Lee Webber – EASD e-Learning

Posted on 28th November 2023 | by Lee Webber

With its comprehensively revised, reorganised and updated course on SGLT-2 inhibitors, launched today, EASD e-Learning signals a new phase in the learning platform’s development.

Recent years have witnessed the ascent of newer treatments for diabetes, in particular of SGLT-2 inhibitors and GLP-1 receptor agonists, combined with a growing appreciation of their potential to help manage not just hyperglycaemia but other comorbidities too. In the case of SGLT-2 inhibitors, this widening understanding has depended upon (and in turn has prompted) a steady stream of new trials investigating the cardiorenal benefits of this drug class.

EASD e-Learning has been tracking these developments ever since the platform launched five years ago. Modules on SGLT-2 inhibitors were among its first launches in 2018, and as new trials have reported, additional modules have been added to keep learners abreast of developments – resulting in the course expanding to a total of nine modules.

As Dr Eleanor D Kennedy, EASD e-Learning’s Programme Director, explains: “The last five years have been an exciting period of innovation in diabetes research and care, presenting the EASD’s fledgling e-Learning platform with wonderful opportunities to help diabetes professionals keep abreast of the latest developments. The platform is now moving beyond its initial growth phase and able to focus on consolidating and rationalising content to improve the learner experience. We are thrilled to relaunch our SGLT-2 inhibitors course with new content that is fully up to date and consolidated into fewer, more comprehensive modules. This should reduce the amount of time learners require to complete the course, and make it easier for them to access the information they want on specific aspects of the drug class.”

The new SGLT-inhibitor course has been condensed down to four modules. The first (written and presented by Professor David Matthews) is not much changed from the original module 1 of this course, providing an introductory history of the drug class and explanation of their mode of action. The second (also from Professor Matthews), like its predecessor focuses on the gliflozins’ efficacy and safety but has been radically revised to reflect the latest trial results and real-world evidence, providing an overview of all aspects of the SGLT-2 inhibitors’ performance, including glycaemia, renal glucose excretion, blood pressure and weight change.

Modules 3 (from Professor John Wilding) and 4 (from Professor Miles Fisher) delve deeper into the drugs’ cardiorenal benefits – Professor Wilding examining the role of SGLT-2 inhibitors in renal protection for people with diabetes; Professor Fisher looking at their role in cardiovascular disease, heart failure in particular.

All four modules include extensive animations to illustrate the drug class’s mechanism of action as well as the results of key Phase 3 trials. As with all the EASD e-Learning courses, each module includes two or more case studies enabling users to apply their learning to practical clinical scenarios. The comprehensive end-of-module assessment, which learners can take in order to obtain their certificate of completion, is also heavily tilted towards clinical practice.

The new course entirely replaces the original nine-module course, so learners who have completed modules on the EASD e-Learning platform’s SGLT-2 inhibitors course are invited to renew their knowledge by undertaking these new modules. The older modules have now been retired from the site and are no longer available. However, anyone who has already completed one of the older modules and passed the end-of-module assessment is still able to obtain a certificate of completion from their ‘My account’ page.

To enrol on the new course, go to SGLT-2 inhibitors.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 23rd November 2023 | by Lee Webber

A new study reported in Diabetologia looks at the risk factors for developing diabetes among a cohort of pregnant women after giving birth. The research shows that decline in beta cell function is ranked as more important than excess adiposity or insulin resistance in progressing from normal glucose tolerance to prediabetes and diabetes in this population. Dr Susan Aldridge reports.

Excessive weight gain, insulin resistance and beta cell dysfunction are all associated with the development of type 2 diabetes, but we don’t know which of the three is most important, particularly in the early stages when normal glucose tolerance (NGT) progresses to dysglycaemia. Identifying this key risk factor could help focus prevention efforts.

A practical limitation in addressing this question is how best to find a normoglycaemic population to study that is likely to show sufficient rates of progression to prediabetes or diabetes within the time window of a research study. Pregnant women comprise a population that fits the bill because any degree of dysglycaemia in pregnancy increases the risk of future type 2 diabetes, particularly among those who develop gestational diabetes mellitus (GDM). So women with recent gestational diabetes that then reverts to NGT could provide a good model for studying early events in progression to prediabetes and diabetes.

Ravi Retnakaran at Mount Sinai Hospital in Toronto and colleagues elsewhere have used this approach to rank the contributions made by adiposity, insulin resistance and beta cell dysfunction to the development of prediabetes and diabetes. They carried out metabolic measurements over a period of five years in a cohort of women who reflected the full spectrum of gestational glucose tolerance, from NGT through mild dysglycaemia to GDM. All had reverted to NGT at three months postpartum.

Metabolic measurements

This study was carried out at Mount Sinai Hospital as part of a prospective observational cohort programme that is looking at the relationship between maternal glucose tolerance in pregnancy and metabolic function in the years after giving birth. All pregnant women are screened for GDM at 24 to 28 weeks with a 50 g glucose challenge test (GCT) followed by an oral glucose tolerance test (OGTT) if the GCT result is abnormal. Women were recruited into this new study before or after the GCT, including those with an abnormal GCT to enrich the cohort with those with varying degrees of dysglycaemia. Therefore, the cohort reflected a broad range of future risk of prediabetes and diabetes.

Participants had serial metabolic measurements at three months, one year, three years and five years postpartum. They had an OGTT during which blood samples were taken for measurement of glucose and insulin at fasting and at 30, 60 and 120 minutes post-challenge. These measurements allowed assessment of glucose tolerance status, insulin sensitivity/resistance and beta cell function.

Progressors and non-progressors

There were 302 women in the study of whom 213 maintained NGT over the next five years (non-progressors), while 89 developed either prediabetes or diabetes (progressors), which affected 76 and 12 women respectively. There were no significant differences between the two groups at baseline with respect to age, ethnicity, family history of diabetes or duration of breastfeeding. However, progressors had a higher prevalence of GDM in the recent pregnancy, higher BMI and higher fasting glucose and 2 h glucose, although all the glucose measurements were still in the normal range. They also had greater insulin resistance and poorer beta cell function. And, as the five-year study trajectory progressed, these differences persisted. Insulin sensitivity/resistance actually worsened in both groups, but more so in the progressors.

What was more striking was a deterioration in beta cell function in progressors over this time, while it remained relatively stable among non-progressors. Further analysis, using various statistical models, was able to identify and rank predictors of progression at baseline. These were, in rank order, 2 h glucose on OGTT, recent GDM, BMI and age. A separate analysis also confirmed that beta cell function at baseline is the predominant pathophysiological determinant of future dysglycaemia. And the measure of beta cell function over the time of the study also emerged as being inversely associated with prediabetes/diabetes. In contrast, time-varying adiposity was not associated with progression and results for insulin resistance gave conflicting findings.

Focus on beta cell dysfunction

Previous studies have consistently identified excess adiposity, insulin resistance and beta cell dysfunction as pathophysiological factors for type 2 diabetes. However, since all three frequently co-exist, dissecting their relative contributions to the condition has been challenging, leading to conflicting findings. The design of this new study, with a population of postpartum women, some of whom are at risk of developing prediabetes or diabetes within a five-year period, may have the capacity to disentangle the relative contributions of these three risk factors.

Although the generalisability of this study cannot be assumed given that it was focused on pregnant women, the authors say that there are three reasons why it does have clinical relevance. First, the International Diabetes Federation has reported that maternal hyperglycaemia now affects one in six pregnancies around the world. Second, those who do have hyperglycaemia in pregnancy have an increased risk of type 2 diabetes in the future. Finally, women of childbearing age are the group that has experienced the greatest rise in the prevalence of diabetes in Canada (where the study took place) in recent years. Therefore, a better understanding of the pathophysiology of progression from postpartum NGT to prediabetes and diabetes is important in addressing the growing burden of diabetes among women.

The authors also point out that although adiposity, insulin sensitivity and beta cell function all differed between progressors and non-progressors, only beta cell function showed a differential decline over time in the former group. This is consistent with other research showing a decline in beta cell function prior to a diagnosis of diabetes. This new study adds to these findings by also identifying beta cell dysfunction both at baseline and across the follow-up period as being the main determinant of progression from NGT to prediabetes and diabetes.

The analysis done in the study also quantifies the magnitude by which beta cell dysfunction exceeds excess adiposity and insulin resistance in this regard. Taken together, these findings support a pathophysiological model where the impact of weight gain and insulin resistance on diabetes risk may ultimately be mediated by how they affect the secretory function of the beta cells.

This study’s findings have implications for both clinical practice and research. It is usually recommended that women with GDM undergo postpartum assessment of glucose tolerance by OGTT rather than by fasting glucose alone. This is supported by the finding in the baseline analysis mentioned above that, even when normoglycaemic, the 2 h fasting glucose value clearly surpasses the fasting glucose as a predictor of progression to prediabetes/diabetes in the first five years postpartum. It is also notable that the 2 h glucose measurement at three months postpartum also ranked higher than traditional risk factors such as BMI, age and ethnicity. This perhaps supports its use in future surveillance of women with GDM.

The study also highlights declining beta cell function as the central factor that should be targeted when designing interventions aimed at preventing diabetes in women who have had glucose intolerance in pregnancy. To this end, the authors are conducting a randomised placebo-controlled trial of the SGLT-2 inhibitor empagliflozin for the preservation of beta cell function among women with recent GDM.

To read this paper, go to: Retnakaran R, Ye C, Kramer CK, Hanley AJ, Connelly PW, Sermer M, Zinman B. Deteriorating beta cell function is the dominant determinant of progression from normal glucose tolerance to prediabetes/diabetes in young women following pregnancy. Diabetologia 24 August 2023. https://doi.org/10.1007/s00125-023-05994-5

To learn more, enrol on the EASD e-learning course ‘Gestational diabetes mellitus (GDM)’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 22nd November 2023 | by Lee Webber

Recent research suggests that there is much more to obesity than elevated body mass index. The latest findings on the role of liver fat and metabolically healthy obesity were under discussion at the 59th Annual Meeting of the EASD. Dr Susan Aldridge reports.

The findings of the DiRECT trial of a low-calorie diet for type 2 diabetes remission are well known and are being applied to further our understanding of the pathophysiology of obesity. At one year, 46% of participants were in remission and at two years, 36% were still in remission. “This is way above what we thought would be a clinically useful outcome,” said Professor Roy Taylor of Newcastle University, who led the study with Professor Mike Lean of Glasgow University. “Our findings surpassed expectations and, in fact, this has tended to distract from the pathophysiological studies that led up to it.”

These started with the ‘twin cycle’ hypothesis that excess food over a period of time leads to excess liver fat, which is exported to the pancreas where beta cells are exposed to it, leading to beta cell dysfunction and type 2 diabetes. Professor Taylor and his team investigated this hypothesis in the Counterpoint study, in which rapid weight loss through a low-calorie diet led to a decrease in liver and pancreatic fat (confirmed by MRI), normalisation of liver insulin sensitivity and a decrease in plasma triglycerides. There was then a gradual increase in beta cell function and insulin sensitivity, confirming the twin cycle hypothesis. There were similar findings in the DiRECT study in a range of body mass index (BMI) from 27 to 45.

“The earliest sign of type 2 diabetes is muscle insulin resistance, which causes de novo lipogenesis after meals that then shifts fat to the liver,” explained Professor Taylor. “There is then insulin resistance in the liver, which is tightly coupled to liver fat accumulation. Plasma glucose goes up and insulin tries to compensate, which stimulates lipogenesis and the whole lipogenesis circuit reverberates.”

But, as the American physician Roger Unger pointed out in animal experiments, it was only in susceptible mice that overfeeding caused diabetes. The fat would just ‘bounce off’ the islets of rats who were not susceptible. Corresponding to that monogenic effect in rats, there must be a polygenic effect in humans. “We must bear in mind that the vast majority of people who are very large do not have type 2 diabetes,” said Professor Taylor. “Does the twin cycle hypothesis alone really explain type 2 diabetes? What about normal weight people? We know from the UK Prospective Diabetes Study – the very study that has taught us all we know about type 2 diabetes – that 35% of participants had a BMI of less than 25.”

Professor Taylor and his team published their work on the personal fat threshold in 2015. This explains that individuals have differing susceptibility to fat excess, due to a differing capacity of subcutaneous tissue to hold it. They tested this hypothesis in the recently published ReTUNE study, which involved people with type 2 diabetes and BMI 21 to 27. The study was designed for stepwise weight loss in 5% steps and this only went to 15% for those not in remission.

Studies were done at each point and, at 52 weeks, there was no average weight gain. Body fat was 32% at baseline and 28% at one year, while the thickness of visceral fat also decreased, though it was still more than in the controls.

Liver fat, which was three times greater than in the controls, and very-low-density lipoprotein (VLDL) triglycerides also fell to normal with weight loss. And 70% of these ‘slim’ people achieved remission. Put simply, data from DiRECT and ReTUNE suggest that liver fat is increased in type 2 diabetes over a range of BMI. There is more information in Professor Taylor’s book ‘Life without Diabetes’ (all profits to Diabetes UK) and at go.ncl.ac.uk/reverse-diabetes.

“So type 2 diabetes is a state of excess fat inside the liver and pancreas, irrespective of BMI,” concluded Professor Taylor. “The person with type 2 diabetes has become too heavy for their own body and the condition is caused by having more fat in the liver and pancreas than can be tolerated by the individual. The aetiology of type 2 diabetes does not, therefore, relate to the conventional definition of obesity based on BMI.”

The puzzle of metabolically healthy obesity

As Professor Taylor observed, most people with obesity do not have type 2 diabetes and obesity does not necessarily go hand-in-hand with other comorbidities. So is it possible to be healthy and have obesity?

“Obesity receives a lot of attention nowadays as the driver for the pathophysiology of type 2 diabetes,” said Dr Matthias Blüher at the Helmholz Diabetes Center, Germany. “If you speak to people in the outpatient clinic, they tell you the main goal for the next year is to lose weight. It’s very hard to find people who are happy with their body weight.”

Obesity can kill because there are so many obesity-related conditions and comorbidities, most of which are improved by weight loss. There is some indirect evidence from the Swedish Obese Subjects trial that significant weight loss through surgery – say 20 to 30% – is associated with increased survival. Until recently, though, there was no evidence that weight loss reduces cardiovascular endpoints. Now we have top-line results from the SELECT trial of weekly semaglutide, which shows a 20% reduction in major adverse cardiovascular events (MACE) with 16% weight loss. “That suggests you need double-digit weight loss to get to these hard endpoints like cardiovascular events and mortality,” said Dr Blüher.

“However, we are all aware that there are people – 15 to 20% in some cohorts – who are obese but protected from cardiovascular and metabolic diseases,” he continued. This metabolically healthy obesity (MHO) is defined by having blood pressure < 130/85 mmHg; HDL-C > 1.03 mmol/l (men); HDL-C > 1.3 mmol/l (women); triglycerides < 1.7 mmol/l; HbA1c < 6% and fasting glucose < 6.1 mmol/l.

The prevalence of MHO is 2-19% for men and 7-28% for women, depending on how strict a definition is used. Data from the UK shows that those with MHO still have a higher risk of cardiovascular disease. Looking at underweight, normal weight, overweight and obese individuals with respect to the number of metabolic syndrome components (0-3) they had, researchers found a higher risk of heart failure, stroke and myocardial infarction by both BMI and number of components they had. So an underweight person with more abnormalities had a higher risk within a weight category and people with, say, one abnormality had a higher risk the greater their BMI. “This shows that obesity and overweight in themselves increase the risk of cardiovascular disease, even in the absence of metabolic abnormalities,” said Dr Blüher.

To discover whether MHO Is it a distinct phenotype, Dr Blüher and his team carried out RNA sequencing of the adipose tissue of 1479 people and used artificial intelligence to identify six clusters, four of which have been characterised as being metabolically healthy, metabolically unhealthy, having high basal cortisol or hyperinsulinaemia.

They then carried out clamp experiments that showed how insulin sensitivity varied with BMI. With some, as expected, insulin sensitivity increased with lower BMI and vice-versa. However, for a given BMI, there were some outliers who were very insulin resistant with a raised HbA1c to match. “One explanation might lie in the adipose tissue, for those with low insulin sensitivity have immune cells in adipose tissue and more hypertrophy,” said Dr Blühers.

He went on to describe MHO in terms of size, sites and cytes. Size refers to adipocyte size – the larger they are, the more metabolically unhealthy. If you compare people of the same BMI and age, some have bigger adipocytes than others. Is there, then, a threshold in adipocyte size where the risk of type 2 diabetes increases? One of his studies has shown a steep rise in adipocyte size and diabetes risk in both French and German cohorts.

Site refers to accumulation of liver and pancreatic fat, independent of BMI, as discussed by Professor Taylor. Those with high insulin sensitivity have low visceral fat. Finally, cyte refers to inflammation of adipose tissue. Large adipocytes are more likely to go into apoptosis and attract macrophages to get rid of the remnants.

From these data, Dr Blüher and his team have developed a model which aligns with Professor Taylor’s work. “There are safe depots for fat and weight gain like subcutaneous adipose tissue, but these may expand by increase in adipocyte size and number,” he said. Hypertrophy of adipocytes leads to abnormal adipose tissue function via autophagy, inflammation, hypoxia and apoptosis.

“From genome-wide association studies, we know that there are genes that decide whether adipocytes expand and if you are more likely to develop stress in adipose tissue. So there may be genetic factors involved and this is, of course, under investigation,” he said. “There may also be environmental factors, which are poorly understood, such as persistent organic pollutants, plasticisers and pesticides that may contribute to the pathophysiology of adipose tissue function.” He and his team are investigating these. The adipose tissue is a ‘safe’ place to store these compounds, which may be good for the body as a whole, but maybe not for adipose tissue.

Defining obesity

“BMI is not a good indicator of obesity-related outcomes,” said Dr Blüher. He prefers the Edmonton Obesity Staging System, with stages 0-4 in terms of medical, mental or functional problems. Here MHO falls into stage 0 and stage 4 is end-stage obesity. This system is independent of BMI and there are other staging systems that say it’s more important to take account of the comorbidities and risk factors than BMI, waist circumference or body fat mass. For instance, when it comes to the effect of obesity on mortality, research shows that the Edmonton system does predict mortality, while BMI does not.

“My therapeutic goal for someone in stage 0 obesity would be to make sure they don’t gain more weight,” he said. “In stages 1 and 2, I think we can achieve remission, like remission of type 2 diabetes, and remove the risk of obesity-related disease, where with weight loss of 10 to 15% we can bring people back to a lower stage of obesity. But weight loss would be less useful in stage 3 or 4 when someone might already have had a myocardial infarction or be on dialysis.”

Similarly, weight loss can be used to convert metabolically unhealthy obesity (MUO) with risk factors as explained above. “We have used bariatric surgery to do this and hope in future to use pharmacotherapy, so MUO is a reversible phenotype,” said Dr Blüher. With this approach, the person might still be obese in terms of BMI. “A useful target for weight loss need not be leanness or a BMI of less than 25,” he continued. “The achievable goal is to have a person with obesity, but without the cardiometabolic challenges.”

They also found significant changes in cell type in visceral and subcutaneous fat on weight loss, with visceral fat rebuilding adipose tissue and fewer immune cells in subcutaneous fat, as if they were trying to go back to their original composition.

To learn more, enrol on the EASD e-Learning course ‘Obesity and diabetes’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 16th November 2023 | by Lee Webber

Factors other than hyperglycaemia influence complications for both mother and baby in a pregnancy affected by type 1 diabetes. New metabolomic findings from the CONCEPTT trial, reported in Diabetologia, shed light on the details of complex metabolic changes that occur during these pregnancies, highlighting the importance of maternal nutrition and early pregnancy. Dr Susan Aldridge reports.

Pregnancy outcomes in type 1 diabetes remain suboptimal despite improvements in glycaemic control in recent years. For instance, the Continuous Glucose Monitoring in Women with Type 1 Diabetes in Pregnancy Trial (CONCEPTT) found that 60% of infants were still large for gestational age (LGA). This suggests that processes other than glucose metabolism may be involved in this complication because these women had improved antenatal glucose control. It is likely that LGA also involves altered carbohydrate, protein and fat metabolism, and it is influenced by factors including maternal obesity, gestational weight gain, dietary quality and maternal lipids, as well as glycaemia.

Neonatal hypoglycaemia affects 25% of offspring from type 1 pregnancies and is associated with foetal hyperinsulinism. It has been attributed to suboptimal maternal glycaemia during late pregnancy and birth, although this may also occur earlier in pregnancy. Meanwhile, pregnant women with type 1 diabetes have a five times higher risk of pre-eclampsia than healthy women and this can be predicted with first trimester biomarkers, including leptin and glucose, and protein-related biomarkers at 28 weeks. However, the relative contributions of carbohydrate, lipid and protein metabolism to the development of pre-eclampsia in type 1 pregnancies are unclear.

Claire Meek, Zoe Stewart and other members of the CONCEPTT team have used samples from the trial to examine the pathophysiology associated with these complications in more detail. They looked at metabolomic and lipidomic changes associated with modifiable risk factors for suboptimal pregnancy outcomes. These risk factors were hyperglycaemia, maternal BMI, gestational weight gain and habitual diet, while the adverse pregnancy outcomes were LGA, offspring adiposity, neonatal hypoglycaemia, offspring hyperinsulinism and pre-eclampsia.

CONCEPTT involved 225 women with type 1 diabetes recruited in early pregnancy or when planning a pregnancy, 174 of whom gave additional serum samples at 12, 24 and 36 weeks to create the biorepository on which this study is based.

Metabolomic and lipidomic changes

Maternal hyperglycaemia

Maternal time above range was associated with increased lipids in maternal blood suggestive of de novo lipogenesis rather than other sources of fatty acids. Given that de novo lipogenesis is a physiological pathway associated with using up excess glucose, it is highly likely to be active in diabetes in pregnancy.

Cord blood was enriched in carnitines, which are cofactors in β- oxidation of fatty acids – a process of generating ATP in conditions of low glucose availability. The authors consider this a surprising finding worthy of further investigation because β- oxidation generally occurs after, not before, birth. However, they note that few studies have looked at foetal fuel utilisation in pregnancies affected by diabetes.

The findings also demonstrate a link between maternal hyperglycaemia and adiposity in the offspring, associated with the presence of carnitines, which may indicate the foetus dissipating excess fuel received from the maternal circulation.

Offspring size and adiposity

During the first trimester, there were no metabolomic changes in maternal blood associated with LGA, but by 24 weeks, a pattern emerged that features multiple metabolites likely to promote or sustain excessive foetal growth. There was evidence of increased steroid hormone production and increased activity of the tricarboxylic acid cycle and β- oxidation pathway, all of which suggests abundant energy production. But neonatal adiposity showed dramatically different metabolic profiles from LGA, suggesting that increased size overall (LGA) and adiposity are not the same thing in the context of type 1 diabetes pregnancy. Further exploration of the underlying mechanisms is warranted.

Neonatal hypoglycaemia and hyperinsulinism at birth

Both neonatal hypoglycaemia and hyperinsulinism at birth – marked by the presence of cord C-peptide – were associated with metabolite changes during the period of foetal pancreatic development. Early pregnancy maternal triacyl glycerol abundance was linked with neonatal hypoglycaemia, while both lipids and phenols are linked to cord C-peptide.

Previous research has suggested that lipid storage is likely to be prioritised over lipid mobilisation in early pregnancy. The authors believe that the increased abundance of lipids in early pregnancy could be the result of insufficient dietary intake (hyperemesis gravidarum), insufficient insulin dosing or in response to certain dietary patterns, such as a low-carbohydrate diet, which would promote lipogenesis, or the direct impact of a high-fat diet. Meanwhile, saccharin and structurally related phenols were consistently related to cord C-peptide. These findings suggest that maternal diet in early pregnancy is a key determinant of offspring metabolic health at birth. They also raise the possibility that offspring beta cell function – amount of C-peptide – could be modulated by maternal diet in pregnancy.

Pre-eclampsia

Pre-eclampsia was associated with increased abundance of phosphatidylethanolamines (PEs), which are likely to have come from vascular cell membranes during the first two trimesters. This suggests that the endothelial damage that leads to pre-eclampsia may occur from early in pregnancy.

Meanwhile, the pattern of multiple metabolic changes in pre-eclampsia suggests high energy requirements throughout pregnancy, with utilisation of lipid energy sources during the first trimester and protein during the second and third trimesters. Catabolism of protein provides branched-chain amino acids and aromatic amino acids, which can act as substrates for gluconeogenesis. The involvement of branched-chain fatty acids is particularly marked in this metabolomic analysis, although it is not clear why they would be involved in gluconeogenesis. Their presence has been associated with insulin resistance in other studies. It is possible that placental insufficiency induces insulin resistance to improve the glucose supply to the foetus.

There were relatively few women with pre-eclampsia in this study, but previous work with women without diabetes has shown some similarities in metabolic changes. However, phosphatidylserines were most predictive of pre-eclampsia in women without diabetes, while PEs were more prominent in this study.

Clinical implications

Type 1 diabetes pregnancy is associated with altered carbohydrate, lipid and protein metabolism from the first trimester and this strongly predicts perinatal complications. Inadequate insulin, as a master regulator of carbohydrate, protein and lipid metabolism, is a likely unifying cause, according to the authors.

This study demonstrates, for the first time, a possible metabolic link between maternal hyperglycaemia and offspring adiposity mediated partially though altered maternal and offspring lipid metabolism. Increases in the abundance of many classes of lipids were common in all analyses. These were likely to be caused by insufficient insulin, which is the key pathophysiological feature of type 1 diabetes.

These findings suggest that, despite improved access to continuous glucose monitoring and insulin pumps, current efforts to address hyperglycaemia are not fully correcting the underlying abnormalities leading to complications.

We know that maternal diet influences insulin dose requirements, but the study also found an association between cord C-peptide and various metabolic changes in the first trimester that may be linked with maternal dietary intake of sugar substitutes, high-glycaemic-index carbohydrates and phenol compounds. This suggests that maternal diet might be a key modifiable determinant of offspring health, independent of maternal glycaemia. Future research on optimising insulin dosing from the first trimester, with better matching of insulin to dietary intake and insulin resistance, would improve maternal and neonatal health.

Traditionally, approaches to identifying and treating women at risk of LGA, neonatal hypoglycaemia and pre-eclampsia have focused on mid-to-late pregnancy. This new study suggests that early pregnancy is also important in determining outcomes. New strategies should therefore be developed to optimise access to care in the first trimester.

To read this paper, go to: Meek CL, Stewart ZA, Feig DS, Furst S, Neoh SL, Koulman A, Murphy HR on behalf of the CONCEPTT collaborative group. Diabetologia online 24 August 2023. https://doi.org/10.1007/s00125-023-05989-2

To learn more, enrol on the EASD e-Learning course ‘Pregestational diabetes in pregnancy’:

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 15th November 2023 | by Lee Webber

The benefits of SGLT-2 inhibitors for people with type 2 diabetes and chronic kidney disease (CKD) have been amply demonstrated in recent years. So is it time to prescribe them to all those who have both conditions or should certain groups be treated with caution? This key clinical question was under debate at the 59th EASD Annual Meeting. Dr Susan Aldridge reports.

The title of the debate was ‘All people with diabetes and CKD should be on SGLT-2 inhibitors by default’ and a vote taken at the start showed 66% of delegates in favour of the motion. Hoping to shore up his majority by the end of the session, Dr Andrew Frankel, Consultant Nephrologist at Imperial College Kidney & Transplant Institute, opened with: “We have a huge problem. For the last 15 to 20 years, the number of people requiring end-stage kidney treatment has increased year on year, but the message I want to give you is that we also have a huge issue ahead of us. If you travel outside Europe, if you go to the Middle East and the Far East, they are already facing a deluge of diabetic kidney disease (DKD).”

This is because the people with diabetes and CKD, including end-stage kidney disease, currently being cared for started their journey 15 years ago when the number of people with diabetes was significantly fewer than it is now. So the numbers are going up all the time. “The second factor – and this is a good thing – is that with modern diabetes and cardiovascular interventions, individuals with diabetes are living longer,” he continued. “But longer duration is associated with decreased estimated glomerular filtration rate (eGFR) and a greater likelihood of developing CKD and cardiorenal complications.”

Today, people with diabetes and CKD are more likely to die of cardiovascular disease, but in 10 years’ time that will no longer be true. “End-stage renal disease is growing by 50 to 300% and that will truly bankrupt the system,” said Dr Frankel. “The fantastic news for me as a kidney doctor interested in diabetic kidney disease is that we now have excellent treatment.”

As in with heart failure, there are now ‘pillars’ of treatment for DKD, with angiotensin receptor blockers (ARBs), ACE inhibitors, SGLT-2 inhibitors, finerenone and blood pressure medications, as well as glycaemic and lipid control and lifestyle management to reduce cardiovascular risk.

“SGLT-2 inhibitors have been a key treatment for CKD and we have had this data now for nine years,” he said. “But in the UK, the number of people who should be on them that actually are is exceedingly small. We must do better.”

There are the various cardiovascular trials, the heart failure trials and the three renal trials – CREDENCE, DAPA-CKD, EMPA-KIDNEY. These involved different populations, with and without diabetes, but have all shown the same results with respect to hospitalisation for heart failure and hard endpoints of CKD progression. SGLT-2 inhibitors also reduce the decline in eGFR, need for dialysis and renal death. “The earlier you intervene and lift up that progression pathway, the better the outcome for the individual in terms of the need for dialysis or transplant,” he said. In a post-hoc analysis of the CREDENCE trial, among people who start out with an eGFR in the 40s, canagliflozin delays the need for dialysis by 13 years, so there are real benefits to the individual, population health and the population health economy.

Dr Frankel went on to highlight some points about the EMPA-KIDNEY trial, which involved a broad range of participants, with and without diabetes, and had an endpoint of cardiovascular death or kidney disease progression. A significant number did not have albuminuria. The outcome was strongly positive, with a 30% reduction in kidney disease progression, irrespective of starting eGFR. “There is no loss of efficacy with declining kidney function, which is a really important point to remember because I want to convince you about the extremes in CKD – the well preserved and the poorer kidney function.”

In EMPA-KIDNEY, there was a predetermined analysis using the slope of eGFR decline, where a 0.5 to 1.0 reduction in decline per month is considered meaningful and an accepted surrogate outcome for disease progression. “If you focus on those with no albuminuria, empagliflozin is abrogating age-related decline in eGFR,” he said, “so it is effective both at the end of the spectrum where you’ve got advanced kidney disease and at the other end with no albuminuria.”

Also, a post-hoc analysis of DECLARE showed that dapagliflozin was able to reduce the appearance of microalbuminuria. “So maybe we should put all people with diabetes on SGLT-2 inhibitors because we know that ACE inhibitors and ARBs do not work for primary prevention, but SGLT-2 inhibitors may do,” said Dr Frankel.

Addressing concerns

Dr Frankel has talked to many diabetes specialist nurses and clinicians about their worries over SGLT-2 inhibitors to reassure them. “The Oxford Trials Unit has carried out a meta-analysis that looked at absolute risk and absolute benefit of SGLT-2 inhibitors and found the balance to be way, way in favour for the person taking them in terms of kidney disease progression, acute kidney injury, cardiovascular death or hospitalisation for heart failure,” he said. “We have to keep that in mind, but it doesn’t mean that we don’t do things safely – educating so that people with diabetes know how to use sick-day guidance, for instance.”

What about SGLT-2 inhibitors in type 1 diabetes where there have so far been no large trials. “I’m putting this as a challenge because I think you need to do this,” he said. “We know that the trials that have been undertaken did demonstrate reductions in albuminuria.” The UK Kidney Association does recommend considering SGLT-2 inhibitors for people with type 1 diabetes if their eGFR is 20 or more – that is, relatively preserved – and if they have a urinary albumin-to-creatinine ratio of 25 or more, despite maximum ARB/ACE inhibitor medication. “But you need to be sure to do ketone monitoring and be under the strict direction of the diabetes team, which is one reason I’m here to talk to you,” said Dr Frankel. “We’ve started doing this and many other units have for those who are at high risk of progression.”

Conclusion – in favour

We face a healthcare emergency in terms of cardiorenal complications of diabetes. “You might think you see a lot of DKD now, but you wait – you will see a tsunami of DKD in the next 10 years,” said Dr Frankel.

We now have therapeutic options that can demonstrably slow down progression of cardiorenal complications and improve cardiorenal outcomes and quality of life. SGLT-2 inhibitors are central to that strategy. “As a healthcare community, we need to manage this problem proactively and effectively,” said Dr Frankel. “Aside from their excellent glycaemic benefits, we know that providing people with diabetes with SGLT-2 inhibitors gives better long-term quality of life, reduces the risk of cardiovascular complications and slows down progression of kidney disease, such that more people will likely avoid the need for dialysis in their lifetime.

“In an era of increasing medical specialisation, we become very ‘siloed’ in the UK, which is why I’m so pleased to be here – I tell all my trainees ‘we are all diabetologists now’. Because if you walk around the general medical wards or renal units, it’s all diabetes. However, diabetologists are the system leaders and we are going to need your help to ensure that all who can benefit from SGLT-2 inhibitors receive them,” he concluded.

The case against universal SGLT-2 inhibitors

Professor Daniel van Raalte from Amsterdam University Medical Centers took to the stage to urge caution when prescribing SGLT-2 inhibitors to people with diabetes and CKD. But first he said: “I agree that CKD is a major health problem and it’s also very clear that the SGLT-2 inhibitors are the strongest kidney protective drugs out there. It’s also very worrying that there are a lot of people worldwide that should receive these drugs that don’t.”

He went on to say that the important words in the motion being debated were ‘all’ and‘default’. “We have to think about which groups are not suited to SGLT-2 inhibitors or where we lack evidence,” he said. “I think, from this point of view, my opponent has been skating on thin ice. For each group, we must have data on safety and efficacy to be sure we ‘first do no harm’.”

First, there are people with type 1 diabetes, although Professor van Raalte agreed that SGLT-2 inhibitors will work for some. “But there is an issue and it is a pretty big one – the occurrence of DKA, which has been a consistent finding in the trials,” he said. “The mortality of DKA requiring hospitalisation is 0.2 to 1.2%, which is low, but is true only in countries with good healthcare.”

There is also the danger of euglycaemic DKA – he cited a case of a young woman in the Amsterdam area who died because of this and, from the mechanism of the drug, it is difficult to prevent it. “Although there are guidelines on mitigating the risk of DKA, I think we have to be careful not to underestimate it,” he continued. “People in trials are motivated with frequent study visits where they learn about DKA mitigation. The risk in the real world is higher.”

The good news is that further trials of SGLT-2 inhibitors in type 1 diabetes are ongoing, including the recently announced Steno 1 study. There are also technical developments in continuous ketone measurement, which might help reduce DKA risk, while a new trial on finerenone may show it to be a better option without the DKA risk. “I hope I’ve convinced you that not all patients with type 1 diabetes should be on SGLT-2 inhibitors,” concluded Professor van Raalte.

Then there is the issue of the type of patient with respect to kidney function. There is no data on those with an eGFR below 20 or for those with kidney failure. “So we don’t know if the drug is safe and has efficacy in these cases,” he said. “And if you’re on dialysis, will the drug give cardiovascular protection? Note that statins do not prevent cardiovascular disease, despite lowering cholesterol, in people on dialysis or with a kidney transplant. So we have to be really careful not to blindly assume that these drugs are going to be efficacious in this group.”

Meanwhile, genital mycotic infection and urinary tract infections (UTIs) are known side-effects of SGLT-2 inhibitors. People with a transplanted kidney are at particularly high risk of these infections because they take immunosuppressants and have abnormal kidney anatomy. UTIs are associated with loss of kidney function and are the main reason why kidney transplant recipients are admitted to hospital with septic shock. “So we really have to be careful,” he warned.

He cited the ongoing RENAL LIFECYCLE trial of dapagliflozin, which includes kidney transplant recipients, those on dialysis and with stage 4 and 5 CKD, with and without type 2 diabetes, among its 1500 participants. “This will shed light on whether these drugs have efficacy and are safe in these populations,” he said. “Putting them on these drugs by default is jumping the gun.”

What about the frail elderly, who are not usually included in studies like EMPA-REG and already have a higher risk for UTIs? One study shows that 25% of elderly people stopped SGLT-2 inhibitors because of UTIs. There is also the increased risk of hypotension, which could lead to a fall among the elderly. And another study shows that elderly people with kidney disease usually die of other things, so maybe there is less need to treat those who are in nursing homes and with an eGFR of less than 40, for instance.

Finally, there are non-responders. “SGLT-2 inhibitors are great drugs, but not everyone benefits from them – maybe finerenone is a better option,” said Professor van Raalte, who concluded his presentation by urging delegates to talk to their patients about the benefits and risks of SGLT-2 inhibitors.

Professor van Raalte’s arguments proved persuasive – when a final vote was taken there was a dramatic switch in opinion, with only 28% being for the motion and 72% against.

To learn more, enrol on the EASD e-Learning course ‘SGLT-2 inhibitors’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 9th November 2023 | by Lee Webber

A number of drugs that mimic or enhance incretin agonism are now being used for glucose lowering in diabetes. They have proven cardiovascular safety and may even reduce cardiovascular complications. A new review in Diabetologia looks at the impact of incretin therapies on microvascular outcomes, such as nephropathy and retinopathy. Dr Susan Aldridge reports.

In the last 20 years, glucagon-like peptide-1 receptor agonists (GLP-1RAs, incretin mimics) and dipeptidyl peptidase-4 inhibitors (DPP-4is, incretin enhancers) have been developed as glucose-lowering agents for people with type 2 diabetes. New glucose-lowering agents now need to go through cardiovascular outcome trials (CVOTs) to prove safety before regulatory approval. These have shown cardiovascular safety for DPP-4is, while GLP-1RAs actually reduce major cardiovascular events.

What is less clear is whether these incretin-based therapies also reduce microvascular complications because CVOTs do not report microvascular outcomes in detail, nor were they designed to do so. Clearly, though, the impacts – positive or negative – of GLP-1RAs and DPP-4is on microvascular complications are highly relevant for people with type 2 diabetes who may be using these therapies long-term.

Both therapies increase GLP-1 agonism, which is associated with the attenuation of various pathological processes involved in microvascular disease. These include reduction of reactive oxygen species production, decreased inflammation and improved vascular function. DPP-4is also increase stromal cell-derived factor-1 (SDF-1), which is associated with neovascularisation and tissue repair.

Rodent studies have already demonstrated several benefits of these agents in prevention or reversal of nephropathy, retinopathy and neuropathy. However, evidence from human studies is, so far, limited. What we do know about the impact of incretin therapies on various microvascular outcomes in people with type 2 diabetes is described in a review by Jonathan Goldney from the University of Leicester and colleagues.

Nephropathy

Individual CVOTs have not shown a reduction in the risk of hard renal endpoints with GLP-1RAs, but the trials do show a consistent reduction in albuminuria compared with placebo. And meta-analyses have now confirmed a risk reduction for a renal composite outcome too. The ongoing FLOW trial of semaglutide versus placebo, which is powered for a composite renal outcome excluding albuminuria, is underway to clarify the situation.

The mechanism behind the renoprotective effect of GLP-1 RAs is probably multifactorial, with GLP-1 receptors in the kidney likely playing an important role. One meta-analysis has suggested that reduction in systolic blood pressure by GLP-1 RAs explains away most of the reduction in nephropathy, while another found that HbA1c reduction was responsible. However, weight reduction from GLP-1 RAs appears not to play a role in reducing the risk of nephropathy.

When it comes to DPP-4is, two of the CVOTs (CARMELINA and SAVOR-TIMI) showed a reduction in albuminuria, although to a lesser extent than with GLP-1RAs. However, a meta-analysis showed that this did not translate into a decrease in composite renal outcomes. So when it comes to nephropathy, both GLP-1RAs and DPP-4is appear to improve albuminuria, but only GLP-1RAs improve the more clinically meaningful composite renal outcomes.

There are two possible reasons for this difference. GLP-1RAs are incretin mimics and therefore have a much higher degree of GLP-1 agonism than DPP-4is, which are only incretin enhancers. Furthermore, some of the benefits of GLP-1 agonism could be offset via the increase in SDF-1 with DPP-4is, as SDF-1 is associated with a number of pathological changes, such as natriuresis and renal hyperfiltration.

Retinopathy

The SUSTAIN-6 trial has shown that semaglutide increases the risk of retinopathy complications. However, other CVOTs and meta-analyses have shown no difference in ocular outcomes between GLP-1RAs and placebo. There has been much debate over why retinopathy risk was greater in SUSTAIN-6. Participants in this trial had a high prevalence of background retinopathy and post-hoc analysis has suggested that those without pre-existing retinopathy were at no greater risk of ocular events. So adverse outcomes on semaglutide might be limited to those who already have retinopathy. Furthermore, compared with other CVOTs, SUSTAIN-6 participants did have higher HbA1c, as the trial did not specify an upper limit. When on semaglutide, therefore, their fall in HbA1c was relatively large. It has been seen previously that a rapid fall in HbA1c on GLP-1RAs is associated with worsening retinopathy and this is backed by meta-analysis.

The Diabetes Control and Complications Trial (DCCT) also showed that intensive glucose control was associated with a larger fall in HbA1c from baseline and worsening retinopathy at six and/or 12 months. However, over a mean follow-up of 6.5 years in the DCCT, the overall risk of retinopathy was actually reduced with intensive therapy compared with conventional treatment. Given that SUSTAIN-6 had an observation period of approximately two years, it is not clear whether a longer run would have seen the reversal of the negative relationship between semaglutide and retinopathy. The ongoing FOCUS trial, which is comparing semaglutide and placebo, will investigate further, reporting retinopathy progression at five years as its primary outcome.

For DPP-4is, a retrospective cohort study of German electronic records, with 630 patients, showed that vildagliptin use was associated with a lower incidence of retinopathy. Similar observations come from a smaller study of 82 patients in South Korea showing that DPP-4is are associated with reduced progression of retinopathy. However, a meta-analysis of interventional studies suggests that DPP-4is may actually increase the risk of retinopathy. Similar to the use of GLP-1 RAs, this increased risk may be related to the reduction in HbA1c.

Together, these findings suggest caution in the use of semaglutide and DPP-4is with respect to retinopathy risk. There is debate over why the protective benefits of incretin therapies for the eye seen in pre-clinical studies were not reflected in CVOTs. Maybe this is due to physiological differences between rodents and humans or the lack of GLP-1 receptors within the retina, in contrast to the kidneys and nerves. For DPP-4is, the increase in SDF-1 may be harmful due to its neovascular effect, which could cause proliferation and damage resembling the pathophysiology of retinopathy.

Peripheral neuropathy

Only a few studies on peripheral neuropathy have been done in humans, most of them with fewer than 100 participants. In the two larger studies – an observational study from the US national claims database OptumLabs Data Warehouse with 8252 patients and the GRADE trial, with 5047 – no difference in the incidence of neuropathy was seen in comparison with other glucose-lowering therapies.

With DPP-4is, two large observational studies of electronic medical records have suggested a decreased incidence of neuropathy with both vildagliptin and sitagliptin compared with sulphonylureas. However, findings from clinical trials are mixed, with only one showing a 19.5% reduction in small fibre peripheral neuropathy with linagliptin compared with placebo. It is not clear why these findings differ, but it could be related to differences in comparator, different DPP-4is, different measures of neuropathy and varying statistical power.

So, although the evidence is inconclusive, it looks as if DPP-4is are more promising than GLP-1 RAs when it comes to reducing the incidence of peripheral neuropathy. This is backed by an observational study showing that liraglutide appears to be associated with a higher incidence of neuropathy than sitagliptin. This may be linked to the increase in SDF-1 that occurs with DPP-4is.

Other microvascular complications

Given that incretin therapies may decrease peripheral neuropathy risk, could they also protect against autonomic nervous system disorders such as cardiac autonomic neuropathy (CAN), gastroparesis and erectile dysfunction? It is not clear how GLP-1 agonism affects the autonomic nervous system, but the underlying mechanisms may be more complex than those related to peripheral neuropathy. For instance, there are GLP-1 receptors in the carotid body, whose activation decreases the sympathetic response to high plasma glucose and/or insulin.

Conversely, GLP-1RAs cause an increased heart rate, while other studies report decreased vagal tone and heart rate variability. There are inconsistencies in the literature, but evidence does suggest that GLP-1RAs could lead to autonomic imbalance and CAN.

It is also difficult to determine whether incretins may help reduce autonomic neuropathy that contributes to gastroparesis as GLP-1 receptor activation in the stomach delays gastric emptying. However, long-term glucose lowering might protect against neuropathy-induced gastroparesis, as suggested by the findings of the DCCT/EPIC follow-up.

Finally, erectile function depends upon healthy vascular and nervous function, both of which may be impaired in diabetes and which incretin therapies may be able to modify. There are few data, although the REWIND trial of dulaglutide did find a small reduction in erectile dysfunction incidence compared with placebo.

Finally, vascular damage may cause other microvascular pathologies, such as microvascular cardiac angina and cerebral small vessel disease. It may also reduce microvascular flow reserve in skeletal muscle. All three complications have been associated with type 2 diabetes. However, the impact of incretin therapies on these outcomes has not been well studied in humans so far.

In summary

Incretin therapies differ in their effect on microvascular disease by both drug type and outcome. There is now high-quality evidence showing that GLP-1RAs reduce the risk of adverse renal outcomes, while DPP-4is do not. It is not clear whether GLP-1RAs cause or worsen diabetic retinopathy, but the risk may be higher among those with background retinopathy or higher HbA1c, particularly with semaglutide. Adequately powered, long-term clinical trials are now needed to clarify the retinopathy risk. Clinical caution with DPP-4is and retinopathy is also advised.

Meanwhile, there is little clinical evidence that GLP-1RAs reduce the incidence of neuropathic complications – namely peripheral neuropathy, CAN, gastroparesis and erectile dysfunction. Similarly, the relationship between DPP-4is and neuropathy remains unclear, though it is more promising for peripheral neuropathy.

Going forward, all trials on incretin therapies should report the incidence of microvascular complications in order to enable meta-analysis and improve understanding. Finally, the mechanisms by which incretins exert their positive or negative effects on microvascular outcomes are likely to be multifactorial. Since they are poorly understood, this would also be a fruitful avenue for further research so that these therapies can achieve their full potential in preventing microvascular complications in type 2 diabetes.

To read this paper, go to: Goldney J, Sargeant JA, Davies MJ. Incretins and microvascular complications of diabetes: neuropathy, nephropathy and microangiopathy. Diabetologia 19 August 2023. https://doi.org/10.1007/s00125-023-05988-3

To learn more, enrol on the EASD e-Learning course ‘GLP-1 receptor agonists’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 8th November 2023 | by Lee Webber

The latest research into hypoglycaemia was under discussion at the 59th Annual Meeting of the EASD. The ‘To hell with the hypo’ session covered topics ranging from a tool to predict nocturnal hypos and new forms of glucagon to the impact of food insecurity and how people with diabetes manage their hypo risk. Dr Susan Aldridge reports.

First, there is new hope when it comes to avoiding those dreaded nocturnal hypos. Dr Thomas Kronborg of the Steno Diabetes Center in Nordjylland explained: “I sat down with my colleagues at Steno and we discussed whether it would be useful to have some kind of alarm system based on continuous glucose monitoring (CGM) data, so that every night you could pull out your phone and see if you’re at risk of night-time hypo, rather than being woken up in middle of night with an alarm. Could we use data on what happened in the day with respect to food, insulin and exercise to predict the possibility of a hypo later on?”.

They were able to build such a predictive model and then test it in the DIAMONT study. In this randomised clinical trial involving 400 participants, the model could predict 68% of nocturnal hypos. Dr Kronborg believes that the accuracy of the model could now be improved upon by getting rid of the false positives. This new tool promises to be a useful add-on to CGM technology that could help people with diabetes take preventive action if it looks like a nocturnal hypo is on the way.

Meanwhile, Professor Stewart Harris who is Diabetes Canada Chair in Diabetes Management at Western University, Canada, noted that little is known about how people with diabetes actually manage their risk of hypoglycaemia. So he and his team used data from the iNPHORM study to address this knowledge gap with 1,687 participants with type 1 and type 2 diabetes. The findings may explain why there is still so much hypoglycaemia, much of which is not reported to healthcare professionals – there were surprisingly low numbers taking obvious precautions against hypos. For instance, only 28% took measures to avoid hypos during exercise while 14% practised due vigilance regarding their food intake and 22% checked their blood glucose after treating a hypo. These figures were derived from the always/often response on a Likert scale.

“There are clearly gaps in self-management of hypo risk, especially in type 2 diabetes,” Professor Harris concluded. “The results of our study can hopefully guide tailored clinical efforts and infrastructure to support positive self-management behaviour among people with diabetes who are at risk of hypoglycaemia.”

Meanwhile, many people with diabetes will be looking forward to weekly insulins, which are currently under intense clinical development. But will a weekly dose of insulin increase the risk of hypoglycaemia? Professor Tadej Battelino from the University of Ljubljana stepped forward to reassure, with findings from a post-hoc analysis of the ONWARDS 2 and ONWARDS 4 trials of the weekly insulin icodec in people with type 2 diabetes. In ONWARDS 2, participants switched from a basal insulin to icodec, which was compared with daily insulin degludec, while ONWARDS 4 was a basal-bolus switch to icodec plus insulin aspart compared with insulin glargine and insulin aspart.

The mean hypo duration with icodec proved to be similar to that of the comparator insulins, with median times in hypoglycaemia being 40 minutes or less. Furthermore, most episodes did not develop into level 2 hypoglycaemia. “The most important message is that, despite the long half-life of icodec, its use did not lead to prolonged duration of level 1 and 2 hypos compared with a daily insulin,” Professor Battelino concluded.

Glucagon to the rescue

Various new formulations and applications of glucagon are under development, which will be of interest to those wanting a fast and effective way of treating a hypo. One example is glucagon packaged in a nasal spray. Dr Andreas Holstein from Klinikum Lippe Detmold in Germany presented findings from the SIMPLEST study, which looked at the impact of nasal glucagon on real-life experiences of severe hypoglycaemia.

This was a web-based survey of people treated with insulin and owning glucagon, and healthcare professionals who had prescribed it. Of the 153 people with diabetes in the study, 75% had high fear of hypoglycaemia, 49% had impaired awareness of hypoglycaemia and 64% had experienced severe hypoglycaemia, which they treated with either sugars or glucagon, mainly in the form of the nasal spray.

The findings of SIMPLEST have been very encouraging, with participants reporting less worry when driving, less need to attend hospital with a hypo and less concern about being a burden to others, for instance. “Nasal glucagon positively affected quality of life for people with diabetes,” said Dr Holstein. “It helped them avoid fear and promoted confidence and ease.” Meanwhile, 90% of healthcare professionals in the SIMPLEST survey said that they preferred the nasal spray to reconstituted glucagon as it requires less teaching time for their patients than the traditional powder form, which has to be reconstituted with water before use.

Then there is dasiglucagon, a ready-to-use glucagon analogue in a liquid formulation packaged in a pen, which corrects a hypo in six to eight minutes. Dr Casper Nielsen, from Gentofte Hospital in Denmark, presented findings from a trial of dasiglucagon in post-bariatric hypoglycaemia (PBH), a serious complication affecting up to 50% of those who have had bariatric surgery.

The randomised crossover clinical trial of 120 micrograms of dasiglucagon involved 24 patients who had had Roux-en-Y gastric bypass and had PBH more than three times a week. They were treated with dasiglucagon for four weeks and the time spent in level 1 hypoglycaemia was reduced by 33% (17 minutes a day) and in level 2 hypoglycaemia by 54% (6 minutes a day). “There was no increase in time above range but a small increase in time in range, which was reassuring, and less need for rescue therapy after a hypo,” added Dr Neilsen. “In conclusion, dasiglucagon is a potentially effective new therapeutic option for treatment of PBH, although larger confirmatory studies are warranted.”

Hypos in hospital

Severe hypoglycaemia (SH) sometimes requires hospital admission, particularly when it leads to coma, which is more likely among children as it is harder for them to communicate hypo symptoms. Dr Beata Mianowska from the Medical University of Lodz, Poland, presented her study on how the frequency of hypoglycaemic coma in children has changed over the years.

The current rate is three to seven episodes per 100 patient-years, according to the International Society for Pediatric and Adolescent Diabetes. She measured the rate of coma per 100 patient-years for 303 participants for the period 2018-2021, using the same methodology as for previous studies for the periods 1996-1999 and 2011-2014. Rates for those periods were 8.5% and 5.3%, compared with 2.2% for the new survey. She noted that age and HbA1c did not influence the rate of coma, but longer duration of diabetes did increase the risk. Looking at time of day when the coma occurred, there has been a striking decrease in night-time hypoglycaemic coma. “The decrease in rate of childhood hypoglycaemia coma over time may be because of improvement in diabetes pharmacotherapy and advances in diabetes technology,” she concluded.

Diabetic ketoacidosis (DKA) is the other reason why people with diabetes may require hospital admission. Dr Soon Song, from Sheffield Teaching Hospitals, discussed the comorbidities, clinical characteristics and mortality outcomes among people with type 1 and type 2 diabetes who were admitted for SH or DKA emergencies between January 2019 and June 2023. He noted that most of those with SH had type 2 diabetes while those with DKA and recurrent admissions were more likely to have type 1 diabetes. And of those with type 2 diabetes admitted with DKA, 30% were on SGLT-2 inhibitors.

When it came to comorbidities, the type 2 diabetes patients tended to be older and have a higher Charlson Index score, which indicates a greater burden of comorbid conditions. These included cardiorenal disease, cognitive impairment, cancer and liver and respiratory disease. Those with type 2 diabetes were also more likely to die after the diabetic emergency and time to death was shorter. Thus, concluded Dr Song, SH and DKA can be indicators of poor long-term survival. “There is a common misconception that severe hypoglycaemia can only occur when someone is on a sulphonylurea or insulin,” he said. “However, hypoglycaemia may also be a manifestation of the comorbidity and a sign of organs shutting down, particularly the liver.”

Food insecurity and hypos

Finally, Professor Alexandria Ratski-Leewing, a colleague of Professor Harris at Western University, returned to the iNPHORM study to examine the link between food insecurity and SH, an issue that has been poorly addressed until now. Food insecurity is defined as a consistent lack of food because of an individual’s economic situation and can be seen as a marker of low socioeconomic status. It may lead to difficulty in managing diabetes which, in turn, may increase the risk of hypoglycaemia. Professor Ratski-Leewing and her team asked the question, “In the last 12 months, did you cut the size of, or cut out, meals because of lack of money?” and found that this was so for 20% of the iNPHORM cohort.

Clinical data from iNPHORM revealed that those with food insecurity were more than twice as likely to experience SH. “This is the first study to quantify the impact of food insecurity on level 3 hypoglycaemia in the US-wide population with type 1 or type 2 diabetes who are on insulin or secretagogues,” she said. “It highlights the need for improved clinical and public health strategies to mitigate the impact of food insecurity on the health of people with diabetes.”

To learn more, enrol on the EASD e-Learning course ‘Hypoglycaemia’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 2nd November 2023 | by Lee Webber

A new population-based study, reported in a recent issue of Diabetologia, uses confocal microscopy to show that dysfunctional glucose metabolism is linked to corneal neurodegeneration. The findings suggest that nerve damage may start well before the onset of type 2 diabetes and early tight control of glycaemia may help protect from both corneal damage and diabetic neuropathy. Dr Susan Aldridge reports.

The damage inflicted by hyperglycaemia may start long before the onset of type 2 diabetes. The authors of this paper have previously shown links between adverse glucose metabolism and various measures of neurodegeneration, for example. Chronic hyperglycaemia also leads to the formation of advanced glycaemic end-products (AGEs), which initiate neurodegeneration. Since AGEs have intrinsic fluorescence, they can be measured non-invasively as skin autofluorescence (SAF). The authors have shown that AGEs assessed as SAF are associated with lower retinal nerve fibre layer thickness.

Current methods for monitoring central and peripheral nervous system activity are costly and time consuming and therefore not suitable for routine and large-scale use. There is a need for a sensitive and practical method for detecting early hyperglycaemia-mediated neurodegeneration.

Therefore, Sara Mokhtar and Frank van der Heide from Maastricht University and colleagues have looked at how hyperglycaemia affects morphological changes in small nerve fibres, using confocal microscopy to assess corneal nerve degeneration. Confocal microscopy has the advantage of being an in-vivo, non-invasive and sensitive method for assessing neurodegeneration.

Previous research has suggested that hyperglycaemia does affect the corneal nerve fibres and that these changes can also be an early indicator of diabetic neuropathy, which could allow timely diagnosis and intervention. However, these studies had a number of limitations – they were not population-based, did not control for lifestyle and cardiovascular risk factors and did not investigate the link between glycaemia and corneal nerve fibre damage in detail. This new study used data from a large and well-characterised population-based cohort study – the Maastricht Study – to look at whether a more adverse glucose metabolism status and higher measures of glycaemia are associated with neurodegeneration using corneal confocal microscopy to obtain various measures of corneal nerve fibre damage.

The Maastricht Study

The Maastricht Study is an observational prospective population-based study that includes many people with type 2 diabetes. Its main focus is on the aetiology, pathophysiology, complications and comorbidities of type 2 diabetes. This current study comprised 3471 participants, of whom 729 had type 2 diabetes and 509 had prediabetes. The researchers took measures of glucose metabolism status and glycaemia, including SAF. Using confocal microscopy, they also measured corneal nerve bifurcation density, corneal nerve density, corneal nerve length and corneal nerve fractal dimension.

Together, these measures give a detailed picture of the state of the corneal nerve and were combined and analysed to give a composite Z-score. Statistical analysis accounted for a number of potential confounding factors, such as age, sex, hypertension, smoking and so on, which might contribute to hyperglycaemia and corneal neurodegeneration.

Hyperglycaemia and the corneal nerve

Overall, participants with a lower composite Z-score for corneal nerve fibre measures were older and had an adverse cardiovascular risk profile. Those with type 2 diabetes and prediabetes also had lower Z-scores. When it came to specific measures of glycaemia, higher measures of fasting plasma glucose, 2-h post-load glucose, HbA1c, SAF and duration of diabetes were all associated with a lower Z-score. In general, directionally similar associations were noted for the individual corneal nerve fibre measures that contribute to the composite Z-score. Moreover, these associations were linear across glucose metabolism categories, which implies that glycaemia-associated corneal nerve damage starts well before the onset of type 2 diabetes.

This is the first large population-based study to investigate glycaemia-associated corneal nerve damage across glucose metabolism categories with adjustment for a large number of previous potential confounding factors. This is also the first study to show a linear association between fasting plasma glucose, 2-h post-load glucose, SAF and duration of diabetes with corneal nerve measures.

These new findings are in line with the ‘ticking clock hypothesis’, which states that glycaemia-induced microvascular and neuronal deterioration is a continuous process, starting long before the onset of type 2 diabetes, gradually worsening through prediabetes and as type 2 diabetes progresses. They are comparable to previous findings on retinal nerve fibre layer thickness, brain structural abnormalities, peripheral nerve function and heart rate variability – all measures of neurodegeneration and/or neural dysfunction.

Additionally, this study shows that AGEs are involved in the pathophysiology of corneal neurodegeneration. SAF, which reflects the accumulation of AGEs in the skin, was significantly associated with lower composite Z-score for corneal nerve measures. And this was the case even after adjusting for fasting plasma glucose, 2-h post-load glucose or HbA1c.

Implications for clinical practice

This study suggests that early glycaemic control is essential for the prevention of neurodegeneration, both in the cornea and maybe elsewhere. Glycaemia-associated morphological changes in the corneal nerves seems to be a process that starts well before the onset of type 2 diabetes. Whether early intervention to reduce hyperglycaemia can prevent this requires further study.

Also, corneal neurodegeneration may be a biomarker for diabetic neuropathy. Therefore, measuring corneal nerve fibres could be a relatively inexpensive way of detecting the early stages of neuropathy. The authors say that their findings suggest that corneal degeneration starts before the development of clinical sensory neuropathy, so can be seen as an early warning sign. In conclusion, corneal confocal microscopy could be used to detect neurodegeneration and neuropathy at the very earliest stages of type 2 diabetes pathophysiology.

To read this paper, go to: Mokhtar SBA, van der Heide FCT, Oyaert KAM, van der Kallen CJH, Berendschot TTJM, Scarpa F, Colonna A, de Galan BE, van Greevenbroek MMJ, Dagnelie PC, Schalkwijk CG, Nuijts RMMA, Schaper NC, Kroon AA, Schream MT, Webers CAB, Stehouwer CDA. (Pre)diabetes and a higher level of glycaemia measures are continuously associated with corneal degeneration assessed by corneal confocal microscopy: the Maastricht Study. Diabetologia 17 August 2023 https://doi.org/10.1007/s00125-023-05986-5

To learn more, enrol on the EASD e-Learning courses ‘Management of hyperglycaemia in type 2 diabetes’ and ‘Diabetic foot disease’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 1st November 2023 | by Lee Webber

Disparities in health burdens were explored at the American Diabetes Association’s 83rd Scientific Sessions. Lisa Buckingham reports.

Individuals from underrepresented groups in the US suffer from chronic kidney disease (CKD) at a rate that is higher than White individuals, said Titilayo Ilori, Assistant Professor at Boston University School of Medicine. Similarly, the burden extends to other under-represented groups living across the world. Racism is a factor that amplifies the effects of diabetes and kidney disease, she said, especially in the US, and it should be a focus for all of us as clinicians, researchers and epidemiologists.

Professor Ilori started with a global view with the first example being the Glasgow effect – a tale of two areas in Glasgow, UK, called Calton and Lenzie. There is a 28-year life expectancy gap between the two areas and one in four men in Calton will die before they’re 64. Income levels have been associated with poor health and a shorter lifespan but epidemiologists believe that poverty alone does not appear to account for this disparity. The Economist puts it like this: ‘It is as if a malign vapour rises from the Clyde at night and settles in the lungs of sleeping Glaswegians’.

In the US, if you catch the Metro from the southeast of downtown Washington to Montgomery County in Maryland, life expectancy rises about a year and half for every mile travelled. A 24-year gap exists between both ends of the line. In these two examples is a vivid and palpable social gradient in health and understanding the pervasive factors is crucial for us to improve health.

Why do we treat people and send them back to the conditions that make them sick? Professor Ilori used the example of a patient with multiple social and emotional problems and the clinician thinking, ‘is this a red or blue pill problem?’. Is it beyond us as clinicians to help solve these problems, she asked.

Disparities in prevalence

Prevalence of CKD is three times higher in Black Americans than White Americans. The lifetime risk of end-stage kidney disease (ESKD) is four times higher in Black Americans than White Americans. It’s also 1.2-1.3 times higher in American Indians and Hispanic Americans. The median age of onset of kidney disease is almost 10 years earlier in Black Americans versus Non-Hispanic White Americans, with Black Americans presenting as early as 30 years old.

With regard to disparities in the risk factors for CKD, the risk of having a diabetes diagnosis is 77% higher among African Americans, 66% higher among Latino/Hispanic Americans and 18% higher among Asian Americans. Obesity prevalence is 1.5 times higher in Black and Hispanic Americans compared with White Americans and CKD attributable to hypertension is 12 times higher in Black Americans compare with Non-Hispanic White Americans.

Professor Ilori highlighted a study that looked at the proportional mortality from kidney disease in the US (the proportional mortality refers to the percentage of deaths due to kidney disease over the number of deaths from all causes). The highest percentage is found in Filipino Americans, even higher than Non-Hispanic Black Americans, the second highest group.

We do know that genetic factors play a significant role, she said. Not specifically with diabetic kidney disease but the two risk variants of APOL1: G1 and G2, which were discovered in 2010, explain 70% of the excess risk of CKD in African Americans. However, not all African Americans with APOL1 high-risk status develop CKD, suggesting that there is a gene-to-gene or gene-to-environment interaction acting on the individuals with a background of high risk.

Social determinants of health

Much research is focusing on gene-to-environment but what is the impact of the social determinants of health (SDOH)? The World Health Organization (WHO) defines these as the conditions in which people live, grow, work and age, and these circumstances tend to distribute money and power in different ratios at the global, national and local levels. They create a social stratification that is responsible for a lot of health inequities but the interesting thing about SDOH is that they are all amplified by structural racism. In fact, much epidemiological research has shown that social and environmental influences are highly significant, contributing to between 45% and 60% of the variation in health status.

Next, she looked at race versus genetics versus ancestry.

Race is a concept defined by society, not by genes. It’s true that people around the world differ genetically due to their ancestry and that people’s racial identity may be statistically correlated with their ancestry
It is shaped by geographical, cultural, sociopolitical forces so the definition changes over time and geography
There is no national consensus for definitions of race and ethnicity
Self-reported race and ethnicity can mean something different depending on location and cultural norms; a person’s racial identification is therefore highly subjective
Race does not mean ancestry – ‘biological races are not a current scientific concept and often reinforce historical biases’ (The Atlantic, 2018)
Genetic ancestry is the genetic origin of one’s population and ancestry is a predictor of genetic variants of disease within a population or an individual

With regard to racism and health, she highlighted a 2019 paper stating that:

Racism includes a complex array of social structures, interpersonal interactions and beliefs by which the grouping peer categorises people into socially constructed ‘races’
It creates a racial hierarchy in which individuals from under-represented groups are disempowered, devalued and denied access to resources
Racism is often systemic or structural

She showed the ‘house that racism built’, adapted from Dr Williams of the Harvard School of Public Health. Racism is a societal system that includes political, legal, economic, religious, cultural and historical forces but people often tie racism to the actions of an individual perpetrator such as a healthcare professional who’s denying equitable care to an under-represented group. This narrow perspective ignores structural racism in healthcare, which is structured to be of advantage to some populations and disadvantage many of the under-represented groups.

Discrimination can get under your skin, said Professor Ilori, and it’s known as the allostatic load – the cumulative impact of physical wear and tear related to maladaptive stress patterns that predispose individuals to disease. How? You have the early life adversity and stress exposure that lead to behavioural, psychological and inflammatory responses to these stressors that may affect endothelial dysfunction and atherosclerosis, leading to diseases such as kidney disease as well as diabetes.

When you look at structural racism affecting kidney pathophysiology, there are two possible pathways – it could act through SDOH leading to food insecurity, inappropriate housing, exposure to pollutants, access to health insurance etc and lifestyle implications such as high ingestion of cooked meat, hyperglycaemia and high blood pressure, but there could also be a general biological impact whereby structural racism increases allostatic load, alters gene expression, increases nervous system activity and leads to altered metabolism of insulin and other hormones. Downstream, you then get hyperfiltration, estimated glomerular filtration rate (eGFR) decline and renin-angiotensin-aldosterone system (RAAS) activation and inflammation.

With regard to the impact of segregation, Professor Ilori highlighted a study showing that Black patients on dialysis with ESKD who lived in counties where Black and White residents live apart from each other experience greater mortality compared with Black patients who live in counties with less segregation.

She then covered disempowerment – a downstream effect of structural racism. Tackling it is crucial for improving health and health equity because if a person is not in control of their life, decisions to improve health will be difficult. Furthermore, disempowering people and depriving them of control can lead to stress and a greater risk of physical and mental illness.

So what do we tell our patients, she asked. To just keep swimming? Some of the interventions to address structural racism and SDOH in diabetic kidney disease were recently addressed at a workshop day at the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Here are some of the takeaways:

We need to delineate institutional racism from structural and accelerate research on both
There needs to be proper interpretation of race variables in research, equations and algorithms.
There needs to be effective policy and authentic antiracist research from within the affected community and cultivated by the community
We need to develop frameworks that explicitly outline the link between structural racism and CKD, especially in individuals with diabetes

For research into structural racism and DKD, we need to:

Allow for a more nuanced approach to understanding disparities at subgroup levels that may be hidden – for example, ‘Asian’ could be Japanese, Indian, Korean, Cambodian, Filipino or Chinese
Develop new measurement approaches to capture the multifaceted nature of structural racism as a systemic sum of exposures and not just a single variable

As scientists and physicians, she said, we should constantly and rigorously ask ‘how might racism be operating here?’ and focus on what discriminatory policies and practices might be identified that produce and/or sustain racial inequity.

To promote structural interventions, we need to:

– Promote interventions that can address major structures or drivers of health such as economic status, educational attainment, built environment, community support and access to care

– Look at how multi-level interventions are going to be needed as we map out the frameworks that link structural racism to DKD. We need to look for interventions that will address structural racism at the patient, provider and system level, interventions that will address the multiple levels of structural drivers eg food security and advance health equity through new healthcare models

– Foster research by and for the community and develop community partnerships. Having non-academic stakeholders as partners is crucial to optimising antiracial intervention.

The question remains, said Professor Ilori, why have we continually failed to achieve health equity despite improvements in certain areas of civil rights? She likened it to the pattern on the sides of a soccer ball with each side of it as a societal institution like a carbon atom that perpetrates institutional racism – structural racism derives its strength from the interconnections between all of these carbon atoms. If you just focus on one aspect of it, you just create a pit in the ball, but it retains its structure.

In summary:

Disparities exist in diabetes and kidney disease
Structural racism is a major factor in these disparities
Structural racism amplifies SDOH
We need to work on frameworks that explicitly outline the link between structural racism and CKD
We need effective policy and authentic antiracist research from within the affected community and subsequently cultivated by it

To learn more about diabetic kidney disease, enrol on the EASD e-Learning course ‘Diabetes and the kidney’.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.

Posted on 26th October 2023 | by Lee Webber

Glucagon-like peptide-1 agonists have improved outcomes for people with type 2 diabetes in recent years with their glucose-lowering and weight-loss effects. This has fuelled interest in the therapeutic potential of the incretin hormones in other conditions and an invited review in a recent issue of Diabetologia looks at current research and the future of these therapies in obesity and non-alcoholic fatty liver disease. Dr Susan Aldridge reports.

In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs) have had a big impact in the treatment of type 2 diabetes owing to their clinically relevant and sustained effects on glycaemic control and body weight, combined with cardioprotection. GLP-1RAs are also being used in the treatment of obesity.

Meanwhile, the therapeutic potential of another incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is now being revealed through its application in a combination therapy. The dual GIP receptor (GIPR)/GLP-1RA tirzepatide has shown superior efficacy to semaglutide in reducing HbA1c and body weight in people with type 2 diabetes. The emergence of co-agonists like tirzepatide, which is already approved for type 2 diabetes, has kindled interest in the actions of these two incretin hormones in metabolically relevant tissues such as the liver, muscle and adipose tissue.

In addition, the discovery of poly-agonist drugs that activate multiple gut-brain pathways may further transform the management of metabolic diseases other than type 2 diabetes, including obesity and non-alcoholic fatty liver disease (NAFLD). A new review by Tina Vilsbøll at the Steno Diabetes Center Copenhagen and colleagues looks at current and future research into the application of incretins beyond type 2 diabetes.

Incretins for obesity

The first incretin-based treatment to be approved for the management of overweight and obesity was liraglutide 3 mg once-daily, followed by semaglutide 2.4 mg once weekly. Meanwhile, Phase III trials on tirzepatide, which has already shown dramatic weight loss in individuals with overweight and obesity, are due to be completed later this year.

The efficacy and safety of liraglutide was investigated in the Satiety and Clinical Adiposity – Liraglutide Evidence (SCALE) programme. These trials included people with overweight (BMI ≥ 27 kg/m²) and one or more weight-related complications, including type 2 diabetes, or people with obesity (BMI ≥ 30 kg/m²) with or without complications. Daily liraglutide 3 mg led to an additional 4-5% weight loss compared with placebo, which was sustained after three years of treatment.

These results were exceeded by weekly semaglutide in the Semaglutide Treatment Effect in People with Obesity (STEP) programme in a similar population with overweight or obesity, where mean weight loss of 6.2% was observed after 68 weeks of treatment in those with type 2 diabetes, while those without diabetes lost as much as 10.3-12.5% of their body weight in the same time. Then, in a head-to-head trial of semaglutide versus liraglutide, the mean total body weight loss was 15.8% versus 6.4%.

There is a continuous decline in body weight for the first 60 weeks of semaglutide treatment, then a stable body weight for up to 104 weeks with continued treatment. However, discontinuation of semaglutide after 20 weeks leads to a regain of body weight, whereas maintaining treatment allows continued weight loss over an additional 48 weeks of treatment. This suggests that lifelong treatment is necessary to maintain weight loss. Recently, semaglutide 2.4 mg weekly has been investigated for the growing problem of childhood obesity. In children receiving lifestyle intervention as well, semaglutide resulted in 16.7% weight loss compared with placebo.

The future of obesity treatment

Research into incretin-based treatment for overweight and obesity is looking at the potential of combining GLP-1 receptor agonism with the targeting of other peptide hormones to achieve synergistic effects. The dual agonist tirzepatide is the trailblazer in this area. In the most recent trial, in which those with diabetes were excluded, tirzepatide produced weight loss of 11.9%, 16.4% and 17.8% with increasing doses of 5 mg, 10 mg and 15 mg, respectively. And 83.5% of those in the 15 mg group lost a clinically significant 10% or more of their body weight.

In another trial, adults with overweight or obesity and type 2 diabetes had a mean weight loss of 12.8% and 14.7% on 10 mg and 15 mg tirzepatide compared with just 3.2% on placebo. And in the group treated with 15 mg tirzepatide, 48% lost 15% or more of their body weight.

Tirzepatide has not yet been compared head-to-head with semaglutide 2.4 mg in those with overweight or obesity, but when compared with semaglutide 1 mg in those with type 2 diabetes, doses of 5 mg, 10 mg and 15 mg tirzepatide achieved significantly greater weight loss. However, it’s still not clear whether the GIPR component of tirzepatide exerts its effects by GIPR agonism or antagonism.

The combined GIPR antagonist and GLP-1RA, AMG 133 (Amgen’s obesity therapy), showed a weight loss of 14.5% after 12 weeks in a recent Phase I trial. This compound is poised to enter Phase II and the results are awaited with interest. Clearly more research is needed into the role of GIPR as a therapeutic target in obesity. Currently, several co- and tri-agonists targeting the GLP-1, GIP and glucagon receptor (GCGR) are in development for metabolic conditions, including obesity. Earlier research has shown a synergistic effect of co-infusions of GLP-1 and glucagon on food intake, so GCGR agonism may provide an additive effect due to increased energy expenditure.

However, balancing the weight-loss effect of glucagon receptor agonism with its hyperglycaemic effect is a challenge, so combining this with the glucose-lowering effect of GLP-1R and GIPR agonism is necessary. The GIPR/GIP-1R/GCGR tri-agonist (known as LY3437943) has been compared with dulaglutide 1.5 mg and placebo in a Phase I study in people with type 2 diabetes. Dose escalation of the tri-agonist to 12 mg once weekly over a period of 12 weeks led to an additional weight loss of 9 kg compared with both the placebo and dulaglutide.

Another approach has been to combine cagrilinitide, a long-acting amylin analogue, with semaglutide. In a Phase I study, this combination (at 2.4 mg of each component) resulted in an impressive 17.1% weight loss compared with 9.8% weight loss with semaglutide 2.4 mg alone.

Incretins for NAFLD

In NAFLD, fat accumulation in the liver can lead to inflammation (non-alcoholic steatohepatitis or NASH) and fibrosis, which can lead to NASH-related cirrhosis, currently the fastest-growing indication for liver transplantation in the Western world. The exact pathophysiology of NAFLD is unknown, but features such as metabolic disturbances, lipotoxicity, the gut microbiome, insulin resistance and inflammation are all involved – and there is a close link with obesity, type 2 diabetes and metabolic syndrome. Unsurprisingly, then, NAFLD is on the increase all around the world.

Currently, there is no pharmacotherapy for NAFLD/NASH, so the condition is managed by lifestyle change and treating cardiometabolic risk factors. Incretin-based therapies may be able to address this urgent unmet need by targeting the underlying hormonal and metabolic pathways thought to be involved in NAFLD/NASH.

In preclinical studies, GLP-1RAs have been shown to improve hepatocyte function and hepatic insulin sensitivity, as well as reducing the lipotoxicity of adipose tissue. These benefits arise from both weight loss and mechanisms that are independent of body weight reduction. This review lists all of the randomised controlled trials to date evaluating the potential of GLP-1RAs in NAFLD/NASH. The largest and longest trial to date includes 320 participants with NASH and fibrosis receiving daily semaglutide 0.1 mg, 0.2 mg or 0.4 mg versus placebo. Semaglutide resulted in a dose-dependent reduction of liver enzymes and greater NASH resolution after 72 weeks of treatment.

Meanwhile, the effects of 2.4 mg semaglutide once weekly are being explored in 1,200 participants in a Phase III trial with a combined primary endpoint of resolution of NASH without worsening fibrosis, improvement of liver fibrosis without worsening steatohepatitis and time to first liver-related clinical event. A recent meta-analysis based on data from randomised controlled trials confirms that GLP-1RAs are associated with reduced liver fat, improved liver enzymes and greater histological resolution of NASH without worsening of liver fibrosis.

GIP has been less well studied in NAFLD/NASH, but 52 weeks of treatment with tirzepatide reduces liver fat and improves liver enzymes compared with insulin degludec. Meanwhile, tirzepatide at 5 mg, 10 mg and 15 mg doses is in a Phase II trial in 196 participants with overweight or obesity and biopsy-confirmed NASH.

GLP-1RAs may work well in combination therapy for NAFLD/NASH because most of their mechanisms do not directly target the liver. Dual and triple agonists have led to improvements in lipid metabolism and hepatic steatosis, and research has shown that they may have additional effects on histological NASH features compared with GLP-1RAs alone and that these may be independent of weight loss. There are also several trials underway of combinations of GLP-1RAs with other peptide agonists or small molecule therapeutics. This review provides a useful overview of clinical trials in this area for readers who wish to take a deeper dive into this area.

In conclusion

So far, the therapeutic potential of GLP-1RAs – either alone or in combination with other peptide agonists – for the treatment of overweight/obesity and NAFLD/NASH appears to be huge, with no major safety concerns. Moreover, based on the reduction in major cardiovascular events that has been observed among people with type 2 diabetes in cardiovascular outcome trials, further trials in overweight and obesity have been initiated. These trials are looking at the ability of semaglutide and tirzepatide to reduce cardiovascular disease and mortality. This will potentially expand the clinical benefit of these therapies and establish a benchmark for overweight/obesity therapies in the future. Indeed, as the development of additional gut hormone poly-agonists progresses, obesity pharmacotherapy may become as efficient as bariatric surgery – currently the gold standard – for weight loss. The authors conclude that developments in incretin-based therapies promise to reshape the treatment landscape and improve outcomes for people with obesity and NAFLD.

To read this paper, go to: Andreasen CR, Andersen A, Vilsbøll T. The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease. Diaebtologia online 27 July 2023. https://doi.org/10.1007/s00125-023-05966-9

To learn more, enrol on the EASD e-Learning course ‘GLP-1 receptor agonists‘.

Any opinions expressed in this article are the responsibility of the EASD e-Learning Programme Director, Dr Eleanor D Kennedy.