In Reply: Beyond histologic improvement in MASH

In Reply: We thank Dr. Najam and colleagues for their thoughtful commentary on our review.¹ Their observations align with and extend several nuances that merit direct acknowledgment.

Regarding surrogate end points, we agree that histologic resolution of steatohepatitis and fibrosis-stage reduction, while validated as regulatory end points by the US Food and Drug Administration, are imperfect proxies for long-term clinical outcomes. The concern raised by Najam and colleagues is well-founded: fibrosis stage remains the strongest independent predictor of liver-related mortality in metabolic dysfunction–associated steatohepatitis (MASH).² Whether histologic improvement achieved through pharmacotherapy translates into sustained reduction of major liver events will require longer follow-up. The ESSENCE (Effect of Semaglutide in Subjects With Noncirrhotic Nonalcoholic Steatohepatitis) trial³ demonstrated MASH resolution in 62.9% of patients and fibrosis improvement in 36.8% at 72 weeks with semaglutide 2.4 mg, though 240-week outcome data remain pending.

On treatment durability, the STEP-4 (Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity)⁴ data highlighting weight regain after semaglutide withdrawal reinforce a point we consider critical: MASH is a chronic, relapsing condition requiring sustained management strategies. This parallels the paradigm already established in other chronic liver diseases, where indefinite therapy is the norm rather than the exception. Cost, tolerability, and access, particularly in lower-resource settings, are legitimate barriers that must inform clinical guidelines and health policy discussions.

Regarding endoscopic bariatric therapies, we concur that current evidence, including the Abad et al⁵ trial and the Nunes et al⁶ meta-analysis, reflects early-phase data with limited histologic end points. We presented these interventions as emerging options for select patients, not as established standards of care, and we support the call for multicenter randomized controlled trials with biopsy-confirmed outcomes.

We appreciate this engagement and share the authors’ conviction that broader, more durable, and equitably accessible therapies remain an unmet need in MASH.

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