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SGLT2 inhibitors for primary prevention of cardiovascular events

Sodium glucose cotransporter 2 (SGLT2) inhibitors have been approved for the treatment of type 2 diabetes mellitus since 2012. Early clinical trials with these agents demonstrated their capacity not only for lowering glucose but also for reducing weight and blood pressure, thus addressing several important components of the metabolic syndrome. The EMPA-REG study, the cardiovascular outcome study of empagliflozin, revolutionized our view of the drug and class while demonstrating robust reduction in major adverse cardiovascular events (MACE; hazard ratio [HR] [95% confidence interval (CI)] 0.86 [0.74, 0.99]), hospitalization for heart failure (HHF; HR [95% CI] 0.65 [0.50, 0.85]) as well as marked improvement in renal outcomes (HR [95% CI] 0.61 [0.53, 0.70]). All patients included in the study had established atherosclerotic cardiovascular disease (ASCVD); thus, the effect of these agents on the primary prevention of cardiovascular events in patients with diabetes remained unknown. The CANVAS program, which was published thereafter, included a mixed patient population with and without ASCVD, although the majority had established ASCVD. MACE was reduced with canagliflozin vs placebo (HR [95% CI]) 0.86 [0.75, 0.97]) and there was a trend to a greater effect in those with previous ASCVD (HR [95%CI] 0.82 [0.72, 0.95]) vs those without (HR [95% CI] 0.98 [0.74, 1.3]), interaction P value 0.18. HHF and renal outcomes showed robust reduction regardless of risk category. The majority of patients included in the cardiovascular outcome study of dapagliflozin — the DECLARE trial — had only risk factors but not established ASCVD. This trial thus presented a unique opportunity to assess the benefit of an SGLT2 inhibitor on the primary prevention of cardiovascular events. Dapagliflozin demonstrated a reduction in the co-primary composite endpoint of hospitalization for heart failure/cardiovascular death (HHF/CVD; HR [95% CI] 0.83 [0.73, 0.95]) yet did not achieve statistically significant superiority with respect to the second co-primary outcome of MACE (HR [95% CI] 0.93 [0.84, 1.03]). The renal benefits of dapagliflozin were of similar magnitude to those observed with empagliflozin and canagliflozin and were observed irrespective of risk status. A meta-analysis study assessed the cardiorenal outcomes of the three SGLT2 inhibitors with respect to their impact on primary vs secondary prevention of cardiovascular outcomes. The effect of the agents on MACE was dependent upon risk status — whereas benefit was shown in those with established ASCVD (HR [95% CI] 0.86 [0.80, 0.93]) yet not in primary prevention cohorts (HR [95% CI] 1.00 [0.87, 1.16]), interaction P value 0.05. Contrariwise, the robust reduction of HHF was independent of preexisting ASCVD (interaction P value 0.38), or history of heart failure (interaction P value 0.76). Similarly, the renal benefit was observed in patients with and without established ASCVD (interaction P value 0.71), although it was more pronounced in those with preserved renal function (interaction P value 0.026). According to these data, one may simply state that SGLT2 inhibitors carry no benefit in the primary prevention of cardiovascular events. However, this statement, DOI: 10.1111/1753-0407.13004