Comparative efficacy of interventions on nonalcoholic fatty liver disease (NAFLD): A PRISMA-compliant systematic review and network meta-analysis

Abstract

Background: The prevalence of nonalcoholic fatty liver disease (NAFLD) has significantly increased over the last decades. Despite existence of several interventions, there remains unclear which interventions work the best.

Methods: A systematic review and network meta-analysis of randomized trials comparing efficacy of all treatment options in NAFLD were performed to determine comparative efficacy and safety of interventions in the management of NAFLD. Several electronic databases were searched up to Nov 15, 2015. Outcomes include liver histological outcomes (i.e., fibrosis), all-cause mortality, cirrhosis, and safety. A network meta-analysis was applied to estimate pooled risk ratios (RR). Quality of evidence was assessed using GRADE criteria.

Results: A total of 44 studies (n = 3802) were eligible. When compared with placebo, obeticholic acid (OCA) was the only intervention that significantly improved fibrosis with RR (95% CI) of 1.91 (1.15, 3.16), while pentoxyfylline (PTX) demonstrated improved fibrosis without statistical significance with RR (95% CI) of 2.27 (0.81, 6.36). Only thiazolidinedione (TZD) and vitamin E use resulted in significant increase in resolution of NASH, while OCA, TZD, and vitamin E significantly improved other outcomes including NAS, steatosis, ballooning, and inflammation outcomes. Quality of evidence varied from very low (i.e., metformin, PTX on mean change of ballooning grade) to high (OCA, TZD, vitamin E on improving histological outcomes). Limitations of this study were lack of relevant long-term outcomes (e.g., cirrhosis, death, safety), possible small study effect, and few head-to-head studies.

Conclusions: Our study suggests potential efficacy of OCA, TZD, and vitamin E in improving histologic endpoints in NAFLD. These findings are however based on a small number of studies. Additional studies are awaited to strengthen this network meta-analysis.

Figure 1

Network map of binary outcomes for improvement of histological outcomes. A, Fibrosis. B, Resolution of NASH (nonalcoholic steatohepatitis). C, NAFLD activity score (NAS). D, Steatosis. E, Ballooning degeneration. F, Lobular inflammation. Met = metformin, PP = phospholipid, PTX = pentoxifyline, PUFA = polyunsaturated fatty acid, TZD = thiazolidinedione, UCDA = ursodeoxycholic acid, Vit C = vitamin C, Vit E = vitamin E.

Figure 2

Forest plot summary of network estimates of interventions compared with placebo (cointervention: advise of weight and diet control) on histological outcomes. A, Fibrosis. B, Resolution of NASH (nonalcoholic steatohepatitis). C, NAFLD activity score (NAS). D, Steatosis. E, Ballooning degeneration. F, Lobular inflammation. ^∗Quality of evidence was graded based on GRADE Working Group: High = we are very confident that the true effect lies close to that of the estimate of the effect, Moderate = we are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different, Low = our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect, Very low = we have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect. NAS = nonalcoholic fatty liver disease (NAFLD) activity score, NASH = nonalcoholic steatohepatitis, PP = phospholipid, PTX = pentoxifyline.