Sitagliptin

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

Clinical studies have shown no pharmacokinetic differences between men and women of single- or multiple-dose sitagliptin [3, 4]. According to the original manufacturer, no clinically relevant pharmacokinetic sex differences have been shown [5].

In a Japanese retrospective cohort study (in total 87 678 patients), dose levels of sitagliptin were compared before and after the safety alert on the risk of serious hypoglycemic events with the combination sitagliptin and high-dose sulfonylureas. Women were prescribed lower mean daily doses of sitagliptin both before and after the safety alert (before; women : 59.6 ± 21.8 mg, men: 63.4 ± 24.4 mg, after; women: 57.2 ± 20.1 mg, men: 61.6 ± 23.7 mg) [6]. However, the original manufacturer does not recommend any dose adjustment based on patient’s sex [5].

Effects

 A placebo-controlled trial assessed the effect of sitagliptin treatment on cardiovascular (CV) outcomes in a prospective study in patients with type 2 diabetes and atherosclerotic vascular disease (10 374 men, 4297 women), the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) [7]. Sex differences in management and outcomes of the TECOS trial were analyzed [8]. The primary composite outcome of CV death, myocardial infarction, stroke, or hospitalization for unstable angina occurred in 418 women (9.7%) and 1272 men (12.3%; 3.48 vs 4.38 events/100 participant-years, adjusted HR 0.64, 95% CI 0.55-0.74). Women also had a significantly lower risk of secondary CV outcomes and all-cause death (1.58 vs 1.74 events/100 participant-years [adjusted HR 0.55, 95% CI 0.42-0.71) and all-cause death (2.18 vs 2.56 events/100 participant-years, adjusted HR 0.54, 95% CI 0.43-0.67) [8]. Differences in baseline characteristics of patients enrolled in the TECOS trial [7] was examined (10416 men, 4308 women). The prespecified clinical target goals in baseline characteristics were chosen to reflect those consistent with international guidelines at the time of the trial’s inception. The results showed that women were consistently less likely to reach the prespecified treatment target goals assessed at the time of study enrollment (SBP<140 mmHg, DBP<80 mmHg, LDL cholesterol <2.6 mmol/L, aspirin use, and statin use), with the exception of non-smoking status [9].

The effect on metabolic control and on CV risk evolution obtained by “add-on” persistent sitagliptin treatment (100 mg once daily) in a cohort of Italian participants with type 2 diabetes was assessed using the UK Prospective Diabetes Study (UKPDS) Risk Engine (RE). Analysis of sex differences in CV risk evolution evaluated by UKPDS RE (106 men, 64 women) showed a significantly lower CV risk in women (1.33 in men vs 1.12 in women in UKPDS after 48 months) [10].

A post-hoc analysis of pooled data from seven sitagliptin phase II and III clinical trials exploring the factors associated with the glucose-lowering efficacy of sitagliptin treatment in Japanese patients with type 2 diabetes (698 men, 370 women) showed no association between HbA1c changes and patient’s sex [11].

Adverse effects

A study evaluated the relative risk of hypoglycemic events in patients (691 men, 481 women) treated with sitagliptin or glipizide after adjusting for the most recently measured HbA1c value. The adjusted hazard ratio for women on either of the two studied drugs was 2.05, indicating that women had a twofold increase in risk of experiencing confirmed hypoglycemia relative to men. In multivariate analysis, female sex was one of the factors associated with a higher risk of hypoglycemia [12].

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 (SGLT2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors was evaluated in an observational study from Taiwan. The subgroup analysis showed a lower risk of incident atrial fibrillation for SGLT2 inhibitors (9091 men, 6515 women) versus DPP-4 inhibitors (6911 men, 5472 women) in women compared to men with type 2 diabetes (HR men 0.51, HR women 0.70, p interaction =0.10) [13].

The fracture incidence among participants (10374 men, 4297 women) in the TECOS trial [7] was examined [14]. Although sitagliptin, compared with placebo, was not associated with a higher fracture risk (HR 1.03), adjusted analyses showed a significantly independently increased fracture risk in women (HR 1.95) [14].

A study with data on sitagliptin ever and never users (93858 men, 77860 women) derived from the Taiwan’s National Health Insurance evaluated the risk of heart failure hospitalization. Male sex was significantly associated with a higher risk of heart failure hospitalization in patients ever treated with sitagliptin (HR 1.033 men vs women) [15].

Reproductive health issues

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

Other information (utelämna om inte tillämpligt)

Data from the Italian Medicines Agency (AIFA) Monitoring Registry on drug utilization, safety and effectiveness of exenatide, sitagliptin, and vildagliptin showed that the risk of treatment discontinuation of sitagliptin was lower in men than women (20446 men, 18365 women). The authors discuss the relationship between discontinuation rates and adverse effects such as hypoglycemia [16].

An Italian multicenter, case-control, retrospective observational study investigated the effect of sitagliptin as an add-on treatment to standard care insulin administration in patients with type 2 diabetes who were hospitalized with COVID-19 (238 men, 100 women). A time to clinical endpoint subgroup analysis comparing men versus women in the sitagliptin-treated group as compared with those in the standard-of-care group did not show any difference in the clinical outcomes within the group of treatment (HR men 0.44, HR women 0.42) [17].