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Novel Therapeutics Emerge for Treating NAFLD via Endocrine Pathways

There are currently no US Food and Drug Administration-approved therapies for nonalcoholic fatty liver disease (NAFLD), though multiple endocrine-based therapeutic options show promise for treating hepatic lipogenesis and insulin resistance.

This was a topic of discussion during a session led by Steven Grinspoon, MD, who is a professor of medicine, chief of the Metabolism Unit, and director of the Nutrition Obesity Research Center at Harvard Medical School in Cambridge, Massachusetts.

He started his presentation with an overview of critical endocrine pathways in the development of NAFLD/NASH, which may contribute to the pathogenesis via prehepatic and intrahepatic mechanisms.

“Critically, the insulin resistance and increased substrate flux to the liver lead to increased de novo lipogenesis, which is really the primary mechanism for a hepatic triglyceride buildup,” Dr Grinspoon explained. “In addition, there are other mechanisms, such as decreased lipid export and decreased lipid oxidation, which may contribute.”

Selective insulin resistance plays a large role in the development of NAFLD, Dr Grinspoon went on to say. Increased Insulin in the context of insulin resistance increases de novo lipogenesis and leads to an increase in intrahepatic lipid.

Then, he spoke about some strategies for treatment.

GLP‑1 Agonists

Because no medications are approved by the FDA for treating NAFLD specifically, other agents are often used according to their indications to help reduce the risk of developing NAFLD/NASH. For instance, GLP-1 agonists are marketed for treating diabetes and have salient properties related to lipid metabolism and insulin sensitivity in the liver.

“GLP‑1 agonists increase insulin secretion, but importantly act to reduce insulin resistance decrease appetite, and delay gastric emptying,” Dr Grinspoon said. “Critically these agents reduce weight and likely reduce substrate flux to the liver.”

In addition to weight loss, GLP-1 agonists can help decrease hepatic glucose production, increase glucose uptake, and increase lipolysis.1 Liraglutide has also been shown in early phase trials to improve NAFLD/NASH for patients without diabetes2, and the effects are independent of weight loss.3 However, GLP-1 agonists are not yet approved for this indication.

“This is a promising class of agents, but whether they'll work specifically as standalone agents in NAFLD/NASH needs to be proven in larger phase 3 trials,” Dr Grinspoon said.

Thyroid Hormone (TH) Receptor β Agonists

These agents, Dr Grinspoon said, increase cholesterol metabolism through effects on bile acid  metabolism; reduce fatty acid synthesis in the liver, which leads to fatty acid triglyceride breakdown; promote liver regeneration; prevent apoptosis; and reduce inflammation.

“The β receptors are located primarily in the liver, the pituitary, and the hypothalamus,” Dr Grinspoon explained. “This is the genius of these receptor agonists in that they activate the β receptor typically on the liver.”

Specifically, resmetirom (MGL-3196) was developed to decrease lipid levels. Results of a 36-week randomized controlled trial4 showed that resmetirom had significantly decreased liver fat among patients with biopsy-confirmed NASH, and it significantly improved NASH resolution without fibrosis worsening.

“I think the jury is still out on the safety of this class of agents, though resmetirom appeared safe in this phase 2 study,” Dr Grinspoon said. “But there's a very large phase 3 trial with 2,000 participants that's now underway.”

Fibroblast Growth Factor 21 (FGF21)

These agents enhance β‑cell function in the pancreas, suppress hepatic lipogenesis, increase β oxidation, upregulate thermogenic genes in the brown adipose tissue, and have anti‑inflammatory effects on macrophages. These effects may decrease appetite and sugar intake, thereby reducing steatosis.

In a small study4, pegbelfermin (BMS-986036) was shown to significantly reduce liver fat, improve low-density lipoprotein cholesterol and alanine aminotransferase levels, increase adiponectin levels, and decrease PRO‑C3, a profibrotic marker.

“It's a fairly small study, but an interesting compound that may be further evaluated in larger studies in the future,” Dr Grinspoon concluded.

Growth-Hormone–Releasing Hormone (GHRH) Analog Therapy

GHRH is released from the hypothalamus and triggers pulsatile release of growth hormone from the pituitary gland. The growth hormone then acts on the liver to increase IGF‑1.

An early mouse study5 found that knock out of the growth hormone receptor is associated with increased hepatic triglyceride content and upregulation of genes associated with increased lipid uptake, de novo lipogenesis, and liver inflammation. When IGF-1 levels were restored in these mice, there was only a partial restoration of normal liver fat levels implying direct effects of GH signaling on liver fat accumulation.

“There are a number of specific mechanisms that are contributing to NAFLD, which may be important targets for therapeutics in NAFLD/NASH,” Dr Grinspoon concluded. “Specifically, targeting insulin resistance, hepatic lipogenesis. and reduced growth hormone signaling in the liver may reduce NAFLD/NASH. Clearly, further studies are needed to translate these observations to clinically effective therapies.”

—Amanda Balbi

 

REFERENCES

  1. Yan J, Yao B, Kuang H, et al. Liraglutide, sitagliptin, and insulin glargine added to metformin: the effect on body weight and intrahepatic lipid in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease. Hepatology. 2019;69(6):2414-2426. https://doi.org/10.1002/hep.30320
  2. Armstrong MJ, Gaunt P, Aithal GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study. Lancet. 2016;387(10019):679-690. https://doi.org/10.1016/S0140-6736(15)00803-X
  3. Armstrong MJ, Hull D, Guo K, et al. Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis. J Hepatol. 2016;64(2):399-408. https://doi.org/10.1016/j.jhep.2015.08.038
  4. Sanyal A, Charles ED, Neuschwander-Tetri BA, et al. Pegbelfermin (BMS-986036), a PEGylated fibroblast growth factor 21 analogue, in patients with non-alcoholic steatohepatitis: a randomised, double-blind, placebo-controlled, phase 2a trial. Lancet. 2018;392(10165):2705-2717. https://doi.org/10.1016/S0140-6736(18)31785-9
  5. Liu Z, Cordoba-Chacon J, Kineman RD, et al. Growth hormone control of hepatic lipid metabolism. Diabetes. 2016;65(12):3598-3609. https://doi.org/10.2337/db16-0649