Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes

Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6

W. David Strain, MD; Ofir Frenkel, MD; Martin A. James, FRCP; Lawrence A. Leiter, MD; Søren Rasmussen, PhD; Peter M. Rothwell, FMedSci; Maria Sejersten Ripa, DMSc; Thomas C. Truelsen, TC, DMSc; Mansoor Husain, MD

Disclosures

Stroke. 2022;53(9):2749-2757. 

In This Article

Abstract and Introduction

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 (P interaction >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.

Graphic Abstract: A graphic abstract is available for this article.

Introduction

As the prevalence of diabetes is rapidly increasing, the number of people with complications, including stroke, is expected to increase.[1] Epidemiological studies show that diabetes increases the risk of stroke by ≈2-fold.[2] The prevalence of stroke was 18.6% in people with type 2 diabetes (T2D) in 2015.[3] People with diabetes are more likely to have a stroke at a younger age, with worse outcomes and higher risk for recurrence compared with those without diabetes.[4,5] The 10-year recurrence rate of stroke was reported to be 11.2% in people who had a stroke,[6] and those with diabetes had 45% to 60% higher risk of stroke recurrence than those without diabetes.[7,8] This suggests that diabetes is an independent risk factor for stroke recurrence.[8] Among the subtypes of strokes, cerebral small vessel disease is more common in people with T2D, compared with those without T2D. Thus, prevention of stroke, including all its subtypes, should be a major concern in the clinical management of people with diabetes.

Accumulating evidence suggests that GLP-1 RAs (glucagon-like peptide-1 receptor agonists) may reduce the risk of stroke beyond their glycemic impact in people with T2D.[9–14] Currently, there are 5 available subcutaneous (SC) GLP-1 RAs (exenatide, lixisenatide, liraglutide, dulaglutide, and semaglutide)[15,16] and one oral formulation (once-daily oral semaglutide).[15] In a large meta-analysis of recent cardiovascular outcome trials, GLP-1 RAs were reported to reduce the risk of stroke significantly in people with T2D compared with placebo (hazard ratio [HR], 0.83 [95% CI, 0.76–0.92]; P=0.0002).[14] The American Heart Association/American Stroke Association as well as endocrinology and cardiology guidelines recommend the use of GLP-1 RAs with evidence of cardiovascular benefit for individuals at high/very high cardiovascular risk regardless of glycemic control to reduce the risk of future vascular events.[7,17,18] Despite the short duration of the trials, semaglutide has demonstrated a consistent reduction in major adverse cardiovascular events (MACEs) in the SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes), with once-weekly SC semaglutide,[19] and the PIONEER (Peptide Innovation for Early Diabetes Treatment) 6 trial, with once-daily oral semaglutide.[20]

The present post hoc analysis, therefore, aimed to examine the effect of semaglutide, irrespective of whether administered subcutaneously or orally, on stroke risk, stratified by subtype, in people with T2D at high cardiovascular risk, using pooled data from the SUSTAIN 6 and PIONEER 6 trials.

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