Semaglutide lowers stroke risk in type 2 diabetes with high CV risk

A post hoc analysis of the SUSTAIN 6 and PIONEER 6 trials has found that semaglutide reduces incidence of any stroke in people with type 2 diabetes (T2D) at high cardiovascular (CV) risk vs placebo.

Epidemiological studies show that diabetes increases the risk of stroke by approximately two-fold. [Lancet 2010;375:2215-2222] Prevalence of stroke exceeds 15 percent in people with T2D. [Endocrinol Diabetes Metab 2019;doi:10.1002/edm2.76] Furthermore, people with diabetes are more likely to have a stroke at a younger age, with worse outcomes and higher risk for recurrence vs those without diabetes. [Eur Heart J 2018;39:2376-2386]

“Accumulating evidence suggests that glucagon-like peptide 1 receptor agonists [GLP-1 RAs] may reduce the risk of stroke beyond their glycaemic impact in people with T2D, and the American Heart Association/American Stroke Association as well as endocrinology and cardiology guidelines recommend the use of GLP-1 RAs for individuals at high/very high CV risk regardless of glycaemic control to reduce the risk of future vascular events,” wrote the researchers. [Stroke 2021;52:e364-e467] “Present post hoc analysis, aimed to examine the effect of semaglutide, irrespective of whether administered subcutaneously [SC] or orally, on stroke risk, stratified by subtype, in people with T2D at high CV risk, using pooled data from the SUSTAIN 6 and PIONEER 6 trials.” [Stroke 2022;53:2749-2757]

SUSTAIN 6 and PIONEER 6 were global, randomized, phase III trials (n=6,480) assessing the CV safety of once-weekly SC and once-daily oral semaglutide vs placebo, respectively. People with T2D aged ≥50 years with established CV disease, chronic heart failure or chronic kidney disease, or aged ≥60 years with CV risk factors were included in both trials.

Treatment with semaglutide was associated with a reduced risk of any first stroke in the trials vs placebo (incidence rate, 0.8 vs 1.1 events per 100 patient-years of observation [PYO]; hazard ratio [HR], 0.68; 95 percent confidence interval [CI], 0.46–1.00; p=0.048), with no difference in effect between stroke subtypes (ischaemic stroke: incidence rate, 0.7 vs 1.0 events per 100 PYO; HR, 0.72; 95 percent CI, 0.47–1.08; p=0.11) (haemorrhagic stroke: incidence rate, 0.1 vs 0.1 events per 100 PYO; HR, 0.50; 95 percent CI, 0.12–1.99; p=0.32).

Compared with placebo, treatment with semaglutide lowered the risk of stroke irrespective of prior stroke. HRs for risk of any stroke with semaglutide vs placebo were 0.60 (95 percent CI, 0.37–0.99; 0.5 vs 0.9 events per 100 PYO) and 0.89 (95 percent CI, 0.47–1.69; 2.7 vs 3.0 events per 100 PYO) in those without and with prior stroke, respectively.

In subgroup analysis, the risk of any stroke was generally lower in the semaglutide vs placebo group, except for those with prior atrial fibrillation (AF) and those aged ≥75 years. “Of note, the incidence of any stroke was nominally reduced in the semaglutide group in those without history of prior stroke [incidence rate, 0.5 vs 0.9 events per 100 PYO; HR, 0.60; 95 percent CI, 0.37–0.99] vs placebo,” highlighted the researchers.

With semaglutide vs placebo, the incidence rate of major adverse CV events was significantly lower among people without prior stroke (2.8 vs 3.8 events per 100 PYO; HR, 0.74; 95 percent CI, 0.59–0.92; p=0.007) and numerically lower in those with prior stroke (5.2 vs 6.0 events per 100 PYO; HR, 0.86; 95 percent CI, 0.54–1.36; p=0.52).

“Although HbA_1c lowering of  by GLP-1 RAs may mediate their effect on CV outcomes, GLP-1 RAs can deliver a positive impact on risk of stroke directly, as they exert beneficial effects on smooth muscle cell, endothelial cell, and immune cell function through GLP-1 receptor–dependent and –independent pathways. Treatment with GLP-1 RAs is also considered to exert a neuroprotective effect and may reduce the risk of ischaemic strokes,” proposed the researchers. [Cell Metab 2018;27:740-756; Cardiovasc Diabetol 2019;doi:10.1186/s12933-019-0896-z]