Sodium‐Glucose Cotransporter‐2 Inhibitors and Primary Prevention of Atherosclerotic Cardiovascular Disease: A Meta‐Analysis of Randomized Trials and Systematic Review

BACKGROUND: Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors reduce atherosclerotic cardiovascular disease (ASCVD) events in patients with prior ASCVD and type 2 diabetes; however, this benefit is uncertain in patients without established ASCVD. METHODS AND RESULTS: Large‐scale cardiovascular outcome randomized controlled trials or their prespecified subgroup analyses were selected, evaluating SGLT2 inhibitors versus placebo for primary prevention of ASCVD (inception, March 2023). The primary outcome was atherosclerotic major adverse cardiovascular events (MACEs), which was a composite of cardiovascular mortality, myocardial infarction, and stroke. The secondary outcomes were individual components of MACEs and all‐cause mortality. The outcomes were reported as random‐effect relative risk (RR) with a 95% CI. This analysis, comprising 23 987 patients enrolled in 5 randomized controlled trials with a mean follow‐up duration of ≈135 weeks, found no significant reduction in atherosclerotic MACEs with SGLT2 inhibitors in comparison to placebo (RR, 0.85 [95% CI, 0.71–1.01]; P=0.07; I(2)=44). There were no significant differences in cardiovascular mortality (RR, 0.93 [95% CI, 0.77–1.14]; P=0.50; I(2)=0), myocardial infarction (RR, 0.88 [95% CI, 0.69–1.11]; P=0.28; I(2)=23), and stroke (RR, 0.84 [95% CI, 0.62–1.16]; P=0.29; I(2)=46). SGLT2 inhibitors significantly improved all‐cause mortality (RR, 0.85 [95% CI, 0.72–1.0]; P=0.04; I(2)=23). On subgroup analyses, the use of SGLT2 inhibitors led to significant reductions in MACEs (RR, 0.74 [95% CI, 0.61–0.89]; P=0.001), myocardial infarction (RR, 0.67 [95% CI, 0.47–0.97]; P=0.03), and stroke (RR, 0.61 [95% CI, 0.41–0.91]; P=0.01) primarily in patients with chronic kidney disease along with type 2 diabetes, whereas these benefits were not observed in patients with type 2 diabetes without chronic kidney disease. CONCLUSIONS: SGLT2 inhibitors significantly reduced atherosclerotic MACEs in subjects having both chronic kidney disease and type 2 diabetes without established ASCVD.