Linafexor, a Pulsatile FXR Agonist, Augments Low-Dose Semaglutide for Weight Loss in Adults with Obesity, MASH, and Type 2 Diabetes
- Design
- Randomized trial · 62 participants · Intermediate outcome
- Match to healthy normal-weight adults aged 55–75
- Different populationINDIRECT: all participants had obesity (body-mass index 30– 45 kg/m²), treatment-naive type 2 diabetes and MASH.
- Could weight loss explain it?
- Not applicableNot applicable for the primary outcome, which is weight change itself. The visceral-fat and liver-enzyme changes were reported alongside weight change and correlated with it; no mediation analysis is described.
- Study tier
- PreliminaryPRELIMINARY: a preprint (not peer reviewed) of a small randomized, double-blind phase 2 trial with 62 participants over 16 weeks.
- Assessment
- Version 4 · Two reviewers differed; settled by a recorded ruling · Nov 11, 2026
Study facts come from the paper. Population match, weight-loss explanation and study tier are our judgments, made against the reference group of healthy normal-weight adults aged 55–75. This item has not been peer reviewed.
In 62 adults with obesity, type 2 diabetes and fatty liver disease (MASH), all taking low-dose semaglutide, this randomized trial added either linafexor or placebo for 16 weeks. Weight fell by 6.17% with the combination versus 2.91% with semaglutide plus placebo, and gastrointestinal side effects were similar (23.3% vs. 18.8%). Because everyone took semaglutide, the trial tests the add-on drug rather than semaglutide itself, and it is a preprint that has not been peer reviewed.
01Findings
What the study reported
- Drugs
- Semaglutide
- Dose
- 0.5 mg once weekly
- Treatment duration
- 16 weeks
- Comparator
- placebo (added to semaglutide 0.5 mg once weekly in both arms)
- Primary outcome
- percentage change in body weight at week 16
- Effect
- Linafexor plus semaglutide vs placebo plus semaglutide: weight change −6.17% vs. −2.91% (treatment difference, −3.26%; 95% CI, −5.35 to −1.18; P=0.003); at least 5% weight loss 53.3% vs. 28.1% (P=0.046); visceral adipose tissue difference −13.85 cm² (P=0.035)
- 95% confidence interval
- 95% CI, −5.35 to −1.18
- P value
- P=0.003
- Follow-up
- week 16
- Adverse events
- Gastrointestinal adverse events were comparable (23.3% vs. 18.8%), with no treatment-related serious adverse events or discontinuations
- Limitations
- A small, 16-week phase 2 trial reported as a preprint; both arms received semaglutide, so the randomized contrast tests linafexor rather than semaglutide itself.
Who was studied
- Bmi min
- 30
- Obesity status
- obesity required (body-mass index, 30– 45 kg/m²)
- Diabetes status
- type 2 diabetes required (treatment-naive)
- Baseline condition
- obesity, type 2 diabetes and MASH
- Sample size
- 62
- Inclusion exclusion
- obesity (BMI 30– 45 kg/m²), treatment-naive type 2 diabetes, MASH (MRI-PDFF ≥10%)
Study quality details
- Study design
- Randomized controlled trial
- Sample size
- 62
- Randomization
- yes
- Blinding
- double-blind
- Comparator
- placebo (added to semaglutide 0.5 mg once weekly in both arms)
- Follow up duration
- week 16
- Outcome type
- intermediate
- Replication
- not assessed
- Consistency with other evidence
- not assessed
- Population applicability
- INDIRECT
- Statistical precision
- CI reported: 95% CI, −5.35 to −1.18
- Risk of bias
- not assessed
- Peer review status
- no
02Funding
Funding and conflicts
- Funding
- not reported in abstract
- Industry funded
- Unclear
- Manufacturer
- not stated in source
- Sponsor role
- not reported in abstract
- Author conflicts
- not reported in abstract
- Independent replication
- unknown
Funding is shown on every study and never used to score it.
04Source
The source, as retrieved
Abstract
<h4>ABSTRACT</h4> 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/m²), 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 cm²; P=0.035), the liver enzymes alanine aminotransferase and γ-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 ).
Where this record came from
| Source | Retrieved | Identifier |
|---|---|---|
| europepmc | Oct 25, 2026 | PPR:PPR1347309 first ingestion |
| europepmc | Nov 1, 2026 | PPR:PPR1347309 duplicate matched on doi |
| medrxiv:medrxiv | Nov 1, 2026 | 10.64898/2026.10.18.26365821 duplicate matched on doi |
| owner-review | Nov 6, 2026 | reviewed_by set to Carrie Schluter (2026-11-05) on the owner's own confirmation. The assessment is unchanged and still the auto-classifier's, so its extracted values stay withheld under the 2026-10-18 decision. |
| reextract | Nov 6, 2026 | dose: '4 mg' -> '0.5 mg'. Q-043: manufacturer and drug_details.dose re-extracted by auto-classifier-v1.2. manufacturer no longer reads companies named only in the authors' conflicts statement (IN-062) and refuses a multi-company roster; dose is tied to the GLP-1 agent by name, never reads a concentration, and records a multi-dose design whole. Every other value is carried forward unchanged. Owner decision IN-064 option 1, 2026-11-06. |
| reextract | Nov 6, 2026 | drug_details.dose: '0.5 mg' -> '0.5 mg once weekly'. Q-043: manufacturer, drug_details.dose and the funding fields re-extracted by auto-classifier-v1.2. manufacturer no longer reads companies named only in the authors' conflicts statement (IN-062) and refuses a multi-company roster; dose is tied to the GLP-1 agent by name, never reads a concentration, records a multi-dose design whole and keeps a frequency written beside the amount; industry_funded, sponsor_role and funding_source read the conflicts statement's own sponsor sentences, a supplier counting as partial. Every other value is carried forward unchanged, evidence_level included. Owner decisions IN-064, 2026-11-06. |