30th June 2024, A/Prof Chee L Khoo
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Just in case you are not aware, there will be a tsunami of patients with metabolic dysfunction associate fatty liver disease (MAFLD) or metabolic dysfunction associated steatotic liver disease (MASLD) coming to you over the next few years. Part of the reason is to do with the better recognition of the condition and we are now detecting them more with biomarkers, imaging and a high index of suspicion. One of the more common complications is fibrosis which will lead to cirrhosis. Fibrosis with or without cirrhosis increases the risk of hepatocellular carcinoma. What do we have in our armamentarium to treat MASLD? Does anything work to reduce the fibrosis?
Fibrosis stage is the most important determinant of outcome including complications and mortality in case of MASH, whereas mere steatosis has no predictive value [1]. The pathogenesis of MAFLD-associated fibrosis is complex and relates to many complicated drivers and diverse mechanisms, such as high-concentration hepatic free fatty acid (FFA)-induced mitochondrial dysfunction, oxidative stress, endoplasmic reticulum (ER) stress and inflammation, subsequent hepatocyte apoptosis, and extracellular matrix (ECM) formation, which also involves the interaction of immunity and genetic and epigenetic regulations (2,3). Elevated hepatic FFA concentration is still considered the most critical stage in the development of MAFLD while the activation of hepatic stellate cells (HSCs) is the key pathogenic event for the development of liver fibrosis (4).
In the liver, FFA is either oxidised by the mitochondria or re-esterified back into triglycerides. When there is excessive FFA, they serve as substrates for the generation of lipotoxic lipids that activate the inflammatory cascade which lead to liver cell damage and induce cell death (apoptosis) and/or cell necrosis (2). Neutrophils remove the apoptotic cells and stimulate liver fibrosis. In addition to the pro-inflammatory cascade, there is mitochondrial dysfunction, activation and proliferation of hepatic stellate cells and breakdown of intestinal barrier. All these add further to the inflammatory cascade.
If we can eliminate the aetiology of the liver fibrosis, liver fibrosis can stop progressing or even regresses. Serial liver biopsy has proved that bariatric metabolic surgery can effectively promote the regression of liver fibrosis in patients with non-alcoholic steatohepatitis (NASH) (5). Thus, eliminating the aetiology of chronic liver injury is the vital goal of antifibrotic therapy. Not all causes of chronic liver injury can be effectively removed, especially for MAFLD-related liver fibrosis.
Reversing the MAFLD is not that tricky but reversing fibrosis is a different story. Reducing activated HSCs is an essential target of antifibrotic therapy. On the one hand, we can reduce the number of HSCs by promoting senescence and apoptosis. Antiretroviral drugs against HIV can enhance the proliferation of hepatocytes and the apoptosis of HSCs (6). Some studies have shown that peroxisome proliferator-activated receptor gamma (PPARγ) is a crucial mediator of HSCs activation and phenotypic changes and can affect the state of HSCs in the quiescent phase. The addition of PPARg agonists in vitro and in vivo can reduce the activation of HSCs and promote the degradation of the ECM (7). Moreover, reducing collagen production, enhancing ECM degradation, and changing ECM’s spatial conformation and matrix stiffness are also exploration targets for antifibrotic therapy (8,9).
Drug categories for MASLD:
- Agents acting on lipid syntheses and fat accumulation, such as glucagon-like peptide 1 (GLP-1) agonists, ACC inhibitors, Fanitol X receptor (FXR) agonists, and PPAR-a/d agonists
- Agents acting on cellular stress and apoptosis, including vitamin E and caspase inhibitors
- Agents that acting on immune and inflammatory response, such as C-C chemokine receptor type 2 and type 5 antagonists
- Agents that directly target the fiber formation process, such as LOXL2 monoclonal antibodies
- Antiangiogenic drugs can improve liver fibrosis, such as recombinant vascular endothelial growth factor (rVEGF) and bevacizumab
There are no GLP1 receptors in the liver and while GLP1RA has been shown to improve MAFLD, improvement in fibrosis is more elusive. Thus, combination of GLP1RA with an anti-fibrotic agent has shown to be promising. In a small exploratory clinical trial, semaglutide in combination with farnesoid X receptor agonist cilofexor and/or the acetyl-coenzyme A carboxylase inhibitor firsocostat has been shown to improve steatosis, liver biochemistry, and non-invasive tests of fibrosis compared with semaglutide alone in patients with NASH (13).
The SYNERGY-NASH trial was a phase 2, multi-centre, double-blind, randomised, placebo-controlled trial involving participants with biopsy-confirmed metabolic dysfunction associated steatotic hepatitis (MASH) and stage F2 or F3 (moderate or severe) fibrosis (10). Participants were 18 – 80 years of age and had a BMI between 27 and 50, with or without type 2 diabetes mellitus. Participants were randomly assigned in a 1:1:1:1 ratio to receive maintenance treatment with tirzepatide at doses of 5 mg, 10 mg, or 15 mg or to receive placebo. The primary end point was resolution of MASH without worsening of fibrosis at 52 weeks. A key secondary end point was an improvement (decrease) of at least one fibrosis stage without worsening of MASH.
Results
Most of the participants were White (86%) or Asian (12%), with 36% identifying as Hispanic or Latino. The mean age was 54.4 years, and the mean BMI was 36.1; a total of 57% were women, and 58% had type 2 diabetes mellitus. Overall, 57% had stage F3 fibrosis; the incidence was higher in the placebo and 5-mg tirzepatide groups than in the other groups.
The mean percentage change in body weight was −10.7%, −13.3%, and −15.6% in the 5-mg, 10-mg, and 15-mg tirzepatide groups, respectively, as compared with −0.8% in the placebo group.
In a post hoc analysis, ALT levels had normalized (defined as a level of ≤30 U per liter at week 52 in participants with a baseline level of >30 U per liter) in 47%, 64% and 75% of the participants in the 5-mg, 10-mg and 15-mg tirzepatide groups, respectively and in 12% of those in the placebo group.
Resolution of MASH
Like other GLP1RA (e.g liraglutide and semaglutide), you would expect tirzepatide to improve the MAFLD part but improving the fibrosis part may be difficult (11,12). Of the 190 participants in the trial, 157 had liver biopsy results at the end of the trial for analysis. Only 10% in the placebo group had resolution of MASH without worsening of fibrosis. Resolution of MASH was seen in 44% in the 5-mg tirzepatide group, 56% in the 10-mg tirzepatide group and 62% in the 15-mg tirzepatide group (P<0.001 for all three comparisons).
Improvement in fibrosis
30% of the placebo group had an improvement of at least one fibrosis stage without worsening of MASH. With the tirzepatide groups, there was an improvement of at least one fibrosis score in 55%, 51% and 51% in the 5mg, 10mg and 15mg respectively.
There appeared to be an association between greater degrees of weight reduction and higher incidences of MASH resolution without worsening of fibrosis, but the relationship with weight reduction was less apparent for reduction in fibrosis without worsening of MASH.
Adverse events
Adjudicated cases of progression to cirrhosis occurred in four participants (3%) in the tirzepatide groups and in two participants (4%) in the placebo group. There was no evidence of drug-induced liver injury. One adjudicated major adverse cardiovascular event (a transient ischemic attack) occurred in the 5-mg tirzepatide group. Gallbladder-related adverse events were reported in four participants (3%) in the tirzepatide groups and in one participant (2%) in the placebo group. No cases of acute pancreatitis were reported.
It is hypothesised that the improvement in MASH will eventually lead to improvement in fibrosis but it takes time. MASH resolution after bariatric surgery occurs more rapidly than regression of fibrosis. A longitudinal study showed that a higher percentage of patients had an improvement of at least one fibrosis stage at 5 years after surgery than at 1 year (6).
In summary, improvement in obesity and FFA metabolism can improve MASH. Improvement in MASH should ultimately improve fibrosis in these patients. The SYNERGY-MASH is a Phase 2 trial lasting 52 weeks. Larger and longer trials are needed to further assess the efficacy and safety of tirzepatide for the treatment of MASH. We must not forget that in light of the associated metabolic syndrome, concomitant cardiovascular disease remains the major cause of death in patients with MASLD. The presence of MASH is an independent predictor of cardiovascular disease [14].
References:
- Taylor R.S. Taylor R.J. Bayliss S. et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis. Gastroenterology. 2020; 158 (e12): 1611-1625
- Friedman SL, Neuschwander-Tetri BA, Rinella M, Sanyal AJ. Mechanisms of Nafld development and therapeutic strategies. Nat Med. (2018) 24:908–22.
- Peiseler M, Schwabe R, Hampe J, Kubes P, Heikenwälder M, Tacke F. Immune mechanisms linking metabolic injury to inflammation and fibrosis in fatty liver disease – novel insights into cellular communication circuits. J Hepatol. (2022) 77:1136–60. 63. Alkhouri N,Herring R,
- Huang C, Gao X, Shi Y, Guo L, Zhou C, Li N, et al. Inhibition of hepatic Ampk pathway contributes to free fatty acids-induced fatty liver disease in laying hen. Metabolites. (2022) 12:825.
- Lassailly G, Caiazzo R, Ntandja-Wandji L-C, Gnemmi V, Baud G, Verkindt H, et al. Bariatric surgery provides long-term resolution of nonalcoholic steatohepatitis and regression of fibrosis. Gastroenterology. (2020) 159:1290–1301.e5.
- Martí-Rodrigo A, Alegre F, Moragrega ÁB, García-García F, Martí-Rodrigo P, Fernández-Iglesias A, et al. Rilpivirine attenuates liver fibrosis through selective Stat1-mediated apoptosis in hepatic stellate cells. Gut. (2020) 69:920–32.
- Zhang Q, Xiang S, Liu Q, Gu T, Yao Y, Lu X. Ppar antagonizes hypoxia-induced activation of hepatic stellate cell through cross mediating Pi3k/Akt and Cgmp/Pkg signaling. PPAR Res. (2018) 2018:6970407.
- SunW-Y, Gu Y-J, Li X-R, Sun J-C, Du J-J, Chen J-Y, et al. B-Arrestin2 deficiency protects against hepatic fibrosis in mice and prevents synthesis of extracellular matrix. Cell Death Dis. (2020) 11:389.
- Klepfish M, Gross T, Vugman M, Afratis NA, Havusha-Laufer S, Brazowski E, et al. Loxl2 inhibition paves the way for macrophage-mediated collagen degradation in liver fibrosis. Front Immunol. (2020) 11:480.
- 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.
- 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: 679-90.
- Newsome PN, Buchholtz K, Cusi K, et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med 2021; 384: 1113-24.
- KablerH, Kayali Z,Hassanein T, Kohli A, et al. Safety and efficacy of combination therapy with semaglutide, cilofexor and firsocostat in patients with non-alcoholic steatohepatitis: a randomised, open-label phase II trial. J Hepatol. (2022) 77:607–18.
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