Title: Effects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus
Abstract: HomeCirculationVol. 139, No. 22Effects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes Mellitus Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBEffects of Canagliflozin on Heart Failure Outcomes Associated With Preserved and Reduced Ejection Fraction in Type 2 Diabetes MellitusResults From the CANVAS Program Gemma A. Figtree, MBBS, DPhil, Karin Rådholm, MD, PhD, Terrance D. Barrett, PhD, Vlado Perkovic, MBBS, PhD, Kenneth W. Mahaffey, MD, Dick de Zeeuw, MD, PhD, Greg Fulcher, MD, David R. Matthews, DPhil, BM, BCh, Wayne Shaw, DSL and Bruce Neal, MB, ChB, PhD Gemma A. FigtreeGemma A. Figtree Gemma A. Figtree, MBBS, DPhil, Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales, NSW 2065, Australia. Email E-mail Address: [email protected] Kolling Institute, Royal North Shore Hospital and University of Sydney, Australia (G.A.F., G.F.). The George Institute for Global Health, University of New South Wales, Sydney, Australia (G.A.F., K.R., V.P., B.N.). Search for more papers by this author , Karin RådholmKarin Rådholm The George Institute for Global Health, University of New South Wales, Sydney, Australia (G.A.F., K.R., V.P., B.N.). Division of Community Medicine, Primary Care, Department of Medicine and Health Sciences, Faculty of Health Sciences, Linköping University, Department of Local Care West, County Council of Östergötland, Sweden (K.R.). Search for more papers by this author , Terrance D. BarrettTerrance D. Barrett Janssen Research & Development, LLC, Raritan, NJ (T.D.B., W.S.). Search for more papers by this author , Vlado PerkovicVlado Perkovic The George Institute for Global Health, University of New South Wales, Sydney, Australia (G.A.F., K.R., V.P., B.N.). Search for more papers by this author , Kenneth W. MahaffeyKenneth W. Mahaffey Stanford Center for Clinical Research, Department of Medicine, Stanford University School of Medicine, CA (K.W.M.). Search for more papers by this author , Dick de ZeeuwDick de Zeeuw Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, The Netherlands (D.d.Z.). Search for more papers by this author , Greg FulcherGreg Fulcher Kolling Institute, Royal North Shore Hospital and University of Sydney, Australia (G.A.F., G.F.). Search for more papers by this author , David R. MatthewsDavid R. Matthews Oxford Centre for Diabetes, Endocrinology and Metabolism and Harris Manchester College, University of Oxford, United Kingdom (D.R.M.). Search for more papers by this author , Wayne ShawWayne Shaw Janssen Research & Development, LLC, Raritan, NJ (T.D.B., W.S.). Search for more papers by this author and Bruce NealBruce Neal The George Institute for Global Health, University of New South Wales, Sydney, Australia (G.A.F., K.R., V.P., B.N.). Faculty of Medicine, University of New South Wales, Sydney, Australia (B.N.). Imperial College London, UK (B.N.). Search for more papers by this author Originally published17 Mar 2019https://doi.org/10.1161/CIRCULATIONAHA.119.040057Circulation. 2019;139:2591–2593Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: March 17, 2019: Ahead of Print Patients with type 2 diabetes mellitus are at high risk of developing heart failure (HF).1 Sodium glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated, in large-scale trials, to reduce the risk of HF events in patients with type 2 diabetes mellitus deemed to be at high risk based on established cardiovascular disease or multiple risk factors.2–4 However, it is unclear whether benefits are experienced across the broad spectrum of HF patients that includes those with preserved ejection fraction (HFpEF) and those with reduced ejection fraction (HFrEF).The goal of the present analyses was to define the potentially distinct effects on HF events with preserved versus reduced ejection fraction (EF) in the CANVAS (Canagliflozin Cardiovascular Assessment Study) Program. Participants with type 2 diabetes mellitus aged ≥30 years with a history of symptomatic atherosclerotic cardiovascular disease or aged ≥50 years with 2 or more risk factors for cardiovascular disease were randomized to receive canagliflozin or placebo and followed up as described previously.3 Patients with New York Heart Association functional class IV HF were excluded. Use of other background therapy for glycemic management, treatment of HF, and other risk factor control was according to best practice. The trials comprising the CANVAS Program (CANVAS and CANVAS-R [–Renal]) were approved by the ethics committees at each site, and all participants provided written informed consent. The primary outcome for the CANVAS Program was the composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. HF events were initially assessed by an end point adjudication committee using a prespecified set of criteria. The assignment of each event as being in the context of preserved or reduced EF was done by a retrospective secondary review of the medical record data by one of the members of the original adjudication committee who was blinded to individual participant treatment assignment (G.A.F.). Echocardiography or left ventriculography performed as part of routine clinical care was used to make the determination of EF. HFpEF was defined as an HF event for which EF of ≥50% was documented during the HF admission. HFrEF was defined as an HF event for which EF was documented as <50% during the HF admission, or there was a prior report of reduced EF with no documented evidence of recovery. All other events were defined as HF with unknown EF (HFuEF).There were 10 142 patients in the CANVAS Program, with a mean follow-up of 188.2 weeks. Mean age was 63.3 years; 35.8% of participants were women; and 65.6% had a history of cardiovascular disease, including 1461 (14.4%) with a history of HF at baseline (with no requirement for preserved or reduced EF classification). A total of 276 of the 10 142 participants had a fatal or hospitalized HF event during follow-up, and 61 of these participants had >1 HF event. In total, there were 101 participants who had a first HF event of preserved EF, 122 who had a first HF event with reduced EF, and 61 who had a first HF event with unknown EF. The number of first HF events adds to >276 participants because 8 patients experienced a first HF event of >1 type (eg, unknown EF event in year 1 followed by reduced EF event in year 2).Participants who had an HFpEF event were more likely to be female (37.6% versus 16.4%; P<0.001) than those with HFrEF events and were more likely to have a history of hypertension (96.0% versus 86.9%; P=0.014). Those who had HFpEF events also had a higher mean systolic blood pressure at baseline than those who had an HFrEF event (142.8 mm Hg versus 134.4 mm Hg; P<0.001), a higher prevalence of microvascular disease (65.4% versus 51.6%; P=0.041), a lower prevalence of macrovascular disease (65.4% versus 77.9%; P=0.038), and a higher body mass index (37.2 kg/m2 versus 33.7 kg/m2; P<0.001).Overall, as previously reported, canagliflozin reduced fatal or hospitalized HF events compared with placebo (hazard ratio, 0.70; 95% CI, 0.55–0.89).2 As shown in the Figure, the hazard ratios were 0.69 (95% CI, 0.48–1.00) for HFrEF events, 0.83 (95% CI, 0.55–1.25) for HFpEF events, and 0.54 (95% CI, 0.32–0.89) for HFuEF events. In the sensitivity analysis in which HFuEF events were assumed to be HFpEF, the updated hazard ratio for HFpEF events was 0.71 (95% CI, 0.52–0.97), and when HFuEF events were assumed to be HFrEF events, the updated hazard ratio for HFrEF events was 0.64 (95% CI, 0.48–0.86). Analyses adjusted for competing risk of death were performed with the Fine and Gray analysis approach and produced similar findings.Download figureDownload PowerPointFigure. Effects of canagliflozin vs placebo on all fatal or hospitalized HF and on HF with preserved ejection fraction, reduced ejection fraction, and unknown ejection fraction. HF indicates heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HFuEF, heart failure with unknown ejection fraction; and HR, hazard ratio.In summary, canagliflozin reduced the overall risk of HF events in patients with type 2 diabetes mellitus and high cardiovascular risk, with no clear difference in effects on HFrEF versus HFpEF events. This may provide some hope for patients with diabetes mellitus and HFpEF, in which no prior intervention has been shown to have clear clinical benefits. However, this study was limited by its reliance on EF measurements at the time of the event and not at baseline, and additional data from dedicated HFpEF trials are required.AcknowledgmentsThis study was supported by Janssen Research & Development, LLC. The authors thank all investigators, study teams, and patients for participating in these studies. The authors thank the following people for their contributions to the statistical monitoring/analyses and the protocol development, safety monitoring, and operational implementation over the duration of both studies: Lyndal Hones, Lucy Perry, Sharon Dunkley, Qiang Li, Severine Bompoint, Laurent Billot, Mary Lee, Joan Lind, Roger Simpson, Mary Kavalam, Frank Vercruysse, Elisa Fabbrini, Richard Oh, Ngozi Erondu, Mehul Desai, and Norm Rosenthal. Medical writing support was provided by Kimberly Dittmar, PhD, of MedErgy, and was funded by Janssen Global Services, LLC. Canagliflozin has been developed by Janssen Research & Development, LLC, in collaboration with Mitsubishi Tanabe Pharma Corporation.Sources of FundingThis study was supported by Janssen Research & Development, LLC.DisclosuresDr Figtree has received research support from the cofunded National Health and Medical Research Council and Heart Foundation (Australia) Fellowship and from Heart Research Australia, as well as compensation from Janssen for serving on the adjudication panel of the CANVAS Program. Dr Rådholm has received funding from the Rolf Luft Foundation for Diabetes Research, Fellowship in Memory of Jeanette Bonnier. Drs Barrett and Shaw are full-time employees of Janssen Research & Development, LLC. Dr Perkovic has received research support from the Australian National Health and Medical Research Council (Senior Research Fellowship and Program Grant); served on steering committees for AbbVie, Boehringer Ingelheim, GlaxoSmithKline, Janssen, Novartis, and Pfizer; and served on advisory boards or as a speaker at scientific meetings for AbbVie, Astellas, AstraZeneca, Bayer, Baxter, Bristol-Myers Squibb, Boehringer Ingelheim, Durect, Eli Lilly, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, Pharmalink, Relypsa, Retrophin, Roche, Sanofi, Servier, and Vitae. Dr Mahaffey’s financial disclosures can be viewed at http://med.stanford.edu/profiles/kenneth-mahaffey. Dr de Zeeuw has served on advisory boards or as a speaker for Bayer, Boehringer Ingelheim, Fresenius, Mundipharma, and Mitsubishi Tanabe; on steering committees or as a speaker for AbbVie and Janssen; and on data safety and monitoring committees for Bayer. Dr Fulcher has received research support from Novo Nordisk and has served on advisory boards and as a consultant for Janssen, Novo Nordisk, Boehringer Ingelheim, and Merck Sharp & Dohme. Dr Matthews has received research support from Janssen; has served on advisory boards and as a consultant for Novo Nordisk, Novartis, Eli Lilly, Sanofi-Aventis, Janssen, and Servier; and has given lectures for Novo Nordisk, Servier, Sanofi-Aventis, Eli Lilly, Novartis, Janssen, Mitsubishi Tanabe, and Aché Laboratories. He currently serves as President of the European Association for the Study of Diabetes. Dr Neal has received research support from the Australian National Health and Medical Research Council Principal Research Fellowship and has served on advisory boards or as a consultant for Janssen and Merck Sharp & Dohme, with any consultancy, honoraria, or travel support paid to his institution. The George Institute for Global Health holds multiple additional commercial contracts with a diverse range of entities.Footnoteshttps://www.ahajournals.org/journal/circData sharing: Data from this study will be made available in the public domain via the Yale University Open Data Access Project (http://yoda.yale.edu/) once the product and relevant indication studied have been approved by regulators in the United States and European Union and the study has been completed for 18 months.Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01032629 and NCT01989754.Gemma A. Figtree, MBBS, DPhil, Kolling Institute of Medical Research, Royal North Shore Hospital, Pacific Highway, St Leonards, New South Wales, NSW 2065, Australia. Email gemma.[email protected]edu.auReferences1. Cavender MA, Steg PG, Smith SC, Eagle K, Ohman EM, Goto S, Kuder J, Im K, Wilson PW, Bhatt DL; on behalf of the REACH Registry Investigators. 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