By David Fiore, MD
Professor of Family Medicine, University of Nevada, Reno
Dr. Fiore reports no financial relationships relevant to this field of study.
SYNOPSIS: In a meta-analysis of eight studies (five pioglitazone, three rosiglitazone) involving 516 patients with biopsy-proven nonalcoholic steatohepatitis, pioglitazone was found to improve fibrosis between six and 24 months. The clinical significance and potential harms of this treatment remain to be determined.
SOURCE: Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis:
A meta-analysis. JAMA Intern Med. Published online Feb. 27, 2017. doi: 10.1001/jamainternmed.2016.9607. [Epub ahead of print].
Nonalcoholic fatty liver disease (NAFLD) ranges from a benign incidental finding to nonalcoholic steatohepatitis (NASH) and eventually can lead to fibrosis and liver failure. Unfortunately, there is no established treatment for NASH, which is the second leading cause of liver transplantation.1-3 Previous studies have demonstrated that early NASH (NASH Clinical Research Network Scale F0-F2) has minimal effect on morbidity and mortality, but advanced fibrosis (F3-4) predicts poor outcomes.4,5 Reversal of fibrosis has been demonstrated with improvement of associated clinical conditions and weight loss, but there are no approved treatments directed at NASH specifically.6 Based on studies in diabetic patients and a prior meta-analysis by one of the current authors, the current meta-analysis was designed to assess the effect of thiazolidinedione therapy in NASH with advanced fibrosis.6
Using an inclusive search strategy, the authors identified 12,553 studies, of which 216 unique publications met inclusion criteria. Of those, only 16 were randomized, controlled trials assessing thiazolidinedione treatment of NAFLD. Only eight included post-treatment histological assessment. Of those eight studies, five were on pioglitazone and three on rosiglitazone, and included 516 patients. The primary outcome was improvement in advanced fibrosis, defined as an improvement in the NASH Clinical Research Network Scale from F3-4 to F0-2. Secondary outcomes were at least a one-point improvement in fibrosis of any stage and NASH resolution. Adverse effects of thiazolidinedione therapy, including weight gain, lower limb edema, congestive heart failure, bone fractures, cancer, and anemia, also were examined. Studies were abstracted by two of the authors independently, and agreement was good to excellent, with K statistics of 0.88 for study selection and 0.92 for quality assessment. Six trials were believed to contain low risk of bias (the two trials with higher risk of bias both evaluated rosiglitazone). Statistical heterogeneity was low for all outcomes evaluated.
Pooled results of the randomized, controlled trials demonstrated that thiazolidinedione therapy was associated with improvement in advanced fibrosis, and the effect size was significant — both when looking at all patients with NASH and only patients with NASH and advanced fibrosis at baseline. Further, patients with and without diabetes had similar improvements, and the observed beneficial effects of thiazolidinedione were restricted to the effects of pioglitazone.
As for adverse effects, thiazolidinedione therapy was associated with a mean 2.7% weight gain compared with controls and a higher odds ratio for lower limb edema (2.36) without any significant difference in agents, randomized, controlled trials, or trial duration. There was no increase in congestive heart failure, but this outcome was reported in only half the studies.
COMMENTARY
In addition to the exciting findings from this study, this meta-analysis has some strengths that often are missing from other meta-analyses. Primary among them are the high quality of the studies overall and the heterogeneity of the studies included. On the other hand, only 516 patients were included in the eight studies, and only 197 of those patients were on pioglitazone. Although it’s impressive that the authors found a benefit from treatment with pioglitazone, the small numbers do not allow discussion of treatment harms (other than the documented weight gain) with any confidence. This is especially concerning given the FDA’s recent warning that pioglitazone may be associated with bladder cancer, as well as concerns about congestive heart failure.7,8 Although the finding that pioglitazone reduced fibrosis in patients with NASH is very exciting, it must be tempered with the realization that we still do not know if it improves clinical outcomes such as ascites, encephalopathy, the need for liver transplant, or death rates. Even if pioglitazone can reduce liver-related complications of NASH, many of these patients have significant comorbidities that may affect their lives regardless of regression of liver fibrosis. Therefore, quality of life and overall mortality studies will be required to address this issue.
Our quandary is how to treat patients with NASH, given that progression is variable, there are no approved medical treatments, lifestyle changes are effective but difficult, and NASH with advanced fibrosis often is fatal. Clearly, the first step in all patients with NASH is aggressive lifestyle changes, with a focus on alcohol avoidance and weight loss.9 After that, the question remains: Which patients are likely to benefit from drug treatment, specifically with pioglitazone, given the lack of data about patient-oriented outcomes, such as ascites, need for transplant, and death, and the lack of information about adverse effects? It seems that a reasonable approach is to start (or continue) pioglitazone in diabetic patients with NASH and advanced fibrosis while holding off on starting pioglitazone in those with less advanced NASH unless there is another indication. Patients with advanced fibrosis who are not diabetic present an especially difficult dilemma given the high probability of poor outcomes combined with the lack of convincing data about the benefits of drug treatment. In these patients, a careful discussion of the pros and cons of treatment with shared decision-making would be most appropriate.
Although this meta-analysis gives us hope, the small number of patients and lack of outcome data on adverse effects must give us pause. With any meta-analysis, it’s always important to remember that “three second graders don’t equal a sixth grader.” That is, we need larger studies to confidently evaluate the benefits and (most importantly) the harms of new medical therapies.
REFERENCES
- Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-2023.
- Wong RJ, Aguilar M, Cheung R, et al. Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Gastroenterology 2015;148:547-555.
- Singal AK, Guturu P, Hmoud B, et al. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013;95:755-760.
- Ekstedt M, Hagström H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61:1547-1554.
- Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver fibrosis, but no other histologic features, is associated with long-term outcomes of patients with nonalcoholic fatty liver disease. Gastroenterology 2015;149:389-397.e10.
- Musso G, Cassader M, Rosina F, Gambino R. Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): A systematic review and meta-analysis of randomised trials. Diabetologia 2012;55:885-904.
- U.S. Food and Drug Administration Drug Safety Communications. Updated FDA review concludes that use of type 2 diabetes medicine pioglitazone may be linked to an increased risk of bladder cancer. Published online Dec. 12, 2016. Available at: http://bit.ly/2mM7c2j.pdf. Accessed March 21, 2017.
- Erdmann E, Charbonnel B, Wilcox RG, et al; PROactive Investigators. Pioglitazone use and heart failure in patients with type 2 diabetes and preexisting cardiovascular disease: Data from the PROactive study (PROactive 08). Diabetes Care 2007;30:2773-2778.
- Nseir W, Hellou E, Assy N. Role of diet and lifestyle changes in nonalcoholic fatty liver disease. World J Gastroenterol 2014;20:9338-9344.
In a meta-analysis of eight studies (five pioglitazone, three rosiglitazone) involving 516 patients with biopsy-proven nonalcoholic steatohepatitis, pioglitazone was found to improve fibrosis between six and 24 months.
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