A new study in Diabetologia finds that people with type 2 diabetes who are socioeconomically disadvantaged are less likely to be prescribed incretin-based therapies, including GLP-1 receptor agonists, even though they may have more to gain from such treatments. The authors suggest a number of ways of moving forward so that better value for money for society can be obtained from these new cardioprotective therapies. Dr Susan Aldridge reports. 

Low socioeconomic status has a negative impact on morbidity and mortality and is also a risk factor for type 2 diabetes via mediators including obesity, alcohol, reduced physical activity, stress, low health literacy and limited access to healthy food and exercise facilities. The result is often poor diabetes management and increased risk of cardiovascular complications.

Disparities in care, including the unequal use of incretin-based therapies, are also influenced by socioeconomic status. The incretin-based therapies are glucose-lowering drugs, including glucagon-like peptide-1 receptor agonists (GLP-1 RAs), dipeptidyl peptidase-4 (DPP-4) inhibitors and the recently developed dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 RAs, such as tirzepatide. The ADA and EASD recommend use of agents that have demonstrated cardiovascular benefit in those individuals with type 2 diabetes with cardiovascular risk. Certain GLP-1 RAs are included among these agents and emerging data suggests that tirzepatide, too, may have cardioprotective effects.  

In a new review, Apostolos Tsapas and colleagues at Aristotle University of Thessaloniki, Greece, have summarised real-world evidence on the use of incretin-based therapies in clinical practice across the socioeconomic spectrum. They look at socioeconomic disparities in the adoption of these therapies, the possible factors driving these and how these might be addressed in the future. The study consisted of a literature search focusing on incretin-based therapy use with regard to the following aspects of socioeconomic status: area-level indexes, income, education, sociodemographic variables. 

Area-level indexes and income

One study in the US showed that individuals with type 2 diabetes and cardiovascular disease with increased area-level socioeconomic deprivation were less likely to receive GLP-1 RAs compared with those living in more privileged areas. In Australia, the Index of Relative Socioeconomic Disadvantage ranks areas according to information on income, education, employment, occupation, housing and other indicators. A study assessing the relationship between use of incretin-based therapies and the Index found that those in the most disadvantaged areas were consistently less likely to receive GLP-1 RAs, while the opposite was so for DPP-4 inhibitors.

The study also found a connection between low socioeconomic status and a reduced probability of receiving SGLT-2 inhibitors, while no such relationship was observed for metformin, sulphonylureas or insulin. And, according to a UK study, when fully accounting for various confounding factors, those belonging to the most deprived group, as identified by the Index of Multiple Deprivation, had a lower likelihood of being prescribed GLP-1 RAs.  

In another study from the US, the odds of being treated with a GLP-1 RA were greater among individuals with diabetes who had a high household income compared with those whose annual income was less than $50,000. Higher income individuals were also more likely to be on GLP-1 RAs in the All of Us Research Program, a US contemporary cohort study. Finally, in Denmark, metformin-treated patients with a high household income were more likely to initiate second-line treatment with a GLP-1 RA compared with those with a low household income. 

Education and sociodemographic factors

Education is often used as an indicator of socioeconomic status because it captures the knowledge-related assets of a person and determines their future employment, occupation and income. In the US, those with a high-school education had lower odds of receiving a GLP-1 RA prescription in comparison with those who had a postgraduate degree. Similarly, in the All of Us Research Program, a higher percentage of those who went to college were on GLP-1 RAs compared with those with less than a high-school diploma. In Denmark, the probability of initiating a GLP-1 RA was higher in those with a college education compared with lower educational levels. 

In addition, multinational data from the global DISCOVER programme suggested that those who had less than 13 years of education had lower odds of receiving a GLP-1 RA than a sulphonylurea. Similar, although less marked, associations with education level and drug utilisation were also found for DPP-4 inhibitors, but not for insulin.

Meanwhile, sociodemographic factors, such as race/ethnicity and age can also influence the uptake of newer medications. For instance, retrospective cohort data from the US suggest that, compared with White individuals with type 2 diabetes, Asian, Black and Hispanic individuals were less likely to receive GLP-1 RA therapy. In the UK, compared with White individuals, Asian and Black minorities were more likely to be prescribed metformin or sulphonylureas than GLP-1 RAs or SGLT-2 inhibitors. And in Denmark, inequalities in GLP-1 RA therapy between those with a high income and those with a low income were more pronounced in immigrants than the native Danish population. Finally, in the US, older age has been associated with a lower probability of receiving GLP-1 RAs or SGLT-2 inhibitors in those with type 2 diabetes and atherosclerotic cardiovascular disease.  

Drivers of inequalities in incretin-based therapy

The authors have identified some key mechanisms that underlie the inequalities reported above. Firstly, people may simply not be able to afford incretin-based therapies and this will, of course, vary according to the country where they live. In a system that provides universal reimbursement, such as the UK and many other European countries, access to these therapies may be more equitable because the treatments are available to more of the population, regardless of their financial status. However, access to GLP-1 RAs is not consistent across European populations. For example, in the UK, they can only be prescribed to people with type 2 diabetes who also have obesity, while other countries do not impose such restrictions. 

Where insurance coverage is not universal, as in the US, people with lower socioeconomic backgrounds may face barriers in accessing these therapies, due to higher out-of-pocket costs or limited insurance coverage. In the US, for instance, many states lack expanded Medicare coverage and one study has shown that even Medicare beneficiaries are less likely to receive GLP-1 RAs than those with private insurance. A similar trend has been uncovered in Germany, with private health insurance being a strong predictor of GLP-1 RA prescription.

The disparity in use of GLP-1 RAs according to income is currently being exacerbated by the current global shortage of semaglutide and dulaglutide, which is being driven, in part, by increasing off-label use for weight loss. So a considerable proportion of limited supply is being redirected towards well-off individuals seeking weight reduction, regardless of their diabetes status. This situation disproportionately affects those of lower socioeconomic status with type 2 diabetes and cardiovascular disease, who are totally dependent upon affordable reimbursement to access these medications. 

Secondly, there is the issue of actual access to incretin-based therapies. People living in rural or disadvantaged areas may find it hard to get to an appointment with a diabetes specialist who is well-versed in these new drugs. Finding a pharmacy that stocks them may be another challenge. Primary care physicians may not be fully aware of the cardiovascular benefits of incretin-based therapies and may be reluctant to prescribe them, even to their patients with cardiovascular disease. And, of course, most people with type 2 diabetes are treated in primary care. Research has confirmed that diabetologists and endocrinologists are more likely to prescribe GLP-1 RAs, perhaps because they are more familiar with injectables. 

Thirdly, disadvantaged groups have been consistently reported to have lower health literacy than more privileged groups in society and this has been associated with poorer health outcomes and decreased uptake of therapeutic and preventive interventions. Those with low health literacy may find it difficult to understand health information and communicate effectively with healthcare professionals. 

In some countries, they may be confused about insurance coverage options and the availability and out-of-pocket costs of GLP-1 RAs. These concerns may lead them to avoid or postpone treatment. Furthermore, those with low health literacy are less likely to be well-informed about the cardiovascular benefits of GLP-1 RAs and might not feel confident in trying to access, or get a referral, to a diabetes specialist in order to get a prescription. And during a consultation with a healthcare provider, they may find it challenging to raise their concerns about cost or the need for subcutaneous administration. Language and cultural barriers may also arise. 

Finally, on the other side of the consultation, there may be conscious or unconscious bias on the part of the healthcare provider. A recent study has shown that GLP-1 RAs are less likely to be prescribed to patients from lower socioeconomic backgrounds or minority groups, who are perceived to be less compliant to treatment and medical advice, or unable to afford the cost of these drugs. 

Increasing societal benefit from incretin-based therapy

Reflecting on the above, the authors propose some strategies for increasing the uptake of incretin-based therapy. There are consistent data from clinical trials supporting the use of incretin-based therapies, particularly GLP-1 RAs, in socioeconomically disadvantaged people. They have much to gain as they are at increased risk of cardiovascular complications in type 2 diabetes and should therefore be a priority for receiving these treatments. 

Addressing barriers to accessing incretin-based therapies is vital for increasing and widening their uptake. This might mean providing transportation to appointments for those living in rural or low-income regions and increasing the availability and retention of both primary care and specialist staff in underserved areas. Meanwhile, primary care physicians’ familiarity with GLP-1 RAs should be improved through targeted education, training and resources, given that most people with type 2 diabetes are treated in primary care. 

The authors emphasise that the availability of beneficial medications at low cost is the key to increasing their value for money from a broader societal perspective. This is especially pertinent when it comes to considering the newer, high-cost incretin-based therapies such as semaglutide or tirzepatide. 

A recent study from the US concluded that, as a first-line therapy, the cost of GLP-1 RAs needs to fall by at least 70% to be cost-effective in comparison with metformin. Another Australian study says that GLP-1 RAs are not cost-effective at current prices for either primary or secondary cardiovascular prevention – although SGLT-2 inhibitors are. Similar findings emerged from an analysis of data from 67 low- and middle-income countries. Finally, a review from high-income countries has suggested that GLP-1 RAs were not cost-effective compared with DPP-4 inhibitors, sulphonylureas or thiazolidinediones. 

These economic evaluations highlight the need for country-specific strategies to improve the cost-effectiveness of GLP-1 RAs. These would include collaborative efforts between governments and pharmaceutical companies to lower drug prices, establish product listing agreements and promote generics. The authors note that the manufacturer of liraglutide and semaglutide has recently enjoyed a significant increase in market cap, reflecting its robust financial position. Thus, there is scope for negotiating lower prices for these medications without adversely impacting company profitability or scope for research and investment.

Improving health literacy in people with type 2 diabetes can help them appreciate the importance of preventing cardiovascular complications and help them actively participate in discussion with their physicians about potentially cardioprotective drugs. Through shared decision-making, patients may be more able to accept co-payments for these drugs and overcome barriers such as the need for injection with GLP-1 RAs. This collaborative approach can enhance treatment adherence and persistence, ultimately leading to better outcomes. 

Finally, it is necessary to address physician-patient barriers. This can be a complex issue, requiring a multifaceted approach, including implicit bias training and promoting diversity within healthcare professions. The former helps healthcare professionals to become aware of any unconscious prejudice that might be affecting their decision-making and contributing to disparities in prescribing incretin-based therapies. The latter creates a more inclusive healthcare environment, which may help promote better understanding of those from disadvantaged groups.  

In conclusion

The authors have highlighted disparities in the uptake of incretin-based therapies, particularly GLP-1 RAs, in people with type 2 diabetes according to socioeconomic status. An essential first step in addressing this problem is advocating for a reduction in the price of GLP-1 RAs, which would improve their value for money for society at large. This approach would complement other measures, such as increasing accessibility, improving health literacy and overcoming physician-patient barriers. 

However, much of the evidence informing this paper comes from the US and findings may not be generalisable to other settings, so additional research on uptake disparities and context-specific strategies for improvement is needed. Collaborative efforts to implement these strategies will boost the societal outcomes of the incretin-based therapies and improve health outcomes for those with type 2 diabetes.

To read this paper, go to: Karagiannis T, Bekiari E, Tsapas A. Socioeconomic aspects of incretin-based therapy. Diabetologia 12 July 2023. https://doi.org/10.1007/s00125-023-05962-z

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

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

Increasing the knowledge of all healthcare professionals involved with diabetes can improve glycaemic outcomes and care transitions. A Diabetes Champion programme was discussed at the American Diabetes Association’s 83rd Scientific Sessions. Lisa Buckingham reports. 

Diabetes education is a key component to positive outcomes for those living with diabetes, but there are not enough diabetes educators to go around and not everyone gets referred to them, said Dr Lucille Hughes, Assistant Vice President of the Diabetes Education and Program Design for Catholic Health, Long Island, New York. It’s therefore critical to develop programmes for the extended care team to be able to develop the skills and knowledge they need to impart information to people living with diabetes. Hence, she said, the Diabetes Champion programme. 

Dr Hughes outlined the programme she created in 2008. It’s a nine-week programme with an hour for each session and around 600 people have completed it so far. Its purpose is to promote and increase knowledge of all licensed care givers in the area of diabetes.

It has eight typical subject areas:

  • Pathophysiology of diabetes 
  • Medications
  • Medical nutrition therapy 
  • Blood glucose monitoring 
  • Diabetes technology 
  • Acute and chronic complications 
  • Problem solving and leadership skills
  • Patient education

What’s key, she said, is to remember that the topics covered should depend on the participants on the course – for example, if the participants are all inpatient staff, when she talks about acute and chronic complications, she would go over insulin-drip protocols and transition from drips to subcutaneous insulin infusion, but if they were care coordinators, the information on complications would be in the context of the information they need to impart to individuals that are newly discharged. 

All participants receive a portfolio with a welcome letter, a pretest, a learning-needs assessment in which they rate their current knowledge and confidence level in various areas (the same assessment is taken at the end of the programme) and a class schedule. Teaching consists of PowerPoints, handouts and a competency exam. She always includes a graduation and gift pack at the end. 

It’s a voluntary programme and no one is forced to attend. She has found that the people that attend want to do more for the patient, but don’t have the knowledge and confidence to do so.

With regard to lessons learned over the years, Dr Hughes discussed what she has changed such as shifting from it from a programme for nurses (it used to be known as the Diabetes Nurse Champion programme) to one for all disciplines; class sizes need to be fairly small (around 20); you must change the curriculum constantly to make sure it’s current, and tailor it based on the needs assessment of the discipline you’re teaching. She also covered the benefits of teaching online – COVID-19 allowed her to pivot to online delivery and this means reaching a much wider audience. Timing is also key, she said – cultivate respect by always starting on time and ending on time, especially as healthcare professionals may worry about courses that run over.

The outcomes have been impressive – for example, pre-test scores on insulin and its administration average at 40% whereas post-test scores are 100%, so it makes a real difference. 

With regard to sustainability, Dr Hughes offers a full-day ‘Keeping the skills alive’ programme once a year. This keeps participants engaged and current in their knowledge, she said. 

The title of the course is ‘Improve glycaemic outcomes and care transitions’ and what she’s noticed over years of teaching is an uptake of referrals from the participants. They often call with questions – perhaps something they’ve learned in class but don’t have the complete confidence to act on it. During each class, the number of referrals to the outpatient Diabetes Education Program increased by an average of five patients per class. 

Providers are also calling, she said, because the Diabetes Champions are telling them that they exist and they’re getting more referrals from those providers. Hypoglycaemic events have also decreased, as measured by the Society of Hospital Medicine. 

In summary:

  • Design the curriculum to meet the needs of the participants.
  • Use the data you collect to truly customise the curriculum – for example, she said, if she gets a majority saying they have zero confidence with inulin pumps, she spends more time on that part of the curriculum.
  • Use the programme evaluation for future classes.
  • The most important lesson she learned was that 100% of participants had either a personal connection to diabetes or a desire to improve their knowledge; advanced degrees did not equate to knowledge regarding diabetes care, management and education.

To learn more, enrol on the EASD e-Learning course ‘Patient education and support’.

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

Suzie Normanton, Feedback Lead in the EASD e-Learning team, reports on the range of external feedback received by the platform during the first six months of 2023 – and highlights how this feedback has resulted in improvements to the e-Learning programme.

Feedback is an important part of our external quality assurance programme, providing assurance that our e-Learning platform meets the expectations of our international community of healthcare professional learners by matching up to standards and a commitment to continuous quality improvement.

Currently, our key sources of external feedback include learners (healthcare professionals working in all aspects of diabetes care and research, all over the world), accrediting organisations (the UK’s Royal College of General Physicians and Royal College of Physicians) and other organisations that have endorsed modules on the platform (Primary Care Diabetes Society). Looking ahead to 2024, we are also hoping to gain accreditation from the European Accreditation Council for Continuing Medical Education (EACCME).

Learner feedback

Here are some examples of external feedback over the last six months, and how we have responded to them.

  • Ten learners have contacted us to request help with setting up an account or with the process of obtaining and downloading a certificate of completion; one learner recently responded to express their thanks, saying, “Yes, now it worked perfectly. Thank you for all your help!”. Another said, “That’s great, thank you. I am connected with many other colleagues who are always looking for CPD opportunities, so I’d be happy to pass on the details of your courses.”
  • When asked how they would rate their satisfaction with a specific module, of 38 learners who answered this question, 32% said they were ‘very satisfied’
  • 100% of learners agreed that the module is at the right level for their current knowledge
  • Whilst some learners said all parts of the module they studied were useful, the clinical case studies were also highlighted

Qualitative feedback included the following comments:

  • My understanding of diabetes neuropathy has vastly improved thanks to this course (Diabetic neuropathy: Module 1)
  • This course has significantly enhanced my knowledge and comprehension of diabetes neuropathy (Diabetic neuropathy: Module 2)
  • Latest advancements. (Non-alcoholic fatty liver disease: Module 2)

How could our modules be improved? 

The module authors are reviewing feedback in this section, which will be addressed via the periodic review process and include:

  • More data on adverse effects (GLP-1 receptor agonists: Module 2)
  • No change, excellent content (Real-world evidence: Module 2)
  • If possible to have a handout at the end as slides (Diabetes and Hajj: Module 1)
  • More data on adverse effects (Gestational diabetes: Module 1)
  • Just perfect (Lifestyle intervention: Module 1)
  • Include more explanations of the lifestyle non-pharmaceutical interventions and the impact versus therapy (Lifestyle intervention: Module 1)
  • More cases (SGLT-2 inhibitors: Module 8 and Module 9)
  • Simplify incidence (Diagnosis of type 1 diabetes: 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 learned from one of our modules to their own practice. Here are some of the examples we have received in recent months.

Learners stated that they will apply their learning from a specific module to their practice by:

  • “Applying my learning when prescribing GLP-1 RAs during my diabetic clinic” (GLP-1 receptor agonists: Module 1)
  • “Educating patients and healthcare providers” (Diabetes and the Hajj: Module 1)
  • “Changing my thought process regarding diabetes pathogenesis. It made me more wise” (Lifestyle intervention: Module 1)
  • “Applying the stepwise approach for diagnosis and management of patients” (Non-alcoholic fatty liver disease: Module 2)

Learners also said:

“My goal is to enhance the management of diabetic neuropathy in order to provide better care for my patients.” (Diabetic neuropathy: Module 3)

“As a healthcare provider, I plan to conduct foot screenings for my patients.” (Diabetic neuropathy: Module 3)

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]

Feedback from accrediting and endorsing organisations

Real-world evidence: Module 1

“The module explores the value attached to real-world evidence (RWE) in clinical decision making, which has significantly increased in recent years. The author uses examples taken from diabetes treatment to illustrate what RWE is and why it is important.”

Obesity and diabetes: Module 1

“Very useful module – good explanations, good changes of format – e.g. case studies, talking heads and graphs.”

Suggested changes included:

Feedback:     Could you provide a list of all references in each module as a PDF?

Response:     We are currently testing a method of doing this.

Feedback:     Add an optional pre-module interactive learning exercise to help with a base understanding of real-world evidence versus randomised control trials, and real-world evidence more generally.

Response:     We have discussed this feedback with the module authors and are planning to introduce.

Don’t forget you can also sign up for our newsletter to keep up to date with all

new EASD e-Learning courses and Horizons: EASD e-Learning – Provided by

leading diabetes academics (easd-elearning.org).

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

One in five people with type 2 diabetes have a normal or low body weight, with reduced muscle mass relative to their fat mass. A new study reported in Diabetologia shows that they have more to gain from strength training than weight loss when it comes to glycaemic control. Dr Susan Aldridge reports. 

While the majority of people with type 2 diabetes are overweight or obese, around 20% have a healthy weight with a BMI of 25 or less. This is known as normal-weight type 2 diabetes – it is now recognised as being a particular phenotype and it’s more common among Asians and older people. Normal-weight type 2 diabetes is associated with sarcopenia or loss of muscle mass, and research has suggested that this feature mediates the elevated mortality risk seen in this phenotype compared with diabetes with overweight.

Exercise is always recommended for people with type 2 diabetes. Guidelines are similar to those for the general population: three to five days per week of moderate-to-vigorous aerobic activity to reach a minimum duration of 150 min per week, plus two to three sessions of strength training. Trials comparing the impact of aerobic versus strength exercise on HbA1c have mostly been carried out in people with type 2 diabetes who also have overweight or obesity. For instance, the Diabetes Aerobic and Resistance Exercise (DARE) study and the Health Benefits of Aerobic and Resistance Training in individuals with type 2 diabetes (HART-D) study both found a combination of aerobic and strength training to be superior to either modality on its own in lowering HbA1c.

Individuals with obesity have both increased fat mass and increased lean muscle mass, while those with normal-weight type 2 diabetes are more likely to have a different body composition – namely, sarcopenia, especially related to their fat mass, which is known as relative sarcopenia. This suggests that the most effective exercise training for those with normal-weight type 2 diabetes may not be the same as for those who have overweight and obesity. That is why Yukari Kobayashi at Stanford University and colleagues set up the Strength Training Regimen for Normal Weight Diabetics (STRONG-D) study, which looks at the effects of strength training alone, aerobic training alone and a combination of the two upon glycaemic control in normal-weight people with diabetes. They hypothesised that these individuals might respond better to strength training than aerobic training, given their phenotype. The study looked at changes in body composition and muscle strength from these interventions and how these impacted HbA1c.

Focus on strength training

The 186 participants, of whom 83% were Asian, were assigned to either strength training only (ST), aerobic training (AER) or a combination of the two (COMB), which they did for three days a week for nine months. Strength training consisted of two sets of upper-body exercises (bench press, seated row, shoulder press and pull-down), three sets of leg exercises (leg press, extension and flexion) and abdominal crunches and back extensions. They worked up, increasing weight, to eight to 12 repetitions in a set. 

The aerobic group worked on a treadmill or exercise bike to 50-80% of their metabolic equivalent of task, which is energy expenditure related to their weight. Combination was two strength-training sessions and a slightly reduced amount of aerobic training. The primary outcome was change in HbA1c and secondary outcomes were changes in body composition and muscle strength at nine months. 

Mean HbA1c was 59.6 mmol/mol at the start of the trial and 131 participants actually completed it with data for analysis. At the end, there was a significant mean decrease in HbA1c in the ST group of 0.44%, compared with non-significant decreases of 0.35% in the COMB group and 0.24% in the AER group. Therefore, strength training alone was better than aerobic training or a combination of the two in reducing HbA1c levels in normal-weight individuals and combination training had an intermediate effect. Strength training also increased appendicular (arms and legs) lean mass relative to fat mass and was an independent predictor of a reduction in HbA1c. 

This was the first clinical trial of exercise in normal-weight individuals but there was no significant difference in the AER or COMB group. Of course, the findings need to be confirmed in further, larger studies, but there is no reason not to apply a recommendation of strength training immediately to people with normal-weight diabetes, the authors say.

In the STRONG-D study, only the ST group showed a significant reduction in HbA1c, which suggests a potentially unique benefit of strength training in normal-weight individuals with type 2 diabetes. In comparison with the strength-training groups in the HART-D and DARE studies, the ST group achieved a higher absolute mean reduction in HbA1c. The participants in STRONG-D had a lower fat mass and much lower lean mass than the participants in the other two studies. Given that 80% of the insulin-mediated glucose uptake occurs in skeletal muscle or lean mass, it may be important to look at increasing lean mass for improving glycaemic control in this population. 

Focus on body composition

An important finding of STRONG-D is that body composition – increase in lean mass, loss of fat mass – was independently associated with a reduction in HbA1c, while an increase in lean mass or decrease in fat mass alone was not. This adds to the growing body of evidence that estimates of muscle mass adjusted for fat mass show stronger associations with metabolic abnormalities than lean mass alone. 

Strength training led to increased muscle mass relative to decreased fat mass and it is this that seems to be more beneficial for lowering HbA1c in individuals with normal-weight HbA1c. In contrast, individuals with overweight or obesity can lower HbA1c by lowering fat mass. At present, there isn’t enough data to support body composition as a central target for exercise training in type 2 diabetes. However, these new findings, along with previous studies that have shown a relationship between body composition and cardiovascular mortality, show the benefits of strength training in the normal-weight diabetes population. 

Furthermore, weight loss is well established as being associated with a reduction in HbA1c in people with overweight or obesity and type 2 diabetes. In the STRONG-D study, significant weight loss was found only in the AER group and there was no relationship between weight loss and reduction in HbA1c. Thus, the most effective exercise regimen for overweight and obese individuals with type 2 diabetes may not necessarily be applicable to normal-weight individuals with type 2 diabetes. 

The findings of STRONG-D make an important contribution to exercise recommendations for lean individuals with type 2 diabetes. They could also inform personalised exercise recommendations for different diabetes phenotypes. In the current clinical guidelines for people with type 2 diabetes, there are no recommended strength-training regimens, so the authors used the strength-training programme from the HART-D study. 

In conclusion, the STRONG-D study shows that strength training alone was effective and superior to aerobic training alone for reducing HbA1c levels in individuals with normal-weight type 2 diabetes. Individuals with normal-weight type 2 diabetes present with relative sarcopenia and achieving increased muscle mass relative to decreased fat mass via strength training plays an important role in glycaemic control in this population. The findings of this study could help refine physical activity recommendations in type 2 diabetes by weight status.  

To read this paper, go to: Kobayashi Y, Long J, Dan S, Johannsen NM, Talamoa R, Raghuram A, Chung S, Kent K, Basina M, Lamendola C, Haddad F, Leonard Mb, Church TS, Palaniappan L. Strength training is more effective than aerobic exercise for improving glycaemic control and body composition in people with normal-weight type 2 diabetes: a randomised controlled trial.

Diabetologia 26 July 2023. https://doi.org/10.1007/s00125-023-05958-9

To learn more, enrol on the EASD e-Learning course ‘Management of hyperglycaemia in type 2 diabetes’.

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

Two weekly insulins are well into clinical development, with trials showing promising results so far. An expert panel at the American Diabetes Association’s 83rd Scientific Sessions discussed how these new medications might ease the diabetes burden, particularly for those with type 2 diabetes. Dr Susan Aldridge reports. 

The prospect of a daily insulin injection may delay intensification of treatment in type 2 diabetes, as well as adding to diabetes burden. Weekly insulin may alleviate these issues, so promising results from trials with insulin icodec and insulin efsitora have generated excitement in the diabetes community.  “Weekly insulin has been shown to improve health-related quality of life,” said Dr Juan Frias, Managing Director of Velocity Clinical Research. “It has the potential to improve persistence and adherence, and hopefully this will translate into improved short- and long-term outcomes.”

The pharmacokinetic profile of a weekly insulin is flat, meaning fewer hypos, and it can also be co-formulated with a GLP-1 receptor agonist, which has a complementary mode of action. The development of weekly insulins relies on extending the half-life of the insulin molecule which, as a peptide, has a short half-life, requiring continuous infusion or frequent injection. Drug delivery systems can overcome this by creating lipid particle or polymeric systems containing insulin, which allow for slower absorption from subcutaneous tissues.

Efsitora is a fusion protein with two single chain insulin molecules and the Fc region of an immunoglobulin G molecule, with a molecular weight of 50 kilodaltons. Meanwhile, icodec (the other weekly insulin in clinical development) is strongly – but reversibly – bound to albumin, creating a subcutaneous insulin reservoir. Efsitora has been developed by Eli Lilly and is in Phase 3 clinical trials with the QWINT programme, while Novo Nordisk’s icodec is in Phase 3 trials with the ONWARD programme. 

“Efsitora has a half-life of 17 days because of its slow absorption from the subcutaneous space,” explained Dr Frias. “It also has reduced insulin receptor affinity and reduced renal clearance – this leads to a recycling effect, which is important in the prolongation of its action. It achieves a dose-dependent decrease in fasting blood glucose with a nadir between days four and six in type 2 diabetes.” 

Meanwhile, icodec has three amino-acid substitutions in its insulin chain, which reduces enzymatic degradation. It also has lower insulin receptor-binding affinity, which slows insulin receptor-mediated clearance, as well as improved solubility, allowing for a U700 formulation, which is good for weekly administration. 

In summary, molecular modifications and methodologies confer biological properties, including those relating to pharmacokinetics and pharmacodynamics, on these weekly insulins making them suitable for once-weekly dosing. 

Clinical trials update

Ildiko Lingvay, Professor of Medicine at the University of Texas Southwestern Medical Center, reviewed the clinical trials on the two weekly insulins. There have been three Phase 2 trials in the QWINT programme, all involving people with type 2 diabetes, who were either insulin naïve or switching from another basal insulin, with efsitora against glargine as comparator. 

There has also been a trial involving people with type 1 diabetes on multiple daily injections (MDI). Meanwhile, the ONWARDS Phase 3 programme with icodec has also involved people with type 2 diabetes, except for ONWARDS 6, which includes those with type 1 diabetes, and has similarly looked at those who are insulin naïve and switching from another basal insulin against insulin glargine or insulin degludec. Professor Lingvay went on to review the data so far via a series of questions. 

First and foremost, do the weekly insulins lower glucose as you would expect for a basal insulin? “In each of the Phase 2 trials, HbA1c lowering matches – or is even lower than – that of the comparator, and there is the same finding for the Phase 3 programme where we have results,” said Professor Lingvay. “So, yes, absolutely they do.” What about hypos? “Looking at insulin-naïve patients with level 2 or 3 hypos, there were very few, but there is a more mixed picture for insulin-experienced patients making the switch, with a very small absolute increase,” she said. In addition, there was no difference in duration of a hypo between the weekly insulins and their comparators.

For Time in Range and Time below Range, there was very little difference between the weekly insulin and comparator, save for a statistically significant difference in favour of icodec in the ONWARDS 1 trial where Time in Range was better, Time above Range less and Time below Range about the same.  

Since the insulin dose in a weekly insulin is so large, there have naturally been concerns over the impact of accidentally taking an extra dose. There has been a separate study on this, which shows that comparable numbers got clinical hypoglycaemia with an extra dose between the weekly insulin and insulin glargine. “So you might get a low, but it’s not going to be any worse than taking an extra dose of a daily insulin,” said Professor Lingvay. There is also no difference in response whether you inject the insulin in the thigh, abdomen or upper arm. Finally, Professor Lingvay’s analysis of 11 studies shows that people do gain weight when they start the insulin, but this is related more to HbA1c levels than the type of insulin.  

She also referred to the IcoSema Phase 3 trial programme, with a combination of icodec and semaglutide, and hopes results will be ready for next year’s ADA meeting.  

“From my patients’ point of view, the biggest benefit is only having to take one shot of insulin instead of seven in the week,” Professor Lingvay concluded. “Everything else is similar. The weekly insulins are expected to reduce barriers to treatment, reduce treatment burden and improve quality of life. All of these are important features for our patients.” 

Patient and provider perspectives

Chantal Mathieu, Professor of Medicine at KU Leuven, Belgium, and President of the EASD, began by sharing some statements from participants in the weekly insulin trials, such as, “Why are you even asking me whether I would prefer to administer one injection a day or one a week?”.

“One participant in the ONWARD 4 study, who had been on MDI for five years said, at the end of the trial, ‘You need to keep giving me the weekly insulin,’” said Professor Mathieu. “I replied, ‘But what is the difference because you need your daily mealtime insulin anyway’. Her response was, ‘Every injection I can avoid is a plus. What a relief it was that I did not have to give my basal insulin every day during the trial’. I was even more surprised that this participant was so angry with me that I couldn’t keep giving her the weekly insulin. So I saw great enthusiasm for weekly insulins among patients.”

Views among providers were different, though. Endocrinologists feared major stacking of insulin with weekly injections and thus prolonged hypoglycaemia, which would be impossible to manage. Diabetes educators said that with so much insulin on board, people will gain a lot of weight. Primary care providers, on the other hand, were more positive saying: “Oh, this is nice. So we can now give insulin in the same way as we give GLP-1 receptor agonists”. 

“There are some diverse opinions out there,” said Professor Mathieu, “but Ildiko showed the benefits of weekly insulins very nicely in her talk – convenience, improved health-related quality of life and a less overwhelming sense of treatment burden.” 

Who should get weekly insulin?

Professor Mathieu turned to an issue that will be of major concern to providers. Which patients do we want to use weekly insulins? “Hypoglycaemia was my biggest fear,” she admitted. “But the clinical data show only a slight increase and this was the biggest surprise. And it was mainly induced by mealtime insulin rather than basal. I do think the jury is still out on the place of weekly insulins in those with type 1 diabetes, but I would give money to have a once-weekly insulin in some of my adolescent patients. However, we will use personalised medicine and decide who with type 1 diabetes can benefit because, in the trials, there was an increase in hypos in those who started with a very nice HbA1c.” 

Turning to efsitora, this increase in hypos in participants with type 1 diabetes wasn’t seen as in ONWARDS 6 with icodec, but Time in Range was only in the 50% range, which is a concern. “So when considering a weekly insulin in type 1 diabetes, I think it depends upon baseline HbA1c,” said Professor Mathieu.

Clinicians will also want advice on initiating a weekly insulin. From the Phase 3 trials on icodec, Professor Mathieu would advise that you do as you would when initiating an insulin-naïve individual on glargine and so a one-time 50% loading dose, then titrate 20U up or down depending on glucose measurements. With efsitora, which is earlier in clinical development, initiating is more of an exploratory process where starting doses are still being evaluated and it is hoped there will be firmer guidance by next year.

What about people on MDI? The ONWARDS 4 trial showed some very interesting data. If you have a weekly insulin on board, you need less mealtime insulin. “This was quite spectacular,” said ProfessorMathieu. “There was almost no titration needed of the mealtime insulin. As clinicians we will have to take this on and bring the mealtime insulin down. It opens up new perspectives for us. Perhaps with once-weekly insulins, we will have fewer people needing MDI. Maybe, if we combine it with a GLP-1 receptor agonist, we can get rid of mealtime insulin, making the burden of insulin treatment in type 2 diabetes a lot less.”

So, in summary, weekly insulins will first and foremost be for people with type 2 diabetes in need of a basal insulin and for some with type 1 diabetes as well. We know that people like weekly insulins as the ONWARDS trials have Patient Reported Outcomes that mention treatment satisfaction, convenience and flexibility. Of course, questions remain and some of the knowledge gaps are about the impact of exercise, intercurrent illness, fasting and hospitalisation. We also need more information about weekly insulins in pregnancy, the elderly and in children. “So we will need communication and education, in particular for primary care, nurses, diabetes educators, dietitians, surgeons, internists, paediatricians and patients,” concluded Professor Mathieu.  

Future outlook for weekly insulins

Dr Ronald Goldenberg of LMC Diabetes & Endocrinology, Toronto, said,“There have been incredible innovations in the half-life of insulins and we’ll probably be able to prescribe icodec sometime in 2024 and efsitora in 2025.” This is because the efficacy and safety data in type 2 diabetes is very encouraging, as is that on therapeutic inertia, adherence and treatment satisfaction. “In fact, efficacy and safety in the ONWARDS trials show superiority for the weekly insulin over the daily comparator.” he said. “So if you have a choice for insulin-naïve patients, I think clinicians will favour the once-weekly. In the type 2 diabetes space, there is good efficacy and safety. The data on efsitora is encouraging too, but we need to wait for the Phase 3 trial results.” 

The ability to prescribe a once-weekly basal insulin really helps in type 2 diabetes. “We know that initiation of insulin is often delayed and 30% of patients decline it, then 38% of the decliners eventually start on insulin, with mean time to initiation of more than two years,” said Dr Goldenberg. Even then, uptitration is slow and insufficient in the six months after initiation. In the trials, the insulin-naïve patients had diabetes duration of 10 to 12 years. The availability of weekly insulin will allow earlier initiation and titration.  

However, Dr Goldenberg sounded some cautions. “There will need to be some education around the fear of high doses. There is also some complexity around different regimes for insulin-naïve patients and those who are switching from another insulin when it comes to initiation and titration, but this can be addressed with apps and smart pens.” 

Then there is the issue of cost and access. “Banting would roll over in his grave if he saw what was happening with the cost of insulin in recent years,” said Dr Goldenberg. “Things are getting better in the US, with various programmes to reduce the cost, but the big question is will weekly insulins be accessible and affordable?”.

And then there is type 1 diabetes, where the go-ahead for weekly insulins is currently at a red light. “We need more information before we can go forward with this,” he said. “We need a deeper dive into the hypos seen in the ONWARDS 6 trial. Who were the patients most affected, what were their characteristics and so on?”.

So, in conclusion, Dr Goldenberg agreed with Professor Mathieu that initiating weekly insulins in type 2 diabetes is a ‘no brainer’ and he thinks that for some patients in the future, the combination of a weekly basal insulin and a GLP-1 receptor agonist could well be the way forward.  

To learn more, enrol on the EASD e-Learning course ‘Management of hyperglycaemia in type 2 diabetes’.

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

The presence of severe mental illness can worsen cardiovascular morbidity and mortality suggests a study based on a nationwide type 2 diabetes cohort, reported in Diabetes Care. This high-risk group therefore merits special attention when it comes to prevention and management of heart disease. Dr Susan Aldridge reports.

People who have severe mental illness (SMI), including schizophrenia, bipolar disorder and major depression, have a 10 to 20 years shorter life expectancy than the general population. This premature mortality is largely due to a higher risk of physical disease, particularly cardiovascular disease (CVD), where diabetes is a major risk factor. Having SMI is also associated with a two to three-fold higher risk of type 2 diabetes – a risk that may even be on the increase.  

While we already know that depression in people with diabetes is associated with increased risk of CVD and cardiac death, other complications and all-cause mortality, fewer studies have focused on severe depression, schizophrenia and bipolar disorder. In the few existing studies, SMI is consistently associated with an increased risk of mortality among people with diabetes, but findings on associations between SMI and macrovascular and microvascular complications have been inconsistent. 

In a new study, Caroline Jackson of the University of Edinburgh and on behalf of the Scottish Diabetes Research Network Epidemiology Group, looked at a large, nationally representative diabetes cohort to determine the association between SMI and clinical outcomes. Their aim was to determine the independent effects of schizophrenia, bipolar disorder and major depression on the risk of major CVD events, CVD-specific mortality and all-cause mortality in people with type 2 diabetes. 

The study drew upon data from the Scottish Diabetes Research Network National Diabetes Dataset (SDRN-NDS), which covers 99% of people with diabetes in Scotland. It includes information on type of diabetes, sociodemographics, routine diabetes care, including retinopathy screening, and linked acute and psychiatric hospital records and death records. The study population comprised 259,875 adults diagnosed with type 2 diabetes in Scotland between 2004 and 2018 whose data could be linked with hospital and death records. 

The primary outcomes were major CVD events – myocardial infarction (MI) or stroke – in the whole cohort and also in the subgroup without a history of CVD, CVD-specific mortality and all-cause mortality. Secondary outcomes were related to other diabetes complications, consisting of retinopathy, renal replacement therapy and lower-limb amputation.

Characteristics of people with SMI and type 2 diabetes

The SDRN-NDS hospital record data revealed that 2,621 (1%) of this cohort had a diagnosis of schizophrenia, 1,211 (0.5%) had bipolar disorder and 7,903 (3%) had depression. The cohort was mainly of White ethnicity and there was a higher prevalence of type 2 diabetes among those from more deprived areas. This was even more striking among those with SMI. For instance, more than one-third of those with schizophrenia came from the most deprived fifth of areas in Scotland. 

Diabetes was diagnosed at a younger mean age in those with a history of schizophrenia (52.1 years), bipolar disorder (57.5 years) or depression (58.9 years), compared with those without a history of SMI (60.8 years). 

Furthermore, history of prior CVD, comorbidity and high cholesterol at the time of diabetes diagnosis were also more common among those with depression and bipolar disorder compared with those without SMI. This wasn’t seen for those with schizophrenia, maybe reflecting their younger age at diabetes diagnosis. Smoking, history of alcohol use disorder and overweight or obesity were also more common among those with SMI.

The impact of SMI

The researchers carried out a statistical analysis that adjusted for all the factors that could affect the findings – sociodemographics, HbA1c, hypertension, smoking and so on. This fully adjusted model helped clarify the link between the presence of SMI and health outcomes. 

During a mean of 6.9 years of follow-up, there were nearly 25,000 major CVD events. All three SMIs were associated with an increased risk of having a major CVD event. The hazard ratios were 1.07, 1.37 and 1.22, for schizophrenia, bipolar disorder and depression, respectively, for the fully adjusted model. The association was similar, whether or not the individual had a history of CVD. 

There were also 51,029 deaths occurring during a mean follow-up of 7.1 years. Deaths from CVD were higher among those with SMI than those without, with hazard ratios of 2.38 for schizophrenia, 1.70 for bipolar disorder and 1.84 for depression. This was for a model adjusted for sociodemographic factors – the hazard ratios were attenuated only slightly when the fully adjusted model was applied, so there is a persistent higher risk of CVD mortality in all groups with SMI and type 2 diabetes. Similar increased risk also applied to all-cause mortality. 

When it came to the secondary outcomes, numbers with lower limb amputation and renal replacement therapy were low – at around 0.6% and 0.2%, respectively – in those with and without a history of SMI. Referable retinopathy occurred in around 5% of both groups. Numbers for these three complications were too low to make comparisons between those with and without SMI in this study. 

Previous studies of SMI and macrovascular complications among people with diabetes report conflicting findings. For instance, a study from South Korea found a similar excess risk of heart attack and stroke among those with diabetes and schizophrenia, bipolar disorder or depression. A Taiwanese study found an association between clinical depression with diabetes and increased risk of acute coronary syndrome and stoke. And these new findings also echo those of a Danish study that found that SMI, as a composite exposure, was associated with higher CVD risk – although that was more broadly defined than in the current study. In contrast, however, there have been two studies that actually reported a lower risk of CVD events among people with schizophrenia or major depression. 

Only two previous studies have reported an association between SMI and CV-specific mortality in diabetes, with similar findings. There has also been a meta-analysis of studies examining depression of any severity and the risk and the risk of CV mortality in people with diabetes – again with similar findings. And the observed excess all-cause mortality among people with diabetes and SMI compared with no mental illness is consistent with previous literature. This new study adds to scarce data on bipolar disorder, which has been less studied in this context in comparison with schizophrenia and major depression. 

Underlying reasons

The mechanisms behind the increased CVD morbidity and mortality among those with diabetes and SMI shown by this new study are complicated and poorly understood. We already know that shared risk factors for poor physical and mental health include low socioeconomic status, adverse childhood experiences and lifestyle. In this study, the higher prevalence of smoking, overweight and obesity and comorbidities was made evident through statistical analysis that adjusted for these factors and showed an attenuation of the risk. Meanwhile, a study from Denmark of people with type 2 diabetes showed that excess mortality among those with depression was largely explained through smoking, physical activity and comorbidities. 

There is also emerging evidence that brain insulin resistance might be part of the pathophysiology of schizophrenia and bipolar disorder. This might go some way to explaining poorer diabetes outcomes in those with SMI. 

Inequalities in care for physical disease may also explain the poorer outcomes among those with SMI and diabetes. A recent study from Denmark reports lower rates of diabetes monitoring and achievement of HbA1c and cholesterol targets in those with SMI, compared with those without. However, disparities in care do not explain the findings in this new study – in Scotland, receipt of diabetes care processes is actually similar or better in those with SMI than for those without. 

It may be that this does not translate into optimal treatment of those with CVD risk factors or established CVD. Previous studies of populations with and without diabetes have uncovered suboptimal CVD risk management in those with SMI. The excess risk of CV death in people with diabetes and SMI found in this new study may reflect more severe cardiovascular events and potential differences in cardiac care, both in the acute phase and subsequently. For instance, previous work from these authors has shown that patients with SMI were less likely to receive coronary revascularisation after MI, were less likely to survive for 30 days post-MI and were more likely to have a further vascular event than those without mental illness. 

Cardiac and metabolic adverse effects of some antipsychotic medications may also play a role in poorer outcomes. The impact of antipsychotic and antidepressant drugs upon CV and mortality outcomes in people with diabetes is an underinvestigated topic. 

This new study shines a light on an area where previous studies are scarce or contradictory and addresses a number of limitations and gaps in the literature. It draws on data from a nationally representative cohort of people with diabetes with and without SMI. This large study population and long follow-up allowed the researchers to investigate individual SMIs, analyse specific CVD outcomes and obtain reliable, precise effect estimates for outcomes. The richness of the diabetes register allowed associations to be adjusted for key lifestyle factors, which hasn’t always been done in other studies. Finally, the study also adds to scarce data on associations between SMI and CVD-specific mortality in people with diabetes and on all-cause mortality in those with bipolar disorder specifically. 

In conclusion, among people with new-onset type 2 diabetes, those with a prior history of SMI have a markedly higher risk of major CVD events, CVD-specific mortality and all-cause mortality than people with no mental illness. Some of this excess risk is due to modifiable risk factors, including smoking, alcohol misuse and obesity, highlighting the need for effective lifestyle modification in people with SMI. However, there are other emerging mechanisms, including possible shared pathophysiology between SMI and diabetes, which require further investigation. 

Another future avenue of research should be the role of psychotropic medication use and receipt of optimal cardiac care in primary and secondary care settings. Meanwhile, effective prevention and management of cardiovascular risk factors is needed in this high-risk group to improve clinical outcomes. 

To read this paper, go to: Fleetwood KJ, Wild SH, Licence KAM, Mercer SW, Smith DJ, Jackson CA on behalf of the Scottish Diabetes Research Network Epidemiology Group. Diabetes Care 2023;46:1363–1371. https://doi.org/10.2337/dc23-0177

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

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

When it comes to reducing carbohydrates in the diet, should people with diabetes opt for moderate intake or very low? Two viewpoints were presented at the recent American Diabetes Association’s 83rd Scientific Sessions. Lisa Buckingham reports.

Arguing that moderate carbohydrate eating is best, Dr Carol Kirkpatrick, Clinical Scientist at Midwest Biomedical Research Adjunct Faculty at Idaho State University, began by discussing the variety in definitions of carbohydrate-restricted dietary patterns within randomised controlled trials, which make it hard to evaluate evidence. Her team created a clearer definition and this is what she referred to throughout: Based on 2,000 calories per day: Moderate = 26-44% of calories from carbohydrate per day (130-220 g); Low = 10-25% (50-125 g); Very low = <10% (20-50 g). 

Starting with weight management, she highlighted a study comparing carbohydrate-restricted diets with higher carbohydrate diets, which found that while short-term weight loss was greater with low or very-low-carbohydrate dietary patterns, the effect was lost beyond 12 months. This can be partly due to difficulties with adherence to severe carbohydrate restriction (although we can acknowledge that it’s difficult for patients to adhere to any dietary pattern, she said).

A 2022 meta-analysis looked at the dose-dependent effect of carbohydrate restriction on different cardiometabolic risk factors. There was a significant decrease in bodyweight at six months as carbohydrate intake reduced; however, by 12 months, the significant effect did not remain. 

My stance, said Dr Kirkpatrick, is that moderate carbohydrate is best – this was demonstrated by a meta-analysis, which showed that 35% carbohydrate at 12 months showed the greatest difference in bodyweight compared with the lower and higher intake of carbohydrate. Perhaps, she said, people were better able to adhere to the moderate intake as carbohydrate restriction is difficult to adhere to, especially in the long-term. 

With regard to effect on lipoprotein lipids, a review of the evidence and several meta-analyses since showed that when it comes to LDL cholesterol levels, there is a very low response. Some patients do achieve lower LDL, especially if they’re able to lose adiposity. However, she said, some experience an increase, especially if they have a genetic susceptibility, and a high intake of foods rich in saturated fatty acids can also contribute. It’s therefore important that if a patient chooses to restrict carbohydrates, they replace those foods with unsaturated fats. In general, triglycerides decrease and HDL cholesterol goes up. 

Returning to the dose-response study, the greatest reduction in LDL cholesterol at six months was seen at 40% carbohydrate, which is line with Dr Kirkpatrick’s ‘moderate carbohydrate is best’ stance. 

She drew attention to another 2020 meta-analysis, which showed that a moderate carbohydrate intake resulted in the lowest increase in LDL cholesterol, compared with low- and very-low-carbohydrate intake. For triglycerides, with each reduction in carbohydrate intake, triglyceride levels decreased, so the most significant decrease was seen in the very-low-carbohydrate bracket. 

However, said Dr Kirkpatrick, when it comes to cardiovascular health, we’re not entirely sure what that means – we know that elevated triglyceride levels are associated with cardiovascular risk but what we’re looking for is the overall atherogenic particles in the bloodstream and LDL and non-HDL cholesterol gives us that information. Therefore, we should look at the results in the presence of both triglyceride lowering as well as what’s happening with LDL and non-HDL cholesterol. When we do this, we see that a moderate-carbohydrate intake allows a decrease in triglycerides without an increase in LDL cholesterol. 

Next, she looked at the effect of carbohydrate intake on HbA1c. Research consistently shows beneficial effects at all levels of carbohydrate restriction. The lower they go, the greater the decrease in HbA1c although this does wane at 12 months at all levels of intake.

Dr Kirkpatrick highlighted the PREDIMED and CORDIOPREV studies on cardiovascular health – both of these are dietary intervention studies showing a decrease in cardiovascular events with a Mediterranean dietary pattern – in both, she pointed out, the dietary pattern was moderate carbohydrate. 

In terms of observational studies, which she acknowledged have their limitations, we see that extreme intakes of carbohydrate is associated an increased risk of all-cause mortality – here, she showed a 2018 cohort analysis showing that lower carbohydrate intake of less than 40% was associated with an increased risk of all-cause mortality, compared with a moderate carbohydrate intake of 50%, and at the other end of the spectrum, too high an intake (>70%) was also associated with an increased risk of all-cause mortality.

Her take-home messages were:

  • Benefits of carbohydrate-restricted dietary patterns were achieved at moderate carbohydrate intakes – triglycerides and HbA1c values improve more with severe carbohydrate restriction but the effect wanes with longer duration. 
  • Very low carbohydrate intakes are difficult to maintain and lower carbohydrate intake is associated with increased mortality in cohort studies.  
  • Recommended healthy dietary patterns can be moderate in carbohydrate, with replacement being healthy protein foods and unsaturated fatty acids and the Mediterranean diet pattern has the strongest evidence of benefit.

The argument for very-low-carbohydrate intake

Dr Dina Griauzde, Assistant Professor of Internal Medicine at the University of Michigan, stepped in to present on behalf of Professor William S Yancy from the Duke Lifestyle & Weight Management Centre, to make the case for very-low-carb eating. 

The case for very-low-carb eating centres around improvement of glycaemic control and not increasing cardiovascular risk (likely lowering it). 

Low-carb diets are often referred to as fad diets, she said, but it’s important to note that they have been around for over a century, showing a quote from Dr Elliott Proctor Joslin in 1923 discussing the restriction of carbs. It was the only treatment for type 1 diabetes before the advent of exogenous insulin and the Joslin Diabetic Diet recommended just 15g of carbohydrate per day (2% of daily calories).

The first study she drew attention to was a small inpatient feeding study of adults with type 2 diabetes who initially ate a high-carb diet for seven days followed by a transition to a two-week period of a very-low-carb eating pattern (20g of carbohydrate per day). During the low-carb phase, glucose and insulin levels were substantially lower and HbA1c decreased from 7.3% to 6.8% over 14 days. We don’t see that effect with medication, she said – a very-low-carbohydrate diet is the most potent tool we have to help patients achieve glycaemic control.

She then outlined the Carbohydrate-Insulin Model, which explains why carbohydrate is considered more obesogenic:

  • Dietary carbohydrate (sugar or starch) raises serum glucose and insulin.
  • A carbohydrate-restricted diet reduces the diet contribution to serum glucose, which then lowers insulin levels.
  • Insulin is a potent stimulator of lipogenesis (fat storage) and a potent inhibitor of lipolysis (fat burning).
  • Lowering insulin level (or dose) leads to burning of stored body fat, raising serum ketones and lowering body weight. 

The idea that dietary carbohydrate can drive overeating was represented in data from a paediatric feeding trial in which a small cohort of boys with overweight or obesity had three evaluations. During each evaluation period, they consumed a diet with different carbohydrate content. They found that those who had consumed a higher carbohydrate meal ate more and had higher glucose and insulin responses, as compared with those who ate a lower carbohydrate meal. 

Next, she highlighted a systematic review of 13 trials in which dietary carbohydrate was restricted to less than 45% of total daily energy per day and these data were consistent with Dr Kirkpatrick’s data – the degree of improvement in glycaemic status was associated with greater carbohydrate restriction. 

A meta-analysis of 56 trials was next, comparing diet effects on glycaemia in type 2 diabetes with a total of 4937 participants and comparing nine diets. It concluded that: ‘For reducing HbA1c, the low-carbohydrate diet was ranked as the best dietary approach followed by the Mediterranean diet and Palaeolithic diet, compared with a control diet. 

She then moved on to discuss the role of a very-low-carbohydrate diet in relation to cardiovascular disease (CVD). One of the criticisms of this diet pattern is that it’s high in saturated fat and this potentiates CVD risk. However, in a meta-analysis of 21 studies, the intake of saturated fat was not associated with coronary heart disease (CHD), stroke or CVD.

We can take this one step further, said Dr Griauzde, by saying that saturated fat (when consumed as part of a very-low-carb diet) may actually improve key measures of cardiometabolic health. She showed a small study of 40 adults with metabolic dysfunction – it involved 12 weeks of eating 1500 calories per day. Participants on the very-low-carb diet had significantly greater improvements in key measures of cardiometabolic health, such as body mass index and triglycerides. She drew attention to the fact that small LDL (which is more atherogenic than larger LDL particles) increased to a greater extent in individuals following the low-fat diet. Total serum fatty acids (SFAs) decreased to a significantly greater extent in the low-carb group despite a three- to fivefold increase in saturated fat intake. 

The take-home points were: 

  • Low carbohydrate intake leads to rapid reduction in glucose and lower insulin levels.
  • The lower the carbohydrate, the lower the blood glucose trends. 
  • In patients with diabetes, very-low-carb eating also lowers medication requirements more than other eating plans.
  • Blood pressure decreases, serum HDL increases and triglycerides decrease.
  • LDL cholesterol does not typically increase AND small LDL decreases.

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

A new study, based on type 1 diabetes audit data and reported in Diabetes Care, shows that failure to engage with services, hyperglycaemia and diabetic ketoacidosis peak in late adolescence. Therefore, innovative approaches to optimising glycaemia during the transition from paediatric to adult care are needed to avoid later-life complications. Dr Susan Aldridge reports. 

In young people who have type 1 diabetes, hyperglycaemia increases during adolescence and continues to do so as they transition to adult services. Data from the T1D Exchange Clinical Network confirm this and their 2016-2018 report shows that glycaemic control in those aged 15 to 18 years has deteriorated further, despite increased use of diabetes technology.  

It is generally assumed that it is the transition from paediatric to adult services at the age of 16 to 18 years, with changes in continuity and support, which leads to hyperglycaemia at this stage of life. There are also personal psychological issues and the influence of growth-related hormonal change on insulin requirements to consider. Whatever the cause, even these few years of hyperglycaemia can have long-term consequences, as seen from the follow-up of the Diabetes Control and Complications Trial.

In a new study, Naomi Holman at Imperial College London and colleagues looked at data from diabetes audits in England and Wales to investigate the age-related changes in HbA1c measurement, HbA1c levels and hospital admissions for diabetic ketoacidosis (DKA) in children and young people.

Exploring the age-related trajectory of hyperglycaemia

The National Diabetes Audit (NDA) for England and Wales collects data on people of all ages with a diabetes diagnosis from primary care records and adult specialist diabetes services. Each audit includes data for a 15-month period from 1 January to 31 March in the following year. Meanwhile, the National Paediatric Diabetes Audit (NPDA) collects data on children and young people from paediatric diabetes services in England and Wales for a 12-month time period from 1 April to 31 March in the following year. 

The researchers identified sequential cohorts of people with type 1 diabetes aged between five and 30 years from the 2017/2018, 2018/2019 and 2019/2020 data collections of the NDA and NPDA, from which they created a pooled cohort of 93,125 individuals. Then, for each year of age, the latest HbA1c measurement was identified and recorded, along with hospital admissions for DKA. 

The existence of an HbA1c record was used as a measure of clinic attendance and engagement with health services. The proportion of records lacking an HbA1c measurement was low (around 5%) up to age 16 and then it rose rapidly, peaking at 22.3% at age 21 for men and 17.3% at age 19 to 20 years for women. It then fell gradually to 17.9% for men and 13.1% for women at the age of 30. This reflects a peak in lack of engagement with services around the ages of 19 to 21, which never falls back to the level achieved in childhood.  

As has been previously observed, HbA1c rises with age, peaking in young adulthood, then falling again. At the age of nine, median HbA1c was 60 mmol/mol for males and 61 mmol/mol for females, peaking at age 19 at 72 mmol/mol for young men and 74 mmol/mol for young women. By the age of 39, it had fallen to 68 mmol/mol for men and 66 mmol/mol for women. Between the ages of 16 and 22 years, median HbA1c was consistently higher for women than men. 

When it came to glycaemic control, those aged 20 had the lowest proportion reaching a target of 58 mmol/mol or lower. And the greatest proportion of those with a very high HbA1c (more than 86 mmol/mol) was among young men aged 17 (31.4%) and young women aged 18 (35.8%). These age-related patterns persisted after adjustment for ethnicity, social deprivation and duration of diabetes. 

Finally, annual prevalence of one or more hospital admissions for DKA rose from 2% for boys and 1.4% for girls at the age of six, to a peak of 7.9% at age 19 for young men and 12.7% at age 18 for young women. After this, prevalence fell and, at age 30, it was 4.3% for men and 5.4% for women. Each year from the age of nine, the proportion of females with one or more annual hospitalisations for DKA was significantly higher than in males.

A significant drop in attendance

This analysis of over 93,000 individuals in England and Wales highlights the changes that occur when children with type 1 diabetes pass through adolescence to early adulthood. We’ve learned that almost all children have annual records for HbA1c – only 5% do not – reflecting faithful attendance at clinic. When they transition to adult services between the ages of 16 and 20, this proportion drops to around 80%. Median HbA1c, along with hospitalisation for DKA, starts to rise earlier but peaks around the time of transition. It then decreases again, but never goes back to childhood levels. 

So the HbA1c upward trend starts before, and continues after, the transition period. This hyperglycaemia pattern reflects that found in the SWEET project, which compiled data on 66,418 individuals with type 1 diabetes from 22 centres across 19 countries. It found that, from 2016 to 2018, HbA1c rose steadily from the age of six to 18 years. The scale in the rise of HbA1c from age nine to 18 years was 12 mmol/mol for males and 11 mmol/mol for females, and is similar to the 11 mmol/mol increase in HbA1c reported in another study for a combined cohort of individuals living in Germany or Austria and the US. 

The sudden increase at age 17 to 19 years in those lacking annual HbA1c records suggests a dramatic reduction in attendance at clinic at the time of changing provision from paediatric to adult. This age is also a time of increasing psychological and social pressures – leaving home for university, for instance. Adolescence is a time of profound psychological change for all young people and the more so if they have to manage a chronic condition like diabetes. The need for continual self-care is relentless and can create a considerable burden. Both very high HbA1c levels and DKA have been associated with insulin omission and psychological stress. An additional personal and clinical challenge is the effects of the surge in puberty-associated growth hormones. This demands physiologically matched adjustments of insulin, which will only add to the burden. 

While this study was not designed to identify the underlying reasons for lack of engagement, the authors suggest that it is likely due to a combination of personal and health-service factors. Whatever the reasons, this lack of engagement in late adolescence is concerning – research shows that people with type 1 diabetes for whom routine care processes have not been recorded are at increased risk of future morbidity and mortality. This is particularly so for those with the highest HbA1c levels and repeated admissions for DKA. 

This study found greater adverse changes among young women with type 1 diabetes. They were less likely to reach a glycaemic target of 58 mmol/mol and more likely to have an HbA1c of more than 86 mmol/mol. And, between the ages of 15 and 25, they were more likely to have at least one episode of DKA, compared with men of the same age. One reason for this inequality might be the higher prevalence of disordered eating among women. Psychological and societal pressures, including approaches to body image and peer pressure, may play out differently between men and women in this age group. 

The authors point out that this new study may even underestimate problematic hyperglycaemia among children and young people. The data comes from routine health records, which means that it is limited to those individuals who are actually engaging with health services. It therefore misses those who are potentially at greatest risk. The peak age for highest HbA1c coincides with the peak age for lack of records. One-third of the cohort had HbA1c of 86 mmol/mol or more at a time when another fifth had not even had their HbA1c recorded. While we can’t know for sure, it is likely that non-attenders have high HbA1c. So the scale of the increase in HbA1c in the late teens might be even greater than that recorded in this study. 

In conclusion, these findings point to the need for novel approaches to the support of children and young adults with type 1 diabetes. The aim should be to flatten the rise in HbA1c during the teenage years and reduce the peak in DKA admissions that occurs around the same time. It is clear from this study that improved, innovative, well-resourced and age-appropriate service designs oriented to deliver optimal diabetes care over the course of adolescence to young adulthood are warranted.

To read this paper, go to Holman N, Woch E, Dayan C, Warner J, Robinson H, Young B, Elliott J. National trends in hyperglycaemia and diabetic ketoacidosis in children, adolescents and young adults with type 1 diabetes: a challenge due to age of stage of development or is new thinking about service provision needed? Diabetes Care 2023; 46(7): 1404–1408. https://doi.org/10.2337/dc23-0180

To learn more about how to manage patients after the transition into adult care, enrol on the EASD e-Learning course ‘Management of type 1 diabetes in adults’.

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

There are more people on the move around the world than ever before, so it is crucial to understand the specific factors that affect immigrants’ health. An expert panel discussed the latest research on immigration and diabetes at the recent American Diabetes Association’s 83rd Scientific Sessions. Dr Susan Aldridge reports. 

One theme that often comes up when discussing the health of migrants is the ‘healthy immigrant’ paradox, whereby a recent migrant has better health than a native of the country they are arriving in. This benefit tends to disappear over time, with future generations’ health becoming more like that of native people. 

Megha Shah, Assistant Professor at Emory University School of Medicine, took up the discussion with reference to the Hawaii-Los Angeles-Hiroshima study. Started in 1970, this study showed how adapting to a Western diet has led to an increase in diabetes among Japanese people emigrating to the US over the last 50 years compared with those who remained in their native country. “Native Japanese people have a certain lifestyle, but when they emigrate, their risk of diabetes and obesity increases,” said Professor Shah. “But that’s only one community and we have much variation in diabetes risk depending on where someone comes from.” 

The immigrant paradox does not always hold true. There are particular risk factors – namely acculturation, social context and environmental exposures – that the next generations of an immigrant family experience compared with the first generation and these will affect their health going forward. 

Professor Shah went on to give some multigenerational findings in the US that highlight the heterogeneity in the health of immigrant populations. The Sacramento Area Latino Study on Aging (SALSA) showed that second and third generation Mexican adults have a greater risk of diabetes, with acculturation having little impact. However, in the California Men’s Health Study, involving a multi-ethnic cohort, there was a gradient of risk with increasing years in American culture – so there was a greater risk of diabetes for the second generation than for the first. 

Finally, there was the MASALA (Mediators of Atherosclerosis in South Asians Living in America) study, which showed the impact of three different acculturation styles – separation (preference for South Asian lifestyle), integration (equal preference for South Asian and US lifestyles) and assimilation (preference for US lifestyle) – upon type 2 diabetes risk. Women in the integration group had the lowest risk of type 2 diabetes and prediabetes, at 16.4% and 29.7%, while those in the separation group had the highest risk at 29.3% and 31.5%. No such differences were observed among male participants. 

Professor Shah is involved in the Community Engaged Needs Assessment of South Asians in Atlanta (CENSAA) study where they are partnering with the Indian community to collect data and explore their health needs related to cardiometabolic disease risk, looking at differences between those born in India (473 participants) and those born in Atlanta (837 participants). 

A survey was launched, which showed that obesity was higher in those born in the US, although they were more likely to do the recommended 150 minutes a week of physical activity, while those born in India have more hypertension and more diabetes. They went back to the respondents for more detail and found health belief/attitudes, sense of identity and interaction with healthcare systems seemed to be key factors for the prevalence of cardiometabolic disease. “We need future cohort studies to be more diverse, spanning generations,” concluded Professor Shah. “We need to understand diabetes trajectories through the generations to provide etiological insights into the development of diabetes and inform prevention efforts.” 

Tailoring prevention studies

Dr Mary Beth Weber of the Emory Global Diabetes Research Center then spoke about how diabetes prevention efforts could be tailored to take account of cultural influences. For example, we know that South Asians describe food at social events as being very important. Much of it can be very rich, but turning it down on health grounds can lead to tension, eroding the social support that is so important. “Culture is important in driving behaviours,  particularly those of interest for diabetes prevention,” she said. “It impacts self-care behaviour and adherence. So, when designing interventions, do consider cultural aspects throughout the whole process.”

There are several frameworks that can guide researchers with this, such as the ADAPT guidance, which emphasises stakeholder involvement early and often to adapt an intervention to a new context (such as taking cultural influences into account). However, there are still large gaps in provision. A 2015 review of cultural adaptations to the US Diabetes Prevention Programme (DPP) found that very few actually used cultural adaptation frameworks and there was a limited rationale for modifications made. “If you take nothing else away from today, here is the number-one thing we need to do better – we need to document what we are doing to make programmes culturally appropriate because documentation is frequently absent, vague or superficial,” said Dr Weber. “So do report on how or why adaptations were made and link them to the evaluation, so we can see which adaptations are the most effective. I argue that this would be worth its weight in gold for moving this field forward.” 

In addition, it is important to let the community that will be taking up the programme be your guide. “Speak early and often,” Dr Weber continued. “Educate, if needed, but listen too. Work at the ‘speed of trust’, taking the time to build that trust. That needs to be built into the timeline of studies.” 

It is also important to understand your intervention and why it might work for your target population, using feedback from stakeholders. This includes understanding what the core components are that might be driving change. One example of a good prevention programme that reflects these principles is the SHAPE programme, which is an adaptation of the DPP for South Asians, with a focus on portion sizes of foods such as rice and bread. Dr Weber concluded by urging delegates to be sure to write up and publish similar examples to share with the healthcare and wider community. 

Mind your language

Alicia Fernandez, Professor of Medicine at the University of California San Francisco, began her talk on the impact of English proficiency on diabetes care with a simple question to the audience. In a healthcare encounter via a professional interpreter, is patient comprehension, on average, similar to that during an encounter with a language-concordant physician? The answer is no – comprehension is a lot less when an interpreter is involved. 

A study from a New York emergency room compared consultations with two state-of-the-art interpretation systems and a language-concordant physician. When patients were asked if they understood the explanation for their condition, 33% and 39% said yes for the interpreters compared with 59% for the physician. When it came to understanding the instructions for aftercare following discharge, the figures were 33%, 38% and 63%, respectively.  

Dr Fernandez and colleagues have looked at this issue in Kaiser Permanente Latino patients who have diabetes and have either good English or limited English. The two groups were compared and then analysed by whether those with limited English were seen by Spanish-speaking doctors. “There was a big difference, in that those seen by a doctor who did not speak Spanish were more likely to feel lack of trust, that they were treated poorly, not shown respect and that the doctor was not listening,” she said. 

The use of an interpreter instead of a language-concordant physician also has a clinical impact, leading to more medication errors, less understanding of medication labels and less understanding of follow-up and discharge instructions. 

Dr Fernandez also referred to the DISTANCE study, which involved 20,000 Kaiser Permanente patients speaking five languages and including 3193 Latino participants. Ten per cent of White participants had poor glycaemic control, compared with 18% of Latino participants with good English and 21.4% with limited English. And the proportions with poor glycaemic control were 16.1% and 27.8%, depending on whether or not they consulted with a Spanish-speaking physician. No such effect was seen for blood pressure or LDL-cholesterol levels. 

Clearly this issue is worth further investigation but, as Dr Fernandez put it, it is difficult to set up a randomised controlled trial on the basis of patients either seeing, or not seeing, a language-concordant physician, as they would presumably all prefer the former. However, her team was able to carry out a trial looking at the impact of switching from a language non-concordant to language-concordant doctor over the course of the study (as patients are used to seeing different physicians in clinic). At the end, the group that switched to the concordant doctor had much better glycaemic control. 

“Switching to a doctor that speaks Spanish improves glycaemic control, but there was no impact of switching on blood pressure or LDL-cholesterol,” noted Dr Fernandez. “So there is something about glycaemic control that is particularly sensitive to language barriers.” 

Analysis of consultations shows that less counselling goes on in discordant languages. Giving examples from her own conversations with Chinese patients who had limited English, she said the conversation is more limited and there are fewer questions, less empathy and less attention given to the patient’s point of view. So this might feed into poorer glycaemic control with less discussion about insulin and diet and, overall, less trust, comprehension and satisfaction.  

Another angle to consider is that with low English literacy often comes low health literacy. Most older immigrants tend to have limited education compared with those who are younger. This can feed into comprehension of health messaging. For example, a survey on knowledge about sugar-sweetened beverages among Spanish speakers showed that while many knew sodas were high in sugar, they did not realise that horchata and agua fresca, which are popular drinks in the community, also contain a lot of sugar.

So what is the way forward? “We obviously don’t all speak all languages, so check back more on comprehension,” said Dr Fernandez. “I will force myself to make an empathic statement and make sure the interpreter makes it too. And always be sure to elicit the patients’ point of view. Arranging for language-concordant diabetes and other health educators is probably one of the most important things we can do.” 

Finally, what about technology? A study of Google Translate translating into Chinese and Spanish and then back into English found potentially life-threatening errors. “If you are going to use this technology, go for simple sentences and plain language, and do not use without oversight from someone,” she warned. Furthermore, machine interpretation by phone technology is not yet ready for clinical use. 

In conclusion, language barriers create difficulties for people with diabetes and their clinicians. They make healthcare less patient-centric, leading to more diabetes distress and may also affect glycaemic control. More needs to be done to facilitate language access and language-concordant diabetes care.  

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

In the latest EASD e-Learning module, leading experts in diabetes care and research guide learners through the latest ADA/EASD consensus report on managing type 2 diabetes.

The first of two new modules on the management of hyperglycaemia in type 2 diabetes launches today. The module, titled ‘ADA/EASD 2022 consensus report – background, rationale and components of care’, outlines key components of the much-lauded report, sharing insights into how they were produced and the rationale behind them. A second module, due to launch in 2024, will take a closer look at the central concept of personalised care and how to implement the report.

The list of authors and presenters of the new module reads like a roll call of leading diabetes experts from around the world. They include Professors Melanie Davies and John Buse (co-chairs of the report writing group), plus Professors Peter Rossing, Tsvetalina Tankova, Geltrude Mingrone, Vanita Aroda and Dr Billy Collins – all of whom were also members of the writing group. Professor Buse paid tribute to the positive impact that the diversity of the group had on the final report. 

“We tried to get representation from the primary care community, people that are more accustomed to dealing with complications, methodologists in meta-analysis and subgroup analyses… We also tried to get a heterogeneous group with regards to geographical representation, gender, etc. I think the representation that we’ve had from the primary care community, from epidemiologists, really has rounded out the recommendations in a very positive way.” 

Professor Davies agrees: “I think it’s much more holistic, so we’ve really taken that step from emphasising the person-centred approach, the really holistic approach to management. I think this time there’s a bigger focus on implementation… We’ve got all this great evidence, we know in some ways what we should be doing but getting that into practice, that’s probably been a bit more of a focus this time round.”

Another area of difference between the new consensus report and its previous iterations is the greater emphasis on social determinants of health. Says Professor Buse: “The way I like to talk about it is, as a provider, getting into the head, the heart and the home of the person with diabetes, to really try to understand what it takes to make things work. That’s another big section that’s been added this year: practical pointers for providers with regard to making things work.”

These two modules replace the existing modules in EASD e-Learning’s ‘Management of hyperglycaemia in type 2 diabetes’ course, which focused respectively on the 2018 consensus report and its 2019 update. EASD Programme Director Dr Eleanor D Kennedy commented: “Our modules on the 2018 and 2019 consensus reports have been two of the most popular and highly rated modules on the platform and were among the first EASD e-Learning modules to be accredited for continuing professional education by the UK’s Royal College of General Practitioners. We hope these two new modules will be similarly well received.” 

Enrol today on the new module at Management of hyperglycaemia in type 2 diabetes module 1 ‘ADA/EASD 2022 consensus report – background, rationale and components of care’.

Certificates of completion

The modules on the 2018 consensus report and its 2019 have now been retired and are no longer available on the platform. However, anyone who has successfully completed the older modules and passed the end-of-module assessment will still be able to access their certificates of completion on their ‘My account’ page.

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