Mortality and Cardiovascular Benefits of SGLT-2 Inhibitors in Type 2 Diabetes

Are the mortality and cardiovascular benefits of SGLT-2 inhibitors limited to patients with type 2 diabetes who have established cardiovascular disease and renal disease?

Studies have shown that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control, reduce body weight, and lower the incidence of heart failure and renal disease in the treatment of type 2 diabetes. However, the 2021 ADA guideline recommends sodium-glucose cotransporter 2 (SGLT2) inhibitors as a secondary agent in the management of type 2 diabetes for patients with established cardiovascular disease (CVD) and chronic kidney disease (CKD) or with high-risk indicators for CVD and CKD. Current recommendation are derived from trials that only include participants with established CVD, specifically the results of the EMPA-REG OUTCOME, EMPEROR-Reduced, VERTIS CV, DAPA-HF, and SOLOIST-WHF trials. Therefore, the benefit of SGLT-2 inhibitors is uncertain in reducing mortality and cardiovascular outcomes across the spectrum of baseline risk.

The study in this discussion is a Bayesian meta-analysis of 53 randomized controlled trials with 88,390 participants to compare SGLT-2 inhibitors with placebo, with at least 24 weeks of randomized treatment and follow-up, to prevent CVD in adults with type 2 diabetes. The primary outcome was all-cause mortality, and the key secondary outcome was cardiovascular mortality. To examine the association between the magnitude of treatment effects for each SGLT-2 inhibitor across the spectrum of baseline risk, the authors used three different approaches, including the Bayesian meta-regression to measure the average cardiovascular risk, the sensitivity analyses between primary prevention (without established CVD) and secondary prevention (with established CVD), and the sensitivity analyses for trials or subgroups of patients with established CVD. 

There was positive to strong evidence that empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of all-cause mortality (empagliflozin: RR 0.79; 95% Crl 0.63 to 0.97; canagliflozin: RR 0.86; 95% Crl 0.69 to 1.05; dapagliflozin: RR 0.85; 95% Crl 0.72 to 1.01) and cardiovascular mortality (empagliflozin: RR 0.78; 95% Crl 0.61 to 1.00; canagliflozin: RR 0.83; 95% Crl 0.63 to 1.05; dapagliflozin: RR 0.88; 95% Crl 0.71 to 1.08). The probabilities for the RR < 1.00 were 98.7%, 93.6%, and 96.5% respectively for all-cause mortality and 97.5%, 94.4%, and 90.1% respectively for cardiovascular mortality. The evidence for ertugliflozin and sotagliflozin is limited. 

Compared with placebo, empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin reduced the incidence of hospitalization for heart failure by 34% (RR 0.66; 95% Crl 0.52 to 0.79), 36% (RR 0.64; 95% Crl 0.51 to 0.81), 26% (RR 0.74; 95% Crl 0.61 to 0.91), and 37% (RR 0.63; 95% Crl 0.45 to 0.89), respectively. The probabilities for RR < 1.00 ranged from 99.3% to 100% for these agents. Besides, empagliflozin, canagliflozin, and dapagliflozin have positive evidence in reducing the risk for acute myocardial infarction; however, the evidence did not meet the threshold considered clinically significant. For stroke prevention, the evidence is inconclusive, and empagliflozin showed an increased risk of stroke, which means further research is required to clarify the effect. 

Current guidelines and previous meta-analyses only focused on the effects of SGLT-2 inhibitors in patients with established CVD or at high risk of cardiovascular risk. Nevertheless, this study is the most recent and most comprehensive analysis of over 50 randomized controlled trials that studied the effect of SGLT-2 inhibitors. As a result, the treatment effects of these agents versus placebo do not vary across the spectrum of baseline risk. One of the limitations of this study is that the author did not evaluate the safety profile or the adverse events since it was beyond the scope of the study. Therefore, clinicians should consider the safety profile for SGLT-2 inhibitors in making recommendations.

Practice Pearls:

• The evidence for all-cause and cardiovascular mortality benefits are positive-to-strong for empagliflozin, canagliflozin, and dapagliflozin across all spectrum of baseline risk.
• Adult patients with type 2 diabetes at the highest absolute risk of all-cause and cardiovascular mortality will receive a more significant absolute benefit from SGLT-2 inhibitors.
• This most recent, most comprehensive meta-analysis may warrant a change in guideline recommendations regarding the place of SGLT-2 inhibitors for patients with type 2 diabetes. 

Odutayo, Ayodele et al. “Sodium-Glucose Cotransporter 2 Inhibitors, All-Cause Mortality, and Cardiovascular Outcomes in Adults with Type 2 Diabetes: A Bayesian Meta-Analysis and Meta-Regression.” Journal of the American Heart Association, e019918. September 13. 2021.

American Diabetes Association. “9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2021.” Diabetes care vol. 44, Suppl 1 (2021): S111-S124.

Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy