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

Abstract

Background: The EMPA-REG OUTCOME trial showed that empagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), reduces the risk of hospitalization for heart failure (HHF) by 35%, on top of standard of care in patients with type 2 diabetes (T2D) and established CV disease (CVD). The EMPagliflozin compaRative effectIveness and SafEty (EMPRISE) study aims to assess empagliflozin's effectiveness, safety, and healthcare utilization in routine care from 08/2014 through 09/2019. In this first interim analysis, we investigated the risk of HHF among T2D patients initiating empagliflozin vs. sitagliptin, a dipeptidyl peptidase-4 inhibitor (DPP-4i). Methods: Within two commercial and one federal (Medicare) claims data sources in the U.S., we identified a 1:1 propensity-score (PS) matched cohort of T2D patients ≥18 years initiating empagliflozin or sitagliptin from 08/2014 through 09/2016. 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 (HR) and 95% confidence intervals (CI) were estimated controlling for over 140 baseline characteristics in each data source and pooled by fixed-effects meta-analysis. Results: After PS-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 to 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. Results were consistent in patients with and without baseline cardiovascular disease, and for both empagliflozin 10 mg or 25mg daily dose; analyses comparing

Effects of sodium‐glucose cotransporter‐2 inhibitors on the cardiovascular and renal complications of type 2 diabetes

“…The CV safety of SGLT‐2is has been assessed in randomized placebo‐controlled CVOTs of patients with T2D and established CVD or varying levels of CV risk, as well as in real‐world studies of patients who newly initiated SGLT‐2i therapy (CVD‐REAL, CVD‐REAL 2, EMPRISE and EASEL) . A 14% reduction in the risk of major adverse CV events (MACE) (CV death, MI or ischaemic stroke; primary safety end point) with SGLT‐2is compared with placebo was observed in the EMPA‐REG OUTCOME trial, in which more than 99% of patients had established CVD, and in the CANVAS trial in patients with established CVD (66%) or multiple CV risk factors (Table ) .…”

“…Similarly, the EASEL study confirmed a significantly lower risk of the composite of all‐cause mortality or hospitalization for HF (43%) or the composite of all‐cause mortality, non‐fatal MI or non‐fatal stroke (33%) among US patients with established CVD at baseline . In an interim analysis of the real‐world EMPRISE study, US patients initiating empagliflozin therapy within routine care showed a 50% reduction in the risk of hospitalization for HF (primary diagnosis) compared with those using sitagliptin . A population‐based US cohort study also showed a 30%‐49% reduction in the risk of hospitalization for HF with canagliflozin compared with other glucose‐lowering drugs (dipeptidyl peptidase‐4 inhibitor [DPP‐4i], GLP‐1RA, or sulphonylurea therapy) …”

“…Of note, the patient populations of the CVD‐REAL, CVD‐REAL 2 and EMPRISE studies included a lower proportion of patients with established CVD (13%‐27%) than were enrolled in the CVOTs, as discussed above. The duration of follow‐up for the real‐world studies was shorter (5.3 months‐1.6 years) than that for the CVOTs (3.1‐4.2 years) .…”

“…Of note, the patient populations of the CVD‐REAL, CVD‐REAL 2 and EMPRISE studies included a lower proportion of patients with established CVD (13%‐27%) than were enrolled in the CVOTs, as discussed above. The duration of follow‐up for the real‐world studies was shorter (5.3 months‐1.6 years) than that for the CVOTs (3.1‐4.2 years) . Despite these differences, the real‐world studies consistently showed reductions in the risk of CV events, including HF, among patients with T2D from across diverse geographic locations, including Asia Pacific (Australia, Japan, Singapore, and South Korea), the Middle East (Israel), North America (Canada and the USA), and Europe (Denmark, Germany, Norway, Sweden, and the UK) .…”

“…The duration of follow‐up for the real‐world studies was shorter (5.3 months‐1.6 years) than that for the CVOTs (3.1‐4.2 years) . Despite these differences, the real‐world studies consistently showed reductions in the risk of CV events, including HF, among patients with T2D from across diverse geographic locations, including Asia Pacific (Australia, Japan, Singapore, and South Korea), the Middle East (Israel), North America (Canada and the USA), and Europe (Denmark, Germany, Norway, Sweden, and the UK) . These real‐world studies provide further support for the potential class effect of SGLT‐2is on CV outcomes in patients with T2D …”