Beyond Weight Loss: Comparative Effects of Tirzepatide Plus Low-Energy Ketogenic Versus Low-Calorie Diet on Hepatic Steatosis and Stiffness in MASLD

Abstract

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 β-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^®. 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 -12.5%, p < 0.001; LSM -22.7%, p < 0.001) versus LCD (CAP -6.7%, p = 0.014; LSM -9.2%, 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.

Keywords: FibroScan; MASLD; hepatic steatosis; ketogenic diet; liver stiffness; nutritional ketosis; tirzepatide.

Figure 1

Flow chart comparing a 12-week TZP + LEKT vs. TZP + LCD on total body weight, clinical status, and FibroScan parameters. LEKT = low-energy ketogenic therapy; LCD = low-calorie diet.

Figure 2

Box plots show baseline and 12-week follow-up changes in body weight (A), LSM (B), and CAP (C) in both groups studied. Horizontal bars represent median values. Lower and upper boundaries of the box represent the first and the third quartiles, respectively. Lower and upper error bars represent the minimum and the maximum values, respectively. TZP = tirzepatide; LEKT = low-energy ketogenic therapy; LCD = low-calorie diet. ^a 12-week follow-up vs. baseline; ^b 12-week follow-up TZP + LEKT vs. LCD.

Figure 3

Synergistic mechanisms of tirzepatide and low-energy ketogenic therapy in MASLD. Tirzepatide (TZP) improves insulin sensitivity, and it reduces hepatic glucose production and lipogenesis via dual GIP/GLP-1 receptor agonism. Low-energy ketogenic therapy (LEKT) promotes nutritional ketosis, leading to increased β-hydroxybutyrate levels, PPAR-α activation, and inhibition of the NLRP3 inflammasome, which collectively reduce hepatic inflammation and enhance fatty acid oxidation. Both interventions converge on the AMPK–PGC-1α–SIRT1 axis, resulting in improved hepatic autophagy, mitochondrial function, and redox balance. This shared metabolic convergence leads to reductions in hepatic steatosis and fibrosis, as observed in the clinical outcomes. Legend: (→) indicates stimulation or directional flow; (↑) indicates upregulation or increased activity; (↓) indicates downregulation or suppression; (T) indicates convergence of mechanistic pathways shared by TZP and LEKT.