Semaglutide may be associated with a lower risk of stroke compared with empagliflozin in adult patients with type 2 diabetes, according to a real-world observational study. The analysis included data from over 15,000 patients across 703 academic and community clinical sites in the United States between 2019 and 2024.
Investigators conducted two target trial emulations using electronic health record data. The primary analysis compared semaglutide with empagliflozin, and the secondary analysis compared dulaglutide with empagliflozin. All patients were at least 45 years old and hadn't received a glucagon-like peptide-1 receptor agonist (GLP-1 RA) or sodium-glucose cotransporter-2 (SGLT-2) inhibitor in the prior year.
In the primary comparison, 7,899 patients treated with semaglutide were propensity score–matched to 7,899 patients treated with empagliflozin. The median follow-up was 2.2 years. The primary outcome was a composite of mortality, myocardial infarction (MI), or stroke.
At 3 years, the cumulative incidence of the composite outcome was 5.9% for semaglutide and 6.9% for empagliflozin. The hazard ratio (HR) was 0.89 (95% confidence interval [CI] = 0.78–1.02), indicating a modest but not statistically significant lower risk with semaglutide.
Among individual outcomes, stroke showed the largest difference. Stroke incidence was lower with semaglutide, with an HR of 0.62 (95% CI = 0.43–0.89). For MI, the HR was 0.85 (95% CI = 0.68–1.05), and for all-cause mortality, 0.97 (95% CI = 0.81–1.15).
Secondary outcomes showed greater weight loss and better glycemic control with semaglutide. At 12 months, patients lost an average of 4.3 kg (standard deviation [SD] = 7.6) with semaglutide compared with 3.2 kg (SD = 6.2) with empagliflozin. Hemoglobin A1c decreased by 0.34 percentage points (SD = 1.52) with semaglutide and by 0.18 percentage points (SD = 1.32) with empagliflozin.
Subgroup analyses showed semaglutide offered greater benefit in patients younger than 65 years, with an HR of 0.76 (95% CI = 0.61–0.96), but not among those 65 years and older (HR = 1.02, 95% CI = 0.86–1.22). Patients with baseline HbA1c below 7% also saw more benefit (HR = 0.74, 95% CI = 0.56–0.97).
Geographic differences were observed. The benefit for semaglutide was most evident in southwestern Pennsylvania, where patients had greater access to care, insurance coverage, and telemedicine. In that subgroup, the HR was 0.75 (95% CI = 0.63–0.90).
In the secondary analysis comparing dulaglutide with empagliflozin (n = 6,093 per group), no statistically significant differences were found. The HR for the composite outcome was 1.03 (95% CI = 0.90–1.16).
Limitations included the observational design, lack of cause-specific mortality data, and reliance on prescription records rather than confirmed medication use.
The study was funded by the American Heart Association.
Source: Annals of Internal Medicine