Pioglitazone decreases diabetes, stroke risks in patients with prediabetes, cerebrovascular disease

Yehuda Handelsman, MD, FACP, FACE, FNLA

In the early 2000s, both available thiazolidinediones, rosiglitazone and pioglitazone, were leading in the management of diabetes. In the mid-2000s the drugs in this class faced many obstacles, and their use diminished greatly. In fact, rosiglitazone was nearly eliminated, implicated in causing cardiovascular death, a charge of which it was recently exonerated by the FDA. Pioglitazone, despite better CV data, was not only dragged down by the fate of rosiglitazone, but was marred by its own issues, specifically an FDA warning on potentially causing bladder cancer. But then shortly following the clearing of rosiglitazone, a 10-year FDA-mandated study concluded that pioglitazone did not increase risk for bladder cancer (Lewis JD, et al. JAMA. 2015;doi:10.1001/jama.2015.7996), and recently a large European study reached the same conclusion (Korhonen P, et al. BMJ. 2016;doi:10.1136/bmj.i3903).

Health care stakeholders prefer diabetes medications that have effects beyond glycemia. Pioglitazone, which is now generic and inexpensive, may present an option for therapy. Several recent studies highlight the advantages that pioglitazone may have beyond glucose control.

In the IRIS trial, in a large group of subjects with no diabetes yet with metabolic syndrome and insulin resistance, pioglitazone showed a 24% reduction of secondary ischemic stroke and transient ischemic attack (Kernan WN, et al. N Engl J Med. 2016;doi: 10.1056/NEJMoa1506930). These results are in line with PROactive, an older study with pioglitazone, in people with diabetes (Dormandy JA, et al. Lancet. 2005. 366:1279-1289); although the primary outcome was barely missed, the secondary outcome results displayed reduction of stroke by 47% and myocardial infarction by 28%. In both studies, it seemed that reduction of glucose had no specific role in the CV outcome. Regardless of mechanism of action, which remains unclear, the final result is a fact.

Inzucchi and colleagues revealed that pioglitazone prevented diabetes by 51% in this population. These results support the findings of ACT NOW where pioglitazone reduced progression to diabetes by 72% and improved CV risk, significantly reducing the progression of carotid intima media thickness (a surrogate measure of atherosclerosis) by 31.5% (Defronzo RA, et al. BMC Endocr Disord. 2009;doi:10.1186/1472-6823-9-17). Of note in both trials, once pioglitazone was stopped, the progression to diabetes resumed.

Cusi and colleagues showed a reduction with pioglitazone of 58% in nonalcoholic fatty liver disease activity, and 51% had resolution of NASH as well as reduced hepatic triglyceride content. Of note the metabolic and histologic improvements seen in 18 months persisted over 36 months of therapy. This is the first pharmaceutical intervention to show such a significant effect on NASH.

Many health care systems restrict their members to use only the least expensive medications, typically generics. Until recently the only available agents were metformin, sulfonylureas and human insulin (whose price lately has also become quite high). Both insulin and sulfonylureas increase hypoglycemia when used in low doses.

All of a sudden pioglitazone becomes an attractive option. It is generic and inexpensive; recent trials highlight its safety and its efficacy beyond glucose control. In people with prediabetes and early diabetes, it may improve NAFLD and NASH and prevent diabetes. Not causing hypoglycemia, pioglitazone offers an attractive alternative to sulfonylurea as the second drug beyond metformin. It is recommended to use low-dose pioglitazone 15-30 mg, which helps to reduce its side effects. I propose that we are witnessing the comeback of pioglitazone.