PMID- 32877652 OWN - NLM STAT- MEDLINE DCOM- 20201013 LR - 20210504 IS - 1474-547X (Electronic) IS - 0140-6736 (Linking) VI - 396 IP - 10254 DP - 2020 Sep 19 TI - SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. PG - 819-829 LID - S0140-6736(20)31824-9 [pii] LID - 10.1016/S0140-6736(20)31824-9 [doi] AB - BACKGROUND: Both DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin) trials showed that sodium-glucose co-transporter-2 (SGLT2) inhibition reduced the combined risk of cardiovascular death or hospitalisation for heart failure in patients with heart failure with reduced ejection fraction (HFrEF) with or without diabetes. However, neither trial was powered to assess effects on cardiovascular death or all-cause death or to characterise effects in clinically important subgroups. Using study-level published data from DAPA-HF and patient-level data from EMPEROR-Reduced, we aimed to estimate the effect of SGLT2 inhibition on fatal and non-fatal heart failure events and renal outcomes in all randomly assigned patients with HFrEF and in relevant subgroups from DAPA-HF and EMPEROR-Reduced trials. METHODS: We did a prespecified meta-analysis of the two single large-scale trials assessing the effects of SGLT2 inhibitors on cardiovascular outcomes in patients with HFrEF with or without diabetes: DAPA-HF (assessing dapagliflozin) and EMPEROR-Reduced (assessing empagliflozin). The primary endpoint was time to all-cause death. Additionally, we assessed the effects of treatment in prespecified subgroups on the combined risk of cardiovascular death or hospitalisation for heart failure. These subgroups were based on type 2 diabetes status, age, sex, angiotensin receptor neprilysin inhibitor (ARNI) treatment, New York Heart Association (NYHA) functional class, race, history of hospitalisation for heart failure, estimated glomerular filtration rate (eGFR), body-mass index, and region (post-hoc). We used hazard ratios (HRs) derived from Cox proportional hazard models for time-to-first event endpoints and Cochran's Q test for treatment interactions; the analysis of recurrent events was based on rate ratios derived from the Lin-Wei-Yang-Ying model. FINDINGS: Among 8474 patients combined from both trials, the estimated treatment effect was a 13% reduction in all-cause death (pooled HR 0.87, 95% CI 0.77-0.98; p=0.018) and 14% reduction in cardiovascular death (0.86, 0.76-0.98; p=0.027). SGLT2 inhibition was accompanied by a 26% relative reduction in the combined risk of cardiovascular death or first hospitalisation for heart failure (0.74, 0.68-0.82; p<0.0001), and by a 25% decrease in the composite of recurrent hospitalisations for heart failure or cardiovascular death (0.75, 0.68-0.84; p<0.0001). The risk of the composite renal endpoint was also reduced (0.62, 0.43-0.90; p=0.013). All tests for heterogeneity of effect size between trials were not significant. The pooled treatment effects showed consistent benefits for subgroups based on age, sex, diabetes, treatment with an ARNI and baseline eGFR, but suggested treatment-by-subgroup interactions for subgroups based on NYHA functional class and race. INTERPRETATION: The effects of empagliflozin and dapagliflozin on hospitalisations for heart failure were consistent in the two independent trials and suggest that these agents also improve renal outcomes and reduce all-cause and cardiovascular death in patients with HFrEF. FUNDING: Boehringer Ingelheim. CI - Copyright (c) 2020 Elsevier Ltd. All rights reserved. FAU - Zannad, Faiez AU - Zannad F AD - Centre d'Investigations Cliniques Plurithematique 1433, Universite de Lorraine, Institut National de la Sante et de la Recherche Medicale 1116, Centre Hospitalier Regional Universitaire de Nancy, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France. Electronic address: f.zannad@chru-nancy.fr. FAU - Ferreira, Joao Pedro AU - Ferreira JP AD - Centre d'Investigations Cliniques Plurithematique 1433, Universite de Lorraine, Institut National de la Sante et de la Recherche Medicale 1116, Centre Hospitalier Regional Universitaire de Nancy, French Clinical Research Infrastructure Network, Investigation Network Initiative-Cardiovascular and Renal Clinical Trialists, Nancy, France. FAU - Pocock, Stuart J AU - Pocock SJ AD - Department of Medical Statistics, London School of Hygiene & Tropical Medicine, London, UK. FAU - Anker, Stefan D AU - Anker SD AD - Department of Cardiology and Berlin Institute of Health Center for Regenerative Therapies, German Centre for Cardiovascular Research Partner Site Berlin, Charite Universitatsmedizin, Berlin, Germany. FAU - Butler, Javed AU - Butler J AD - Department of Medicine, University of Mississippi School of Medicine, Jackson, MS, USA. FAU - Filippatos, Gerasimos AU - Filippatos G AD - National and Kapodistrian University of Athens School of Medicine, Athens University Hospital Attikon, Athens, Greece. FAU - Brueckmann, Martina AU - Brueckmann M AD - Boehringer Ingelheim International, Ingelheim, Germany; Faculty of Medicine, University of Heidelberg, Mannheim, Germany. FAU - Ofstad, Anne Pernille AU - Ofstad AP AD - Medical Department, Boehringer Ingelheim Norway KS, Asker, Norway. FAU - Pfarr, Egon AU - Pfarr E AD - Boehringer Ingelheim International, Ingelheim, Germany. FAU - Jamal, Waheed AU - Jamal W AD - Boehringer Ingelheim International, Ingelheim, Germany. FAU - Packer, Milton AU - Packer M AD - Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, TX, USA; Imperial College London, London, UK. LA - eng PT - Journal Article PT - Meta-Analysis PT - Research Support, Non-U.S. Gov't DEP - 20200830 PL - England TA - Lancet JT - Lancet (London, England) JID - 2985213R RN - 0 (Angiotensin Receptor Antagonists) RN - 0 (Benzhydryl Compounds) RN - 0 (Glucosides) RN - 0 (Sodium-Glucose Transporter 2 Inhibitors) RN - 1ULL0QJ8UC (dapagliflozin) RN - EC 3.4.24.11 (Neprilysin) RN - HDC1R2M35U (empagliflozin) SB - IM CIN - Nat Rev Cardiol. 2020 Nov;17(11):681. PMID: 32929192 MH - Aged MH - Angiotensin Receptor Antagonists/therapeutic use MH - Benzhydryl Compounds/*adverse effects/therapeutic use MH - Body Mass Index MH - Case-Control Studies MH - Cause of Death/trends MH - Clinical Trials as Topic MH - Death MH - Diabetes Mellitus, Type 2/complications MH - Drug Therapy, Combination MH - Female MH - Glomerular Filtration Rate/drug effects/physiology MH - Glucosides/*adverse effects/therapeutic use MH - Heart Failure/classification/*drug therapy/physiopathology MH - Hospitalization/statistics & numerical data MH - Humans MH - Male MH - Middle Aged MH - Neprilysin/antagonists & inhibitors MH - Patient Outcome Assessment MH - Sodium-Glucose Transporter 2 Inhibitors/*adverse effects/therapeutic use MH - Stroke Volume/*drug effects EDAT- 2020/09/03 06:00 MHDA- 2020/10/21 06:00 CRDT- 2020/09/03 06:00 PHST- 2020/08/03 00:00 [received] PHST- 2020/08/10 00:00 [revised] PHST- 2020/08/11 00:00 [accepted] PHST- 2020/09/03 06:00 [pubmed] PHST- 2020/10/21 06:00 [medline] PHST- 2020/09/03 06:00 [entrez] AID - S0140-6736(20)31824-9 [pii] AID - 10.1016/S0140-6736(20)31824-9 [doi] PST - ppublish SO - Lancet. 2020 Sep 19;396(10254):819-829. doi: 10.1016/S0140-6736(20)31824-9. Epub 2020 Aug 30.