Sodium glucose co-transporter-2 (SGLT-2) inhibitors are recommended as mono- or combined therapy in the management of type 2 diabetes. A recent large multi-center randomized trial showed reduction in the cardiovascular adverse outcomes with empagliflozin, compared with placebo [1]. On subgroup analysis by gender, the risk of all-cause mortality, and cardiovascular mortality appeared to be reduced only in men [1]. In addition, some studies had suggested possible gender differences in the risk of cardiovascular events in patients with type 2 diabetes [2, 3]. Therefore, we aimed to explore the impact of gender on the cardiovascular benefits observed with SGLT-2 inhibitors in type 2 diabetes.


A detailed explanation of the methods was discussed in a prior publication [4]. A comprehensive search of the MEDLINE, CENTRAL, Web of Science, Embase and databases was conducted without language restrictions from inception until July 2016 for randomized trials that compared SGLT-2 inhibitors with placebo in patients with type 2 diabetes, and reported cardiovascular outcomes. The outcomes of interest were all-cause mortality, and cardiovascular mortality. Two parallel teams of reviewers independently collected the data of interest. Any inconsistencies were resolved by consensus. A weighted estimate of the overall percentage of women in the SGLT-2 inhibitors arm was calculated with 95% confidence interval (CI). Intention to treat summary odds ratios (OR) were calculated with P values of <0.05 and 95% CI for statistical significance by the Peto method, given the paucity of events. Heterogeneity was assessed by I 2 statistic test, where values <25%, 25–50% and >50% were corresponding to low, moderate and high degrees of heterogeneity, respectively. Random effects meta-regression was conducted to explore the gender effect using the percentage of women included in the SGLT-2 inhibitor arm of each trial with a P value of <0.1 for statistical significance. Trials with zero events in either arm were excluded from the meta-regression analysis. A subgroup analysis was also performed according to the percentage of females in the treatment arm of each trial, with a cut level of 50%. All analyses were conducted using STATA version 14 (STATA Corporation; College Station, Texas, USA).

This article is based on previously conducted studies and does not involve any new studies of human or animal subjects performed by any of the authors.


A total of 22,256 patients from 26 trials were included. The overall percentage of women in SGLT-2 inhibitors arm was 58% (95% CI 54–62%). The overall incidence of all-cause mortality (OR = 0.72, 95% CI 0.60-0.86, P < 0.001, I 2 = 0%), and cardiovascular mortality (OR = 0.67, 95% CI 0.53–0.84, P = 0.001, I 2 = 23%) were lower with SGLT-2 inhibitors compared with placebo. Meta-regression analysis for trials reporting at least one event in either arm suggested a possible incremental increase in the OR for all-cause mortality and cardiovascular mortality as the percentage of women in the SGLT-2 inhibitor arm increased (P = 0.07 and 0.08, respectively) (Fig. 1). A subgroup analysis according to the percentage of females included in each trial illustrated a significant reduction in all-cause mortality when the percentage of females was ≤50% (OR = 0.70, 95% CI 0.60–0.84, P < 0.001, I 2 = 0%) but not when it was >50% (OR = 1.07, 95% CI 0.40–2.87, P = 0.90, I 2 = 0%). The same was true for cardiovascular mortality (OR = 0.66, 95% CI 0.53–0.81, P < 0.001, I 2 = 0% versus OR = 1.72, 95% CI 0.37–8.06, P = 0.49, I 2 = 0%, respectively).

Fig. 1
figure 1

Random effect meta-regression analysis of all-cause mortality (a) and cardiovascular mortality (b) odds ratio with SGLT-2 inhibitors according to the mean percentage of females in each trial. CI confidence interval, SGLT-2 sodium glucose co-transporter-2. * A total of 26 trials reported all-cause mortality and 14 trials reported cardiovascular mortality


This meta-regression and subgroup analysis of 26 randomized trials demonstrated a possible gender influence on the cardiovascular benefits observed with SGLT-2 inhibitors, with an incremental decrement in benefit as the percentage of women included in the SGLT-2 inhibitor arm was higher. Although EMPA-REG OUTCOME trial showed a significant reduction in adverse cardiovascular outcomes with empagliflozin, approximately 70% of the patients were men [1]. A subgroup analysis of EMPA-REG OUTCOME trial suggested that there might be possible gender differences: hazard ratio (HR) 0.62, 95% CI 0.50–0.77 in men, versus HR 0.91, 95% CI 0.63–1.32 in women for all-cause mortality [5]. These speculations are further supported by our analysis. Experimental animal studies had suggested that the expression of SGLT-2 co-transported protein and SGLT-2 inhibitors metabolism are different in males compared with females [6]; however, these findings were not supported in human studies [7]. Some studies have shown that cardiovascular morbidity and mortality are more pronounced in diabetic women compared with men, despite adherence to the guideline recommended therapies, as a result of the higher risk factor profile and increased atherogenic potential in women [2, 3].


In conclusion, gender might influence the cardiovascular benefits observed with SGLT-2 inhibitors in patients with type 2 DM. Future randomized trials are required to confirm these findings.