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Clinical trials have shown inconsistent long-term cardiovascular safety of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with type 2 diabetes.
Randomized controlled trials (RCTs) comparing a SGLT2 inhibitor with placebo or other glucose-lowering drugs, with a minimal of 2 years and 1000 patient-years of follow-up. Trial included in cardiovascular outcome analysis also had to have cardiovascular outcomes predefined and independently adjudicated. We performed meta-analysis with trial sequential analysis (TSA) to determine the long-term cardiovascular and non-cardiovascular safety and efficacy of SGLT2 inhibitors.
Nine trials with 23035 patients were included. SGLT2 inhibitors were associated with a statistically significant reduction in risk of MACE (odds ratio [OR]: 0.87; 95% confidence interval [CI]: 0.79 to 0.96; P=0.005; number needed to treat [NNT]: 291), all-cause mortality (OR: 0.80; 95% CI: 0.67 to 0.96; p=0.02; NNT: 137), cardiovascular mortality (OR: 0.78; 95% CI: 0.60 to 1.00; p=0.05; NNT: 161), hospitalization for heart failure (OR: 0.67; 95% CI: 0.56 to 0.81; p<0.001; NNT: 119), hospitalization for heart failure or cardiovascular death (OR: 0.73; 95% CI: 0.62 to 0.87; p<0.001; NNT: 73), and progression of albuminuria (OR: 0.75; 95% CI: 0.61 to 0.92; p=0.006; NNT: 19). No significant differences in risk of non-fatal myocardial infarction or non-fatal stroke were found. TSA of MACE and all-cause death confirmed the findings and suggested that future trials might not be required as this significant association is unlikely to be changed. SGLT2 inhibitors significantly reduced incidences of hypoglycemia and acute kidney injury, but were associated with a modestly higher incidence of urinary tract infection, and a 3-fold higher risk of genital infection in both female and male patients. SGLT2 inhibitors significantly reduced HbA1c level compared with controls, with a weighted mean difference of –0.39% (95% CI: –0.52 to –0.26).
Our meta-analysis provides robust reassurance about the long-term cardiovascular non-cardiovascular safety of SGLT2 inhibitors with sustained efficacy in reducing markers of vascular risk. SGLT2 inhibitors showed remarkable cardiovascular- and renal-protective benefits, and should be considered in type 2 diabetes patients with high risk for cardiovascular disease.