Pioglitazone May Improve NASH Histology for Many Patients

Pam Harrison

February 27, 2017

The thiazolidinedione pioglitazone improves advanced fibrosis as well as fibrosis of any stage in nonalcoholic steatohepatitis (NASH), even in patients without diabetes, a meta-analysis suggests. A similar benefit was not seen with rosiglitazone.

"Nonalcoholic steatohepatitis is becoming a major public health issue and is a leading cause of liver transplant," Giovanni Musso, MD, from Humanitas Gradenigo Hospital, Turin, Italy, and colleagues observe.

"The new finding in this meta-analysis is that treatment with the antidiabetic drug pioglitazone reverses the more advanced stages of liver disease in NASH regardless of the presence of diabetes, which provides a rationale for evaluating the effect of this drug on clinical outcomes in this subgroup of patients at higher risk of liver-related complications," they added.

The study was published online February 27 in JAMA Internal Medicine.

The meta-analysis included eight randomized controlled trials (RCTs), five of which evaluated pioglitazone; the other three involved rosiglitazone. The doses used during each of the trials ranged from 4 to 8 mg for rosiglitazone and from 30 to 45 mg for pioglitazone. The duration of treatment ranged from 6 to 24 months. The overall analysis included 516 patients.

"Pooled results of RCTs showed that thiazolidinedione therapy was associated with improved advanced fibrosis [and] the effect size was significant when considering all patients with NASH," the authors report. The investigators defined improvement in advanced fibrosis as a drop in fibrosis stage from F3-F4 to F0-F2 on liver biopsy.

Specifically, the combined results for all studies showed that treatment with thiazolidinedione therapy improved advanced fibrosis by more than threefold compared with no treatment (odds ratio [OR], 3.15; 95% confidence interval [CI], 1.25 - 7.93; P = .01).

"Secondary outcomes were at least a 1-point improvement in fibrosis of any stage and NASH resolution," the researchers add. On the basis of this definition, thiazolidinedione therapy improved fibrosis of any stage by 66% (OR, 1.66; 95% CI, 1.12 - 2.47; P = .01), which was more than threefold more likely to lead to a resolution of NASH with an OR of 3.22 (95% CI, 2.17 - 4.79; P < .001) compared with no treatment


Results were similar for patients who did not have diabetes, among whom an almost threefold improvement in advanced fibrosis (OR, 2.95; 95% CI, 1.04 - 10.90; P = .02), a 76% improvement in fibrosis of any stage (OR, 1.76; 95% CI, 1.02 - 3.03; P = .02), and an almost 3.5-fold greater likelihood of NASH resolution (OR, 3.40; 95% CI, 1.95 - 5.93; P < .001) were observed again compared with no treatment.

Importantly, however, only pioglitazone treatment was associated with favorable changes in liver histology: the effect of rosiglitazone was nonsignificant in any of the RCTs examined. Patients who received treatment with a thiazolidinedione gained a mean of 2.7% body weight relative to patients in the control groups, and treatment was also associated with a 2.36-fold higher (95% CI, 1.15 - 4.84; P = .02) risk for lower limb edema.

However, because the number of the studies included in the meta-analysis was limited, and they were of relatively short duration, the authors may have been unable to detect more serious adverse events.

Trials Did Not Report Clinical Outcomes

In an accompanying editorial, Hal Yee Jr, MD, PhD, from the University of California in San Francisco, points out that although investigators did show that pioglitazone improved histological features in patients with NASH, the trials involved did not report on clinical outcomes.

"Although liver histological status is a commonly used surrogate outcome in evaluating the efficacy of treatments for other hepatic conditions, it might not correlate as well with clinical outcomes in patients with NASH, who are often obese and have type 2 diabetes and other complications of metabolic syndrome," he elaborates. These patients' risk of dying from a myocardial infarction or a stroke may therefore outweigh any morbid effects from NASH, Dr Yee points out.

Dr Yee was also not convinced that pioglitazone is that safe, pointing to warnings from the US Food and Drug Administration about the possible risk for bladder cancer and congestive heart failure associated with its use, both of which could pose potentially serious risks to patients. "Most individuals with NASH do not develop clinical sequelae of liver disease," Dr Yee writes. "It is only in patients with advanced hepatic fibrosis that poorer outcomes are observed. Hence, there is no reason to consider treating patients with NASH who do not have evidence of advanced fibrosis," he adds. For the great majority of patients, counseling on how to lose weight, increase exercise, and avoid excessive alcohol consumption should be the standard approach until more data confirm that treatment improves clinical outcomes, Dr Yee concludes.

The authors and editorialist have disclosed no relevant financial relationships.

JAMA Intern Med. Published online February 27, 2017. Article full text, Editorial full text

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