Fewer first strokes in T2DM patients after GLP-1RA treatment
Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6
Introduction and methods
As DM patients are more likely to have a stroke at a younger age, with worse outcomes and a higher recurrence risk than those without DM [1,2], stroke prevention is highly important in DM. Based on growing evidence, GLP-1RAs may reduce stroke risk in T2DM patients, even beyond glycemic control [3-8].
Aim of the study
The authors aimed to examine the effect of the GLP-1RA semaglutide on stroke risk, stratified by stroke subtype, in T2DM patients at high CVD risk.
In an exploratory post-hoc analysis, data from two global phase 3 RCTs were pooled: the SUSTAIN 6 and PIONEER 6 trial. In the SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes), patients were randomized to once-weekly 0.5 or 1 mg semaglutide subcutaneous or placebo , whereas once-daily 14 mg semaglutide orally or placebo was used in the PIONEER (Peptide Innovation for Early Diabetes Treatment) 6 study . Inclusion criteria for both trials were: (1) T2DM; and (2) age ≥50 years with established CVD (f.e., MI, stroke, TIAs), chronic HF, or chronic kidney disease; or age ≥60 years with CVD risk factors.
The main outcomes were time to first occurrence of any type of stroke (fatal and nonfatal) and stroke subtypes (ischemic, hemorrhagic, or unknown). In a subgroup analysis, treatment effects on time to occurrence of any stroke were assessed across different subgroups, including prior stroke, prior MI or stroke, prior AF, age, sex, eGFR and systolic blood pressure. In addition, the impact of prior stroke on the effect of semaglutide versus placebo on time to first MACE was investigated.
- Of the 6480 participants from both trials, 106 (1.6%) had a stroke (1.0 event/100 patient-years of observation [PYO]).
- Semaglutide reduced the incidence of any first stroke compared with placebo (0.8 vs. 1.1 events/100 PYO; hazard ratio [HR]: 0.68; 95% CI: 0.46–1.00; P = 0.048). When stratified to stroke subtypes, no difference in treatment effect was observed.
- Among the ischemic strokes, only the risk of small-vessel occlusion was reduced with semaglutide treatment compared with placebo (0.3 vs. 0.7 events/100 PYO; HR: 0.51; 95% CI: 0.29–0.89; P = 0.017).
- In the subgroup analysis, the risk of any stroke tended to be lower in the semaglutide group than in the placebo group, except in patients with prior AF and those aged ≥75 years, although these differences were not statistically significant.
- Semaglutide decreased the risk of any stroke in patients without prior stroke compared with placebo (0.5 vs. 0.9 events/100 PYO; HR: 0.60; 95% CI: 0.37–0.99) but not in those who had a history of stroke (2.7 vs. 3.0 events/100 PYO; HR: 0.89; 95% CI: 0.47–1.69) (P for interaction with prior stroke = 0.35).
- There were no significant interactions between treatment effects on risk of any stroke and the subgroups, except for prior AF (interaction P = 0.025), although the number of events was very low in the group with prior AF (7 events in semaglutide group vs. 1 event in placebo group).
- Semaglutide reduced the risk of first MACE in patients without prior stroke compared with placebo (2.8 vs. 3.8 events per 100 PYO; HR: 0.74; 95% CI: 0.59–0.92; P = 0.007) but not in those with prior stroke (5.2 vs 6.0 events per 100 PYO; HR: 0.86; 95% CI: 0.54–1.36; P = 0.52).
- There were no significant interactions between treatment effects on MACE risk and the prior stroke subgroup (interaction P = 0.56).
In T2DM patients with high CVD risk, semaglutide reduced the risk of any first stroke compared with placebo, regardless of prior stroke. Semaglutide’s effect was mainly due to a lower risk of small-vessel occlusion.