Reduced Mortality With Sodium-Glucose Cotransporter–2 Inhibitors in Observational Studies
Avoiding Immortal Time Bias
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Sodium-glucose cotransporter–2 inhibitors (SGLT2i), the most recent class of medications to treat type 2 diabetes mellitus, have been the object of large randomized controlled trials and observational studies to assess their effectiveness on major disease outcomes. The EMPA-REG OUTCOME randomized trial (Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes) of >7000 patients with type 2 diabetes mellitus who had established cardiovascular disease reported a significant 32% reduction in all-cause mortality (hazard ratio, 0.68; 95% confidence interval, 0.57–0.82) with the SGLT2i empagliflozin. The CANVAS randomized trials program (Canagliflozin Cardiovascular Assessment Study) with >10 000 patients with type 2 diabetes mellitus, 66% with cardiovascular disease, reported a lesser 13% nonsignificant reduction in all-cause death (hazard ratio, 0.87; 95% confidence interval, 0.74–1.01) with the SGLT2i canagliflozin.
Two observational studies of these effects in real-world clinical practice diverged from the randomized controlled trials by reporting astonishing reductions in mortality with these drugs.1,2 The CVD-REAL study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of SGLT-2 Inhibitors), using data from 6 countries on >150 000 new users of SGLT2i matched to the same number of new users of other antihyperglycemic agents (AHAs), reported a significant 51% lower rate of all-cause death with SGLT-2i in comparison with other AHAs (on-treatment hazard ratio, 0.49; 95% confidence interval, 0.41–0.57).1 In the EASEL study (Evidence for Cardiovascular Outcomes With Sodium Glucose Cotransporter 2 Inhibitors in the Real World), using data from the US Department of Defense on >12 000 new users of …