Liraglutide

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

The pharmacokinetics of a single-dose liraglutide has been investigated in healthy men and women in a clinical trial (16 men, 16 women). When adjusted for body weight, pharmacokinetics of liraglutide were similar in men and women [3].

A population pharmacokinetic analysis based on two different trials with liraglutide treatment (811 men, 2112 women), showed that liraglutide exposure was 24% lower in men than in women of comparable body weight (mean AUC ratio 0.76, [90% CI; 0.74, 0.78]). This corresponds to 32% greater exposure in women compared with men at comparable body weight. Since the 90% CI for this effect was outside of the bioequivalence limits, a patient’s sex was considered to have a pharmacokinetically relevant effect on liraglutide exposure [4].

The FDA prescribing information states that based on the results of a population pharmacokinetic analyses, women have 25% lower weight-adjusted clearance of liraglutide compared with men [5]. The European product information states that patient’s sex had no clinically meaningful effect on the pharmacokinetics of liraglutide based on the results of population pharmacokinetic data analysis of men and women, and a pharmacokinetic study in healthy subjects [6]. However, both the European and American product information state that based on the pharmacokinetics of liraglutide, no dosage adjustment according to sex is necessary [5, 6].

Safety, tolerability and pharmacokinetics of liraglutide in adolescents (12-17 years) with obesity was assessed in a 5-week randomized, double-blind, placebo-controlled trial (7 boys, 14 girls). A joint analysis that included data from a similar study with liraglutide in adults with obesity (3 adolescent males, 10 adolescent females, 18 adult males, 11 adult females) was performed. Liraglutide exposure was 23% lower in male participants than in female participants (0.77 [0.65; 0.92], 90%CI) [7].

In a pharmacokinetic and exposure-response meta-analysis (1137 PK observations from 116 patients), the influence of patient sex was on liraglutide exposure in pediatric patients with diabetes type 2, was evaluated. Relative exposure of liraglutide was lower in boys than in girls (ratio: 0.72 [95% CI: 0.62; 0.85]) [8].

Effects

In the pivotal efficacy phase 3 trials for liraglutide and when clinically treating diabetes type 2 patients, liraglutide is used as an adjunct treatment to metformin. Evaluation of liraglutide’s sex differences in effect and safety is therefore complicated due to the lack of liraglutide monotherapy studies.The efficacy and safety of liraglutide versus glimepiride (as adjunct treatments to metformin), in achieving glycemic control was assessed in Italian patients with type 2 diabetes mellitus (75 men, 104 women). The women with liraglutide had stronger reduction in HbA1c level than men (-1.5 vs -0.75). The study also showed the impact of female sex in predicting a better glycemic response to liraglutide even after adjustment for age, duration of diabetes, and BMI. There were no sex differences in body weight, waist circumference, or blood pressure [9].

Adverse events

In a post-hoc analysis of the DURATION-6 study (comparing exenatide once weekly and liraglutide in 499 men and 412 women), the incidence of gastrointestinal adverse events (AEs) was analyzed in 245 men and 205 women with liraglutide. A greater proportion of women than men reported gastrointestinal AEs from liraglutide (48.3% in women vs 35.5% in men, p<0.01) [10].

Reproductive health issues

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