Exploring the heterogeneity of the effects of SGLT-2 inhibitors in cardiovascular outcome trials

Abstract

Background and aim: The interpretation of discrepancies across cardiovascular safety trials (CVOT) with SGLT-2 inhibitors in the incidence of major cardiovascular events (MACE) and mortality is complex, because of heterogeneity in trial protocols and baseline characteristics of patients enrolled. Aim of this analysis is the exploration of possible determinants of heterogeneity of relative risk reduction for major cardiovascular events (MACE) and all-cause mortality. Methods and results: Incidence of events (MACE and mortality) in intervention and control groups and baseline characteristics of patients were extracted for each trial (EMPAREG, CANVAS, and DECLARE). For studies including both primary and secondary prevention cohorts, those two subgroups were considered separately. Metaregression analysis was used to assess the association of relative risk reduction with baseline characteristics of patients, including observed incidence of events with placebo. The estimated reduction in the incidence of MACE associated with SGLT-2 inhibitors showed a significant association with the incidence of MACE in the control group, suggesting that a greater effect was observed in trials enrolling patients at higher risk (Slope À0.008 [À0.023; 0.007], p Z 0.31). A higher proportion of patients treated with statins, bblockers and insulin at baseline was associated with a greater reduction of MACE, but not of mortality. Conclusions: In CVOT trials, the magnitude of the effect of SGLT-2 inhibitors on MACE is driven by absolute risk of enrolled patients; as a consequence, the estimated risk reduction is lower in primary prevention cohorts, which have a lower risk. This result supports the hypothesis of a class effect of SGLT-2 inhibitors on MACE. jo urnal homep age: www.el sevie r.co m/locate/nm cd

Effects of glucose‐lowering agents on cardiovascular and renal outcomes in subjects with type 2 diabetes: An updated meta‐analysis of randomized controlled trials with external adjudication of events

“…Despite apparently different results in trials with different molecules, the analysis of RCTs with GLP‐1 RA did not show any relevant heterogeneity. For both drug classes, the risk reduction of MACE was also associated with a significant reduction in all‐cause mortality, thus confirming previous results 9,12,51 …”

“…For both drug classes, the risk reduction of MACE was also associated with a significant reduction in all-cause mortality, thus confirming previous results. 9,12,51 There are two other therapeutic options, besides GLP-1 RA and SGLT2i, which are associated with a significant reduction in the risk of 3-point MACE: metformin and pioglitazone. Metformin had already been associated with a reduction of MACE, 15,52 whereas results on pioglitazone were contrasting.…”

Sodium glucose cotransporter 2 inhibitors: mechanisms of action in heart failure

“…This is explained by the fact that patients in the EMPA-REG OUTCOME study had a higher risk of death at baseline and the management used was secondary prevention. In contrast, in the other two studies, patients without CVD required a longer observation time before the beneficial effects of treatment became apparent [27].…”

“…Further disparities between these studies may also result from different clinical characteristics of the patient populations studied (in the EMPA-REG OUTCOME trial only patients with confirmed CVD, and in other studies patients both with and without confirmed CVD) [27]. Such a difference explains the period of time taken for divergence of the lines illustrating mortality in the studied groups.…”

“…As mentioned above, the basic evidence for favourable CV outcomes of SGLT2is (empagliflozin, canagliflozin and dapagliflozin) was obtained mainly in three randomised clinical trials: EMPA-REG OUTCOME, CANVAS and DECLARE-TIMI 58 [1-9, 19, 27]. These three clinical trials differed not only in the studied drug but also in relation to the studied patient population [27].…”