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

J Clin Endocrinol Metab. 2020 Sep 1;105(9):3025-3035. doi: 10.1210/clinem/dgaa321.

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.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Benzhydryl Compounds / therapeutic use*
  • Blood Glucose / drug effects
  • Blood Glucose / metabolism
  • Cardiotonic Agents / therapeutic use*
  • Cardiovascular Diseases / etiology
  • Cardiovascular Diseases / mortality
  • Cardiovascular Diseases / prevention & control*
  • Cardiovascular System / drug effects
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / epidemiology
  • Female
  • Follow-Up Studies
  • Glucosides / therapeutic use*
  • Glycated Hemoglobin A / drug effects
  • Glycated Hemoglobin A / metabolism
  • Heart Disease Risk Factors*
  • Heart Failure / etiology
  • Heart Failure / mortality
  • Heart Failure / prevention & control
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Retrospective Studies
  • Risk Assessment
  • Risk Factors
  • Treatment Outcome

Substances

  • Benzhydryl Compounds
  • Blood Glucose
  • Cardiotonic Agents
  • Glucosides
  • Glycated Hemoglobin A
  • empagliflozin

Associated data

  • ClinicalTrials.gov/NCT01131676