Pharmacotherapy in metabolic-dysfunction-associated steatotic liver disease: an updated review of the past, present and a promising future

Ciardullo S, Monti T, Perseghin G. High prevalence of advanced liver fibrosis assessed by transient elastography among US adults with type 2 diabetes. Diabetes Care. 2020;44:519–25.

PubMed  Google Scholar 

Medscape. FDA Approves First Drug for MASH — medscape.com. Accessed 29-01-2025

Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62:720–33.

CAS  PubMed  Google Scholar 

Vázquez-Carrera M. Unraveling the effects of PPARβ/δ on insulin resistance and cardiovascular disease. Trends Endocrinol Metab. 2016;27:319–34.

PubMed  Google Scholar 

Cusi K, Isaacs S, Barb D, Basu R, Caprio S, Garvey WT, et al. American association of clinical endocrinology clinical practice guideline for the diagnosis and management of nonalcoholic fatty liver disease in primary care and endocrinology clinical settings. Endocr Pract. 2022;28:528–62.

PubMed  Google Scholar 

Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.

CAS  PubMed  Google Scholar 

Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, et al. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med. 2010;362:1675–85.

CAS  PubMed  PubMed Central  Google Scholar 

Cusi K, Orsak B, Bril F, Lomonaco R, Hecht J, Ortiz-Lopez C, et al. Long-term pioglitazone treatment for patients with nonalcoholic steatohepatitis and prediabetes or type 2 diabetes mellitus: a randomized trial. Ann Intern Med. 2016;165:305.

PubMed  Google Scholar 

Musso G, Cassader M, Paschetta E, Gambino R. Thiazolidinediones and advanced liver fibrosis in nonalcoholic steatohepatitis: a meta-analysis. JAMA Intern Med. 2017;177:633.

PubMed  PubMed Central  Google Scholar 

Lefere S, Puengel T, Hundertmark J, Penners C, Frank AK, Guillot A, et al. Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆. J Hepatol. 2020;73:757–70.

CAS  PubMed  Google Scholar 

Francque SM, Bedossa P, Ratziu V, Anstee QM, Bugianesi E, Sanyal AJ, et al. A randomized, controlled trial of the pan-PPAR agonist lanifibranor in NASH. N Engl J Med. 2021;385:1547–58.

CAS  PubMed  Google Scholar 

Ratziu V, Harrison SA, Francque S, Bedossa P, Lehert P, Serfaty L, et al. Elafibranor, an agonist of the peroxisome proliferator−activated receptor−α and −δ, induces resolution of nonalcoholic steatohepatitis without fibrosis worsening. Gastroenterology. 2016;150:1147-1159.e5.

CAS  PubMed  Google Scholar 

Genfit. Genfit-announces-results-interim-analysis-resolve-it-phase-3. 2024. Accessed 29-01-2025.

Kaul U, Parmar D, Manjunath K, Shah M, Parmar K, Patil KP, et al. New dual peroxisome proliferator activated receptor agonist-Saroglitazar in diabetic dyslipidemia and non-alcoholic fatty liver disease: integrated analysis of the real world evidence. Cardiovasc Diabetol. 2019;18:80.

PubMed  PubMed Central  Google Scholar 

Gawrieh S, Noureddin M, Loo N, Mohseni R, Awasty V, Cusi K, et al. Saroglitazar, a PPAR-α/γ agonist, for treatment of NAFLD: a randomized controlled double-blind phase 2 trial. Hepatology. 2021;74:1809–24.

CAS  PubMed  Google Scholar 

Goyal O, Nohria S, Goyal P, Kaur J, Sharma S, Sood A, et al. Saroglitazar in patients with non-alcoholic fatty liver disease and diabetic dyslipidemia: a prospective, observational, real world study. Sci Rep. 2020;10:21117.

CAS  PubMed  PubMed Central  Google Scholar 

Jani RH, Pai V, Jha P, Jariwala G, Mukhopadhyay S, Bhansali A, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared with placebo in type 2 diabetes mellitus patients having hypertriglyceridemia not controlled with atorvastatin therapy (PRESS VI). Diabetes Technol Ther. 2014;16:63–71.

CAS  PubMed  PubMed Central  Google Scholar 

Pai V, Paneerselvam A, Mukhopadhyay S, Bhansali A, Kamath D, Shankar V, et al. A multicenter, prospective, randomized, double-blind study to evaluate the safety and efficacy of saroglitazar 2 and 4 mg compared to pioglitazone 45 mg in diabetic dyslipidemia (PRESS V). J Diabetes Sci Technol. 2014;8:132–41.

CAS  PubMed  PubMed Central  Google Scholar 

Sarin SK, Sharma M, Koradia P, Duseja A, Bhatia S, Dixit VK, et al. A prospective, multi-center, double-blind, randomized trial of Saroglitazar 4 mg compared to placebo in patients with nonalcoholic steatohepatitis. Hepatol Int. 2020;14:1–470.

Google Scholar 

Nissen SE. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA. 2005;294:2581.

CAS  PubMed  Google Scholar 

Henry RR, Lincoff AM, Mudaliar S, Rabbia M, Chognot C, Herz M. Effect of the dual peroxisome proliferator-activated receptor-α/γ agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet. 2009;374:126–35.

CAS  PubMed  Google Scholar 

Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med. 2022;387(21):1923–34.

PubMed  Google Scholar 

Nakajima A, Eguchi Y, Yoneda M, Imajo K, Tamaki N, Suganami H, et al. Randomised clinical trial: pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα), versus placebo in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2021;54(10):1263–77.

CAS  PubMed  PubMed Central  Google Scholar 

Jin T, Weng J. Hepatic functions of GLP-1 and its based drugs: current disputes and perspectives. Am J Physiol Endocrinol Metab. 2016;311:E620–7.

PubMed  Google Scholar 

Bernsmeier C, Meyer-Gerspach AC, Blaser LS, Jeker L, Steinert RE, Heim MH, et al. Glucose-induced glucagon-like peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease. PLoS ONE. 2014;9: e87488.

PubMed  PubMed Central  Google Scholar 

Armstrong MJ, Gaunt P, Aithal GP, Barton D, Hull D, Parker R, 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;387:679–90.

CAS  PubMed  Google Scholar 

Kuchay MS, Krishan S, Mishra SK, Choudhary NS, Singh MK, Wasir JS, et al. Effect of dulaglutide on liver fat in patients with type 2 diabetes and NAFLD: randomised controlled trial (D-LIFT trial). Diabetologia. 2020;63:2434–45.

CAS  PubMed  Google Scholar 

Cusi K, Sattar N, García-Pérez L, Pavo I, Yu M, Robertson KE, et al. Dulaglutide decreases plasma aminotransferases in people with Type 2 diabetes in a pattern consistent with liver fat reduction: a post hoc analysis of the AWARD programme. Diabet Med. 2018;35:1434–9.

CAS  PubMed  Google Scholar 

Newsome PN, Buchholtz K, Cusi K, Linder M, Okanoue T, Ratziu V, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384:1113–24.

CAS  PubMed  Google Scholar 

Loomba R, Abdelmalek MF, Armstrong MJ, Jara M, Kjær MS, Krarup N, et al. 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;8:511–22.

CAS  PubMed  PubMed Central  Google Scholar 

Arai T, Atsukawa M, Tsubota A, Ono H, Kawano T, Yoshida Y, et al. Efficacy and safety of oral semaglutide in patients with non-alcoholic fatty liver disease complicated by type 2 diabetes mellitus: a pilot study. JGH Open. 2022;6:503–11.

PubMed  PubMed Central  Google Scholar 

Newsome PN, Sanyal AJ, Engebretsen KA, Kliers I, Østergaard L, Vanni D, et al. Semaglutide 2.4 mg in participants with metabolic dysfunction-associated steatohepatitis: baseline characteristics and design of the phase 3 ESSENCE trial. Aliment Pharmacol Ther. 2024;60:1525–33.

CAS  PubMed  PubMed Central  Google Scholar 

Gastaldelli A, Cusi K, Fernández Landó L, Bray R, Brouwers B, Rodríguez Á. Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): a substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial. Lancet Diabetes Endocrinol. 2022;10:393–406.

CAS  PubMed  Google Scholar 

Ludvik B, Giorgino F, Jódar E, Frias JP, Fernández Landó L, Brown K, et al. Once-weekly tirzepatide versus once-daily insulin degludec as add-on to metformin with or without SGLT2 inhibitors in patients with type 2 diabetes (SURPASS-3]: a randomised, open-label, parallel-group, phase 3 trial. Lancet. 2021;398:583–98.

CAS  PubMed  Google Scholar 

Loomba R, Hartman ML, Lawitz EJ, Vuppalanchi R, Boursier J, Bugianesi E, et al. Tirzepatide for metabolic dysfunction-associated steatohepatitis with liver fibrosis. N Engl J Med. 2024;391:299–310.

CAS  PubMed  Google Scholar 

Sanyal AJ, Bedossa P, Fraessdorf M, Neff GW, Lawitz E, Bugianesi E, et al. A phase 2 randomized trial of survodutide in MASH and fibrosis. N Engl J Med. 2024;391:311–9.

CAS  PubMed  Google Scholar 

Uhlén M, Fagerberg L, Hallström BM, Lindskog C, Oksvold P, Mardinoglu A, et al. Tissue-based map of the human proteome. Science. 2015;347:1260419.

PubMed  Google Scholar 

Comments (0)

No login
gif