Linagliptin

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].

Pharmacokinetics and dosing

According to the original manufacturer [3], no dosage adjustment for linagliptin is necessary based on a patient’s sex. No clinically relevant differences in the pharmacokinetics of linagliptin based on a population pharmacokinetic analysis of Phase I and Phase II data were found between men and women [3, 4].

Effects

In the total of 8 phase III randomized controlled trials evaluating efficacy and safety of linagliptin in patients with type 2 diabetes (5,239 patients in total of which 3,319 were treated with linagliptin), the reductions in HbA1c were similar in men and women [3]. A pooled analysis of three phase III trials (1102 men, 1122 women) studied the efficacy and safety of linagliptin according to patient baseline characteristics. The effect of linagliptin (the placebo-adjusted mean difference in % HbA1c reductions after 24 weeks) was similar in both men and women [5].

Adverse effects

In the safety analysis (1120 men, 1138 women) of three phase III trials, the incidence of overall adverse events (AEs), AEs leading to discontinuation, or serious AEs was similar in both men and women who received linagliptin versus placebo [5].

The effects of linagliptin vs glimepiride on accelerated cognitive decline (ACD) were assessed in the randomized double-blind, active-controlled CAROLINA-COGNITION study (1960 men, 1203 women) [6]. This study was part of the CAROLINA trial evaluating cardiovascular safety of linagliptin versus glimepiride (n=6033) [7]. In the secondary analyses, no difference between men and women in the effects of linagliptin versus glimepiride on ACD at week 160 were found (OR 1.05 men vs OR 0.96 women, p= 0.58) [6].

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) [8].

A retrospective case-control study (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) [9].

Reproductive health issues

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