Steatotic liver disease - Emerging treatments

Resmetirom

Resmetirom is a liver-directed, partial agonist of thyroid hormone receptor-beta which reduces intrahepatic triglycerides. It has been approved by the Food and Drug Administration (FDA), under the accelerated approval pathway, for the treatment of patients with noncirrhotic metabolic dysfunction-associated steatohepatitis (MASH) with moderate to advanced fibrosis (consistent with stages F2 to F3 fibrosis) in conjunction with diet and exercise.[121][122] It is also approved in Europe for the same indication. The approval has provided a treatment option for patients with significant liver scarring for the first time. The phase 3 trial is ongoing and has found resmetirom to be superior to placebo with respect to resolution of MASH and improvement in liver fibrosis by at least one stage.[121][123] Resmetirom is not recommended for patients with compensated or decompensated cirrhosis, those with concomitant uncontrolled active liver diseases (e.g., autoimmune hepatitis, primary biliary cholangitis), those with acute cholecystitis, or those who have moderate or heavy alcohol intake.[122] If patients have thyroid abnormalities, resmetirom therapy may be started once thyroid function has been optimized.[122] The American Association for the Study of Liver Diseases advises to discontinue resmetirom if hepatotoxicity develops.[122]

Fibroblast growth factor 21 (FGF21) analogs

Efruxifermin is a long-acting Fc-fusion FGF21 analog. Treatment with efruxifermin reduced hepatic fat fraction significantly more than treatment with placebo in one phase 2A trial.[124] The phase 2B HARMONY trial showed promising results wherein an improvement in liver fibrosis and resolution of MASH was noted over 24 weeks in patients with F2 or F3 fibrosis who were treated with efruxifermin.[125] Pegozafermin is a glycopegylated FGF21 analog that has shown improvements in fibrosis in patients with MASH in one phase 2B trial.[126] A phase 3 trial (ENLIGHTEN-Fibrosis) to evaluate safety and efficacy of pegozafermin in MASH is in progress.[127] The FDA has granted breakthrough therapy designation to efruxifermin and pegozafermin for the treatment of MASH. Pegbelfermin is a pegylated human FGF21 analog that can reduce hepatic fat fraction and improve metabolic factors and biomarkers of hepatic injury and fibrosis.[128] Clinical trials (FALCON1 and FALCON2) have evaluated the performance of pegbelfermin in patients with MASH and bridging fibrosis or compensated cirrhosis.[128][129][130][131] Both trials failed to meet the primary endpoints.[129][130] Pegbelfermin was generally well tolerated during the treatment.[129][130]

Pan-peroxisome proliferator-activated receptor (PPAR) agonists

The PPAR nuclear receptor transcription factors (alpha, delta, and gamma) regulate many aspects of metabolism, primarily lipid storage, fatty acid oxidation and uptake, and triglyceride turnover. In a phase 2B trial the pan-PPAR agonist lanifibranor was associated with resolution of MASH and improvement of fibrosis, compared with placebo.[132] A phase 3 trial is in progress.[133]

Sodium-glucose cotransporter-2 (SGLT2) inhibitors

SGLT2 inhibitors (e.g., dapagliflozin, empagliflozin) prevent renal reabsorption of glucose. Studies have shown that treatment with SGLT2 inhibitors reduces liver fat content.[91][134] Other studies have reported an improvement in serum liver enzymes and improvement in steatotic liver disease (SLD) in patients with type 2 diabetes and metabolic dysfunction-associated steatotic liver disease (MASLD).[135] One randomized, open-label trial evaluated combination therapy of empagliflozin plus pioglitazone in patients with type 2 diabetes and MASLD.[136] The study reported significant reduction in liver fat and stiffness compared with monotherapy in this patient group. Another double-blind, randomized controlled trial found that treatment with dapagliflozin led to significantly improved outcomes in patients with MASH without worsening of fibrosis, as well as fibrosis improvement without worsening of MASH, compared with placebo.[137]

Pentoxifylline

Pentoxifylline inhibits production of tumor necrosis factor-alpha, which has been hypothesized to contribute to the progression of MASH. Two small randomized placebo-controlled trials found that pentoxifylline is safe and well tolerated in patients with MASH.[138][139] One study reported improved histologic features after 12 months of treatment with pentoxifylline; the other found that biochemical and histologic features did not differ significantly between treatment arms at 12 months.[138][139] Any beneficial effects of pentoxifylline are likely mediated through decreasing lipid oxidation.[140]

Glucagon-like peptide-1 (GLP-1) agonists

Both liraglutide and semaglutide have led to histologic resolution in patients with MASH in separate multicenter, double-blinded, randomized, placebo-controlled phase 2 trials.[141] However, liraglutide also demonstrated less progression of fibrosis, which was not evident with semaglutide. Semaglutide can be considered for treating type 2 diabetes mellitus or obesity in patients with MASH, as it provides cardiovascular benefit and improves MASH.[3]

Dual GLP-1/glucagon receptor agonists

Dual GLP-1/glucagon receptor agonists are under development. Pemvidutide is being investigated for the treatment of obesity and MASH. A phase 2B trial (IMPACT) to evaluate safety and efficacy of pemvidutide in MASH is in progress.[142] Efinopegdutide has shown a significantly greater reduction in the liver fat content in patients with MASLD, compared with semaglutide.[143] A phase 2B trial in patients with MASH is in progress.[144] The FDA has granted fast-track designation to pemvidutide and efinopegdutide for the treatment of MASH.

Omega-3 fatty acids

Systematic review and meta-analyses suggest that omega-3 supplementation may decrease liver fat and lower aminotransferases in patients with MASLD.[145][146] The optimal dose is currently not known.[145]

L-carnitine

L-carnitine is a quaternary amine that has been shown to beneficially modulate lipid profile, glucose metabolism, oxidative stress, and inflammatory response. One study demonstrated a significant improvement in laboratory and histological parameters.[147]

Aramchol

Aramchol is a fatty acid-bile acid conjugate that has been shown to safely reduce liver fat content in patients with MASH in small studies.[148]

Aspirin

One prospective cohort study reported significantly lower odds of MASH and fibrosis in patients with biopsy-proven MASLD who took daily aspirin, compared with nonregular aspirin users. Daily aspirin users had a lower risk of fibrosis progression, compared with nonregular aspirin users. The relationship appeared to be duration-dependent, with the greatest benefit seen after 4 years of aspirin use.[149]

Ervogastat/clesacostat

Ervogastat/clesacostat is a combined therapeutic agent. Ervogastat is a diacylglycerol O-acyltransferase 2 (DGAT2) inhibitor, and clesacostat is an acetyl-CoA carboxylase (ACC) inhibitor. This therapy showed efficacy in one phase 2A trial for reducing liver fat with a favorable safety and tolerability profile.[150] Ervogastat/clesacostat has received fast-track designation by the FDA for the treatment of MASH.[151]