Safety and tolerability of pioglitazone

Abstract

Pioglitazone HCl, a new thiazolidinedione (TZD), has been developed for the treatment of type 2 diabetes. The drug was tested in several trials that included over 5,000 subjects. Of these, over 3,500 subjects received active treatment. At doses between 15±45 mg pioglitazone was well tolerated with dropouts due to adverse events being similar in pioglitazone and placebo groups. The main side effect of treatment was mild to moderate peripheral oedema. Oedema was not associated with signs or symptoms of congestive cardiac failure, and there was no excess of adverse events in the cardiovascular system in the pioglitazone-treated patients. Weight increases were seen during treatment with pioglitazone, with most weight gain in the early period of the treatment, which then stabilised. It has been shown to be due to increases in subcutaneous fat. Despite weight gain, the favourable effects of pioglitazone on glycaemic control and lipids were maintained. In laboratory tests, small decreases in haemoglobin and haematocrit were seen due to haemodilution. However, anaemia was not reported more often with pioglitazone than with placebo and no patients were discontinued due to anaemia associated with pioglitazone. A thorough analysis of results of liver tests revealed no evidence of hepatotoxicity with pioglitazone. The safety profile of pioglitazone demonstrated by clinical trials is supported further by safety data from the market in USA and Japan, where the drug has been widely prescribed for over a year. A safety and tolerability profile, similar to that seen in clinical trials, has been reported.

PPARgamma agonists in the treatment of type II diabetes: is increased fatness commensurate with long-term efficacy?

“…88 Also, on a longterm basis the TZDs seem to promote weight gain ( Figure 6). Long-term treatment with Pioglitazone monotherapy is accompanied by substantial weight gain, 89 and this weight gain may likely be even higher when provided in combination with sulphonylureas or insulin, and it may be speculated whether this weight gain will increase with continuous treatment. The cause of the weight gain in humans is unclear, but is presumably because of increased fat deposition, the inherent mechanism of PPARg activation.…”

Influence of Quercetin on Diabetes-Induced Alteration in CYP3A Activity and Bioavailability of Pioglitazone in Rats

“…If given along with a sulphonylurea or insulin, it often leads to severe hypoglycemia [22,23] . In view of this risk factor, its bioavailability is therapeutically crucial in view of possible pharmacokinetic drug-drug interactions.…”

The clinical effectiveness and cost-effectiveness of pioglitazone for type 2 diabetes mellitus: a rapid and systematic review

“…One published study review 76 found no change in patients on pioglitazone or placebo, but reported that diastolic blood pressure tended to show small decreases in those receiving pioglitazone, compared with placebo.…”

“…English translations of these papers are available from Takeda UK Ltd, although six of these are not readily available in the public domain. One full study report 62 and two review articles 63,76 relating to trials PNFP-010 and PNFP-027 are available in English.…”

“…A review of the safety and tolerability of pioglitazone 76 includes a figure combining data from the monotherapy and combination studies, which shows weight changes over a period of up to 60 weeks (European and Japanese studies) and 96 weeks (US studies). Although the text of the paper states that "weight increases tended to occur over the first months of treatment and then stabilised", this is not in fact born out by the figure itself.…”