Dapagliflozin

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].In Sweden, men are 80% more likely to use sodium-glucose-cotransporter 2 (SGLT2) inhibitors compared to women [3]. In a nationwide cohort study from the US, men and women were as likely to start SGLT2 inhibitor treatment when initiating a glucose lowering medication [4].

Pharmacokinetics and dosing

Pooled data from clinical pharmacology studies (349 men, 89 women) showed that women had a greater mean dapagliflozin AUC of 23%, even though Cmax was not increased [5]. In a population pharmacokinetic model (634 men, 619 women), mean dapagliflozin AUC at steady state was 22% higher in women than in men [5]. These differences have not been found to have any clinically relevant impact and therefore no dose adjustment has been considered necessary according to patient’s sex [6].

Data from three clinical studies of single-dose (2.5, 5 and 10 mg) orally administered dapagliflozin in both adult (39 men, 27 women) and pediatric (24 boys, 15 girls) patients with type 2 diabetes mellitus were analyzed to examine the relationship between dapagliflozin exposure and response. A comparable exposure-response relationship of dapagliflozin was found for both the adult and pediatric patients, and a patient's sex was identified as a significant covariate on dapagliflozin maximum effect (Emax) [7].

Effects

According to clinical studies performed by the original manufacturer, treatment with dapagliflozin as monotherapy and in combination with metformin, glimepiride, pioglitazone, sitagliptin, or insulin reduced HbA1c at week 24 compared to control in both men and women [6]. Pooled data from several phase III studies show minimal differences in efficacy between men and women (data not shown) [5]. However, Korean post-marketing surveillance data from a longitudinal prospective study on patients (982 men, 1025 women) with type 2 diabetes mellitus who were prescribed dapagliflozin (10 mg/day) showed a stronger HbA1c reduction in men compared to women [8].

The effects of SGLT2 inhibitors in type 2 diabetes in men and women were assessed in a study including the patients in the four cardiovascular outcome trials (EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI-58 and CREDENCE trials). There was no sex difference in the risk ratios, SGLT2 inhibitors vs control, for cardiovascular efficacy outcomes or death. In all the 4 trials included in the study there were fewer women than men: CANVAS Program 35.8% women, CREDENCE trial 33.9% women, EMPA-REG OUTCOME trial 28.8%, and DECLARE-TIMI-58 trial 37.4% [9].

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 [9].

Data from randomized placebo-controlled clinical trials report a higher frequency of genital mycotic infections and urinary tract infections in women than men treated with dapagliflozin. Genital mycotic infections incidence rates vary from 4.3-13.2% in women and 2.0-3.3% in men. Urinary tract infections incidence rates vary from 2.8-11.9% in women and 2.0-3.5% in men. The incidence of infections was not dose-related [10-16]. In the professional patient advice for dapagliflozin, it is stated that patients with a history of genital mycotic infections or uncircumcised males are at greater risk [6].

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 for diabetic ketoacidosis associated with SGLT-2 inhibitors (122 281 men, 86 476 women), using health care data from Canada and the United Kingdom. Dapagliflozin was associated with a 1.86 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].  

In a study assessing the safety of dapagliflozin in 5405 men and 3169 women, the frequencies of fractures and malignancies were balanced between the dapagliflozin and placebo patient group, and with no difference  found between men and women [19].

The incidence of reported episodes of atrial fibrillation and atrial flutter from high-risk patients with type 2 diabetes mellitus in the DECLARE-TIMI-58 trial was decreased by dapagliflozin treatment. No effect modification was seen by patient’s sex [20].

Reproductive health issues

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

Other information

An international randomized, double-blind, placebo-controlled Phase III study (100 men, 80 women) showed a greater decrease in total body weight in men (-2.8 kg) at 24 weeks with dapagliflozin compared to women (-1.2 kg) [11].