TZDs and cancer

The thiazolidinediones, otherwise known as the TZDs or glitazones, have had a troubled history. Troglitazone, the first agent in the class, was launched in 1997 and withdrawn in 2000. Rosiglitazone and pioglitazone were launched in 2000, but rosiglitazone was withdrawn in many countries in 2010 because of adverse cardiovascular effects, and pioglitazone was withdrawn in France and Germany in 2012 because of an increased rate of bladder cancer in men. The TZDs are agonists acting upon the nuclear PPAR-gamma receptor, and modulate expression of a large number of genes with metabolic and other actions. This pleiotropic range of actions may help to explain the wide range of unwanted effects associated with their use. These consequences do however include potentially useful effects upon some types of cancer, and (like metformin) TZDs are currently in clinical trial as adjuvants to cancer therapy.

Background

The glitazones, also known as thiazolidinediones (TZDs), have been widely used in the treatment of diabetes. Troglitazone, the first drug in the class, was introduced in 1997 but withdrawn in 2000 because of acute liver injury. Rosiglitazone and pioglitazone took its place, and have been used as second or third line agents after metformin but prior to insulin therapy. The decision to prescribe TZDs was thus closely associated with this stage in the progression of type 2 diabetes. In 2010 rosiglitazone was withdrawn from many countries or had severe restrictions put upon its use because of an excess of cardiovascular events, and pioglitazone is less widely used because of adverse effects such as weight gain, fluid retention and osteoporosis.

The glitazones are peroxisome proliferator-activated receptor gamma (PPAR-γ) agonists that activate nuclear PPAR-γ receptors in the body; their useful clinical action is to improve insulin sensitivity in the peripheral tissues, but they also activate AMPK[1]. This action, similar to the proposed biologic mechanism for metformin, suggested a possible role in reducing the risk of tumor development [2][3], and as such, they are also currently being studied in small to large randomized trials in the prevention or treatment of various cancers[4].

Ironically, however, pioglitazone has also been implicated in an increased risk of bladder cancer.

Pioglitazone and Bladder Cancer

RCT Evidence

PROactive, a large placebo-controlled clinical trial of pioglitazone published in 2005, reported bladder cancer in 14 of 2605 [0.54%] participants in the pioglitazone arm vs. six of 2633 [0.23%] participants in the placebo arm over an average follow-up of 2.9 years[5]. Subsequent blinded review by the Drug Safety Monitoring Committee concluded the increased number of bladder cancer cases was not likely to be related to pioglitazone use[6].

Observational Evidence

Following the publication of two large observational studies,[7][8]France and Germany suspended pioglitazone from their markets in June of 2011. Reviews of pioglitazone by international drug regulatory agencies in United States, Europe and Canada subsequently concluded that there was a positive risk to benefit balance, but warned against use of pioglitazone in those at a higher risk of developing bladder cancer.[9]

A recently published summary of the evidence suggests an overall 22% increased risk of bladder cancer among individuals with type 2 diabetes that used pioglitazone as compared with those who used other (non-pioglitazone) glucose lowering agents to manage their diabetes.10 The significantly increased risk was observed after a minimum of 12 months use (38% increased risk for 13-24 months of pioglitazone use and 45% increased risk for use longer than 24 months). Similarly, cumulative doses of more than 10,500mg of pioglitazone were significantly associated with bladder cancer (22% increased risk for cumulative 10,500 to 28,000 mg of pioglitazone and 64% increased risk with cumulative doses over 28,000 mg). The study did not suggest an association with the TZD rosiglitazone (Avandia®, GlaxoSmithKline), although there was limited evidence available.[10]

References

  1. ^ Tachibana K et al. The role of PPARs in cancer. Review Article. PPAR Research 2008;1-15.

  2. ^ Burton JD et al. Potential of peroxisome proliferator-activated receptor gamma antagonist compounds as therapeutic agents for a wide range of cancer types. PPAR Research 2008:1-7.

  3. ^ Perez-Ortiz JM et al. Potential benefits of glitazones for cancer and vascular disease. Current Drug Therapy 2008;3:111-125.

  4. ^ Jiralerspong S et al. Metformin and pathologic complete response to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 2009;27:3297-302.

  5. ^ Dormandy JA et al. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005Oct.8;366(9493):1279–89

  6. ^ Dormandy J et al. Safety and Tolerability of Pioglitazone in High-Risk Patients with Type 2 Diabetes. Drug Saf. 2009;32(3):187–202

  7. ^ Scotte. Risque de cancer de la vessie chez les personnes diabétiques traitées par pioglitazone en France : une étude de cohorte sur les données du SNIIRAM et du PMSI [Internet]. afssaps.fr. Paris; 2011 [cited 2011Sep.27]. p. 1–41. Available from: http://www.afssaps.fr/var/afssaps_site/storage/original/application/b42a6bf9a1b63c3dbec7388d3914687b.pdf

  8. ^ Lewis JD et al. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011Apr.;34(4):916–22.

  9. ^ Update on ongoing review of pioglitazone-containing medicines [Internet]. ema.europa.eu. 2011 [cited 2011Nov.22]. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2011/06/news_detail_001275.jsp&mid=WC0b01ac058004d5c1&murl=menus/news_and_events/news_and_events.jsp&jsenabled=true

  10. ^ Colmers IN et al. Use of thiazolidinediones and the risk of bladder cancer among people with type 2 diabetes: a meta-analysis. CMAJ 2012;184:E675-83.

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