Adults with type 2 diabetes randomly assigned Actos therapy were more likely to experience a reduction in nonalcoholic steatohepatitis activity vs. those assigned a placebo, according to study findings published in Annals of Internal Medicine.
In a single-center, parallel-group study, Kenneth Cusi, MD, FACP, FACE,chief of the division of endocrinology, diabetes and metabolism at the University of Florida in Gainesville and Endocrine Today Editorial Board member, and colleagues analyzed data from 101 patients with prediabetes or type 2 diabetes (confirmed via oral glucose tolerance test) and histologically confirmed nonalcoholic steatohepatitis activity (NASH). After baseline measurements (OGTT, euglycemic insulin clamp, DXA scan and liver biopsy), researchers assigned patients to a 500-kcal deficit diet and then randomly assigned them to 30 mg daily Actos (pioglitazone, Takeda Pharmaceuticals), titrated at 2 months to 45 mg daily (n = 50; mean age, 52 years; 72% men; 28% white; 48% with type 2 diabetes), or placebo (n = 51; mean age, 49 years; 69% men; 22% white; 55% with type 2 diabetes) for 18 months. At 18 months, patients again underwent metabolic measurements and a liver biopsy; those on pioglitazone were asked to continue therapy for another 18 months while participants in the placebo group whose NASH resolved were asked to discontinue use; those with persistent disease were invited to initiate pioglitazone therapy for 18 months.
The primary outcome was a reduction of at least two points in the nonalcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis at 18 months.
Within the cohort, 18 patients (nine in each group) withdrew from the study before 18 months after being informed in 2011 about a potential risk for bladder cancer with pioglitazone. An additional four patients in each group withdrew during the open-label phase (months 18 to 36) for similar reasons.
Researchers found that more patients assigned to pioglitazone achieved the primary outcome vs. those assigned placebo (58% vs. 17%; P < .001); more patients in the pioglitazone group also had resolution of NASH vs. placebo (51% vs. 19%; P < .001). Pioglitazone therapy also was associated with improvement in individual histologic scores, including fibrosis score, with progression of any fibrosis during 18 months occurring in 12% of pioglitazone patients vs. 28% of placebo patients (P = .039).
Pioglitazone also reduced hepatic triglyceride content from 19% to 7% vs. 15% to 11% in the placebo group, and improved adipose tissue, hepatic and muscle insulin sensitivity (P < .001 for all). All 18-month metabolic and histologic improvements persisted during 36 months of therapy.
There were no between-group differences for adverse events; weight gain was greater with pioglitazone (2.5 kg).
“This histologic benefit, combined with improvement in the mean fibrosis score, suggests that pioglitazone may alter the natural history of the disease,” the researchers wrote. “Evidence of this was the reduction in fibrosis progression over 18 months in patients treated with pioglitazone compared with those receiving placebo.”
The study results are likely to change management of patients with type 2 diabetes and fatty liver, Cusi told Endocrine Today. Pioglitazone, he said, could potentially become for NASH what metformin is to the treatment of type 2 diabetes.
“Until this study, we lacked definitive long-term treatment evidence of safety and benefit for such patients,” Cusi said in an interview. “This study shows now that if you have type 2 diabetes, or even prediabetes, and you take pioglitazone, more than half [of patients] have resolution of NASH. What this means is that endocrinologists will have to think about whether the patient has a fatty liver or not as they consider their second-line therapy after metformin.
“This really is a big game changer,” Cusi said. “NASH may lead to end-stage liver disease, and is currently the second cause of liver transplantation in the United States. We have a drug that may change the natural history of liver disease, prevent the onset of type 2 diabetes as shown in ACT NOW, and ameliorate the risk for coronary artery disease or that of stroke, as recently shown by Kernan et al this year in the New England Journal of Medicine. The cost of pioglitazone will decrease over time, as it currently has a generic formulation, and its safety profile has been tested for over 15 years with issues such as bladder cancer having been cleared from the study published by Lewis et al in JAMA last year. Now endocrinologists will think about and diagnose NASH more often in daily practice, having a safe and effective treatment option at hand.– by Regina Schaffer