Vildagliptin

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

In an open, parallel-group, clinical study, young and elderly healthy volunteers (20 men, 20 women) received a single dose of 100 mg vildagliptin. No clinically relevant differences in pharmacokinetic parameters were observed between men and women [3-5]. No dose adjustment based on patient’s sex is necessary [6].

Effects

Vildagliptin inhibits the enzyme dipeptidyl-peptidase-4 (DDP-4), which increases endogenous levels of incretin hormones, resulting in improved glucose-dependent insulin secretion. Inhibition of DDP-4 by vildagliptin is not affected by patient’s sex [3, 4]. No clinically relevant outcome studies have been found.

A post-hoc analysis [7] of the EDGE study [8] assessed inter-regional differences in baseline characteristics and response to treatment intensification with dual oral antidiabetic drugs in patients with type 2 diabetes (23,990 men, 19,801 women) [7]. Vildagliptin add-on therapy to metformin allowed more patients to achieve glycemic target HbA1c <7% without hypoglycemia or weight gain ⩾ 3% at 12 months (the secondary end point, SEP), across regions. Subgroup analysis showed that women aged ⩾45 years less often attained glycemic target without significant weight gain ⩾5% compared with women aged <45 years (OR 0.876) [7]. Study results for women compared to men were not presented.

Adverse effects

A large meta-analysis (7458 men, 6112 women) reported that vildagliptin was not associated with an increased risk of cardiovascular or cerebrovascular events, neither in men nor in women, relative to comparative drugs [4].

Using Korean insurance claims data, the potential association between the use of DPP-4 inhibitors and increased risk of developing bullous pemphigoid was assessed (684 men, 656 women). The use of DPP-4 inhibitors was associated with a significant increase in the risk of developing bullous pemphigoid (OR 1.58) with vildagliptin having the highest OR (1.81). Subgroup analyses showed an association in men (OR 1.91) and with vildagliptin being the most high-risk DPP-4 inhibitor (OR 2.70) [9].

A retrospective case-control study from Israel (190 men, 220 women) showed a 3-fold increased risk for bullous pemphigoid in patients with diabetes treated with DPP-4 inhibitors (adjusted OR for vildagliptin 10.7 and for linagliptin 6.7). The association of DPP-4 inhibitor use with bullous pemphigoid was independent of the use of metformin and was stronger among men (OR 4.46; 95% CI, 2.11-9.40) than women (OR 1.88; 95% CI, 1.73-18.01) [10]. 

Another retrospective case-control study from France and Switzerland (90 men, 93 women) compared patients with diabetes and bullous pemphigoid with age- and sex-matched control patients with diabetes. The study showed that DPP-4 inhibitors were associated with an increased risk of developing bullous pemphigoid (adjusted OR 2.64; 95% CI 1.19-5.85), with vildagliptin showing the highest risk (adjusted OR 3.57; 95% CI 1.07-11.84). Sex-stratified analysis indicated that the effect of a DPP-4 inhibitor on bullous pemphigoid onset was higher in men (adjusted OR 4.36; 95% CI, 1.38-13.83) than women (adjusted OR 1.64; 95% CI 0.53-5.11) [11].

A per-protocol supplementary analysis of a vildagliptin post-marketing study (2692 men, 2132 women) compared the risk of peripheral edema between vildagliptin monotherapy and combination therapy with sulfonylurea. Men of average age (62 years) prescribed vildagliptin are estimated to have approximately 13 times higher risk of peripheral edema if they have a prior history of the condition (HR 12.84, 95 %CI 4.96–33.23), whilst no such relationship is observed for women of average age (HR 1.44, 95 %CI 0.32–6.40) [12].

The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 (SGLT2) inhibitors versus 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].

Reproductive health issues

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