Weekly Journal Scan: The ESSENCE of metabolic risk: targeting metabolic dysfunction-associated steatohepatitis with semaglutide

This comment refers to ‘Phase 3 Trial of Semaglutide in Metabolic Dysfunction–Associated Steatohepatitis’, which was published in the New England Journal of Medicine, https://doi.org/10.1056/NEJMoa2413258. The ESSENCE trial is a company-funded, Phase 3, multicentre, randomized, double-blind, placebo-controlled trial evaluating the efficacy of once-weekly subcutaneous semaglutide in adults with biopsy-confirmed metabolic dysfunction-associated steatohepatitis and liver fibrosis Stage 2 or 3.1 A total of 1197 patients were enrolled across 253 clinical sites in 37 countries and randomized in a 2:1 ratio to receive either semaglutide with dose escalation up to 2.4 mg or placebo for 240 weeks. The results presented here refer to a planned interim analysis (Part 1) conducted at Week 72, involving the first 800 patients who completed both baseline and follow-up liver biopsy after 72 weeks of treatment.1 Patient eligibility and disease staging were based on the Non-alcoholic Steatohepatitis Clinical Research Network (NASH CRN) fibrosis scale (range 0–4, with 4 indicating cirrhosis) and a non-alcoholic fatty liver disease activity score (NAS) of ≥4. The NAS (range 0–8) combines steatosis, lobular inflammation, and hepatocyte ballooning; scores ≥5 indicate definite NASH, while scores ≤3 exclude it.2 The primary endpoints focus on histologic events, i.e. the resolution of steatohepatitis (a NAS of 0 for hepatocyte ballooning and 0–1 for lobular inflammation) without worsening of liver fibrosis and a reduction in liver fibrosis (≥1-stage improvement on the NASH CRN fibrosis scale) without worsening of steatohepatitis. Any increase from baseline in ballooning, inflammation, or steatosis was considered a worsening of steatohepatitis.1 The trial is ongoing and blinded for Part 2, which will evaluate clinical outcomes, specifically focusing on cirrhosis-free survival over the full 240-week follow-up period. The study population was predominantly White (68%), with a mean age of 56 years, 57% being female, and 56% having Type 2 diabetes. Obesity was common (73%); the mean body mass index was 35. About two-thirds had Stage 3 fibrosis and one-third Stage 2. At Week 72, the primary endpoint of steatohepatitis resolution without worsening of liver fibrosis was achieved in 62.9% of semaglutide-treated vs 34.3% of placebo-treated patients [estimated difference: 28.7% points; 95% confidence interval (CI), 21.1–36.2; P < .001]. The second primary endpoint, fibrosis improvement by ≥1 stage with no worsening of steatohepatitis, occurred in 36.8% vs 22.4%, respectively (estimated difference: 14.4 percentage points; 95% CI, 7.5–21.3; P < .001). Confirmatory secondary endpoints, controlled for multiplicity, were tested hierarchically. Combined resolution of steatohepatitis and fibrosis reduction was reported in 33% of the patients treated with semaglutide and 16% with placebo (P < .001). The mean body weight decreased by −10.5% with semaglutide vs −2.0% with placebo (P < .001). No statistically significant difference in bodily pain scores was observed. Semaglutide was associated with improvements in liver enzymes, glycaemia, insulin resistance, high-sensitivity C-reactive protein, lipids, and liver stiffness as measured by transient elastography (−20% from baseline).1 Adverse events leading to early trial discontinuation occurred in 2.6% of patients receiving semaglutide and 3.3% of those on placebo. Serious adverse events occurred in 13.4% of patients in both groups. Gastrointestinal disorders—particularly nausea (36% vs 13%), diarrhoea (27% vs 12%), constipation (22% vs 8%), and vomiting (19% vs 6%)—were more frequent with semaglutide. A small proportion of these gastrointestinal events were classified as serious (2.5% vs 1.5%). The incidence of acute pancreatitis was low (0.4% vs 0.5%) and similar in the two groups. Overall, nine deaths occurred (three semaglutide and six placebo), with no clear pattern of causes.1 Metabolic dysfunction-associated steatotic liver disease, characterized by excess hepatic fat, affects over 30% of adults worldwide and up to 45% in certain regions such as South America and the Middle East.3,4 Its progressive form, metabolic dysfunction-associated steatohepatitis (MASH), is histologically defined by steatosis, lobular inflammation, and hepatocellular ballooning and can progress to fibrosis, cirrhosis, and hepatocellular carcinoma.5 Metabolic dysfunction-associated steatohepatitis is increasingly recognized as a systemic metabolic disorder with major cardiovascular implications. Pathophysiological drivers—insulin resistance, visceral adiposity, chronic inflammation, and altered lipid metabolism—are shared with atherosclerotic cardiovascular disease (ASCVD), Type 2 diabetes mellitus (T2DM), chronic kidney disease, and certain types of extrahepatic cancers.5–7 These mechanisms help explain the increased incidence of major adverse cardiovascular events in this population, with ASCVD now being the leading cause of death among patients with MASH.5,8 Despite its growing prevalence and clinical burden, no pharmacologic therapy has been broadly approved for MASH until recently. Management is largely focused on lifestyle interventions, weight loss, and treatment of associated metabolic comorbidities, such as T2DM and dyslipidaemia. However, recent advances have begun to reshape the therapeutic landscape.9 The Food and Drug Administration’s conditional approval of resmetirom, a liver-directed, oral thyroid hormone receptor-β agonist, represents a breakthrough in the treatment of non-cirrhotic MASH with moderate to advanced fibrosis. Approval was based on the Phase 3 MAESTRO-NASH trial, which demonstrated efficacy in achieving either MASH resolution without worsening fibrosis or fibrosis improvement without worsening MASH—both surrogate histological endpoints considered predictive of long-term clinical benefit.10,11 In parallel, the ESSENCE trial is evaluating semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with proven cardiometabolic benefits,12 for its potential to address the upstream metabolic dysfunction that drives hepatic lipotoxicity, inflammation, and fibrogenesis in MASH. Consistent with previous studies, semaglutide improved key cardiometabolic parameters—glycaemia, insulin resistance, lipid profiles, inflammatory markers (e.g. hs-CRP), and body weight—as well as liver histology, reflecting a direct effect on the underlying pathophysiology of the disease.8 The trial’s strength lies in its rigorous, repeated biopsy-based design and consistent efficacy across all prespecified endpoints. No new safety signals emerged, and the safety profile was consistent with the existing evidence for semaglutide.12 Gastrointestinal adverse events were the most frequent, while no liver-related safety concerns were observed. While ESSENCE provides compelling evidence for semaglutide as a potential cornerstone in MASH therapy, several questions remain to be addressed. First, the absolute difference in fibrosis improvement between semaglutide and placebo was relatively modest, particularly considering the 22% placebo responder rate that was twice as high as expected (10%). Prior data from the MAESTRO-NASH trial with resmetirom indicate that ∼15% of patients were already on GLP-1 RA at baseline and still had Stage 2 or 3 fibrosis on their liver biopsy.10 Although these patients were on lower doses (e.g. semaglutide 1 mg weekly) or different GLP-1 agents, the open issue is that not all patients will benefit equally, and combination therapy will likely be necessary in a substantial proportion. Another key question is the role of weight loss in driving histologic improvement. The trial has not clarified whether responders were also those who achieved significant weight loss, or if semaglutide conferred benefits independent of weight change. The steatohepatitis resolution rate of 34% observed in the placebo group (vs 10% expected), despite a 2% reduction in body weight, raises questions about the causal relationship between the two, and/or the peculiar features of the enrolled population. This distinction is clinically important, as not all patients achieve significant weight loss with GLP-1 RAs, and the response threshold required for hepatic benefit—if any—remains unclear. While overall efficacy is demonstrated, the precise mechanism(s) by which semaglutide improves liver histology warrants further investigation. Additional limitations include the relatively short duration of follow-up (72 weeks) in relation to long-term liver and cardiovascular outcomes, the underrepresentation of certain ethnic groups, and the exclusion of patients with cirrhosis or advanced comorbidities, which may limit generalizability of the results. Data regarding alcohol consumption, genetic polymorphisms as a determinant of therapeutic response, and changes in body composition during therapy were also lacking. Finally, given the small number of lean patients, definitive conclusions of a potential benefit in this population cannot be made. Part 2 of the ESSENCE trial, which will expand the cohort to 1200 patients and extend follow-up to 240 weeks with a third liver biopsy, will address some of these gaps. It will also evaluate hard clinical endpoints such as progression to cirrhosis, liver decompensation, need for transplant, and mortality. As more data become available, especially from long-term follow-up, a clearer understanding is expected regarding treatment durability, predictors of response, and the potential role of semaglutide within a broader therapeutic framework for MASH. In conclusion, the interim results of the ESSENCE trial position semaglutide as a promising therapeutic option for MASH. By targeting the upstream metabolic dysfunction that underlies hepatic injury, semaglutide acts at the root of MASH, offering a comprehensive therapeutic approach. Understanding how agents like semaglutide influence both hepatic progression and cardiovascular risk is essential to optimizing care in this complex, multisystem condition. G.L. reports personal fees from Astra Zeneca, Boehringer Ingelheim, Novo Nordisk, Daiichi Sankyo, Sanofi, and Novartis and reports grant support (to the Institution) for investigator-initiated research from the American Heart Association, the Italian Ministry of University and Research, and the Italian Ministry of Health (Grant: ‘Ricerca Corrente’). C.P. reports personal fees from AbbVie and past grant support (to the Institution) for investigator-initiated research from AIFA (Italian Drug Agency), Bayer, Cancer Research UK, and European Commission; he chaired the Scientific Advisory Board of the International Aspirin Foundation.