Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6

Abstract

Background: GLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.

Methods: SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed 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 cardiovascular event was analyzed according to prior stroke.

Results: A total of 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 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 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 major adverse cardiovascular event and prior stroke (Pinteraction >0.05 for all).

Conclusions: Semaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline.

Registration: URL: https://www.

Clinicaltrials: gov; Unique identifier: NCT01720446 and NCT02692716.

Keywords: atrial fibrillation; blood pressure; myocardial infarction; peptides; prevalence.

Figures

Figure 1.

Aalen-Johansen plots for time to first occurrence of any stroke* with the pooled semaglutide versus placebo in people with type 2 diabetes (T2D) at high cardiovascular (CV) risk, based on pooled data from the SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) trials. *Included fatal and nonfatal strokes. The cumulative incidence rates for time to first stroke were calculated using Aalen-Johansen method, adjusting for all-cause death as a competing risk. The hazard ratio was estimated from a Cox regression model stratified by trial with treatment (pooled semaglutide vs placebo) as a factor. HR indicates hazard ratio.

Figure 2.

Effect of semaglutide versus placebo on risk of any stroke and stroke subtypes in people with type 2 diabetes (T2D) at high cardiovascular (CV) risk, based on pooled data from the SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) trials. Data for any stroke and those subtypes based on the TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria have been included (transient ischemic attacks were not included in this analysis). Any stroke (including fatal and nonfatal strokes) and the 3 main subtypes were confirmed by the trial-specific Event Adjudication Committee. A Cox proportional hazards model stratified by trial with treatment (pooled semaglutide vs placebo) as a factor was used to examine treatment effects. The trial-specific analysis showed that the treatment effects were homogenous across SUSTAIN 6 (hazard ratio [HR], 0.65 [95% CI, 0.41–1.03]) and PIONEER 6 (HR, 0.76 [95% CI, 0.37–1.56]), Pinteraction=0.73. *Ischemic strokes were subcategorized according to TOAST criteria, by an external, blinded reviewer. †Included patients with ≥2 causes of stroke, undetermined cause despite extensive evaluation, and cause of stroke not known due to cursory evaluation. n indicates number of patients with specified stroke type; N, number of patients in the treatment group; and N/A, not applicable.

Figure 3.

Effect of semaglutide versus placebo on risk of any stroke stratified by prior stroke, prior myocardial infarction (MI) or stroke, age, sex, systolic blood pressure (SBP), and estimated glomerular filtration rate (eGFR) in people with type 2 diabetes (T2D) at high cardiovascular (CV) risk, based on pooled data from the (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) trials. A Cox proportional hazards model stratified by trial with treatment (pooled semaglutide vs placebo) by subgroups as a fixed factor was used to examine treatment effects across the subgroups. AF indicates atrial fibrillation; and HR, hazard ratio.