Tirzepatide and Muscle Outcomes in Obesity (TIRMO)

Effects of Tirzepatide on Skeletal Muscle in Obesity

This study is evaluating whether a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, can affect the function, structure and metabolism of skeletal muscles in adults with obesity. Participants, premenopausal females with obesity, will receive either tirzepatide or placebo over 24 weeks. Researchers will assess body weight, body composition, muscle strength and functional performance, neuromuscular function and will perform muscle biopsies before and after treatment to study molecular and histological changes following treatment. The goal of this study is to investigate the effects of tirzepatide on skeletal muscle function, quantity, quality and metabolism in adults with obesity as well as clarify the molecular and structural adaptations in skeletal muscle during tirzepatide-induced weight loss, addressing an important gap in understanding the impact of incretin-based therapies on muscle health.

Study Overview

• Status: Recruiting
• Conditions: Obesity (Disorder)
• Intervention / Treatment: Drug: Tirzepatide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Prof. Mojca Jensterle Sever, MD, PhD; Phone Number: 0038631312977; Email: mojca.jensterlesever@kclj.si
• Study Contact Backup: Name: Andrijana Koceva, MD; Phone Number: 0038630248963; Email: andrijana_koceva@yahoo.com

Study Locations

• Slovenia
  • Ljubljana, Slovenia, 1000
    • Recruiting
    • Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana
    • Contact: Prof. Andrej Janež, MD, PhD; Phone Number: 0038615223564; Email: andrej.janez@kclj.si
    • Principal Investigator: Prof. Mojca Jensterle Sever, MD, PhD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Female sex
• Age between 18 and 50 years
• BMI between 30 kg/m² and 40 kg/m²
• Stable body weight within the three months preceding study enrolment (defined as ≤ 5% change)
• No prior pharmacological or surgical interventions for obesity treatment
• Commitment to use barrier contraception and absence of plans for pregnancy within 8 months following enrolment

Exclusion Criteria:

• Sarcopenic obesity
• Pregnancy or lactation
• Postmenopausal status
• Diabetes
• Immobility
• Personal history of malignancy
• Personal history of pancreatitis
• Personal history of major depressive episodes
• Personal history of myopathy
• Personal or family history of medullary thyroid carcinoma
• Current treatment with metformin or systemic corticosteroids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo; Placebo (saline solution) will be administered via subcutaneous injection once weekly with dose escalation following the same schedule (2.5 mg equivalent increments every 4 weeks) to preserve blinding integrity.
Experimental: Tirzepatide	Drug: Tirzepatide; Tirzepatide is a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist. It will be administered via subcutaneous injection once weekly in a dose-titration scheme: starting at 2.5 mg and increased every 4 weeks by 2.5 mg up to a maximum of 15 mg, based on tolerability.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Body Mass and Composition	Measured primarily as changes in body weight and body composition measured by dual-energy X-ray absorptiometry (DXA).	Baseline to Week 24
Change in Quadriceps Muscle Strength	Change in maximal knee extensor torque normalized to body mass (Nm/kg) will be evaluated using an isokinetic dynamometer.	Baseline to Week 24

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in MRI-derived Skeletal Muscle Composition and Myosteatosis	Muscle volume and muscle fat fraction will be quantified using magnetic resonance imaging (MRI).	Baseline to Week 24
Change in Molecular Markers in Vastus Lateralis Muscle: Gene-level Differential Expression	Transcriptome-wide RNA-sequencing will be performed on vastus lateralis muscle biopsies from all participants (depending on sample quality and RNA integrity) before and after the intervention to identify differentially expressed genes associated with tirzepatide treatment. Differential gene expression will be reported as log2 fold change (log2FC) between post and pre-intervention, derived from normalized RNA-sequencing read counts. Statistical significance will be summarized using false discovery rate (FDR)-adjusted p-values.	Baseline to Week 24
Change in Molecular Markers in Vastus Lateralis Muscle: Pathway-level Enrichment Analysis	Pathway-level changes will be reported using normalized enrichment scores (NES) derived from gene set enrichment analysis (GSEA), together with false discovery rate (FDR)-adjusted q-values for biological processes including mitochondrial function, lipid metabolism, insulin signaling, inflammation, muscle atrophy, and myogenesis.	Baseline to Week 24
Change in Intramyocellular Lipid Content (IMCL) in Vastus Lateralis Muscle	Assessed by Oil Red O staining using a standard protocol. IMCL will be quantified as the proportion of Oil Red O-positive area per fibre and averaged across available fibres per section per time point. Microscopy imaging and analysis settings will be kept consistent across time points, and assessors will be blinded to group/time.	Baseline to Week 24
Change in the Muscle Fiber Diameter of Type I and Type II Fibers	Muscle fiber diameter will be measured on the biopsy section using routine light microscopy. Fiber typing (type 1 vs type 2) will be performed by standard immunohistochemistry for myosin heavy chain isoforms. The metric is mean minimal Feret diameter in micrometers, averaged across available fibers of same type.	Baseline to Week 24

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Handgrip Strenght	Change in maximal handgrip strength, normalized to body mass, will be assessed using a handheld dynamometer.	Baseline to Week 24
Changes in Lower-Limb Functional Performance	Change in lower-limb functional performance assessed using standardized sit-to-stand testing.	Baseline to Week 24
Change in 6-Minute Walk Test (6MWT)	The six-minute walk test (6MWT) will be used to assess functional exercise capacity. The outcome will be the total distance walked (meters) over 6 minutes on a flat corridor, following standardized guidelines.	Baseline to Week 24
Spatial Transcriptomics Analysis of Vastus Lateralis Muscle Biopsy Samples	Potential exploratory: Feasibility-dependent analysis of spatial transcriptomic profiles in skeletal muscle biopsy. The objective is to identify treatment-related changes in spatial gene expression patterns in skeletal muscle tissue sections. A subset of approximately 8 patients (paired pre- and post-treatment muscle biopsy samples) will be selected for downstream analyses based on transcriptomic profiles obtained from the full RNA-seq dataset.	Baseline to Week 24
Electrophysiological Assessment of Motor Responses in Skeletal Muscles	Potential exploratory: Electrophysiological recordings of motor responses (compound muscle action potentials, CMAP) will be assessed to evaluate potential changes in peripheral motor nerve excitability and neuromuscular function.	Baseline to Week 24

Collaborators and Investigators

• Sponsor: University Medical Centre Ljubljana
• Investigators: Principal Investigator: Mojca Jensterle Sever, Prof.MD, PhD, Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana

Study record dates

Study Major Dates

• Study Start (Estimated): January 1, 2026
• Primary Completion (Estimated): December 1, 2026
• Study Completion (Estimated): March 1, 2027

Study Registration Dates

• First Submitted: December 5, 2025
• First Submitted That Met QC Criteria: January 23, 2026
• First Posted (Actual): January 28, 2026

Study Record Updates

• Last Update Posted (Actual): January 28, 2026
• Last Update Submitted That Met QC Criteria: January 23, 2026
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: Obesity; Muscle strength; Myosteatosis; Muscle mass; Muscle function; Skeletal muscle; Tirzepatide; Muscle quality; Muscle transcriptomics
• Additional Relevant MeSH Terms: Nutrition Disorders; Overnutrition; Body Weight; Overweight; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Obesity; Amino Acids, Peptides, and Proteins; Proteins; Glucagon-Like Peptide-1 Receptor; Glucagon-Like Peptide Receptors; Receptors, G-Protein-Coupled; Receptors, Cell Surface; Membrane Proteins; Receptors, Gastrointestinal Hormone; Receptors, Peptide; Tirzepatide
• Other Study ID Numbers: TIRMO-0120-121/2025-2711-6

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: De-identified individual participant data (IPD) to be shared will include demographic data, basic clinical measurements, body composition assessment, laboratory results, muscle strength and function assessment data, molecular data and histological features from skeletal muscle biopsies. All shared data will be fully de-identified, and no directly identifiable personal information will be included.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No