Effects of semaglutide on stroke subtypes in type 2 diabetes: post hoc analysis of the randomised SUSTAIN 6 & PIONEER 6

Abstract

Background: Glucagon-like peptide-1 receptor agonists, including semaglutide, may reduce stroke risk in people with type 2 diabetes (T2D). This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with T2D at high cardiovascular (CV) risk. Methods: SUSTAIN 6 and PIONEER 6 were randomised CV outcome trials of subcutaneous and oral semaglutide in people with T2D at high CV risk, respectively. Time to first stroke and stroke subtypes were analysed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction p-values. Risk of major adverse CV event (MACE) was analysed according to prior stroke. Results: 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 vs 1.1 events/100 PYO; HR 0.68, 95%CI 0.46–1.00;p=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 vs 0.7 events/100 PYO; HR 0.51, 95%CI 0.29–0.89;p=0.017). HRs for risk of any stroke with semaglutide versus placebo were 0.60 (95%CI 0.37–0.99; 0.5 vs 0.9 events/100 PYO) and 0.89 (95%CI 0.47–1.69; 2.7 vs 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (pinteraction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of MACE and prior stroke (pinteraction>0.05 for all). Conclusions: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with T2D at high CV risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline. Clinical Trial Registration Information: SUSTAIN 6: NCT01720446 (https://clinicaltrials.gov/ct2/show/NCT01720446); PIONEER 6: NCT02692716 (https://clinicaltrials.gov/ct2/show/NCT02692716).