Empagliflozin and the Risk of Heart Failure Hospitalization in Routine Clinical Care

Abstract

Background: The EMPA-REG OUTCOME trial (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients) showed that empagliflozin, a sodium-glucose cotransporter-2 inhibitor, reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes mellitus (T2D) and established cardiovascular disease. The EMPRISE (Empagliflozin Comparative Effectiveness and Safety) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from August 2014 through September 2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin versus sitagliptin, a dipeptidyl peptidase-4 inhibitor.

Methods: Within 2 commercial and 1 federal (Medicare) claims data sources in the United States, we identified a 1:1 propensity score-matched cohort of T2D patients ≥18 years old initiating empagliflozin or sitagliptin from August 2014 through September 2016. The HHF outcome was defined as a HF discharge diagnosis in the primary position (HHF-specific); a broader definition was based on a HF discharge diagnosis in any position (HHF-broad). Hazard ratios (HRs) and 95% CIs were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis.

Results: After propensity-score matching, we identified 16,443 patient pairs who initiated empagliflozin or sitagliptin. Average age was approximately 59 years, almost 54% of the participants were males, and approximately 25% had records of existing cardiovascular disease. Compared with sitagliptin, the initiation of empagliflozin decreased the risk of HHF-specific by 50% (HR, 0.50; 95% CI, 0.28-0.91), and the risk of HHF-broad by 49% (HR, 0.51;95% CI, 0.39-0.68), over a mean follow-up of 5.3 months. The results were consistent in patients with and without baseline cardiovascular disease, and for empagliflozin at both the 10- and 25-mg daily doses; analyses comparing empagliflozin versus the dipeptidyl peptidase-4 inhibitor class, and comparing sodium-glucose cotransporter-2 inhibitor versus dipeptidyl peptidase-4 inhibitor classes also produced consistent findings.

Conclusions: The first interim analysis from EMPRISE showed that compared with sitagliptin, the initiation of empagliflozin was associated with a decreased risk of HHF among patients with T2D as treated in routine care, with and without a history of cardiovascular disease.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03363464.

Keywords: comparative effectiveness research; diabetes mellitus, type 2; dipeptidyl peptidase-4 inhibitors; empagliflozin; heart failure; sodium-glucose cotransporter-2 inhibitor.

Figure 1.. Flowchart of overall study population of empagliflozin vs. sitagliptin initiators

ESRD: end stage renal disease; HIV: human immunodeficiency virus; DPP-4: dipeptidyl peptidase-4; PS: propensity score

Figure 2.. Cumulative incidence of hospitalization for heart failure comparing empagliflozin vs. sitagliptin initiators *

HHF: hospitalization for heart failure; HHF-broad: broad definition of HHF; HHF-specific: narrow definition of HHF. * Analyses were 1:1 propensity score- matched among new users of the study agents. †Discharge diagnosis of HF in the primary position ‡Discharge diagnosis of HF in any position