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Randomized Controlled Trial
. 2019 Mar 12;139(11):1384-1395.
doi: 10.1161/CIRCULATIONAHA.118.037778.

Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial

David Fitchett  1 , Silvio E Inzucchi  2 , Christopher P Cannon  3 , Darren K McGuire  4 , Benjamin M Scirica  3 , Odd Erik Johansen  5 , Steven Sambevski  6 , Stefan Kaspers  6 , Egon Pfarr  6 , Jyothis T George  6 , Bernard Zinman  7
Affiliations
Randomized Controlled Trial

Empagliflozin Reduced Mortality and Hospitalization for Heart Failure Across the Spectrum of Cardiovascular Risk in the EMPA-REG OUTCOME Trial

David Fitchett et al. Circulation. .

Abstract

Background: In the EMPA-REG OUTCOME trial (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) in patients with type 2 diabetes mellitus and atherosclerotic cardiovascular disease, in comparison with placebo, empagliflozin reduced the risks of 3-point major adverse cardiovascular events (3-point MACE), cardiovascular and all-cause death, and hospitalization for heart failure. We investigated whether these effects varied across the spectrum of baseline cardiovascular risk.

Methods: Cardiovascular death, all-cause mortality, 3-point MACE, and hospitalization for heart failure in the pooled empagliflozin and placebo groups were analyzed in subgroups by prior myocardial infarction and stroke at baseline, and by estimated baseline cardiovascular risk based on the 10-point TIMI (Thrombolysis In Myocardial Infarction) Risk Score for Secondary Prevention.

Results: Of 7020 patients who received the study drug, 65% had a prior myocardial infarction or stroke, and 12%, 40%, 30%, and 18% were at low, intermediate, high, and highest estimated cardiovascular risk according to TIMI Risk Score for Secondary Prevention (≤2, 3, 4, and ≥5 points, respectively). In the placebo group, 3-point MACE occurred during the trial in 7.3%, 9.4%, 12.6%, and 20.6% of patients at low, intermediate, high, and highest estimated baseline risk, respectively. Relative reductions in risk of cardiovascular death, all-cause mortality, 3-point MACE and hospitalization for heart failure with empagliflozin versus placebo were consistent in patients with and without prior myocardial infarction and/or stroke and across subgroups by TIMI Risk Score for Secondary Prevention at baseline ( P>0.05 for randomized group-by-subgroup interactions).

Conclusions: Despite all patients having atherosclerotic cardiovascular disease, patients in EMPA-REG OUTCOME demonstrated a broad risk spectrum for cardiovascular events. Reductions in key cardiovascular outcomes and mortality with empagliflozin versus placebo were consistent across the range of cardiovascular risk.

Clinical trial registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01131676.

Keywords: cardiovascular diseases; carotid artery diseases; death, sudden, cardiac; diabetes mellitus, type 2; sodium-glucose transporter 2.

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Figures

Figure 1.
Figure 1.
Cardiovascular (CV) outcomes and mortality in the placebo group by presence or absence of prior myocardial infarction (MI) or stroke at baseline. Descriptive data in patients who received study drug. MACE indicates major adverse cardiovascular events.
Figure 2.
Figure 2.
Cardiovascular (CV) outcomes and mortality with empagliflozin versus placebo in subgroups stratified by presence or absence of prior myocardial infarction (MI) and stroke at baseline. Cox proportional hazards regression analyses in patients who received study drug. HR indicates hazard ratio; and MACE, major adverse cardiovascular events.
Figure 3.
Figure 3.
Cardiovascular (CV) outcomes and mortality with empagliflozin versus placebo by history of myocardial infarction (MI) at baseline. Cox regression analyses in patients who received study drug. HR indicates hazard ratio.
Figure 4.
Figure 4.
Cardiovascular (CV) outcomes and mortality with empagliflozin versus placebo by history of stroke at baseline. Cox regression analyses in patients who received study drug.
Figure 5.
Figure 5.
Cardiovascular (CV) outcomes and mortality in the placebo group by estimated CV risk according to 10-point TIMI Risk Score for Secondary Prevention at baseline: low, ≤2 points; intermediate, 3 points; high, 4 points; and highest, ≥5 points. Descriptive data in patients who received study drug. MACE indicates major adverse cardiovascular events.
Figure 6.
Figure 6.
Cardiovascular (CV) outcomes and mortality with empagliflozin versus placebo by estimated CV risk according to 10-point TIMI Risk Score for Secondary Prevention at baseline: low, ≤2 points; intermediate, 3 points; high, 4 points; and highest, ≥5 points. Cox proportional hazards regression analyses in patients who received study drug. HR indicates hazard ratio; and MACE, major adverse cardiovascular events.
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