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Editorials

What have we learnt from the rosiglitazone saga?

BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d1354 (Published 17 March 2011) Cite this as: BMJ 2011;342:d1354
  1. Victor M Montori, professor of medicine,
  2. Nilay D Shah, assistant professor of health services research
  1. 1Knowledge and Evaluation Research Unit, Mayo Clinic, Rochester, MN 55902, USA
  1. montori.victor{at}mayo.edu

That regulators, prescribers, and patients all have a role in promoting patient safety

The linked study by Loke and colleagues (doi:10.1136/bmj.d1309) summarises the observational evidence of the adverse cardiovascular effects of thiazolidinediones (glitazones) in patients with type 2 diabetes.1 Meta-analyses of randomised trials yielded similar results: both available glitazones increase the risk of heart failure, with a higher risk of heart failure, myocardial infarction, and mortality with rosiglitazone than with pioglitazone. The process of accruing this evidence has confirmed the apparently narrow interest in profits of corporations that bring drugs to the marketplace.2 Much has also been revealed about the roles that regulators, prescribers, and patients can play in promoting patient safety.

In North America, regulators used safety alerts to increase prescribers’ awareness of the increased risk of cardiovascular side effects with glitazones. Boxed warnings followed. The use of glitazones declined—more so for rosiglitazone than for pioglitazone, with threefold differences across US states in the use of rosiglitazone well into 2009.3 In September 2010, as revelations emerged of potential impropriety in the evaluation of its safety and the European Medicines Agency recommended the suspension of the drug in Europe, North American regulators decided to keep rosiglitazone on the market with restrictions. The published explanation (www.fda.gov/Drugs/DrugSafety/ucm241411.htm) suggests that the Food and Drug Administration trusted clinicians and patients to balance the risks and benefits of this agent in the few patients for which the alternatives seemed less desirable or safe. Research should be undertaken to understand what occurs when drugs are left on the market with strong warnings. Also, the local regulation of drug use deserves more scrutiny. In particular, how do drug formularies, often the subject of local decisions, contribute to the persistent use of rosiglitazone and to the observed geographical variations in its use?

The best available evidence suggests limited or no benefit of intensified glycaemic control for patients with type 2 diabetes.4 Intensive glycaemic control reduces the risk of myocardial infarction by 15% but does not reduce the risk of death from a cardiovascular event. In addition, it does not benefit other microvascular or macrovascular complications, it greatly increases the risk of hypoglycaemia, and it may reduce quality of life as a result of the burden of treatment.5 Paradoxically, current guidelines still advocate tight glycaemic control for most patients with type 2 diabetes.6

In pursuing tight control, prescribers must remember that antihyperglycaemic agents have important differences. There are crucial safety differences between glitazones,1 and between glitazones and drugs in other classes (for example, metformin may prevent cancer7 and cardiovascular events8). Glitazones can improve glycaemic control without hypoglycaemia, but weight gain, myocardial infarctions (for rosiglitazone), heart failure, bone fractures, possibly bladder cancer (for pioglitazone), and higher out of pocket costs should restrain the thoughtful prescriber. In the occasional patient with uncontrolled diabetes and symptomatic hyperglycaemia who is unable or unwilling to take insulin, pioglitazone may offer an acceptable compromise. This group is too small, however, to justify the position of pioglitazone as the eighth leading prescription drug in the United States, with total sales of $3.4bn (£2.1bn; €2.5bn) in 2009.9 Clearly, more caution when selecting antihyperglycaemic agents is warranted.

Unfortunately, regulators and prescribers do not seem to have learnt from the rosiglitazone saga. Consider the case of the newest diabetes agents, dipeptidyl peptidase 4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists. Regulators approved these agents relatively quickly, trusting the manufacturers to conduct cardiovascular safety trials. While these agents’ mechanisms of action excite diabetologists, marketers tout their favourable short term features, including low risk of hypoglycaemia, neutral or favourable effect on weight, and ease of administration. Dipeptidyl peptidase 4 inhibitors accounted for more than 14% of the diabetes drug market in 2010 even though not one study supports the long term efficacy (in reducing diabetes complications) or safety of these agents.10

Effective and efficient evidence based tools are freely available for patients and clinicians to compare the available antihyperglycaemic options (http://kercards.e-bm.info).11 Armed with unbiased information patients can consider these agents in light of their own goals and circumstances (although patients are the target of intense drug marketing in the US). Current guidelines do not recommend involving patients (or the use of decision aids) in decisions about drugs for treating diabetes.12 Yet, becoming engaged and informed seems to be the way for patients to avoid harm.

The rosiglitazone story says much about how healthcare has become less about promoting patients’ interests, alleviating illness, promoting function and independence, and curing disease, and much more about promoting other interests, including those of the drug industry. Has the corruption of healthcare advanced so far that it is unreasonable, even naive, to expect responsible drug companies, enlightened regulators, and thoughtful prescribers?

Notes

Cite this as: BMJ 2011;342:d1354

Footnotes

  • Research, doi:10.1136/bmj.d1309
  • Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; not externally peer reviewed.

References