04/09/2023
Management of NAFLD involves treating the liver disease itself as well as associated metabolic comorbidities, including diabetes, obesity, and hyperlipidemia. A recent clinical practice guideline from the American Association for the Study of Liver Diseases (AASLD) recommended that pharmacologic treatment aimed primarily at improving liver disease be limited to patients with biopsy-proven NASH and fibrosis, since patients without fibrosis generally have a favorable prognosis. As such, first-line treatment for most patients should focus on lifestyle intervention or pharmacologic treatment targeting diagnosed diabetes, obesity, or dyslipidemia. The AASLD guidelines recommend weight loss via hypocaloric diet and increased exercise, with a target of at least 7–10% weight loss to improve the majority of the histopathological features of NAFLD. The group recommends against metformin or GLP-1 agonists and recommends pioglitazone (a thiazolidinedione) in patients with biopsy-proven NASH, regardless of diabetes status, but recommends against using pioglitazone in NAFLD patients without fibrosis.
Consistent with the AASLD recommendation against metformin use in NAFLD patients, studies of metformin found no difference from placebo in steatosis, fibrosis, NAFLD activity score, or resolution of NASH. While weight and glucose control were improved with metformin, treatment with metformin did not substantially impact liver disease.
Studies of pioglitazone in NASH patients found benefits in liver function, liver fat, and NASH resolution, though significant increases in weight may be cause for concern. A recent systematic review and network meta-analysis by Sridharan et al. was consistent with our findings: pioglitazone was found to be associated with better response than standard care (odds ratio 3.8, 95% CI, 2.0 to 7.4). Evidence for other thiazolinediones was more limited and had somewhat mixed results, but findings were generally consistent with those for pioglitazone: liver fat and function and glucose measures improved, but weight also increased.
While the AASLD guidelines recommend against using GLP-1 agonists in NASH patients, we found some evidence that liraglutide improves liver fat, liver function, and HbA1c and is effective at resolving NASH and reducing weight. Exenatide performed less well but also resulted in significant reductions in liver fat and weight.
The strengths of our study include the use of systematic review processes to identify all relevant studies that meet pre-defined inclusion criteria, assessment of the internal validity (i.e., quality) of included studies, and overall evaluation of the strength of evidence using an established approach. Limitations of the present review include restriction to English-language publications and restriction to randomized trials, which may have limited generalizability to real-world populations. Larger studies with longer follow-up are needed to better quantify the long-term benefits and harms of diabetes medications to treat NAFLD, since the disease state itself, as well as many of the common metabolic conditions associated with NAFLD, are chronic conditions with long natural histories. Additionally, longer and larger studies may provide further information on clinical health outcomes and uncommon adverse effects.
Up to one in three people have something called non-alcoholic fatty liver disease (NAFLD), but many of them have no idea
