IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2-Is) have emerged as standard therapy for heart failure. We aim to assess the safety of SGLT2-Is in patients with a high risk of cardiovascular disease.Areas coveredAn electronic database search was conducted for randomized control trials comparing SGLT2-Is to placebo in patients with a high risk of cardiac disease or heart failure. Data were pooled for outcomes using random-effect models. The odds ratio (OR) and 95% confidence interval (CI) were used to compare eight safety outcomes between the two groups. The analysis included ten studies with 71 553 participants, among whom 39 053 received SGLT2-Is; 28 809 were male and 15 655 were female (mean age, 65.2 years). The mean follow-up period was 2.3 years with the range being 0.8–4.2 years. The SGLT2-Is group had a significant reduction in AKI (OR = 0.8;95% CI 0.74–0.90) and serious adverse effects (OR = 0.9; 95% CI 0.83–0.96) as compared to placebo. No difference was found in fracture (OR = 1.1; 95% CI 0.91–1.24), amputation (OR = 1.1; 95% CI 1.00–1.29), hypoglycemia (OR 0.98;95% CI 0.83–1.15), and UTI (OR = 1.1; 95% CI 1.00–1.22). In contrast, DKA (OR = 2.4; 95% CI 1.65–3.60) and volume depletion (OR = 1.2; 95% CI 1.07–1.41) were higher in SGLT2-Is group.Expert opinion/commentaryThe benefits of SLGT2-Is outweigh the risk of adverse events. They may reduce the risk of AKI but are associated with an increased risk of DKA and volume depletion. Further studies are warranted to monitor a wider range of safety outcomes of SGLT2-Is.