SYNERGY-NASH: trial summary, limitations and UK relevance

Key findings

SYNERGY-NASH evaluated tirzepatide (5, 10 and 15 mg weekly doses) against placebo in adults with biopsy-confirmed MASH and significant liver fibrosis (F2-F3). Tirzepatide demonstrated MASH resolution without worsening of fibrosis in a substantially greater proportion of participants than placebo at 52 weeks, and the key secondary endpoint of fibrosis improvement without worsening of MASH was also reported favourably. These findings extend tirzepatide's evidence base beyond weight and glycaemic outcomes into biopsy-confirmed liver histology, a stringent endpoint requiring paired liver biopsies. Readers should consult the primary NEJM 2024 publication for exact reported proportions and confidence intervals.

Safety summary

GI adverse events (nausea, diarrhoea, constipation) were the most frequently reported tolerability signal, consistent with the wider tirzepatide programme. No new hepatic or other organ-system safety signals were highlighted in the primary publication.

Limitations

• Evidence is from a phase 2b-scale, biopsy-based study rather than a larger registrational outcomes trial; a larger confirmatory phase 3 programme is in progress.
• Biopsy-based design necessarily limits sample size and generalisability compared with non-invasive-endpoint trials.
• 52-week duration cannot establish long-term hepatic outcomes such as progression to cirrhosis or liver-related mortality.
• Population restricted to F2-F3 fibrosis — does not directly address earlier (F0-F1) or later (F4/cirrhosis) fibrosis stages.

UK relevance

Directly relevant to UK NICE and MHRA consideration of tirzepatide for MASLD/MASH given the absence of a currently licensed pharmacotherapy specifically for MASH with fibrosis in UK hepatology pathways.