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Long-term liver outcomes after metabolic surgery in compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis

Nature Medicine volume 31, pages 988–995 (2025)Cite this article

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Abstract

No therapy has been shown to reduce the risk of major adverse liver outcomes (MALO) in patients with cirrhosis due to metabolic dysfunction-associated steatohepatitis (MASH). The Surgical Procedures Eliminate Compensated Cirrhosis In Advancing Long-term (SPECCIAL) observational study compared the effects of metabolic surgery and nonsurgical treatment in patients with obesity and compensated histologically proven MASH-related cirrhosis. Using a doubly robust estimation methodology to balance key baseline characteristics between groups, the time-to-incident MALO was compared between 62 patients (68% female) who underwent metabolic surgery and 106 nonsurgical controls (71% female), with a mean follow-up of 10.0 ± 4.5 years. The 15 year cumulative incidence of MALO was 20.9% (95% confidence interval (CI), 2.5–35.9%) in the surgical group compared with 46.4% (95% CI, 25.6–61.3%) in the nonsurgical group, with an adjusted hazard ratio of 0.28 (95% CI, 0.12–0.64), P = 0.003. The 15 year cumulative incidence of decompensated cirrhosis was 15.6% (95% CI, 0–31.3%) in the surgical group compared with 30.7% (95% CI, 12.9–44.8%) in the nonsurgical group, with an adjusted hazard ratio of 0.20 (95% CI, 0.06–0.68), P = 0.01. Among patients with compensated MASH-related cirrhosis and obesity, metabolic surgery, compared with nonsurgical management, was associated with a significantly lower risk of incident MALO. In the absence of approved medical therapies for compensated MASH-related cirrhosis, metabolic surgery may represent a safe and effective therapeutic option to influence the trajectory of cirrhosis.

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Fig. 1: Flow diagram for the identification of eligible patients for inclusion in the study.
Fig. 2: Cumulative incidence estimates for composite endpoints and mean trend curves of change in weight and HbA1c in the overlap-weighted patients.

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Data availability

The dataset generated during the current study is not publicly available to preserve patient confidentiality. However, the dataset is available from the corresponding author to academic investigators following receipt of a signed data-sharing agreement and after reviewing the study protocol (approved by a local institutional review board or research ethics committee), statistical analysis plan and publication plan. The CCHS institutional review board and the Law Department must approve the request before sharing the de-identified data. The corresponding author will respond to these requests within 2 months of receipt.

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Acknowledgements

We acknowledge M. E. Satava and R. Burton, both from Cleveland Clinic, for their help in collecting some of the data. These individuals received no additional compensation, outside of their usual salary, for their contributions.

Author information

Authors and Affiliations

  1. Bariatric and Metabolic Institute, Department of General Surgery, Cleveland Clinic, Cleveland, OH, USA

    Ali Aminian, Abdullah Aljabri, Sarah Wang, Hana Rosen, Eileen Arnold & Rickesha Wilson

  2. Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA

    James Bena & Alex Milinovich

  3. Department of Pathology, Cleveland Clinic, Cleveland, OH, USA

    Daniela S. Allende

  4. MASLD Research Center, Division of Gastroenterology and Hepatology, University of California at San Diego, San Diego, CA, USA

    Rohit Loomba

  5. Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, VCU School of Medicine, Richmond, VA, USA

    Arun J. Sanyal

  6. Fatty Liver Program, Arizona Liver Health, Chandler, AZ, USA

    Naim Alkhouri

  7. Division of Gastroenterology and Hepatology, Cleveland Clinic, Cleveland, OH, USA

    Jamile Wakim-Fleming, Sobia N. Laique, Srinivasan Dasarathy & Arthur J. McCullough

  8. Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, OH, USA

    Steven E. Nissen

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Contributions

A. Aminian, R.L., A.J.S., N.A. and S.D. contributed to the study concept and design. A. Aminian, A. Aljabri, S.W., D.S.A., H.R., E.A., R.W. and A.M. were involved in data acquisition. J.B. performed the statistical analysis. All authors contributed to the interpretation of data. A. Aminian prepared the first draft of the paper. All authors critically revised the paper for intellectual content and clarity and approved the final version for submission. A. Aminian and S.E.N. provided the administrative support and supervised this work.

Corresponding author

Correspondence to Steven E. Nissen.

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Competing interests

A. Aminian reported receiving research grants from Medtronic and Ethicon. He serves as a consultant for Medtronic, Ethicon and Eli Lilly. R.L. serves as a consultant or advisory board member for 89Bio, Alnylam, Arrowhead Pharmaceuticals, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Cirius, CohBar, DiCerna, Galmed, Gilead, Glympse Bio, Intercept, Ionis, Metacrine, NGM Biopharmaceuticals, Novo Nordisk, Pfizer, Sagimet and Viking Therapeutics. In addition, his institution has received grant support from Allergan, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Galmed Pharmaceuticals, Genfit, Gilead, Intercept, Inventiva, Janssen, Madrigal Pharmaceuticals, NGM Biopharmaceuticals, Novartis, Pfizer, pH Pharma and Siemens. He is also cofounder of Liponexus. A.J.S. has stock options in Genfit, Tiziana, Indalo, Durect, Inversago and Galmed. He has served as a consultant to AstraZeneca, Salix, Tobira, Takeda, Janssen, Gilead, Terns, Merck, Madrigal, NGM Biopharmaceuticals, Sagimet, Valeant, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Hemoshear, Novartis, Inventiva, Enyo, Akero, 89Bio, Novo Nordisk, Pfizer, Amgen, Genentech, Regeneron, Alnylam, Hanmi, LG Chem, Histoindex, Theratechnologies, Intercept, Target-RWE, Surrozen, Zydus, Path AI, Exhalenz and Genfit. His institution has received grant support from Gilead, Salix, Tobira, Bristol Myers Squibb, Pfizer, Intercept, Merck, AstraZeneca, Malinckrodt and Novartis. He receives royalties from Elsevier and UptoDate. N.A. has received research funding from 89Bio, Akero, AbbVie/Allergan, Better Therapeutics, Boehringer Ingelheim, Bristol Myers Squibb, Corcept, Galectin, Genentech, Genfit, Gilead, Healio, Hepagene, Intercept, Inventiva, Ionis, Madrigal, Merck, NGM, Noom, NorthSea, Novo Nordisk, Perspectum, Pfizer, Poxel, Viking and Zydus; has attended speaker bureaus for AbbVie/Allergan, Alexion, Echosens, Eisai, Exelixis, Gilead, Intercept, Perspectum, Salix and Theratechnologies; and has acted as a consultant for AbbVie/Allergan, Echosens, Gilead, Intercept, Madrigal, Novo Nordisk, Perspectum, Pfizer and Zydus. S.E.N. reported receiving grants to perform clinical trials from AbbVie, AstraZeneca, Amgen, Bristol Myers Squibb, Eli Lilly, Esperion Therapeutics Inc, Medtronic, MyoKardia, New Amsterdam Pharmaceuticals, Novartis and Silence Therapeutics. The other authors declare no competing interests.

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Nature Medicine thanks Hao Ma, Geltrude Mingrone, Eric Sheu, Raj Vuppalanchi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Michael Basson, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 Cumulative incidence estimates of major adverse liver outcomes in the overlap-weighted patients.

A Kaplan Meier graph shows the cumulative incidence of the primary composite endpoint, incident MALO, in the nonsurgical control group and separately after Roux-en-Y gastric bypass and sleeve gastrectomy. P value is for overall 2-sided comparison of 3 groups from the Cox proportional hazards model.

Extended Data Table 1 Follow-up status over the course of 15 years for patients who were not censored for developing the primary end point
Full size table
Extended Data Table 2 Estimated comparisons of body weight and HbA1c over time
Full size table
Extended Data Table 3 Total number of observations and number of distinct patients with available measurements after each time-point following the index date for body weight and HbA1c values by treatment groups
Full size table
Extended Data Table 4 E-value for the effect of metabolic surgery on study endpoints (and its upper limit of 95% CI) in fully-adjusted Cox models
Full size table

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Aminian, A., Aljabri, A., Wang, S. et al. Long-term liver outcomes after metabolic surgery in compensated cirrhosis due to metabolic dysfunction-associated steatohepatitis. Nat Med 31, 988–995 (2025). https://doi.org/10.1038/s41591-024-03480-y

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