Incretin therapy: should adverse consequences have been anticipated?

In a linked investigation (doi:10.1136/bmj.f3680), Cohen shines a spotlight on the safety of the incretins—drugs for the treatment of diabetes that mimic or enhance the biological effects of glucagon-like peptide-1 (GLP-1).1 Her investigation raises important questions as to the nature of the dialogue between drug companies and the regulators, and the extent to which potentially harmful effects of these drugs have been hidden from prescribers and patients.

The drugs that have transformed the modern treatment of chronic illness—β blockers, angiotensin converting enzyme inhibitors, and statins—are typically inhibitors of defined molecular pathways, with consequences that are relatively predictable. By contrast, the incretins are agonists that act on multiple targets with multiple effects. They are “magic shotguns” rather than “magic bullets.”

The thiazolidinediones—nuclear receptor agonists that modulate the activity of numerous genes—are good examples of this. They were introduced with great fanfare, but unwanted effects such as weight gain, fluid retention, and osteopenia have limited their use in the management of diabetes. Troglitazone, the first in class, was withdrawn because of hepatic injury; rosiglitazone was withdrawn from most countries in 2011 because of cardiovascular problems; and pioglitazone has been implicated in bladder cancer.

In each case the potential problem was spotted early in development but the regulatory response …