Empagliflozin

Additional information

Studies indicate that men in the early middle age have a higher prevalence of type 2 diabetes mellitus compared with women in the same age group [1]. In Sweden, the age-standardized prevalence of pharmacologically and non-pharmacologically treated diabetes was 56% for men and 39% for women in 2012 [2].More men than women had heart failure in the Swedish population in 2021 across all age strata combined, 523 men and 346 women per 100 000 inhabitants. In the dominating age-span 80 years and older, the prevalence of heart failure was 3.1% among women and 4.9% among men [3]. Heart failure with preserved ejection fraction (HFpEF) is more common in women, while heart failure with reduced and mid-range ejection fraction are more common in men [4].In Sweden, men are almost twice  as likely to use sodium-glucose-cotransporter 2 (SGLT2) inhibitors compared to women, regardless of indication [5]. In a nationwide cohort study from the US, men and women with diabetes were as likely to start SGLT2 inhibitor treatment when initiating a glucose lowering medication [6].

Pharmacokinetics and dosing

A population pharmacokinetic analysis of empagliflozin was performed from phase I, II and III studies in 2761 individuals with type 2 diabetes mellitus. Compared to men, women had 11% lower clearance and approximately 10-15% higher AUC of empagliflozin [7].

Effects

More than 34.000 individuals with type 2 diabetes treated with SGLT2 inhibitors including empagliflozin, were included in a meta-analysis of randomized clinical trials [8]. The analysis reported an 11% risk reduction of a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction (MACE), a 23% risk reduction of a composite endpoint of cardiovascular death or hospitalization and a 45% risk reduction of renal disease progression. There were no indications that the levels of risk reduction relative to placebo differed between men and women. Similar findings were reported in a secondary analysis of the placebo-controlled EMPA-REG OUTCOME trial (5016 men, 2004 women) which showed that empagliflozin reduced MACE, hospitalization for heart failure and or incident or worsening nephropathy to a similar extent in men and women [9].A meta-analysis of clinical trials evaluated empagliflozin among individuals with heart failure with reduced ejection fraction (HFrEF), with or without diabetes type 2 [10]. First cardiovascular death or hospitalization for heart failure was studied across prespecified subgroups of patients. There were no indications that the levels of risk reduction relative to placebo differed between men and women, neither in pooled analyses (dapagliflozin + empagliflozin) nor among the 1426 men and 437 women exposed to empagliflozin [10].In a population exposure-response analyses of empagliflozin from Phase I, II and III studies of individuals type 2 diabetes mellitus, the maximum reduction of fasting plasma glucose (Gmax) was 11% lower in women than in men [7], whereas a similar study has reported a 12% higher Gmax in women than in men [11]. No clinically relevant difference between men and women was noted in urinary glucose excretion [11] or in terms of HbA1c reduction or other measures of efficacy [7].No differences in body weight, waist circumference, index of central obesity or visceral adiposity index between men and women with type 2 diabetes mellitus treated with empagliflozin were observed in analysis of data from five randomized placebo-controlled studies (1846 men, 1454 women) [12].

Adverse effects

SGLT2 inhibitor treatment was associated with similar relative risks in men and women for the safety outcomes of amputation, fracture, genital infection and urinary tract infection when analyzing data from four cardiovascular outcome trials [13]. Empagliflozin treatment has been associated with a 3-4 times increased incidence of mycotic genital infections (GMI) in both men and women, as compared to placebo. The population of interest has mainly been individuals with type 2 diabetes. Women are at a particular risk of this adverse event since their absolute risk of mycotic genital infections is markedly higher compared with men [9, 14] . In a meta-analysis of randomized clinical trials, GMI occurred among 3.1% (10 mg) and 1.6% (25 mg) in men, compared with 5.4% (10 mg) and 6.4% (25 mg) in women treated with empagliflozin [14]. The frequency of GMI among the placebo treated was 0.4% in men and 1.5% in women in pooled data of placebo-controlled clinical studies provided by the pharmaceutical company [15]. In a clinical setting the incidence of GMI associated with SGLT2 inhibitor treatment may be higher than numbers reported from clinical trials. For example, in a retrospective safety analysis of another SGLT2 inhibitor (dapagliflozin), the incidence of genital mycotic infection was around 13% among the treated women [16].In an observational study with data from UK primary care, genital infections that occurred within the first month of treatment were associated with a 50% increased risk for subsequent discontinuation with both SGLT2 inhibitors and DPP4 inhibitors [17].A population-based cohort study with new-user design evaluated the risk of diabetic ketoacidosis associated with SGLT2 inhibitors (122 281 men, 86 476 women), using health care data from Canada and the United Kingdom. Empagliflozin was associated with a 2.5 risk increase compared with DPP-4 inhibitors (121 991 men, 86 766 women) which served as reference. No difference in risk among men and women was shown [18].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).