Can the cardiovascular risk reductions observed with empagliflozin in the EMPA‐REG OUTCOME trial be explained by concomitant changes seen in conventional cardiovascular risk factor levels?

Abstract

Aim:The EMPA-REG OUTCOME trial demonstrated a significant reduction in cardiovascular (CV) outcomes in patients with type 2 diabetes given empagliflozin, a selective sodium-glucose cotransporter-2 inhibitor. We performed post-hoc analyses of this trial examining the degree to which empagliflozin-induced changes in conventional CV risk factors might explain the observed CV benefits. Materials and methods:We estimated three-year EMPA-REG OUTCOME CV event rates using a type 2 diabetes-specific clinical outcomes simulation model applied to annual patient-level data. Variables included were atrial fibrillation, smoking, albuminuria, HDL-cholesterol, LDL-cholesterol, systolic blood pressure, HbA1c, heart rate, white cell count, haemoglobin, estimated GFR, and prior histories of ischaemic heart disease, heart failure, amputation, blindness, renal failure, stroke, myocardial infarction or diabetic ulcer. Multiple simulations were performed for each participant to minimize uncertainty and optimize confidence interval precision around CV risk point estimates. Observed and simulated cardiovascular relative risk-reductions were compared.Results: Model-predicted relative risk reductions were smaller than those observed in the trial, with empagliflozin-associated changes in conventional CV risk factor values appearing to explain only 12% of the observed relative risk reduction for allcause death (4% of 32%), 7% for CV death (3% of 39%) and 15% for heart failure (4% of 29%). Conclusions:Empagliflozin-associated changes in conventional CV risk factors in EMPA-REG OUTCOME appear to explain only a small proportion of the CV and allcause death reductions observed. Alternative risk-reduction mechanisms need to be -2 -explored to determine if the observed CV risk changes can be explained by other factors, or possibly by a direct drug-specific effect.

Effects of the SGLT2 Inhibitor Dapagliflozin on Energy Metabolism in Patients With Type 2 Diabetes: A Randomized, Double-Blind Crossover Trial

“…How SGLT2is exert their remarkable effects on CV and renal outcomes is not fully understood. For example, only 12% of the relative risk reduction for all-cause death caused by SGLT2is could be explained by the combined changes in conventional CV risk factors ( 4 ).…”

Effects of empagliflozin versus placebo on cardiac sympathetic activity in acute myocardial infarction patients with type 2 diabetes mellitus: the EMBODY trial

“…Previous basic studies have reported that dapagliflozin reduced the sympathetic marker and suppresses prolonged ventricular repolarization [ 46 , 47 ]. Indeed, SGLT2 inhibitors have been shown to affect several other common modifiable risk factors and comorbidities associated with cardiovascular diseases, such as BW, renal function, uric acid level, and plasma lipid level [ 1 – 3 , 48 , 49 ]. Taken together, the results of the present study were comparable with those of previous studies [ 1 – 3 ].…”

Sodium‐glucose cotransporter 2 inhibitor effects on heart failure hospitalization and cardiac function: systematic review

“…In two post hoc analyses of EMPA‐REG OUTCOME data, simulation of the effects of empagliflozin compared with placebo on conventional CVD risk factors accounted for only 15% and 37% of the observed reduction in HHF risk observed in patients with T2DM and CVD. 54 , 55 …”

“…In two post hoc analyses of EMPA-REG OUTCOME data, simulation of the effects of empagliflozin compared with placebo on conventional CVD risk factors accounted for only 15% and 37% of the observed reduction in HHF risk observed in patients with T2DM and CVD. 54,55 A plethora of mechanisms outside of changes in conventional CVD risk factors have been proposed for how SGLT2is may improve HF outcomes (Figure 3A). However, not all have been the focus of RCT studies, which are reviewed in the following sections.…”