SGLT2 Inhibitors Show High Cardiovascular- and Renal-Protective Effects in T2D

This meta-analysis provides significant reassurance regarding the cardiovascular and long-term noncardiovascular safety of SGLT2 inhibitors.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors showed high cardiovascular- and renal-protective effects as well as good long-term noncardiovascular safety with sustained efficacy in patients with type 2 diabetes, according to findings published in the Journal of the American Heart Association.

Researchers performed a meta-analysis with trial sequential analysis of randomized controlled trials and adjusted observational studies. Each had a minimum of 26 weeks and 2000 patient-years of follow-up. For studies examining long-term noncardiovascular safety and efficacy, only randomized controlled trials with at least 2 years and 1000 patient-years of follow-up were included. For cardiovascular outcomes analysis, 5 studies with 351,476 patients were included.

Results of the meta-analysis showed that SGLT2 inhibitors significantly reduced the risk for major adverse cardiac events (hazard ratio [HR] 0.80; 95% CI, 0.69-0.92; P =.002), all-cause mortality (HR 0.67; 95% CI, 0.54-0.84; P <.001), cardiovascular mortality (HR 0.77; 95% CI, 0.60-0.98; P =.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 <.001), and progression of albuminuria (HR 0.68; 95% CI, 0.58-0.81; P <.001). The researchers found no difference in the risk for nonfatal stroke. Analyses limited to randomized controlled trials showed similar results.

Trial sequential analysis provided firm evidence that SGLT2 inhibitors reduced major adverse cardiac events, all-cause mortality, and hospitalization for heart failure by 20%. However, evidence remains inconclusive for cardiovascular mortality.

The researchers analyzed 9 randomized controlled trials to examine long-term noncardiovascular efficacy. SGLT2 inhibitors reduced the incidence of hypoglycemia and acute kidney injury, but increased the risk for urinary tract and genital infections.

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“Our meta-analysis provides robust reassurance regarding the cardiovascular and long-term noncardiovascular safety of SGLT2 inhibitors, with sustained efficacy in reducing a range of markers of vascular risk,” the researchers wrote. “SGLT2 inhibitors showed remarkable cardiovascular and renal protective benefits and might be considered as preferred for [patients with] type 2 diabetes with established or at high risk for cardiovascular disease,” they concluded.

Limitations of the meta-analysis include the following: 1) results were analyzed for study-level data but not for patient-level data, and patient-level data could improve the accuracy of the findings. 2) Potential publication bias could not be ruled out. 3) There were considerable differences in the analyses of several outcomes, which may be caused by differences in trial populations, baseline comorbidities, and treatment regimens. 4) Most of the study patients were white; caution should therefore be used when generalizing to other populations.


Zhang X-L, Zhu Q-Q, Chen Y-H, et al. 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 online January 20, 2018]. J Am Heart Assoc. doi:10.1161/JAHA.117.007165