Novo Nordisk extends its ESSENCE story into lean disease with week 72 liver enzyme and non-invasive marker improvements in 106 adults with MASH and liver scarring and BMI below 27 kg/m² versus placebo, against an ESSENCE Part 1 base of 62.9% versus 34.3% MASH resolution without worsening fibrosis and 36.8% versus 22.4% fibrosis improvement without worsening steatohepatitis that supported accelerated FDA approval in August 2025 for MASH with moderate to advanced fibrosis. [1][2] The lean subgroup sits far from the ESSENCE mean BMI of 34.6 kg/m² and offers no histology responder rates, confidence intervals or subgroup safety, while fibrosis benefit already looked fragile in the Japanese subgroup at 36.5% versus 28.9% and in a dedicated NASH cirrhosis Phase 2 with odds ratio 0.28 favoring placebo numerically. [3] Competitive pressure comes from tirzepatide with 44-62% MASH resolution in SYNERGY-NASH as a randomized Phase 2 dual GIP/GLP-1 agonist and pooled dual/triple polyagonists with relative risk 1.49 for fibrosis improvement, alongside resmetirom as the 2024 accelerated histology precedent via thyroid hormone receptor-beta. [4][5] Payer risk is already defined by semaglutide economics at 185,646 dollars per QALY requiring 67% reduction to 50,000 dollars and budget impact above 40 million dollars per year. [6] The announcement is hypothesis-generating for an overlooked population, not a pathway to expanded approval on markers alone.
106-patient post hoc BMI below 27 analysis reports only liver enzymes and non-invasive markers at week 72 versus placebo, below ESSENCE dual histology standard that supported approval.
| Indication | Metabolic dysfunction-associated steatohepatitis (MASH) with liver scarring |
| Drug | Semaglutide 2.4 mg |
| Mechanism of Action | GLP-1 RA |
| Company | Novo Nordisk |
| Trial Phase | Phase 3 |
| Trial Acronym | ESSENCE |
| Category | Clinical Trial Event |
| Sub Category | Topline Results Positive |
| Therapeutic Area | Gastroenterology & Hepatology |
| Patient Subpopulation | Adults with MASH and liver scarring with BMI < 27 kg/m² |
| Subgroup Size | 106 participants |
| Follow-up Duration | 72 weeks |
| Conference Name | The Liver Meeting® 2026 (AASLD) |
| Presentation Type | Oral presentation |
| Key Liver Enzyme Improvements | ALT, AST |
| Key Fibrosis Biomarker Improvements | ELF score, PRO-C3 |
| Trial Randomization | 1,197 participants randomized 2:1 (semaglutide 2.4 mg vs. placebo) |
| Regulatory Status | FDA accelerated approval |
| Approved Indication (Semaglutide 2.4 mg) | MASH with moderate-to-advanced liver scarring (fibrosis), not with cirrhosis |
Novo Nordisk's Semaglutide Shows Liver Marker Improvements in Non-Obese MASH Patients
Novo Nordisk announced results from a post hoc analysis of the phase 3 ESSENCE trial, revealing that once-weekly semaglutide 2.4 mg improved liver-related measures in a specific subgroup. The analysis included 106 adults with metabolic dysfunction-associated steatohepatitis (MASH) and liver scarring who had a BMI below 27 kg/m². At week 72, participants receiving semaglutide 2.4 mg showed improvements in liver enzymes and non-invasive markers of disease activity and fibrosis compared to placebo. These findings were presented at The Liver Meeting® 2026 in Denver, Colorado, highlighting potential benefits for a patient population often overlooked.
- The post hoc analysis specifically focused on a subgroup of 106 adults with MASH and liver scarring who had a BMI below 27 kg/m², a population that has received less attention in MASH research. At week 72, semaglutide 2.4 mg demonstrated significant improvements in key liver injury markers such as ALT (ETR 0.61) and AST (ETR 0.67), alongside improvements in the FAST score for disease activity (ETD -0.13) compared to placebo.
- Semaglutide 2.4 mg also showed favorable results for non-invasive fibrosis biomarkers, including the ELF score (ETD -0.45) and PRO-C3 (ETR 0.82), providing crucial information on fibrosis progression in addition to biopsy-based endpoints. These consistent improvements across various measures of liver injury, disease activity, and fibrosis suggest a broad positive impact on liver health in this specific patient group.
- These findings supplement previously reported histologic data for this subgroup, reinforcing the message that MASH can affect people of any body type and that body size alone should not define the seriousness of the disease or treatment considerations. The results contribute to a growing body of evidence supporting the potential of semaglutide 2.4 mg in managing MASH across a wider spectrum of patients, including those not classified as obese.
Semaglutide 2.4 mg's Impact on Liver Markers in Non-Obese MASH
In the Phase 3 ESSENCE trial (NCT04822181), once-weekly subcutaneous semaglutide at a dose of 2.4 mg was evaluated in 1197 patients with biopsy-defined MASH and fibrosis stage 2 or 3, with interim analysis at week 72 in the first 800 patients. Resolution of steatohepatitis without worsening of fibrosis occurred in 62.9% of patients in the semaglutide group and in 34.3% in the placebo group (estimated difference, 28.7 percentage points; 95% confidence interval [CI], 21.1 to 36.2; P<0.001), while reduction in liver fibrosis without worsening of steatohepatitis was reported in 36.8% versus 22.4% (estimated difference, 14.4 percentage points; 95% CI, 7.5 to 21.3; P<0.001). Combined resolution of steatohepatitis and reduction in liver fibrosis was reported in 32.7% versus 16.1% (estimated difference, 16.5 percentage points; 95% CI, 10.2 to 22.8; P<0.001), with mean change in body weight of -10.5% with semaglutide and -2.0% with placebo, and gastrointestinal adverse events more common in the semaglutide group.
In the Phase 2 SYNERGY-NASH trial (NCT04166773), once-weekly subcutaneous tirzepatide at 5 mg, 10 mg, or 15 mg was evaluated for 52 weeks in participants with biopsy-confirmed MASH and stage F2 or F3 fibrosis. The percentage of participants who met criteria for resolution of MASH without worsening of fibrosis was 10% in the placebo group, 44% in the 5-mg tirzepatide group (difference vs. placebo, 34 percentage points; 95% CI, 17 to 50), 56% in the 10-mg group (difference, 46 percentage points; 95% CI, 29 to 62), and 62% in the 15-mg group (difference, 53 percentage points; 95% CI, 37 to 69) (P<0.001 for all three comparisons). The percentage with improvement of at least one fibrosis stage without worsening of MASH was 30% in the placebo group, 55% in the 5-mg group, 51% in the 10-mg group, and 51% in the 15-mg group, with the most common adverse events in the tirzepatide groups being gastrointestinal events, and most mild or moderate in severity.
In a 48-week Phase 2 trial (1404-0043; NCT04771273), once-weekly subcutaneous survodutide, a dual agonist of glucagon receptor and GLP-1 receptor, at 2.4, 4.8, or 6.0 mg was evaluated in adults with biopsy-confirmed MASH and fibrosis stage F1 through F3. Improvement in MASH with no worsening of fibrosis occurred in 47% in the 2.4-mg group, 62% in the 4.8-mg group, and 43% in the 6.0-mg group, as compared with 14% in the placebo group (P<0.001 for the quadratic dose-response curve as best-fitting model). A decrease in liver fat content by at least 30% occurred in 63%, 67%, 57%, and 14%, respectively, and improvement in fibrosis by at least one stage occurred in 34%, 36%, 34%, and 22%, respectively. Adverse events more frequent with survodutide than placebo included nausea (66% vs. 23%), diarrhea (49% vs. 23%), and vomiting (41% vs. 4%), while serious adverse events occurred in 8% with survodutide and 7% with placebo.
The ESSENCE Trial: Design and Endpoints for MASH
Recent biopsy-driven trials in metabolic dysfunction-associated steatohepatitis (MASH) with fibrosis share a randomised, double-blind, placebo-controlled architecture, with histologic improvement assessed by paired liver biopsy and MRI-based fat quantification as supportive measures. Populations focus on adults with biopsy-confirmed MASH and stage F2-F3 fibrosis, while primary endpoints center on MASH resolution without fibrosis worsening and fibrosis improvement without MASH worsening.
| Trial | Phase and Design | Population | Treatment Arms and Duration | Primary Endpoint |
|---|---|---|---|---|
| HARMONY (NCT04767529) | Multicentre, randomised, double-blind, placebo-controlled, phase 2b trial at 41 centres in the USA | Adults aged 18-75 years with biopsy-confirmed MASH (non-alcoholic fatty liver disease activity score of 4 or higher and score of 1 or higher for steatosis, ballooning, and lobular inflammation) with F2 or F3 fibrosis; 128 randomly assigned | Subcutaneous efruxifermin 28 mg once weekly or 50 mg once weekly or placebo; evaluation at week 24 and week 96 | Improvement in liver fibrosis (decrease ≥1 stage) without worsening of MASH at week 24; end-of-treatment evaluation at week 96 included fibrosis improvement without MASH worsening and MASH resolution without fibrosis worsening |
| Dapagliflozin in MASH (NCT03723252) | Multicentre, double blind, randomised, placebo controlled trial at six tertiary hospitals in China | 154 adults with biopsy diagnosed MASH, with or without type 2 diabetes | 10 mg dapagliflozin orally once daily or matching placebo for 48 weeks | MASH improvement (defined as a decrease of at least 2 points in non-alcoholic fatty liver disease activity score (NAS) or a NAS of ≤3 points) without worsening of liver fibrosis (defined as without increase of fibrosis stage) at 48 weeks |
| Survodutide Phase 2 (NCT04771273) | 48-week, phase 2 randomised trial with 24-week rapid-dose-escalation phase followed by 24-week maintenance phase | Adults with biopsy-confirmed MASH and fibrosis stage F1 through F3; 293 received at least one dose | Once-weekly subcutaneous survodutide 2.4 mg or 4.8 mg or 6.0 mg or placebo in 1:1:1:1 ratio | Histologic improvement (reduction) in MASH with no worsening of fibrosis |
| ESSENCE (NCT04822181) | Two-part, phase 3, randomised, multicentre trial | Participants with biopsy-proven MASH and fibrosis stage 2 or 3; first 800 randomised included 250 (31.3%) with stage 2 and 550 (68.8%) with stage 3, mean age 56 years, 57.1% female, mean body mass index 34.6 kg/m, 55.5% with type 2 diabetes | Subcutaneous semaglutide 2.4 mg versus placebo; Part 1 histology, Part 2 clinical outcomes | Resolution of steatohepatitis and no worsening of liver fibrosis, and improvement in liver fibrosis and no worsening of steatohepatitis |
| DD01-DN-02 (NCT06410924) | Randomised, double-blind, multicentre, placebo-controlled, phase 2 trial at 12 outpatient sites in the USA | Adults aged 18-70 years with obesity or overweight (BMI ≥25 kg/m) with liver fat content 10% or higher with metabolic risk factors, or biopsy-confirmed MASH with non-alcoholic fatty liver disease activity score of at least 4; 67 enrolled, 33 to DD01 and 34 to placebo | Once-weekly subcutaneous DD01 40 mg or matched placebo over 48 weeks, dose-escalated over 2 weeks | Proportion with at least a 30% relative reduction in liver fat by MRI-PDFF at week 12 |
Addressing Unmet Needs in MASH, Especially for Lower BMI
MASH is a progressive form of metabolic dysfunction-associated steatotic liver disease, linked to hepatic and extra-hepatic complications and substantial healthcare costs. Despite its clinical and economic impact, real-world evidence on disease progression and costs in Germany is limited, and understanding disease progression in real-world settings remains a major unmet need.
Late recognition and underdiagnosis in routine practice. Among 4710 patients with MASH (prevalence: 0.15%), 39.4% had documented ESLD during follow-up. Disease progression to ESLD occurred in 26.0% of patients without baseline ESLD (n = 922/3490), whereas 4.0% of patients with baseline ESLD (n = 48/1188) progressed to a more severe ESLD stage during follow-up, with a mean time to first progression of approximately 25.3 months. Over a quarter of identified patients with MASH already had advanced liver disease at baseline, suggesting potential underdiagnosis or late recognition in routine clinical practice.
High-burden ESLD stages driving mortality, transplant need and costs. Progression was defined by transitions through end-stage liver disease (ESLD) stages: compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma and liver transplantation. Patients with ESLD incurred annual costs of €12,737 versus €4928 for those without ESLD. Progression to hepatocellular carcinoma and liver transplantation resulted in predicted costs of €12,948 and €75,719 per patient-year, respectively. Mortality was significantly higher among patients with ESLD (incidence rate ratio: 4.65; 95% CI: 3.76-5.79).
Heterogeneous high-risk populations with cirrhosis and cardiometabolic comorbidities. NASHDetection was 86% accurate at identifying 2695 MASH patients. At the time of their diagnosis, the median age was 57 years; 55.4% had cirrhosis at baseline, with 34.0% having evidence of decompensation and 10.8% with hepatocellular carcinoma. The most common comorbidities were hypertension (61.9%), hyperlipidemia (47.4%), and type 2 diabetes mellitus (41.5%). Multiple comorbidities were associated with all-cause mortality, including type 2 diabetes mellitus (hazard ratio (HR): 1.36; confidence interval (CI): 1.07-1.73), heart failure (HR: 1.45; CI: 1.01-2.08), and peripheral artery disease (HR: 1.72; CI: 1.04-2.85).
Lack of globally established pharmacotherapy and need for fibrosis-directed and combination strategies. Despite multiple therapeutic approaches under investigation, no globally approved standard pharmacotherapy currently exists. Clinical trials evaluating therapies such as GLP-1 receptor agonists, THR-β agonists, pan-PPAR agonists, FGF21 analogues, and bariatric surgery were reviewed. Efruxifermin demonstrated a higher relative risk (RR) of 1.97 (95% CI 1.21 to 3.19, I = 0%, P = 0.006) for achieving improvement in fibrosis by ≥ 1 stage without worsening of MASH in 325 patients with biopsy-proven MASH and stage F1-F4 fibrosis. Bariatric surgery showed MASH resolution in 56-70% of cases, though challenges remain regarding incomplete fibrosis reversal and the lack of long-term outcome data.
Need for noninvasive identification, monitoring and trial enrichment for fibrosis and cirrhosis. Diagnosis of metabolic dysfunction-associated steatohepatitis (MASH) requires histology. The MR-MASH score identified MASH with an AUC = .88 (95% CI .83-.93) and was validated with an AUC = .86 (95% CI .77-.92). The MASH Resolution Index included MRI-PDFF, ALT and aspartate aminotransferase, with an AUC of 0.81 (95% CI 0.69 to 0.93) in the derivation cohort and AUC 0.83 (95% CI 0.76 to 0.91) in external validation. Trials should enroll high-risk patients (defined as those with clinically significant portal hypertension [CSPH], Child Turcotte Pugh A cirrhosis, and magnetic resonance elastography measurements > 6.5 kPa), plan 3-5 years of follow-up and enroll using noninvasive criteria.
Semaglutide 2.4 mg's Evolving Role in the MASH Landscape
The years 2024 and 2025 marked a paradigm shift with the first-ever FDA approvals of pharmacologic agents for MASH. Resmetirom (Rezdiffra), a THR-β agonist, received FDA-accelerated approval (March 2024) and European Commission conditional marketing authorization (August 2025) as the first licensed MASH-specific therapy for adults with stage F2 or F3 fibrosis. In the MAESTRO-NASH trial, resmetirom achieved MASH resolution in 26%-30% versus 10% placebo and fibrosis improvement in 24%-26% versus 14% placebo at 52 weeks. In the F2 and F3 fibrosis subset among 917 patients, MASH resolution was achieved by 25.7% in the 80-mg group, 29.9% in the 100-mg group, and 9.5% in the placebo group, with respective percentages with fibrosis improvement of 26.5%, 28.9%, and 17.3%. Semaglutide 2.4 mg (Wegovy) received conditional accelerated approval in the US for treatment of MASH with significant or advanced liver fibrosis (stage F2/F3), with semaglutide additionally receiving accelerated FDA approval and EU marketing authorization for MASH following the ESSENCE trial.
Semaglutide 2.4 mg once weekly has evolved as a weight-centric, pleiotropic agent in non-cirrhotic MASH with F2-F3 fibrosis. Semaglutide 2.4 mg (Wegovy) demonstrated a 28.7% delta over placebo in MASH resolution in the ESSENCE trial, with fibrosis improvement by at least one stage seen with semaglutide in 37% versus 22% after 72 weeks. These benefits parallel weight loss and are accompanied by improved metabolic outcomes, including better glucose control and lipid profiles, as well as consistent benefits for cardiovascular and renal health. In patients with NASH-related cirrhosis in the randomised, placebo-controlled phase 2 trial (NCT03987451), once-weekly subcutaneous semaglutide 2.4 mg did not significantly improve fibrosis or achievement of NASH resolution versus placebo after 48 weeks, with improvement in liver fibrosis of one stage or more without worsening of NASH in five [11%] of 47 patients in the semaglutide group vs seven [29%] of 24 in the placebo group. The treatment's safety profile is manageable, with gastrointestinal issues being the most frequent side effects, including nausea, diarrhoea, and vomiting, and no new safety concerns have been identified.
Beyond the two approved monotherapies, the therapeutic landscape is rapidly evolving with incretin-based dual and triple agonists, metabolic modulators, and combination approaches representing key frontiers. In the 52-week, double-blind, randomized, placebo-controlled SYNERGY-NASH trial (NCT04166773), tirzepatide achieved MASH resolution in 44-62% of patients, with greater body weight reductions observed in responders for MASH resolution (-16.0% vs. -7.0%) and for fibrosis improvement (-13.6% vs. -9.8%). Recent investigations into GLP-1/GIP RA (tirzepatide) and Glucagon/GLP-1 RA (survodutide) have shown higher rates of MASH resolution and fibrosis improvement, while lanifibranor, a pan-peroxisome proliferator-activated receptor (pan-PPAR) agonist, demonstrated improvements in lipid profiles (HDL-C +9.87%, triglycerides -26.90%) but did not achieve a statistically significant improvement in fibrosis (OR 1.26, p = 0.08). Fibroblast growth factor 21 (FGF21) analogues significantly increased the likelihood of achieving ≥1-stage fibrosis improvement (RR: 2.25, CI: 1.25-4.03) compared with placebo across 10 RCTs (total: 1113 patients with F1-F4 fibrosis). The recent conditional approval of resmetirom and semaglutide is kickstarting the therapeutic armamentarium for MASH, with the position of combination therapy shifting toward add-on strategies evaluated in clinical practice, as is already occurring with resmetirom and semaglutide.
Frequently Asked Questions
References
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