Empagliflozin

Additional information

For type 1 diabetes mellitus when diagnosed under the age of 15, the prevalence between boys and girls is similar. In adult populations of patients with both type 1 and 2 diabetes, the differences between the sexes in prevalence seem to vary depending on several factors such as incidence of disease, age groups and ethnicities studied.  Studies indicate that men in the early middle age display a higher prevalence of type 2 diabetes mellitus compared with women in the same age group [1]. In a nationwide population-based pharmaco-epidemiological study in Sweden, the total age-standardized prevalence of pharmacologically and non-pharmacologically treated diabetes (2012) was 56% for men and 39% for women [2].

Pharmacokinetics and dosing

A population pharmacokinetic analysis of empagliflozin was performed from phase I, II and III studies in 2761 persons with type 2 diabetes mellitus. Compared to men, women had 11% lower clearance and approximately 10-15% higher AUC of empagliflozin [5].

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 [6]. 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 [7].

A meta-analysis of clinical trials evaluated empagliflozin among individuals with heart failure with reduced ejection fraction (HFrEF), with or without diabetes type 2 [8]. 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 [8].

In a population exposure-response analyses of empagliflozin from Phase I, II and III studies in persons with type 2 diabetes mellitus, the maximum reduction of fasting plasma glucose (Gmax) was 11% lower in women than in men [5], whereas a similar study has reported a 12% higher Gmax in women than in men [9]. No clinically relevant difference between men and women was noted in urinary glucose excretion [9] or in terms of HbA1c reduction or other measures of efficacy [5].

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) [10].

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 [11].

Empagliflozin treatment has been associated with increased incidence of genital infections in both men and women, as compared to placebo [5, 7]. In a meta-analysis of randomized clinical trials genital mycotic infections (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 [12]. The frequency of GMI among the placebotreated were 0.4% in men and 1.5% in women in pooled data of placebo-controlled clinical studies provided by the pharmaceutical company [13].

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 [14].

A population-based cohort study with new-user design evaluated the risk for 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 [15].

Reproductive health issues

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