In a welcome return for ‘The briefing room’, a group of diabetes research luminaries examine the rise to prominence of medications that work by stimulating receptors for GIP and GLP-1 – and where things may be headed next.

“The GIP story is a real rollercoaster,” says Professor Cliff Bailey. “Although GIP originally stood for gastric inhibitory polypeptide, it subsequently became shown to stimulate insulin secretion. So it became a glucose-dependent insulinotropic peptide… Also, originally, GIP was identified as a 43-amino acid peptide and then later it was realised that it was only 42. So we never really knew whether the initial experiments that we did were entirely justified.”

The story is representative of a field of research that seems to have been singularly marked by false starts (a similar misreading of the amino acid sequence of the bioactive form of GLP-1 complicated its early investigation). Fast forward to today, though, and we can look back on a trail of medications based on these compounds, each one more effective than the last – and in ways that may have surprised the original investigators. 

It’s a trail that is compellingly described by the participants in this second edition of ‘The briefing room’. These include – as well as Cliff Bailey – Professors Stefano Del Prato, Baptist Gallwitz, Francesco Giorgino, chaired admirably by Michael Nauck. Between them, they describe how numerous obstacles were overcome (the role of the venomous saliva of the Gila monster reptile is a particularly vivid plot twist) and the true potential of these medications was gradually revealed.

The twists and turns are compelling. But it’s the range of properties at the story’s heart that really stand out. As Michael summarises: “Insulin secretion was stimulated, glucagon was suppressed without a risk of hypoglycaemia, appetite was reduced, caloric intake was reduced, body weight was reduced in the long run. We had effects on glucagon, we have effects on the cardiovascular system that translate into real benefits preventing myocardial infarction, stroke and the mortality associated with such events. And there always was an improvement from agent to agent, showing a very large potential.”

So what does the future hold? “I certainly am not in a position to say how far this will go,” says Michael. “I hope that there is still some potential left for future development. The most recent development is co-agonists stimulating both GIP and GLP-1 receptors. It’s called ‘twincretins’ because it combines the action of the two original incretin hormones and it has smashing results in terms of glycaemic control, leading patients into the normal range of HbA1c and allowing reduction in body weight by 20% or more, which probably contributes to a major benefit in terms of metabolic health and cardiovascular consequences. We also have to admit that there remain some open questions, which, of course, is always good for scientists like us. Because they offer a chance that we will find out details of the mechanisms, which then will lead to better future developments of drugs that incorporate this new knowledge that we still have to work on.”

Get the full story in the second episode of ‘The briefing room’, ‘Incretin-based medications’.

Professors Michael Nauck, Stefano Del Prato, Francesco Giorgino and Baptist Gallwitz will be participating in a live EASD e-Learning Q&A session on this topic, chaired by Professor Chantal Mathieu, at the EASD conference on Wednesday 21st September at 12.00 in the Virchow Hall.

Many people with diabetes have to cope with the significant health challenges presented by living with more than one chronic condition. To launch EASD e-Learning’s new course on conditions commonly associated with type 1 and type 2 diabetes, Professor Bruce Wolffenbuttel’s module focuses on comorbidities in type 1 diabetes.

Comorbidities in type 1 diabetes – not only other autoimmune-related conditions but obesity too – have significant implications for treatment and quality of life. “We all think of diabetes as a glucose disease where we to try to attain as good control as possible,” says Professor Bruce Wolffenbuttel, Emeritus Professor of Endocrinology and Metabolism at the University of Groningen, The Netherlands. “We try to treat hypertension and try to treat dyslipidaemia. But other diseases that coincide with type 1 diabetes also need attention from the diabetes team – they should be an integral part of diabetes care.”

Obesity, although more commonly discussed in the context of type 2 diabetes and not strictly speaking a comorbidity, is the first topic Bruce addresses in his module. It’s an important issue for people with type 1 diabetes, with long-term follow-up in the DCCT EDIC study showing sizeable increases in body weight over time. As Bruce points out, intensive insulin treatment may itself play a part in this – not least by encouraging excessive carbohydrate intake to combat hypoglycaemia. Whatever the cause, this weight gain translates into significant consequences for both the treatment of diabetes and the development of complications (cardiovascular, in particular) – raising blood pressure and increasing both intima-media thickness and coronary calcifications.

The module’s main focus, though, as might be expected, is on autoimmune comorbidities. As a condition that originates in autoimmunity, it makes sense that type 1 diabetes should overlap with other autoimmune disorders, and Bruce shows data from the UK Biobank that explains, at least in part, why some of these so often go hand in hand. Type 1 diabetes, hypothyroidism and coeliac disease, for example, all share a similar risk in the HLA system, located on chromosome 6. 

Of the autoimmune comorbidities associated with type 1 diabetes, the most prevalent are the thyroid disorders, coeliac disease and vitamin B12 deficiency –  all of which have a significant impact on quality of life. These are all explored in detail. Bruce’s central point – that identifying and treating these comorbidities should be an integral part of the care provided by the diabetes team – is well served by this module, which provides vital information practitioners will require to plan the diagnosis, monitoring and treatment of people with type 1 diabetes and comorbidities.

For Professor Wolffenbuttel’s module, ‘Type 1 diabetes and comorbidity’, enroll on the new EASD e-Learning course ‘Multimorbidity and diabetes’, launching today.Professor Wolffenbuttel will be participating in a live EASD e-Learning Q&A session with Professor Cees Tack titled ‘Comorbidities in type 1 and type 2 diabetes’ at the EASD conference on Tuesday 20th September at 13.00 in the Virchow Hall.

Recent clinical trial data have led to new guidelines on managing heart failure with reduced ejection fraction, which promise to add years of life for people with the condition, many of whom also have diabetes. The need to adopt the Four Pillars of these new guidelines without delay was under discussion at the recent ADA conference, as Dr Susan Aldridge reports.

Speaking at the American Diabetes Association (ADA) Scientific Sessions this summer, Dr Patricia Campbell, Heart Failure Lead at Southern Trust Northern Ireland, reviewed best practice in diagnosis and treatment of people with heart failure with reduced ejection fraction (HFrEF). ”It’s important in the patient’s heart failure journey that they’re diagnosed early and accurately,” she says. “In the UK, 80% of patients are diagnosed when they’re already in hospital with an acute decompensated heart failure episode. This really is suboptimal, because heart failure is persistent and progressive. The pressure and volume overloads during acute decompensation drive cardiac remodelling, reduce contractile function and cause progression of the disease. So, after each episode, the patient never quite gets back to their previous level of functioning.”

On the other hand, we do know that optimisation of medical therapy early in the journey can prevent multiple hospitalisations and slow disease progression. “So, if there’s one message to take home from today it’s ‘think about BNP’. You guys [in your diabetes clinics] are looking after patients that I haven’t met yet, but they do have risk factors for heart failure. So, if someone has vague symptoms and you’re not sure what they’re related to, think about measuring their BNP.”

The Four Pillars of heart failure therapy

Most people with heart failure will already be on ACE inhibitors and beta blockers. However, the so-called Four Pillars of medication recommended in the most recent heart failure guidelines from the American Heart Association and other organisations are: angiotensin-receptor blockers/neprilysin inhibitors (ARNI, e.g. sacubitril/valsartan), beta blockers, mineralocorticoid receptor antagonists (MRA) and SGLT-2 inhibitors. Most of these have level A evidence for their efficacy in heart failure. For instance, the most recent trials on SGLT-2 inhibitors – DAPA-HF and EMPEROR-Reduced – show a 25% reduction in death or hospitalisation for heart failure with a number needed to treat of 21 over an 18-month follow-up. “In cardiovascular terms, that is an extremely low number needed to treat and therefore high-quality value medicine.” Dr Campbell says. 

She warns against clinical inertia. “You might think ‘I’ve got a patient in my practice with heart failure and they’re doing fine, so I’m not inclined to change anything’. Intuitively, we know that if a patient is newly diagnosed, or admitted to hospital, they are not stable and that warrants a change in therapy. We tend to think any stable heart failure is not at risk, but that is false. They are at risk of a decompensation episode if they have intercurrent illness, a new arrhythmia or atrial fibrillation, and are then at risk of sudden cardiac death.  These medicines are shown to reduce death or hospitalisation for heart failure, so we have to overcome our clinical inertia, even in the stable heart failure patient.”

Why these Four Pillars? Because each of these medicines acts on a different pathophysiological pathway – their mechanisms are independent and additive and their benefits are incremental. “So, the goal has changed from the last guidelines and it is now to implement as many of them as possible as quickly as possible,” says Dr Campbell. 

If you’re still not sure, because your patient is fine and they haven’t been in hospital in a few years, there is still a reason to change. Dr Campbell pointed to recent trial data, comparing comprehensive with conventional treatment, which showed that for a 55-year-old patient who is not particularly symptomatic, comprehensive treatment gave an extra 8.3 years of event-free survival, while a 65-year-old enjoyed an extra 6.3 years. “We are doing our patients a disservice if we are not maximising their medicines,” she says.

Implementing the Four Pillars

There are three changes to the way heart failure medication should be managed, according to the new guidelines. First, speed matters. “We have been too slow in introducing lifesaving therapies in the past, because we were doing it systematically according to the appearance of trial data,” Dr Campbell noted. Second, prioritise initiation of the Four Pillars and up-titrate afterwards. And third, there is no fixed or preference for the sequence of introducing these medications. “So, we are moving away from the approach that was vertical, step-wise, with titration to full dose of each drug before adding the next. It was chronological – based on order of completion of trials and assuming the most effective and well-tolerated treatments were developed first. This delays initiation of life-saving treatments that are immediately beneficial.”

For there is data from the CHARM-HFrEF trials on ARBs and from EMPHASIS-HF on MRAs that show the benefits start early, within two to four weeks. “These benefits happen, even when patients are in the early stages of being up-titrated. Even if you’re on tiny doses of an ARB or MRA, you’re still getting benefit. The same is true with SGLT-2 inhibitors. So, give the four pillars of care as soon as possible, and then up-titrate.”

She also suggests ignoring conventional sequencing and instead do these three steps. First, give the beta blocker and SGLT-2, then the ARNI and finally the MRA. This should all be achievable within three to four weeks, with up-titration to follow. This is in contrast to conventional sequencing, which takes six months or more.

Having said this, implementation should be individualised and adapted to the patient in front of you, according to their symptoms, functional status, renal function and comorbidities. “Also, you really should be getting these medications initiated before discharge from hospital after acute heart failure,” Dr Campbell advises. “It’s a time when you’ve got so many vital signs in front of you – lab results, and so on  – whereas we know in the real world there are multiple problems, such as patients not getting seen quickly enough after discharge or not often enough thereafter.”  

Barriers to implementation

Doctors worry that SGLT-2 inhibitors reduce estimated glomerular filtration rates (eGFR), for patients with heart failure often also have chronic kidney disease. It is the slight dip in eGFR on initiation that is the source of this concern. However, in the longer term, SGLT-2 inhibitors actually reduce the underlying decline in eGFR that occurs with chronic kidney disease. We also know from DAPA-HF and EMPEROR-Reduced that they reduce the risk of end-stage kidney disease and renal or cardiac death.

The presence of hyperkalaemia is also not a reason for not initiating these therapies, because both MRAs and dapagliflozin have been shown to reduce it. And when it comes to blood pressure, Dr Campbell notes that “A lot of heart failure patients won’t have a good, robust blood pressure, but SGLT-2 inhibitors are self-titrating in that those with lowest blood pressure get the lowest blood pressure drop and those with the highest blood pressure get the highest drop and this equalises out over time. So, low blood pressure should not be a reason not to start MRAs, SGLT-2 inhibitors and beta blockers.” Finally, SGLT-2 inhibitors have also been shown to have benefit for patients who are frail, so again, don’t hold back from using them in this group either. 

For more on this topic, enrol on the following EASD e-Learning courses:

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

The cost-of-living crisis being experienced around the world is not just about energy and food prices. It also encompasses access to healthcare and affordability of therapies. According to findings presented at the recent ADA Scientific Sessions, these costs are hitting people with heart failure hard, particularly those in lower socioeconomic classes, who are already disproportionately affected by the condition. Dr Susan Aldridge reports.

The social determinants of health are extremely important and are tied to outcomes. This is as true in heart failure as in other chronic conditions. Speaking at the American Diabetes Association’s (ADA) conference this summer, Dr Shahzeb Khan, Duke University School of Medicine, pointed to a study of hospitalisation for heart failure (HHF) in young adults from 2004 to 2018, which showed an increase over this time. “Of particular interest is that 50% of these hospitalisations occurred in households in the lowest quartile of household income,” he says.

There was also a relationship between living in a ‘food desert’ and recurrent HHF and all-cause hospitalisations. A food desert is a low-income area with limited access to healthy foods. Another study showed that 63% of choices about healthy food and beverages are mediated by expenditure, so a healthy lifestyle is seen by many as a privilege.

Many health conditions are disproportionately clustered in poorer regions, Shahzeb says. But when it comes to healthcare, patients of lower socioeconomic status are more likely to face health inequalities and to have comorbidities. They have fewer interactions with primary care and are more likely to ‘end up’ in secondary care.   

Socioeconomic status and heart failure

A study looking at more than 40,000 patients from the Swedish Heart Failure Registry found that Class 4 heart failure was twice as common in the lowest compared with the highest socioeconomic class.

“What was even more worrisome is that patients of lower socioeconomic class had a 15% lower use of heart failure devices and medical therapies,” says Shahzeb. “They also had a higher comorbidity burden, including diabetes. And, although they were more likely to have heart failure, they were less likely to be admitted to hospital with it and receive an implantable cardiac defibrillator or anticoagulants.”

He was involved in another study on differences between rural and urban regions in mortality from heart failure, ischaemic heart disease and stroke, using the Centers for Disease Control and Prevention database. “Our study showed that people from rural areas had a much higher mortality from heart failure compared with people from metropolitan areas,” he says. “This can be linked to multiple factors, including access to healthcare, financial constraints and lower levels of health education.”  

There has been a very recent study of the global disparities in prescription of guideline-recommended drugs for heart failure with reduced ejection fraction. It covered more than 8000 patients hospitalised for acute heart failure in 44 countries. A lower proportion of patients in lower- and middle-income countries were on guideline-recommended therapy and, to make matters worse, they were also on lower doses. “This study clearly shows that that improved access to medicines, globally, is direly needed,” says Shahzeb.

Turning to heart failure in the USA, one study showed that one in six patients forgo or delay care, with more than half of these saying they do so because of cost. These patients are, unsurprisingly, more likely to appear in an emergency room and actually end up with higher annual inpatient and total healthcare costs. There are very similar findings for atherosclerotic cardiovascular disease, where one in two families of non-elderly patients with the condition have difficulty in paying medical bills.

Financial toxicity

Shahzeb went on to describe a study of healthcare spending by families with large employer coverage between 2003 and 2018. “This shows that out-of-pocket spending is rising steadily and has increased by 67% over that period. Patients with heart failure and their families are experiencing very large out-of-pocket healthcare expenses.” The study found that one in seven families with a member who has heart failure – and as many as one in four low-income families with a member who has heart failure – experience so-called ‘financial toxicity’. This means spending over 20% of their post-subsistence income on healthcare expenses per year. The main contributors to this out-of-pocket spending are insurance premiums and medications costs. “Therefore, financial toxicity represents an additional challenge for families of patients with heart failure, especially those on low incomes,” Shahzeb concludes.

“There is a huge difference in the best therapy available and the best therapy actually being delivered,” he continues. A US study on sacubitril/valsartan, which is now recommended for management of patients with heart failure found that, despite FDA approval, less than 3% of heart failure patients were taking it within the first 18 months. This may be associated with out-of-pocket costs, for this drug costs far more than other heart failure medications. 

Meeting the challenge  

“Now that we know that socioeconomic status has a huge impact on heart failure outcomes, we need to assess cardiologists’ knowledge, attitudes and practices on cost discussions and cost-conscious care,” says Shahzeb. “There is a lack of evidence on the quality of cost discussions between patients and physicians and, even in the guidelines, there is very little on how to conduct these discussions.”

He has some pilot study-based descriptive data on patients’ views and goals on cost discussions for heart failure treatment and says: “They may feel uncomfortable discussing costs with their physicians. We have very little information on patient perspectives on how to conduct such complex discussions.”

He is therefore working on the development and validation of a heart failure-related financial navigation programme for recently diagnosed patients. This includes one-to-one discussions, financial education, budget worksheets and appropriate counselling. There will also be research on financial toxicity and, ultimately, Shahzeb hopes that patient contributions to high-value therapies can be minimised. Addressing the socioeconomic aspects of heart failure, including costs, should hopefully improve outcomes.

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

A refreshed version of the EASD e-Learning website launches this week, with a cleaner, more user-friendly design.

As part of a wide-ranging redesign, changes to EASD e-Learning’s site navigation make it easier for learners to access the different types of information they want, to identify the experts who have contributed to a specific course, and to share content with other people.

Welcoming the new site’s launch, EASD e-Learning Programme Director Dr Eleanor D Kennedy, commented: “Course content is now presented in a way that allows learners to see at a glance who the authors are before enrolling on a course. And it’s much easier to share Horizons content with other colleagues, so they too can keep up to date with new innovations in diabetes care and research. We hope these and other changes to the site will help build a thriving community of EASD e-Learning users, improving diabetes knowledge and treatment around the world.”

Bigger reach, greater scope

The redesign follows a period of rapid expansion for the EASD e-Learning platform. Since its launch in 2018, the platform has grown to include over 80 modules on a wide range of topics. It now has around 8,000 healthcare professional subscribers and is regularly accessed by thousands more, from every region of the world. In addition to its e-Learning modules, the site now offers additional types of content – in particular in its ‘Horizons’ section, which includes weekly news reports on diabetes innovations from journals and conferences, and films on hot topics in diabetes.

“Providing a range of content types, not just modules, has enabled us to offer greater immediacy to learners and respond more quickly to important changes in the diabetes environment – such as COVID-19,” said Dr Kennedy. “With so much content, though, it had become a challenge to make sense of it all within the old site design. By making the navigation clearer and establishing distinct areas for our course content and Horizons, learners can now move more easily between the different types of information.”

Other innovations include:

  • Well-structured, easy-to-follow navigation, with new portals and crumb trails to guide learners through the site
  • A new ‘My account’ page, making it easier for learners to track their progress through a course and download certificates of completion and reflective learning
  • Module authors credited on the course listing, so learners can see who writes and presents course content before enrolling
  • A new ‘Meet the experts’ section detailing all the course content authors, complete with biographies
  • Easy-to-use options for sharing Horizons content by email or Tweet

Improvements will not stop there, though. “This redesign was inspired and informed by learner feedback,” says Dr Kennedy. “It’s very much an ongoing project and needs ongoing feedback from users to help us make more improvements to the content and user journey – improvements that will bring us closer to our goal of being the world’s leading information hub for diabetes knowledge.”

In a new series of films on Horizons, leading researchers and clinicians from around the world talk about the journal articles that have left a deep impression on their understanding and practice in the field of diabetes.

Scientific discovery is a slow, painstaking business. Eureka moments are few and far between. Even so, it’s the breakthroughs that stick in the mind. Those turning points – usually accompanied by a much pored-over journal article and hinging on the sharing and accumulation of knowledge over many years – when, for the scientific community, the penny finally drops and our collective understanding advances.

The history of diabetes research is unusually blessed with such moments. The Diabetes Control and Complications Trial, which conclusively demonstrated the importance of tight glycaemic (and blood pressure) control in preventing the complications of type 1 diabetes. The United Kingdom Prospective Diabetes Study, which did much the same for type 2 diabetes. And of course, just over a century ago, the discovery of insulin itself.

We wanted to know which trial results and articles had been breakthrough moments for our authors and collaborators. Starting earlier this year, whenever we were filming a module or panel discussion, we began asking presenters or participants to choose the diabetes-related journal article that had had the biggest impact on them, and to explain how it had affected their understanding of diabetes and their practice as a researcher or clinician. The result is a new film series -‘Gamechangers’ – which starts on Horizons this week.

To kick the series off, EASD President Professor Stefano Del Prato chooses two articles, separated by 20 years but closely connected by subject (the effects of phlorizin on glycaemia and insulin secretion) and ultimately by their potential to transform the treatment of diabetes:

Rossetti L, Shulman GI, Zawalich W, De Fronzo RA. Effect of Chronic Hyperglycemia on In Vivo Insulin Secretion in Partially Panceatectomized Rats. J Clin Invest. 1989 (Oct):80; 1037-1044. https://pubmed.ncbi.nlm.nih.gov/3308956/

Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. EMPA-REG OUTCOME Investigators. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. NEJM. 2015 (Nov): 2117-2128. https://pubmed.ncbi.nlm.nih.gov/26378978/

Watch the first film in the ‘Gamechangers’ series, ‘New vision, new treatment’ presented by Professor Stefano Del Prato, launching this week on Horizons.

For more on this topic, enrol on the following EASD e-Learning course:

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

It’s an increasingly popular way to lose weight and improve health, but which intermittent fasting method should we be prescribing to patients with overweight and obesity? This question was addressed at the ADA’s latest conference. Lisa Buckingham reports.

As we battle the obesity pandemic, intermittent fasting (IF) has been cited as a potentially valuable tool. But what do we mean by intermittent fasting? And with several versions available, which is likely to be most effective and sustainable for people with overweight and obesity?

Speaking at the American Diabetes Association’s scientific sessions this summer, Krista Varady, professor of nutrition at the University of Illinois, USA, defined IF as an umbrella term that covers several types of eating pattern. Alternate-day fasting (ADF) – 500 calories on fast days and whatever you want on feast days; the 5:2 diet – two 500-calorie fast days per week and five feast days; and, by far the most popular, time-restricted eating (TRE) – an eating window of, say, eight hours and fasting for 16 hours.

Professor Vardy’s team did a trial on ADF, which investigated whether fasting plus aerobic exercise can treat non-alcoholic fatty liver disease (NAFLD). The trial design included an ADF group, which ate 600 calories on fast days; an exercise group that exercised five times per week for 60 minutes at moderate intensity; an ADF plus exercise group and a control group of usual diet. It was a three-month study and adherence was excellent. Participants had a liver-fat percentage of around 17%.

In the ADF plus exercise group, liver fat was significantly reduced (-5.5%) versus the exercise group (-1.3%) and control (-0.2%), but was not significant versus ADF alone (-2.3%). Bodyweight was significantly reduced in the combination group (-4.6%) versus exercise and control groups, but not versus ADF (-5.1%).

For liver enzymes, ADF plus exercise saw alanine aminotransferase (ALT) reduced versus control only. Aspartate aminotransferase (AST) remained unchanged. The combination group also saw promising changes in indicators of glycaemic control – fasting glucose, insulin, insulin resistance and waist circumference were reduced versus control only.

Overall, she said, they didn’t see much difference between the combination group and the ADF group, but the results of the combination were still positive.

With regard to ADF, Professor Varady said she is often asked whether people overeat on feast days. From their research, the answer is no. People typically eat only 10% (200 kcal) more than baseline, and report that they become more in touch with their hunger and fullness cues. It’s this inability to overeat on the feast days that leads to the weight loss.

Another study that they did five years ago asked whether fasting or daily calorie restriction is better for weight loss. It was one of the first studies on IF and – at 12 months – remains one of the longest: six months of weight loss followed by six months of weight maintenance. They had an ADF group, a calorie-restriction (CR) group and control of usual diet.

ADF and CR subjects lost the same amount of weight (6%) by month six, and this weight loss was maintained by month 12. ADF and CR also had similar effects on body composition, with one not being better than the other in terms of fat mass lost.

Professor Varady moved on to discuss time-restricted eating (TRE). This tends to be more popular than ADF, she said, as it’s easier to achieve, although the weight loss is not as high. When to place the eight-hour window is another question she’s often asked and the answer is that it’s healthier to place it earlier in the day as our bodies are more insulin sensitive in the mornings. However, starting the window at, say, 8 am was found to result in high dropout rates in trials because you can’t eat after 4 pm.

She pointed out that it’s still a very new field with little data behind it. She and her team did a three-month trial of TRE, with a window of eating from 10-6, to look at whether it actually works for weight loss versus a control group of usual diet with no timing restrictions. Adherence was very high.

Participants lost 2.6% bodyweight versus control. It’s easier to stick to than ADF, said Professor Varady, but weight loss is slower. However, the most interesting finding was that eating within an eight-hour window reduced energy intake by 350 kcal without calorie counting, simply because you have fewer hours in which to eat. The average American eats within a 14-hour window.

Finally, she drew attention to their work looking at whether a shorter eating window produces more weight loss. This trial compared a four-hour window (3-7 pm) with a six-hour window (1-7 pm), with a control of usual diet with no timing restrictions.

Participants lost the same amount of weight (3.2%), but the four-hour group lost it slightly faster than the six-hour group. Both groups saw similar reductions in fasting insulin (15%) and insulin resistance (20%), with no change in fasting glucose. No changes were seen in blood pressure or in lipids, but Professor Varady attributed this to the participants being in the healthy range at baseline.

An interesting point was raised about diet quality. One of the trial reviewers asked if the diet was of sufficiently high quality to make it safe if when people are eating in such a short window of time. After looking into this, the researchers found that diet quality was not compromised – people ate less of everything but it was in the same proportions as unrestricted eating.

For physicians that would like to prescribe these diets, Professor Varady provided some practical considerations and lessons from their research. Firstly, there is an adjustment period – it takes about 10 days to adjust to the new meal regimen and it’s worth letting patients know that those first days might be challenging. They may also experience headaches, but these subside when enough water is taken on. Secondly, patients can exercise and many feel a boost of energy while fasting, so there’s no need to change routine. Lastly, alcohol is permitted in moderation during the eating window with TRE, and on the feast days during ADF.

They are not suitable for children under 12, pregnant women, adults over 70 and people with eating disorders.

As for which diet to choose, Professor Varady said that it’s up to the person and what fits their lifestyle. She summarised that ADF is harder to follow and you need to count calories, but it has a faster weight loss of about 10-15 lb in three months. TRE is easier to follow with no calorie counting but has a slower weight loss of 5-10 lb in three months.

Studies have not extended beyond 12 months so it’s hard to say whether it works for long-term weight maintenance and more long-term data is needed.

For more on diet and lifestyle interventions in diabetes, enrol on the following EASD e-Learning module:

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

A new review, reported in a recent issue of Diabetologia, looks at glycaemic thresholds for the appearance of the signs and symptoms of hypoglycaemia in people with and without type 1 diabetes. These appear at lower glucose levels for people with diabetes and, also of note, the thresholds for appearance of autonomic and neuroglycopenic symptoms are similar, contrary to popular belief. Dr Susan Aldridge reports.

Hypoglycaemia is an ongoing challenge for many people with type 1 diabetes as a consequence of their treatment with insulin. Therefore, any new research that sheds light on the underlying physiological and biochemical processes is welcome, as it may lead to ways of avoiding hypos or making them easier to manage.

When glucose levels fall into the hypoglycaemic range, a counterregulatory hormonal response is triggered. First, there is suspension of insulin production by the beta cell, followed by the release of several hormones – namely glucagon, adrenaline, noradrenaline, cortisol and growth hormone. Then we get autonomic (warning) symptoms, which hopefully will lead to a behavioural response – usually, ingesting fast-acting carbohydrate. The autonomic symptoms include sweating, anxiety, tremor, palpitations and feeling hot and tingling. These are usually thought to precede neuroglycopenic symptoms like difficulty speaking, confusion, dizziness, irritability, blurred vision and drowsiness, which are a sign that the brain is being starved of glucose.

The impact of varying degrees of hypoglycaemia on counterregulatory response can be studied by a method called the hyperinsulinaemic clamp. Insulin is infused into a participant to cause glucose levels to fall, alongside a variable glucose infusion titrated against frequent glucose measurements to achieve a state of hypoglycaemia at various predefined plateau values. At each plateau, hormone concentrations and symptom scores can be recorded to define the glucose levels at which responses occur.

We know there is variability both between and within individuals of the thresholds where these responses occur. They are also influenced by factors such as prior exposure to hypoglycaemia and hyperglycaemia, age and duration of diabetes. Factors specific to type 1 diabetes can influence counterregulatory and symptom responses so the corresponding glycaemic thresholds differ from those for people without diabetes. To explore this, Clementine Verhulst from Radboud University Medical Centre, Nijmegen, The Netherlands and colleagues in Denmark and the UK, carried out a systematic literature review of hyperinsulinaemic clamp studies in people with, and without, type 1 diabetes.

They looked at 63 papers, published between 1980 and 2018, involving 1332 participants. Eleven included only people with type 1 diabetes, 26 only those without diabetes and 26 included both.

Glycaemic thresholds for hormone responses and symptoms

The glycaemic thresholds for eliciting hormone responses all occurred at lower median glucose levels in people with type 1 diabetes than in those without diabetes – 3.4 versus 3.8 mmol/l for adrenaline, 3.0 versus 3.2 for noradrenaline, 2.8 versus 3.5 for cortisol and 3.2 versus 3.8 for growth hormone. For glucagon, the threshold for people without diabetes was 3.8 mmol/mol (this was not reached for people with diabetes). Neither duration of diabetes nor glycaemic control measured by HbA1c was associated with the glycaemic threshold level for any of the hormones measured.

The glycaemic threshold for the appearance of both autonomic and neuroglycopenic symptoms did not differ, occurring at a median of 3.0 mmol/l in people with diabetes and 3.4 mmol/l in those without diabetes. And, as found for the hormone responses, neither duration of diabetes nor HbA1c was associated with the threshold level of symptom responses in people with diabetes.

Implications of this study

This review shows that for people without diabetes, hormone responses to hypoglycaemia occur between 3.2 and 3.8 mmol/l, while lower glucose levels were required to elicit symptom responses. Hormone and symptom responses occur at lower glucose levels in people with type 1 diabetes.

Based on hypoglycaemic glucose clamp studies dating back to the 1980s, it has been assumed that the physiological response to hypoglycaemia in people without diabetes occurs at glucose levels below 3.9 mmol/l, with the release of glucagon and adrenaline, while symptoms occur at levels below 3.3 to 3.5 mmol/l. This new study suggests that both hormone and symptom responses actually occur at much lower glucose levels on average, in people with and without diabetes.

In people with type 1 diabetes, glycaemic thresholds occur at lower levels (0.2 to 0.7 mmol/l and 0.4 mmol/l lower for hormone and symptom responses, respectively) than they do for people without diabetes. There is a wide range of thresholds, though, for people with diabetes, suggesting greater variability within this population. This could be for a number of reasons – different prior exposure to hypos, loss of glucagon secretion, blunted adrenaline and noradrenaline responses and impaired hypo awareness. In fact, this study did find that those with impaired awareness had lower thresholds for appearance of autonomic symptoms and release of adrenaline. This is in line with other research which finds that recurrent hypos, which often occur in those with impaired awareness, shifts glycaemic thresholds for hormone responses to lower values.

The study also found that strict glycaemic control – low HbA1c – does not have an impact on glycaemic thresholds. This is important, for low HbA1c, resulting from strict glycaemic control, is often assumed to be associated with greater exposure to hypos and higher HbA1c with less exposure. This new finding suggests that advising people to relax their HbA1c target in order to avoid hypos won’t actually work, as the glycaemic threshold remains the same.

Another finding challenges conventional wisdom around hypos – that the threshold for autonomic and neuroglycopenic symptoms is actually the same. It’s generally been assumed, though, that autonomic symptoms, like sweating and palpitations, appear before neuroglycopenic symptoms, such as difficulty in thinking or speaking – that is, symptoms appear in a hierarchy. This assumption may have arisen because autonomic symptoms are more immediately obvious. Neuroglycopenic symptoms might only become apparent if someone is engaged in a task requiring information processing. This is important when it comes to educating people about hypos, because they are usually told about this hierarchy, when this study shows that it does not actually exist.  

Finally, what does this new study tell us about the definition of hypoglycaemia? The American Diabetes Association (ADA) defines hypoglycaemia non-numerically as ‘all episodes of an abnormally low plasma glucose concentration that expose the individual to potential harm’. What actually constitutes a hypo is still under debate – and is important to people with type 1 diabetes. The findings of this new study acknowledge that glucose levels below which hormone and symptom responses appear show high intra- and interindividual variability – and this should be acknowledged in this ongoing debate.

Finally, the authors caution that their analysis was based on data obtained during experimental hypoglycaemia. Evidence from spontaneous hypoglycaemia occurring in everyday life is also needed to complement discussions on how hypos are to be defined. 

In conclusion, these new findings may inform clinical practice when supporting and educating people with type 1 diabetes about hypos. Hopefully, they will also inspire further research into the detailed understanding of hypoglycaemia and inform discussion on its definition. 

To read this paper, go to:

Verhulst C, Fabricius T, Teerenstra S, Kristensen PL, Tack CJ, McCrimmon RJ, Heller S, Evans ML, Amiel S, Pedersen-Bjergaard U, de Galan BE, Hypo-RESOLVE consortium. Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review. Diabetologia. 22 July 2022. https://pubmed.ncbi.nlm.nih.gov/35867127/

For more on this topic, enrol on the following EASD e-Learning course:

See also Professors Stephanie Amiel and Rory McCrimmon’s contribution to our series ‘The long and the short of it’, ‘Cognitive function and hypoglycaemia’.

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

Falls and fractures are more common among people with diabetes, with osteoporosis likely the underlying cause. Bone health, therefore, was under discussion at the ‘complications compendium’ session at the recent American Diabetes Association (ADA) Scientific Session. Dr Susan Aldridge reports back.

The World Health Organisation defines osteoporosis as a ‘systematic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.’ Addressing the ADA session, Dr Rodrigo Valderrabano of Brigham and Women’s Hospital, who has an interest in bone metabolism, noted his appreciation of that emphasis on bone quality, because it’s important in the context of diabetes. He went on to note the high toll exacted by post-fracture morbidity and mortality. For 25% of people are institutionalised after a hip fracture, 40% are confined to a wheelchair, 60% have no recreation, while the mortality rate for women is 20% and up to 40% for men. 

Earlier research has shown that fractures can occur in those with normal bone density, which is particularly important for people with diabetes. Type 1 diabetes is 

associated with low bone density for a number of reasons – for instance, if children get it early in life, they don’t develop their peak bone density. In type 2 diabetes, however, bone density is actually elevated, as was seen in findings from Women’s Health Initiative. “This was so curious when we discovered this,” says Rodrigo. “It would be expected to reduce fracture risk, but there is a wealth of data showing that both type 1 and type 2 diabetes are associated with higher fracture risk at all sites.”

Underlying mechanisms

There are multiple hormonal interactions that could contribute to mechanisms of bone fragility in diabetes –  feeding back from the pancreas to maturation of osteoblasts and also from osteoblasts to the pancreas. Also, when there is longstanding hyperglycaemia, the person may develop end-stage glycation end products, which can attach to hydroxyapatite in bone and decrease bone turnover. Furthermore, there can also be a reciprocal relationship, with low levels of bone turnover biomarkers being associated with insulin resistance and incident diabetes.

“It’s also well known that diabetes is associated with an increased rate of falls, which may be modulated by microvascular complications, and this risk is extremely high in those treated with insulin,” Rodrigo adds. Unpublished data on 220,000 people in Taiwan shows that the number of fractures increases with age and the number of microvascular complications. “So, if you see someone in clinic with complications, even if their bone density is normal, you should still consider them at high risk for falls and fractures. Lower the bar for osteoporosis treatment.”

The Taiwan study also shows that fracture risk increases with HbA1c – 8 to 9% was associated with a 24% increased risk and 9 to 10% with a 41% increased risk of hip fractures. So, aim for an HbA1c below 8%, to reduce the risk of fracture.

Bone health should also be a consideration when selecting diabetes medications. Sulphonylureas and insulin increase the risk of falls and fractures, probably because they increase the risk of hypoglycaemia. Thiazolidinediones also increase the risk, maybe because they shift differentiation of mesenchymal stem cells towards adipogenesis and away from osteogenesis. Of the SGLT-2 inhibitors, dapagliflozin does not affect bone turnover markers or bone mineral density, but canagliflozin is associated with bone loss and an increased risk of hip fracture. “This is a drug you might not want to use in someone with fractures or known osteoporosis,” Rodrigo warns. 

Assessing bone health in diabetes

Rodrigo says it’s a good idea to go through the FRAX (fracture risk assessment tool) algorithm, which gives the 10-year probability of a fracture, at least occasionally with people who have diabetes and initiate osteoporosis treatment accordingly. 

“The effect of type 2 diabetes is actually similar to that of rheumatoid arthritis (RA) in FRAX,” he advises. “So one potential strategy would be to just click the RA button in FRAX and get a better estimation of the risk of someone with type 2 diabetes.”

Trabecular Bone Score (TBS) is a newer technology – it’s a software that gets laid onto the regular DEXA (bone density) scan to try to assess the bone quality. “As of last year, this was approved by insurance here, so we’ll see it pop up more and more,” Rodrigo says. To illustrate, he showed two spine scans with very similar bone densities but the bone quality, as revealed by TBS, was very different and you could see holes in the bone in the person with a low TBS. “People who have low TBS [tend to] fracture more, independently of bone density. This has been looked at in people with diabetes and it does a better job than bone density.” He advises using TBS with FRAX, to give a better idea of fracture risk. And, as it’s software, you can go back and apply it to existing bone scans.

“We should have a lower bar for osteoporosis testing,” Rodrigo concludes. “Ask your person with diabetes to stand up in front of you. If it takes them longer than just a few seconds, that’s someone who might be going to have trouble with falls and fractures. And why not consult your friendly neighbourhood ‘bonehead’ [bone health specialist]? There’s sure to be one lurking around your institution.”

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

Previous research has shown that both type 1 and type 2 diabetes are associated with increased morbidity and mortality from COVID-19 infection. However, we don’t know if this increased risk arises from diabetes itself or its associated comorbidities, such as obesity and heart disease – or whether both are important. A new analysis, reported in a recent issue of Diabetologia, from the French CORONADO study of people hospitalised for COVID-19, shows that diabetes is an independent risk factor for a worse prognosis. Dr Susan Aldridge reports.

Early on in the COVID-19 pandemic, diabetes was found to be associated with an increased risk of severe outcomes, including death. Several studies subsequently confirmed this, including a whole-population analysis from England, showing an increase of COVID-19 related mortality, and a greater risk of COVID-19- related death or intensive care unit admission in Scotland – both studies comparing people with and without diabetes. But it’s not known whether this increased risk relates to diabetes itself, or to its comorbidities – or maybe both.

While there have been studies looking at the impact of single comorbidities, none has looked at how the burden of multimorbidity might affect COVID-19 outcomes in diabetes. However, there has been a review of observational studies that suggests that those whom the authors define as having a ‘more severe course’ of diabetes, and therefore more comorbidities, have a poorer COVID-19 prognosis compared with those who have ‘a milder course’ of diabetes.

To address the need to clarify the relationship between diabetes, multimorbidity and COVID-19 outcomes, the CORONADO team in France has carried out a dedicated study.

The CORONADO study

The Coronavirus SARS-CoV-2 and Diabetes Outcomes (CORONADO) study is a French nationwide study, with both retrospective and prospective data collection, looking at the phenotypic characteristics and prognosis of people with diabetes admitted to hospital with COVID-19 between 10 March and 10 April 2020. As such, it was well set up for carrying out this new study, whose objective was to determine whether diabetes is a prognostic factor for COVID-19, independent of age and diabetes-associated comorbidities. The diabetes cohort was matched 1:1 for age, sex and date of admission to hospital with participants who did not have diabetes. The researchers then compiled a measure known as the Charleson comorbidity index (CCi) for each participant, from their medical records. The CCi is used to capture comorbidities associated with mortality risk and, for the purposes of the study analysis, two versions were used – with diabetes either included or excluded as a comorbidity. The primary composite outcome set for the study was invasive mechanical ventilation (IMV) and/or death within 7 days or 28 days.

Diabetes and COVID-19 outcomes

There were 2210 people with diabetes matched with 2210 people without the condition in this study. Most had type 2 diabetes and, compared with the matched individuals, they were more likely to have obesity, hypertension, dyslipidaemia and/or cardiovascular disease, as you’d expect, and so their CCi, with and without diabetes included, was higher. And, on admission, the individuals with diabetes had higher blood glucose levels and lower estimated glomerular filtration rates (eGFRs).

Invasive mechanical ventilation and/or death within seven days occurred in 29.0% of the diabetes group compared with 21.6% of those without diabetes, and in 34.8% and 28.4%, respectively, within 28 days. Each individual outcome – IMV and death – occurred more frequently in those with diabetes.

A statistical analysis of the data showed that diabetes is independently associated with worse COVID-19 prognosis irrespective of comorbidity burden in a population hospitalised for the infection in France during the first wave of the pandemic. These findings add to other research showing that diabetes confers susceptibility to infectious disease, particularly influenza and pneumonia. Such susceptibility was also reported during the 2009 H1N1 influenza pandemic and in the more recent MERS-CoV outbreak.

Explaining the impact of diabetes on morbidity and mortality from COVID-19 is beyond the scope of this paper, but is urgently in need of further investigation. It’s been suggested that hyperglycaemia might play a role. The nationwide survey report from Scotland did find an association between HbA1c and COVID-19 severity, but the authors didn’t find that in the current study. And the study of the UK population found an increased risk of COVID-19 death in people with diabetes irrespective of their HbA1c level. However, the current study did notice a link between higher plasma glucose at admission and COVID-19 severity. The higher glucose could merely be a result of infection, or it may interfere with the immune response, worsening the outcome.

The authors note that their study was carried out during the first wave of the pandemic. Prevention and treatment of COVID-19 have improved since then. Further studies are needed to see if this has also improved outcomes, specifically for those with diabetes. Also, the population studied was severely ill, so we don’t know if the worse outcomes for those with diabetes would also be observed in the general population.

Unfortunately, as we know, COVID-19 has not gone away. As healthcare systems gear up to deal with further waves of infection during the autumn and winter months, these findings should be used to plan and target specific interventions to reduce COVID-19 morbidity and mortality among those with diabetes.

To read this paper, go to: Cariou B, Wargny M, Boureau A-S, Smati S, Tramunt B, Desailloud R, Lebeault M, Amadou C, Ancelle D, Belkau B, Bordier L, Borot S, Bourgeon M, Bourron O, Cosson E, Eisinger M, Gonfroy-Leymarie C, Julia J-B, Marchand L, Meyer L, Seret-Begeue D, Simon D, Sultan A, Thivolet C, Vambergue A, Vatier C, Winiszewski P, Saulner P-J, Bauduceau B, Gourdy P, Hadjadj S and on behalf of the CORONADO investigators. Impact of diabetes on COVID-19 prognosis beyond comorbidity burden: the CORONADO initiative. Diabetologia online 15 June 2022. https://doi.org/10.1007/s00125-022-05734-1

For more on the CORONADO initiative, watch Professor Samy Jadjadj’s contribution to our series Diabetes and COVID-19, Answering questions of risk.

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