Background To investigate the individual profile of each SGLT2 (sodium‐glucose cotransoporter‐2) inhibitor in patients with different backgrounds. Methods and Results This study included 21 placebo‐controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all‐cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53–0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56–0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60–0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis. Conclusions The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.