AimSodium-glucose cotransporter 2 inhibitors (SGLT2is) can improve long-term cardio-renal outcomes in patients with diabetes, heart failure (HF), or renal failure. We aimed to investigate the association of SGLT2is with the risks of various cardiovascular and reproductive diseases.MethodsLarge-scale randomized trials enrolling more than 1000 participants and assessing SGLT2is were included. Outcomes of interest were the various serious adverse events related to cardiovascular or reproductive diseases. Meta-analysis was done to generate pooled risk ratio (RR) and 95% confidence interval (CI).ResultsWe included 14 large trials and evaluated 169 types of cardiovascular and reproductive diseases. SGLT2is were significantly associated with the lower risks of 13 types of cardiovascular diseases, e.g., cardiac failure chronic (RR 0.70, 95% CI 0.57-0.87), cardiac failure congestive (RR 0.74, 95% CI 0.66-0.83), acute cardiac failure (RR 0.72, 95% CI 0.60-0.86), coronary artery disease (RR 0.75, 95% CI 0.58-0.97), ischemic cardiomyopathy (RR 0.72, 95% CI 0.52-0.99), atrial fibrillation (RR 0.88, 95% CI 0.78-0.99), bradycardia (RR 0.72, 95% CI 0.53-0.99), and hypertension (RR 0.70, 95% CI 0.54-0.91). SGLT2is were not significantly associated with 18 types of reproductive diseases, e.g., adenomyosis, endometrial hyperplasia, and metrorrhagia. Although SGLT2is were observed to have a significant association with a higher risk of uterine prolapse, the 95% CI of RR for this outcome was relatively wide.ConclusionThis meta-analysis confirms the benefits of SGLT2is against chronic congestive HF again; reveals the possible benefits of SGLT2is against acute HF, myocardial infarction, arrhythmias, and hypertension; and identifies that SGLT2is are safe in general for the reproductive system.