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

Diabetologia (2021)Cite this article

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

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

US$ 39.95

Tax calculation will be finalised during checkout.

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

References

  1. 1.

    Zelniker TA, Wiviott SD, Raz I et al (2019) SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 393(10166):31–39. https://doi.org/10.1016/S0140-6736(18)32590-X

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    McMurray JJV, Solomon SD, Inzucchi SE et al (2019) Dapagliflozin in Patints with Heart Failure and Reduced Ejection Fraction. N Engl J Med 381(21):1995–2008. https://doi.org/10.1056/NEJMoa1911303

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Packer M, Anker SD, Butler J et al (2020) Cardiovascular and Renal Outcomes with Empagliflozin in Heart Failure. N Engl J Med 383:1413–1424. https://doi.org/10.1056/NEJMoa2022190

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Gouni-Berthold I, Berthold HK, Mantzoros CS, Bohm M, Krone W (2008) Sex disparities in the treatment and control of cardiovascular risk factors in type 2 diabetes. Diabetes Care 31(7):1389–1391. https://doi.org/10.2337/dc08-0194

    Article  PubMed  PubMed Central  Google Scholar 

  5. 5.

    Wiviott SD, Raz I, Bonaca MP et al (2019) Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes. N Engl J Med 380(4):347–357. https://doi.org/10.1056/NEJMoa1812389

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Wiviott SD, Raz I, Bonaca MP et al (2018) The design and rationale for the Dapagliflozin Effect on Cardiovascular Events (DECLARE)-TIMI 58 Trial. Am Heart J 200:83–89. https://doi.org/10.1016/j.ahj.2018.01.012

    CAS  Article  PubMed  Google Scholar 

  7. 7.

    Cahn A, Raz I, Bonaca M et al (2020) Safety of dapagliflozin in a broad population of patients with type 2 diabetes: Analyses from the DECLARE-TIMI 58 study. Diabetes Obes Metab 22(8):1357–1368. https://doi.org/10.1111/dom.14041

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Sarma AA, Braunwald E, Cannon CP et al (2019) Outcomes of Women Compared With Men After Non-ST-Segment Elevation Acute Coronary Syndromes. J Am Coll Cardiol 74(24):3013–3022. https://doi.org/10.1016/j.jacc.2019.09.065

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Zinman B, Inzucchi SE, Wanner C et al (2018) Empagliflozin in women with type 2 diabetes and cardiovascular disease - an analysis of EMPA-REG OUTCOME(R). Diabetologia 61(7):1522–1527. https://doi.org/10.1007/s00125-018-4630-2

    Article  PubMed  Google Scholar 

  10. 10.

    Neal B, Perkovic V, Mahaffey KW et al (2017) Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med 377(7):644–657. https://doi.org/10.1056/NEJMoa1611925

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Perkovic V, Jardine MJ, Neal B et al (2019) Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med 380(24):2295–2306. https://doi.org/10.1056/NEJMoa1811744

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Ptaszynska A, Johnsson KM, Parikh SJ, de Bruin TW, Apanovitch AM, List JF (2014) Safety profile of dapagliflozin for type 2 diabetes: pooled analysis of clinical studies for overall safety and rare events. Drug Saf 37(10):815–829. https://doi.org/10.1007/s40264-014-0213-4

    CAS  Article  PubMed  Google Scholar 

  13. 13.

    Zinman B, Wanner C, Lachin JM et al (2015) Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N Engl J Med 373(22):2117–2128. https://doi.org/10.1056/NEJMoa1504720

    CAS  Article  PubMed  Google Scholar 

  14. 14.

    Cannon CP, Pratley R, Dagogo-Jack S et al (2020) Cardiovascular Outcomes with Ertugliflozin in Type 2 Diabetes. N Engl J Med 383(15):1425–1435. https://doi.org/10.1056/NEJMoa2004967

    CAS  Article  PubMed  Google Scholar 

Download references

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.

Author information

Affiliations

  1. TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA

    Michelle L. O’Donoghue, Sabina A. Murphy, Deepak L. Bhatt, Marc S. Sabatine & Stephen D. Wiviott

  2. Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Eri T. Kato

  3. Diabetes Unit, Hadassah Hebrew University Hospital, Jerusalem, Israel

    Ofri Mosenzon, Avivit Cahn & Itamar Raz

  4. Torre Medica Providencia, Guadalajara, Mexico

    Marisol Herrera

  5. Department of Endocrinology, Medical University, Sofia, Bulgaria

    Tsvetalina Tankova

  6. Faculty Hospital Hradec Kralove, Hradec Kralove, Czech Republic

    Alena Šmahelová

  7. 2nd Division of Cardiology, Ca’ Granda Niguarda Hospital, Milan, Italy

    Piera Merlini

  8. BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden

    Ingrid Gause-Nilsson & Anna Maria Langkilde

  9. Division of Cardiology, University of Texas Southwestern Medical Center, and Parkland Health and Hospital System, Dallas, TX, USA

    Darren K. McGuire

  10. Institute of Ageing and Chronic Disease, University of Liverpool, Liverpool, UK

    John P. H. Wilding

  11. Li Ka Shing Knowledge Institute, St Michael’s Hospital, University of Toronto, Toronto, ON, Canada

    Larry A. Leiter

  12. Cardiovascular Division, Brigham and Women’s Hospital, Boston, MA, USA

    Deepak L. Bhatt

Authors
  1. Michelle L. O’Donoghue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eri T. Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ofri Mosenzon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Sabina A. Murphy
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Avivit Cahn
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Marisol Herrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tsvetalina Tankova
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alena Šmahelová
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Piera Merlini
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ingrid Gause-Nilsson
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Anna Maria Langkilde
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Darren K. McGuire
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. John P. H. Wilding
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Larry A. Leiter
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Deepak L. Bhatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Itamar Raz
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Marc S. Sabatine
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Stephen D. Wiviott
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

ESM 1

(PDF 142 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

Keywords

  • Cardiovascular outcomes
  • Clinical trials
  • SGLT2 inhibitors
  • Women