Effect of Dapagliflozin on Cardiovascular Outcomes According to Baseline Kidney Function and Albuminuria Status in Patients With Type 2 Diabetes: A Prespecified Secondary Analysis of a Randomized Clinical Trial

Abstract

Importance: Sodium-glucose cotransporter 2 inhibitors, such as dapagliflozin, promote renal glucose excretion and reduce cardiovascular (CV) deaths and hospitalizations for heart failure (HHF) among patients with type 2 diabetes. The relative CV efficacy and safety of dapagliflozin according to baseline kidney function and albuminuria status are unknown.

Objective: To assess the CV efficacy and safety of dapagliflozin according to baseline estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio (UACR).

Design, setting, and participants: This secondary analysis of the randomized clinical trial Dapagliflozin Effect on Cardiovascular Events-Thrombolysis in Myocardial Infarction 58 compared dapagliflozin vs placebo in 17 160 patients with type 2 diabetes and a baseline creatinine clearance of 60 mL/min or higher. Patients were categorized according to prespecified subgroups of baseline eGFR (<60 vs ≥60 mL/min/1.73 m2), urinary albumin to creatinine ratio (UACR; <30 vs ≥30 mg/g), and of chronic kidney disease (CKD) markers using these subgroups (0, 1, or 2). The study was conducted from May 2013 to September 2018.

Interventions: Dapagliflozin vs placebo.

Main outcomes and measures: The dual primary end points were major adverse cardiovascular events (myocardial infarction, stroke, and CV death) and the composite of CV death or HHF.

Results: At baseline, 1265 patients (7.4%) had an eGFR below 60 mL/min/1.73 m2, and 5199 patients (30.9%) had albuminuria. Among patients having data for both eGFR and UACR, 10 958 patients (65.1%) had an eGFR equal to or higher than 60 mL/min/1.73 m2 and an UACR below 30 mg/g (mean [SD] age, 63.7 [6.7] years; 40.1% women), 5336 patients (31.7%) had either an eGFR below 60 mL/min/1.73 m2 or albuminuria (mean [SD] age, 64.1 [7.1] years; 32.6% women), and 548 patients (3.3%) had both (mean [SD] age, 66.8 [6.9] years; 30.5% women). In the placebo group, patients with more CKD markers had higher event rates at 4 years as assessed using the Kaplan-Meier approach for the composite of CV death or HHF (3.9% for 0 markers, 8.3% for 1 marker, and 17.4% for 2 markers) and major adverse cardiovascular events (7.5% for 0 markers, 11.6% for 1 marker, and 18.9% for 2 markers). Estimates for relative risk reductions for the composite of CV death or HHF and for major adverse cardiovascular events were generally consistent across subgroups (both P > .24 for interaction), although greater absolute risk reductions were observed with more markers of CKD. The absolute risk difference for the composite of CV death or HHF was greater for patients with more markers of CKD (0 markers, -0.5%; 1 marker, -1.0%; and 2 markers, -8.3%; P = .02 for interaction). The numbers of amputations, cases of diabetic ketoacidosis, fractures, and major hypoglycemic events were balanced or numerically lower with dapagliflozin compared with placebo for patients with an eGFR below 60 mL/min/1.73 m2 and an UACR of 30 mg/g or higher.

Conclusions and relevance: The effect of dapagliflozin on the relative risk for CV events was consistent across eGFR and UACR groups, with the greatest absolute benefit for the composite of CV death or HHF observed among patients with both reduced eGFR and albuminuria.

Trial registration: ClinicalTrials.gov Identifier: NCT01730534.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Zelniker reported receiving grants from Deutsche Forschungsgemeinschaft during the conduct of the study; personal fees from AstraZeneca and Boehringer Ingelheim; and grants from the Austrian Science Fund outside the submitted work. Dr Raz reported receiving personal fees from AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, CameraEyes, Concenter BioPharma and Silkim, DarioHealth, Dermal Biomics, Eli Lilly and Company, Exscopia, FuturRx, GlucoMe, Insuline Medical, Johnson & Johnson, Medial EarlySign, Merck Sharp & Dohme, Novartis, Novo Nordisk, Orgenesis, Panaxia, Pfizer, Sanofi, SmartZyme Innovation, and Teva. Dr Mosenzon reported receiving grants and personal fees from AstraZeneca, Bristol Myers Squibb, and Novo Nordisk; grants from AstraZeneca and Novo Nordisk provided through Hadassah Hospital outside the submitted work; personal fees from AstraZeneca during the conduct of the study; and personal fees from Boehringer Ingelheim, BOL Pharma, Eli Lilly, Johnson & Johnson, Merck Sharp & Dohme, Novartis, Novo Nordisk Eli Lilly, Merck Sharp & Dohme, and Sanofi. Dr Dwyer reported receiving personal fees from AstraZeneca during the conduct of the study; personal fees from Bayer, Boehringer Ingelheim, CSL Behring, and Novo Nordisk; nonfinancial support from the Collaborative Study Group; and personal fees from Amgen, Ironwood pharmaceuticals, NLI, Sanofi, and the US Food and Drug Administration outside the submitted work. Dr Heerspink reported receiving institutional research grant support from AstraZeneca during the conduct of the study; institutional research grant support and personal fees from AbbVie, Bayer, Boehringer Ingelheim, Chinook; CSL Behring, Dimeri, and Janssen; and institutional support via personal fees from Gilead, Mitsubishi Tanabe, Mundipharma, Novo Nordisk, and Retrophin outside the submitted work. Dr Cahn reported receiving personal fees and grants from AstraZeneca during the conduct of the study and personal fees from Bayer, Boehringer Ingelheim, Elli Lilly, GlucoMe, Medial EarlySign, Merck Sharp & Dohme, Novo Nordisk, and Sanofi outside the submitted work. Ms Goodrich and Dr Im are members of the Thrombolysis in Myocardial Infarction (TIMI) Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott Laboratories, Amgen, Anthos Therapeutics, Aralez, AstraZeneca, Bayer, BRAHMS GmbH, Critical Diagnostics, Daiichi Sankyo, Eisai, Genzyme, Gilead, GlaxoSmithKline, HealthCare Pharmaceuticals Inc, Intarcia, Janssen, MedImmune, Merck & Co, Novartis, Pfizer, Poxel, Quark Pharmaceuticals, Regeneron Pharmaceuticals Inc, Roche Diagnostics, Siemens Healthcare Diagnostics, Takeda, The Medicines Company, and Zora Biosciences. Dr Bhatt discloses the following relationships: Advisory Board: Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, MyoKardia, PhaseBio, PLx Pharma, Regado Biosciences; Board of Directors: Boston VA Research Institute, Society of Cardiovascular Patient Care, TobeSoft; Chair: American Heart Association Quality Oversight Committee; Data Monitoring Committees: 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), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), Population Health 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), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today’s Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Research Funding: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Lexicon, Eli Lilly, Medtronic, MyoKardia, Owkin, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi, Synaptic, The Medicines Company; Royalties: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); Site Co-Investigator: Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. Dr Leiter reported receiving institutional research grant funds and personal fees from AstraZeneca; and personal fees from Boehringer Ingelheim, Eli Lilly and Company, GlaxoSmithKline, Janssen, Lexicon, Merck, Novo Nordisk, Sanofi, and Servier outside the submitted work. Dr McGuire reported receiving personal fees from Afimmune, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, CSL Behring, Eli Lilly and Company, Esperion, GlaxoSmithKline, Lexicon, Metavant, Merck & Co, Novo Nordisk, Pfizer, and Sanofi outside the submitted work. Dr Wilding reported receiving institutional research grant support and personal fees from AstraZeneca and Novo Nordisk during the conduct of the study; and personal fees via the institution from Astellas, Boehringer Ingelheim, Eli Lilly and Company, Janssen, Napp, Mundipharma, Novo Nordisk, Rhythm Pharmaceuticals, Sanofi, and Wilmington Healthcare, outside the submitted work. Drs Gause-Nilsson and Langkilde are employees and shareholders of AstraZeneca. Dr Gause-Nilsson also reported receiving personal fees from BioPharmaceuticals Research & Development during the conduct of the study. Dr Sabatine reported receiving institutional research grants to the TIMI Study Group at Brigham and Women’s Hospital during the conduct of the study from Amgen, AstraZeneca, Bayer, Daiichi Sankyo, Eisai, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, and Takeda; personal fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol Myers Squibb, CVS Caremark Consulting, DalCor, Dr. Reddy’s Laboratories, Dyrnamix, Esperion, IFM Therapeutics, Intarcia, Janssen Research and Development, Merck, Novartis, and The Medicines Company outside the submitted work; and being a member of the TIMI Study Group. Dr Wiviott reported receiving institutional research grants to the TIMI Study Group at Brigham and Women’s Hospital during the conduct of the study from AstraZeneca, Arena, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly, Janssen, Merck, and Sanofi-Aventis; receiving personal fees from Arena, AstraZeneca, Agerion, Allergan, Angelmed, Boehringer Ingelheim, Boston Clinical Research Institute, Bristol Myers Squibb, Daiichi Sankyo, Eisai, Eli Lilly and Company, Icon Clinical, Janssen, Lexicon, Merck & Co, Servier, St Judes Medical, and Xoma; having a spouse who is an employee of Merck outside the submitted work; and being a member of the TIMI Study Group. No other disclosures were reported.

Figures

Figure 1.. Kaplan-Meier Curves for Composite of Cardiovascular (CV) Death and Hospitalization for Heart Failure (HHF) and for Composite of Major Adverse Cardiovascular Events (MACE) Myocardial Infarction, Ischemic Stroke, and CV Death, Stratified by Treatment and Number of Markers of Chronic Kidney Disease (CKD)

Solid lines indicate treatment with placebo; dashed lines, treatment with dapagliflozin.

Figure 2.. Relative Effect of Dapagliflozin vs Placebo on Cardiovascular (CV) Events and Absolute Risk Difference Between Dapagliflozin and Placebo by Number of Markers of Chronic Kidney Disease

ACM indicates all-cause mortality; eGFR, estimated glomerular filtration rate (in units of mL/min/1.73 m2); HHF, hospitalization for heart failure; HR, hazard ratio; MACE, major adverse cardiovascular events; and UACR, urinary albumin to creatinine ratio (in units of mg/g).