A new paper in Diabetologia describes how a unique dataset of HbA1c measurements drawn from the UK Biobank reveals the extent of undiagnosed diabetes. The findings suggest that population-wide screening could lead to earlier clinical diagnosis, earlier intervention and, perhaps, fewer long-term complications. Dr Susan Aldridge reports.

Screening can detect undiagnosed diabetes earlier than either symptomatic or incidental diagnosis. This allows for earlier intervention – lifestyle change, medication or both – which may reduce the risk of later complications.

There are already diabetes screening programmes in many countries, which differ according to their eligibility criteria and population coverage. In England, there is the NHS Health Check, which was initiated in 2009 and provides screening for high-risk adults aged 40-74, while the American Diabetes Association (ADA) recommends that all US adults aged 35 or older be screened.

Studies on these programmes are important as they can tell us how many cases of undiagnosed diabetes are identified by screening. However, since there is a direct link between screening and diagnosis in these studies, they don’t measure how much earlier diagnosis by screening occurs compared with diagnosis in routine clinical care. This would reveal the reduction in the time people are living with undiagnosed diabetes that could be achieved by screening and help policymakers decide whether it is worth the investment.

The UK Biobank is a population-based cohort of over 500,000 UK residents aged 40-70 at enrolment (between 2006 and 2010). HbA1c is measured on enrolment, but the results are not fed back to participants or their clinicians. These measurements therefore represent a rich resource that uncouples screening from diagnosis because the Biobank is also linked to participants’ routine healthcare data up to 10 years post-enrolment. This allows assessment of the prospective time to diabetes diagnosis in routine care following an elevated (≥48 mmol/mol) HbA1c at enrolment among those who did not have a pre-existing diabetes diagnosis.

Dr Nicholas Thomas, Dr John Dennis and colleagues from the Exeter Centre of Excellence in Diabetes (EXCEED), UK, have used this UK Biobank data to estimate the reduction in time to diagnosis that could be achieved by implementing population-level HbA1c screening compared with routine care. They also looked at the participant characteristics associated with longer time to diagnosis.

Mining the UK Biobank

The study started with a cohort of 179,923 participants from the UK Biobank who had both an enrolment HbA1c measurement and available longitudinal primary care data up to 2016/2017. Of these, 13,077 proved to have a pre-existing diabetes diagnosis, leaving a study population of 166,846 participants.

Undiagnosed diabetes was defined as having an HbA1c measurement of ≥48 mmol/mol at enrolment. Time to diabetes diagnosis in routine care was calculated as the time between the HbA1c measurement and the date of a code for diabetes, prescription for glucose-lowering medication, HbA1c of ≥48 mmol/mol, fasting glucose of ≥7.0 mmol/l or random/two-hour postprandial glucose of ≥11.1 mmol/l in primary care medical records or records of a code for diabetes in secondary care medical records.

In total, 1% – 1703 – of the study group had undiagnosed diabetes, which is an extra 13% of diabetes cases relative to the 13,077 who had a pre-existing diagnosis. This gives us a rough idea of the possible extent of undiagnosed diabetes among the UK population. Compared with those in the study population with HbA1c <48 mmol/mol, those with undiagnosed diabetes were, on average, older, had a higher BMI, were more likely to be male, live in more deprived areas and self-report being of non-White ethnicity. They were similar in most respects to those with a pre-existing diagnosis, but were more likely to self-report being of non-White ethnicity (median 11.4% vs 9.8%) and had a slightly higher BMI (median 30.9 vs 30.1 kg/m2).

Time to diagnosis

So how did these participants with undiagnosed diabetes fare over the next few years? Most of them – 87.7% – did receive a clinical diagnosis of diabetes during the median of 7.3 years follow-up. During this time, HbA1c tended to increase – the median value for those who had it measured at diagnosis in primary care was 58.2 mmol/mol.

However, this increase wasn’t inevitable – 6.9% of the participants who had undiagnosed diabetes at enrolment in the Biobank subsequently had HbA1c below 48 mmol/mol recorded in primary care, but half of this group subsequently received a diabetes diagnosis.

Median time to diagnosis varied slightly with the year the participants had enrolled in the Biobank – for 2008, it was 2.3 years; for 2009, 2.2 years; for 2010, it was significantly shorter at 1.8 years. The EXCEED team quote 2.2 years as median delay time to diagnosis based on this study population. Having a higher BMI and higher enrolment HbA1c were both associated with a shorter time to diagnosis, but there was no clear evidence of an association between age, ethnicity or socioeconomic status and time to diabetes diagnosis.

The value of HbA1c screening

This is the first study to use real-world clinical data to show how much earlier a diabetes diagnosis might be made by implementing a population-based screening programme. It shows that HbA1c screening at UK Biobank enrolment could have identified these cases of undiagnosed diabetes a median of 2.2 years earlier before receiving a clinical diagnosis in routine care.

This finding is similar to that of the Ely study of 40-65 year olds, which compared outcomes for participants randomised to screening at five-yearly intervals with outcomes for those receiving no screening. The reduction in time to diagnosis was 3.3 years.

Meanwhile, the prevalence of undiagnosed diabetes of 1% found in this study population is similar to the 1.4% estimate derived by modelling done by Diabetes UK, confirmed by a 2003-2005 UK National Screening Committee (NSC) pilot, which also showed a prevalence of 1.4%. The prevalence of undiagnosed diabetes in older populations has been found to be higher, with the NSC study showing a prevalence of 2.8% in those over 40 and, in the Ely study, 4.5%.

The finding that male sex, higher HbA1c and BMI >30 kg/m2 are associated with shorter time to diagnosis suggests that clinicians are more likely to screen men and those with obesity. The relative delay in diagnosis for women is interesting as it does not arise from differences in age, BMI, HbA1c deprivation or ethnicity. This association between sex and delayed diagnosis has not been observed in other studies, so maybe this is peculiar to UK primary care or to the UK Biobank cohort. The link with higher HbA1c and earlier diagnosis is easily explained by those with higher blood glucose being more likely to have diabetes symptoms earlier, prompting earlier diagnosis.

A key strength of this study was that the systematic baseline HbA1c assessment of UK Biobank participants was not fed back to either them or their clinicians, providing the EXCEED team with a unique dataset to evaluate the benefits of HbA1c screening on time to diagnosis compared with diagnosis in routine care. In this study, 87.7% of those with undiagnosed diabetes eventually received a clinical diagnosis of the condition, while only 6.9% reverted to an HbA1c below the diagnostic threshold.

A limitation is that the UK Biobank is not a representative UK cohort – previous studies show that participants have better health outcomes, are from less deprived areas and are more likely to be of White ethnicity than the general UK population. Given the known association between non-White ethnicity and higher social deprivation and increased risk of diabetes, the rate of undiagnosed diabetes is likely to be higher in the wider UK population than in the UK Biobank cohort.

In addition, those volunteering for the Biobank are likely to be more health conscious than average, as are volunteers in other research studies. This means they may have more healthcare appointments and are likely to be diagnosed sooner. This suggests that population-based screening initiatives could identify even more cases of undiagnosed diabetes and reduce time to diagnosis more than the 2.2 years seen in this study.

Finally, most of the cohort had not accumulated sufficient follow-up data to reliably evaluate the impact of delayed diagnosis upon diabetes complications. The UK Prospective Diabetes Study (UKPDS) showed that earlier intensive blood-glucose control reduces the risk of later complications. We would therefore expect earlier diagnosis to lead to fewer complications in the long term. However, thus far, trials of screening interventions have not shown a significant reduction in all-cause mortality. This is worthy of further exploration when more recent UK Biobank-linked primary care data become available.

To read this paper, go to: Young K, McGovern A, Barroso I, Hattersley A, Jones A, Shields B, Thomas N, Dennis J. The impact of population-level HbA1c screening on reducing diabetes diagnostic delay in middle-aged adults: a UK Biobank analysis. Diabetologia online 22 November 2022. https://doi.org/10.1007/s00125-022-05824-0

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

There are exciting developments in diabetes technology happening right now, which can help lighten the daily burden of managing the condition. The challenge of making the latest diabetes devices and monitoring more accessible was discussed at ‘Revolutionising Diabetes Care: Celebrating 100 Years of Insulin Therapy’, a recent online conference organised by the Royal College of Physicians and Surgeons of Glasgow. Dr Susan Aldridge reports.

People living with type 1 diabetes are faced with a large number of decisions to make and tasks to do on any given day. “In the words of Professor Simon Heller, ‘type 1 diabetes is the most challenging long-term condition to self-manage,’ and I couldn’t agree more,” said Dr Emma Wilmot, founder of the Diabetes Technology Network UK (DTN-UK). She went on to review the current and future impact of the three types of technology available today to help in the self-management of type 1 diabetes: continuous glucose monitoring, connected pens and closed loop.

Glucose monitoring

In the 100 years since the discovery of insulin, glucose monitoring has transitioned from urine dipstick testing to fingerprick blood testing in the 1970s, which was then the standard of care for many decades. Then, in 2014, the introduction of flash glucose monitoring meant that continuous glucose monitoring (CGM) became affordable and that has led to substantial change.

“If you don’t live with type 1 diabetes, it can be hard to appreciate the difference that CGM can make to your quality of life,” said Dr Wilmot. “Let’s say I want you to drive to Park St in Leeds. I’ll let you have a car and a satnav. No problem? But you can only view your satnav four times during this journey. If that makes you feel a little uncomfortable, that’s great because that’s what we’ve been asking people with type 1 diabetes to do for decades. So what you really want to do is to have unlimited views of your satnav throughout your journey – check where you are, what direction you’re going in and reflect on your journey so far. That’s what continuous access to glucose data allows people with type 1 diabetes to do.”

Clinicians are starting to understand the benefits of CGM for people living with type 1 diabetes – recent research has shown reductions in HbA1c after starting flash monitoring, as well as a decrease in hospital admissions for diabetic ketoacidosis (DKA) and hypoglycaemia, ambulance callouts and severe hypos. “Many international datasets have started to replicate these findings, so as a consequence we’re seeing an increase in access to flash and real-time CGM,” said Dr Wilmot.

However, a key criticism has been that the data from randomised clinical trials came from adults whose glucose was already well-controlled, so there was a call from the National Institute for Health and Care Excellence (NICE) for trials in those with more unstable glucose levels. This led to the Diabetes UK-funded Flash UK randomised controlled trial, which illustrated a 0.5% improvement in HbA1c in the intervention group and an increase in the numbers reaching their target glucose.

The findings led to new NICE guidance in 2022 to offer flash or real-time CGM to adults with type 1 diabetes, depending on their preferences, needs, characteristics and functionality of available devices. “What’s also great is that the ADA/EASD consensus on the management of type 1 diabetes recommends CGM as the standard of care,” said Dr Wilmot. “So there have been huge advances. The challenge now is in delivering CGM.”

In type 2 diabetes, the evidence for CGM is not quite as convincing, so NICE recommends it only in certain circumstances, namely when someone has severe or recurrent hypos, impaired awareness of hypoglycaemia, a disability impairing their ability to self-monitor or needs to do eight or more tests a day.

In the future, a key challenge for clinicians will be choosing a glucose monitoring device. A recent review showed a wide range of new devices coming onto the market – 28 non-invasive optical devices, six non-invasive fluid sampling devices and 31 minimally invasive glucose monitoring devices. Several ‘bloodless’ products are now commercially available. “We, as clinicians, will need to understand what level of evidence is available before we can feel confident offering a device to people with diabetes, as having regulatory approval doesn’t necessarily mean evidence from randomised clinical trials will be replicated in the real world,” Dr Wilmot warned. 

Connected pens

The mainstay of insulin therapy is still multiple daily injections. “Even with better glucose monitoring, we’re often left guessing what insulin doses have been given and when,” said Dr Wilmot. While she advises people to record their doses, either in notes or on an app, she acknowledges that this adds to the self-management burden. “In 2023, surely there are better ways of doing this? That’s exactly what connected pens can offer. In the 1980s, the move from insulin vials to pens was a huge leap forward. The next revolution is here, in terms of more pens giving connected data.”

There are many products in development with all the big insulin companies getting involved. Some healthcare professionals may already have experience of the NovoPen 6, which automatically records insulin doses given. Data from Sweden show that connected pens are associated with fewer missed boluses and more time in range.

The technology also has to make sense to the person living with diabetes for wider take-up. Integration with glucose data will be key, as will decision support with bolus calculation, and recording last dose and insulin on board. This will give more useful and meaningful data reports and, of course, bolus reminders will also be useful going forward.

A consultation with someone using a pen is not as meaningful and data-driven as it would be if they were using a pump. “For me, connected pens are that opportunity to bridge the gap between pen and pump with data reports,” said Dr Wilmot. “You have insulin, carbs and glucose data all in one place.” 

Closed loop

Before closed-loop systems became commercially available, a lot of tech-savvy people with diabetes built their own systems. While these worked well, healthcare professionals often felt uneasy about DIY closed loop because of the medico-legal implications. However, the US Food and Drug Administration (FDA) has now authorised Tidepool, which is an automated insulin dosing loop built from a DIY system, so there has been rapid progress.

There are now three different closed-loop algorithms commercially available (Medtronic 780G, Tandem Control IQ, CamAPS FX), which are licensed for paediatric use onwards. “For me, the key take-home message is that, across a range of trials, they deliver impressive time in range – generally over 70% – with typically half the amount of hypoglycaemia that you’d see with a pump or multiple daily injections,” said Dr Wilmot. “So I think closed loop is the future – people describe them to me in clinic as being life changing. The future is now and it’s about how we deliver this life-changing technology.”

Dr Wilmot and colleagues have been part of the NHS England closed loop pilot study for people on a pump and flash monitor and having HbA1c above 69 mmol/mol. In her own centre, 63 participants started on closed loop between August and September 2021. She gave an example of a young man who was really struggling and was missing a lot of boluses. In just two weeks on closed loop, his time in range increased from 12% to 51% and his glucose management indicator dropped from 91 to 67 mmol/mol. “This may not be as good as results from the randomised controlled trials, but was certainly enough of an improvement to keep this young man freer of complications than he would have been previously,” said Dr Wilmot.

The data from the NHS England pilot has been analysed by the Association of British Clinical Diabetologists (ABCD), submitted to NICE and submitted for publication. “To give you a flavour of the findings, there are the results from the Midlands – Derby, Nottingham, Leicester – where, across our centres, we’re seeing a 16.7 mmol/mol reduction in HbA1c,” said Dr Wilmot. “I cannot think of another intervention that delivers such a staggering improvement in glycaemic control.”

Data like this is opening the doors to wider access. Closed loop is now to be recommended to over 100,000 people with type 1 diabetes as NICE has published draft recommendations covering those with HbA1c of 64 mmol/mol or above using at least one of either pump, flash monitor or real-time CGM, plus those who are pregnant or planning to get pregnant. “This is absolutely huge,” said Dr Wilmot. “The key focus is going to be delivering this technology to people with diabetes over the decades to come.”

She went on to look at where closed loop systems are going in the future. At the moment, systems are linked, but people will want more flexibility in choosing their sensors and pumps and getting them to talk to one another. In 2019, the FDA authorised the first interoperable automated insulin delivery controller and it’s hoped that many devices will go down that route.

Dr Wilmot would also like to see continual evolution of the shape, size, battery life and physical interactions with closed loop systems. Also on the wishlist is infusion sets improved for convenience and longevity and, of course, key to all this is affordability and reimbursement.

With current closed loop systems, there is still a need to count carbs and have it work out the insulin dose, but there is a lot of work going on internationally to go to fully automated systems. Other developments we may see in the future include algorithms adapted to ultra-rapid insulin, alternative routes of insulin delivery, such as intraperitoneal and multi-hormone closed loops. There could also be additional inputs to closed loop systems such as motion sensing and sensing when the user is having a meal, and sensors that look for additional signals such as ketones, active insulin and lactate.

“I think to realise the potential of diabetes technology, we have to overcome some key barriers,” said Dr Wilmot. “For instance, do we have the workforce to deliver closed loop at scale? We also have significant variation across diabetes services in the uptake of insulin pumps and, if we’re to make closed loop more widely available, this drastically needs to change.” 

And, of course, to deliver any of these technologies at scale, healthcare professionals must feel confident in using them. That is one of the key aims of the Diabetes Technology Network UK, which has produced a number of best practice guides (abcd.care/dtn). The Network will continue to make sure the guidance is there to support healthcare professionals who want to increase their confidence in this area.

“My take-home message for you is that for people living with diabetes, basic care has changed dramatically,” Dr Wilmot concluded. “It should now be CGM plus connected pen. We should then be moving forward and, although we typically think insulin pump at the moment, forget that, for we should be thinking closed loop. That’s what’s coming and I’m very excited about it.”

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

As Muslims around the world embark on a month of Ramadan fasting, for the latest episode in our series ‘The long and the short of it’, Professor Wasim Hanif and Dr Sarah Ali deliver a timely reminder of the importance of pre-Ramadan assessments for people with diabetes – and highlight recent developments that mean it may be time to reassess our approach to risk stratification.

Fasting during the month of Ramadan is one of the Five Pillars of Islam – the obligations Muslims must satisfy in order to live a good and responsible life. For those with diabetes, however, Ramadan fasting poses certain serious risks, including hyper- and hypoglycaemia, diabetic ketoacidosis (DKA), hyperosmolar hyperglycaemic state (HHS) and dehydration.

Nevertheless, despite the fact that the Qu’ran specifically exempts people with serious medical conditions such as diabetes, many people with diabetes still prefer to fast. Says Dr Sara Ali: “It’s important to remember that people who live with diabetes quite often do not perceive themselves as being ill or unwell. Indeed, that’s something we encourage as diabetes healthcare professionals. We encourage people to live a full life whilst having diabetes. So that means that when they come to the month of Ramadan, they want to be like other people, people who don’t have diabetes. They want to be able to fast.”

Steps healthcare professionals need to take to support their patients with diabetes who wish to fast during Ramadan – whether by empowering them to do so safely or, where appropriate, advising them against it – are briefly covered here, though the presenters recommend exploring this in more detail via the EASD’s eight e-Learning modules on the topic (several of which are presented by Professor Hanif himself).

What makes this film so compelling, though, is its reflection on recent developments that promise to have a profound effect on our approach to assessing the risks relating to Ramadan fasting for people with diabetes. Chief among these is the impact of new technologies, testing technologies in particular. Continuous glucose monitoring (CGM) has made it safer for people with diabetes to fast, particularly those with type 1 or insulin-treated type 2, who previously might have been advised not to fast. Says Dr Ali: “This is a really exciting time for people. Anecdotally, we all know, we’ve had people with type 1 diabetes who’ve wanted to fast and this is actually now giving them the opportunity to do so, safely.”

Professor Hanif agrees: “It used to be a battle telling people with type 1 diabetes not to fast, or just to fast for one day. But now with the closed loop systems, I am feeling more confident. There’s a lot of data coming from across the globe, small studies and small subsets of patients, but giving a kind of indication that people with type 1 diabetes on closed loop systems who monitor themselves closely, can fast safely. And I think that is a big shift because a lot of people with type 1 diabetes would like to fast for religious reasons, social or cultural reasons, and I think that is going to be quite fascinating.”

There is also the question of Ramadan’s timing, which changes every year according to the lunar calendar. In the northern hemisphere the fasts are getting shorter and there will come a time when Ramadan falls in winter months, putting it at odds with guidelines that were written at the time of summer when the fasts were very much longer.” Says Professor Hanif: “Somebody with type 1 diabetes cannot go without food for 18–20 hours. But now that’s changing, it’s time to really look at these risk scores and see how we could allow more people to fast.”

Might that include women with diabetes who are pregnant? “There still isn’t enough data on pregnancy and fasting,” says Dr Ali. “Pregnancy itself is an exemption to fasting. But of course, we do see people who wish to fast when they are pregnant. And if you’ve got diabetes, I think our recommendations will still be that you should not fast. Things may change with the advent of the technology and we’re giving technology a lot more to women with pregnancy and diabetes. But I think that we would still say that women with pre-existing diabetes who are pregnant should not fast. One thing that might be more interesting in the future is gestational diabetes. There are some studies coming from the Middle East… I still don’t think we’re in a place to say that women with or without diabetes should fast, but that might come in the future.”

See the full-length version of Professor Hanif and Dr Ali’s discussion on Horizons this week or watch the short version.

For more on this topic, enrol on the EASD e-Learning course Diabetes and Ramadan.

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

Translated transcripts available

To coincide with the start of Ramadan, EASD e-Learning is now offering learners the option to download transcripts of some of its most popular modules translated into Arabic. This is part of an ongoing project to make our content available in languages other than English.

Courses for which transcripts translated into Arabic are now available include the following:

Translated transcripts are also available in Chinese (Mandarin) for the following courses:

For other translated content coming onto the site over the coming months, watch out for the globe icon on the site.

Diabetes in Europe has become a rapidly accelerating public health crisis. That is why the EASD and other major stakeholders have come together to form the European Diabetes Forum, which aims to translate research and best practice into policy that will achieve better diabetes care for people in Europe. A recent article in Diabetologia introduces the Forum and its strategic plans on integrated care, data and registries, and digital diabetes and self-management. Dr Susan Aldridge reports.

Professor Chantal Mathieu, President of EASD, and her colleagues introduce the European Diabetes Forum (EUDF) by explaining why the initiative is so necessary at this time. They describe diabetes in Europe as “an emergency hiding in plain sight”. One person in 11 (61 million people) lives with diabetes in Europe today. That is more than the population of Italy. Worse still, there is no sign of this public health crisis slowing down, for diabetes prevalence in the European region is set to grow by a further 13% by 2045, according to the latest data from the International Diabetes Federation (IDF).

In a statement that will strike a chord with all those who live with diabetes, the authors go on to say: “Diabetes remains one of the most undertreated and underestimated of all common medical conditions. Society has no real sense of what living with diabetes means: the sheer scale of the health indicators one must constantly track and trace; the omnipresent threat of complications; the fear and anxiety about the future.”

People with diabetes suffered disproportionately during the COVID-19 pandemic, being more likely to be hospitalised or die from the infection, as well as missing out on their regular health checks during lockdown. Diabetes also has a severe impact on healthcare economies, with an annual expenditure of around €170 billion. Indirect costs include decreased productivity, sick leave, disability, early retirement and premature death.

Meanwhile, type 2 diabetes is increasingly affecting people at a younger age, and young-onset diabetes is more aggressive. Furthermore, IDF data shows that the Europe region has the highest number of children and adolescents with type 1 diabetes, with a total of 295,000. 

Faced with this enormous challenge, the scientific and medical communities, and people with diabetes themselves, have of course approached policy makers. But they do so from different angles, which tends to dilute the overall message, leading to policy inertia rather than the urgent action that is needed, according to the authors.

The European Diabetes Forum

The EUDF emerged after several years of preparation and research by Dr John Nolan of EASD and was founded in 2019 as a non-profit organisation under Belgian law by the following organisations: EASD, EFSD (European Foundation for the Study of Diabetes), FEND (Federation of European Nurses in Diabetes) and JDRF (Juvenile Diabetes Research Foundation). After the launch, PDCE (Primary Care Diabetes Europe), SFD (Société Francophone du Diabète) IDF Europe and ISPAD (International Society for Pediatric and Adolescent Diabetes) joined as members. EUDF also has a number of pharmaceutical and medical technology companies as supporting collaborators.

The EUDF is a platform for bringing together stakeholders from across the European diabetes landscape to present a harmonised voice on the diabetes community’s needs to governments, regulators, payers and others. During the pandemic, non-communicable diseases like diabetes got less political attention. So EUDF action may be even more critical during the post-pandemic era to help push diabetes care back up the agenda. 

The mission of EUDF is “to ensure the translation of research and clinical evidence into policy actions towards better diabetes care at a national level.” As well as working at the European level, the EUDF also supports translation of its efforts to national and regional initiatives. At present, a number of national/regional forums are at various stages of development – successful examples are the Belgian and Romanian Forums at www.belgiandiabetesforum.be and www.forumdiabet.ro

So far, the EUDF has identified three main areas of policy focus: integrated care, data and registries and digitalisation and empowerment of self-care. To ensure delivery in these, three Strategic Forums were created during 2021 to generate policy recommendations. After appointing a chair and around 15 expert members, each Forum defined its work plan and key deliverables. All members and chairs are working as volunteers.

All recommendations from the three Forums can be found at https://www.eudf.org/our-work/recommendations

Integrated care

“Integrated care represents efficiency and value for money, and it needs to be at the foundation of diabetes healthcare in every setting and country in Europe.” (EUDF)

A number of models and pilot schemes around Europe show that integrated care plays an important role in the quality, efficacy and efficiency of diabetes management. However, there are still many gaps in the level of integration across care systems. In part, this reflects differences in infrastructure and resources across Europe. The failure to fully integrate care results in inefficiency and suboptimal clinical performance. This, in turn, drives up care costs and increases the health burden on people living with diabetes. 

The EUDF considers that diabetes care should be redesigned to better meet the needs of those living with the condition. The use of technology, addressing inequalities in diabetes care and addressing psychosocial concerns should be considered during such redesign. Healthcare professionals should focus more on supporting integrated care models and pathways, rather than just following routine. And, at the system level, this approach should be supported by constructing transferable principles that can be applied across divergent healthcare systems. 

With all the above in mind, the EUDF proposes strategies to improve integration in all diabetes care settings. These include implementing assessment models and developing patient-centred pathways for diabetes care. Also, educational curricula need to be revised and incentives put in place to encourage cooperation and teamwork within and between primary and secondary care settings.

Data and registries

“It takes more than a registry to improve care, we need to use data to raise awareness and initiate action to improve outcomes for people with diabetes.” (EUDF)

The EUDF is well aware that the diabetes community in Europe has launched several programmes over the last decades, including the St Vincent Declaration, with the vision of improving outcomes. These projects, although ambitious, generally resulted in only incremental improvements. One reason was that, in most countries, the outcomes of diabetes care could not be monitored accurately because of the absence of quality registries. In Europe today, most diabetes data are estimated, rather than robust, with a few exceptions. Registries, where they exist, are a source of valuable scientific data but are not applied as often as they perhaps could be to significantly improve diabetes care.

The Forum sets out what is needed to create a meaningful, working diabetes registry. First, decision-makers must accept that changes are needed. Second, a dedicated team should be given the authority to develop a registry at local or regional level and manage it, with the mandate to improve agreed standards of care. Finally, following successful regional efforts, a broader European registry should be rolled out.

Diabetes registries will help enable a more evidence-based and data-driven approach to diabetes management. For instance, they will contribute to quality control and better adherence to guidelines and track performance across clinics and regions, helping to identify reasons for variation in outcomes. All of this can help reduce costly complications. An example of a registry that works well is the global paediatric SWEET registry (www.sweet-project.org).

Policy makers, health authorities, healthcare professionals, industry and people with diabetes should work together to create registries throughout Europe, where they do not already exist, and expand and strengthen those that do. The EUDF has already set out recommendations on the governance of registries, on procedural aspects like data input and the indicators that should be included and implementation strategies. 

Digitalisation and empowerment of self-care

“Creating an environment where successful digital solutions can be easily shared throughout Europe to support their people with diabetes.” (EUDF)

At the moment, there are two distinct trends around the use of digital tools in diabetes care. On the one hand, physicians sometimes seem reluctant to introduce or use these tools. On the other hand, there is a rapid increase in the development of intuitive digital tools to meet the needs of people living with diabetes.

There is evidence that digital support via an app or online improves the empowerment of people with diabetes, leading to better self-management and decision-making. And improving self-management is the key to achieving a high level of compliance with therapy, which should lead to better health outcomes, with reduced risk of complications and a better quality of life. Here, digital tools, including apps, can serve as the patient-facing interface for digitally enabled care. They enable better day-to-day support, greater flexibility and connectedness, which can enable remote monitoring and more data-driven decision-making.

Many EU countries are starting to devise policy to support health and diabetes apps. The EUDF suggests creating an environment where digital solutions that prove successful for people with diabetes in one country can be shared easily with other countries, stakeholders and organisations to broaden their reach within Europe. The Forum wants to accelerate this process with recommendations on how to develop a user-centred app, implementing a best-access pathway for apps and supporting the integration and uptake of high-quality apps into the healthcare system.

The path forward for the EUDF

The EUDF has been working with the WHO and WHO Europe to align messages and discuss priorities and is accredited as a ‘non-state actor’ for WHO Europe. The EUDF has welcomed the WHO’s Global Diabetes Compact and wants to work further to refine its coverage targets to European standards.

Meanwhile, there are currently several opportunities in the European policy environment to advance this work. The European Commission has launched ‘Healthier Together – EU non-communicable diseases initiative’, which is a comprehensive roadmap to guide and support member states in addressing the challenge of highly prevalent non-communicable diseases, including diabetes. The EUDF and its members have given their input on the priorities of this initiative and provided examples of best practices. They are now working at member state level to implement these examples. Countries and stakeholders can apply for support for policy projects and interventions, via EU funding, mainly from EU4Health.

In addition, a Joint Action on cardiovascular disease and diabetes, funded under the 2022 EU4Health Work Programme has been launched. Member states can submit proposals to the European Commission for the development and implementation of the Programme. The EUDF will continue to engage with these opportunities and encourage country experts and its own partners to contribute.

In conclusion, although diabetes is one of the greatest health challenges that Europe faces today, we can address it by using the tools available and taking the necessary policy actions. All of Europe’s major diabetes stakeholders have now come together in the EUDF to generate ideas and recommendations. Driving forward solutions in integrated care, registries and digitalisation and self-care will promote a more person-centric and data-driven approach to diabetes management, which should result in fewer complications, improved quality of life and more efficient use of clinical resources.

The EUDF will continue to act as an expert partner to promote these efforts. The authors end by saying: “Our vision is to achieve better outcomes for people with diabetes and enable healthcare systems to cope with a devastating epidemic that can no longer be swept aside. The time to act is now.”

To read this article, go to: Mathieu C, Soderberg J, Del Prato S, Felton A-M, Cos X, de Beaufort C, Gautier J-F, Hauck B, Forbes A, Heine R, Schwarz P and Tobeyns B on behalf of the European Diabetes Forum. The European Diabetes Forum: a forum for turning the tide on diabetes in Europe. Diabetologia 17. November 2022. https://doi.org/10.1007/s00125-022-05831-1

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

Over the one hundred years since its first use, insulin has undoubtedly saved many lives, yet it still does not fully meet the needs of people living with diabetes. However, there is cause for optimism, according to Melanie Davies CBE, Professor of Diabetes Medicine at the University of Leicester. She discussed improvements in insulin formulation and delivery – past, present and future – at ‘Revolutionising Diabetes Care: Celebrating 100 Years of Insulin Therapy’, a recent online conference organised by the Royal College of Physicians and Surgeons of Glasgow. Dr Susan Aldridge reports.

The original insulin was extracted from the pancreases of cows and pigs. When demand from people with diabetes looked as if it would exceed supply from animal sources, the semi-synthetic insulins were developed and entered general use from the 1970s – several with improved properties are now available. “However, there is still a significant unmet need for insulin,” said Professor Davies. Currently, up to 40% of people with diabetes worldwide – 150 to 200 million people – need it.

Fear of injection may be why there are often delays in initiation of insulin therapy, particularly among people with type 2 diabetes who could benefit. 

“Injections are still undoubtedly a major burden to insulin therapy,” said Professor Davies. Research shows that up to one third of people are not adherent to insulin, 93% would prefer to control their glucose without needing to inject and 59% of physicians identified multiple injections as a difficulty in diabetes care.

Meanwhile, people with type 1 diabetes have between one and three severe hypos per year, and those with type 2 diabetes have around one such event. Severe hypoglycaemia causes many emergency visits every year and has a serious impact on both health and quality of life. 

Innovation in insulins

Modern insulins do go some way to addressing these unmet needs. For instance, longer acting insulins mean fewer injections. They can be injected just once a day and now weekly insulin analogues are in development. “A once-weekly insulin could redefine diabetes management by reducing injections from 365 to 52 a year,” said Professor Davies. And research so far on weekly insulins shows that they can achieve comparable glucose lowering and safety to daily insulins. For instance, the ONWARD series of trials is studying insulin icodec, a weekly insulin. ONWARD2 looked at switching people with type 2 diabetes from insulin degludec to insulin icodec and showed a slight benefit in HbA1c and more participants reaching their 7% (53 mmol/mol) target with icodec, as well as more satisfaction with treatment.

The ideal insulin would be exactly like endogenous insulin and there have been many attempts to create a synthetic insulin that would mimic natural physiology and, in particular, to make it more hepatoselective. Natural insulin is distributed more to the liver than the periphery, whereas with synthetic insulins, distribution tends to be 50:50.

Basal insulin peglispro (BIL) is a more hepatoselective insulin. In the IMAGINE trial, which reported in 2015, BIL was compared with insulin glargine in a 78-week study involving people with type 1 and type 2 diabetes. “The results were really very impressive,” Professor Davies said. Mean HbA1c was 7.06% (54 mmol/mol) on BIL and 7.43% (58 mmol/mol) on insulin glargine. “You don’t often see such an improvement in HbA1c with analogue insulins and a reduction of 0.4% is clinically meaningful,” she continued.

BIL also had the advantage of reducing body weight by around 2 kg on average – another drawback of insulin being weight gain – and it reduced the rate of nocturnal hypos, although it did increase the rate of hypos overall. However, development of BIL had to be discontinued because of lipohypertrophy at the injection site and increases in liver enzymes and liver fat. However, efforts to develop a more hepatoselective insulin continue. 

Focus on insulin delivery

On insulin delivery, “this is where some of the exciting data exists and may be paradigm shifting,” said Professor Davies. For instance, so-called smart insulins are glucose responsive, which can already be achieved to a certain extent with continuous glucose monitoring and responsive pumps.

There are also innovations in insulins formulated in a glucose-sensitive polymer matrix that are in animal or early-stage clinical trials and may be introduced into diabetes care over the next few years. And the technical revolution in terms of apps and connected insulin pens has allowed progress such that 80% time in range is now achievable with hybrid closed loop systems.

Of course, oral insulin is perhaps the ultimate goal when it comes to insulin delivery. Discussions around oral insulin started back in the 1920s and it has always been pursued with enthusiasm. The various barriers in the gastrointestinal tract that prevent the delivery of peptide have been studied in detail and there has been some success with the delivery of oral peptides, such as GLP-1.

There has been development of pulmonary and nasal insulins on the way to an oral version, but these have not been particularly successful. Exubera, an inhaled insulin, was withdrawn from the US market in 2007 for commercial reasons and Afrezza, another inhaled insulin, is beset by practical issues. And then there is Oramed, a nanoparticle-based oral insulin, which got as far as a phase-3 clinical trial in type 2 diabetes. Unfortunately, results reported in January this year showed that Oramed is no better than placebo in lowering HbA1c, so the product has now been withdrawn.

“There have been significant advances in insulin therapy in the last 100 years,” Professor Davies concluded. “While there has been no breakthrough yet in oral insulin, there has been progress in basal insulins, while advances in diabetes technology like pumps and continuous glucose monitoring have improved our ability to make the most of the potential of insulin for people living with diabetes.”

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

Pregnancies complicated by diabetes are on the increase and pose risks for mother and baby. The role of diabetes technology in improving outcomes in these pregnancies was under discussion at ‘Revolutionising Diabetes Care: Celebrating 100 Years of Insulin Therapy’, a recent online conference organised by The Royal College of Physicians and Surgeons of Glasgow (RCPSG). Dr Susan Aldridge reports.

Before the advent of insulin, women with type 1 diabetes and their babies simply did not survive. Then, in 1933, one of the first studies of the use of insulin in pregnancy noted a preponderance of ‘giant babies’ – some weighing more than 5kg – in a cohort of 608 infants born to 155 mothers with diabetes.

Now known as large-for-gestational-age (LGA) babies, 63% of the babies born in this study were affected by this complication. Writing in the New England Journal of Medicine in 1941, Dr Martin Nothmann said, “Diabetes is more unfavourable for the child than the mother – in this regard, insulin cannot accomplish much.”

“The most recent snapshot [from the National Diabetes in Pregnancy audit (NPID)] tells us that today we have one in 10 pregnancies with potentially preventable serious adverse outcomes – that is, still birth, newborn death or birth defect, and this applies across both type 1 and type 2 diabetes,” said Helen Murphy, Professor of Medicine at the University of East Anglia and Chair of NPID. “Early-onset type 2 diabetes has been increasing, so we are now seeing more women in pregnancy with type 2 than those with type 1.”

In 2002/03, at the time of the first Confidential Enquiry into Maternal and Child Health (CEMACH) report, there were 1707 type 1 diabetes pregnancies and only 652 affected by type 2, whereas in 2019-2020, there were 4175 type 1 and 5085 type 2 pregnancies. And this is occurring at a time when NHS maternity services are already stretched.

“What’s also really important is the different patient characteristics,” said Professor Murphy. Women with type 1 are predominantly White, while those with type 2 are more likely to be from ethnic minority groups and are much more likely to live in areas of deprivation. The data shows that 42% of type 2 pregnancies occur among women living in the most deprived areas, while just 5% live in the least deprived areas. “It is vital moving forward that we plan our services such that resources are targeted to these high-risk women,” said Professor Murphy.

Focus on maternal glucose levels

Maternal glucose levels at the time of conception are crucial in determining the outcome of a pregnancy. The National Institute for Health and Care Excellence (NICE) recommends that all women with diabetes aim for an HbA1c of 6.5% (48 mmol/mol). “We know, however, that very few women achieve this,” said Professor Murphy. “But as HbA1c rises – from 7% [53 mmol/mol] and above – there is a sharp increase in congenital malformations among infants born to women with type 1 and type 2. So the single most important message for anyone looking after women of reproductive years is that they should be offered access to safe, effective forms of contraception until HbA1c is as good as it can get for pregnancy.”

Taking adequate folic acid and achieving target glucose levels are key markers in preparing for pregnancy. Half of all women with type 1 diabetes take 5 mg folic acid, compared with only 20% of those with type 2 diabetes. With HbA1c, 15% with type 1 diabetes reach the glucose target and just over 35% with type 2 diabetes. “This means that 65% of those with type 2 do not,” said Professor Murphy. “Most are on metformin, so they are diagnosed but not treated to target and only 18% of these women of reproductive age are treated with insulin before pregnancy. That is something that seriously needs to change.”

Which women are most likely to achieve their glucose target? For type 1 diabetes, it is women in the 35-44 age group and those with the shortest duration of diabetes, therefore having some endogenous insulin secretion. Younger women, those living in deprived communities, those with longer duration and those with higher BMI are the least likely to get to target. The data are similar for type 2 diabetes, although deprivation has less of an impact as most of these women already live in deprived communities.

Professor Murphy then turned to the effects of glucose on obstetric and neonatal complications. If HbA1c is more than 6.1% (43 mmol/mol), there’s a high risk of preterm delivery, which is similar for type 1 and type 2 diabetes. Also, 50% of women with HbA1c between 6.1-6.5% (43-48 mmol/mol) will have a baby that is LGA. “So the key message from this data is that we need to target tighter glycaemia in the second half of pregnancy,” she said. “And, of course, to do that, we need better insulins and better methods for glucose monitoring.”

Rates of stillbirth and neonatal death have decreased in recent years. However, there is concern that stillbirths in type 2 pregnancy may be starting to increase, which needs to be watched very closely in the next few years. “The key modifiable factor in perinatal death in type 1 and type 2 is having HbA1c more than 43 mmol/mol,” said Professor Murphy. Data show a higher risk for women with type 2 diabetes, suggesting that they are particularly vulnerable to above-target glycaemia during the second and third trimesters. If a woman can get to target by 24 weeks, it will significantly reduce the risk of stillbirth.

Continuous glucose monitoring

Using better technology to monitor glucose does help women personalise their insulin delivery. Professor Murphy was involved in the CONCEPTT trial, which compared real-time continuous glucose monitoring (CGM) with fingerstick glucose monitoring in women with type 1 diabetes during pregnancy or pregnancy planning. CGM led to a 7% increase in time in range (TIR), equivalent to an extra 100 minutes a day in range throughout the pregnancy.

The outcomes showed that these small improvements in glycaemic control led to significant benefits for the infant, with reduced rates of LGA, neonatal hypoglycaemia and neonatal intensive care unit admission. “It is this data that led to the UK being one of the first countries in the world to offer CGM to all women with type 1 diabetes to help support them to reach their glucose target and improve neonatal outcomes,” said Professor Murphy. “We are just beginning to see the impact of that as it rolls out across the NHS. We now have national audit data for over 1,000 real-world CGM users and we’re optimistic that some of these benefits we’ve seen in the randomised trial will be replicated in this real-world data set.”

During this rollout, education and support of healthcare professionals is key to helping women understand the importance of reaching their glucose targets. “We have learned that women find these glucose targets, particularly TIR, very intuitive and accessible and, of course, this data sits on their own phones, so they have it to hand,” said Professor Murphy. A series of webinars has been developed to support this rollout, focusing on the use of CGM at the various stages of pregnancy, including delivery and in the postnatal period.

Targets for hyper- and hypoglycaemia are now firmly established in clinical practice for managing women with type 1 diabetes. For TIR (3.5 to 7.8 mmol/l), this should be 70% of the time with less than 25% above 7.8 mmol/l and less than 1% below 3 mmol/l. Women with type 2 diabetes may benefit from aiming for 90-100% TIR.

Mean glucose is also important, where the target should be 6-6.5 mmol/l. ”Achieving these targets, even with the latest CGM and insulin pumps, is hard work and, in my view, automated insulin delivery will take over from insulin pumps and we will have CGM linked to an algorithm that is linked to insulin delivery,” said Professor Murphy. “This will eliminate a lot of the work for women with type 1 diabetes, although with the systems that are available today, carb counting and meal bolusing are still required.”

Hybrid closed loop in pregnancy

Professor Murphy has also been involved in trials of the CamAPS-FX hybrid closed loop system – developed by Professor Roman Hovorka’s team in Cambridge – in type 1 diabetes pregnancy. These have produced some very promising overnight and 24-hour data and the results will be published in the next few months. “What I can share with you today is our experience of supporting women using closed loop,” she said. “Not all women will be able to achieve perfect glycaemic control but, in our experience, with the right education and support, most women should have the same results as outside of pregnancy, which is an increase of 7-10% in TIR.”

Working with colleagues from Scotland, Professor Murphy’s team has done a series of interviews with healthcare professionals looking after women using closed loop in pregnancy. “This is coming and it’s coming soon,” she said. “We’re going to see far more women choosing to use automated or hybrid closed loop systems, so we are starting to look at what we need to do, as healthcare professionals, to roll this out across the NHS.”

The first step in this roll-out is support and education of diabetes teams. One of the messages from the above survey is that all women should be offered these technologies, wherever they’re being looked after. “That does present some challenges, so we need to upskill the workforce right across the UK,” Professor Murphy said. “However, I’m optimistic because we managed to roll out CGM in the real world during the pandemic and I do think that, in the next few years, we’re going to see the rollout of hybrid closed loop for women who are either pregnant or planning a pregnancy.”

Even in the absence of trial data – which will follow shortly – qualitative data from women using the systems is so powerful, she continued. “We’re getting reports of women who are able to stay in paid employment and are having better relationships with healthcare professionals. Most important of all, they’re finding that using this technology allows them to enjoy the pregnancy experience and achieve better glucose outcomes.”

This is illustrated by the words of one woman interviewed, who took six years to become pregnant. “The 246 days of pregnancy meant 17,000 units of insulin, 216 jabs and 70% TIR,” she said. “The technology I was able to use throughout made the journey as stress-free as possible!”

“The challenge for us is to make sure that we can deliver these technologies to all women to improve their experiences of pregnancy and achieve the best possible outcomes for their babies,” Professor Murphy concluded.

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

Suzie Normanton, EASD e-Learning’s Accreditation and Feedback Lead, reports on the feedback we’ve received over recent months – and what’s been done to address it.

Learner feedback aims to give learners a voice and help the EASD e-Learning team to understand what is working well but also to enable us to make changes that will improve the experience for learners engaging with our programme. Feedback helps us to keep our courses up to date and evidence based – and to identify and resolve technical issues.

It is also important that learners know their feedback is taken seriously. The e-Learning team aims to review regularly the learner feedback it receives from learners who complete the module feedback form or email us via [email protected]. We try to respond as quickly as possible to resolve reports of technical or content issues and to keep the person providing feedback informed of our actions.

September to December 2022

This four-month period saw a fall in the number of learner feedback forms about individual modules submitted. Eight learners provided feedback, with some learners completing forms about more than one module they engaged with, resulting in 16 forms being completed.

As you engage with one or more of our e-Learning modules, we would encourage you to complete our short learner feedback form as this does help us monitor the quality of our courses and modules, identify any errors and feed into our periodic review process to ensure our courses and modules remain up to date and relevant. Alternatively, we welcome feedback on any aspect of our e-Learning programme and you can contact us direct via: [email protected]

What you have said recently about our courses and modules?

When asked to rate their satisfaction with a module, every learner said they were either very satisfied (87%) or satisfied (13%) with the module they had engaged with.

Which parts of the module were most useful?

  • 57% of the forms we received reported that all parts of the module were useful

Qualitative feedback included the following:

  • I enjoyed the presentation. The lecture and transcript format were helpful to review. (Technology and type 1 diabetes, module 1)
  • The explanation of the cause of type 2 diabetes and the details about trials (Lifestyle intervention, module 1)
  • Clear explanations. The suggested ways to counsel patients. (Lifestyle intervention, module 1)
  • Explaining how in the future we could guide our treatment using genetics and microbiome (Phenotypic variability, module 1)
  • Clinical cases (Obesity and diabetes, module 1)

How could our modules be improved?

Of the 16 forms received, 13 (81%) stated that no improvements were needed. The specific suggestions for module improvement included:

  • Perhaps a brief explanation of the drugs in the case studies. I’m a health coach for DPP, so we only discuss lifestyle interventions. (Lifestyle intervention, module 1)
  • More case discussions, especially on unexpected complications. (Diabetic ketoacidosis, module 1)

Clinical application of learning

One type of feedback we are always particularly interested to receive is information about how learners plan to apply what they have learnt from our modules to their own practice. Here are some of the examples from recent months of how learners stated they would apply learning from a module in their practice:

  • Improving my DKA management skill, educating on DKA prevention. (Diabetic ketoacidosis, module 1)
  • Being better able to explain the cause of prediabetes and diabetes to my patients (Obesity and diabetes, module 1)
  • Being better able to deal with more detailed questions from the group as I now have a greater understanding of the mechanisms involved, so I’ll be better equipped to explain why group members who are not overweight a) are prediabetic and b) would benefit from weight loss. (Lifestyle intervention, module 1)
  • Having developed a better understanding of the topic and certainly will do my clinics with better confidence now. (Technology and type 1 diabetes, module 1)

Please do continue to send us your feedback, either by filling in the learner feedback form when you complete a module or directly via: [email protected].

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

SGLT-2 inhibitors and GLP-1 receptor agonists have benefits that go beyond glucose-lowering in diabetes. A new study, reported in Diabetologia, looked at the cost-effectiveness of these medications. The findings may lead to more widespread use and could reduce heart and kidney complications for those living with type 2 diabetes. Dr Susan Aldridge reports.

Recent clinical trials have shown that SGLT-2 inhibitors and GLP-1 receptor agonists reduce the incidence of cardiovascular and kidney disease in people with type 2 diabetes, independently of their glucose-lowering effect. For instance, SGLT-2 inhibitors reduce hospitalisation for heart failure (HF) by 33% and end-stage kidney disease (ESKD) by 35%, while GLP-1 receptor agonists reduce myocardial infarction (MI) by 10% and stroke by 17%. SGLT-2 inhibitors have also been shown to reduce the incidence of cardiovascular and kidney disease in people without diabetes as well, suggesting that their use has benefit independent of HbA1c levels.

In light of this evidence, the recently updated American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) consensus guidelines for treatment of people with type 2 diabetes recommend the use of SGLT-2 inhibitors and GLP-1 receptor agonists for those with, or at risk of, cardiovascular and kidney disease. However, uptake of these medications, particularly the GLP-1 receptor agonists, among people with type 2 diabetes has been limited so far.

A crucial barrier is their high cost. Previous cost-effectiveness analyses of these medications have tended to focus on their glucose-lowering effect. To expand their use earlier in the course of diabetes, and irrespective of HbA1c, we really need to know how cost-effective they are in terms of their cardiovascular and kidney benefits.

Accordingly, Jedidiah Morton of Monash University, Australia, and colleagues, have constructed a model using a real-world population with type 2 diabetes to assess the cost-effectiveness of widespread use of SGLT-2 inhibitors and GLP-1 receptor agonists, considering only major cardiovascular and kidney outcomes.

Modelling the health economics of type 2 diabetes

The model used real-world, individual-level data capturing the probable incidence and costs of ESKD, non-fatal hospitalisations for MI, HF, stroke and all-cause mortality among people with type 2 diabetes in Australia from 2020 to 2040. This data came from the National Diabetes Services Scheme and national hospital and mortality data.

Baseline health states were assigned using data from 2010 to 2019 and the population was then ‘aged’ in yearly cycles, using probability data to track incidence of the above events (ESKD and so on) to build up the model. Additionally, a cohort of new-onset type 2 diabetes was added each year.

Outcomes were total probable cases of ESKD, hospitalisation for MI, HF and stroke, years of life lived, quality-adjusted life years (QALYs), healthcare costs and societal costs. The primary outcome was incremental cost-effectiveness ratio (ICER), which is the cost per QALY gained, with the willingness-to-pay threshold set at per QALY. Put simply, cost-effectiveness would be achieved if the ICER was less than or equal to $AU28,000.

Outcomes were evaluated in two different populations: the total population with type 2 diabetes and the secondary prevention population, which was everyone with type 2 diabetes who had prior cardiovascular disease (CVD) – either an actual admission from 2010 to 2019 or a modelled admission from 2020 to 2040 for MI, HF or stroke.

The researchers modelled four different scenarios. In the first two, the use of SGLT-2 inhibitors or GLP-1 receptor agonists was increased to 75% of the total type 2 diabetes. In the third and fourth scenarios, this increase was confined to the secondary prevention population. The four scenarios were compared with the use of these medications in 2019 – the last year for which data was available – which was around 20% for SGLT-2 inhibitors and 5% for GLP-1 receptor agonists. These figures were about the same for people with and without prior cardiovascular disease. The impact of the increased use of the two medications in the four scenarios was calculated using data from recent meta-analyses of major outcomes trials for SGLT-2 inhibitors and GLP-1 receptor agonists. 

Focus on cost-effectiveness

The prevalence of diabetes in Australia was projected to grow from 1.13 million in 2020 to 1.45 million in 2040. Compared with current use of 20% of SGLT-2 inhibitors, increasing their use to 75% in the total population with type 2 diabetes would result in a gain of 400,018 extra years of life and 176,446 QALYs, according to this model.

The corresponding ICER for healthcare costs would be AU$23,717, taking into account the cost of the medication and setting it against the healthcare cost reductions from having fewer diabetes complications. The secondary prevention population numbered 95,247 people and 75% SGLT-2 inhibitor use would lead to a gain of 29,357 QALYs and an ICER of AU$8878.

For GLP-1 receptor agonists, the corresponding figures for the whole type 2 diabetes population were 460,028 extra years of life and 200,932 QALYs. The ICER was calculated as $AU100,705, again taking into account a reduction in healthcare costs arising from wider use of these medications. For the secondary prevention population, GLP-1 receptor agonists used for 75% would lead to a gain of 36,090 QALYs and an ICER of AU$79,742.

These findings suggest that use of SGLT-2 inhibitors is probably cost-effective in both the total and secondary prevention populations. However, the analysis suggests that GLP-1 receptor agonists are not likely to be cost-effective from a healthcare or societal perspective at current prices. This has important policy implications, suggesting that reimbursement criteria that limit use of SGLT-2 inhibitors, where they exist, should perhaps be re-considered. Currently, too many people living with type 2 diabetes are missing out on the benefits of these medications, which this new study shows to be a worthwhile investment in their future health.

This is the first cost-effectiveness analysis of its kind. Other studies have excluded cardiovascular or kidney benefits or modelled the populations used in cardiovascular outcomes trials, which represent only 20 to 60% of people with type 2 diabetes. Most of those studies have also found SGLT-2 inhibitors to be cost-effective.

This new study extends these findings by showing cost-effectiveness of SGLT-2 inhibitors, regardless of their effects on glucose levels. This doesn’t mean everyone with type 2 should be on them, however, nor does this study address other considerations about their widespread use.

Interpretation of the findings on GLP-1 receptor agonists is more complex. If you look only at cardiovascular benefit, they are not cost-effective in either the total type 2 diabetes population or those with existing cardiovascular disease. However, GLP-1 receptor agonists lead to weight loss and have less risk of hypoglycaemia compared with sulphonylureas and insulin, and are very effective glucose-lowering medications. None of these benefits was considered in this study.

Further analyses taking a more detailed look at the GLP-1 receptor agonists’ cost-effectiveness are needed. This is important because there is already a high burden of CVD in type 2 diabetes and, with an ageing population, stroke in particular is becoming more common. These are outcomes that could be improved by an increased uptake of GLP-1 receptor agonists.

To read this paper, go to: Morton J, Marquina C, Shaw J, Lieu D, Polkinghorne K, Ademi Z, Magliano D. Projecting the incidence and costs of cardiovascular and kidney complications of type 2 diabetes with widespread SGLT2i and GLP-1 RA use: a cost-effectiveness analysis. Diabetologia online 21 November 2022. https://doi.org/10.1007/s00125-022-05832-0

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

Diabetic retinopathy was one of the hot topics at the recent International Diabetes Federation (IDF) meeting. The session covered the latest research into retinal dysfunction and the challenges of setting up national diabetic eye screening in the Philippines. Dr Susan Aldridge reports.

Diabetic retinopathy is part of the systemic disease that is diabetes, so glycaemic control is particularly important. “The Diabetes Control and Complications Trial showed that intensive therapy reduces the onset and progression of diabetic retinopathy,” said Dr Tom Gardner, ophthalmologist at the Juvenile Diabetes Research Foundation (JDRF) Centre of Excellence, University of Michigan. “I point this out because ophthalmologists should be part of the diabetes team. Even so, the challenge persists – in the US, the number of patients with diabetic macular oedema has continued to increase since 2009 and it is the main cause of vision loss in diabetes.”

In addition, glycaemic control is less than perfect with only a minority of people with diabetes meeting targets for HbA1c, blood pressure and cholesterol. If anything, this proportion is decreasing. 

The advent of anti-vascular endothelial growth factor (VEGF) drugs has made a major impact in vision loss and given another option besides photocoagulation. However, peripheral vision still declines after both treatments. “So the anti-VEGF drug is helpful in stabilising the condition but there’s more to the story,” said Dr Gardner.

The current drugs target only VEGF but there have been attempts to target other molecules involved in vascular degeneration, such as faricimab, which is bivalent against VEGF and angiopoietin-2, and has been shown to be non-inferior to the VEGF inhibitor aflibercept. “This is not a major advance but another step forward in trying to understand vascular pathology of diabetic retinopathy,” Dr Gardner said.

It’s also very important to understand which people with diabetes are most at risk of losing their vision. The FIELD study led the way in this kind of prediction, being a retrospective of sight-threatening diabetic retinopathy analysis using an algorithm involving male sex, diabetic retinopathy at baseline, HbA1c and use of fenofibrate (which reduces risk). It shows where the individual is on the progression curve. This is particularly helpful in selecting people for clinical trials. 

Widespread retinal dysfunction

“So far, the available therapies only target the vascular part of the disease – that’s important but not the whole story,” Dr Gardner said. He gave an example of a patient whose eyes could not adapt to dim light. This was not a vascular condition but meant his rods and cones weren’t functioning properly. “We would not pick that up from a photo or examination,” he said, “so it’s important to look at the whole retina and what’s there besides the blood vessels.”

All the retinal cell types are damaged in retinopathy and this begins in the preclinical stage with vascular leakage and occlusion. There is also neuronal apoptosis – particularly in the inner layer of the retina – and astrocyte dysfunction, which is not well understood but is probably important for regulation of synapses.

Furthermore, microglial activation means that there is activation of the immune system within the retina, as well as other abnormalities that may affect electrical function and morphology.

“It is now becoming clear that the whole retina is affected in diabetic retinopathy, not just the vasculature,” Dr Gardner explained. In his lab in Michigan, they’re now looking for cells in the retina that make the macromolecules essential for function. These experiments are helping them to gain a deeper understanding of how the retina works normally to provide vision and how it’s impaired in diabetes.

Put simply, the different functions of the retina should be integrated but because of the dysfunction of so many cell types beyond the vasculature, disintegration occurs, leading to vision impairment. “The retina is a very highly metabolic, electrical tissue whose job is to provide electrical signals,” said Dr Gardner. “It is a sensory organ, so diabetic retinopathy can be seen as a type of sensory neuropathy.”

Retinal screening in the Philippines

Away from retinal research, Dr Paolo Antonio Silva, ophthalmologist and Chief of Diabetic Medicine at Joslin Diabetes Center, described a joint telemedicine project between the Joslin, Queen’s University Belfast and the Philippine Eye Research Institute. This is known as the UK-Philippines Remote Retinal Evaluation Collaboration in Health: Diabetic Retinopathy (REACH-DR). Its aim is to move retinal screening away from tertiary centres to a wider geographical area, using less expensive, more accessible and portable imaging devices.

These mobile hand-held imaging devices are currently in various stages of development – undergoing validation studies, for example – and can be integrated into smartphone or mobile computing. So far, in the early treatment of diabetic retinopathy, the quality of the retinal image using three different hand-held devices has proven similar to that in a standard retinal photo. 

These hand-held devices can be used in community screening programmes where their size, accuracy and ease of use are particularly useful. “Based on these results, we then wanted to carry out a local cost-effectiveness analysis with the Philippines Department of Health and found that the use of a hand-held camera with mydriasis was the best approach,” Dr Silva said.

The REACH team is also starting to apply artificial intelligence (AI) and deep learning (a machine learning technique that teaches computers to do what comes naturally to humans) at the point of care. This will allow for more effective triage of diabetic retinopathy cases and improvement of workflow with less central load.

However, despite the promise of AI, there is a limited number of publications on its application to diabetic retinopathy and the currently approved AI algorithms are not universally generalisable. “There is an under-representation of some populations, which affects the accuracy of AI,” said Dr Silva. This is because 172 countries don’t have the required publicly available ophthalmic datasets and this may perpetuate health inequality in the application of AI. “So there is a need to create clinically useful AI systems that are based on diverse demographics and understand why, how and when different AI systems work in different settings,” he said.

It may be early days, but the REACH Diabetic Retinopathy team is laying the foundations for retinal screening in a country with limited resources, which is good news for people with diabetes everywhere.

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

A new study, reported in Diabetologia, shows that vigorous exercise on a bike or using a home video helps protect pancreatic beta cells from apoptosis induced by endoplasmic reticulum-induced stress. The benefits were seen in people with or without type 1 or type 2 diabetes, shedding light on the role of physical activity in preventing or delaying the onset of the condition. Dr Susan Aldridge reports.

Loss of functional pancreatic beta cells drives the development and progression of diabetes. In type 1 diabetes, research into therapies has focused on the immune system. For instance, teplizumab, an anti-CD3 antibody recently approved by the Food and Drug Administration (FDA), significantly delays the onset of the condition in high-risk individuals, buying them precious time without the burden of diabetes. However, many treated with teplizumab will still go on to develop type 1 diabetes, so there is clearly a need for other therapies that can protect beta cells in both type 1 and type 2 diabetes.

Signals of endoplasmic reticulum (ER) stress are present in the beta cells of people with type 1 and type 2 diabetes. And several forms of monogenic diabetes are caused by mutations in genes involved in the response to ER stress. The underlying mechanism of ER stress involves accumulation of mis-or unfolded proteins in the ER lumen, which leads to beta cell apoptosis if it continues. ER stress can be reproduced in vitro by exposing human islets to proinflammatory cytokines and chemical ER stressors such as thapsigargin.

Therefore, agents that can restore normal ER function could perhaps provide a therapeutic strategy in diabetes. Tauroursodeoxycholic acid and imatinib are two compounds that have already been shown to reduce ER stress and protect beta cells in pre-clinical models of diabetes. Imatinib also showed modest but transient protection of beta cells in a clinical trial in people with recent-onset type 1 diabetes.

Physical exercise is an important non-pharmacological element in diabetes prevention and management. It improves glycaemic control in people with type 1 and type 2 diabetes by improving insulin sensitivity, stimulating glucose uptake by skeletal muscle cells and reducing weight. It also decreases circulating lipids, blood pressure and risk of cardiovascular complications. A combination of aerobic and resistance exercise is recommended, with interval aerobic training probably being more beneficial than continuous aerobic training.

Studies in animal models and human islets have also suggested that physical exercise has a direct effect upon beta cells. In an earlier study, Alexandra Coomans de Brachène of the Université Libre de Bruxelles, along with her colleagues, have shown that serum from eight healthy young male participants who performed moderate-intensity continuous exercise training for eight weeks protected beta cells from proinflammatory cytokines and thapsigargin. This protection was observed in primary human islets and the human beta cell line EndoC-βH1.

They have now extended this study to assess the impact of different forms of exercise on ER-stressed human beta cells in a larger cohort of individuals with and without diabetes.

Exercising to protect beta cells

Two separate groups of participants took part in this study – a group of healthy younger people and a mixed group of older people with or without type 1 or type 2 diabetes, and of different ancestral origins. All participants had VO2peak, their maximal oxygen uptake (a measure of aerobic fitness), measured on an exercise bike at the start of the study. The 46 healthy participants – 26 female, 20 male – were assigned to one of four different physical exercise regimes carried out three times a week over an eight-week period.

Another five healthy participants acted as controls, doing their normal physical activity only. The intervention groups consisted of stationary bike high-intensity interval training (HIIT), adapted sprint interval training (aSIT), vigorous-intensity continuous training (VICT) or high-intensity functional training performed at home (HIFT). The three bike-training regimes were carried out in the authors’ laboratory and differed with respect to the proportion of VO2peak worked at. The HIIT regime consisted of six bouts of two minutes at a load of 90% VO2peak interspersed with two minutes active rest at 50% VO2peak. The aSIT regime was 12 bouts at 30 seconds at 125%VO2peak interspersed with two minutes of active rest. And the VICT regime was 28 continuous minutes at a load of 70% VO2peak.

Meanwhile, the HIFT consisted of videos with four bouts of 30 seconds of whole-body exercises such as squats, lunges and jumping jacks, interspersed with 30 seconds of active rest. The difficulty and number of repetitions of the exercises increased from video one to video four, and the participants progressed through the series during the eight-week intervention period.

To evaluate the possible impacts of diabetes and ancestry on the beta cell-protective effects of exercise, 36 individuals who had type 1 or type 2 diabetes or no diabetes and were of Belgian origin (European ancestry) or were Belgians of Moroccan, Turkish or African origin (non-European ancestry) participated in the study.

For comparison, participants without diabetes were matched to those with type 1 and type 2 diabetes based on sex and similar age. They took part in training three times a week for 12 weeks, consisting of stationary bike HIIT training, similar to that described above, and strength-training exercises involving the four main muscle groups – namely, chest press, lateral pulldown, leg press and leg curl. They did three sets of 10 repetitions of these.

Blood was collected from all participants prior to the study and after four, eight and 12 weeks of training to obtain serum. Then EndoC-βH1 cells were treated with thapsigargin in the presence of serum to see if this ‘exercised serum’ protected the cells from ER stress. Thapsigargin alone would have triggered ER stress and beta cell apoptosis.

Fluorescence microscopy was then used to count apoptotic cells after staining them with a DNA-binding dye and RNA was extracted from the beta cells to assess any changes in gene expression from exposure to ‘exercised serum’.  

Positive findings

In the experiments involving the younger, healthy volunteers, there was significant protection against thapsigargin-induced beta cell apoptosis after four weeks of exercise for the three exercise bike regimes and after eight weeks for the home exercise. Since no major differences were found between the different types of exercise, the results were pooled and re-analysed according to sex.

There was significant exercise-mediated beta cell protection with a 29-32% reduction in apoptosis in women and 27-40% decrease among men. When pooling results for all 46 participants, there was a 28-35% decrease in apoptosis at four and eight weeks. Serum was also collected from 13 of the participants two months after the training and the protective effects were still seen. Sera from the control group did not confer any protection against thapsigargin, confirming the role of exercise.

When it came to participants with diabetes, they were older than the healthy participants, had a lower starting VO2peak  and those with type 2 diabetes were obese. Serum from the individuals in this group who did not have diabetes significantly protected human beta cells from thapsigargin-induced apoptosis after four, eight and 12 weeks of training. Furthermore, ‘exercised serum’ from participants with type 1 or type 2 diabetes was also protective, reducing apoptosis by 45% and 26%, respectively, after 12 weeks of training.

Finally, to determine whether ancestry affected the response, data was pooled from the three groups and split into those of European and non-European origins. Again, serum conferred significant protection against apoptosis. Therefore, neither the presence of diabetes nor ancestral origin influence the protective effects of physical exercise against ER stress-induced beta cell apoptosis. 

How exercise might protect beta cells

What about the mechanism driving the beta cell protection conferred by exercise? RNA analysis of the beta cells exposed to ‘exercised serum’ showed reduction in expression of two pro-apoptosis genes, CHOP and DP5,and in the XBP1s gene, which is involved in ER stress. These changes are consistent with exercise conferring protection on beta cells via reduction in ER stress and apoptosis.

When exercised, skeletal muscle and other tissues release substances called exerkines into the bloodstream. A recent study showed that one exerkine, known as clusterin, protects rodent beta cells from metabolic stress. The authors therefore carried out an additional experiment to see if clusterin could reproduce the beneficial effects of ‘exercised serum’ in human beta cells. They found that clusterin reduced thapsigargin-induced cell death by 31-42% at two concentrations.

The mRNA expression of DP5 was also significantly reduced at the higher dose of clusterin. Taken together, these findings suggest that the mechanism of beta cell protection afforded by exercise involves muscle or multi-organ crosstalk with beta cells, mediated by circulating exerkines. Further experiments will help clarify the molecular pathways involved in this mechanism.

In practical terms, the finding that home-based exercise protected beta cells as well as gym-based exercise is important, as people can access these benefits via videos or apps rather than needing access to equipment. In the four training regimes, participants spent at least 50% of their time at their maximum heart rate. Whether beta cell protection would also result from mild to moderate exercise, such as brisk walking, remains to be determined.

In summary, serum from people with or without type 1 or type 2 diabetes after eight to 12 weeks of regular vigorous exercise confers beta cell protection against ER stress. The benefit also persists after the intervention. This shows the unexpected potential of exercise training in preserving beta cells.

Exercise training should therefore be tested in larger trials for its benefits as a non-pharmacological intervention in people who are at risk of either type 1 or type 2 diabetes. This could prove to be an effective way of preserving endogenous insulin secretion and beta cell health, as well as having cardiovascular and other health benefits. 

To read this paper, go to: Coomans de Brachène A, Scoubeau C, Musuaya E, Costa-Junior JM, Castela A, Carpentier J, Faoro V, Klass M, Cnop M, Eizirik D. Exercise as a non-pharmacological intervention to protect pancreatic beta cells in individuals with type 1 and type 2 diabetes. Diabetologia 19 November 2022. https://doi.org/10.1007/s00125-022-05837-9

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