Long-term treatment with the thiazolidinedione pioglitazone is safe and effective for patients with prediabetes or type 2 diabetes and nonalcoholic steatohepatitis (NASH), according to results of a randomized single-center study published online June 21 in the Annals of Internal Medicine.
Researchers led by Kenneth Cusi, MD, an endocrinologist at the University of Florida and Malcom Randall Veterans Affairs Medical Center in Gainesville, Florida, found long-term metabolic and histologic improvement associated with 3 years of pioglitazone, suggesting this drug may halt NASH progression and alter the natural history of the disease.
By 18 months, 58% of patients treated with pioglitazone had achieved the study's primary endpoint of histologic improvement vs 17% of placebo recipients (treatment difference, 41 percentage points; 95% confidence interval, 23 - 59 percentage points; P < .001). Pioglitazone's effect was even more evident in those patients who had definite NASH at baseline, with 67% of them achieving the primary outcome (P < .001) vs 17% for placebo (P < .001).
Overall, 51% patients who received pioglitazone achieved NASH resolution vs 19% in the placebo arm (treatment difference, 32 percentage points; 95% confidence interval, 13 - 51 percentage points; P < .001).
"Because the intervention proved to be safe and effective, these results may encourage early diagnosis and treatment of patients with prediabetes or [type 2 diabetes] and NASH," Dr Cusi and associates write.
At this time, NASH management focuses on improving metabolic parameters through weight loss, reduced insulin resistance, and improved diabetes control. "Although weight loss of 5% or greater may improve NASH, most affected persons are unable to achieve or sustain this amount of weight loss. Thus, pharmacologic therapies targeting NASH would be welcome additions to the therapeutic toolbox," write Eduardo Vilar-Gomez, MD, PhD, from the University of Seville, Spain, and Leon A. Adams, MBBS, PhD, from the University of Western Australia, Nedlands, in an accompanying editorial.
The randomized double-blind, placebo-controlled trial included 101 patients, of whom 87 had histologically confirmed NASH; 49% had prediabetes and 51% had type 2 diabetes. Patients were recruited between 2008 and 2014 from outpatient clinics and the general population in San Antonio, Texas, and tested at The University of Texas Health Science Center at San Antonio and randomly assigned to daily pioglitazone (n = 50) at 30 mg (titrated to 45 mg/day) or placebo (n = 51) for 18 months. They were also asked to follow a hypocaloric diet with a daily deficit of 500 kcal.
The mean age in the placebo and pioglitazone groups was 49 and 52 years, respectively, and both groups were predominantly Hispanic (73% and 62%, respectively) and male (69% and 72%, respectively). At baseline, 55% of participants in the placebo group and 48% of those in the pioglitazone group had diabetes. NASH was histologically confirmed in 88% and 84% in the two groups, respectively.
The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score (NAS) in two different histologic categories and no worsening of fibrosis.
Liver biopsies were performed at 0, 18, and 36 months, and at the 18-month biopsy, patients who failed to show histologic resolution of NASH were asked either to continue with or start on the drug. Eighty-three patients completed the first 18 months, and 63 completed the open-label phase of an additional 18 months.
The intervention group showed higher rates of improvement in the composite NAS and no worsening of fibrosis. Significant improvement was also evident in each of the three score components (steatogenesis, inflammation, and ballooning), and as mentioned earlier, NASH resolved in 51% of pioglitazone patients vs 19% of placebo recipients (P <0.001). Improvements seen at 18 months endured over the course of 36 months.
There was no significant intergroup difference, however, in fibrosis, with 39% in the intervention group vs 25% in the placebo group showing improvement. The change in the mean fibrosis score was also marginal with pioglitazone over placebo (−0.5 vs 0.0; P = .039).
Although the drug reduced fibrosis progression rates by 16 percentage points compared with placebo (12% vs 28% for placebo; P = .039), an additional 18 months of therapy did not yield more improvement beyond that observed at the 18-month biopsy.
The overall rate of adverse events was similar in both groups, although pioglitazone produced a modest weight gain of 2.5 kg vs placebo at 18 months, suggesting the weight control diet did not work. "The limited effect of a prescribed diet with a deficit of 500 kcal/d was consistent with prior lifestyle studies and highlights the need for trials to determine more efficacious long-term dietary interventions," Dr Cusi and colleagues write.
The authors also note the need for research to see whether reversing steatosis or NASH with pioglitazone in patients with prediabetes may prevent progression to type 2 diabetes mellitus. "This is important to address at a time when 37.2% of U.S. adults (86 million) have prediabetes," Dr Cusi and coauthors write. They called for research to compare the effects of pioglitazone in prediabetic patients vs those with type 2 diabetes mellitus and to study the drug's effects in more advanced hepatic fibrosis.
The editorialists suggest that according to a previous rosiglitazone trial, histologic improvement with this class of drugs coincides with initial gains in insulin sensitivity, likely during the first 6 months, and levels off when these stabilize.
In addition, as discontinuing pioglitazone in patients with NASH has been associated with worsening insulin sensitivity and liver outcomes, "a rationale for long-term treatment may be to reduce fibrosis progression rather than to normalize liver histologic parameters," Dr Vilar-Gomez and Dr Adams write.
They point out, however, that the trial was unable to identify a clinical profile for responders, and that only half of pioglitazone recipients had NASH resolution. Furthermore, only about 50% of patients in both groups had diabetes at baseline, and since the trial did not compare outcomes in diabetic vs prediabetic participants, "whether efficacy differs according to the presence of prediabetes or diabetes remains uncertain." In addition, it is not clear whether insulin sensitizers or other agents can reverse fibrosis.
"Whether physicians should include pioglitazone in the therapeutic arsenal for diabetic patients with NASH is unclear on the basis of this [randomized controlled trial," Dr Vilar-Gomez and Dr Adams write, adding that the risks of serial liver biopsies make confirmatory studies impractical.
Still, they recommend adding pioglitazone to the therapeutic toolbox for high-risk NASH and diabetes patients. "[T]he primary obstacle to the widespread use of pioglitazone remains its safety profile," they write. "Thus, treatment should be considered for patients at the greatest risk (those with NASH and fibrosis) and should be balanced against the common risk for weight gain and the uncommon risks for fracture and heart failure."
This study was supported by the Burroughs Wellcome Fund and the American Diabetes Association, with additional support from the National Center for Research Resources; the University of Texas Health Science Center, San Antonio, Clinical Research Center and Research Imaging Center; and the Veterans Affairs Medical Research Fund. Dr Cusi reported nonfinancial support from Takeda Pharmaceuticals (which provided the study medication and placebo), grants from Novartis and Janssen Research & Development, and consultancies for Eli Lilly and Company, Tobira Therapeutics, and Pfizer outside the submitted work. The other authors and editorialists commentators have disclosed no relevant financial relationships.
Ann Intern Med. Published online June 21, 2016. Article abstract, Editorial extract
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Cite this: Pioglitazone Improves Fatty Liver in Prediabetes, Diabetes - Medscape - Jul 05, 2016.