Dr. Chetan Kalal delivered the invited lecture “Weight loss and beyond: The Comprehensive Benefits of Treating MASH” at IMPA 2026 — addressing a question that is now central to hepatology practice: when we treat MASH, what exactly are we treating for? The answer, as the evidence now shows, goes far beyond the number on a weighing scale.
The Core Argument: Weight Loss Is a Means, Not the End
For years, the therapeutic goal in metabolic-associated steatohepatitis (MASH) was framed primarily as weight reduction. Lose enough weight, and the liver improves. This framing is not wrong — but it is incomplete, and in clinical practice it is often counterproductive. Patients who achieve only modest weight loss may still derive substantial hepatic benefit. And patients who achieve significant weight loss through unsustainable means may rebound, negating hepatic gains.
The more precise framing is this: treating MASH targets hepatic inflammation, fibrosis progression, cardiometabolic risk, and HCC risk — and weight loss is one of several mechanisms through which these endpoints are reached.
Advisory Roles — Novo Nordisk & Eli Lilly
Dr. Kalal’s invited lecture at IMPA 2026 is informed by his advisory panel roles with Novo Nordisk and Eli Lilly — the two companies leading GLP-1 and GLP-1/GIP agonist development for obesity and metabolic liver disease. As a hepatologist on these panels, his focus is the liver-specific evidence: fibrosis endpoints, patient selection in advanced fibrosis, safety in compensated cirrhosis, and the interaction between immunosuppression and GLP-1 agents in post-transplant patients. This clinical depth is what separates a hepatology perspective on GLP-1 therapy from a general metabolic medicine or endocrinology perspective.
In MASH, the liver biopsy does not show “excess weight.” It shows steatosis, hepatocyte ballooning, lobular inflammation, and fibrosis. These are the targets. Weight loss addresses them indirectly — via reduced hepatic lipid flux, improved insulin sensitivity, and reduced adipose-derived inflammatory signalling. Any intervention that hits these mechanisms effectively is a valid MASH treatment, whether or not it produces dramatic weight loss.
What Does “Treating MASH” Actually Achieve?
1. Fibrosis regression
Fibrosis stage is the strongest predictor of liver-related outcomes in MASH — not steatosis grade, not MASH activity score. Fibrosis regression — even by one stage — is associated with significantly reduced risk of cirrhosis, hepatic decompensation, and liver-related mortality. The landmark MASH trials (resmetirom MAESTRO-NASH, semaglutide NASH CRN trial) demonstrate histological fibrosis improvement that is clinically meaningful, not merely statistical.
- Resmetirom (Rezdiffra): In MAESTRO-NASH, fibrosis improvement by ≥1 stage without MASH worsening: 24.2% (80mg) and 25.9% (100mg) vs 14.2% placebo. MASH resolution: 25.9% and 29.9% vs 9.7% placebo. (NEJM 2024)
- Semaglutide 2.4mg: MASH resolution in 62.9% vs 34.3% placebo; fibrosis improvement 37.0% vs 22.4% (NEJM 2021 — the cirrhosis-free population data)
- Weight loss >10% body weight: pooled data show ~65% achieve MASH resolution; >10% weight loss predicts fibrosis regression
2. Cardiometabolic risk reduction
MASH patients die more often from cardiovascular disease than from liver disease — cardiovascular mortality accounts for approximately 25% of deaths in MASH cohorts. Treating MASH-driving metabolic dysfunction — insulin resistance, dyslipidaemia, adipose inflammation — reduces CVD risk in parallel with liver benefit. This is the “beyond weight loss” component that is often undersold to patients and referring physicians.
GLP-1 receptor agonists (semaglutide, liraglutide) and dual GLP-1/GIP agonists (tirzepatide) have now demonstrated cardiovascular outcome benefits in large RCTs (SELECT trial for semaglutide 2.4mg: 20% reduction in MACE). A patient treated for MASH with semaglutide is simultaneously reducing their risk of MI and stroke.
3. HCC risk reduction
MASH is a risk factor for HCC even in the absence of cirrhosis — a critical distinction from most other liver diseases. Treating MASH effectively reduces HCC risk. Observational data show GLP-1 RA use in MASH/T2DM populations is associated with reduced HCC incidence. Mechanistic data suggest reduced hepatic lipotoxicity, reduced oxidative stress, and reduced IGF-1 signalling as contributing factors.
4. Quality of life and extrahepatic organ protection
Effective MASH treatment reduces hepatic inflammation and fibrogenic signalling. Patients report improvement in fatigue, abdominal discomfort, and overall metabolic wellbeing. Renal protection (GLP-1 RAs have demonstrated nephroprotective effects) is an additional extrahepatic benefit relevant to the typical MASH patient who often has concurrent CKD.
GLP-1 Receptor Agonists — The Current Frontline for MASH with Obesity
For MASH patients with obesity and/or type 2 diabetes, GLP-1 receptor agonists are now established first-line treatment, combining:
- Weight reduction (semaglutide 2.4mg: average 15–17% body weight; tirzepatide: up to 22%)
- Direct hepatic benefit via reduced lipid flux, reduced glucotoxicity, and possible direct hepatocyte GLP-1R signalling
- Glycaemic control
- Cardiovascular risk reduction (proven in SELECT, SUSTAIN-6, LEADER)
- Histological MASH improvement (MASH resolution, fibrosis regression in controlled trials)
Tirzepatide (GLP-1/GIP dual agonist): SURMOUNT-1 and SURMOUNT-2 showed dramatic weight loss (up to 22.5% from baseline). The SYNERGY-NASH phase 3 trial specifically in MASH is ongoing — interim data strongly positive for MASH resolution. Expected to reach the MASH pharmacotherapy arsenal in 2025–2026.
The practical MASH algorithm at Gleneagles Hospital Mumbai in Dr. Kalal’s hepatology practice:
- Fibrosis staging (FIB-4 → FibroScan ± biopsy) — identify who has significant fibrosis and who urgently needs treatment
- For MASH + obesity/T2DM with F1–F3: semaglutide or tirzepatide (primary), with resmetirom as add-on for significant fibrosis
- Metabolic optimisation: dietary counselling, exercise prescription, diabetes management
- 6–12 month reassessment with non-invasive tools
- Escalate to bariatric surgery or transplant evaluation if fibrosis progresses despite pharmacotherapy
The Practical Message for IMA Physicians
General practitioners and internists encounter MASH daily — it is the most common chronic liver disease in their patient population. Dr. Kalal’s message at IMPA 2026 was direct:
- Don’t wait for significant liver symptoms before acting on MASH — by the time symptoms appear, fibrosis is usually advanced
- A FIB-4 score from routine bloods takes 30 seconds to calculate and stratifies your patient’s liver risk immediately
- Starting a GLP-1 RA for a diabetic-obese patient with fatty liver on ultrasound is treating their liver, their heart, and their glucose simultaneously — it is one of the highest-value prescriptions in modern medicine
- Refer to hepatology when FIB-4 >1.30, when FibroScan shows significant stiffness, or when MASH is suspected in a non-diabetic lean patient (lean MASH — a distinct and underdiagnosed entity)
Dr. Chetan Kalal is Associate Director, Hepatology & Transplant Medicine, Gleneagles Hospital Mumbai. DM (Hepatology), MRCP (UK). Maharashtra’s first DM Hepatologist. Invited Faculty at IMPA 2026, Obesity Masterclass 2026, LTSICON 2026, LIVERCON 2026, CRITICON 2026, and Organising Secretary of Grand Rounds in Hepatology 2026 (INASL Mid-Term). Consults at: drchetankalal.com/book. Virtual consult for NRI and international patients: drchetankalal.com/virtual-consult.
Frequently Asked Questions
Does treating MASH with GLP-1 drugs actually improve the liver?
Yes — with high-quality clinical trial evidence. Semaglutide 2.4mg (Wegovy) achieved MASH resolution in 62.9% of patients vs 34.3% with placebo in the phase 3 NASH CRN trial. Fibrosis improved in 37% vs 22% with placebo. Resmetirom (Rezdiffra, FDA-approved March 2024) achieved MASH resolution in 29.9% vs 9.7% placebo with fibrosis improvement in 25.9% vs 14.2%. These are histological endpoints — actual liver tissue improvements, not surrogate markers.
Is MASH reversible?
Steatosis and inflammation (MASH without advanced fibrosis) are highly reversible — both with weight loss and with pharmacotherapy. Fibrosis is partially reversible — regression of one or more fibrosis stages is achievable in a proportion of patients with effective treatment. Established cirrhosis is not reversible, but its progression can be arrested and complications prevented.
Who should I refer to a hepatologist for MASH?
Any of: FIB-4 >1.30 on routine bloods; FibroScan >8 kPa; liver enzymes persistently elevated despite metabolic control; fatty liver on ultrasound in a non-obese, non-diabetic patient (lean MASH); patient being considered for bariatric surgery (requires pre-op hepatology clearance); MASH with suspected HCC (any liver nodule >1cm on background of MASH).
Medical disclaimer: This article is for educational purposes and does not constitute personalised clinical advice. For assessment of fatty liver disease or MASH, book a consultation with Dr. Chetan Kalal.
About the Author
Dr. Chetan Kalal — MBBS, MD (Internal Medicine), DM Hepatology (ILBS, New Delhi) — is the First DM Hepatologist of Maharashtra and Associate Director, Hepatology & Liver Transplant, at Gleneagles Hospital Mumbai. He has 26 peer-reviewed publications and serves on the APASL AARC Expert Panel. Fellow, National Academy of Medical Sciences (FNAMS). Learn more · Book appointment
