An exploration of the heterogeneity in effects of SGLT2 inhibition on cardiovascular and all-cause mortality in the EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, and CREDENCE trials

Background Large-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression kidney disease. However, the magnitude all-cause death appeared to vary between some studies. Methods We explored impact differences trial methodologies, participant characteristics, types deaths, follow-up duration, intermediate markers risk, drug selectivity for SGLT2 protective effect against fatal events achieved 4 trials. Results The populations differed substantively proportions baseline atherosclerotic disease history (99.2% EMPA-REG OUTCOME 40.6% DECLARE-TIMI 58), macroalbuminuria (88.0% CREDENCE 7.6% CANVAS Program). Meta-regression analyses no clear these (both P > 0.09) or other characteristics mortality benefits (all 0.55). Other (duration, inhibitor, risk) also did not explain heterogeneity observed 0.30). Conclusion No explanation statistical evidence inhibition outcomes could be identified. While had limited power, results raise possibility that variations treatment may at least partly due chance.