The risk of suffering a stroke is massively higher for diabetics than in the general population. New data suggest that dulaglutide reduces the risk of ischemic stroke in diabetic patients when treated for a prolonged period. This is shown by a post-hoc analysis published in 2020 by the REWIND-Study.
GLP-1 receptor agonists (GLP-1-RA) and SGLT-2 inhibitors are among the latest generation of antidiabetic drugs that have been shown to reduce cardiovascular events and mortality [1]. The mechanisms of action of these two substance classes are different and have not yet been fully clarified. GLP-1-RA are active substances which have an analogous structure to human glucagon-like peptide 1 (GLP-1) and lead to glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. Both liraglutide (Victoza®), semaglutide (Ozempic®) and dulaglutide (Trulicity®) have been shown to have cardiovascular benefit in the large endpoint studies (CVOTs*), demonstrating significant risk reduction in terms of 3-point MACE [2,3].
* CVOT = CardioVascularOutcomeTrial
Reduction of stroke incidence
Myocardial infarction and ischemic insults are among the most common and dangerous late sequelae of diabetes [5]. In the REWIND (REsearching cardiovascular events with a Weekly IncretiN in Diabetes) trial, dulaglutide resulted in a 16% reduction in the incidence of stroke compared with placebo (HR: 0.84) [6]. No information was provided by these data on whether dulaglutide protects only against a specific type of stroke and whether it also causes a reduction in the severity of manifest stroke events, as well as which patient groups may benefit most from the protective effects. This was the starting point for a new post-hoc analysis of the REWIND study published in 2020 by a research team led by Dr. Gerstein at McMaster University in Hamilton, Canada [4]. It was shown that after a median treatment duration of 5.4 years, the stroke rate in the dulaglutide condition was 3.2% compared with 4.1% in the placebo condition [4]. Regarding the hemorrhagic variant of stroke, no risk reduction was measurable between the two groups. The study included approximately 9900 men and women with type 2 diabetes and cardiovascular risk factors at a total of 400 sites in 24 countries. Half of the subjects each received dulaglutide 1.5 mg or placebo subcutaneously once a week in addition to standard diabetes therapy. Regarding patient characteristics, the age of the study participants was over 50 years, BMI was >23, HbA1c <9.5%. Standard diabetes treatment included up to two oral glucose-lowering medications with or without basal insulin therapy.
Individual benefit-risk profile
Macroangiopathic damage is a common complication of diabetes and causes disease in 20-40% of all ischemic strokes. About 85% of all stroke events are ischemic insults, i.e. arterial occlusive disease in the brain due to a cerebral circulatory disorder. Hemorrhagic insults account for approximately 15% of all strokes and are a consequence of intracerebral hemorrhage. Ischemic strokes can be triggered by several factors. In addition to hypertension and smoking, obesity and diabetes are among the most important influencing factors. Manifest diabetes leads to a two- to threefold increased risk of stroke [5]. Uninfluenceable risk factors include age, gender, and genetic determinants.
Diabetes treatment tailored to individual conditions is essential. The decision as to which is the adequate therapeutic option should be carefully considered. Optimal adjustment of HbA1c may contribute to risk reduction [5], and other protective mechanisms have not yet been conclusively explored. GLP-1-RA can be combined with both oral antidiabetic agents and insulin. In contrast to SGLT-2 inhibitors, which are administered orally, GLP-1-RA is administered subcutaneously.
Literature:
- Lehmann R, et al: Recommendations of the Swiss Society of Endocrinology and Diabetology (SGED/SSED) for the treatment of type 2 diabetes mellitus, 2020, www.sgedssed.ch
- Compendium
- Lehmann R: Modern diabetes therapy: an update 2020. Prof. Dr. med. Roger Lehmann, VZI Symposium 2020 University, Zurich, 31.01.2020
- Gerstein HC, et al: The effect of dulaglutide on stroke: an exploratory analysis of the REWIND trial. Lancet Diabetes Endocrinol 2020; 8(2): 106-114.
- Stiefelhagen P: Individual prevention: preventing stroke in diabetes. Diabetes Update 2019, https://link.springer.com/content/pdf/10.1007/s11298-019-7318-0.pdf
- Gerstein HC, et al: Dulaglutide and cardiovascular outcomes in type 2 diabetes (REWIND): a double-blind, randomised placebo-controlled trial. The Lancet 2019; 394(10193): 121-130.
GP PRACTICE 2020; 15(6): 48
