Pioglitazone

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].According to the original manufacturer, the mean Cmax and AUC values of pioglitazone is increased 20-60% in women compared to men. HbA1c decreases from baseline were generally greater for women than for men [3,4]. 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 [5, 6].Some studies report sex differences in pioglitazone pharmacokinetics [3, 5], and the dose should be individualized for each patient. However, no dose adjustment is necessary only based on a patient’s sex. High pioglitazone doses are associated with greater risk of fracture in women aged 50 years and older [7].

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 [8]. 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 [9].The risks of all-cause mortality and major cardiovascular events between pioglitazone users and non-users receiving insulin therapy were assessed in a retrospective population-based cohort study in Taiwan (2712 men, 2446 women). The risk of all-cause mortality was lower in pioglitazone users in both men (aHR 0.47, 95% CI; 0.35–0.62) and women (aHR 0.47, 95% CI;0.34–0.65) compared to non-users [10].

Adverse events

Fracture risk with glitazones

Glitazones (pioglitazone, rosiglitazone, troglitazone) have been associated with increased fracture risk. However, results from studies have been inconsistent [11]. Some studies have reported an increased risk only in women (odds ratios varying 1.56-2.23) [7, 12-14], while other studies have reported similar risk in fracture in men and women [15-18]. 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 [17]. One study (48074 men, 36266 women) found that pioglitazone treatment was more strongly associated with fractures than rosiglitazone, in both men and women [18]. Only pioglitazone is available in Sweden.

Fracture risk with pioglitazone

When looking at pioglitazone treatment alone in a meta-analysis (n=3172 patients), neither an increased incidence of fractures (OR=1.18, 95%CI: 0.82 to 1.71) nor an association between fractures and patient’s sex was found [19].The risk of bone fractures from pioglitazone treatment was investigated in study with safety data from a randomized controlled trial (the Insulin Resistance Intervention after Stroke, IRIS, trial) in nondiabetic patients after an ischemic stroke or TIA (2538 men, 1338 women). The risk of any fracture in the pioglitazone group compared with placebo was increased in men but not in women (HR for men, 1.83; 95% CI, 1.36 to 2.48, HR for women, 1.32; 95% CI, 0.98 to 1.78) [20].

Bladder cancer

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 remains incompletely understood [21].Pioglitazone-induced adverse drug reactions (ADRs) including bladder cancer were assessed in 19 904 pioglitazone-related individual case safety reports (PG-ICSRs) from the Vigilyze pharmacovigilance database system. Worldwide, the distribution of overall PG-ICSRs was higher in men (37%) compared to women (30%). Unfortunately, in 34% of the PG-ICSRs, the patient’s sex was not reported. The percentage of PG-ICSRs associated with bladder cancer was fivefold higher in men (27%) than women (6%). In as high as 67% of these PG-ICSRs, the patient’s sex was not reported [22].In a study with data from the National Health Insurance program in Taiwan, the incidence of gout was investigated in diabetics (30 100 pioglitazone users and 90 300 non-pioglitazone users with 52.4% women in each population). The incidence of gout was lower in both men  and women (aHR 0.80 and 0.83, respectively) using pioglitazone than in non-pioglitazone users [23].In a retrospective cohort study in patients with diabetes in Taiwan, pioglitazone use was not associated with Parkinson disease  incidence in users (3696 men, 4210 women) compared to non-users (3696 men, 4210 women) [24].

Reproductive health issues

Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (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  (48 men, 40 women, 65-79 years) showed that 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 [25].

Pioglitazone’s potential effects on basal cortisol levels and the growth hormone-insulin-like growth factor (GH-IGF) axis, was investigated in an interventional study in type 2 diabetes patients with secondary drug failure (28 men, 20 women). IGF-I and adiponectin increased significantly in both men and women, while triglycerides decreased significantly in women only. The authors discuss that increased IGF-I may contribute to improved insulin sensitivity after treatment [26].

In a RCT with patients newly diagnosed with diabetes, the effects of metformin (22 men, 19 women) and pioglitazone (19 men, 31 women) on omentin and leptin concentrations were investigated. After three months, metformin decreased both omentin and leptin concentrations in women, and leptin concentrations only in men. On the other hand, pioglitazone reduced both adipokines only in women, but not men [27].