ABSTRACT
Introduction: There is an urgent as yet unmet need to develop highly effective and safe therapeutics for nonalcoholic fatty liver disease (NAFLD). The remarkable progress in understanding NAFLD pathogenesis allowed the identification of injury pathways which may be recruited as therapy targets.
Areas covered: This article reviews the safety and tolerability data of the NAFLD therapies and explains the mechanistic basis for each of the established and investigational drugs. Treatment targets include: weight loss, anti-metabolic agents such as lipid lowering and anti-diabetic drugs, inflammation, fibrosis and others such as targeting gut microbiota, immune modulation and apoptosis.
Expert opinion: Current therapies continue to remain suboptimal. Weight loss is effective but hard to achieve. Traditional and endoscopic bariatric procedures are promising although more randomized trials are needed and the long-term safety remains to be established. Clinical trials have demonstrated the efficacy of several drugs for the treatment of NASH. Of these, there remains some uncertainty about the long-term safety of vitamin E. Pioglitazone is associated with osteopenia, fluid retention and weight gain. Obeticholic acid causes pruritus in a substantial proportion of subjects and elafibranor has been associated with transient rises in creatinine. Several exciting therapies are under development and results of clinical and post-marketing trials will help elucidate their safety.
Article highlights
The remarkable advances in understanding NAFLD pathogenesis allowed the discovery of injury pathways and new therapy targets, however current treatment continues to remain suboptimal.
Weight loss is proven effective but hard to achieve with lifestyle and diet modifications. Bariatric procedures and surgeries are promising although more randomized trials are needed.
Available literature now proves the efficacy and safety of pioglitazone and demonstrates reduction in cardiovascular risk and all-cause mortality, but restates weight gain and precipitation of heart failure as potential side effects. Vitamin E is effective, however some but not all trials raised a concern over possible increase in all-cause mortality and in prostate cancer.
Pruritus with OCA is a common and dose-dependent side effect and may lead to treatment discontinuation in 3–4% of patients. Decrease in serum HDL levels was also observed with OCA and warrants long-term studies. Elafibranor is associated with transient rises in creatinine.
Several anti-fibrotic agents have shown promise in improving fibrosis in NASH, such as: cenicrivaroc, selonsertib and galectin-3 inhibitor (GR-MD-02). Although available safety data are encouraging, further studies and post-marketing analyses are required.
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Potential competing interests
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Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.