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Dx Dialogues: NASH

Expanding Treatment Options for NASH

Treatment for NASH now includes the first FDA-approved pharmacotherapy.

Expanding Treatment Options for NASH

Written by Annette Boyle. Medically reviewed by Mark Arrendondo, MD.

Treatment of NASH has relied of lifestyle changes, but a new medication offers the first targeted therapy for the disease.

Given the high degree of association between obesity and non-alcoholic steatohepatitis (NASH), the cornerstone of treatment has been weight loss and exercise. Weight loss of just 3% to 5% can reduce fat in the liver and loss of 10% or more of body weight resolves NASH in 90% of patients with 45% seeing fibrosis regression.[1]

Another aspect of diet may also reduce the risk of NASH and development of fibrosis – coffee. A meta-analysis found that drinking two or more cups of caffeinated coffee reduced the relative risk of liver fibrosis in individuals with non-alcoholic fatty liver disease (NAFLD) by 32%.[2]

New pharmacotherapy approved

In March 2024, the U.S. FDA approved the first pharmacotherapy for patients with NASH and stage 2 or 3 fibrosis, the patients at most risk of cirrhosis and hepatocellular carcinoma as well as liver-related and all-cause mortality.

“Previously, patients with NASH who also have notable liver scarring did not have a medication that could directly address their liver damage,” said Nikolay Nikolov, M.D., acting director of the Office of Immunology and Inflammation in the FDA’s Center for Drug Evaluation and Research. “Today’s approval of Rezdiffra will, for the first time, provide a treatment option for these patients, in addition to diet and exercise.”[3]

Rezdiffra (resmetirom) acts as a partial activator of a thyroid hormone receptor beta agonist that reduces fat in the liver. As thyroid hormones regulate liver lipid metabolism, resmetirom’s activation of this thyroid hormone receptor reduces fat in the liver.[4] In the pivotal trial, up to 29.9% of participants treated with resmitirom achieved NASH resolution and no increase in liver scarring and up to 28% of the resmetirom-treated participants saw a reduction in liver scarring and no worsening of NASH.[5]

Emerging and repurposed therapies

Several medications for diabetes also improve NASH, but fewer appear to reduce fibrosis. These include pioglitazone, a thiazolidinedione, and glucagon-like peptide 1 (GLP-1) receptor agonists.

Over a three-year period, 58% of trial participants who took 45 mg of pioglitazone per day in combination with a 500 kcal per day deficit diet achieved a two-point drop in their non-alcoholic fatty liver disease activity score in two histologic categories and 51% resolved NASH entirely compared to 19% of those randomized to diet only. Pioglitazone also reduced mean fibrosis scores, but this was not statistically significantly. Fewer patients demonstrated fibrosis progression compared to placebo, 12% vs 28%, respectively, (p=0.039).[6]  Pioglitazone can cause or worsen heart failure, lead to weight gain, accelerate loss of bone density, damage the liver and increase the risk of bladder cancer.[7]

While semaglutide did not demonstrate improvement in fibrosis in patients with NASH in a 48-week phase 2 trial,[8] two other GLP-1 receptor agonists have shown positive results.

A phase 2 trial of tirzepatide that enrolled 190 participants with biopsy-confirmed NASH and stage 2 or 3 fibrosis found that 44% to 62%, depending on dose, of those receiving tirzepatide achieved resolution of NASH without worsening of fibrosis compared to 10% of those receiving placebo at 52 weeks. Between 51% and 55% of those in the tirzepatide group saw a one stage or better improvement in fibrosis without worsening of NASH versus 30% in the placebo group.[9]

Retatrutide, a novel triple agonist of GLP-1, glucagon receptors and glucose-depended insulinotropic polypeptide, has recently shown outstanding results in resolving NAFLD, with 86% of participants achieving less than 5% liver fat in 24 weeks. Whether retatrutide will also reduce fibrosis remains to be determined, however.[10]

Pegozafermin, a long-acting glycopegylated fibroblast growth factor analogue, has also shown some effectiveness in reduction of fibrosis in patients with NASH and stage 2 or 3 fibrosis. A phase 2b trial found that fibrosis improved by one stage or more in 22% to 27%, (depending on dose) of participants who received pegozafermin once every two weeks for 24 weeks compared to 7% in the placebo group. NASH resolved in 23% to 37% of the pegozafermin group and 2% of the placebo group.[11].

Article Sourcesopen article sources

[1] Vilar-Gomez E, Martinez-Perez Y, Calzadilla-Bertot L, Torres-Gonzalez A, Gra-Oramas B, Gonzalez-Fabian L, Friedman SL, Diago M, Romero-Gomez M. Weight Loss Through Lifestyle Modification Significantly Reduces Features of Nonalcoholic Steatohepatitis. Gastroenterology. 2015 Aug;149(2):367-78.e5; quiz e14-5. doi: 10.1053/j.gastro.2015.04.005. Epub 2015 Apr 10. PMID: 25865049.

[2] Hayat U, Siddiqui AA, Okut H, Afroz S, Tasleem S, Haris A. The effect of coffee consumption on the non-alcoholic fatty liver disease and liver fibrosis: A meta-analysis of 11 epidemiological studies. Ann Hepatol. 2021 Jan-Feb;20:100254. doi: 10.1016/j.aohep.2020.08.071. Epub 2020 Sep 10. PMID: 32920163.

[3] FDA approves first treatment for patients with liver scarring due to fatty liver disease. US FDA. 14 Mar 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

[4] FDA approves first treatment for patients with liver scarring due to fatty liver disease. US FDA. 14 Mar 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-first-treatment-patients-liver-scarring-due-fatty-liver-disease

[5] Harrison SA, Bedossa P, Guy CD, Schattenberg JM, Loomba R, Taub R, Labriola D, Moussa SE, Neff GW, Rinella ME, Anstee QM, Abdelmalek MF, Younossi Z, Baum SJ, Francque S, Charlton MR, Newsome PN, Lanthier N, Schiefke I, Mangia A, Pericàs JM, Patil R, Sanyal AJ, Noureddin M, Bansal MB, Alkhouri N, Castera L, Rudraraju M, Ratziu V; MAESTRO-NASH Investigators. A Phase 3, Randomized, Controlled Trial of Resmetirom in NASH with Liver Fibrosis. N Engl J Med. 2024 Feb 8;390(6):497-509. doi: 10.1056/NEJMoa2309000. PMID: 38324483.

[6] Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, Tio F, Hardies J, Darland C, Musi N, Webb A, Portillo-Sanchez P. Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial. Ann Intern Med. 2016 Sep 6;165(5):305-15. doi: 10.7326/M15-1774. Epub 2016 Jun 21. PMID: 27322798.

[7] Pioglitazone. MedlinePlus. NIH National Library of Medicine. https://medlineplus.gov/druginfo/meds/a699016.html

[8] Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, Lawitz E, Ratziu V, Sanyal AJ, Schattenberg JM, Newsome PN; NN9931-4492 investigators. Semaglutide 2·4 mg once weekly in patients with non-alcoholic steatohepatitis-related cirrhosis: a randomised, placebo-controlled phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Jun;8(6):511-522. doi: 10.1016/S2468-1253(23)00068-7. Epub 2023 Mar 16. PMID: 36934740; PMCID: PMC10792518.

[9] Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, Yoneda M, Behling C, Cummings OW, Tang Y, Brouwers B, Robins DA, Nikooie A, Bunck MC, Haupt A, Sanyal AJ; SYNERGY-NASH Investigators. Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis. N Engl J Med. 2024 Jun 8. doi: 10.1056/NEJMoa2401943. Epub ahead of print. PMID: 38856224.

[10] Sanyal AJ, Kaplan LM, Frias JP, Brouwers B, Wu Q, Thomas MK, Harris C, Schloot NC, Du Y, Mather KJ, Haupt A, Hartman ML. Triple hormone receptor agonist retatrutide for metabolic dysfunction-associated steatotic liver disease: a randomized phase 2a trial. Nat Med. 2024 Jun 10. doi: 10.1038/s41591-024-03018-2. Epub ahead of print. PMID: 38858523.

[11] Loomba R, Sanyal AJ, Kowdley KV, Bhatt DL, Alkhouri N, Frias JP, Bedossa P, Harrison SA, Lazas D, Barish R, Gottwald MD, Feng S, Agollah GD, Hartsfield CL, Mansbach H, Margalit M, Abdelmalek MF. Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH. N Engl J Med. 2023 Sep 14;389(11):998-1008. doi: 10.1056/NEJMoa2304286. Epub 2023 Jun 24. PMID: 37356033; PMCID: PMC10718287.

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