Cardiovascular Benefit of Empagliflozin Across the Spectrum of Cardiovascular Risk Factor Control in the EMPA-REG OUTCOME Trial

Abstract

Context: Control of multiple cardiovascular (CV) risk factors reduces CV events in individuals with type 2 diabetes.

Objective: To investigate this association in a contemporary clinical trial population, including how CV risk factor control affects the CV benefits of empagliflozin, a sodium-glucose cotransporter-2 inhibitor.

Design: Post hoc analysis.

Setting: Randomized CV outcome trial (EMPA-REG OUTCOME).

Participants: Type 2 diabetes patients with established CV disease.

Intervention: Empagliflozin or placebo.

Main outcome measures: Risk of CV outcomes-including the treatment effect of empagliflozin-by achieving 7 goals for CV risk factor control at baseline: (1) glycated hemoglobin <7.5%, (2) low-density lipoprotein cholesterol <100 mg/dL or statin use, (3) systolic blood pressure <140 mmHg and diastolic blood pressure <90 mmHg, (4) pharmacological renin-angiotensin-aldosterone system blockade, (5) normoalbuminuria, (6) aspirin use, (7) nonsmoking.

Results: In the placebo group, the hazard ratio (HR) for CV death was 4.00 (95% CI, 2.26-7.11) and 2.48 (95% CI, 1.52-4.06) for patients achieving only 0-3 or 4-5 risk factor goals at baseline, respectively, compared with those achieving 6-7 goals. Participants achieving 0-3 or 4-5 goals also had increased risk for the composite outcome of hospitalization for heart failure or CV death (excluding fatal stroke) (HR 2.89 [1.82-4.57] and 1.90 [1.31-2.78], respectively) and 3-point major adverse CV events (HR 2.21 [1.53-3.19] and 1.42 [1.06-1.89]). Empagliflozin significantly reduced these outcomes across all risk factor control categories (P > 0.05 for treatment-by-subgroup interactions).

Conclusions: Cardiovascular risk in EMPA-REG OUTCOME was inversely associated with baseline CV risk factor control. Empagliflozin's cardioprotective effect was consistent regardless of multiple baseline risk factor control.

Trial registration: ClinicalTrials.gov NCT01131676.

Keywords: cardioprotective; cardiovascular disease; type 2 diabetes.

© Endocrine Society 2020.

Figures

Figure 1.

CV risk factor control at baseline in EMPA-REG OUTCOME trial. Data on attainment of CV risk factor goals at baseline were unavailable for 85 patients (66 empagliflozin and 19 placebo) (1.2%). *glycated hemoglobin

Figure 2.

Risk of CV outcomes in the placebo group by achievement of CV risk factor goals at baseline: HbA1c

Figure 3.

Effect of empagliflozin versus placebo on CV outcomes across subgroups of achievement of CV risk factor goals at baseline: HbA1c P-value relates to test of homogeneity of treatment group differences among subgroups (test for treatment by subgroup interaction) without adjustment for multiple testing. †Excludes fatal stroke.

Figure 4.

Effect of empagliflozin versus placebo on CV outcomes overall and adjusted for control of HbA1c (†Excludes fatal stroke.