The efficacy and safety of dapagliflozin in women and men with type 2 diabetes mellitus

Abstract

Aims/hypothesis

Women remain underrepresented in clinical trials and those with type 2 diabetes mellitus are at high risk for cardiovascular (CV) events. The sodium–glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin reduces the risk of CV death or heart failure hospitalisations in individuals with type 2 diabetes. Here, we performed a pre-specified analysis to examine whether sex modifies these effects.

Methods

The DECLARE-TIMI 58 trial randomised 17,160 patients with type 2 diabetes with or at risk for atherosclerotic disease to dapagliflozin or placebo (median follow-up 4.2 years). The dual efficacy outcomes were CV death or heart failure hospitalisations, and major adverse cardiovascular events (MACE; CV death, myocardial infarction or ischaemic stroke). The renal-specific composite outcome was a sustained ≥40% drop in eGFR to <60 ml min−1 [1.73 m]−2, new end-stage renal disease or renal death. Cox models were run separately by sex with treatment-by-sex interaction testing for each outcome.

Results

At baseline, women (n = 6422, 37.4%) had higher HbA1c, longer type 2 diabetes duration, and were on fewer glucose-lowering medications. There was no evidence of modification of the effect of dapagliflozin by sex for (1) CV death or heart failure hospitalisations: women (3.8% vs 4.5%; HR 0.84, 95% CI 0.66, 1.07) and men (5.3% vs 6.4%; HR 0.83, 95% CI 0.71, 0.96; pinteraction = 0.90); (2) MACE: women (6.3% vs 6.8%; HR 0.93, 95% CI 0.77, 1.12) and men (10.0% vs 10.7%; HR 0.93, 95% CI 0.83, 1.05; pinteraction = 0.99); or (3) renal-specific composite: women (1.4% vs 2.8%; HR 0.50, 95% CI 0.35, 0.70) and men (1.5% vs 2.5%; HR 0.55, 95% CI 0.42, 0.73; pinteraction = 0.64). The overall safety profile of dapagliflozin was similar for women and men.

Conclusions/interpretation

Dapagliflozin offers comparable CV and renal benefits and a comparable safety profile in women and men.

Funding

AstraZeneca.

Trial registration

clinicaltrials.gov NCT01730534.

Graphical abstract

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Fig. 1
Fig. 2

Data availability

The data will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. However, we encourage parties interested in collaboration and data sharing to contact the corresponding author directly for further discussions.

Abbreviations

ASCVD:

Atherosclerotic cardiovascular disease

CV:

Cardiovascular

DKA:

Diabetic ketoacidosis

DPP-4:

Dipeptidyl peptidase-4

ESRD:

End-stage renal disease

GLP1-RA:

Glucagon-like peptide 1 receptor agonists

HF:

Heart failure

HHF:

Heart failure hospitalisation

LSM:

Least-squares mean

MACE:

Major adverse cardiovascular events

SAE:

Serious adverse events

SGLT2:

Sodium–glucose cotransporter 2

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Data availability

The data will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. However, we encourage parties interested in collaboration and data sharing to contact the corresponding author directly for further discussions.

Funding

The DECLARE-TIMI 58 trial was sponsored by AstraZeneca. The study sponsor was not involved in writing the first draft of the report; had the ability to provide non-binding comments and could not impose any restrictions regarding the publication of the report.

Authors’ relationships and activities

MLOD has received grant funding via Brigham and Women’s Hospital from AstraZeneca, Medimmune, Amgen, Janssen, GlaxoSmithKline, Intarcia and Novartis/Medicines Company; she has received consulting fees from Amgen, AstraZeneca/Medimmune, Novartis, Janssen and CRICO. ETK reports lecture fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, MSD KK, Tanabe-Mitsubishi Pharma and Ono Pharmaceutical and Bayer and a grant from Ono Pharmaceutical. SAM reports institutional research grants to the TIMI Study Group at Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, Aralez, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Daiichi-Sankyo, Eisai, Intarcia, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc., Roche, Siemens Healthcare Diagnostics, Inc., Takeda, The Medicines Company, Zora Biosciences. DLB discloses the following relationships: member of the advisory board for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma and Regado Biosciences; member of the board of directors for: Boston VA Research Institute, Society of Cardiovascular Patient Care and TobeSoft; Chair for the American Heart Association quality oversight committee; member of the following 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; received honoraria from: 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, 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 co-leader, 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); received research funding from: Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, The Medicines Company; received royalties from: Elsevier (Editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease); site co-investigator at: Biotronik, Boston Scientific, CSI, St Jude Medical (now Abbott), Svelte; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Merck, Novo Nordisk, Takeda. LAL reports grants and personal fees from AstraZeneca, grants and personal fees from Boehringer Ingelheim, grants and personal fees from Eli Lilly, grants and personal fees from Janssen, personal fees from Merck, grants and personal fees from Novo Nordisk, grants and personal fees from Sanofi, personal fees from Servier, and grants from GSK and Lexicon. DKM has received honoraria for clinical trial leadership from AstraZeneca, Boehringer Ingelheim, Eisai, Esperion, GlaxoSmithKline, Janssen, Lexicon, Merck Sharpe & Dohme Corp., Merck & Co., Inc., Novo Nordisk, Sanofi, Pfizer Inc., and has received consultancy fees from Afimmune, Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Lilly, Merck & Co., Inc., Novo Nordisk, Metavant, and Sanofi. IGN and AML are AstraZeneca employees. TT is a member of an advisory board for and has received speaking fees from Boehringer Ingelheim, Astra Zeneca, Novo Nordisk, Eli Lilly, Sanofi, Servier and MSD. AC reports grants and personal fees from AstraZeneca and Novo Nordisk and personal fees from Abbott, Eli Lilly, Sanofi, Boehringer Ingelheim, Merck Sharp & Dohme, Medial Early-Sign and GlucoMe. MSS received research grant support through Brigham and Women’s Hospital from: Amgen; Anthos Therapeutics, Inc.; AstraZeneca; Daiichi-Sankyo; Eisai; Intarcia; Medicines Company; MedImmune; Merck; Novartis; Pfizer and has undertaken consultancy for: Althera; Amgen; Anthos Therapeutics; AstraZeneca; Intarcia; Merck.

Funding

The DECLARE-TIMI 58 trial was sponsored by AstraZeneca. The study sponsor was not involved in writing the first draft of the report; had the ability to provide non-binding comments and could not impose any restrictions regarding the publication of the report.

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All authors contributed to the analysis and interpretation of data, provided critical revisions for important intellectual content and gave final approval of the version to be published. MLOD drafted the manuscript and takes full responsibility for the work as a whole, including the current study design, access to data and the decision to submit and publish the manuscript.

Corresponding author

Correspondence to Michelle L. O’Donoghue.

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O’Donoghue, M.L., Kato, E.T., Mosenzon, O. et al. The efficacy and safety of dapagliflozin in women and men with type 2 diabetes mellitus. Diabetologia (2021). https://doi.org/10.1007/s00125-021-05399-2

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Keywords

  • Cardiovascular outcomes
  • Clinical trials
  • SGLT2 inhibitors
  • Women