TY - JOUR
T1 - Efficacy and safety of dapagliflozin in the elderly
T2 - Analysis from the DECLARE-TIMI 58 study
AU - Cahn, Avivit
AU - Mosenzon, Ofri
AU - Wiviott, Stephen D.
AU - Rozenberg, Aliza
AU - Yanuv, Ilan
AU - Goodrich, Erica L.
AU - Murphy, Sabina A.
AU - Bhatt, Deepak L.
AU - Leiter, Lawrence A.
AU - McGuire, Darren K.
AU - Wilding, John P.H.
AU - Gause-Nilsson, Ingrid A.M.
AU - Fredriksson, Martin
AU - Johansson, Peter A.
AU - Langkilde, Anna Maria
AU - Sabatine, Marc S.
AU - Raz, Itamar
N1 - Funding Information:
Funding. The DECLARE–TIMI 58 trial was a collaboration between AstraZeneca and two academic research organizations (TIMI Study Group and Hadassah Medical Organization). Data analyses were performed by the academic TIMI Study Group, which has access to the complete study database, allowing independent analyses of the results; any discrepancies were resolved by discussion. The DECLARE–TIMI 58 publication committee made the decision to submit for publication. DualityofInterest.ThesponsorsoftheDECLARE– TIMI 58 study were initially AstraZeneca and Bristol-Myers Squibb, and AstraZeneca later became the sole sponsor of the study. A.C. reports grants and personal fees from Astra-Zeneca andNovoNordiskandpersonalfeesfrom Abbott, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Medial Early-Sign, and GlucoMe. O.M. reports grants and personal fees from AstraZeneca, Bristol-Myers Squibb, and Novo Nordisk and personal fees from Eli Lilly, Sanofi, Merck Sharp & Dohme, Boehringer In-gelheim, Johnson & Johnson, and Novartis. S.D.W. reports grants from AstraZeneca, Bristol-Myers Squibb, Sanofi, and Amgen, grants and personal fees from Arena, Daiichi Sankyo, Eisai, Eli Lilly, and Janssen, grants and consulting fees from Merck Sharp & Dohme (additionally his spouse is employed by Merck Sharp & Dohme), and personal fees from Aegerion, Allergan, An-gelMed, Boehringer Ingelheim, Boston Clinical Research Institute, Icon Clinical, Lexicon, St. Jude Medical, Xoma, Servier, AstraZeneca, and Bristol-Myers Squibb. E.L.G. and S.A.M. report research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Roche, Takeda, and Zora Biosciences. D.L.B. is affiliated with the following: (advisory board) Cardax, Cereno Scientific, Elsevier Practice Update Cardiology, Medscape Cardiology, PhaseBio, and Regado Biosciences; (board of directors) Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; (chair) American Heart Association Quality Oversight Committee; (data monitoring committee) Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, fundedbyDaiichiSankyo),andPopulationHealth Research Institute; (honoraria) American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org, Vice-Chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim, AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor, Associate Editor), Medtelligence/ ReachMD (CME steering committees), Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and U.S. national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), and WebMD (CME steering committees); (other) Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), and VA CART Research and Publications Committee (Chair); (research funding) Abbott, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb,Chiesi,CSLBehring,Eisai,Ethicon,Ferring Pharmaceuticals, Forest Laboratories, Idorsia, Ironwood, Ischemix, Lilly, Medtronic, PhaseBio, Pfizer, Regeneron, Roche, Sanofi, Synaptic, and The Medicines Company; (royalties) Elsevier (Editor,CardiovascularIntervention: A Companion to Braunwald’s Heart Disease); (site coinvestigator) Biotronik, Boston Scientific, St. Jude Medical (now Abbott), and Svelte; (trustee) American College of Cardiology; and (unfunded research) FlowCo, Fractyl, Merck Sharp & Dohme, Novo Nordisk, PLx Pharma, and Takeda. L.A.L. reports grants and personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; personal fees from Merck Sharp & Dohme and Servier; and grants from GlaxoSmithKline. D.K.M. reports personal fees for clinical trial leadership from GlaxoSmithKline, Janssen, Lexicon AstraZeneca, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Pfizer, Novo Nordisk, Eisai, Esperion, and Lilly and personal fees for consultancy from AstraZeneca, Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novo Nordisk, Metavant, Applied Therapeutics, Sanofi, and Afimmune. J.P.H.W., outside the submitted work, has grants, personal fees for lectures, and consultancy fees (paid to his institution) from AstraZeneca and Novo Nordisk; personal fees for lectures and consultancy fees (paid to his institution) from Boehringer Ingelheim, Janssen, Lilly, Mundipharma, Napp, Sanofi, and Takeda; and consultancy fees (paid to his institution) from Wilmington Healthcare. I.A.M.G.-N., M.F., P.A.J. and A.M.L. are employees of AstraZeneca. M.S.S. reports research grant support through Brigham and Women’s Hospital from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck Sharp & Dohme, Novartis, Poxel, Pfizer, Quark, and Takeda and consulting fees from Alnylam, Anthos Therapeutics, Amgen, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Ionis, Jans-sen Research and Development, The Medicines Company, MedImmune, Merck Sharp & Dohme, and Novartis; M.S.S. is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from Abbott, Aralez, Roche, and Zora Biosciences. I.R. reports personal fees from AstraZeneca, Bristol-Myers Squibb, Boehringer Ingelheim, Concenter Bio-Pharma and Silkim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk, Orgenesis, Pfizer, Sanofi, SmartZyme Innovation, Panaxia, FuturRx, Insuline Medical, Medial EarlySign, CameraEyes, Exscopia, Dermal Biomics, Johnson & Johnson, Novartis, Teva, GlucoMe, and DarioHealth. No other potential conflicts of interest relevant to this article were reported.
Publisher Copyright:
© 2019 by the American Diabetes Association.
PY - 2020/2/1
Y1 - 2020/2/1
N2 - OBJECTIVE: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with ahazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93(95%CI0.81,1.08), 0.97(0.83,1.13), and 0.84 (0.61,1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively). CONCLUSIONS: The overall efficacy and safety of dapagliflozin are consistent regardless of age.
AB - OBJECTIVE: Data regarding the effects of sodium-glucose cotransporter 2 inhibitors in the elderly (age ≥65 years) and very elderly (age ≥75 years) are limited. RESEARCH DESIGN AND METHODS: The Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 assessed cardiac and renal outcomes of dapagliflozin versus placebo in patients with type 2 diabetes. Efficacy and safety outcomes were studied within age subgroups for treatment effect and age-based treatment interaction. RESULTS: Of the 17,160 patients, 9,253 were <65 years of age, 6,811 ≥65 to <75 years, and 1,096 ≥75 years. Dapagliflozin reduced the composite of cardiovascular death or hospitalization for heart failure consistently, with ahazard ratio (HR) of 0.88 (95% CI 0.72, 1.07), 0.77 (0.63, 0.94), and 0.94 (0.65, 1.36) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.5277). Overall, dapagliflozin did not significantly decrease the rates of major adverse cardiovascular events, with HR 0.93(95%CI0.81,1.08), 0.97(0.83,1.13), and 0.84 (0.61,1.15) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.7352). The relative risk reduction for the secondary prespecified cardiorenal composite outcome ranged from 18% to 28% in the different age-groups with no heterogeneity. Major hypoglycemia was less frequent with dapagliflozin versus placebo, with HR 0.97 (95% CI 0.58, 1.64), 0.50 (0.29, 0.84), and 0.68 (0.29, 1.57) in age-groups <65, ≥65 to <75, and ≥75 years, respectively (interaction P value 0.2107). Safety outcomes, including fractures, volume depletion, cancer, urinary tract infections, and amputations were balanced with dapagliflozin versus placebo, and acute kidney injury was reduced, all regardless of age. Genital infections that were serious or led to discontinuation of the study drug and diabetic ketoacidosis were uncommon, yet more frequent with dapagliflozin versus placebo, without heterogeneity (interaction P values 0.1058 and 0.8433, respectively). CONCLUSIONS: The overall efficacy and safety of dapagliflozin are consistent regardless of age.
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U2 - 10.2337/dc19-1476
DO - 10.2337/dc19-1476
M3 - Article
C2 - 31843945
AN - SCOPUS:85078394630
SN - 0149-5992
VL - 43
SP - 468
EP - 475
JO - Diabetes care
JF - Diabetes care
IS - 2
ER -