Polemics of pioglitazone: an appraisal in 2015

Abstract

Pioglitazone is an inexpensive and effective oral drug for the treatment of Type 2 diabetes. It addresses insulin resistance, one of the core pathophysiological defects in Type 2 diabetes, at both the adipose tissue and skeletal muscle level. As a majority of Type 2 diabetics classically exhibit higher insulin resistance, pioglitazone may strike exactly at the Achilles heel in this core pathogenesis. However, with the emerging association of bladder cancer with pioglitazone, French and German regulators were the first to ban or restrict pioglitazone use in 2011. The Indian regulators also suspended pioglitazone, although this ban was revoked within a month. Recently, a 10-year longitudinal study commissioned by US FDA found no association between bladder cancer and pioglitazone. Nevertheless, this controversy created a huge outcry in the medical fraternity. This review article is an overview of the development of this topic and an attempt to provide perspective on this contemporary issue.

Keywords:

• bladder cancer
• cardiovascular mortality
• heart failure
• pioglitazone

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues

• Despite significant advances in diabetes care since the introduction of insulin and metformin, large gaps in the standard of care still remain. Although substantial research has been directed toward β-cell preservation and regeneration without much translational success, very little drug discovery or development is aimed at correcting insulin resistance.

• Although, both thiazolidinediones and metformin lessen resistance to insulin’s actions while facilitating nutrients into tissue, their disease-modifying effects are completely different. While metformin significantly reduces hepatic glucose output, its actions beyond the liver are weak and reduction in peripheral insulin resistance is only indirect through creating an improved physiological environment. In contrast, thiazolidinediones provide significant improvements in insulin resistance and glucose disposal at both adipose tissue and skeletal muscle. Therefore, pioglitazone is currently a better insulin-sensitizing drug compared with metformin.

• All currently used drugs in Type 2 diabetes have side effects and pioglitazone is no exception. It can cause fluid retention, pedal edema, macular edema and may potentiate frank heart failure in pre-existing background. It can also aggravate osteoporosis and incidental fractures in postmenopausal women. However, an astute physician will choose the right patient for a given therapy to avoid these side effects.

• Weighing the beneficial effects of pioglitazone on cardiovascular risk and certain soft surrogate markers (coronary and carotid artery intima–media thickness), it may not be a best option to write off such an inexpensive drug like pioglitazone. Although the efficacy and safety of any pharmacotherapy hinges on its risk:benefit ratio; currently in this case, it appears to be tilted in favor of pioglitazone. However, pharmacovigilance is always necessary when risk is not clearly known.

• Association of bladder cancer with pioglitazone is controversial and not clearly substantiated. A number of confounders and allocation bias across the studies could have been responsible for such statistical association.