particularly given the rapidly rising rates of obesity and its strong association with T2DM. With the emergence of more long-term realworld data, the use of GLP1 agonists will likely increase.

Since the initial trials of sodium-glucose cotransporter-2 (SGLT2) inhibitors reported improvements in declining renal function and proteinuria in 2016, there has been a large volume of randomised control trials and realworld data to support the use of SGLT2 inhibitors as an effective therapy in slowing DKD progression and reducing major adverse cardiac events. While the improvement with glycaemic control is modest, the improvement in renal and cardiac outcomes have demonstrated a strong class effect and have been incorporated as standard care in most proteinuric CKD and heart failure. Interestingly, recent data suggests that the effect of SGLT2 inhibitors seems to be more pronounced in patients with more advanced CKD. Safety data regarding initial greater rates of amputation in early trials have not been replicated since or in real world data, but the increase in UTIs and fungal genital

Excessive activation of the renal endothelin system (particularly renal endothelin-1) has been shown to be an effective mediator of kidney injury in diabetes. The use of the endothelin receptor antagonist atrasentan had shown initial promise as a potential therapy in DKD. Pre-clinical studies demonstrated the efficacy of endothelin-A receptor antagonism in down-regulating the inflammatory and fibrotic effect of endothelin-1. Phase 2 trials showed atrasentan decreased albuminuria in DKD already on maximum RAAS inhibition, however, a large phase 3 trial showed that despite very selective inclusion criteria the adverse effect of oedema and worsening of heart failure was significant. While it may have a role in a highly selected patient population, its side-effect profile will preclude its adoption as a standard therapy.

With the role of RAAS inhibition in DKD being well elucidated, the downstream inhibition of aldosterone has been examined in the treatment of DKD in patients on a maximally tolerated ACE inhibitor or ARB.

When considering treatment options for established DKD, several agents are effective in slowing progression and reducing morbidity and mortality

The mineralocorticoid receptor (MR), which binds aldosterone, has been studied in detail and its overactivation in both cardiac and renal disease is well established and implicated in inflammation, fibrosis, and cardiovascular disease. The MR is a nuclear receptor expressed in a variety of tissues throughout the body, most pertinently in this case the kidney and heart. The MR is a promiscuous receptor and can be activated by other steroid hormones, namely cortisol and progesterone. The steroidal MR antagonists (MRAs) spironolactone and eplerenone have been shown to improve morbidity and mortality in heart failure with reduced ejection fraction (HFrEF), but not heart failure with preserved ejection fraction (HFpEF). The main limitation in the use of spironolactone is gynaecomastia and hyperkalaemia. Eplerenone was developed as a more selective MRA with trial data showing an incidence of gynaecomastia no different than placebo.

The novel agent finerenone has been developed as a non-steroidal MRA in an effort to mitigate the off-target effects of MR inhibition, with two large RCTs demonstrating its efficacy in DKD and cardiovascular disease (CVD) with no increase in sex hormone mediated sideeffects. Higher rates of hyperkalaemia compared to placebo were again noted, particularly in patients with lower eGFRs, but perhaps lower when compared to spironolactone.

Targeting inflammation in DKD

While the established therapies discussed above focus primarily on neurohormonal modulation in an effort to slow and ameliorate end organ damage in diabetes, the role of inflammation in the pathogenesis of diabetes and DKD has become increasingly apparent. Inflammation is a vital element in the armamentarium of the host defence, with several highly conserved pathways conducting its initiation, progression, and resolution to ensure an effective and

effectively controlled process to remove pathogens and enable tissue repair. This is a regulated and finite process in the healthy host under physiological conditions. A dysregulated inflammatory response is notable and notorious as the underlying mechanism for sepsis in an acute setting, but chronic and lowgrade inflammation results in fibrosis, functional decline and ultimately can lead to organ failure.

With regard to T1DM, the role of inflammation and autoimmunity in its aetiology has been well established. Inflammation in pancreatic islet beta-cells results in cell depletion and loss of function. Findings from experimental models and observational studies in humans demonstrate a key role for macrophages in islet beta-cell inflammation in obesity and T2DM, driven largely by responses to a family of cytokines including IFN-, TNF-, and IL-1. Islet autoimmunity might also contribute to the functional decline of beta-cells during the course of T2DM.

The role of obesity as a driver of inflammation has been delineated and the mechanisms by which it contributes to insulin resistance has been identified in several studies. The metabolic function of adipose tissues is the storage of fat, with the expansion of adipose deposits, especially abdominal deposition, being associated with T2DM, CVD and insulin resistance. Adipose tissue is an active endocrine organ, which expresses a variety of cytokines and chemokines to regulate energy utilisation, with derangements in its function having demonstrable effects. In situations where the ability to store calories as white fat is exceeded, ectopic deposition in non-adipose tissues (skeletal muscle, liver, kidney, pancreas) occurs where it exerts what has been termed a lipotoxic effect on the nonadipose tissue in question, by invoking an inflammatory response, an example of sterile inflammation.

The role of inflammation in the development of microvascular and macrovascular damage in diabetes has led to the investigation of antiinflammatory-based therapies. Such approaches are well known in the contemporary practice of medicine, from the use of NSAIDs in acute inflammatory pain, to the corticosteroid dexamethasone and the IL-6 receptor antibody tocolizumab in the cytokine storm of severe Covid-19. However, despite the use of anti-inflammatory strategies in certain circumstances, concerns exist regarding impairing the host response in other circumstances leading to inadequate response to exogenous pathogens. Several examples of this are evident in the literature, for example, the TESTING trial, which examined the use of methylprednisolone in IgA nephropathy. A statistically-significant reduction in kidney function decline was noted with the use of the steroid, but excess infections and mortality in the treatment group mandated termination of the trial prematurely and redesign at a lower dose of steroid in an effort to reduce this adverse effect (which was ultimately unsuccessful).

Baricitinib, an inhibitor of the JAKSTAT inflammatory pathway, has been investigated in patients with DKD, with phase 2 trial data demonstrating a significant reduction in albuminuria, a key indicator of DKD progression. In patients with T2DM and kidney disease, a randomised phase 2 trial demonstrated therapeutic potential of the anti-inflammatory CCR2 antagonist CCX140-B, with significant reductions in albuminuria when given in addition to standard care. While there is caution with respect to targeting DKD with anti-inflammatories, inflammation remains a plausible target to pursue, and it is worth noting that many of the established medicines currently used in practice, such as RAAS and SGLT2 inhibitors, have been demonstrated to exert anti-inflammatory effects.

Looking ahead: How can we improve the diagnosis and treatment of DKD?

The precision medicine era promises individual level healthcare decisions whereby your genetic, proteomic and metabolomic biomarker makeup will guide diagnosis and tailored pharmacotherapy. Central to this model of precision medicine is the need for accurate biomarkers, and for a long time this has been a challenge for DKD. However, technological advances in recent years are beginning to address this problem, now allowing for the simultaneous measurement of

the collagen 4-alpha 3 gene, and the presence of this variant was associated with a thinner glomerular basement membrane. Could carriers of this DNA variant be protected from developing advanced DKD? Armed with this type of genetic information, should we consider such disease-associated DNA variants as simple risk predictors for early diagnosis, or do we attempt to correct the DNA sequence using the latest genome-editing technologies (CRISPR/Cas-9)? Given the complexity of DKD and the likely contribution of many DNA variants to disease risk, it is unlikely we will see the latter for some time, but this is no longer

a ‘single-course, life-long treatment solution’. While we are not quite there yet with DKD, the scenario may arise in the not-too distant future where you can decide on conventional pharmacotherapy or one-shot gene therapy.

numerous proteins and metabolites in DKD patient blood and urine, offering hope for less invasive means of diagnosis and prognosis. As a result, biomarker panels of proteins are being explored as a potential tool to better predict early kidney function decline as compared with or in tandem with more traditional markers – albuminuria and eGFR.

While studies of DNA in patients of many single-gene diseases have proven truly transformative, when searching for changes in the DNA code that might be associated with risk of a complex and multifactorial disease such as DKD, this has proven to be much more challenging. Nevertheless, several large-scale international studies have examined the DNA of patients with DKD, including Irish participants, pointing us to several regions of the human genome that if perturbed may alter one’s risk of developing DKD. One such study led by the GENIE consortium identified a protective DNA variant in

science fiction and such approaches could be closer than you might expect. This year, US-based Verve Therapeutics began a human trial using CRISPR DNA-editing technology to modify the PCSK9 gene in people with heterozygous familial hypercholesterolaemia, a condition that can lead to early-onset atherosclerosis and increased risk of CVD. PCSK9 is a protein involved in lowering LDL cholesterol, and several effective, but expensive, PCSK9 inhibitors are now available for patients. In parallel with these drug development success stories, genetics studies discovered adults with naturally occurring mutations in their PCSK9 gene that seemed to switch off this gene, resulting in low cholesterol levels and overall excellent cardiovascular health. These lucky few had won the genetic lottery by coming up with the wining code. Taking advantage of this, Verve Therapeutics wants to introduce mutations into patient DNA and ultimately switch off the PCSK9 gene to lower LDL cholesterol levels. According to Verve Therapeutics, this would represent

Finally, stem cell therapy promises to revolutionise regenerative medicine for the treatment of many diseases, and diabetes management strategies will surely in time benefit from such developments. For T1DM, the holy grail centres on pancreatic beta cell replacement therapies, allowing for the implantation of insulin-producing beta cells. In this space, in June 2022 the US-based company Vertex Therapeutics announced exciting clinical trial data from the first T1DM patients receiving their beta cell therapy VX-880, demonstrating a remarkable lowering of blood glucose, without the need for regular insulin injections. While we eagerly await more data from this trial and consider the lingering concerns over the necessity for immunosuppressant medications in tandem with stem cell therapies, this has the potential to be a game-changer that could instantly improve the quality-of-life of so many patients with T1DM. This would inevitably have a positive impact on the global prevalence of vascular complications of diabetes, such as DKD.

Conclusion

DKD is a major global health challenge with high prevalence and an absence of predictive biomarkers that allow us to identify those in the population at greatest risk of developing this disease. Current therapies at best halt, but do not reverse kidney damage. Recent advancements in technologies may allow us to identify new diagnostic and prognostic biomarkers, as well as novel gene and cell-based next generation therapies. Such developments may be the only solution to this complex problem. n

References on request

The role of inflammation in the development of microvascular and macrovascular damage in diabetes has led to the investigation of anti-inflammatory-based therapies

Obesity: Effective treatments for the most prevalent disease in Ireland

Obesity is a chronic disease that affects more people in Ireland that any other. The disease of obesity is associated with several other diseases, such as type 2 diabetes, cardiovascular disease, and cancer. The morbidity associated with obesity is so significant that it limits life expectancy.1-3

Terming obesity as a disease is sometimes controversial, as many understand it as a result of poor food choices and a sedentary lifestyle. While these factors can contribute to the development of obesity, there are multiple other factors involved in the pathogenesis of the disease of obesity, including genetic factors and dysregulation of energy metabolism.4

Blaming people with obesity for having obesity because at some point in their lives they ate high-calorie foods, is like blaming people with lung cancer for having cancer because at one point they smoked (even if that was over 20 years ago). The development of the disease of obesity is much more complex than ‘eating too much and doing too little exercise’.4

Many of us who do not have obesity might reflect on our own diet and activity levels and find that we often eat highcalorie foods and do not often take a lot of exercise. In contrast, we might have patients, friends, or family living with obesity who are actively dieting and going for long walks every evening, but remain unable to lose significant amounts of weight and continue to have obesity despite years of trying to lose weight. The evidence for a biological basis for obesity is in the published literature, but it is also all around us in our daily lives.

The lack of understanding of the disease

of obesity contributes to a phenomenon termed ‘obesity stigma’. We live in a society that feels free to openly discriminate against people based on their weight. People living with obesity are often portrayed as unmotivated (‘lazy’) and undisciplined (‘greedy’). The common narrative is that if people have obesity, then it is their fault, and that if they just became motivated and disciplined, then their obesity would resolve.

(approximately 80 per cent), diet and exercise-based interventions do not result in long-term weight loss. 4,6-10 This is not because of a lack of effort on their part. They continue to attend for often intensive research protocols over years, but despite doing so cannot maintain their weight loss. We now know that this is not because people with obesity are lazy and greedy: It is because of maladapted energy homeostasis and genetic predisposition, in concert with multiple biological and external factors, resulting in the development of a disease called obesity. 4

Treatment of the disease

When we stigmatise people living with obesity as unmotivated, undisciplined people who do not take responsibility for their own health and wellbeing, it gives us license to blame them for their poor health, to criticise them for their life choices, and even to decline to employ them. 5 It also allows us to rationalise a clinical approach that apportions all the responsibility on the patient and avoids offering proven clinical interventions that successfully treat the disease of obesity. Given the prevalence of obesity stigma, it is no surprise that obesity is associated with depression, anxiety, reduced social participation, and reduced quality-of-life. 4,5

Over the last three decades, repeated studies have shown that for the vast majority of people living with obesity

For the majority of people who attempt diet and exercise interventions to treat their obesity and lose weight, their physiology defends against weight loss. 4 The first physiological defence mechanism is hunger. Reduction in food intake results in increased hunger. Like many primal reflexes and functions, hunger is unconscious. However, when people on a diet become hungry they can consciously resist their hunger in an effort to lose weight. This can result in some weight loss, but living in a constant state of perceived starvation is very challenging to maintain and requires constant conscious resistance of hunger.

If people do manage to constantly resist hunger and maintain a calorie deficit (ie, consume fewer calories than they expend) then the other major physiological adaptation that helps resist weight loss is activated: This is a reduction in the metabolic rate.4 This mechanism is why people will eventually reach a weightloss plateau, despite sticking to a diet that initially resulted in weight loss, and

We live in a society that feels free to openly discriminate against people based on their weight

continues to result in hunger. During a diet, the metabolism reacts as it would during a famine and energy expenditure is minimised to meet the reduced calorie intake. Therefore, people on a diet will continue to burn fewer calories as long as there is a calorie deficit.

The only way to overcome these mechanisms is to consciously reduce calorie intake to extremely low levels (approximately 600kcal per day), which is unhealthy to maintain and consistent with starvation. Even if someone can achieve this for a time, on reintroduction of normal diet with a calorie intake within recommended limits (eg, 2,000kcal per day) there will be weight

not available at all, then a relatively simple class-based programme can at least offer structured advice on calorie reduction and peer support.

Exercise is an important component of any weight loss programme not because it significantly aids weight loss, but because it helps weight maintenance and minimises the risk of weight regain. Regular exercise is shown to reduce weight regain after successful weight loss achieved with dietary modification. This exercise does not have to be gym-based or exercise therapist-led. Any additional exercise such as walking can be of benefit, but a minimum of 30 minutes a day is needed to gain this benefit.

insulinotropic polypeptide) receptor and GLP-1 (glucagon-like peptide-1) receptor agonist that treats some of the fundamental physiological metabolic dysfunction inherent in the disease of obesity. While not yet available to prescribe in Ireland, the development of tirzepatide has reaffirmed hope that as research continues, medical therapy will soon match the biological effects of bariatric and metabolic surgery and provide patients with even more obesity treatment options.

Surgery

Bariatric and metabolic surgery is the most effective intervention in treating obesity and obesity-associated disease. All procedures are performed laparoscopically with a very low rate of complications. Surgery results in long-term weight loss in the range of 20-to-25 per cent over follow-up periods of 20 years.12-14 It also reduces all-cause mortality and ameliorates obesityrelated diseases in the long-term.12-14

regain as their healthy 2,000kcal a day diet will be in excess of what they are expending by the end of their diet (which could be lower than 1,000kcal per day). 8-10

Given these mechanisms, it is no surprise that for over 80 per cent of people with obesity, diet and exercise interventions alone will not achieve durable weight loss. Of course, this means that as many as 20 per cent of people with obesity will achieve significant weight loss in the long-term as a result of diet and exercise interventions and so a structured diet and exercise programme is a reasonable first-line treatment for obesity if the individual has not completed a structured intervention before.

Ideally, a structured diet and exercise programme would be provided in the public sector and be dietician and/or exercise physiologist-led, with psychologist support. If such a programme is not available then there are commercially available options. If such a programme is

When diet- and exercise-based programmes are unsuccessful, then medical therapy should be considered as next-line therapy. There are four medical options at present – orlistat, liraglutide (at a dose of 3mg daily rather than the 1.8mg dose used for diabetes), naltrexone/bupropion, and semaglutide (at a maximum dose of 2.4mg rather than the 1mg use in the treatment of diabetes). All of these can be prescribed safely in primary care although at the time of writing there are some supply issues with respect to semaglutide. For current prescribing information, please see www.medicines.ie and/or www.hpra.ie/ homepage/medicines.

Ongoing obesity research is resulting in a greater range treatment options. Tirzepatide is a new medical therapy that can produce over 20 per cent weight loss, thus approximately the weight loss achieved with bariatric and metabolic surgery.11 This agent is a once-weekly GIP (glucose-dependent

In diabetes, surgery has particular benefits, and is a more effective treatment for type 2 diabetes than medical care alone. It improves glycaemic control in those with type 2 diabetes, can prevent progression of complications such as diabetic kidney disease, and sometimes results in full remission of type 2 diabetes.12-14 Therefore, surgery is increasingly used to primarily treat diabetes rather than the associated obesity.

Weight loss after surgery is a not a result of physical restriction or calorie malabsorption, as is commonly misunderstood, but is in fact achieved by modulation of appetite and changes to the physiological response to eating.15 After surgery people will experience increased satiety and decreased hunger, which is associated with changes in gastrointestinal hormones such as GLP-1. This reduces appetite and food intake. There is also evidence that surgery increases energy expenditure despite

For the majority of people who attempt diet and exercise interventions to treat their obesity and lose weight, their physiology defends against weight loss

disability, obesity-associated diseases, and a reduction in life expectancy. However, obesity is a disease that can be successful treated. Therefore, people with obesity need to be recognised and offered treatment. Treatment can save lives, reduce morbidity and mortality, and improve psychosocial functioning.

reduced calorie intake, therefore directly addressing the two major components of the disease of obesity.15

Surgery is the only treatment with evidence for long-term weight loss, and reduction in all-cause mortality, and therefore should be considered in all people with obesity. While the perioperative risks are as low as general elective surgery, the long-term effects of these procedures can be intolerable for some, and so the risk of a poor

References

1. Nguyen NT, Magno CP, Lane KT, Hinojosa MW, Lane JS. Association of hypertension, diabetes, dyslipidemia, and metabolic syndrome with obesity: findings from the National Health and Nutrition Examination Survey, 1999 to 2004. J Am Coll Surg. 2008;207(6):928-34

2. Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356:j477

3. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352(11):1138-45

4. Bray GA, Kim KK, Wilding J. World Obesity Federation. Obesity: A chronic relapsing progressive disease process. A position statement of the World Obesity Federation.  Obes Rev. 2017;18(7):715–23

5. Ul-Haq Z, Mackay DF, Fenwick E, Pell JP. Meta-analysis of the association

outcome is more often related to the patient’s response to an expected physiological effect of surgery rather than the result of a complication. Before surgery a comprehensive holistic multidisciplinary assessment is needed to ensure candidates are fully prepared to have an optimal response to surgery.

Conclusion

Obesity is a disease that affects all aspects of human health, resulting in social isolation, economic disadvantage,

between body mass index and health-related quality-of-life among adults, assessed by the SF-36. Obesity 2013;21(3):E322-7

6. Weigle DS. Appetite and the regulation of body composition. FASEB J 1994;8(3):302-10

7. Saper CB, Chou TC, Elmquist JK. The need to feed: Homeostatic and hedonic control of eating. Neuron. 2002;36(2):199-211

8. Unick JL, Neiberg RH, Hogan PE, et al. Weight change in the first two months of a lifestyle intervention predicts weight changes eight years later. Obesity 2015;23(7):1353-6

9. Weigle DS, Sande KJ, Iverius PH, Monsen ER, Brunzell JD. Weight loss leads to a marked decrease in non-resting energy expenditure in ambulatory human subjects. Metabolism. 1988;37(10):930-6

10. Leibel RL, Rosenbaum M, Hirsch J. Changes in energy expenditure resulting from altered body weight. N

We need to do better for people living with obesity, both in terms of our understanding of the disease of obesity as clinicians, and in terms of offering treatment. In 2021, the HSE Model of Care for Obesity was launched (www. hse.ie/eng/about/who/cspd/ncps/obesity/ model-of-care/). This will be the start of a new programme of expanded public sector provision of all treatment options for obesity so that we help people living with obesity to overcome this insidious chronic disease. n

Engl J Med . 1995;332(10):621-8

11. Jastreboff AM, Aronne LJ, Ahmad NN; SURMOUNT-1 Investigators. N Engl J Med 2022;387(3):205-216

12. Sjostrom L, Lindroos AK, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med . 2004; 351(26):2683-93

13. Sjostrom L, Peltonen M, Jacobson P, et al. Bariatric surgery and longterm cardiovascular events. JAMA 2012;307(1):56-65

14. Carlsson LMS, Sjöholm K, Jacobson P, et al. Life expectancy after bariatric surgery in the Swedish Obese Subjects study. N Engl J Med . 2020;383(16):1535-1543

15. Neff KJ, le Roux CW. (2016). Mechanisms of action of bariatric surgical procedures. In: Agrawal, S. (eds) Obesity, bariatric and metabolic surgery. Springer, Cham. doi: 10.1007/978-3-31904343-2_54

Obesity is a disease that affects all aspects of human health, resulting in social isolation, economic disadvantage, disability, obesity-associated diseases, and a reduction in life expectancy

Patient portrayal.

ROBERTO, civil servant; Age: 48 BMI: 39

Abbreviated Prescribing Information

Saxenda® Liraglutide injection 3 mg. Please refer to the full Summary of Product Characteristics (SmPC) before prescribing. Saxenda® 6 mg/ml solution for injection in a prefilled pen. One pre-filled pen contains 18 mg liraglutide in 3 ml. Indication: Adults: Saxenda® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of ≥ 30 kg/m² (obesity) or ≥ 27 kg/m² to < 30 kg/ m² (overweight) in the presence of at least one weight-related comorbidity. Treatment with Saxenda® should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5% of their initial body weight. Adolescents (≥12 years): Saxenda® can be used as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescent patients from the age of 12 years and above with obesity (BMI corresponding to ≥30 kg/m2 for adults by international cut-off points)* and body weight above 60 kg. Treatment with Saxenda should be discontinued and re-evaluated if patients have not lost at least 4% of their BMI or BMI z score after 12 weeks on the 3.0 mg/day or maximum tolerated dose. *See table 1 in SmPC. Posology and administration: Adults: The starting dose is 0.6 mg once daily. Dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least one-week intervals to improve gastro-intestinal (GI) tolerability. If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Adolescents (≥12 years): A similar dose escalation schedule as for adults should be applied. The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached (see SmPC). Adults and Adolescents: Daily doses higher than 3.0 mg are not recommended. Saxenda® is administered once daily at any time, independent of meals, subcutaneously injected in the abdomen, thigh or upper arm, preferably around the same time of the day. Saxenda® must not be administered intravenously or intramuscularly. Saxenda® should not be used in combination with another GLP-1 receptor agonist. When initiating treatment in patients with type 2 diabetes mellitus, consider reducing the dose

Saxenda® Liraglutide injection 3 mg. Please refer to the full Summary of Product Characteristics (SmPC) before prescribing. Saxenda® 6 mg/ml solution for injection in a prefilled pen. One pre-filled pen contains 18 mg liraglutide in 3 ml. Indication: Adults: Saxenda® is indicated as an adjunct to a reduced-calorie diet and increased physical activity for weight management in adult patients with an initial Body Mass Index (BMI) of ≥ 30 kg/m² (obesity) or ≥ 27 kg/m² to < 30 kg/ m² (overweight) in the presence of at least one weight-related comorbidity. Treatment with Saxenda® should be discontinued after 12 weeks on the 3.0 mg/day dose if patients have not lost at least 5% of their initial body weight. Adolescents (≥12 years): Saxenda® can be used as an adjunct to a healthy nutrition and increased physical activity for weight management in adolescent patients from the age of 12 years and above with obesity (BMI corresponding to ≥30 kg/m2 for adults by international cut-off points)* and body weight above 60 kg. Treatment with Saxenda should be discontinued and re-evaluated if patients have not lost at least 4% of their BMI or BMI z score after 12 weeks on the 3.0 mg/day or maximum tolerated dose. *See table 1 in SmPC. Posology and administration: Adults: The starting dose is 0.6 mg once daily. Dose should be increased to 3.0 mg once daily in increments of 0.6 mg with at least one-week intervals to improve gastro-intestinal (GI) tolerability. If escalation to the next dose step is not tolerated for two consecutive weeks, consider discontinuing treatment. Adolescents (≥12 years): A similar dose escalation schedule as for adults should be applied. The dose should be increased until 3.0 mg (maintenance dose) or maximum tolerated dose has been reached (see SmPC). Adults and Adolescents: Daily doses higher than 3.0 mg are not recommended. Saxenda® is administered once daily at any time, independent of meals, subcutaneously injected in the abdomen, thigh or upper arm, preferably around the same time of the day. Saxenda® must not be administered intravenously or intramuscularly. Saxenda® should not be used in combination with another GLP-1 receptor agonist. When initiating treatment in patients with type 2 diabetes mellitus, consider reducing the dose

Crescent

of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues. The safety and efficacy of Saxenda in children below 12 years of age has not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Saxenda® must not be used as a substitute for insulin in patients with diabetes mellitus. Diabetic ketoacidosis has been reported after rapid discontinuation or dose reduction of insulin. There is no clinical experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and therefore Saxenda® is not recommended for use in these patients. Saxenda® is not recommended in patients: aged 75 years or more, treated with other products for weight management, with obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain, with severe renal impairment including end-stage renal disease, with severe hepatic impairment. Saxenda® must be used with caution in patients with mild or moderate hepatic impairment. Saxenda® is not recommended in patients with inflammatory bowel disease and diabetic gastroparesis. Acute pancreatitis has been observed with the use of GLP-1 receptor agonists, patients should be informed of the characteristic symptoms. If pancreatitis is suspected, Saxenda® should be discontinued; if acute pancreatitis is confirmed, Saxenda® should not be restarted. In clinical trials for weight management, a higher rate of cholelithiasis and cholecystitis was observed in patients on Saxenda® than those on placebo, therefore inform patients of characteristic symptoms. Use with caution in patients with thyroid disease. An increase in heart rate was observed with liraglutide in clinical trials. Heart rate should be monitored at regular intervals and patients informed of the symptoms of increased heart rate. For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda® should be discontinued. Patients treated with Saxenda® should be advised of the potential risk of dehydration in relation

of concomitantly administered insulin or insulin secretagogues (such as sulfonylureas) to reduce risk of hypoglycaemia. Blood glucose self-monitoring is necessary to adjust the dose of insulin or insulin-secretagogues. The safety and efficacy of Saxenda in children below 12 years of age has not been established. Contraindications: Hypersensitivity to the active substance or to any of the excipients. Special warnings and precautions for use: Saxenda® must not be used as a substitute for insulin in patients with diabetes mellitus. Diabetic ketoacidosis has been reported after rapid discontinuation or dose reduction of insulin. There is no clinical experience in patients with congestive heart failure New York Heart Association (NYHA) class IV and therefore Saxenda® is not recommended for use in these patients. Saxenda® is not recommended in patients: aged 75 years or more, treated with other products for weight management, with obesity secondary to endocrinological or eating disorders or to treatment with medicinal products that may cause weight gain, with severe renal impairment including end-stage renal disease, with severe hepatic impairment. Saxenda® must be used with caution in patients with mild or moderate hepatic impairment. Saxenda® is not recommended in patients with inflammatory bowel disease and diabetic gastroparesis. Acute pancreatitis has been observed with the use of GLP-1 receptor agonists, patients should be informed of the characteristic symptoms. If pancreatitis is suspected, Saxenda® should be discontinued; if acute pancreatitis is confirmed, Saxenda® should not be restarted. In clinical trials for weight management, a higher rate of cholelithiasis and cholecystitis was observed in patients on Saxenda® than those on placebo, therefore inform patients of characteristic symptoms. Use with caution in patients with thyroid disease. An increase in heart rate was observed with liraglutide in clinical trials. Heart rate should be monitored at regular intervals and patients informed of the symptoms of increased heart rate. For patients who experience a clinically relevant sustained increase in resting heart rate, treatment with Saxenda® should be discontinued. Patients treated with Saxenda® should be advised of the potential risk of dehydration in relation

to GI side effects and take precautions to avoid fluid depletion. Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported. Patients with type 2 diabetes mellitus receiving Saxenda® in combination with insulin and/or sulfonylurea may have an increased risk of hypoglycaemia. Dizziness can be experienced mainly during the first 3 months of treatment, therefore use caution when driving or using machines if dizziness occurs. Episodes of clinically significant hypoglycaemia have been reported in adolescents (≥12 years) treated with liraglutide; patients should be informed about characteristic symptoms of hypoglycaemia and appropriate actions. Fertility, pregnancy and lactation: Saxenda® should not be used during pregnancy or breastfeeding. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda® should be discontinued. Undesirable effects: Very common (≥1/10): headache, nausea, vomiting, diarrhoea, constipation. Common (≥1/100 to <1/10): hypoglycaemia, insomnia, dizziness, dysgeusia, dry mouth, dyspepsia, gastritis, gastro-oesophageal reflux disease, abdominal pain upper, flatulence, eructation, abdominal distension, cholelithiasis, injection site reactions, asthenia, fatigue, increased lipase, increased amylase. Uncommon (≥1/1,000 to <1/100): dehydration, tachycardia, pancreatitis, delayed gastric emptying, cholecystitis, urticaria, malaise. Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, acute renal failure, renal impairment. The SmPC should be consulted for a full list of side effects. Legal category: POM MA number: 5 x 3 ml pre-filled pens EU/1/15/992/003 For complete prescribing information, please refer to the SmPC which is available on www.medicines.ie or by email from infoireland@novonordisk.com or from the Clinical, Medical and Regulatory Department, Novo Nordisk Limited, 1st Floor, Block A, The Crescent Building, Northwood Business Park, Santry, Dublin 9, Ireland.

Date last revised: November 2021.

Adverse events should be reported to the Health Products Regulatory Authority. Information about adverse event reporting is available at www hpra.ie. Adverse events should also be reported to Novo Nordisk on Tel: 1850 665 665 or complaintireland@novonordisk.com

to GI side effects and take precautions to avoid fluid depletion. Signs and symptoms of dehydration, including renal impairment and acute renal failure have been reported. Patients with type 2 diabetes mellitus receiving Saxenda® in combination with insulin and/or sulfonylurea may have an increased risk of hypoglycaemia. Dizziness can be experienced mainly during the first 3 months of treatment, therefore use caution when driving or using machines if dizziness occurs. Episodes of clinically significant hypoglycaemia have been reported in adolescents (≥12 years) treated with liraglutide; patients should be informed about characteristic symptoms of hypoglycaemia and appropriate actions. Fertility, pregnancy and lactation: Saxenda® should not be used during pregnancy or breastfeeding. If a patient wishes to become pregnant, or pregnancy occurs, treatment with Saxenda® should be discontinued. Undesirable effects: Very common (≥1/10): headache, nausea, vomiting, diarrhoea, constipation. Common (≥1/100 to <1/10): hypoglycaemia, insomnia, dizziness, dysgeusia, dry mouth, dyspepsia, gastritis, gastro-oesophageal reflux disease, abdominal pain upper, flatulence, eructation, abdominal distension, cholelithiasis, injection site reactions, asthenia, fatigue, increased lipase, increased amylase. Uncommon (≥1/1,000 to <1/100): dehydration, tachycardia, pancreatitis, delayed gastric emptying, cholecystitis, urticaria, malaise. Rare (≥1/10,000 to <1/1,000): anaphylactic reaction, acute renal failure, renal impairment. The SmPC should be consulted for a full list of side effects. Legal category: POM MA number: 5 x 3 ml pre-filled pens EU/1/15/992/003 For complete prescribing information, please refer to the SmPC which is available on www.medicines.ie or by email from infoireland@novonordisk.com or from the Clinical, Medical and Regulatory Department, Novo Nordisk Limited, 1st Floor, Block A, The Crescent Building, Northwood Business Park, Santry, Dublin 9, Ireland. Date last revised: November 2021.

Adverse events should be reported to the Health Products Regulatory Authority. Information about adverse event reporting is available at www hpra.ie. Adverse events should also be reported to Novo Nordisk on Tel: 1850 665 665 or complaintireland@novonordisk.com

Your patients with obesity have the will. You can offer them the way.

I haVe the will to work out eVery day.

But I still need help to lose weight and keep it off.

Your patients with obesity have the will. You can offer them the way.

I haVe the will to work out eVery day. But I still need help to lose weight and keep it off.

The use of non-insulin pharmacotherapies in type 1 diabetes mellitus: A review

Diabetes is a complex metabolic condition characterised by chronic hyperglycaemia and associated with macro- and microvascular disease. This year marks the 101th year anniversary of the use of insulin by Banting and Best – a discovery which ushered in an unprecedented change in the management of diabetes and allowed treatment of what, up until then, had been a terminal condition.

Despite this, more than a century after this landmark discovery many people with type 1 diabetes (T1DM) live with suboptimal control. The SAGE study by Renard et al found that less than onequarter of people with T1DM aged >24 years have a HbA1c below the target level of 7 per cent/53mmol/mol and many more live with life-limiting complications of poor control.1

Interventions such as continuous glucose monitoring (CGM) and continuous subcutaneous insulin infusions (CSII), have been shown to reduce hypoglycaemia and improve glycaemic control. The Diamond and GOLD studies evaluated the use of CGM in multiple daily injection (MDI) users and were carried out over 24 and 28 weeks, respectively. 2,3 These studies found rates of reduction of HbA1c between 1-and-.5 per cent compared to baseline. A followup of the GOLD trial found that after 18 months the benefits of CGM continue in MDI users and a reduction in HbA1c is preserved. However, the average HbA1c was significantly above target (63.5 or 8.6 per cent). 4 Other real-life observational studies in CGM users found a reduction

from baseline of 0.4 per cent in CGM users after 12 months of therapy. 5

In CSII users a 2010 systematic review found that CSII lowers HbA1c more than conventional MDI use. 6 However, a recent observational study from Denmark found that most people using CSII had a raised HbA1c, and only 30 per cent achieved their target HbA1c.7 This evidence proves that

islet cell, and pancreas transplants, are other potential treatment strategies, however, they are only available in a small number of centres and cannot be readily offered to the majority of patients with T1DM.

Other important issues facing adults with T1DM include comorbid conditions such as obesity, hypertension, kidney disease, and heart failure. Obesity is a particular problem in T1DM and a growing trend. A recent US study of adults with T1DM found that 49 per cent were obese or overweight.9 Many of the drugs now used to treat type 2 diabetes (T2DM) target these comorbid conditions.

although substantial improvements in glycaemia control, hypoglycaemia, and quality-of-life can be introduced using these therapies, only a minority of patients ever reach their glycaemic targets. Additionally, such devices are expensive, can cause issues including alarm fatigue, and, importantly, are not yet universally funded or available to all adults with diabetes. A recent Irish study found that only 10 per cent of the entire population with T1DM use CSII and only 6 per cent of adults use this technology, highlighting the limitations of such technology. 8 Further interventions like immunotherapy,

Currently, insulin is the mainstay of pharmacological therapy in T1DM and patients are not routinely able to benefit from the advantages of these therapies. The aim of this article is to review the literature surrounding the use of non-insulin therapies in the treatment of T1DM. We will evaluate the current evidence and highlight potential therapeutic strategies.

Metformin

Metformin is a biguanide therapy, used in the treatment of hyperglycaemia since the 1950s. It reduces hepatic gluconeogenesis, increases glucose utilisation in the gastrointestinal tract, and promotes a range of anti-inflammatory changes including a reduction in cytokines.10 It is one of the first-line therapies for people with T2DM and is increasingly used in people with T1DM.

Further interventions like immunotherapy, islet cell and pancreas transplants are other potential treatment strategies

Metformin has been shown to reduce insulin doses, improve glucose levels, and reduce metabolic syndrome,11 although improvements in HbA1c are not always seen.12 In adults with long-standing diabetes and multiple cardiovascular disease (CVD) risk factors, it can reduce weight and cholesterol levels without a substantial change in HbA1c.13 In adolescents and young adults, improvements in body mass index (BMI) and HbA1c are seen, but at the expense of more frequent hypoglycaemia.14 Other benefits of metformin in young adults include the reduction of insulin resistance, even in those with normal BMIs.15

Relevant contra-indications of metformin use include renal or severe hepatic impairment, and gastro-intestinal sideeffects are equally common in those with T1DM compared to people with T2DM.

SGLT2 inhibitors and dual inhibitors of SGLT1 and SGLT2

Sodium-glucose co-transporter 2 (SGLT2) inhibitors block the SGLT2 transporter in the proximal renal tubule resulting in excretion of glucose in the urine. SGLT1 inhibitors reduce the intestinal absorption of glucose. Thus, inhibition of SGLT2 or SGLT1 results in a decrease in blood glucose in a manner independent of insulin. SGLT1 and SGLT2 inhibitors have also been combined for the treatment of diabetes. SGLT2 inhibitors are now second-line for the treatment of T2DM in those where heart failure or chronic kidney disease predominates. 25 There is substantial evidence to support the use of SGLT2 inhibitors in the management of T2DM with reduction in HbA1c, weight, and blood pressure, and favourable effects on CVD, progression of microalbuminuria, and heart failure. 26-28

There have been multiple trials to evaluate the safety and efficacy of both SGLT2 inhibitors and SGLT1/2 inhibitors in individuals with inadequately controlled T1DM. The EASE Trials

evaluated the use empagliflozin for the treatment of T1DM. 29 The EASE 2 trial involved the use of empagliflozin 10mg and 25mg, doses currently approved in the treatment of T2DM. The EASE 3 trial also included a lower 2.5mg dose; a dose not currently used in clinical practice for the treatment of T2DM. All doses resulted in a significant reduction in HbA1c with the maximal effect observed at 12 weeks. The reductions in HbA1c were dose dependent, ranging from -0.53 per cent with 25mg, to -0.28 per cent with 2.5mg. Other benefits included weight loss of up to 3.4kg, decreased total daily dose of insulin (TDD), and improvements in systolic blood pressure (SBP). Increased time in range and decreased glycaemic variability were also observed on CGM data without increased hypoglycaemia. However, an increased risk of DKA was observed in a dose-dependent manner, but rates of DKA were comparable to placebo with the use of 2.5mg empagliflozin.

Insulin pump use and female gender were identified as important risk factors for DKA with SGLT2 inhibitor use. Genital infections were also more common with the use of empagliflozin.

The EASE trial results are largely in agreement with other trails of SGLT inhibitors use in T1DM. Table 2 summarises the results reported in trials of SGLT inhibition in T1DM.

Although studies have shown improvements in glycaemic control without weight gain there was also an associated significant increased risk of DKA, which is likely to be even greater in real world clinical practice. Therefore, despite the benefits observed we should proceed with extreme caution.

GLP 1 receptor agonists

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted by intestinal mucosal cells following meal ingestion. Evidence in T2DM has shown that GLP-1 receptor agonists (GLP-1 RA) stimulate insulin secretion, suppress glucagon secretion, and delay gastric

emptying in a glucose-dependant manner. 35 GLP-1 RA are an attractive treatment for T2DM as they lower HbA1c and weight without increased hypoglycaemia. 36 Many GLP-1 RA have also proven cardiovascular benefits in the treatment of T2DM, with reduction in major adverse cardiovascular events, 37 and are recommended second-line in the treatment of T2DM where atherosclerotic CVD predominates. GLP-1 RA, at higher doses than used to treat T2DM, are also used in the pharmacological treatment of obesity without diabetes. 38

Liraglutide has been shown to reduce weight and TDD in T1DM, however, results have varied with reduction in HbA1c. 39-41 A trial with liraglutide 1.2mg over a 12-week duration found weight reduction and decreased TDD, but no difference in HbA1c compared to placebo. 39 Similar results were noted in patients with obesity and T1DM; in this study neither GAD nor C-peptide status affected the response to treatment. 40 However, in the ADJUNCT ONE trial, with a trial duration of 52 weeks, the benefits observed included a modest, dose-dependent reduction in HbA1c (-0.54-to-0.43 per cent), reduced TDD insulin (-5-2 per cent) for the two higher doses of liraglutide (1.8mg and 1.2mg), and weight loss up to 4kg. 41 A greater proportion of those receiving the two higher doses of liraglutide also achieved a HbA1c of less than 7.0 per cent. Interestingly, those with a detectable C-peptide had a greater reduction in HbA1c than those that were C-peptide negative. The main reported adverse effects were increased symptomatic hypoglycaemia and hyperglycaemia with ketosis and GI disturbance, with up to 14 per cent of participants receiving 1.8mg liraglutide prematurely discontinuing the drug due to GI disturbance. These adverse effects may limit their use in those with T1DM. More recently, liraglutide in addition to standard insulin therapy in individuals with newly-diagnosed T1DM showed

similar results to previous studies with reduced TDD, but also improved β cell function, as evidenced by increased secreted C-peptide in the liraglutide group versus placebo, with the effects disappearing six weeks after the final dose of liraglutide. 43 It is possible that the patients with T1DM who would benefit most from these drugs are those that are overweight with concurrent insulin resistance or have some residual insulin or C-peptide secretion.

Semaglutide, a newer agent approved for the treatment of T2DM, has yet to be thoroughly evaluated in T1DM. In small studies, weight loss, reduced HbA1c, and total daily insulin were

noted in many, but not all, patients.16 Concerns regarding semaglutide use in T1DM include gastrointestinal side-effects, but also a worsening of retinopathy. A recent meta-analysis in patients with T2DM found that semaglutide “was not associated

with an increased risk of diabetic retinopathy; however, caution regarding diabetic retinopathy risk is needed for older patients or those with long diabetes duration”.17 This is of particular concern as patients with T1DM often have many years of diabetes before retinopathy appears. The results of a dedicated five-year follow-on study of retinopathy (the FOCUS trial) will provide a more detailed analysis of eye disease.18 Until then, it seems advisable to only initiate semaglutide in those with no diabetic retinopathy or in patients who can be closely monitored with ophthalmology and who are fully informed of the potential risks.

TABLE

* = Insulin doses must be reduced when starting this therapy to avoid severe hypoglycaemia

** = No increase in CVD in patients with T2DM, not studied in T1DM27

***= Decreased in patients with T2DM, not studied in T1DM25-28,37

Semaglutide, a newer agent approved for the treatment of T2DM, has yet to be thoroughly evaluated in T1DM

DPP4 inhibitors

Dipeptidyl peptidase-4 (DPP4) inhibitors are third-line agents used in the treatment of T2DM, though they are often employed earlier in those with renal impairment as they can be safely used. The use of DPP4 inhibitors in T1DM can result in a reduction in insulin doses of up to 2.4 units per day, a non-significant reduction in HbA1c, and few if any harmful effects including hypoglycaemia.19,20 Other areas of interest include the use of DPP4 inhibitors to diminish auto-immune pancreatic beta cell destruction, however, this is still in its infancy and not yet ready for clinical application. 21

Though initially promising, the use of DPP4 inhibitors in T1DM has largely been surpassed by SGLT2 inhibitors and GLP-1 analogues, which have cardiovascular and reno-protective benefits.

Amylin analogues

In functioning pancreatic beta cells, amylin is co-secreted with insulin in response to rising glucose levels.

In adults with T1DM, amylin levels are low/undetectable. Amylin acts to reduce the rate of gastric emptying and reduces post-prandial glucagon release. 22 Pramlintide is commercially available as a pre-meal subcutaneous injection and demonstrated a 0.67 per cent reduction in HbA1c levels over 52 weeks in adults with T1DM. 23 Rates of hypoglycaemia are unchanged in patients receiving this therapy (provided insulin doses were reduced) and weight did not increase and decreased in some studies. 24 Disadvantages of this therapy include nausea and the need to inject pramlintide pre-meal at a separate site to insulin, thus increasing injection burden.

The use of amylin analogues may be of future interest in combination with insulin in closed loop dual-hormone delivery systems. 25

Glucagon

Glucagon is secreted by functioning pancreatic alpha cells in response to hypoglycaemia, fasting, and exercise. In

T1DM, the release of glucagon is impaired, and recurrent episodes of hypoglycaemia attenuates glucagon release. Dual insulin-glucagon pumps have been evaluated and are of particular interest to groups studying exercise-induced hypoglycaemia. 26 This therapy is currently only available as part of randomised controlled trials and is associated with multiple complications including the instability of glucagon preparations, the lack of dual reservoir pumps, and interactions between insulin and frequent glucagon administration. Despite this, the reduction in rates of hypoglycaemia to <1 per cent per day in some studies is undoubtedly impressive and is an active area of ongoing research.

There is some evidence to suggest that SGLT2, SGLT1/2 inhibitors and GLP-1 RA may hold some promise as adjuvant therapies in the treatment of T1DM. However, the key to their use in T1DM lies in identification of which patients will benefit the most with the least risk.

References

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2. Beck RW, Riddlesworth T, Ruedy K, Ahmann A, Bergenstal R, Haller S, et al. Effect of continuous glucose monitoring on glycemic control in adults with type 1 diabetes using insulin injections: The DIAMOND randomised clinical trial. JAMA 2017;317(4):371-8

3. Lind M, Polonsky W, Hirsch IB, Heise T, Bolinder J, Dahlqvist S, et al. Continuous glucose monitoring vs conventional therapy for glycemic control in adults with type 1 diabetes treated with multiple daily insulin injections: The GOLD randomised clinical trial. JAMA . 2017;317(4):379-87

4. Lind M, Ólafsdóttir AF, Hirsch IB, Bolinder J, Dahlqvist S, Pivodic A, et al. Sustained intensive treatment and longterm effects on HbA1c reduction (SILVER Study) by CGM in people with type 1 diabetes treated with MDI. Diabetes Care 2020;44(1):141-9

5. Karter AJ, Parker MM, Moffet HH, Gilliam LK, Dlott R. Association of realtime continuous glucose monitoring with glycemic control and acute metabolic events among patients with insulin-treated diabetes. JAMA 2021;325(22):2273-84

6. Comparative effectiveness and safety of methods of insulin delivery and glucose monitoring for diabetes mellitus. Annals of Internal Medicine. 2012;157(5):336-47

7. Rytter K, Madsen KP, Andersen HU, Cleal B, Hommel E, Nexø MA, et al. Insulin pump treatment in adults with type 1 diabetes in the Capital Region of Denmark: Design and cohort characteristics of the steno tech survey. Diabetes Ther. 2022;13(1):113-

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9. Foster NC, Beck RW, Miller KM, Clements MA, Rickels MR, DiMeglio LA, et al. State of type 1 diabetes management and outcomes from the T1D exchange in 2016-2018. Diabetes Technol Ther 2019;21(2):66-72

10. Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-85

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12. Vella S, Buetow L, Royle P, Livingstone S, Colhoun HM, Petrie JR. The use of metformin in type 1 diabetes: A systematic review of efficacy. Diabetologia. 2010;53(5):809-20

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14. Liu Y, Chen H, Li H, Li L, Wu J, Li H. Effect and safety of adding metformin to insulin therapy in treating adolescents with type 1 diabetes mellitus: An updated meta-analysis of 10 randomised controlled trials. Frontiers in Endocrinology. 2022;13

15. Bjornstad P, Schäfer M, Truong U, Cree-Green M, Pyle L, Baumgartner A, et al. Metformin improves insulin sensitivity and vascular health in youth with type 1 diabetes mellitus. Circulation 2018;138(25):2895-907

16. Mertens J, De winter HT, Mazlom H, Peiffer FW, Dirinck EL, Bochanen N, et al. 751-P: Effect of once-weekly semaglutide on weight change and metabolic control in people with type 1 diabetes – sixmonths results from the Real-World STEMT trial. Diabetes. 2022;71(Supplement_1)

17. Wang F, Mao Y, Wang H, Liu Y, Huang P. Semaglutide and diabetic retinopathy risk in patients with type 2 diabetes mellitus: A meta-analysis of randomised controlled trials. Clin Drug Investig. 2022;42(1):17-28

18. Sharma A, Parachuri N, Kumar N, Saboo B, Tripathi HN, Kuppermann BD, et al. Semaglutide and the risk of diabetic retinopathy – current perspective. Eye 2022;36(1):10-1

19. Wang Q, Long M, Qu H, Shen R, Zhang R, Xu J, et al. DPP-4 inhibitors as treatments for type 1 diabetes mellitus: A systematic review and meta-analysis. J Diabetes Res. 2018;2018:5308582

20. Guo H, Fang C, Huang Y, Pei Y, Chen L, Hu J. The efficacy and safety of DPP4 inhibitors in patients with type 1 diabetes: A systematic review and meta-analysis. Diabetes Research and Clinical Practice 2016;121:184-91

21. Gurgel Penaforte-Saboia J, Couri CEB, Vasconcelos Albuquerque N, Lauanna Lima Silva V, Bitar da Cunha Olegario N, Oliveira Fernandes V, et al. Emerging roles of dipeptidyl peptidase-4 inhibitors in delaying the progression of type 1 diabetes mellitus. Diabetes Metab Syndr Obes. 2021;14:565-73

22. Davis C. Amylin. In: Enna SJ, Bylund DB, editors. xPharm: The Comprehensive Pharmacology Reference. New York: Elsevier; 2007. p1-2

23. Whitehouse F, Kruger DF, Fineman M, Shen L, Ruggles JA, Maggs DG, et al. A randomised study and open-label extension evaluating the long-term efficacy of pramlintide as an adjunct

to insulin therapy in type 1 diabetes. Diabetes Care. 2002;25(4):724-30

24. Ratner RE, Dickey R, Fineman M, Maggs DG, Shen L, Strobel SA, et al. Amylin replacement with pramlintide as an adjunct to insulin therapy improves long-term glycaemic and weight control in Type 1 diabetes mellitus: A one-year, randomised controlled trial. Diabet Med 2004;21(11):1204-12

25. Haidar A, Tsoukas MA, BernierTwardy S, Yale J-F, Rutkowski J, Bossy A, et al. A novel dual-hormone insulinand-pramlintide artificial pancreas for type 1 diabetes: A randomised controlled crossover trial. Diabetes Care 2020;43(3):597-606

26. Wilson LM JP, Castel JR. Role of glucagon in automated insulin delivery. Endocrinol Metab Clin North Am 2020;49:179-202

27. Herrmann K, Zhou M, Wang A, de Bruin TWA. Cardiovascular safety assessment of pramlintide in type 2 diabetes: Results from a pooled analysis of five clinical trials. Clin Diabetes Endocrinol. 2016;2(1):12

28. Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: The ADJUNCT ONE treat-totarget randomised trial. Diabetes Care . 2016;39(10):1702-10

29. Davies MJ, D’Alessio DA, Fradkin J, Kernan WN, Mathieu C, Mingrone G, et al. Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2018;61:2461–98

30. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. New Engl J Med. 2015;373:2117–28

31. Neal B, Perkovic V, Mahaffey KW, De Zeeuw D, Fulcher G, Erondu N, et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. New Engl J Med 2017;377:644–57

32. Mcmurray JJV, Solomon SD, Inzucchi SE, Køber L, Kosiborod MN, Martinez FA, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. New Engl J Med. 2019;381:1995–2008

33. Rosenstock J, Marquard J, Laffel LM, Neubacher D, Kaspers S, Cherney DZ, et al. Empagliflozin as adjunctive to insulin therapy in type 1 diabetes: The EASE trials. Diabetes Care. 2018;41:2560–9

34. Dandona P, Mathieu C, Phillip M, Hansen L, Griffen SC, Tschöpe D, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes (DEPICT-1): 24 week results from a multicentre, double-blind, phase 3, randomised controlled trial. Lancet Diabetes Endocrinol. 2017;5(11):864-76

35. Dandona P, Mathieu C, Phillip M, Hansen L, Tschope D, Thoren F, et al. Efficacy and safety of dapagliflozin in patients with inadequately controlled type 1 diabetes: The DEPICT-1 52-Week Study. Diabetes Care. 2018;41(12):2552-9

36. Garg SK, Henry RR, Banks P, Buse JB, Davies MJ, Fulcher GR, et al. Effects of sotagliflozin added to insulin in patients with type 1 diabetes. New Engl J Med. 2017;377(24):2337-48

37. Buse JB, Garg SK, Rosenstock J, Bailey TS, Banks P, Bode BW, et al. Sotagliflozin in combination with optimised insulin therapy in adults with type 1 diabetes: The North American in Tandem 1 Study. Diabetes Care. 2018;41(9):1970-80

38. Henry RR, Thakkar P, Tong C, Polidori D, Alba M. Efficacy and safety of canagliflozin, a sodium-glucose cotransporter 2 inhibitor, as add-on to insulin in patients with type 1 diabetes. Diabetes Care. 2015;38(12):2258-65

39. Warshauer JT, Bluestone JA, Anderson MS. New frontiers in the treatment of type 1 diabetes. Cell Metabolism. 2020;31:46–61

40. Trujillo JM, Nuffer W, Smith BA. GLP-1 receptor agonists: An updated review of head-to-head clinical studies. Ther Adv Endocrinol and Meta 2021;12:204201882199732

41. Giugliano D, Scappaticcio L, Longo M, Caruso P, Maiorino MI, (28)Bellastella G, et al. GLP-1 receptor agonists and cardiorenal outcomes in type 2 diabetes: An updated meta-analysis of eight CVOTs. Cardiovascular Diabetology. 2021;20

42. Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, et al. Once-weekly semaglutide in adults with overweight or obesity. New Engl J Med 2021;384:989–1002

43. Frandsen CS, Dejgaard TF, Holst JJ, Andersen HU, Thorsteinsson B, Madsbad S. Twelve-week treatment with liraglutide as add-on to insulin in normal-weight patients with poorly controlled type 1 diabetes: A randomised, placebocontrolled, double-blind parallel study. Diabetes Care. 2015;38(12):2250-2257

44. Dejgaard T, Frandsen C, Hansen T, et al. Efficacy and safety of liraglutide for overweight adult patients with type 1 diabetes and insufficient glycaemic control (Lira-1): A randomised, doubleblind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2016;4:221-232

45. Mathieu C, Zinman B, Hemmingsson JU, Woo V, Colman P, Christiansen E, et al. Efficacy and safety of liraglutide added to insulin treatment in type 1 diabetes: The ADJUNCT ONE treat-to-target randomised trial. Diabetes Care. 2016;39(10):1702-10

46. Dejgaard, TF, Frandsen, C, Kielgast, U, et al. Liraglutide preserved insulin secretion in adults with newly diagnosed type 1 diabetes: The NewLira Trial. Diabetes . 2019. doi: 10.2337/ db19-59-OR

ECE 2022 round-up

Priscilla Lynch presents a round-up of research presented at this year’s European Congress of Endocrinology

Effects of Covid-19 infection on the thyroid gland are long-lasting

Severe Covid-19 disease affects thyroid function through a variety of mechanisms and can have a long lasting impact, according to a new study from Dr Ilaria Muller and colleagues from the University of Milan, Italy.

The study followed patients with thyroid dysfunction correlated to Covid-19 disease for one year, to better characterise such thyroid involvement and to follow its evolution over time. The hormone imbalance is usually mild but increases in severe cases of Covid-19. During moderateto-severe Covid-19 disease the occurrence of thyroiditis (inflammation of the thyroid gland) plays an important role in thyroid dysfunction, in addition to other well-known mechanisms mainly acting on the hypothalamus-pituitary-thyroid axis.

Correct thyroid function is crucial to the human body’s metabolism, growth, and

development. The thyroid gland generates extra hormones when the body needs more energy in particular situations, such as when it is growing, cold, or pregnant.

The study looked at more than 100 patients admitted to hospital with severe Covid-19, analysing their thyroid stimulating hormone (TSH) and other indicators. Thyroiditis occurred frequently in the Covid-19 patient population and the thyroid function, as well as inflammatory indicators, returned to normal in nearly all instances shortly after the end of their Covid-19 illness. However, after 12 months thyroiditis regions remained visible at thyroid ultrasound in half of the individuals, even if reduced in size. The thyroid uptake of technetium or iodine, an indicator of thyroid function, was still reduced in four-out-of-six individuals at nine months, although it had mostly recovered after 12 months. The long-term

Body weight influences the chance of developing PCOS

A new study has confirmed a clear relationship between obesity and the chance of developing polycystic ovary syndrome (PCO), with obesity during

childhood and teenage years particularly vital to the disease’s development. This ground-breaking public health research was presented during the 24th European

clinical consequences, if any, are unknown.

“There is a clear link between thyroid dysfunction and Covid-19 disease,” said Dr Muller. “Knowing that thyroid hormones correlate with the disease severity is important, and the fact that the thyroid gland seems directly involved in SARSCoV-2 (Covid-19) viral infection needs to be taken into account.”

The study was presented during the 24th European Congress of Endocrinology, which was held on 21-24 May in Milan, Italy. The Congress brought over 4000 endocrinologists from more than 100 countries together. The Congress also marked the first European Hormone Day and the launch of the Milano Declaration, which aims to encourage national and European decision makers to better integrate endocrinology in European and national health policies.

Congress of Endocrinology.

PCOS is a common condition. Many cases go undiagnosed, but according to

a 2016 study this condition affects up to 10 per cent of women. PCOS can lead to diabetes, infertility, poorer quality-oflife, and pregnancy complications.

The goal of the study was to see if obesity had an impact on the development of PCOS. Dr Laurence Dobbie, Royal Liverpool University Hospital in the UK, and Prof Daniel Cuthbertson, Professor of Medicine at the Royal Liverpool University Hospital, investigated whether obesity and diabetes markers contribute to PCOS development with colleagues from the University of Liverpool.

The study included a genetic analysis, termed mendelian randomisation, of over 110,000 people. The team also

pooled data from 63 other studies, via meta-analysis, to assess how overweight and obesity affect the chance of developing PCOS.

They also showed that girls who are overweight and go on to have a normal adult body weight are still more likely to develop PCOS. The team also reported that obesity and overweight during adolescence are particularly important in the development of the condition.

The study highlighted that BMI, body fat levels and markers indicative of diabetes are vital in PCOS development.

“This study shows that obesity during childhood and teenage years are key factors in the development of PCOS. This opens a way to support women’s health by investing in nutritional and weight management programmes for younger people. This also has the potential to prevent the condition’s consequences, which include poorer quality-of-life, infertility, diabetes, and pregnancy complications,” said Dr Dobbie.

Ramadan fasting can create medical problems for endocrine patients

Ramadan fasting can create complications for patients with endocrine diseases, according to three new studies presented at the 24th European Congress of Endocrinology.

The studies looked into the impact on patients with diabetes and hypothyroidism, and provided a general overview of the frequency of emergency endocrine issues during the month of Ramadan.

High-risk of emergency hospital admission in fasting patients with diabetes

During the holy month of Ramadan in 2021 (April 13 to May 12), Dr Lionel Simeu and his team from Morocco’s IBN Rochd University Teaching Hospital, observed that 150 diabetic patients were rushed to their emergency room with a serious metabolic issue. Diabetic ketosis was the primary reason for admission (57 per cent), while the frequency of hypoglycaemia remained low (2 per cent).

“If fasting during Ramadan is allowed in healthy patients, it must be stopped if a patient’s diabetes is uncontrolled,” said Dr Simeu.

“Therapeutic education and sufficient medical care are essential to avert acute issues.”

Pre-fasting consultation is crucial to manage endocrine conditions

Two studies from UHC IBN Rochd in Casablanca, Morocco, looked at endocrine emergencies during Ramadan in general and in thyroid patients specifically.

Dr Amine Gueddari and his team examined 62 patients who were followed in consultation for hypothyroidism. The researchers wanted to see how fasting throughout Ramadan altered hormone balance and compared the use of L-thyroxine, used to treat an underactive thyroid, 30 minutes before the meal to break the fast at sunset

(iftar) and at the pre-sunrise meal (suhoor).

“Fasting during Ramadan may induce hormonal imbalance in patients with hypothyroidism,” said Dr Gueddari. “It is therefore critical to teach patients how to take their medicine and to follow-up with them after the month of fasting.”

Dr Yousra Settai and her colleagues conducted a prospective study to determine the frequency of endocrine emergencies during Ramadan, and the risk of endocrine decompensation as a result of fasting. The study comprised 47 people who sought medical help for endocrine emergencies during Ramadan 2021.

“Fasting during Ramadan is a spiritual rite for Muslims, but it comes with concerns since it can cause hormonal imbalances,” said Dr Settai.

“We recommend a pre-Ramadan consultation in endocrine patients to adjust the treatment and discuss options.”

The study highlighted that BMI, body fat levels and markers indicative of diabetes are vital in PCOS development

Cushing’s syndrome: A review

Cushing’s syndrome is a rare endocrine disorder and is the state of hypercortisolism resulting from endogenous or exogenous glucocorticoid excess. In Cushing’s syndrome, excess cortisol can arise from outside or inside the body, for example, from using corticosteroid medications, or from a pituitary or adrenal tumour causing the body to make too much cortisol. Exogenous hypercortisolism is the most common cause of Cushing’s syndrome, is mainly iatrogenic, and results from the prolonged use of glucocorticoids.1,4

The true incidence and prevalence of Cushing’s syndrome are not known, but it is estimated to be 40 per million population. It can occur in children, but is typically found in people aged 20-to-50 years, and affects approximately three times as many women as men. 6

Cushing’s syndrome/disease is associated with an increased risk of cardiovascular and metabolic manifestations, as well as respiratory disorders, psychiatric complications, osteoporosis, and infections leading to high rates of morbidity and mortality. Prompt clinical suspicion and early diagnostic work-up and management are necessary to avoid potential adverse outcomes. 2,3

Cushing’s disease is the most common form of endogenous Cushing’s syndrome, accounting for approximately 80 per cent of Cushing’s syndrome cases. 6 Cushing’s disease is characterised by the excessive production of adrenocorticotropic hormone (ACTH) by the anterior pituitary, leading to the release of excess cortisol from the adrenal glands. This is often caused by a pituitary micro adenoma or the result of excess production of corticotrophin-releasing

hormone (CRH) from the hypothalamus. Alternatively, there could be a small growth (ectopic ACTH) in another part of the body, causing the same effect.1,2,4

Pathophysiology

Cortisol, a steroid hormone produced by the adrenal cortex, has several functions in the body, including regulating blood pressure and the immune system, balancing the effect of insulin to keep blood sugar normal, and helping the body to respond to stress. Cortisol is carried to different parts of the body by cortisol binding protein. Almost 90 per cent of cortisol binds to CBG protein

poor wound healing. All these processes involve collagen. High cortisol levels also cause immune disruptions, leads to a decrease in lymphocyte levels, and increases the neutrophils. It causes detachment of the marginating pool of neutrophils in the bloodstream and increases the circulating neutrophil levels. Corticosteroids mediate the downregulation of NF-kappaB, regulation of AMP kinase, glycogen phosphorylase, superoxide dismutase, and many other enzymes. Cortisol inhibits the production of IL-2, TNF alpha, IFN alpha, and gamma. Decreased IL-2 levels prevent the proliferation of T-lymphocytes. 4,5

Causes

The most common cause of Cushing’s syndrome is the use of exogenous glucocorticoids. Endogenous Cushing’s syndrome is divided into corticotropindependent and corticotropinindependent causes.

and has a bioavailability of 60 per cent to 100 per cent. Synthetic corticosteroids have varying bioavailability and potency, but all affect similar pathways. Excess cortisol results in an increased rate of gluconeogenesis, glycogenolysis, and increases insulin resistance. Cortisol directly affects the transcription and translation of enzyme proteins involved in the metabolism of fats, glycogen, proteins synthesis, and the Krebs cycle. It promotes the production of free glucose in the body, elevating glucose levels, and simultaneously increasing insulin resistance. The destruction of protein yields amino acids, which are used in gluconeogenesis. Prolonged catabolism of proteins causes purplish striae of the torso, osteoporosis, and

Corticotropin-dependent causes account for about 80-to-85 per cent of cases; 80 per cent are due to pituitary adenomas (Cushing’s disease), while the remaining 20 per cent are due to ectopic corticotropin syndrome, which is usually due to small-cell carcinoma of the lungs and bronchial carcinoid tumours, but may occur with almost any endocrine tumour.6

Corticotropin-independent Cushing’s syndrome is most often due to a unilateral tumour; adrenal adenoma in 60 per cent and adrenal carcinoma in 40 per cent of cases. Very rare adrenal causes of Cushing’s syndrome are corticotropin-dependent macronodular adrenal hyperplasia, primary pigmented nodular adrenal disease, and McCuneAlbright syndrome. 6

The most common cause of Cushing’s syndrome is the use of exogenous glucocorticoids

Presentation and diagnosis

Patients with hypercortisolism can present with weight gain, hypertension, easy bruising, striae, acne, flushing, poor wound healing, lower limb oedema, fatigue, impaired glucose tolerance, osteoporosis, hyperpigmentation of the skin, mood, and memory changes, amenorrhea, hirsutism, decreased libido, and frequent infections (See Figure 1).

Common physical manifestations of excess cortisol levels include a moon shaped face, a build-up of fat on the back of the neck and shoulders known as ‘buffalo hump’, thinning of the skin, weight gain around the trunk, and thin limbs. Patients with an ACTH-producing pituitary tumour

may develop headaches, visual problems and galactorrhoea. Some patients may develop severe osteopaenia and bone fractures.1 Psychological problems such as cognitive dysfunction and depression are not uncommon. Patients may also have a history of hypertension, peptic ulcer disease, and diabetes.4

Cushing’s syndrome/disease can be challenging to diagnose because there is no single test that accurately diagnoses the condition, and a stepwise approach is required with combinations of appropriate biological and imaging examinations.11

Differentiation of Cushing’s disease from other underlying causes can be difficult

in some cases even with an organised, stepwise diagnostic approach.

Biochemical diagnostic tests to confirm hypercortisolism include salivary and blood serum cortisol testing, 24-hour urinary-free cortisol testing, and low-dose overnight dexamethasone suppression testing. Investigations should be performed when there is no acute concurrent illness, as these can cause false positive results.

The subsequent step after biochemical confirmation is to identify the underlying cause of the excess cortisol production. Investigations to identify the cause of Cushing’s syndrome include plasma ACTH. An elevated ACTH level is consistent with ACTH-dependent Cushing’s syndrome. Inferior petrosal sinus sampling may be performed to aid in determining the source of excess ACTH, and is the most accurate test used to differentiate a pituitary adenoma from ectopic or adrenal Cushing’s syndrome.

The CRH test is used for direct assessment of the pituitary ACTH reserve. Most patients with Cushing’s disease are responsive to this test, whereas patients with the ectopic ACTH syndrome are typically unresponsive. However, patients with a large tumour and an extremely high cortisol level may lack a response in the CRH test. Imaging tests can include MRI and abdominal CT Scan.1,6,11

Treatment

Treatment will depend on the cause. The treatment for iatrogenic Cushing’s syndrome is to taper exogenous steroids. Chronic exposure to steroids can suppress adrenal function and it can take several months for normal adrenal functioning to recover. Therefore, steroids should be slowly tapered allowing adrenal functioning to recover.4

Cushing’s syndrome caused by a pituitary or other tumour that releases ACTH means the tumour be surgically removed, where possible. In some cases, radiation

therapy may be necessary. Following surgery, long-term cortisol replacement therapy may be required. Cushing’s syndrome due to an adrenal or other tumour will also be removed by surgery. If the tumour cannot be removed, medications to help block the release of cortisol are prescribed.7

If a primary ACTH-secreting tumour is found, first-line treatment is surgical resection of the adenoma via transsphenoidal surgery (TSS). Surgical resection can be conducted via an endonasal or sub-labial approach. Overall, remission rates after TSS are in the range of 65-to-90 per cent for microadenomas and less than 65 per cent for macroadenomas. Patients with persistent disease after initial surgery may undergo repeat pituitary surgery despite a lower success rate and increased risk for pituitary insufficiency. The most common complications of this procedure include diabetes insipidus, fluid and electrolyte abnormalities, and neurological deficits. Patients over the age of 64 years have a higher incidence of adverse outcomes. 8

Pituitary radiation therapy can alternatively be used after an unsuccessful TSS. External-beam pituitary radiotherapy is most effective in paediatric patients. The most common complication from this treatment is hypopituitarism, causing growth hormone deficiency. 8

The first choice of treatment for ectopic ACTH-producing tumours is surgical removal. If the tumour is cancerous and has spread, chemotherapy, radiation therapy, or other cancer treatments may be required. Medicines to reduce cortisol levels may also be part of the treatment. If other treatments fail, the adrenal glands may be removed to control Cushing’s syndrome.9

Bilateral adrenalectomy can be used to provide an immediate reduction of cortisol levels in patients with Cushing’s disease. However, these patients will

require lifelong administration of glucocorticoid and mineralocorticoid replacement therapy. A major complication of this treatment is Nelson syndrome, which is the development of ACTH-secreting macroadenomas postbilateral adrenalectomy. 8

Post-treatment testing with 24-hour urine and blood samples are used to detect the level of cortisol. The disappearance of the response to the desmopressin test after surgery may suggest complete removal of the tumour and, therefore, a lower possibility of recurrence. Recurrence of hypercortisolaemia occurs in about a third of patients after initial treatment of Cushing’s disease, therefore, lifelong monitoring is required. 8

can be used to lower cortisol by directly inhibiting synthesis and secretion in the adrenal gland. Metyrapone and ketoconazole are enzyme inhibitors and have rapid onset of action, however, control of hypercortisolism is often lost with corticotropin over secretion in Cushing’s disease. These drugs are not usually effective as long-term treatment and are used mainly for preparation for surgery or as adjunctive treatment after surgery or pituitary radiotherapy.6

Mitotane acts as an adrenolytic drug with delayed onset, but long-lasting action, so control of corticotropin over secretion in Cushing’s disease is maintained.

Medical treatment can also be used in patients who are unwilling or unfit for surgery. Treatment can be used long-term for patients with ectopic corticotropin secretion, however, adrenalectomy may be preferred. Multiple agents are more effective than monotherapy. Etomidate can be used for acute control of severe hypercortisolaemia. 6

Indications for medical therapy include acutely ill patients in preparation for surgery, patients with unknown tumour location or unresectable lesions, patients unfit for surgery, and patients with persistent raised glucocorticoid levels postoperatively. The treatment of choice in most patients is surgical, but the metabolic consequences, including increased tissue fragility, poor wound healing, hypertension, and diabetes mellitus increase the risks of surgery. Drug therapy remains very important for normalising cortisol levels, while awaiting the impact of more definitive treatment. Cortisol hypersecretion must be controlled prior to surgery or radiotherapy if possible.6

Metyrapone, ketoconazole, and mitotane

Medical therapy has also been gaining popularity in the treatment of pituitary tumours. Although surgery is still considered the first-line treatment, pharmacological therapy can control the associated hormonal imbalances. These medical therapies either target the central inhibition of ACTH secretion, adrenal inhibition of steroidogenesis, or glucocorticoid-receptor blockade. Several novel steroidogenesis inhibitors are currently in development and are undergoing clinical trial and some emerging medical therapies are currently under evaluation. Future possible agents that are not yet in clinical trials include heat shock protein 90 inhibitors, testicular orphan receptor 4 inhibitors, histone deacetylase inhibitors, and monoclonal ACTH antibodies.11

Quality-of-life

Comorbidities caused by Cushing’s syndrome/disease can be a significant burden and have a negative effect on

Comorbidities caused by Cushing’s syndrome/disease can be a significant burden and have a negative effect on patients’ quality-of-life

patients’ quality-of-life. Some of the symptoms cause physical changes that can easily be perceived by others and may affect patients’ social interactions. These include facial plethora, weight gain, central obesity, supraclavicular fat accumulation, hirsutism, acne, purple stria, easy bruising, poor wound healing and ulceration, and growth restriction in children. The condition can also involve morbidities that may not easily be perceived externally, but which greatly affect the patient’s life. These include sleep disturbance, fatigue, myopathy, hypertension, alterations of glucose homeostasis, dyslipidaemia, vascular disease, atherosclerosis, menstrual and libido disturbances, hypogonadism, and body composition alterations. Psychological disturbances may also be present, including depression, anxiety, irritability, apathy, and cognitive decline. Healthcare providers can use different strategies to improve patient’s well-being. Screening and management of persistent comorbidities, including psychological aspects, is essential. Treating all comorbidities, patient education, and an understanding and empathic attitude is

important to help improve the patient’s quality-of-life. A multidisciplinary team with collaborating experts is required for the management of this complex condition and a personalised, individualbased approach is necessary to achieve the best outcomes while minimising side-effects and improving the patient’s quality-of-life.10

Prognosis

The prognosis for people with Cushing’s syndrome varies depending on the cause of the disease. Most cases of Cushing’s syndrome can be cured, however, without treatment it can be fatal. The mortality is due to the excess production of glucocorticoids, which can lead to many medical problems. Complications of untreated Cushing’s syndrome/ disease include osteoporosis, which can lead to pathological fractures, often appearing in the foot bones and ribs; hypertension; type 2 diabetes mellitus; infections resulting from an impaired immune response; and reduced muscle mass. For patients who undergo surgery, lifelong treatment with glucocorticoids is necessary. Many individuals with

Cushing’s syndrome show significant improvement with treatment, although some may find recovery complicated by various aspects of the causative illness. Patients need lifelong follow-up with regular monitoring of cortisol levels. Recurrence of disease is not uncommon, and too much or too little cortisol can be life-threatening. The patient must be educated about their condition and the importance of medication and treatment compliance. Patients need to understand that Cushing’s disease is often secondary to another pathophysiology and that they must comply with the treatment regimen for both conditions to help alleviate their disease. They should also be advised to wear or carry a medical alert to inform others about their health status. Close observation and follow-up is important to prevent complications and improve outcomes.

It is anticipated that recent new insights into the pathophysiology of Cushing’s syndrome/disease at the molecular level will eventually lead to more accurate diagnostic tests and more efficacious therapies. n

References

1. Kairys N, Schwell A. (2022). Cushing Disease. StatPearls Publishing. Available at: www.ncbi.nlm.nih.gov/books/NBK448184/

2. Pappachan JM, Hariman C, Edavalath M, Waldron J, Hanna FW. Cushing’s syndrome: A practical approach to diagnosis and differential diagnoses. J Clin Pathol. 2017 Apr;70(4):350-359. doi: 10.1136/jclinpath-2016-203933

3. Buliman A, Tataranu L, Paun D, Mirica A, Dumitrache C. (2016). Cushing’s disease: A multidisciplinary overview of the clinical features, diagnosis, and treatment. J Med Life. 2016 Jan-Mar;9(1):12-18

4. Chaudhry H, Singh G. (2022). Cushing syndrome. StatPearls Publishing.

Available at: www.ncbi.nlm.nih.gov/books/ NBK470218/

5. Pituitary Foundation (2022). Cushing’s disease. Pituitary Foundation UK. Available at: www.pituitary.org.uk/information/ pituitary-conditions/cushings-disease/

6. Willacy H. (2020). Cushing’s syndrome. Patient: Professional articles. Available at: https://rb.gy/og8fk2

7. NHS (2021). Cushing’s syndrome. National Health Service, UK. Available at: www.nhs.uk/conditions/cushingssyndrome/

8. Kairys N, Schwell A, Haddad L. (2022). Cushing disease (Nursing). Available at: www.ncbi.nlm.nih.gov/books/NBK568708/

9. NIH (2022). Cushing’s syndrome. National Institute of Diabetes and Digestive and Kidney Disease. Available at: www.niddk.nih.gov/health-information/ endocrine-diseases/cushings-syndrome

10. Santos A, Resmini E, Martínez Momblán MA, Valassi E, Martel L, Webb SM. Quality-of-life in patients with Cushing’s disease. Front Endocrinol (Lausanne). 2019 Dec 11;10:862. doi: 10.3389/fendo.2019.00862

11. Nishioka H, Yamada S. Cushing’s disease. J Clin Med . 2019 Nov 12;8(11):1951. doi: 10.3390/jcm8111951

12. Figure 1: www.ohsu.edu/braininstitute/cushing-disease-cushing-syndrome

NOVO NORDISK ANNOUNCE THE LAUNCH OF NOVOPEN 6 AND NOVOPEN ECHO PLUS IN IRELAND – SMART INSULIN PENS THAT OFFER DIGITAL CONNECTIVITY FOR PEOPLE WITH DIABETES

Many people with diabetes are still required to manually record their insulin doses, while often only achieving normal blood glucose control for just about half of the day.

A Swedish study conducted by Novo Nordisk from 2017-2018 showed that, in a real-world setting, using the NovoPen 6 smart insulin pen to administer insulin can give people with type 1 diabetes up to two extra hours of glycaemic control per day.

The new NovoPen 6 and NovoPen Echo Plus, which offer digital connectivity to help improve the lives of people living with diabetes, are now available in Ireland. The smart insulin pens automatically record accurate insulin dosing data, such as the date and time of doses, alongside blood glucose monitoring.

Data from NovoPen 6 and NovoPen Echo Plus smart insulin pens can be wirelessly transferred via NFC technology and are compatible with various diabetes management apps and existing in-clinic solutions, where injection

history can be viewed side-by-side with glucose information.

People with diabetes can access their own data and share it simply with their diabetes care team, allowing for more productive and informative conversations.

The pens are compatible with all Novo Nordisk insulins available in Ireland in a 3mL Penfill cartridge.

“Technology is rapidly changing the way we manage and live with diabetes, mainly type 1 diabetes, and is enabling us to manage our condition better and achieve better long-term outcomes. The availability of new technologies, such as smart insulin pens, further enables us to achieve better clinical and quality-of-life outcomes each day and is a welcome diabetes tool in Ireland,” said Dr Kate Gajewska, Clinical Manager for Advocacy and Research, Diabetes Ireland.

“Digital health tools, such as the smart insulin pen, will improve diabetes management by empowering patients with data,” said Prof Derek O’Keeffe, Consultant

Endocrinologist at University Hospital Galway (UHG) and Professor of Medical Device Technology at the University of Galway.

NovoPen 6/NovoPen Echo Plus are now available to purchase in pharmacies in Ireland.

Each NovoPen 6 and NovoPen Echo Plus is expected to last fourto-five years. NovoPen 6/NovoPen Echo Plus comes with a three-year full guarantee and Novo Nordisk will replace any pens that are faulty within that period.

In 2021 Novo Nordisk submitted an application to the HSE for reimbursement of the NovoPen 6 and NovoPen Echo Plus and it is still awaiting an outcome from that process. In the meantime, it believes it is important to make NovoPen 6 and NovoPen Echo Plus available now to those people who wish to use this technology to help manage their diabetes.

Visit www.diabeteswhatsnext.ie for more information on living with diabetes and NovoPen 6 and NovoPen Echo Plus smart insulin pens.

LATEST SOFTWARE UPDATE TO BRING NEW FEATURES TO THE T:SLIM X2 INSULIN PUMP

A new software update is becoming available for the Tandem Diabetes Care t:slim X2™ insulin pump. This latest update makes available new features for pumps currently using Basal-IQ and Control-IQ technology. The new features included in this latest software update will allow:

 Bolus icons to be displayed on the CGM graph

After a bolus has been delivered, users will see a blue square icon on the bottom of the pump’s CGM graph. This feature includes three types of icons that

users might see, depending on the type of bolus delivered.

 Provide a custom alarm to resume insulin

Users will have the ability to set up an alarm after they stop insulin manually to help them to remember to resume insulin delivery.

 Updates to fill cannula selectable options

The preset fill cannula options will be 0.3 units, 0.5 units, and 0.7 units. The default setting is 0.3 units. Custom

amounts can still be inputted. There will also be additional updates for Control-IQ technology users only, which will include adjustments to the frequency of the current high alert, the option to switch between activities, and an additional bolus reminder.

The latest software update will be accessible via the Tandem Device Updater (TDU) system. For more information on accessing the software update, current users should contact the Air Liquide Healthcare customer service team on 1800 12 4912.

THE BRAND NEW MEDICAL INDEPENDENT APP IS COMING SOON!

Toujeo ® DoubleStar™ holds more units per pen than any other basal insulin pen on the market1-4

Shared features with Toujeo ® SoloStar

• Pen size

• 5-second hold time5,6

• 42-day shelf life after first use1

• Same technical platform

*Toujeo ® DoubleStar™ is recommended for patients requiring at least 20 units of basal insulin per day1 References:

Prescribing Information:

Toujeo (insulin glargine 300 units/ml)

Please refer to Summary of Product Characteristics (SmPC) before prescribing.

Presentation: Toujeo SoloStar and DoubleStar pre-filled pens. Each ml contains 300 units of insulin glargine. SoloStar pen contains 1.5ml (450 units) of solution for injection. DoubleStar pen contains 3ml (900 units) of solution for injection.

Indication: Treatment of diabetes mellitus in adults, adolescents and children from the age of 6 years. Dosage and Administration: Toujeo is administered subcutaneously, by injection into the abdominal wall, the deltoid or the thigh, once daily, at any time of the day, preferably at the same time every day. Injection sites must be rotated within a given injection area from one injection to the next in order to reduce the risk of lipodystrophy and cutaneous amyloidosis. The dose regimen (dose and timing) should be adjusted according to individual response. Do not administer intravenously. In type 1 diabetes mellitus, Toujeo must be combined with short-/rapid-acting insulin to cover mealtime insulin requirements. In patients with type 2 diabetes mellitus, recommended daily starting dose is 0.2 units/kg followed by individual dose adjustments. Toujeo can also be given together with other anti-hyperglycaemic medicinal products. Switch between insulin glargine 100 units/ml and Toujeo: Insulin glargine 100 units/ml and Toujeo are not bioequivalent and are not directly interchangeable. When switching from insulin glargine 100 units/ml to Toujeo, this can be done on a unit to unit basis, but a higher Toujeo dose (approximately 10-18%) may be needed to achieve target ranges for plasma glucose levels. When switching from Toujeo to insulin glargine 100 units/ml, the dose should be reduced (approximately by 20%). Switching from other basal insulins to Toujeo: A change of dose and/or timing of the basal insulin and concomitant anti hyperglycaemic treatment may be required. Dose adjustments may also be required if the patient’s weight or lifestyle changes, the timing of insulin dose is changed or other circumstances arise that increase susceptibility to hypo- or hyperglycaemia. Toujeo must not be mixed or diluted with any other insulin or other medicinal products. Close metabolic monitoring is recommended during a switch and in the initial weeks thereafter. SoloStar 1-80 units per single injection in steps of 1 unit and DoubleStar 2-160 units in steps of 2 units. When changing from Toujeo SoloStar to Toujeo DoubleStar, if the patient’s previous dose was an odd number then the dose must be increased or decreased by 1 unit. Toujeo DoubleStar prefilled pen is recommended for patients requiring at least 20 units per day. Special Populations: Insulin requirements may be diminished in the elderly or patients with renal or hepatic impairment. Paediatric: When switching basal insulin to Toujeo, dose reduction of basal and bolus insulin needs to be considered on an individual basis, in order to minimise the risk of hypoglycaemia. The safety and efficacy of Toujeo in children and adolescents below 6 years of age have not been established. Contraindications: Hypersensitivity to insulin glargine or any excipients. Precautions and Warnings: Traceability: In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded. Toujeo is not the insulin of choice for treatment of diabetic ketoacidosis. Patients must be instructed to perform continuous rotation of the injection site to reduce the risk of developing lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin absorption and worsened glycaemic control following insulin injections at sites with these reactions. A sudden change in the injection

References: 1. Toujeo® Summary of Product Characteristics.

Date of preparation: November 2021 | MAT-IE-2101574 (v1.0)

site to an unaffected area has been reported to result in hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, and dose adjustment of antidiabetic medications may be considered. Hypoglycaemia: In case of insufficient glucose control or a tendency to hyper/hypoglycaemic episodes, the patient’s adherence to the prescribed treatment regimen, injection sites and proper injection technique and all other relevant factors must be reviewed before dose adjustment is considered. Particular caution should be exercised, and intensified blood glucose monitoring is advisable for patients in whom hypoglycaemic episodes might be of clinical relevance and in those where dose adjustments may be required. Warning signs of hypoglycaemia may be changed, less pronounced or absent in certain risk groups, potentially resulting in severe hypoglycaemia and loss of consciousness. Risk groups include patients in whom glycaemic control is markedly improved, hypoglycaemia develops gradually, an autonomic neuropathy is present, or who are elderly. The prolonged effect of subcutaneous insulin glargine may delay recovery from hypoglycaemia. Intercurrent illness: Requires intensified metabolic monitoring and often it is necessary to adjust the insulin dose. Insulin antibodies: administration may cause insulin antibodies to form. Use with pioglitazone: Cases of cardiac failure have been reported when pioglitazone was used in combination with insulin, especially in patients with risk factors for development of cardiac heart failure. If the combination is used, patients should be observed for signs and symptoms of heart failure, weight gain and oedema. Pioglitazone should be discontinued if any deterioration in cardiac symptoms occurs. Medication errors: Insulin labels must always be checked before each injection to avoid errors between Toujeo and other insulins. Patients must be instructed to never use a syringe to remove Toujeo from the SoloStar or DoubleStar pre-filled pen, A new sterile needle must be attached before each injection. Needles must not be re-used. Pregnancy and lactation: There is no data from exposed pregnancies in controlled clinical trials. However, there is a large amount of data on use of insulin glargine 100 units/ml in pregnant women indicating no specific adverse effects on pregnancy and no specific malformative nor feto/neonatal toxicity. The use of Toujeo may be considered during pregnancy, if clinically needed. Careful monitoring of glucose control is essential. It is unknown if insulin glargine is excreted in breast milk. Interactions: Substances that affect glucose metabolism may require adjustment of insulin glargine. Adverse Reactions: Very common: Hypoglycaemia. Prolonged or severe hypoglycaemia may be life-threatening. Common: Lipohypertrophy, injection site reactions, including redness, pain, itching, hives, swelling, or inflammation. Legal Category: POM. Marketing Authorisation Number: SoloStar 3 Pen pack: EU/1/00/133/034, DoubleStar EU/1/00/133/038. Marketing Authorisation Holder: Sanofi Aventis Deutschland GmbH, D-65926 Frankfurt am Main, Germany. Further information is available from: Medical Information, Sanofi 18 Riverwalk, Citywest Business Campus, Dublin 24 or contact IEmedinfo@sanofi.com. Date of preparation: July 2020.

Adverse events should be reported. Reporting forms and information can be found at www.hpra.ie; email: medsafety@hpra.ie Adverse events should also be reported to Sanofi Ireland Ltd. Tel: 01 403 5600. Alternatively, send via email to IEPharmacovigilance@sanofi.com

Toujeo ® is available in two pre-filled insulin devices allowing you to choose the most suitable device for your patients