{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T00:23:55Z","timestamp":1792196635607,"version":"4.4.0"},"reference-count":36,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T00:00:00Z","timestamp":1753315200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver condition globally, strongly linked to obesity, insulin resistance, and type 2 diabetes (T2D). Tirzepatide (TZP), a dual GIP\/GLP-1 receptor agonist, improves glycemic control and reduces body weight and the liver fat content in patients with obesity and T2D. However, its effect on liver-specific outcomes such as steatosis and fibrosis remains incompletely characterized. Low-energy ketogenic therapy (LEKT), a nutritional strategy characterized by carbohydrate restriction and nutritional ketosis, may enhance hepatic \u03b2-oxidation and reduce hepatic lipogenesis. To date, however, the combination of TZP and LEKT has not been studied in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). This study aimed to compare the hepatic and metabolic effects of TZP combined with either LEKT or a conventional low-calorie diet (LCD) over a 12-week period. Methods: Sixty adult patients with MASLD undergoing TZP therapy were prospectively assigned to either an LEKT or a conventional LCD, with 30 participants per group. As primary endpoints, the controlled attenuation parameter (CAP, an index of hepatic steatosis) and liver stiffness measurement (LSM, an index of liver fibrosis) were assessed at the baseline and after 12 weeks using FibroScan\u00ae. Secondary outcomes included changes in body mass index (BMI), glycated hemoglobin (HbA1c), and liver enzymes. Adherence to both diet and pharmacological treatment, as well as tolerability, were systematically monitored throughout the intervention period. Results: Both groups showed significant reductions in body weight (TZP + LEKT, p = 0.0289; TZP + LCD, p = 0.0278), with no significant intergroup difference (p = 0.665). CAP and LSM improved significantly in both groups, but reductions were greater in the TZP + LEKT group (CAP \u221212.5%, p &lt; 0.001; LSM \u221222.7%, p &lt; 0.001) versus LCD (CAP \u22126.7%, p = 0.014; LSM \u22129.2%, p = 0.022). Between-group differences were statistically significant for both CAP (p = 0.01) and LSM (p = 0.03). Conclusions: Based on these preliminary findings, we support the hypothesis that the combination of TZP and LEKT may be superior to TZP with an LCD in reducing hepatic steatosis and stiffness in individuals with obesity.<\/jats:p>","DOI":"10.3390\/nu17152409","type":"journal-article","created":{"date-parts":[[2025,7,24]],"date-time":"2025-07-24T09:05:12Z","timestamp":1753347912000},"page":"2409","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Beyond Weight Loss: Comparative Effects of Tirzepatide Plus Low-Energy Ketogenic Versus Low-Calorie Diet on Hepatic Steatosis and Stiffness in MASLD"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3639-6847","authenticated-orcid":false,"given":"Luigi","family":"Schiavo","sequence":"first","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Baronissi, Italy"},{"name":"National Biodiversity Future Center (NBFC), 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Biagio","family":"Santella","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Baronissi, Italy"},{"name":"National Biodiversity Future Center (NBFC), 90133 Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Mingo","sequence":"additional","affiliation":[{"name":"Department of Medicine, Surgery and Dentistry \u201cScuola Medica Salernitana\u201d, University of Salerno, 84081 Baronissi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Rossetti","sequence":"additional","affiliation":[{"name":"General and Bariatric Surgery Unit, Abano Terme Policlinic, 35031 Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcello","family":"Orio","sequence":"additional","affiliation":[{"name":"Medical and Diabetological Center (CMSO), 84123 Salerno, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Pilone","sequence":"additional","affiliation":[{"name":"Public Health Department, University of Naples Federico II, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,7,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/s41572-025-00599-1","article-title":"Metabolic dysfunction-associated steatotic liver disease in adults","volume":"11","author":"Huang","year":"2025","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/S2213-8587(24)00318-8","article-title":"Metabolic dysfunction-associated steatotic liver disease: Heterogeneous pathomechanisms and effectiveness of metabolism-based treatment","volume":"13","author":"Stefan","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_3","unstructured":"European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2024). EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J. Hepatol., 81, 492\u2013542."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"106","DOI":"10.2478\/jtim-2019-0023","article-title":"Effect of Weight Reduction on Histological Activity and Fibrosis of Lean Nonalcoholic Steatohepatitis Patient","volume":"7","author":"Alam","year":"2019","journal-title":"J. Transl. Int. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s13679-024-00597-6","article-title":"Nutritional Strategies for Battling Obesity-Linked Liver Disease: The Role of Medical Nutritional Therapy in Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) Management","volume":"14","author":"Annunziata","year":"2025","journal-title":"Curr. Obes. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1056\/NEJMoa2206038","article-title":"Investigators Tirzepatide Once Weekly for the Treatment of Obesity","volume":"387","author":"Jastreboff","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/S0140-6736(21)01324-6","article-title":"Efficacy and safety of a novel dual GIP and GLP-1 receptor agonist tirzepatide in patients with type 2 diabetes (SURPASS-1): A double-blind, randomised, phase 3 trial","volume":"398","author":"Rosenstock","year":"2021","journal-title":"Lancet"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1056\/NEJMoa2107519","article-title":"Tirzepatide versus Semaglutide Once Weekly in Patients with Type 2 Diabetes","volume":"385","author":"Davies","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/S2213-8587(22)00070-5","article-title":"Effect of tirzepatide versus insulin degludec on liver fat content and abdominal adipose tissue in people with type 2 diabetes (SURPASS-3 MRI): A substudy of the randomised, open-label, parallel-group, phase 3 SURPASS-3 trial","volume":"10","author":"Gastaldelli","year":"2022","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1056\/NEJMoa2401943","article-title":"Tirzepatide for Metabolic Dysfunction-Associated Steatohepatitis with Liver Fibrosis","volume":"391","author":"Loomba","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/apt.18042","article-title":"Randomised clinical trial: Design of the SYNERGY-NASH phase 2b trial to evaluate tirzepatide as a treatment for metabolic dysfunction-associated steatohepatitis and modification of screening strategy to reduce screen failures","volume":"60","author":"Vuppalanchi","year":"2024","journal-title":"Aliment. Pharmacol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.3390\/nu17071216","article-title":"Preliminary Evidence Suggests That a 12-Week Treatment with Tirzepatide Plus Low-Energy Ketogenic Therapy Is More Effective than Its Combination with a Low-Calorie Diet in Preserving Fat-Free Mass, Muscle Strength, and Resting Metabolic Rate in Patients with Obesity","volume":"17","author":"Schiavo","year":"2025","journal-title":"Nutrients"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Emanuele, F., Biondo, M., Tomasello, L., Arnaldi, G., and Guarnotta, V. (2025). Ketogenic Diet in Steatotic Liver Disease: A Metabolic Approach to Hepatic Health. Nutrients, 17.","DOI":"10.3390\/nu17071269"},{"key":"ref_14","first-page":"374","article-title":"Low-carbohydrate ketogenic diets, glucose homeostasis, and nonalcoholic fatty liver disease","volume":"15","author":"Schugar","year":"2012","journal-title":"Curr. Opin. Clin. Nutr. Metab. Care"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.2337\/dc14-0845","article-title":"A very low-carbohydrate, low-saturated fat diet for type 2 diabetes management: A randomized trial","volume":"37","author":"Tay","year":"2014","journal-title":"Diabetes Care"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1038\/nm.3804","article-title":"The ketone metabolite \u03b2-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease","volume":"21","author":"Youm","year":"2015","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1016\/j.cmet.2007.05.002","article-title":"Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states","volume":"5","author":"Badman","year":"2007","journal-title":"Cell Metab."},{"key":"ref_18","first-page":"1","article-title":"Transient Elastography for Assessment of Liver Fibrosis and Steatosis: An Evidence-Based Analysis","volume":"15","author":"Brener","year":"2015","journal-title":"Ont. Health Technol. Assess. Ser."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Sarkar Das, T., Meng, X., Abdallah, M., Bilal, M., Sarwar, R., and Shaukat, A. (2024). An Assessment of the Feasibility, Patient Acceptance, and Performance of Point-of-Care Transient Elastography for Metabolic-Dysfunction-Associated Steatotic Liver Disease (MASLD): A Systematic Review and Meta-Analysis. Diagnostics, 14.","DOI":"10.3390\/diagnostics14222478"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Taru, M.G., Neamti, L., Taru, V., Procopciuc, L.M., Procopet, B., and Lupsor-Platon, M. (2023). How to Identify Advanced Fibrosis in Adult Patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Non-Alcoholic Steatohepatitis (NASH) Using Ultrasound Elastography\u2014A Review of the Literature and Proposed Multistep Approach. Diagnostics, 13.","DOI":"10.3390\/diagnostics13040788"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0140-6736(23)01200-X","article-title":"Tirzepatide once weekly for the treatment of obesity in people with type 2 diabetes (SURMOUNT-2): A double-blind, randomised, multicentre, placebo-controlled, phase 3 trial","volume":"402","author":"Garvey","year":"2023","journal-title":"Lancet"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2909","DOI":"10.1038\/s41591-023-02597-w","article-title":"Tirzepatide after intensive lifestyle intervention in adults with overweight or obesity: The SURMOUNT-3 phase 3 trial","volume":"29","author":"Wadden","year":"2023","journal-title":"Nat. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1001\/jama.2023.24945","article-title":"Continued Treatment with Tirzepatide for Maintenance of Weight Reduction in Adults with Obesity: The SURMOUNT-4 Randomized Clinical Trial","volume":"331","author":"Aronne","year":"2024","journal-title":"JAMA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1056\/NEJMoa2416394","article-title":"Tirzepatide as Compared with Semaglutide for the Treatment of Obesity","volume":"393","author":"Aronne","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1007\/s11695-018-3145-8","article-title":"A 4-Week Preoperative Ketogenic Micronutrient-Enriched Diet Is Effective in Reducing Body Weight, Left Hepatic Lobe Volume, and Micronutrient Deficiencies in Patients Undergoing Bariatric Surgery: A Prospective Pilot Study","volume":"28","author":"Schiavo","year":"2018","journal-title":"Obes. Surg."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1007\/s11695-021-05811-1","article-title":"Low-Calorie Ketogenic Diet with Continuous Positive Airway Pressure to Alleviate Severe Obstructive Sleep Apnea Syndrome in Patients with Obesity Scheduled for Bariatric\/Metabolic Surgery: A Pilot, Prospective, Randomized Multicenter Comparative Study","volume":"32","author":"Schiavo","year":"2022","journal-title":"Obes. Surg."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1007\/s11695-020-05133-8","article-title":"A Randomized, Controlled Trial Comparing the Impact of a Low-Calorie Ketogenic vs a Standard Low-Calorie Diet on Fat-Free Mass in Patients Receiving an Elipse\u2122 Intragastric Balloon Treatment","volume":"31","author":"Schiavo","year":"2021","journal-title":"Obes. Surg."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"iii","DOI":"10.3310\/hta7270","article-title":"Evaluating non-randomised intervention studies","volume":"7","author":"Deeks","year":"2003","journal-title":"Health Technol. Assess."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Adachi, T., Tsunekawa, Y., and Tanimura, D. (2022). Association between the Big Five personality traits and medication adherence in patients with cardiovascular disease: A cross-sectional study. PLoS ONE, 17.","DOI":"10.1371\/journal.pone.0278534"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s13668-018-0235-0","article-title":"Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome","volume":"7","author":"Gershuni","year":"2018","journal-title":"Curr. Nutr. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3594","DOI":"10.1210\/jc.2009-0111","article-title":"Circulating fibroblast growth factor 21 is induced by peroxisome proliferator-activated receptor agonists but not ketosis in man","volume":"94","author":"Christodoulides","year":"2009","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Qi, J., Gan, L., Fang, J., Zhang, J., Yu, X., Guo, H., Cai, D., Cui, H., Gou, L., and Deng, J. (2022). Beta-Hydroxybutyrate: A Dual Function Molecular and Immunological Barrier Function Regulator. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.805881"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1186\/s12933-023-01940-2","article-title":"GIP receptor agonism improves dyslipidemia and atherosclerosis independently of body weight loss in preclinical mouse model for cardio-metabolic disease","volume":"22","author":"Sachs","year":"2023","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"98","DOI":"10.1097\/MOL.0b013e328328d0a4","article-title":"PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure","volume":"20","author":"Auwerx","year":"2009","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12553","DOI":"10.1073\/pnas.1006962107","article-title":"Fibroblast growth factor 21 regulates energy metabolism by activating the AMPK-SIRT1-PGC-1alpha pathway","volume":"107","author":"Chau","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1113\/jphysiol.2006.108506","article-title":"Activation of AMP-activated protein kinase in the liver: A new strategy for the management of metabolic hepatic disorders","volume":"574","author":"Viollet","year":"2006","journal-title":"J. Physiol."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/15\/2409\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T18:15:04Z","timestamp":1760033704000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/17\/15\/2409"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,24]]},"references-count":36,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2025,8]]}},"alternative-id":["nu17152409"],"URL":"https:\/\/doi.org\/10.3390\/nu17152409","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,24]]}}}