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Patient Phenotypes vs. Outcomes in EMPA-REG OUTCOME
Quick Takes
- This post hoc analysis of the EMPA-REG OUTCOME trial used latent class analysis to identify three distinctive phenotypic groups among patients with T2D and established CV disease.
- Empagliflozin, compared with placebo, demonstrated consistent benefits across phenotypes despite differences in the risk of clinical outcomes.
- Additional studies are indicated to better understand the mechanisms associated with these phenotypic groups and the development of CV outcomes and potentially targeted therapies.
Study Questions:
What are the clinical phenotypes of patients with type 2 diabetes (T2D) and cardiovascular (CV) disease and treatment effects of empagliflozin versus placebo across these subgroups?
Methods:
In the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial, overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. The investigators conducted a post hoc analysis, where participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. Latent class analysis (LCA) identified three phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or hospitalization for heart failure (HHF) and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).
Results:
In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non–coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.23-2.71; group 3 vs. 1: HR, 1.86; 95% CI, 1.30-2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p > 0.30).
Conclusions:
The authors concluded that the consistent treatment effect across different phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin.
Perspective:
This post hoc analysis of the EMPA-REG OUTCOME trial used LCA to identify three distinctive phenotypic groups among patients with T2D and established CV disease and reports that empagliflozin, compared with placebo, demonstrated consistent benefits across phenotypes despite differences in the risk of clinical outcomes. These results demonstrate the utility of LCA in identifying clinically distinct phenotypes of subjects with T2D and atherosclerotic CV disease. The phenotypic groups identified had different trajectories of risk and included: 1) a younger population with higher frequency of a previous myocardial infarction at baseline, 2) a predominant noncoronary atherosclerotic disease cluster with more women than in the other clusters, and 3) an advanced coronary artery disease cluster. Additional studies are indicated to better understand the mechanisms associated with these phenotypic groups and the development of CV outcomes and potentially targeted therapies.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Lipid Metabolism, Acute Heart Failure
Keywords: Coronary Artery Disease, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Heart Failure, Metabolic Syndrome, Myocardial Infarction, Myocardial Ischemia, Primary Prevention, Sodium-Glucose Transporter 2, Treatment Outcome, Vascular Diseases
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