Two Tales: One Story
2020; Lippincott Williams & Wilkins; Volume: 142; Issue: 23 Linguagem: Inglês
10.1161/circulationaha.120.051122
ISSN1524-4539
AutoresSubodh Verma, Darren K. McGuire, Mikhail Kosiborod,
Tópico(s)Hyperglycemia and glycemic control in critically ill and hospitalized patients
ResumoHomeCirculationVol. 142, No. 23Two Tales: One Story Free AccessArticle CommentaryPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyRedditDiggEmail Jump toFree AccessArticle CommentaryPDF/EPUBTwo Tales: One StoryEMPEROR-Reduced and DAPA-HF Subodh Verma, MD, PhD Darren K. McGuire, MD, MHSc Mikhail N. KosiborodMD Subodh VermaSubodh Verma Subodh Verma, MD, PhD, FRCSC, Division of Cardiac Surgery, St Michael’s Hospital, University of Toronto, 8th Floor, Bond Wing, 30 Bond Street, Toronto, ON, Canada, M5B 1W8. Email E-mail Address: [email protected] https://orcid.org/0000-0002-4018-8533 St Michael’s Hospital and the University of Toronto, Canada (S.V.). Search for more papers by this author , Darren K. McGuireDarren K. McGuire https://orcid.org/0000-0002-6412-7989 University of Texas Southwestern Medical Center and Parkland Health and Hospital System, Dallas (D.K.M.). Search for more papers by this author , Mikhail N. KosiborodMikhail N. Kosiborod https://orcid.org/0000-0002-3750-9789 Saint Luke’s Mid America Heart Institute and the University of Missouri, Kansas City (M.N.K.). The George Institute for Global Health and the University of New South Wales, Sydney, Australia (M.N.K.). Search for more papers by this author Originally published24 Sep 2020https://doi.org/10.1161/CIRCULATIONAHA.120.051122Circulation. 2020;142:2201–2204Although the sodium-glucose cotransporter-2 (SGLT2) inhibitors were originally developed to manage hyperglycemia in people with type 2 diabetes, they have consistently been found to improve heart failure and kidney outcomes. In contrast to the initial SGLT2 inhibitor outcome trials that demonstrated robust reductions for incident heart failure in people with type 2 diabetes, 2 recent trials—EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; with empagliflozin)1 and DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; with dapagliflozin)2,3—have examined the efficacy of SGLT2 inhibitors to treat patients with heart failure with reduced ejection fraction (HFrEF), with or without type 2 diabetes. We compare the 2 trials and their results.Although both EMPEROR-Reduced (n=3730)1 and DAPA-HF (n=4744)2 enrolled patients with chronic heart failure and a left ventricular ejection fraction of ≤40%, they differed with respect to their NT-proBNP (N-terminal pro-B-type natriuretic peptide) eligibility criteria (Table), with the former requiring a sliding scale NT-proBNP level according to baseline left ventricular ejection fraction. Such a strategy, by design, was used with an intent to target patients with more advanced HFrEF. Indeed, the baseline left ventricular ejection fraction was lower (27% versus 31%) and the median NT-proBNP levels higher (≈1900 pg/mL versus ≈1430 pg/mL) in EMPEROR-Reduced compared with DAPA-HF. However, interestingly, fewer patients in EMPEROR-Reduced were hospitalized for heart failure (HHF) within the preceding 12 months (≈31% versus 47%), and numerically more patients in EMPEROR-Reduced were in New York Heart Association functional class II. Baseline estimated glomerular filtration rate (eGFR) was lower in EMPEROR-Reduced (≈61 mL·min−1·1.73 m-2) compared with DAPA-HF (≈66 mL·min−1·1.73 m-2), and proportionally more EMPEROR-Reduced patients had an eGFR that was ≤60 mL·min−1·1.73 m-2. Both trials recruited similar proportions of patients with and without type 2 diabetes (≈50%). Background therapy for HFrEF was excellent in both trials, with high rates of goal-directed medical therapy including β-blockers, renin-angiotensin-aldosterone system inhibitors, and mineralocorticoid antagonists. The use of sacubitril/valsartan was almost twice as high in EMPEROR-Reduced compared with DAPA-HF but remained still relatively low overall.Table 1. Comparison of the EMPEROR-Reduced and DAPA-HF Trial Design and CohortsEMPEROR-Reduced N=3730DAPA-HF N=4744Median follow-up (mo)≈16≈18Inclusion criteria• LVEF ≤30% and NT-proBNP ≥600 pg/mL (without AF) and ≥1200 pg/mL (with AF)• LVEF 31%–35% and NT-proBNP ≥1000 pg/mL (without AF) and ≥2000 pg/mL (with AF)• LVEF 36%–40% and NT-proBNP ≥2500 pg/mL (without AF) and ≥5000 pg/mL (with AF)• LVEF ≤40% and HHF in past 12 mo and NT-proBNP ≥600 pg/mL (without AF) and ≥1200 pg/mL (with AF)• eGFR ≥20 mL·min−1·1.73 m-2• LVEF ≤40% and NT-proBNP ≥600 pg/mL (without AF) or ≥900 pg/mL (with AF)• LVEF ≤40% and HHF in past 12 mo and NT-proBNP ≥400 pg/mL (without AF) or ≥900 pg/mL (with AF)• eGFR ≥30 mL·min−1·1.73 m-2Demographics and key clinical history of the placebo groups* Age, y66.566.5 Women, %24.423.0 Body mass index, kg/m227.828.1 eGFR, mL·min−1·1.73 m-262.265.5 Diabetes, %49.841.8 Atrial fibrillation, %37.838.0Features of heart failure in the placebo groups Left ventricular ejection fraction (%)27.230.9 Median NT-proBNP, pg/mL19261446 Ischemic cardiomyopathy, %50.757.3 HHF in previous 12 mo, %30.727.4 NYHA class II/III/IV, %75.0/24.4/0.667.4/31.7/1.0Baseline heart failure therapies of the placebo groups, % ACE inhibitor or angiotensin receptor blocker without ARNI68.982.8 β-Blocker94.796.2 MRA72.670.6 ARNI20.710.9 Implantable cardioverter-defibrillator31.826.1 Cardiac resynchronization therapy11.96.9Placebo event rates/100 patient-years, % Cardiovascular death or HHF21.015.3 HHF15.59.8 Cardiovascular death8.17.9 All-cause mortality10.79.5Clinical outcomes hazard ratio or absolute difference (95% CI)Empagliflozin vs placeboDapagliflozin vs placebo Primary outcome†0.75 (0.65–0.86)P<0.0010.74 (0.65–0.85)P<0.001 Cardiovascular death or HHF0.75 (0.65–0.86)0.75 (0.65–0.85) HHF0.69 (0.59–0.81)0.70 (0.59–0.83) Cardiovascular death0.92 (0.75–1.12)0.82 (0.69–0.98) All-cause mortality0.92 (0.77–1.10)0.83 (0.71–0.97) Mean slope of change in eGFR (mL·min−1·1.73 m-2) per year1.731.78 Composite kidney outcome‡0.50 (0.32–0.77)0.71 (0.44–1.16) Change in KCCQ clinical summary score§1.7 (0.5–3.0)1.18 (1.11–1.26)Absolute benefit of treatment – reduction in events per 100 person-years‖Empagliflozin vs placeboDapagliflozin vs placebo CV death/HHF5.23.9Primary outcome in key subgroupsEmpagliflozin vs placeboDapagliflozin vs placebo Diabetes, yes0.72 (0.60–0.87)0.75 (0.63–0.90) Diabetes, no0.78 (0.64–0.97)0.73 (0.60–0.88) eGFR ≥60 mL·min−1·1.73 m-20.67 (0.55–0.83)0.76 (0.63–0.92) eGFR<60 mL·min−1·1.73 m-20.83 (0.69–1.00)0.72 (0.59–0.86) HHF (<12 mo), yes0.79 (0.64–0.99)0.67 (0.56–0.80) HHF (<12 mo), no0.71 (0.60–0.85)0.84 (0.69–1.01) MRA, yes0.75 (0.63–0.88)0.74 (0.63–0.87) MRA, no0.76 (0.59–0.97)0.74 (0.57–0.95) ARNI, yes0.64 (0.45–0.89)0.75 (0.50–1.13) ARNI, no0.77 (0.66–0.90)0.74 (0.65–0.86)Biomarker changes from baseline#Empagliflozin vs placebo(baseline to 52 wk)Dapagliflozin vs placebo(baseline to 8 mo) A1C, %, patients with diabetes–0.16–0.24 Hematocrit, %+2.36+2.41 Systolic blood pressure, mm Hg–0.7–1.27 Weight, kg–0.82–0.87 NT-proBNP, pg/mL**–103–303A1C indicates glycated hemoglobin; ACE, Angiotensin-converting enzyme; AF, atrial fibrillation; ARNI, angiotensin receptor neprilysin inhibitor; CV, cardiovascular; DAPA-HF, Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure; eGFR, estimated glomerular filtration rate; EMPEROR-Reduced, Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction; HHF, hospitalized for heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid antagonist; NT-proBNP, N-terminal pro-B-type natriuretic peptide; and NYHA, New York Heart Association.* Mean values provided for continuous variables.† The primary outcome for EMPEROR-Reduced was a composite of CV death or hospitalization for worsening heart failure; that for DAPA-HF was composite of death from CV causes or worsening heart failure.‡ The composite kidney outcome for EMPEROR-Reduced was chronic dialysis or kidney transplantation or a sustained reduction of ≥40% in the eGFR or a sustained eGFR of <15 mL·min−1·1.73 m-2 in patients with a baseline eGFR of ≥30 mL·min−1·1.73 m-2 or a sustained eGFR of <10 mL·min−1·1.73 m-2 in those with a baseline eGFR of <20 mL·min−1·1.73 m-2; that for DAPA-HF was a sustained decline in the eGFR of ≥50% for ≥28 days, end-stage kidney disease (defined as ≥28 days of eGFR <15 mL·min−1·1.73 m-2, sustained dialysis, or kidney transplantation), or kidney death; and death from any cause.§ The KCCQ clinical summary score (heart failure symptoms and physical limitations domains) for EMPEROR-Reduced was the mean change from baseline at week 52; that for DAPA-HF was the mean change from baseline at month 8.‖ The absolute risk reductions were reported a function of both baseline risk and relative risk reductions.# Mean changes in the absolute values.** NT-proBNP for EMPEROR-Reduced is reported as the median of the adjusted change from baseline to week 52; that for DAPA-HF is the mean change from baseline at month 8.As a reflection of these differences in patient populations, the placebo event rates also differed between the 2 trials. Specifically, for the composite outcome of cardiovascular death or HHF, the event rate per 100 patient-years was 21% in EMPEROR-Reduced versus 15% in DAPA-HF. This was a result of a higher rate of HHF with similar rates of cardiovascular death in both trials (Table). There was remarkable consistency for the outcome of cardiovascular death or HHF―both trials demonstrated a 25% reduction in the groups assigned to the SGLT2 inhibitors, with absolute risk reductions of 5.2 and 3.9 per 100 person-years in EMPEROR-Reduced and DAPA-HF, respectively (number needed to treat: 19 and 21 over a median of 16 and 18 months). There was also noteworthy consistency in the effects on HHF, reduced by ≈30% in both trials. On the other hand, whereas cardiovascular death was numerically (but not significantly) lower in EMPEROR-Reduced (HR [95% CI], 0.92 [0.75–1.12]), it was significantly reduced in DAPA-HF (HR [95% CI], 0.82 [0.69–0.98], P=0.02). Similarly, all-cause mortality was significantly reduced in DAPA-HF but not in EMPEROR-Reduced (Table). With respect to kidney outcomes, both trials reported a similar (and significant) effect of SGLT2 inhibitors to attenuate the decline in the eGFR slope. Although the composite kidney outcome was reduced statistically in EMPEROR-Reduced, this was not the case in DAPA-HF. This may have been a result of the relatively fewer kidney events in DAPA-HF, in part a reflection of higher baseline eGFR entry criteria, and a composite kidney outcome that included a 50% sustained decline in eGFR (versus 40% in EMPEROR-Reduced). In both studies, tolerability was excellent, with no excess drug discontinuation, hypovolemia-related side effects, or hypoglycemia. Genital mycotic infections were higher in those treated with an SGLT2 inhibitor (1.7% versus 0.6% in EMPEROR-Reduced versus DAPA-HF).A closer look at these 2 trials reveals a few issues that merit elaboration. First, the benefits of SGLT2 inhibitors on HFrEF were similar in patients with and without type 2 diabetes and extended down to an eGFR of 20 mL·min−1·1.73 m-2. Second, efficacy was observed on top of goal-directed medical therapy including sacubitril/valsartan and mineralocorticoid antagonists, suggesting that the mechanistic underpinnings of SGLT2 inhibitors are distinct from, and complementary to, established therapies. The modest reduction in NT-proBNP in both trials argues against natriuresis as a dominant mechanism. Both SGLT2 inhibitors afforded marked kidney protection—an observation that amplifies the overall benefit of this strategy because kidney disease and heart failure often coexist and are pathophysiologically and prognostically linked.Although trials are powered for their primary outcome—which was achieved in both studies with a P<0.001—questions have been raised about the apparent differences in cardiovascular death between dapagliflozin and empagliflozin, respectively. In our opinion, these differences reflect statistical power, short follow-up, and a composite outcome that was driven by an excess in HHF (versus a proportionate increase in cardiovascular death events). Why the enrichment strategy in EMPEROR-Reduced resulted in fewer cardiovascular deaths compared with DAPA-HF (389 versus 500 events) is unclear; this may be related to a higher use of angiotensin receptor neprilysin inhibitor, implantable cardioverter-defibrillator, or cardiac resynchronization therapy, fewer patients recruited with a history of HHF within the preceding 12 months, and more patients with New York Heart Association functional class II. Approximately 17% of patients discontinued therapy in EMPEROR-Reduced (versus 11% in DAPA-HF), and vital status was unknown in 21 patients in EMPEROR-Reduced (versus 2 in DAPA-HF). These issues may have affected power, particularly in the context of a shorter median follow-up (16 versus 18 months). The results from both trials fall within the confidence limits from a pooled analysis demonstrating a 14% significant reduction in cardiovascular death (hazard ratio, 0.86 [95% CI, 0.76–0.98]).4 The effects on cardiovascular death are also discordant with EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients–Removing Excess Glucose) in patients with type 2 diabetes, but it is noteworthy that this outcome seems to be much more variable in SGLT2 inhibitor trials (compared with the consistent benefits on HHF and kidney outcomes).Although EMPEROR-Reduced and DAPA-HF represent 2 tales, they tell 1 story in HFrEF. The 2 trials establish SGLT2 inhibitors, independent of diabetes status and glycemic effects, as highly effective and well-tolerated therapies that reduce cardiovascular death/HHF and improve quality of life in HFrEF.5 As a result, these therapies should be considered a key component of goal-directed medical therapy in HFrEF. The challenge now is how to “sequence” these therapies in HFreF and whether inhospital initiation is safe and effective – a question that is being studied in the SOLOIST-WHF trial (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03521934).AcknowledgmentsThe authors thank Hwee Teoh, PhD, an independent medical writer, of HTaq Biomedical Editorial and Education Services Inc, for editorial assistance. No industry support was provided for this work.DisclosuresDr Verma holds a Tier 1 Canada Research Chair in Cardiovascular Surgery and reports receiving research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Sanofi, Sun Pharmaceuticals, PhaseBio, and the Toronto Knowledge Translation Working Group. He is a member of the scientific excellence committee of the EMPEROR-Reduced trial and served as a national lead investigator of the DAPA-HF and EMPEROR-Reduced trials. He is the president of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Dr McGuire has received personal fees for trial leadership and/or consultancy from Boehringer Ingelheim, Janssen Research and Development LLC, Sanofi US, Merck Sharp and Dohme Corp, Eli Lilly USA, Novo Nordisk, GlaxoSmithKline, AstraZeneca, Lexicon Pharmaceuticals, Eisai, Pfizer, Metavant, Applied Therapeutics, Afimmune, and Esperion. Dr Kosiborod has received research grants from AstraZeneca and Boehringer Ingelheim, and consulting honoraria from AstraZeneca, Boehringer Ingelheim, Janssen, Amgen, Novo Nordisk, Eli Lilly, Merck (Diabetes), Sanofi, Applied Therapeutics, Amarin, and Vifor Pharma.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circSubodh Verma, MD, PhD, FRCSC, Division of Cardiac Surgery, St Michael’s Hospital, University of Toronto, 8th Floor, Bond Wing, 30 Bond Street, Toronto, ON, Canada, M5B 1W8. Email subodh.[email protected]caReferences1. Packer M, Anker SD, Butler J, Filippatos G, Pocock SJ, Carson P, Januzzi J, Verma S, Tsutsui H, Brueckmann M, et al.; EMPEROR-Reduced Trial Investigators. Cardiovascular and renal outcomes with empagliflozin in heart failure.N Engl J Med. 2020; 383:1413–1424. doi: 10.1056/NEJMoa2022190CrossrefMedlineGoogle Scholar2. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, et al.. Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381:1995–2008. doi: 10.1056/NEJMoa1911303CrossrefMedlineGoogle Scholar3. Petrie MC, Verma S, Docherty KF, Inzucchi SE, Anand I, Belohlávek J, Böhm M, Chiang CE, Chopra VK, de Boer RA, et al.. Effect of dapagliflozin on worsening heart failure and cardiovascular death in patients with heart failure with and without diabetes.JAMA. 2020; 323:1353–1368. doi: 10.1001/jama.2020.1906CrossrefMedlineGoogle Scholar4. Zannad F, Ferreira JP, Pocock SJ, Anker SD, Butler J, Filippatos G, Brueckmann M, Ofstad AP, Pfarr E, Jamal W, et al.. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials.Lancet. 2020; 396:819–829. doi: 10.1016/S0140-6736(20)31824-9CrossrefMedlineGoogle Scholar5. Kosiborod MN, Jhund PS, Docherty KF, Diez M, Petrie MC, Verma S, Nicolau JC, Merkely B, Kitakaze M, DeMets DL, et al.. Effects of dapagliflozin on symptoms, function, and quality of life in patients with heart failure and reduced ejection fraction: results from the DAPA-HF Trial.Circulation. 2020; 141:90–99. doi: 10.1161/CIRCULATIONAHA.119.044138LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetails December 8, 2020Vol 142, Issue 23Article InformationMetrics Download: 7,054 © 2020 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.120.051122PMID: 32969716 Originally publishedSeptember 24, 2020 Keywordsdapagliflozinempagliflozinheart failureSGLT2 inhibitionPDF download SubjectsClinical StudiesTreatmentHeart Failure
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