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 Patie

<b>Background:</b> Tirzepatide (TZP), a unimolecular dual agonist targeting glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptors, is a promising weight loss agent in obesity. The preservation of metabolically active fat-free mass (FFM), muscle strength (MS), and resting metabolic rate (RMR) is essential for optimizing fat mass (FM) reduction. Although TZP is typically combined with a low-calorie diet (LCD), its impact on FFM is uncertain, and studies on MS and RMR are lacking. Evidence suggests that Low-Energy Ketogenic Therapy (LEKT) may reduce FM while preserving FFM, MS, and RMR. Therefore, this study aimed to compare the effects of an LEKT and an LCD, both combined with TZP, on body weight (BW), FM, FFM, MS, and RMR in patients with obesity. <b>Methods:</b> We prospectively compared the effects of TZP combined with either an LCD or LEKT in 60 patients with obesity (n = 30 per group) over 12 weeks. BW, FM, FFM, MS, and RMR were measured at baseline and after 12 weeks. Clinical parameters, an assessment of dietary compliance, and side effects were also evaluated. <b>Results:</b> At 12-week follow-up, both groups showed a significant BW reduction from baseline (TZP+LEKT, <i>p</i> = 0.0289; TZP+LCD, <i>p</i> = 0.0278), with no significant intergroup difference (<i>p</i> = 0.665). Similarly, FM decreased significantly in both cohorts (TZP+LEKT, <i>p</i> < 0.001; TZP+LCD, <i>p</i> = 0.0185), with the TZP+LEKT group achieving a greater FM loss (<i>p</i> = 0.042). However, the TZP+LCD group exhibited significant declines from baseline in FFM (<i>p</i> = 0.0284), MS (<i>p</i> = 0.0341), and RMR (<i>p</i> < 0.001), whereas we did not observe any significant changes in FFM (<i>p</i> = 0.487), MS (<i>p</i> = 0.691), and RMR (<i>p</i> = 0.263) in the TZP+LEKT group. Intergroup direct comparisons confirmed that the TZP+LCD group experienced significantly greater reductions in FFM (<i>p</i> = 0.0388), MS (<i>p</i> = 0.046), and RMR (<i>p</i> = 0.019). <b>Conclusions:</b> Based on the findings of these preliminary data, we are able to support the hypothesis that TZP+LEKT seems to be superior to TZP+LCD in promoting FM reduction while preserving FFM, MS, and RMR in patients with obesity.