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Background This study aims to evaluate the relative efficacy and safety of sodium‐glucose cotransporter 2 (SGLT2) inhibitors in patients with Type 2 diabetes mellitus (T2DM) and established cardiovascular disease (CVD) or at risk for CVD. Primary efficacy outcomes were cardiovascular (CV) death and hospitalization for heart failure (HFH); primary safety outcomes were major hypoglycemic events and genital mycotic infections. Methods We performed a targeted literature search on PubMed through December 2023 to identify randomized controlled trials (RCTs) assessing the efficacy and safety of sotagliflozin, empagliflozin, canagliflozin, and dapagliflozin in patients with T2DM and established CVD or at risk for CVD. Subsequently, we used a random‐effects network meta‐analysis for an indirect treatment comparison of 4 relevant RCTs, to estimate the relative hazard ratio ([HR], for efficacy outcomes), odds ratio ([OR], for safety outcomes), and 95% confidence interval (CI). Results This study showed key differences in the efficacy and safety among SGLT2 inhibitors. Dapagliflozin (HR, 1.58; 95% CI, 1.19–2.11) and canagliflozin (HR, 1.40; 95% CI, 1.04–1.89) were associated with a higher rate of CV death compared to empagliflozin. Dapagliflozin and empagliflozin decreased the odds of major hypoglycemic events when compared to sotagliflozin (OR, 0.15; 95% CI, 0.03–0.72) and (OR, 0.21; 95% CI, 0.04–0.95), respectively. Canagliflozin increased the odds of major hypoglycemic events when compared to dapagliflozin (OR, 1.55; 95% CI 1.06–2.27). Patients treated with dapagliflozin were more likely to develop genital mycotic infections than with empagliflozin (OR, 2.37; 95% CI, 1.15–5.06). Conversely, canagliflozin reduced the odds of developing genital mycotic infections compared to empagliflozin (OR, 0.48; 95% CI, 0.23–0.99). Conclusions This study revealed notable differences among SGLT2 inhibitors in the likelihood of CV death, major hypoglycemic events, and genital mycotic infections. It provides evidence of comparable efficacy and safety across several other outcomes. These findings underscore the importance of personalizing therapy based on individual patient risk factors.