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Linagliptin

Classification: A

Drug products: Glyxambi, Jentadueto, Trajenta

ATC code: A10BD11, A10BD19, A10BH05

Substances: linagliptin

Summary

The blood glucose lowering effect and the safety of linagliptin have been found similar between men and women in subgroup analysis of phase III trials.

A 3-fold increased risk for bullous pemphigoid in patients with diabetes treated with dipeptidyl peptidase-4 (DPP-4) inhibitors, on a group level, have been found, and the association was independent of the use of metformin and was stronger among men.

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

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).

Updated: 2021-05-11

Date of litterature search: 2021-02-22

References

  1. Gale EA, Gillespie KM. Diabetes and gender. Diabetologia. 2001;44(1):3-15. PubMed
  2. Jansson SP, Fall K, Brus O, Magnuson A, Wändell P, Östgren CJ et al. Prevalence and incidence of diabetes mellitus: a nationwide population-based pharmaco-epidemiological study in Sweden. Diabet Med. 2015;32(10):1319-28. PubMed
  3. Trajenta (linagliptin). EPAR - Product information. European Medicines Agency (EMA) [updated 2020-09-07, cited 2021-03-03] PubMed
  4. Retlich S, Duval V, Graefe-Mody U, Friedrich C, Patel S, Jaehde U, Staab A. Population Pharmacokinetics and Pharmacodynamics of Linagliptin in Patients with Type 2 Diabetes Mellitus. Clin Pharmacokinet. 2015;54(7):737-50.
  5. Del Prato S, Patel S, Crowe S, von Eynatten M. Efficacy and safety of linagliptin according to patient baseline characteristics: A pooled analysis of three phase 3 trials. Nutr Metab Cardiovasc Dis. 2016;26(10):886-92. länk
  6. Biessels GJ, Verhagen C, Janssen J, van den Berg E, Wallenstein G, Zinman B, Espeland MA, Johansen OE. Effects of linagliptin vs glimepiride on cognitive performance in type 2 diabetes: results of the randomised double-blind, active-controlled CAROLINA-COGNITION study. Diabetologia. 2021;64(6):1235-1245. länk
  7. Rosenstock J, Kahn SE, Johansen OE, Zinman B, Espeland MA, Woerle HJ, Pfarr E, Keller A, Mattheus M. Effect of Linagliptin vs Glimepiride on Major Adverse Cardiovascular Outcomes in Patients With Type 2 Diabetes: The CAROLINA Randomized Clinical Trial. JAMA. 2019;322(12):1155-1166. länk
  8. Ling AW, Chan CC, Chen SW, Kao YW, Huang CY, Chan YH, Chu PH. The risk of new-onset atrial fibrillation in patients with type 2 diabetes mellitus treated with sodium glucose cotransporter 2 inhibitors versus dipeptidyl peptidase-4 inhibitors. Cardiovasc Diabetol. 2020;19(1):188. länk
  9. Kridin K, Bergman R. Association of Bullous Pemphigoid With Dipeptidyl-Peptidase 4 Inhibitors in Patients With Diabetes: Estimating the Risk of the New Agents and Characterizing the Patients. JAMA Dermatol. 2018;154(10):1152-1158. PubMed
  10. Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk

Authors: Diana Rydberg

Reviewed by: Carl-Olav Stiller

Approved by: Karin Schenck-Gustafsson