What chance a comeback for the now generic pioglitazone?

Following the good news surrounding the SGLT2 inhibitor, empagliflozin, and the GLP-1 receptor agonist, liraglutide, what chance a comeback for the now generic pioglitazone? Data from the Insulin Resistance Intervention after Stroke (IRIS) trial show that pioglitazone halved the progression to diabetes in people with insulin resistance and cerebrovascular disease. Progression to diabetes was a pre-specified secondary end point of IRIS and occurred in 3.8% of the 1,939 patients randomised to 45 mg/day of pioglitazone compared with 7.7% of 1,937 receiving placebo (P < .0001). This followed on from the main IRIS finding (reported earlier in 2016) that pioglitazone reduced recurrent stroke or myocardial infarction (MI) by 24%.

However, this is not the first time that pioglitazone has been shown to reduce the risk of type 2 diabetes. The Actos Now for Prevention of Diabetes (ACT NOW) (2011) demonstrated a 72% reduction in conversion from impaired glucose tolerance to type 2 diabetes. Pioglitazone has also previously showed cardiovascular benefit in the PROactive trial (2005) with a significant 16% reduction in death, MI, and stroke. These benefits have been overshadowed by concerns over side-effects, which include risk of heart failure, bladder cancer and an increased risk of bony fractures; so what did the 5-year long IRIS reveal about safety?

In IRIS, there was no increased risk for incident cancer with pioglitazone (6.9% vs 7.7%, P = 0.29) or heart failure (2.6% vs 2.2%, P = 0.35), but bone fractures did occur at a higher rate (5.1% vs 3.2%, P < 0.01). The heart failure result was probably due to exclusion of patients with heart failure at baseline and aggressive protocols for managing patients who developed oedema. Also, in IRIS there was no signal for an increase in hip-fracture which might be reassuring. Perhaps the future of piogitazone lies in post-stroke treatment protocols rather than in diabetes guidelines?

Professor Steve Bain

June 2016