Dapagliflozin and new-onset type 2 diabetes in patients with chronic kidney disease or heart failure: pooled analysis of the DAPA-CKD and DAPA-HF trials.

Background: Chronic kidney disease and heart failure are insulin resistant states associated with a high incidence of diabetes. We assessed the effect of dapagliflozin on new-onset type 2 diabetes in a pooled analysis of patient-level data from the DAPA-CKD and DAPA-HF trials.
Methods: This study is a pooled analysis of individual participant data from two phase 3, randomised, double-blind, placebo-controlled, multicentre, clinical trials. Participants with no history of diabetes and HbA _1c less than 6·5% (48 mmol/mol) at baseline were included in this pooled analysis. New-onset type 2 diabetes was a prespecified exploratory endpoint in both DAPA-CKD and DAPA-HF trials and is the focus of this analysis. New-onset type 2 diabetes was identified by serial trial measurements of HbA _1c (two consecutive values ≥6·5% [≥48 mmol/mol]) or following a clinical diagnosis of diabetes between trial visits. Time to new-onset type 2 diabetes was analysed in a Cox proportional Hazards model from random assignment to end of treatment.
Findings: 4003 participants (1398 [34·9%] from the DADA-CKD trial and 2605 [65·1%] from the DAPA-HF trial) were included in our analysis: 1995 (49·8%) had received dapagliflozin and 2008 (50·2%) had received placebo. Over a median follow-up of 21·2 months (IQR 16·0 to 25·4), 126 (6·3%) of 2008 patients in the placebo group (event rate 3·9 per 100 patient-years) and 85 (4·3%) of 1995 patients in the dapagliflozin group (event rate 2·6 per 100 patient-years) developed type 2 diabetes (hazard ratio 0·67 [95% CI 0·51 to 0·88]; p=0·0040). There was no heterogeneity between studies (p interaction 0·77) and there was no clear evidence that the effect of dapagliflozin varied in prespecified subgroups including sex, age, glycaemic status, BMI, glomerular filtration rate, systolic blood pressure, and baseline cardiovascular medication use. More than 90% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA _1c 5·7% to 6·4% [39 to 46 mmol/mol]). Mean HbA _1c remained unchanged (placebo-adjusted change in the dapagliflozin group of -0·01% [95% CI -0·03 to 0·01], -0·1 mmol/mol [95% CI -0·3 to 0·1] at 12 months).
Interpretation: Treatment with dapagliflozin reduced the incidence of new-onset type 2 diabetes in participants with chronic kidney disease and HF without a reduction in HbA _1c .
Funding: AstraZeneca.
Competing Interests: Declaration of interests PR reports funding to his institution from AstraZeneca for participating in the steering committee for DAPA-CKD; has received funding to his institution for advisory boards from Sanofi Avensis and Boehringer Ingelheim; from Bayer, Gilead and Novo Nordisk for steering committees; from Novo Nordisk, Bayer and Eli Lilly for lectures; has received grants from Novo Nordisk; and has held stock in Novo Nordisk in the past 3 years. SEI received funding from AstraZeneca for participating in the steering committee for DAPA-HF; has received consultancy fees from Abbott, VTV Therapeutics, Esperion, Pfizer, and Merck; reports fees for clinical trial committee participation, advisory roles, and travel costs from Boehringer Ingelheim, AstraZeneca, and Novo Nordisk; and honoraria for lectures from Merck, and AstraZeneca. KFD received funding to the University of Glasgow, Glasgow, UK, from AstraZeneca for DAPA-HF; and has received honoraria for lectures from AstraZeneca and Eli Lilly. PSJ reports payment to the University of Glasgow by AstraZeneca for his time working on the DAPA-HF and DELIVER trials, from Novartis for work on the PARADIGM-HF and PARAGON-HF trials, and Novo Nordisk; reports Speakers and advisory board fees from AstraZeneca, Boehringer Ingelheim, and Novartis; and reports Research funding from Boehringer Ingelheim and Analog Devices. LK reports speakers honoriaria from Novo Nordisk, Novartis, AstraZeneca and Boehringer Ingleheim; support from AstraZeneca; and personal fees from Novartis and Bristol Myers Squibb as a speaker. MNK reports payment to his institution for participation in DAPA-HF; has received grant payment to his institution from Boehringer Ingelheim; has received personal fees or fees to his institution, or both, for consultancy from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck, Novo Nordisk, Sanofi, and Vifor Pharma; has received personal honoraria and honoraria to his institution for lectures from AstraZeneca, Boeringer Ingelheim, and Novo Nordisk; has received personal honoraria and honoraria to his institution from Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, Sanofi, and Vifor Pharma for participation on DSMB for advisory boards; and has received study drug for a clinical trial from AstraZeneca and Boehringer Ingelheim. FAM reports personal fees from AstraZeneca. PP reports personal fees for consultancy and speakers bureau from AstraZeneca, Boehringer Ingelheim, Vifor Pharma, Servier, Bayer, Bristol Myers Squibb, Respocardia, Berlin-Chemie, Cibiem, Novartis and RenalGuard; other support for participation in clinical trials from Boehringer Ingelheim, Amgen, Vifor Pharma, Bayer, Bristol Myers Squibb, Cibiem, Novartis and RenalGuard; and research grants to his institution from Vifor Pharma. MSS reports grants from Bayer, Daiichi Sankyo, Eisai, GlaxoSmithKline, Pfizer, Poxel, Quark Pharmaceuticals, and Takeda; grants and personal fees from Amgen, AstraZeneca, Intarcia, Janssen Research and Development, The Medicines Company, MedImmune, Merck, and Novartis; and personal fees from Anthos Therapeutics, Bristol Myers Squibb, CVS Caremark, DalCor, Dyrnamix, Esperion, IFM Therapeutics, and Ionis. MSS received an institutional research grant from AstraZeneca for DAPA-HF; received institutional research grants from Abbott, Amgen, Anthos Therapeutics, Bayer, Daiichi-Sankyo, Eisai, Intarcia, IONIS, The Medicines Company, MedImmune, Merck, Novartis, Pfizer, and Quark Pharmaceuticals; received consulting fees from Althera, Amgen, Anthos Therapeutics, AstraZeneca, Bristol-Myers Squibb, CVS Caremark, DalCor, Dr Reddy's Laboratories, Fibrogen, IFM Therapeutics, Intarcia, MedImmune, Merck, Moderna, and Novo Nordisk; MSS is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women's Hospital from Regeneron, Roche, and Zora Biosciences. SDS received payment to his institution for participation in DAPA-HF; received grants to his institution from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, IONIS, Lilly, Mesoblast, MyoKardia, National Institutes of Health National Heart, Lung, and Blood Institute, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, and US2.AI; received fees for consultancy from Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer-Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta; and received honoraria for lectures from Novartis and AstraZeneca. DLD received funding from AstraZeneca for participating in the steering committee for DAPA-HF; reports consulting fees from AstraZeneca, Frontier Science − Madison Office, and 3D Communication; receives royalties or licenses for Fundamentals of Clinical Trials, Data Monitoring Committees: Practical Perspective, Data Monitoring Committees: A Case Studies Approach, and Statistical Methods for Clinical Trials; has received honoraria for lectures from Vanderbilt University, Nashville, TN, USA, and Harvard University, Cambridge, MA, USA: CME Course on Clinical Trials; and honoraria for participation on data safety monitoring board or advisory boards for Patient Centered Outcome Research Institute, Bristol Meiers Squibb, Sanifit, Tricidia, Boston Scientific, Actelion, Medtronic, Duke University, Lisa Nova, Mesoblast, GlaxoSmithKline, DalCor, and Cardiovascular Research Foundation. OB, ML, AML, MS, BVS, and CK are employees and stockholders of AstraZeneca. GMC received funding from AstraZeneca for participating in the steering committee for DAPA-CKD; has received research support from Amgen; data safety monitoring board participation for Bayer and ReCor; is on the board of directors for Satellite Healthcare; has participated on trial steering committees for Akebia, Gilead, Sanifit, Vertex; and holds stock in Ardelyx, loudCath, Durect, DxNow, Micromatrix, Outset, and Unicycive. FFH is a member of the DAPA-CKD study executive committee and is a study investigator and reports personal fees from Abbvie. RC-R received funding from AstraZeneca for participating in the steering committee for DAPA-CKD; received research grants from GlaxoSmithKline, and Novo Nordisk; has received consulting fees from Boehringer Ingleheim and Chinook; and honoraria for advisory boards or lectures from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Janssen, and Novo Nordisk. RDT received funding from AstraZeneca for participating in the steering committee for DAPA-CKD; has received fees for consultancy from Boehringer Ingelheim, Reata Pharma, and Chinook Pharma. received honoraria for lectures from Medscape and Medical Education Resources; and participated in data safety monitoring boards or advisory boards for Bayer, Viofor, Akebia, and Otsuka. DCW provides ongoing consultancy services to AstraZeneca; has received fees for data safety monitoring board or advisory board activity from Zydus and Gilead; and received personal fees from Bayer, Boehringer Ingelheim, Astellas, GSK, Janssen, Napp, Mundipharma, Vifor, TRicida, Zydus, and Amgen. JJVM reports payment to Glasgow University by AstraZeneca for time spent as principal investigator of DAPA-HF and co-principal Investigator of DELIVER and DETERMINE in heart failure and meetings and other activities related to these trials; AstraZeneca has also paid travel and accommodation for these meetings. These payments were made through a consultancy with Glasgow University and he did not receive personal payments in relation to this trial or drug; has received personal lecture fees from Abbott, Alkem Metabolics, Eris Lifesciences, Hikma, Lupin, Sun Pharmaceuticals, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Servier, and the Corpus; and reports steering committee and travel fees from Cytokinetics, advisor and travel fees from KBP Biosciences; steering committee and travel fees from Amgen, steering committee fees from Bayer, investigator and travel fees from Theracos, consultantcy and travel fees from IONIS, steering committee fees from DalCor, investigator, steering committee, and travel fees from Novartis, investigator, steering committee, and travel fees from GlaxoSmithKline, steering committee fees from Bristol Myers Squibb, consultantcy fees from Boehringer Ingelheim, advisory board fees from Cardurion, and advisory board fees from Alnylam all paid to the University of Glasgow. HJLH reports grant funding and honoraria for consultancy as a member of the steering committee of the DAPA-CKD trial paid to their institution from AstraZeneca; research grants paid to his employer from AstraZeneca, Boehringer Ingelheim, Janssen, and Novo Nordisk for clinical trials; consulting fees, paid to his employer from Abbvie, Boehringer Ingelheim, Travere Pharmaceuticals, and Novo Nordisk; fees for steering committee membership paid to his employer from Bayer, Chinook, CSL Pharma, Janssen, and Gilead; honoraria for lectures from AstraZeneca and Mitsubishi Tanabe; and has received honoraria for advisory board participation for Merck (paid to his employer), Mitsubishi Tanabe, and Mundipharma. All other authors declare no competing interests.
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