Linafexor, a Pulsatile FXR Agonist, Augments Low-Dose Semaglutide for Weight Loss in Adults with Obesity, MASH, and Type 2 Diabetes
- 1Ruijin Hospital, Shanghai Jiao Tong University School of Medicine
Abstract
Glucagon-like peptide-1 (GLP-1) receptor agonists produce less weight loss in people with type 2 diabetes than without, and higher compensatory doses are limited by gastrointestinal adverse events and lean-mass loss--leaving patients with obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH) inadequately treated. We tested whether linafexor, a pulsatile farnesoid X receptor (FXR) agonist, could augment the weight-loss efficacy of low-dose semaglutide in this population while preserving tolerability. In this multicenter, randomized, double-blind, placebo-controlled, phase 2 trial, 62 adults with obesity (body-mass index, 30- 45 kg/m{superscript 2}), treatment-naive type 2 diabetes, and MASH (MRI-PDFF [≥]10%) were assigned to linafexor (4 mg orally once daily) or placebo, each with semaglutide (0.5 mg once weekly), for 16 weeks. The primary outcome was the percentage change in body weight at week 16. Adding linafexor more than doubled weight loss (-6.17% vs. -2.91%; treatment difference, -3.26%; 95% CI, -5.35 to -1.18; P=0.003), and more participants achieved at least 5% weight loss (53.3% vs. 28.1%; P=0.046). Consistent with this, combination therapy further reduced visceral adipose tissue (treatment difference, -13.85 cm{superscript 2}; P=0.035), the liver enzymes alanine aminotransferase and {gamma}-glutamyl transferase, and serum bile acids, whose changes correlated with weight and liver-enzyme improvements--associations absent with monotherapy. Gastrointestinal adverse events were comparable (23.3% vs. 18.8%), with no treatment-related serious adverse events or discontinuations. Thus, in a population with blunted GLP-1 responses, adding linafexor to low-dose semaglutide enhanced weight loss and improved body composition and hepatic measures while preserving tolerability--a dose-sparing, mechanism-complementary strategy (ClinicalTrials.gov number, NCT06492330).
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BibTeX
@misc{zhang2026linafexor,
title = {{Linafexor, a Pulsatile FXR Agonist, Augments Low-Dose Semaglutide for Weight Loss in Adults with Obesity, MASH, and Type 2 Diabetes}},
author = {Y. Zhang and Y. Chen and S. Huang and L. Jiang and Y. Wang and J. Ma and R. Deng and J. Du and L. Xia and Y. Ma and P. Wu and W. Zhang and C. Liu and G. Zhao and G. Wang and M. Qian and H. Lin and F. Yan and G. Ning and H. E. Xu and W. Wang},
howpublished = {medRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.18.26365821},
url = {https://www.medrxiv.org/content/10.64898/2026.10.18.26365821v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Linafexor, a Pulsatile FXR Agonist, Augments Low-Dose Semaglutide for Weight Loss in Adults with Obesity, MASH, and Type 2 Diabetes
AU - Y. Zhang
AU - Y. Chen
AU - S. Huang
AU - L. Jiang
AU - Y. Wang
AU - J. Ma
AU - R. Deng
AU - J. Du
AU - L. Xia
AU - Y. Ma
AU - P. Wu
AU - W. Zhang
AU - C. Liu
AU - G. Zhao
AU - G. Wang
AU - M. Qian
AU - H. Lin
AU - F. Yan
AU - G. Ning
AU - H. E. Xu
AU - W. Wang
PY - 2026
DA - 2026/10/18
PB - medRxiv
DO - 10.64898/2026.10.18.26365821
UR - https://www.medrxiv.org/content/10.64898/2026.10.18.26365821v1
AB - Glucagon-like peptide-1 (GLP-1) receptor agonists produce less weight loss in people with type 2 diabetes than without, and higher compensatory doses are limited by gastrointestinal adverse events and lean-mass loss--leaving patients with obesity, type 2 diabetes, and metabolic dysfunction-associated steatohepatitis (MASH) inadequately treated. We tested whether linafexor, a pulsatile farnesoid X receptor (FXR) agonist, could augment the weight-loss efficacy of low-dose semaglutide in this population while preserving tolerability. In this multicenter, randomized, double-blind, placebo-controlled, phase 2 trial, 62 adults with obesity (body-mass index, 30- 45 kg/m{superscript 2}), treatment-naive type 2 diabetes, and MASH (MRI-PDFF [≥]10%) were assigned to linafexor (4 mg orally once daily) or placebo, each with semaglutide (0.5 mg once weekly), for 16 weeks. The primary outcome was the percentage change in body weight at week 16. Adding linafexor more than doubled weight loss (-6.17% vs. -2.91%; treatment difference, -3.26%; 95% CI, -5.35 to -1.18; P=0.003), and more participants achieved at least 5% weight loss (53.3% vs. 28.1%; P=0.046). Consistent with this, combination therapy further reduced visceral adipose tissue (treatment difference, -13.85 cm{superscript 2}; P=0.035), the liver enzymes alanine aminotransferase and {gamma}-glutamyl transferase, and serum bile acids, whose changes correlated with weight and liver-enzyme improvements--associations absent with monotherapy. Gastrointestinal adverse events were comparable (23.3% vs. 18.8%), with no treatment-related serious adverse events or discontinuations. Thus, in a population with blunted GLP-1 responses, adding linafexor to low-dose semaglutide enhanced weight loss and improved body composition and hepatic measures while preserving tolerability--a dose-sparing, mechanism-complementary strategy (ClinicalTrials.gov number, NCT06492330).
ER -