Practice Update: DIABETES

MY PERSPECTIVE 21

cardiovascular events. They conducted a multicenter, double-blind trial (called the IRAS study), in which 3876 patients who had had a recent ischemic stroke or TIA were randomized to receive either pio- glitazone (45 mg/day) or placebo. After a mean follow-up of 4.8 years, they observed that the primary outcome had occurred in 175 of 1939 patients (9.0%) in the piogli- tazone-treated group and in 228 of 1937 patients (11.8%) in the placebo-treated group (HR for pioglitazone, 0.76; 95% CI, 0.62–0.93; P = 0.007). They also noted that pioglitazone was associated with sig- nificantly less progression to diabetes (HR, 0.48; 95% CI, 0.33–0.69; P< 0.001). As expected, pioglitazone was associated with more weight gain (52.2% vs 33.7% gained >4.5 kg; P < 0.0001) and edema (reported in 35.6% vs 24.9%; P < 0.001). Also, significantly more bone fractures requiring surgery or hospitalization were noted with pioglitazone compared with pla- cebo (5.1% vs 3.2%; P = 0.003). Collectively, these two trials demonstrate that insulin sensitization with pioglitazone can have beneficial effects beyond glu- cose control. In both trials, pioglitazone was generally well-tolerated, with a side-effect profile consistent with that seen in patients with diabetes. Since NAFLD/NASH and cardiovascular disease are common com- plications of type 2 diabetes, these results suggest that we should rethink the role of pioglitazone as we seek to improve global outcomes in patients with type 2 diabetes. References 1. Nissen S, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med 2007;356(24):2457-2471. 2. Cusi K, Orsak B, Bril F, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med 2016;165(5):305-315. 3. Kernan WC, Viscoli CM, Furie KL, et al. Collectively, these two trials demonstrate that insulin sensitization with pioglitazone can have beneficial effects beyond glucose control. In both trials, pioglitazone was generally well-tolerated, with a side- effect profile consistent with that seen in patients with diabetes.

the treatment of nonalcoholic steatohepati- tis (NASH). 2 Nonalcoholic fatty liver disease (NAFLD) and the more serious NASH are two of the more common complications of obesity, insulin resistance, and type 2 diabetes. There is evidence that treat- ment with TZDs decreases hepatic lipid stores, while increasing subcutaneous fat. Cusi and colleagues randomized 101 patients with prediabetes or type 2 diabe- tes mellitus and biopsy-proven NASH to pioglitazone, 45 mg/day, or placebo and observed them for 18 months. This was fol- lowed by an 18-month open-label phase with pioglitazone treatment. They found a decrease of 41 percentage points (95% CI, 23–59 percentage points; P < 0.001) in the primary outcome (a reduction of at least 2 points in the NAFLD activity score in two histologic categories without worsening of fibrosis) in pioglitazone-treated patients compared with controls. Remarkably, 51% of patients treated with pioglitazone had resolution of NASH (P < 0.001). Pio- glitazone treatment also was associated with reduced hepatic triglyceride content, from 19% to 7% (treatment difference, −7 percentage points; 95% CI, −10 to −4 per- centage points; P < 0.001) and improved hepatic and peripheral insulin sensitivity, as expected. This study is important because

NAFLD and NASH are highly prevalent among patients with type 2 diabetes and are associated with significant long-term risks for cirrhosis and hepatocellular carci- noma. Until this study, there were no highly effective medications for these conditions. These data suggest that, in addition to weight loss, treatment with pioglitazone can be considered for patients with NASH. Further larger and longer-term studies will be required before this can become a gen- eral treatment recommendation, however. The second paper featured in Prac- ticeUpdate also explored the use of pioglitazone for a novel indication. Kernan and colleagues studied pioglitazone for the prevention of fatal or nonfatal stroke or myocardial infarction in patients with insulin resistance (but not diabetes) who had previously experienced an ischemic stroke or transient ischemic attack (TIA). 3 Such patients are known to be at high risk for subsequent cardiovascular events. Current preventive therapies addressing lipids, blood pressure, and the coagulation system do not address insulin resistance, which has been identified as an independ- ent risk factor for stroke and myocardial infarction. Thus, the investigators asked whether treatment with the insulin sensi- tizer pioglitazone would prevent further

Pioglitazone after ischemic stroke or transient ischemic attack. N Engl J Med 2016;374(14):1321-1331.

VOL. 1 • NO. 1 • 2017