Dapagliflozin

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 as main diagnosis 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. Women with heart failure are generally older than men. However, the accuracy of data is somewhat inadequate due to risk of underreporting of the diagnosis [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 the adult Swedish population, 7% of the women and 5% of the men are diagnosed with chronic kidney disease (CKD) stage 3-5 [5]. Women are overrepresented among the milder stages of CKD, whereas men are overrepresented in terminal kidney disease [6].In Sweden, men are almost twice as likely to use sodium-glucose-cotransporter 2 (SGLT2) inhibitors compared to women, regardless of indication [7]. 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 [8].

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 [9]. In a population pharmacokinetic model (634 men, 619 women), mean dapagliflozin AUC at steady state was 22% higher in women than in men [9].

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., Patient’s sex was identified as a significant predictor for dapagliflozin maximum effect (Emax) [10]. No dose adjustment has been considered necessary according to patient’s sex [11].

Effects

More than 34.000 individuals with type 2 diabetes treated with SGLT2 inhibitors including dapagliflozin, were included in a meta-analysis of randomized clinical trials [12]. 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 [12]. 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% [13].A meta-analysis of clinical trials evaluated dapagliflozin among individuals with heart failure with reduced ejection fraction (HFrEF), with or without diabetes type 2 [14]. 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 1809 men and 564 women exposed to dapagliflozin [14].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 [11]. Pooled data from several phase III studies show minimal differences in efficacy between men and women (data not shown) [9]. 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 [15].

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]. Dapagliflozin 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 [16]. In a meta-analysis of randomized controlled trials, GMI occurred among 2.8% (5 mg) and 2.7% (10 mg) in men, compared with 8.4% (5 mg) and 6.9% (10 mg) in women treated with dapagliflozin [16]. In other randomized controlled trials, the incidence rates of GMI vary from 4.3-13.2% in women and 2.0-3.3% in men treated with dapagliflozin. 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 [17-22]. In the professional patient advice for dapagliflozin, it is stated that patients with a history of GMI or uncircumcised males are at greater risk [11]. In a clinical setting the incidence of GMI associated with SGLT2 inhibitor treatment may be higher than reported from clinical trials. For example, in a retrospective safety analysis of dapagliflozin, the incidence of GMI was around 13% [22].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 [23]. 

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. 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 [24].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 [25].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 [26].

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) [19].