Mediators of the improvement in heart failure outcomes with empagliflozin in the EMPA‐REG OUTCOME trial

Abstract Background Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial. Methods A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10 mg or 25 mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models. Results MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR = 1.73 (95% CI 1.01–2.98), heart failure hospitalization: HR = 2.64 (95% CI 1.22, 5.72), and new or worsening nephropathy: HR = 3.11 (95% CI 2.17–4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS. Conclusions A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS. Trial registration Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT 01131676

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Can monitoring of intrathoracic impedance reduce morbidity and mortality in patients with chronic heart failure? Rationale and design of the Diagnostic Outcome Trial in Heart Failure (DOT-HF)☆

European Journal of Heart Failure ◽

10.1016/j.ejheart.2008.06.016 ◽

2008 ◽

Vol 10 (9) ◽

pp. 907-916 ◽

Cited By ~ 44

Author(s):

Frieder Braunschweig ◽

Ian Ford ◽

Viviane Conraads ◽

Martin R. Cowie ◽

Guillaume Jondeau ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Morbidity And Mortality ◽

Outcome Trial ◽

Intrathoracic Impedance ◽

Diagnostic Outcome

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Rationale and design of a randomized, double-blind, placebo-controlled outcome trial of ivabradine in chronic heart failure: the Systolic Heart Failure Treatment with the IfInhibitor Ivabradine Trial (SHIFT)

European Journal of Heart Failure ◽

10.1093/eurjhf/hfp154 ◽

2009 ◽

Vol 12 (1) ◽

pp. 75-81 ◽

Cited By ~ 71

Author(s):

Karl Swedberg ◽

Michel Komajda ◽

Michael Böhm ◽

Jeffrey S. Borer ◽

Ian Ford ◽

...

Keyword(s):

Heart Failure ◽

Chronic Heart Failure ◽

Systolic Heart Failure ◽

Double Blind ◽

Heart Failure Treatment ◽

Double Blind Placebo ◽

Failure Treatment ◽

Outcome Trial

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1225-P: The Association between Long-Term Glucose Variability (GV), Cardiovascular (CV) Death, and Heart Failure (HF) Outcomes in the EMPA-REG OUTCOME Trial

Diabetes ◽

10.2337/db19-1225-p ◽

2019 ◽

Vol 68 (Supplement 1) ◽

pp. 1225-P

Author(s):

ANTONIO CERIELLO ◽

ANNE PERNILLE OFSTAD ◽

ISABELLA ZWIENER ◽

STEFAN KASPERS ◽

JYOTHIS GEORGE ◽

...

Keyword(s):

Heart Failure ◽

Glucose Variability ◽

Outcome Trial

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Efficacy of empagliflozin on heart failure and renal outcomes in patients with atrial fibrillation: data from the EMPA‐REG OUTCOME trial

European Journal of Heart Failure ◽

10.1002/ejhf.1663 ◽

2019 ◽

Vol 22 (1) ◽

pp. 126-135 ◽

Cited By ~ 14

Author(s):

Michael Böhm ◽

Jonathan Slawik ◽

Martina Brueckmann ◽

Michaela Mattheus ◽

Jyothis T. George ◽

...

Keyword(s):

Heart Failure ◽

Atrial Fibrillation ◽

Renal Outcomes ◽

Outcome Trial

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Empagliflozin in Heart Failure With Predicted Preserved Versus Reduced Ejection Fraction: Data From the EMPA-REG OUTCOME Trial

Journal of Cardiac Failure ◽

10.1016/j.cardfail.2021.05.012 ◽

2021 ◽

Vol 27 (8) ◽

pp. 888-895

Author(s):

Gianluigi Savarese ◽

Alicia Uijl ◽

Lars H. Lund ◽

Stefan D. Anker ◽

Folkert Asselbergs ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Reduced Ejection Fraction ◽

Outcome Trial

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Series: Cardiovascular outcome trials for diabetes drugs Alogliptin and EXAMINE

British Journal of Diabetes ◽

10.15277/bjd.2019.230 ◽

2019 ◽

Vol 19 (2) ◽

pp. 133-135

Author(s):

Miles Fisher

Keyword(s):

Heart Failure ◽

Cardiovascular Death ◽

Cardiovascular Outcome ◽

Cardiovascular Outcome Trials ◽

Coronary Syndrome ◽

Major Cardiovascular Events ◽

Cardiovascular Outcome Trial ◽

Subsequent Publication ◽

Outcome Trial

EXAMINE was an FDA mandated cardiovascular outcome trial with alogliptin. In contrast to other cardiovascular outcome trials with DPP-4 inhibitors, it was performed in subjects with a recent acute coronary syndrome. EXAMINE compared alogliptin and placebo in 5,380 subjects with type 2 diabetes and demonstrated non-inferiority for major cardiovascular events (cardiovascular death, myocardial infarction, stroke) but not superiority. Data on hospitalisation for heart failure were not included in the principal publication. A subsequent publication showed no overall increase in hospitalisation for heart failure with alogliptin, but when subjects with and without baseline heart failure were separated there was a significant increase in the group without heart failure at baseline. No clear clinical benefit has been established for alogliptin, and there are alternatives such as sitagliptin and linagliptin that are not associated with an increase in hospitalisation for heart failure.

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Series: Cardiovascular outcome trials for diabetes drugs Liraglutide and LEADER

British Journal of Diabetes ◽

10.15277/bjd.2020.267 ◽

2020 ◽

Vol 20 (2) ◽

pp. 142-144

Author(s):

Miles Fisher

Keyword(s):

Heart Failure ◽

Cardiovascular Events ◽

Cardiovascular Death ◽

Cardiovascular Outcome ◽

Secondary Outcome ◽

Major Adverse Cardiovascular Events ◽

Cardiovascular Outcome Trials ◽

Major Cardiovascular Events ◽

Cardiovascular Outcome Trial ◽

Outcome Trial

LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results) was an FDA-mandated cardiovascular outcome trial with liraglutide and was the first trial with a glucagon-like peptide-1 (GLP-1) receptor agonist to demonstrate a significant reduction in cardiovascular events. It compared liraglutide and placebo in 9,340 people with type 2 diabetes and either existing cardiovascular disease or age >60 years with at least one cardiovascular risk factor. LEADER demonstrated superiority for major cardiovascular events (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke), and cardiovascular deaths were significantly reduced, as was all-cause mortality. Hospitalisation for heart failure, which was a secondary outcome, was not significantly reduced. Compared with the EMPA-REG OUTCOME trial, the curves for major adverse cardiovascular events in LEADER separated later, and the absence of a clear effect on hospitalisation for heart failure or on estimated glomerular filtration rate suggests that the mechanism of cardiovascular benefit for liraglutide was different from that for empagliflozin

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Metabolic Syndrome in patients with type 2 diabetes and atherosclerotic cardiovascular disease: A post hoc analyses of the EMPA-REG OUTCOME trial

10.21203/rs.3.rs-64853/v2 ◽

2020 ◽

Author(s):

João Pedro Ferreira ◽

Subodh Verma ◽

David Fitchett ◽

Anne Pernille Ofstad ◽

Sabine Lauer ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Cardiovascular Disease ◽

Metabolic Syndrome ◽

World Health ◽

Atherosclerotic Cardiovascular Disease ◽

Mixed Effect ◽

Renal Outcomes ◽

Outcome Trial

Abstract Background: Patients with type 2 diabetes (T2D) and metabolic syndrome (MetS) are at greater cardiovascular risk than those with T2D without MetS. In the current report we aim to study the characteristics, cardio-renal outcomes and the effect of empagliflozin in patients with MetS enrolled in the EMPA-REG OUTCOME trial. Methods: A total of 7020 patients with T2D and atherosclerotic cardiovascular disease were treated with empagliflozin (10mg or 25mg) or placebo for a median of 3.1 years. The World Health Organization MetS criteria could be determined for 6985 (99.5%) patients. We assessed the association between baseline MetS and multiple cardio-renal endpoints using Cox regression models, and we studied the change in the individual component over time of the MetS using mixed effect models. Results: MetS at baseline was present in 5740 (82%) patients; these were more often white and had more often albuminuria and heart failure, had lower eGFR and HDL-cholesterol, and higher blood pressure, body mass index, waist circumference, and triglycerides. In the placebo group, patients with MetS had a higher risk of all outcomes including cardiovascular death: HR=1.73 (95%CI=1.01-2.98), heart failure hospitalization: HR=2.64 (95%CI=1.22, 5.72), and new or worsening nephropathy: HR=3.11 (95%CI=2.17-4.46). The beneficial effect of empagliflozin was consistent on all cardio-renal outcomes regardless of presence of MetS.Conclusions: A large proportion of the EMPA-REG OUTCOME population fulfills the criteria for MetS. Those with MetS had increased risk of adverse cardio-renal outcomes. Compared with placebo, empagliflozin improved cardio-renal outcomes in patients with and without MetS.

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