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.

2nd Division of Cardiology Ca' Granda Niguarda Hospital Milan Italy

BioPharmaceuticals R and D AstraZeneca Gothenburg Sweden

Cardiovascular Division Brigham and Women's Hospital Boston MA USA

Department of Cardiovascular Medicine Kyoto University Graduate School of Medicine Kyoto Japan

Department of Endocrinology Medical University Sofia Bulgaria

Diabetes Unit Hadassah Hebrew University Hospital Jerusalem Israel

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

Faculty Hospital Hradec Kralove Hradec Kralove Czech Republic

Institute of Ageing and Chronic Disease University of Liverpool Liverpool UK

Li Ka Shing Knowledge Institute St Michael's Hospital University of Toronto Toronto ON Canada

TIMI Study Group Cardiovascular Division Brigham and Women's Hospital Boston MA USA

Torre Medica Providencia Guadalajara Mexico

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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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI PMC

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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 PubMed DOI

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