Rationale and design of the EMPERIAL‐Preserved and EMPERIAL‐Reduced trials of empagliflozin in patients with chronic heart failure

Weizman, Abraham; Ponikowski, Piotr; Brueckmann, Martina; Zeller, Cordula; Macesic, H; Peil, Barbara; Brun, M; Ustyugova, Anastasia; Jamal, Waheed; Salsali, Afshin; Lindenfeld, JoAnn; Anker, SD

doi:10.1002/ejhf.1486

Cited by 46 publications

(33 citation statements)

References 29 publications

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“…Empagliflozin has also been associated with improved peak VO 2 in other non‐randomized studies in patients with established HF 10 . The recent EMPERIAL‐Preserved and EMPERIAL Reduced trials, 31 however, suggested no improvements in functional capacity measured with 6‐minute walk test distance with empagliflozin. Of note, the EMPERIAL trials did not investigate the effects of SGLT2 inhibitors on CRF, particularly on peak VO 2 , like we attempted to do in our trial.…”

Section: Discussionmentioning

confidence: 99%

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

Carbone

Billingsley

Canada

et al. 2020

Diabetes Metabolism Res

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Background Canagliflozin reduces hospitalizations for heart failure (HF) in type 2 diabetes mellitus (T2DM). Its effect on cardiorespiratory fitness and cardiac function in patients with established HF with reduced ejection fraction (HFrEF) is unknown. Methods We conducted a double‐blind randomized controlled trial of canagliflozin 100 mg or sitagliptin 100 mg daily for 12 weeks in 88 patients, and measured peak oxygen consumption (VO2) and minute ventilation/carbon dioxide production (VE/VCO2) slope (co‐primary endpoints for repeated measure ANOVA time_x_group interaction), lean peak VO2, ventilatory anaerobic threshold (VAT), cardiac function and quality of life (ie, Minnesota Living with Heart Failure Questionnaire [MLHFQ]), at baseline and 12‐week follow‐up. Results The study was terminated early due to the new guidelines recommending canagliflozin over sitagliptin in HF: 17 patients were assigned to canagliflozin and 19 to sitagliptin, total of 36 patients. There were no significant changes in peak VO2 and VE/VCO2 slope between the two groups (P = .083 and P = .98, respectively). Canagliflozin improved lean peak VO2 (+2.4 mL kgLM−1 min−1, P = .036), VAT (+1.5 mL kg−1 min−1, P = .012) and VO2 matched for respiratory exchange ratio (+2.4 mL Kg−1 min−1, P = .002) compared to sitagliptin. Canagliflozin also reduced MLHFQ score (−12.1, P = .018). Conclusions In this small and short‐term study of patients with T2DM and HFrEF, interrupted early after only 36 patients, canagliflozin did not improve the primary endpoints of peak VO2 or VE/VCO2 slope compared to sitagliptin, while showing favourable trends observed on several additional surrogate endpoints such as lean peak VO2, VAT and quality of life.

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Section: Discussionmentioning

confidence: 99%

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

Carbone

Billingsley

Canada

et al. 2020

Diabetes Metabolism Res

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“…In contrast to these results, according to the recent press release, the EMPERIAL Reduced and Preserved trials failed to demonstrate an effect of empagliflozin on functional status in patients with HFrEF and HF with preserved ejection fraction (HFpEF), with and without T2DM over a period of 3 months. 20 After these disappointing head-line results became known, the DETERMINE Reduced and Preserved trials (testing the impact of dapagliflozin vs. placebo on quality of life and functional capacity over 3 months) changed their primary endpoint to be quality of life-focused (rather than relying on 6-min walking test distance as originally planned) and they were somewhat increased in size to improve power. Quality of life improvement may, however, need longer periods of time to become apparent (i.e.…”

Section: New Clinical Trials With Sodium-glucose Co-transporter 2 Inhmentioning

confidence: 99%

Sodium–glucose co‐transporter 2 inhibitors in heart failure: beyond glycaemic control. A position paper of the Heart Failure Association of the European Society of Cardiology

Seferović

Fragasso

Petrie

et al. 2020

European J of Heart Fail

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117

104

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Heart failure (HF) is common and associated with a poor prognosis, despite advances in treatment. Over the last decade cardiovascular outcome trials with sodium-glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes mellitus have demonstrated beneficial effects for three SGLT2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) in reducing hospitalisations for HF. More recently, dapagliflozin reduced the risk of worsening HF or death from cardiovascular causes in patients with chronic HF with reduced left ventricular ejection fraction, with or without type 2 diabetes mellitus. A number of additional trials in HF patients with reduced and/or preserved left ventricular ejection fraction are ongoing and/or about to be reported. The present position paper summarises recent clinical trial evidence and discusses the role of SGLT2 inhibitors in the treatment of HF, pending the results of ongoing trials in different populations of patients with HF.

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“…This undoubtedly sounds like exciting news for diabetic patients, especially those with cardiovascular disease, although the cardiovascular protective mechanism is not clear. The sodium glucose cotransporter type 2 (SGLT-2) inhibitor empagliflozin has been demonstrated to reduce cardiovascular mortality by 38% and heart failure (HF) hospitalizations by 35% in patients with type 2 diabetes (T2DM) in the EMPA-REG OUT-COMES clinical trial [1,2]. An early nonrandomized pilot study showed improved left ventricular function when glucagon-like peptide-1 (GLP-1) agonists were infused in patients with acute myocardial infarction and HF [3].…”

Section: Introductionmentioning

confidence: 99%

Effects of antidiabetic drugs on left ventricular function/dysfunction: a systematic review and network meta-analysis

Zhang

Wang

et al. 2020

Cardiovasc Diabetol

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Background: Although a variety of antidiabetic drugs have significant protective action on the cardiovascular system, it is still unclear which antidiabetic drugs can improve ventricular remodeling and fundamentally delay the process of heart failure. The purpose of this network meta-analysis is to compare the efficacy of sodium glucose cotransporter type 2 (SGLT-2) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, metformin (MET), sulfonylurea (SU) and thiazolidinediones (TZDs) in improving left ventricular (LV) remodeling in patients with type 2 diabetes (T2DM) and/or cardiovascular disease (CVD). Methods: We searched articles published before October 18, 2019, regardless of language or data, in 4 electronic databases: PubMed, EMBASE, Cochrane Library and Web of Science. We included randomized controlled trials in this network meta-analysis, as well as a small number of cohort studies. The differences in the mean changes in left ventricular echocardiographic parameters between the treatment group and control group were evaluated. Results: The difference in the mean change in LV ejection fraction (LVEF) between GLP-1 agonists and placebo in treatment effect was greater than zero (MD = 2.04% [0.64%, 3.43%]); similar results were observed for the difference in the mean change in LV end-diastolic diameter (LVEDD) between SGLT-2 inhibitors and placebo (MD = − 3.3 mm [5.31, − 5.29]), the difference in the mean change in LV end-systolic volume (LVESV) between GLP-1 agonists and placebo (MD = − 4.39 ml [− 8.09, − 0.7]); the difference in the mean change in E/e′ between GLP-1 agonists and placebo (MD = − 1.05[− 1.78, − 0.32]); and the difference in the mean change in E/e′ between SGLT-2 inhibitors and placebo (MD = − 1.91[− 3.39, − 0.43]). Conclusions: GLP-1 agonists are more significantly associated with improved LVEF, LVESV and E/e′, SGLT-2 inhibitors are more significantly associated with improved LVEDD and E/e′, and DPP-4 inhibitors are more strongly associated with a negative impact on LV end-diastolic volume (LVEDV) than are placebos. SGLT-2 inhibitors are superior to other drugs in pairwise comparisons.

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Rationale and design of the EMPERIAL‐Preserved and EMPERIAL‐Reduced trials of empagliflozin in patients with chronic heart failure

Cited by 46 publications

References 29 publications

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

The effects of canagliflozin compared to sitagliptin on cardiorespiratory fitness in type 2 diabetes mellitus and heart failure with reduced ejection fraction: The CANA‐HF study

Sodium–glucose co‐transporter 2 inhibitors in heart failure: beyond glycaemic control. A position paper of the Heart Failure Association of the European Society of Cardiology

Effects of antidiabetic drugs on left ventricular function/dysfunction: a systematic review and network meta-analysis

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