Empagliflozin in women with type 2 diabetes and cardiovascular disease – an analysis of EMPA-REG OUTCOME®
The global epidemic of type 2 diabetes affects women and men equally; however, the relative impact on the cardiovascular (CV) system appears greater for women than men when compared with peers without diabetes. Furthermore, women are often under-represented in CV outcome trials, resulting in less certainty about the impact of CV prevention therapies across the sexes. The EMPA-REG OUTCOME® trial, which included 28.5% women, found that empagliflozin, given in addition to standard of care, reduced the risk of CV death by 38%, heart failure (HF) hospitalisation by 35% and a composite endpoint for incident or worsening nephropathy by 39%. Here we report a secondary analysis of the trial to determine the relative effects of empagliflozin in women vs men.
The population studied were individuals with type 2 diabetes (HbA1c 53–86 mmol/mol [7–10%] and eGFR >30 ml min−1 [1.73 m]−2), with established atherosclerotic CV disease. Individuals were randomised to receive empagliflozin 10 mg or 25 mg, or placebo once daily in addition to standard of care, and followed. The trial continued until ≥691 individuals had experienced an adjudicated event included in the primary outcome. All CV outcome events, including HF hospitalisations and deaths were prospectively adjudicated by blinded clinical events committees.
At baseline, the demographic profile of the 2004 women (age ± standard deviation 63.6 ± 8.8 years) compared with the 5016 men (age 63.0 ± 8.6 years) in the trial was largely similar, with the exception that LDL-cholesterol was numerically higher in women (2.5 ± 1.0 vs 2.1 ± 0.9 mmol/l), consistent with lower rates of lipid-lowering therapies (75.4% vs 83.2%). Women were also less likely to have smoked (31.5% vs 69.9%). The annualised incidence rate for women in the placebo group was numerically lower than in men for CV death (1.58% vs 2.19%), numerically higher for HF hospitalisation (1.75% vs 1.33%) and similar for renal events (7.22% vs 7.75%). We did not detect any effect modification by sex within the statistical power restrictions of the analysis for CV death, HF hospitalisation and incident or worsening nephropathy (interaction p values 0.32, 0.20 and 0.85, respectively). Compared with placebo, empagliflozin increased the rates of genital infections in both women (2.5% vs 10.0%) and men (1.5% vs 2.6%).
CV death, HF hospitalisation and incident or worsening nephropathy rate reductions induced by empagliflozin were not different between women and men.
KeywordsCardiovascular disease Heart failure Mortality SGLT2 inhibition Type 2 diabetes Women
Angiotensin receptor blocker
Diastolic blood pressure
Modification of diet in renal disease
Systolic blood pressure
The authors thank the individuals who participated in this trial and I. Wiener and A. Elsaesser (Biostatistics and Data Sciences, Boehringer Ingelheim, Germany) for ADDPLAN post hoc power calculations.
All authors fulfil the International Committee of Medical Journal Editors (ICMJE) criteria for authorship, are fully responsible for all content and editorial decisions, were involved at all stages of manuscript development and have approved the final version. Representatives of Boehringer Ingelheim (UH, JTG, OEJ) were involved in the study design, collection, analysis and interpretation of data; writing the report and the decision to submit the report for publication. BZ is the guarantor of this work.
The EMPA-REG OUTCOME® trial was funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance.
Duality of interest
BZ has received research grants awarded to his institution from Boehringer Ingelheim, AstraZeneca and NovoNordisk (significant), honoraria from Janssen, Sanofi and Eli Lilly and Company (modest), and honoraria from Boehringer Ingelheim, NovoNordisk and Merck (significant). SEI reports honoraria from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eisai, Janssen, Intarcia Therapeutics, Inc., Novo Nordisk, Sanofi/Lexicon, vTv Therepeutics (modest). CW reports honoraria from Bayer, Boehringer Ingelheim, Janssen and Sanofi. UH, JTG and OEJ are employed by Boehringer Ingelheim. DF reports honoraria from Sanofi, Merck & Co., Amgen, AstraZeneca, Eli Lilly and Company (modest) and Boehringer Ingelheim (significant).
- 1.International Diabetes Federation (2015) IDF Diabetes Atlas (7th edition). Available from https://www.idf.org/e-library/epidemiology-research/diabetes-atlas/13-diabetes-atlas-seventh-edition.html. Accessed 20 Oct 2017
- 9.Johansson I, Dahlström U, Edner M, Näsman P, Rydén L, Norhammar A (2015) Risk factors, treatment and prognosis in men and women with heart failure with and without diabetes. Heart 101:1139–1148Google Scholar
- 10.Gopal DM, Kalogeropoulos AP, Georgiopoulou VV et al (2012) Cigarette smoking exposure and heart failure risk in older adults: the health, aging, and body composition study. Am Heart J 164:236–242Google Scholar