Substantial progress has taken place in the two years since our last paper on diabetes – including novel drugs that are driving a paradigm shift in the management of this disease. Dr. Emoke Posan, Chief Medical Officer, North America, has extensive medical and Life industry expertise in this field and here answers key questions for Life underwriters on the latest trends and developments, with a focus on Type 2 diabetes.
Recent decades have seen an emerging obesity and Type 2 diabetes mellitus (T2DM) “twin epidemic”.26 Then came Covid-19. The full interplay between diabetes and Covid is complex and multifactorial.23,38 However, there are a few key points.
New studies show that the global prevalence of T2DM increased at a faster rate over the past two years, and that the risk of developing T2DM increases after a SARS-CoV-2 infection, indeed even months afterwards (see example in figure 1). The increased risk of developing T2DM is linked to both the pandemic’s impact on lifestyle risk (leading to insulin resistance) – namely that it added an extra 3-hour daily average sitting time – and also directly to the SARS-CoV-2 infection (partially via direct pancreas effect, but also some speculations suggest that the virus could possibly cause insulin resistance). The risk of developing T2DM increases in line with Covid severity. Proposals are therefore being made to actively screen for diabetes after recovery from Covid.23,36,38,43,45
Early concerns that SARS-CoV-2 might trigger Type 1 diabetes mellitus (T1DM) in children and young people, as is known from other viruses, remains uncertain.38,45
Figure 1: Incidence of newly diagnosed diabetes after a Covid-19 diagnosis, compared to after an acute respiratory infection. Covid-19 increases the risk of developing Type 2 diabetes. Source: Rathmann et al (2022).36
In addition to increasing the risk of developing diabetes, studies have also shown that having diabetes is a major risk factor for developing severe Covid.23,38
Novel drugs are a new, key team player, playing alongside HbA1C for diabetes glucose control and glucose-independent organ protection.
The overall trend is positive, driven by the effective management of traditional (vascular) diabetes complications. However, non-traditional (non-vascular) diabetes complications are now increasingly being recognized and these are challenging the positive trend. Patient heterogeneity also stands to influence future trends.33,42
Traditional complications – an improving trend
Micro- and macrovascular complications in diabetes and their morbidity and mortality consequences are well known. The leading cause of diabetes mortality has consistently been vascular death (particularly heart attack, stroke and kidney disease).3,20,21 One of the leading cardiac causes of diabetes hospitalization is heart failure (with or without coronary artery disease).9,14
In line with the many advances in diabetes management, the current overall trend for all-cause mortality in diabetes is improving. This, and a number of improving morbidity (hospitalization cause) trends are mainly attributed to reductions in vascular complications33,42 (figure 3a and 3b).
In terms of future trend, it’s also known that vascular complications typically begin to develop years before a diabetes diagnosis, with ‘hidden’ phases of obesity and impaired glucose tolerance.7 This is leading to the call for more pre-diabetes screening and early intervention17 – with the focus being on weight loss – to interrupt or prevent vascular damage caused during this phase, and indeed to hopefully prevent a progression to T2DM. There’s also a positive outlook for preventing and slowing the progression of vascular damage after a diabetes diagnosis. Screening and intervention will therefore be major factors in reducing future diabetes prevalence, mortality and morbidity.
While the trend for traditional complications is improving, new and less well-known mortality and morbidity aspects have recently come to light.
Non-traditional complications – increasing in importance
Firstly, a significant proportion of diabetes mortality and morbidity relates to non-traditional complications. These complications are often unrecognized and/or underestimated.20
Figure 2: Major traditional complications and non-traditional, emerging complications of Type 2 diabetes mellitus (T2DM). Source: Tomic D. et al. 2022.42
There are also a number of often unrecognized cardiac complicationse.g., 3,6,14,16,18,24,28,41 including:
And in contrast to the improving trend of traditional diabetes complications, non-traditional diabetes complications are increasing in prevalence and representing a greater share of diabetes mortality and morbidity (figure 3c) .33 In fact, cancer and dementia have now taken over in some countries/regions as the leading causes of diabetes mortality.42
Figure 3: Hospitalisation rates of diabetes patients due to traditional diabetes specific complications (3a, 3b), including vascular complications, and to other non-traditional diabetes complications (3c). While rates of traditional (mainly vascular) complications have decreased, rates of non-traditional complications have increased. Source: Pearson-Stuttard J. et al.33
Another aspect emerging as important for future mortality and morbidity trends is patient heterogeneity. Studies have shown that diabetes risk, complications and disease progression show significant heterogeneity by patient, leading also to heterogeneity in drug responses.32
The indication is that diabetes management will ultimately need to evolve to take patient heterogeneity into account, i.e., to include precision medicine, to help reduce all diabetes mortality and morbidity risks.17,32
Yes, glucose control concept is one of the main areas in which diabetes management is advancing, but not just because of increasing non-traditional complications.
The clinical focus for diabetes – and therefore also the underwriting focus – has until recently been HbA1C centric; specifically, reducing the HbA1C level, which reflects the 2-3 month average blood glucose levels.
Despite the fact that the HbA1C is well correlated with the risk of cardiovascular events35,37, well managed diabetes, assessed by this marker, does not consistently translate into the avoidance of adverse cardiovascular events. In addition, intensive glucose control strategies have been linked to increased cardiovascular mortality.1,19,25,35
Recent studies and trial results, including innovative new drug classes, have also indicated that the clinical (and underwriting) focus must now shift, with “novel drugs” being a new, key team player, playing alongside HbA1C for glucose control and for additional glucose-independent organ protection (the latter point is a critical advance for diabetics and non-diabetics, which we can discuss after introducing the relevant novel drugs).
As regards to the shifting approach to glucose control, evidence is growing that it’s not just hyperglycaemia (an abnormally high blood glucose level) and hypoglycaemia (an abnormally low blood glucose level), but also abnormal glucose variability and sudden shifts in glucose levels (with or without hypoglycaemia), that are detrimental to diabetes patients.11, 12, 13, 16, 18, 24
Therefore, to improve overall diabetes mortality and morbidity risk, the concept of optimal glucose control is now evolving to also stabilize glucose levels over the short- and long-term via new drug classes and more regular monitoring of glucose levels (new tech being the perfect partner for this). The HbA1C remains important but should no longer be the sole marker for glucose control.11,12
For a concise, deep dive by Dr. Emoke Posan into how optimal glucose control concept is evolving, view the 2022 PartnerRe article:
At the centenary of the discovery of insulin, novel drug classes stand to revolutionize T2DM management in multiple ways, including as the “early intervention” I spoke of previously when we discussed mortality and morbidity trends.
Two of these classes – the GLP-1 agonists and SGLT2 inhibitors – are not entirely new but are referred to as novel classes as their powerful diabetes morbidity and mortality benefits were only confirmed in recent years.
In addition to helping to lower and stabilize glucose levels, these drugs (with some differences by drug class or specific drug), are generally known to reduce cardiovascular mortality in high-risk groups.8,47,48
Importantly, their morbidity and mortality benefit is even more robust for chronic kidney disease4,5,30,34,40 and heart failure4,27,30,46 (for heart failure, SGLT2 inhibitors only), and is irrespective of atherosclerotic cardiovascular disease.3,30
In addition, the mortality and morbidity benefit to diabetics exceeds expectations based on patients’ HbA1C improvements3, indicating that the drugs influence much more than just HbA1C levels.
They are also notably effective for mortality reduction in non-diabetics.3,5,30
These novel drug classes are now incorporated in diabetes guidelines and non-diabetes heart failure and chronic kidney disease guidelines: SGLT2 inhibitors are now a crucial component of foundational therapy for heart failure (for specific groups), and SGLT2 inhibitors and GLP-1 agonists are now components of chronic kidney disease management.
Importantly, given the strong link between obesity and diabetes, these classes are also highly effective at promoting weight loss, particularly the GLP-1 agonists.
There are also reports of positive impacts on atrial fibrillation6, blood pressure and lipid profile.10
What’s more, the combination of GLP-1 agonists and SGLT2 inhibitors has complementary (additive) benefits.10
In recent years, another new diabetes drug class, twincretins, has been developed15,22,31,39, 44 and is now also approved for weight management in obesity.49 Twincretins provide even better glucose control and substantial, sustained weight reduction (figure 4).
Figure 4: T2DM patients’ weight loss over time based on a GLP1-agonist novel drug (Semaglutide) and an even more recently developed twincretin drug (Tirzepatide). Both are powerful weight loss drugs, with twincretins achieving the highest reductions. Source: Frías J.P et al. 2021.22
Beyond these, researchers are continuing to work on avenues for other new drug classes.
The goal of diabetes pharmacotherapy has undergone a paradigm shift – from focusing only on a HbA1C target, to also achieving multiple organ protection – primary organ protection (i.e., prevention) and secondary organ protection (i.e., slowing the progression of an existing organ disease) – and this organ protection is specific to each patient and irrespective of glucose levels. Reaching and maintaining a target HbA1C value remains important, but this will now be done more effectively, in line with new knowledge about the need to avoid large and sudden glucose level fluctuations. Novel drugs are the key new team players for achieving these goals.
There are now two main pharmacotherapy stages:
Beyond improving outcomes for diabetes mortality and morbidity (traditional vascular diabetes complications), it is conceivable that the new approaches to glucose control and pharmacotherapy will also have a positive impact on the development and progression of non-traditional diabetes complications.
Absolutely, lifestyle changes (i.e., nutrition and exercise) and managing all other known risk factors (i.e., stopping smoking, weight loss, blood pressure and lipids), continue to be essential components of preventing and managing diabetes complications.2,3,29 These are all risk factors for cardiovascular health.
As mentioned above, screening and early intervention are becoming increasingly important both prior to and after a diabetes diagnosis, and the all-important T2DM risk factor of obesity can be positively impacted by weight-reducing novel drug classes, in particular by the GLP-1 agonists 15,22, 31,44 and twincretin novel drug classes.15, 31, 39, 49 There are now even indications that significant weight loss could in some cases lead to T2DM remission.50
To summarize. T2DM management is becoming more comprehensive and simultaneously more patient-specific. The selection of novel drug classes (led by individual patient risk assessments) and more frequent or even continuous monitoring of glucose levels, are now used alongside the HbA1C marker, with the aim of improving all-cause diabetes mortality and morbidity risk.
Prevention is also taking on a more central role. Screening for pre-diabetes and early intervention to achieve significant weight loss – again, with specific novel drug classes as the key facilitator – will aim to prevent damage caused during the initial, long, hidden phase of hyperglycemia (when vascular complications develop) and to prevent diabetes from developing. After a diabetes diagnosis, screening high-risk groups for organ damage and early intervention – again with novel drug classes – will prevent or slow the progression of organ damage. In specific groups, significant weight loss may even lead to remission.
Finally, knowing that SARS-CoV-2 infection increases the chance of developing diabetes, a risk that increases with Covid severity, suggests that it would be beneficial to consider actively screening for diabetes after a recovery from Covid.
What all this means for life insurers is quite straightforward. Once the comprehensive management (including the novel pharmacotherapy recommendation) is fully established in clinical practice, the outlook for diabetes patients is likely to substantially improve. In addition, novel drug classes have efficacy beyond diabetes. Combined, these developments open up new possibilities for life product solutions.
Please contact us if you would like to find out more about these developments in diabetes management and/or to discuss the mortality and morbidity impacts or resulting new product initiatives. We would be happy to set up a meeting with you.
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Dr. Emoke Posan, Chief Medical Officer, North America
*: Defined by the presence of myocardial dysfunction in the absence of overt ASCVD (Atherosclerotic cardiovascular disease), valvular disease and other conventional cardiovascular risk factors, such as hypertension and dyslipidemia.
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