Drug Safety

, Volume 32, Issue 3, pp 187–202 | Cite as

Safety and Tolerability of Pioglitazone in High-Risk Patients with Type 2 Diabetes

An Overview of Data from PROactive
  • John Dormandy
  • Mondira Bhattacharya
  • Anne-Ruth van Troostenburg de Bruyn
  • on behalf of the PROactive investigators
Review Article


People with type 2 diabetes mellitus have an excess risk of macrovascular disease and a poorer prognosis. PROactive (PROspective pioglitAzone Clinical Trial In macro Vascular Events) was a landmark study of secondary cardiovascular disease (CVD) prevention in type 2 diabetes that suggested a beneficial effect of pioglitazone therapy on macrovascular outcomes. Previous studies have already shown that pioglitazone has a good safety and tolerability profile in people with type 2 diabetes, but PROactive provided an opportunity to assess tolerability and safety associated with long-term exposure in a vulnerable subpopulation at very high cardiovascular risk. This review discusses all the key safety and tolerability characteristics associated with pioglitazone therapy in PROactive.

As in previous studies, pioglitazone was associated with typical, but manageable, increases in oedema (26.4% vs 15.1% for placebo) and weight gain (mean change of +3.8 kg vs −0.6 kg for placebo). Increased hypoglycaemia with pioglitazone was consistent with improved glycaemic control. Despite more reports of serious heart failure in the pioglitazone group (5.7% vs 4.1% for placebo), there was a proportional improvement in macrovascular outcomes among patients developing heart failure, and absolute rates of macro-vascular events and mortality were similar to those in the placebo group. Liver function tests confirmed the hepatic safety of pioglitazone with long-term use and revealed a tendency to improved hepatic function, which may reflect reductions in liver fat. The comparative incidence of malignancies was similar; however, more cases of bladder neoplasm (14 vs 5) and fewer cases of breast cancer (3 vs 11) were observed in the pioglitazone versus placebo arms of the study. A higher rate of bone fractures observed among pioglitazone-treated female patients (5.1% vs 2.5%) warrants further investigation. Overall, safety and tolerability was predictable, and adverse events were not treatment limiting. These results suggest that any beneficial effects of pioglitazone on macrovascular outcomes are accompanied by good long-term tolerability in this population of very high-risk patients with type 2 diabetes and established CVD.


Heart Failure Placebo Group Rosiglitazone Pioglitazone Glycaemic Control 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



The authors would like to thank Absolute Healthcare Communications for editorial assistance. Funding for this assistance was provided by Takeda Pharmaceuticals.

PROactive was funded by Takeda Europe R&D Centre Ltd, London, UK, and Eli Lilly and Company, Indianapolis, IN, USA. The study was designed by the International Steering Committee, who approved the protocol and amendments. The commercial sponsor of PROactive had two representatives on the International Steering Committee and the same two were also members of the Executive Committee. Access to data was given freely to the Executive Committee and authors and the sponsors have not suppressed any data. Data interpretation, writing of this report and the decision to publish was made by all of the authors.

Professor Dormandy is a member of the Executive Committee. Drs Bhattacharya and van Troostenburg de Bruyn are employees of Takeda Global Research & Development.


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Copyright information

© Adis Data Information BV 2009

Authors and Affiliations

  • John Dormandy
    • 1
  • Mondira Bhattacharya
    • 2
  • Anne-Ruth van Troostenburg de Bruyn
    • 2
  • on behalf of the PROactive investigators
  1. 1.Department of Clinical Vascular Research, Ingelby HouseSt George’s HospitalLondonUK
  2. 2.Takeda Global Research & Development (Europe) LtdLondonUK

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