GLP-1 receptor agonists, thiazolidinediones associated with lower risk of ischemic stroke

While genetically high plasma glucose appears to increase risk of ischemic stroke, treatment with glucose-lowering glucagon-like peptide-1 (GLP-1) receptor agonists or thiazolidinediones may reduce this risk, a recent study found.

The researchers sought to test the hypotheses that high plasma glucose has a causal impact on increased risk of ischemic stroke and that glucose-lowering drugs reduce this risk. Using a Mendelian randomization design, they looked at diagnoses of ischemic stroke among 118,838 individuals with available genotypes from two similar prospective studies of the Danish general population (the Copenhagen General Population Study and the Copenhagen City Heart Study). Nonfasting plasma glucose, total cholesterol, HDL cholesterol, triacylglycerol, and C-peptide levels were measured using standard hospital assays, and other assays were used to identify several genotypes with the strongest effect on plasma glucose. To validate the results and to increase power and generalizability across populations, they conducted a two-sample Mendelian randomization analysis with summary-level data from MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium), including 133,010 individuals without type 2 diabetes, and the MEGASTROKE study, with 34,217 cases with ischemic stroke and 406,111 control participants, including the same genetic variants used in the Copenhagen studies. The researchers also performed meta-analyses combining results from clinical randomized trials on the eight most used glucose-lowering drug classes (GLP-1 receptor agonists, thiazolidinediones, sulfonylureas, dipeptidyl peptidase-4 [DPP-4] inhibitors, sodium-glucose cotransporter-2 [SGLT-2] inhibitors, alpha-glucosidase inhibitors, meglitinides, and metformin) to summarize their effects on the risk of stroke. Results were published online on March 25 by Diabetologia.

During a median of 9.8 years of follow-up, 5,497 Danish individuals had an ischemic stroke. In genetic, causal analyses, a 1 mmol/L (18.0 mg/dL) higher plasma glucose level carried a risk ratio of 1.48 (95% CI, 1.04 to 2.11; P=0.028) for ischemic stroke in the Copenhagen studies. The corresponding risk ratio from the MEGASTROKE study combined with the Copenhagen studies was 1.74 (95% CI, 1.31 to 2.18; P<0.001). In meta-analyses of glucose-lowering drugs, the risk ratio for stroke was 0.85 (95% CI, 0.77 to 0.94) with GLP-1 receptor agonists and 0.82 (95% CI, 0.69 to 0.98) with thiazolidinediones. The reduction observed for the two drugs largely matched what is predicted from their effect on HbA1c levels in trials and from the genetic estimates in the Copenhagen studies combined with the MEGASTROKE study, the authors said. In contrast, there was no statistical evidence that sulfonylureas, DPP-4 inhibitors, SGLT-2 inhibitors, alpha-glucosidase inhibitors, meglitinides, and metformin had an effect on stroke risk.

Limitations of the Mendelian randomization study include a small potential pleiotropic effect of body mass index and the potential for unmeasured factors to have affected the results, the authors noted. They added that a limitation of the meta-analysis is the diagnosis of stroke used in clinical randomized trials.

The findings are relevant because current diabetes guidelines focus on acute coronary syndrome, heart failure, and kidney disease and do not include specific recommendations for patients at high risk of stroke, the authors said. “Inclusion of ischaemic stroke in guidelines on treatment of diabetes and elevated plasma glucose may improve quality of patient diagnosis and care,” they concluded.