Cardiovascular Safety, Long‐Term Noncardiovascular Safety, and Efficacy of Sodium–Glucose Cotransporter 2 Inhibitors in Patients With Type 2 Diabetes Mellitus: A Systemic Review and Meta‐Analysis With Trial Sequential Analysis

• Published in: Journal of the American Heart Association Vol. 7; no. 2
• Main Authors: Zhang, Xin‐Lin, Zhu, Qing‐Qing, Chen, Yu‐Han, Li, Xue‐Ling, Chen, Fu, Huang, Jian‐An, Xu, Biao
• Format: Journal Article
• Language: English
• Published: England John Wiley and Sons Inc 23.01.2018; Wiley
• Subjects: cardiovascular disease; Cardiovascular Diseases - epidemiology; Cardiovascular Diseases - prevention & control; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - epidemiology; Diabetes Mellitus, Type 2 - metabolism; Diabetic Nephropathies - epidemiology; Diabetic Nephropathies - prevention & control; Female; Humans; Kidney - drug effects; Kidney - metabolism; Male; meta‐analysis; Middle Aged; Observational Studies as Topic; observational study; Patient Safety; Protective Factors; randomized controlled trial; Randomized Controlled Trials as Topic; Risk Assessment; Risk Factors; SGLT2 (sodium–glucose cotransporter 2) inhibitor; Sodium-Glucose Transporter 2 - drug effects; Sodium-Glucose Transporter 2 - metabolism; Sodium-Glucose Transporter 2 Inhibitors - adverse effects; Sodium-Glucose Transporter 2 Inhibitors - therapeutic use; Systematic Review and Meta‐Analysis; Time Factors; Treatment Outcome; trial sequential analysis; cardiovascular disease; trial sequential analysis; meta‐analysis; SGLT2 (sodium–glucose cotransporter 2) inhibitor; observational study; randomized controlled trial
• ISSN: 2047-9980; 2047-9980
• DOI: 10.1161/JAHA.117.007165

Background The cardiovascular and long‐term noncardiovascular safety and efficacy of SGLT2 (sodium–glucose cotransporter 2) inhibitors have not been well documented. Methods and Results For cardiovascular outcomes, we performed a meta‐analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies, each with a minimum of 26 weeks and 2000 patient‐years of follow‐up. For long‐term noncardiovascular safety and efficacy outcome analyses, we included only randomized controlled trials with at least 2 years and 1000 patient‐years of follow‐up. Five studies with 351 476 patients were included in cardiovascular outcomes analysis. Meta‐analyses showed that SGLT2 inhibitors significantly reduced the risks of major adverse cardiac events (hazard ratio [HR]: 0.80; 95% confidence interval [CI], 0.69–0.92; P=0.002), all‐cause mortality (HR: 0.67; 95% CI, 0.54–0.84; P<0.001), cardiovascular mortality (HR: 0.77; 95% CI, 0.60–0.98; P=0.03), nonfatal myocardial infarction (HR: 0.86; 95% CI, 0.76–0.98; P=0.02), hospitalization for heart failure (HR: 0.62; 95% CI, 0.55–0.69; P<0.001), and progression of albuminuria (HR: 0.68; 95% CI, 0.58–0.81; P<0.001). No significant difference in nonfatal stroke was found. Analyses limited to randomized controlled trials showed similar findings. Trial sequential analysis provided firm evidence of a 20% reduction in major adverse cardiac events, all‐cause mortality, and hospitalization for heart failure with SGLT2 inhibitors, but evidence remains inconclusive for cardiovascular mortality. Nine randomized controlled trials contributed to long‐term noncardiovascular and efficacy analyses. SGLT2 inhibitors reduced incidence of hypoglycemia and acute kidney injury but increased the risks of urinary tract and genital infections. Conclusions SGLT2 inhibitors showed remarkable cardiovascular‐ and renal‐protective effects and good long‐term noncardiovascular safety with sustained efficacy.