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Pioglitazone

Classification: C

Drug products: Actos, Competact, Pioglitazon Orion, Pioglitazone Accord, Pioglitazone Actavis, Pioglitazone Teva Pharma

ATC code: A10BD05, A10BG03

Substances: pioglitazone, pioglitazone hydrochloride

Summary

Some studies show an increased risk of fractures especially in women but also in men treated with pioglitazone. A comprehensive meta-analysis has shown an increased incidence of bladder cancer in men treated with pioglitazone.

The pattern of adverse events motivates a general cautiousness in treatment of women in particular, but also in men. The risk of bladder cancer in men needs to be considered
.

Additional information

Pharmacokinetics and dosing

According to the original manufacturer, the mean Cmax and AUC values of pioglitazone is increased 20-60% in women compared to men and HbA1c decreases from baseline were generally greater for women than for men [1]. However, other studies (one study 61 men, 63 women, the other 18 men, 19 women) report only small or non-significant sex differences in Cmax and AUC [2, 3].

Although some studies report sex differences in pioglitazone pharmacokinetics [1, 2], no dose adjustment is necessary based on sex alone. However, the therapy should be individualized for each patient to achieve good glycemic control. High pioglitazone doses are associated with greater risk of fracture in women aged 50 years and older, but not in men or women under 50 years of age [4].

Effects

A meta-analysis examining factors associated with reduction in HbA1c from rosiglitazone and pioglitazone, found no impact of sex on the effect size of glitazone therapy on HbA1c [5]. Only pioglitazone is available in Sweden.

A small study in Japanese patients (22 men, 26 women) with type 2 diabetes, showed that pioglitazone is likely to show favorable effects on blood glucose control especially in women with higher fasting plasma glucose levels. More women were in the responder group (18 women vs. 4 men). The responders were those showing >1% of reduction in HbA1c after 12 weeks of treatment with pioglitazone 15 mg/day [6].

Adverse effects

Glitazones (pioglitazone, rosiglitazone, troglitazone) have been associated with increased fracture risk. However, results from studies have been inconsistent [7]. Some studies have reported an increased risk only in women (odds ratios varying 1.56-2.23) [4, 8-10], while other studies have reported similar risk in fracture in men and women [11-14]. However, the clinical significance is unclear, clinical trials are relatively small and men have a lower baseline risk of fracture than women [9]. One systematic review of 5 randomized controlled trials (7001 men, 4400 women) reported an increased risk of fractures among women (odds ratio 2.23) but not among men (odds ratio 1.00) treated with pioglitazone or rosiglitazone [15]. One study (48074 men, 36266 women) found that pioglitazone treatment was more strongly associated with fractures than rosiglitazone, in both men and women [14]. Only pioglitazone is available in Sweden.A meta-analysis (in total 2 321 085 patients) reports an increased incidence of bladder cancer after pioglitazone therapy in men. The mechanisms by which the exposure to pioglitazone causes bladder cancer remain incompletely understood [16].

Reproductive health issues

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

Other information

The influence of pioglitazone on body composition in older non-diabetic overweight/obese men and women during weight loss has been examined (48 men, 40 women, 65-79 years). Pioglitazone reduced abdominal visceral fat in men but not in women. Loss of subcutaneous fat in thigh was attenuated in women taking pioglitazone. This sex differences can be explained by differences in adipose tissue loss from the visceral and subcutaneous compartments during weight-loss trials [17].

Updated: 2019-02-26

Date of litterature search: 2014-08-12

References

  1. Actos (pioglitazone). DailyMed [www]. US National Library of Medicine. [updated 2013-11-01, cited 2014-08-12]. länk
  2. Karim A, Slater M, Bradford D, Schwartz L, Zhao Z, Cao C et al. Oral antidiabetic drugs: bioavailability assessment of fixed-dose combination tablets of pioglitazone and metformin Effect of body weight, gender, and race on systemic exposures of each drug. J Clin Pharmacol. 2007;47:37-47. PubMed
  3. Karim A, Zhao Z, Slater M, Bradford D, Schuster J, Laurent A. Replicate study design in bioequivalency assessment, pros and cons: bioavailabilities of the antidiabetic drugs pioglitazone and glimepiride present in a fixed-dose combination formulation. J Clin Pharmacol. 2007;47:806-16. PubMed
  4. Bilik D, McEwen LN, Brown MB, Pomeroy NE, Kim C, Asao K et al. Thiazolidinediones and fractures: evidence from translating research into action for diabetes. J Clin Endocrinol Metab. 2010;95:4560-5. PubMed
  5. Phatak HM, Yin DD. Factors associated with the effect-size of thiazolidinedione (TZD) therapy on HbA(1c): a meta-analysis of published randomized clinical trials. Curr Med Res Opin. 2006;22:2267-78. PubMed
  6. Tajiri Y, Takei R, Mimura K, Umeda F. Indicators for the efficacy of pioglitazone before and during treatment in Japanese patients with type 2 diabetes. Diabetes Technol Ther. 2007;9:429-37. PubMed
  7. Lecka-Czernik B. Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr Osteoporos Rep. 2010;8:178-84. PubMed
  8. Loke YK, Singh S, Furberg CD. Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis. CMAJ. 2009;180:32-9. PubMed
  9. Aubert RE, Herrera V, Chen W, Haffner SM, Pendergrass M. Rosiglitazone and pioglitazone increase fracture risk in women and men with type 2 diabetes. Diabetes Obes Metab. 2010;12:716-21. PubMed
  10. Habib ZA, Havstad SL, Wells K, Divine G, Pladevall M, Williams LK. Thiazolidinedione use and the longitudinal risk of fractures in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2010;95:592-600. PubMed
  11. Meier C, Kraenzlin ME, Bodmer M, Jick SS, Jick H, Meier CR. Use of thiazolidinediones and fracture risk. Arch Intern Med. 2008;168:820-5. PubMed
  12. Douglas IJ, Evans SJ, Pocock S, Smeeth L. The risk of fractures associated with thiazolidinediones: a self-controlled case-series study. PLoS Med. 2009;6:e1000154. PubMed
  13. Jones SG, Momin SR, Good MW, Shea TK, Patric K. Distal upper and lower limb fractures associated with thiazolidinedione use. Am J Manag Care. 2009;15:491-6. PubMed
  14. Dormuth CR, Carney G, Carleton B, Bassett K, Wright JM. Thiazolidinediones and fractures in men and women. Arch Intern Med. 2009;169:1395-402. PubMed
  15. Jonas D, Van Scoyoc E, Gerrald K, Wines R, Amick H, Triplette M, Runge T. Drug Class Review: Newer Diabetes Medications, TZDs, and Combinations: Final Original Report . Oregon Health & Science University. PubMed
  16. He S, Tang YH, Zhao G, Yang X, Wang D, Zhang Y. Pioglitazone prescription increases risk of bladder cancer in patients with type 2 diabetes: an updated meta-analysis. Tumour Biol. 2014;35:2095-102. PubMed
  17. Shea MK, Nicklas BJ, Marsh AP, Houston DK, Miller GD, Isom S et al. The effect of pioglitazone and resistance training on body composition in older men and women undergoing hypocaloric weight loss. Obesity (Silver Spring). 2011;19:1636-46. PubMed
  18. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-05.] länk
  19. Jansson SP, Andersson DK, Svärdsudd K. Prevalence and incidence rate of diabetes mellitus in a Swedish community during 30 years of follow-up. Diabetologia. 2007;50:703-10. PubMed

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Mia von Euler, Expertrådet för endokrinologiska och metabola sjukdomar

Approved by: Karin Schenck-Gustafsson