ESJ Featured Article of the Month – January 2025

Glucagon-like peptide-1 (GLP-1) receptor agonists have revolutionised the treatment of diabetes and obesity. The structure of GLP-1 was described in the 1980s, along with its function: stimulating insulin secretion after eating, sending satiety signals to the brain and slowing the transit of food through the gut. ¹ The first drug mimicking the action of endogenous GLP-1 was developed in 2005 (exenatide). Since then, we have witnessed a slew of RCTs demonstrating the beneficial effects of GLP-1 receptor agonist (RA) agents: GLP-1RAs induce significant weight loss in people with  obesity and in patients with diabetes they improve glycaemic control and reduce the risk of major adverse cardiovascular events (MACE).^2,3 There is also evidence that GLP-1RAs reduce MACE in patients with heart failure and obesity, and can improve symptoms, blood pressure and CRP levels in patients with obstructive sleep apnoea and obesity.^4,5

A notable exception from this raft of trials are studies investigating GLP-1 agonists after stroke.

It is in this context that Moelgg and colleagues present their research, online first in European Stroke Journal this month. ⁶ Leveraging data from the STROKE-CARD, a registry of consecutive patients with ischaemic stroke in Innsbruck Austria, Moelgg and colleagues describe the prevalence of pre-diabetes and diabetes at the time of stroke, and after 1-year follow-up.

Prediabetes was defined in this study as HbA1c values of 5.7-6.4% (equivalent to 39-47mmol/L) and type 2 diabetes mellitus as HbA1c ≥6.5% (≥48 mmol/L), analysed on fasting blood samples. Of 884 patients included, at baseline 44.6% were normoglycemic, 33.9% had prediabetes and 21.5% had type 2 diabetes mellitus (DM2). Of those with DM2, most already knew about the diagnosis prior to their stroke, but there were 38 new diagnoses.

At 1-year, there were 17 new cases of DM2, an increase of 1.9 percentage points (pp, 95% CI –2.0 to 5.8).  There were 90 new patients in the pre-diabetes range, a 10.2 percentage point increase (95% CI 5.7 to 14.7) and a corresponding decrease in normoglycaemia.

The only factor significantly associated with a transition from normoglycaemia to pre-diabetes was statin use (aOR 2.51, 95% CI 1.08-6.38). Statin use doubled after stroke compared with baseline. This signal has recently been demonstrated in a meta-analysis of 19 statin trials: use of low-intensity statin was associated with a 1.3% increase per-year of developing diabetes, while high-intensity statin use was associated with a 4.8% increased risk of developing diabetes per year. Importantly, this small increase in risk of developing diabetes does not outweigh the overall reduction in cardiovascular events due to statin use and statins remain a key component of stroke secondary prevention. ^7,8

Moelgg and team then searched ClinicaTrials.gov for planned trials of GLP-1RA and SGLT-2 inhibitors in stroke patients. They identified 6 ongoing trials investigating these drugs in patients with diabetes mellitus after stroke, but only one of these planned for assessment of cardiovascular outcomes. There were no trials planned evaluating these drugs for secondary prevention of stroke.

These researchers make the astute point that a quarter of the STROKE-CARD cohort would meet the inclusion criteria for the SELECT trial which evaluated semaglutide in patients with obesity but without diabetes and demonstrated a significant reduction in cardiovascular events (HR 0.80, 95% CI 0.72-0.90) at 34 months. ⁹ This underscores the feasibility of recruiting patients after stroke to potential RCTs of GLP-1RAs.

In a systematic review and meta-analysis of GLP-1RAs in stroke,  in 82,140 participants from 11 trials, GLP-1RA use was associated with a 16% relative risk reduction in stroke compared to placebo (HR 0.85, 95% CI 0.77-0.93), with a number needed to treat of 200. ¹⁰ This supports the scientific rationale for RCTs of these agents for secondary prevention of stroke.

Our ESO Guidelines for secondary prevention of stroke, recommend in patients with diabetes and stroke, we should target treatment to achieve a HbA1c <7% or 53mmol/L, and there is a weak recommendation to consider pioglitazone to reduce the risk of recurrent stroke. There is no mention of SGLT2-Is or GLP1RAs which speaks to the need for more studies examining the efficacy of these drugs specifically in patients with diabetes and stroke. ⁸

This research study highlights some important take home points for stroke clinicians:

We need to be mindful of the high prevalence of diabetes and pre-diabetes in stroke patients, and be vigilant for patients transitioning to prediabetes and diabetes, over time.

This study also highlights the unmet need for RCTs to investigate whether GLP-1RAs can reduce the risk of recurrent stroke and MACE in patients with stroke, with or without comorbid diabetes and/or obesity.

Moelgg K, Karisik A, Scherer L, et al. Prediabetes and diabetes mellitus type II after ischemic stroke. European Stroke Journal. 2025;0(0). doi:10.1177/23969873241304301

Prediabetes and diabetes mellitus type II after ischaemic stroke Moelgg et al

https://journals.sagepub.com/doi/full/10.1177/23969873241304301

Online first 7 Jan 2025

—

References

1. Drucker DJ. Discovery of GLP-1-Based Drugs for the Treatment of Obesity. N Engl J Med 2024.
2. Marso SP, Bain SC, Consoli A, et al. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes. N Engl J Med 2016; 375(19): 1834-44.
3. Jastreboff AM, Aronne LJ, Ahmad NN, et al. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med 2022; 387(3): 205-16.
4. Malhotra A, Grunstein RR, Fietze I, et al. Tirzepatide for the Treatment of Obstructive Sleep Apnea and Obesity. N Engl J Med 2024; 391(13): 1193-205.
5. Kosiborod MN, Abildstrøm SZ, Borlaug BA, et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N Engl J Med 2023; 389(12): 1069-84.
6. Moelgg K, Karisik A, Scherer L, et al. Prediabetes and diabetes mellitus type II after ischemic stroke. European Stroke Journal 2025: 23969873241304301.
7. Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomised blinded statin trials: an individual participant data meta-analysis. Lancet Diabetes Endocrinol 2024; 12(5): 306-19.
8. Dawson J, Béjot Y, Christensen LM, et al. European Stroke Organisation (ESO) guideline on pharmacological interventions for long-term secondary prevention after ischaemic stroke or transient ischaemic attack. Eur Stroke J 2022; 7(3): I-ii.
9. Lincoff AM, Brown-Frandsen K, Colhoun HM, et al. Semaglutide and Cardiovascular Outcomes in Obesity without Diabetes. N Engl J Med 2023; 389(24): 2221-32.
10. Adamou A, Barkas F, Milionis H, Ntaios G. Glucagon-like peptide-1 receptor agonists and stroke: A systematic review and meta-analysis of cardiovascular outcome trials. Int J Stroke 2024; 19(8): 876-87.