Emerging Treatments and Drug Repositioning for NAFLD and NASH

By Dr. Chinta SidharthanReviewed by Lily Ramsey, LLMAug 9 2024

Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver ailments that is not related to alcohol consumption, autoimmunity, or drug or viral exposure. A sedentary lifestyle and an unhealthy diet are the major causes of NAFLD, and the disease is associated with various metabolic syndromes such as dyslipidemia, obesity, and hypertension.

In a recent review published in the European Journal of Medicinal Chemistry, a team of researchers examined the current research on drug candidates and molecular targets being clinically tested for the treatment of non-alcoholic steatohepatitis (NASH) and NAFLD.

​​​​​​​Study: Decreasing the Burden of Non-Alcoholic Fatty Liver Disease: from Therapeutic Targets to Drug Discovery Opportunities. Image Credit: SoftSheep/Shutterstock.com

Background

Close to 30% of the global population suffers from NAFLD, primarily due to unhealthy dietary patterns and a lack of adequate physical activity. However, some genetic factors are believed to increase the susceptibility to NAFLD.

Apart from its associations with metabolic syndromes such as hypertension, obesity, and dyslipidemia, NAFLD is also believed to increase the risk of type 2 diabetes mellitus.

The disease can begin in the benign stages of steatosis or non-alcoholic fatty liver but progress to NASH, cirrhosis, or even hepatocellular carcinoma.

While the mechanisms through which fat accumulates in the liver have been extensively studied, the underlying mechanisms of the multifactorial pathophysiology of NAFLD and NASH remain unclear and hinder the development of effective treatment methods.

The present review examined the current disease management guidelines for NAFLD and NASH and discussed the clinical studies being conducted to identify novel molecular targets and test new drug candidates.

The researchers also discussed the strategies, such as drug repositioning, that are being used to reduce the time taken to approve new drugs.

Existing Therapeutic Options

While the global prevalence of NASH is estimated to be just over 5%, the progression from NAFLD to NASH is predicted to be substantial over the next decade.

Furthermore, since the comorbidities and complex pathogenesis of NAFLD make it difficult to treat effectively, the lifestyle changes that are often recommended to improve symptoms of NAFLD are also not adequate to treat NASH. The researchers covered some of the recommended and approved therapeutic options currently available for NASH and NAFLD.

Non-specific pharmacotherapy such as pioglitazone, vitamin E, statins, and agonists for the glucagon-like peptide-1 (GLP-1) receptor have often been recommended for NASH along with substantial modifications to the lifestyle.

Pioglitazone is an anti-diabetic medication that targets the peroxisome proliferator-activated receptor (PPAR) gamma and is believed to reduce hepatic fat. However, it is associated with adverse effects such as weight gain and increased risk of cancer.

Vitamin E carries a similar risk of malignancy but is recommended for non-diabetic individuals with NASH to reduce inflammation and steatosis.

Statins have been recommended for patients with NASH based on their ability to lower inflammation and improve lipid profiles. Still, adverse reactions such as cognitive impairments and muscle pain indicate that they should be used carefully. The GLP-1 receptor agonist semaglutide has been promising in improving metabolic profiles.

The therapies currently approved for NASH and NAFLD include resmetirom, which specifically targets the thyroid hormone receptor β in the liver and has effectively lowered cholesterol and body weight and decreased hepatic steatosis without adverse cardiovascular effects.

Novel Drugs and Molecular Targets

The lack of effective pharmacotherapy to lower the inflammation and liver fibrosis in NAFLD and NASH has resulted in a greater focus on novel drug discovery and exploring new molecular targets.

New agonists of PPAR, such as gemfibrozil and saroglitazar, are being explored to effectively improve liver function without many of the side effects of previous PPAR agonists.

A wide range of anti-diabetic medications are also being examined to lower the exacerbation of NASH and NAFLD due to type 2 diabetes. These include metformin, the approved adenosine monophosphate-activated protein kinase activator, and GLP-1 agonists such as tirzepatide.

Sodium-glucose co-transporter-2 inhibitors such as canagliflozin have also shown promise in improving metabolic profiles in patients with NAFLD.

While clinical trials examining dipeptidyl peptidase-4 inhibitors have reported metabolic parameter improvements, their effect on lowering liver fibrosis and fat has been inconsistent, warranting more robust clinical trials.

The review also discussed a range of other molecular targets and novel therapeutic options for NAFLD, including lipid-lowering agents, acetyl-coenzyme A carboxylase inhibitors, ligands for the farnesoid X receptor, redox modulators, cannabinoid antagonists and agonists, A3 adenosine receptor agonists, and several anti-inflammatory, anti-fibrotic, and anti-apoptotic agents.

Rational Drug Discovery and Design

The focus of current pharmacological research on NAFLD has shifted towards multitarget compounds aimed at multiple metabolic pathways. In preclinical models, Farnesoid X receptors, PPAR agonists, and free fatty acid receptor one agonist have effectively lowered inflammation, fibrosis, and liver damage.

Mitochondria-associated antioxidants are also being explored as multitarget compounds for their ability to mitigate damage due to oxidative stress.

Drug repositioning, where existing, withdrawn, and failed candidates are repurposed for new targets and uses, is also being applied as a faster drug development option for NAFLD.

This process uses existing safety profiles while reducing developmental time and costs. Niclosamine, niacin, and telmisartan are repositioned drugs that have shown promise in lowering fibrosis, damage, and inflammation in NASH and NAFLD.

Conclusions

Overall, the review presented a comprehensive yet concise examination of the current status of NAFLD and NASH therapy and the pharmacological options explored to develop novel drugs and identify new molecular targets to treat liver damage, fibrosis, and inflammation in NAFLD.

The researchers also discussed the research on developing multitarget drugs and repositioning existing drugs to treat NAFLD.