Precision Obesity Medicine: Genetic Prediction of Response to GLP-1/GIP Agonists. (Diagenix)

Prediction of Response to GLP-1/GIP Receptor Agonists in Obesity Using Genetic Risk Score and SNP Profiling: A Prospective Cohort Study.

Obesity is a chronic multifactorial disease with a strong genetic component. Although glucagon-like peptide-1 (GLP-1) receptor agonists such as semaglutide and dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonists, such as tirzepatide, are highly effective treatments for obesity, substantial inter-individual variability in weight loss response remains. Genetic factors may contribute to these differences in treatment outcomes.

The aim of this prospective cohort study is to investigate whether a Genetic Risk Score (GRS) and selected obesity-related single nucleotide polymorphisms (SNPs) can predict weight loss response to semaglutide or tirzepatide in adults with obesity. Participants initiating treatment with either medication will undergo clinical, biochemical, and genetic assessment at baseline and will be followed for six months. The study will evaluate the association between genetic markers and treatment response and develop predictive models integrating genetic and clinical variables. The findings may contribute to the development of personalized treatment strategies for obesity.

Study Overview

• Status: Recruiting
• Conditions: Obesity (Disorder); Anti-obesity Agents; Precision Medicine
• Intervention / Treatment: Drug: Semaglutide or Tirzepatide

Detailed Description

Obesity is a chronic disease resulting from complex interactions between genetic, environmental, and behavioral factors. Genetic influences account for a substantial proportion of obesity susceptibility, with heritability estimates ranging from 40% to 75%. Genome-wide association studies have identified numerous genetic variants associated with body mass index, appetite regulation, energy homeostasis, and metabolic function.

Glucagon-like peptide-1 (GLP-1) receptor agonists and dual GIP/GLP-1 receptor agonists have significantly improved the pharmacological management of obesity. Semaglutide and tirzepatide produce clinically meaningful weight reduction and improvement in metabolic outcomes. However, treatment response varies considerably among individuals, and the factors underlying this variability are not fully understood.

Genetic Risk Scores (GRS), which combine the effects of multiple obesity-related genetic variants, have emerged as potential tools for predicting disease risk and therapeutic response. Their role in predicting response to anti-obesity pharmacotherapy remains largely unexplored.

This prospective observational cohort study aims to evaluate whether a GRS and selected obesity-related single nucleotide polymorphisms (SNPs) can predict weight loss response to semaglutide or tirzepatide in adults with obesity.

Eligible participants initiating treatment with semaglutide or tirzepatide will be consecutively recruited and followed for six months. At baseline, demographic, clinical, anthropometric, biochemical, and genetic data will be collected. Approximately 18 obesity-related SNPs, including variants in genes involved in appetite regulation, energy balance, and glucose metabolism, will be analyzed. An additive Genetic Risk Score will be calculated based on the cumulative number of risk alleles.

The primary outcome will be percentage weight loss at six months. Participants will subsequently be classified according to treatment response. Associations between genetic markers, GRS categories, and treatment outcomes will be evaluated using multivariable regression models. Receiver operating characteristic (ROC) curve analyses will be performed to assess the predictive performance of genetic and combined genetic-clinical models.

The study is expected to identify genetic predictors of response to GLP-1/GIP receptor agonist therapy and contribute to the development of precision medicine approaches in obesity management. Improved prediction of treatment response may facilitate individualized therapeutic selection, optimize clinical outcomes, and reduce the trial-and-error approach currently used in obesity pharmacotherapy.

• Study Type: Observational
• Enrollment (Estimated): 220

Contacts and Locations

• Study Contact: Name: Maria P Yavropoulou, MD, MSc, PDH; Phone Number: +306936159517; Email: myavropoulou@med.uoa.gr
• Study Contact Backup: Name: Maria Evangelia Koloutsou, MD; Phone Number: +306986606272; Email: mkoloutsou@med.uoa.gr

Study Locations

• Greece
  • Athens, Greece, 11527
    • Recruiting
    • Laiko General Hospital, Athens
    • Contact: Maria Evangelia Koloutsou, MD; Phone Number: +306986606272; Email: mkoloutsou@med.uoa.gr
    • Contact: Maria Yavropoulou, MD, MSc, PHD; Phone Number: +306936159517; Email: myavropoulou@med.uoa.gr
    • Principal Investigator: Nikolaos Tentolouris, Prof
    • Sub-Investigator: Maria Evangelia Koloutsou, MD

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

Adults with obesity receiving semaglutide or tirzepatide as part of routine clinical care. Participants will undergo clinical, biochemical, and genetic assessment and will be followed prospectively for six months to evaluate the association between genetic risk score, obesity-related genetic variants, and weight loss response.

Description

Inclusion Criteria:

Age ≥18 years BMI ≥40 kg/m² or ≥37 kg/m² with comorbidities Initiation of semaglutide or tirzepatide

Exclusion Criteria:

Prior bariatric surgery Secondary causes of obesity Active malignancy Chronic pancreatitis Family history of medullary thyroid carcinoma

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Semaglutide or Tirzepatide; Adults with obesity initiating treatment with semaglutide or tirzepatide as part of routine clinical care. Participants are followed prospectively for 6 months to evaluate weight loss response and its association with genetic risk score.	Drug: Semaglutide or Tirzepatide; Adults with obesity initiating treatment with semaglutide or tirzepatide as part of routine clinical care. Participants are followed prospectively for 6 months to evaluate weight loss response and its association with genetic risk score.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage weight loss at 6 months	Percentage change in body weight from baseline to 6 months following treatment with semaglutide or tirzepatide. The association between weight loss response and genetic risk score (GRS) as well as obesity-related single nucleotide polymorphisms (SNPs) will be evaluated.	6 months

Collaborators and Investigators

• Sponsor: National and Kapodistrian University of Athens

Publications and helpful links

General Publications

• Wilding JPH, Batterham RL, Calanna S, Davies M, Van Gaal LF, Lingvay I, McGowan BM, Rosenstock J, Tran MTD, Wadden TA, Wharton S, Yokote K, Zeuthen N, Kushner RF; STEP 1 Study Group. Once-Weekly Semaglutide in Adults with Overweight or Obesity. N Engl J Med. 2021 Mar 18;384(11):989-1002. doi: 10.1056/NEJMoa2032183. Epub 2021 Feb 10.
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LifeLines Cohort Study; Brennan EP, Choi M, Dastani Z, Drong AW, Eriksson P, Franco-Cereceda A, Gadin JR, Gharavi AG, Goddard ME, Handsaker RE, Huang J, Karpe F, Kathiresan S, Keildson S, Kiryluk K, Kubo M, Lee JY, Liang L, Lifton RP, Ma B, McCarroll SA, McKnight AJ, Min JL, Moffatt MF, Montgomery GW, Murabito JM, Nicholson G, Nyholt DR, Okada Y, Perry JRB, Dorajoo R, Reinmaa E, Salem RM, Sandholm N, Scott RA, Stolk L, Takahashi A, Tanaka T, van 't Hooft FM, Vinkhuyzen AAE, Westra HJ, Zheng W, Zondervan KT; ADIPOGen Consortium; AGEN-BMI Working Group; CARDIOGRAMplusC4D Consortium; CKDGen Consortium; GLGC; ICBP; MAGIC Investigators; MuTHER Consortium; MIGen Consortium; PAGE Consortium; ReproGen Consortium; GENIE Consortium; International Endogene Consortium; Heath AC, Arveiler D, Bakker SJL, Beilby J, Bergman RN, Blangero J, Bovet P, Campbell H, Caulfield MJ, Cesana G, Chakravarti A, Chasman DI, Chines PS, Collins FS, Crawford DC, Cupples LA, Cusi D, Danesh J, de Faire U, den Ruijter HM, Dominiczak AF, Erbel R, Erdmann J, Eriksson JG, Farrall M, Felix SB, Ferrannini E, Ferrieres J, Ford I, Forouhi NG, Forrester T, Franco OH, Gansevoort RT, Gejman PV, Gieger C, Gottesman O, Gudnason V, Gyllensten U, Hall AS, Harris TB, Hattersley AT, Hicks AA, Hindorff LA, Hingorani AD, Hofman A, Homuth G, Hovingh GK, Humphries SE, Hunt SC, Hypponen E, Illig T, Jacobs KB, Jarvelin MR, Jockel KH, Johansen B, Jousilahti P, Jukema JW, Jula AM, Kaprio J, Kastelein JJP, Keinanen-Kiukaanniemi SM, Kiemeney LA, Knekt P, Kooner JS, Kooperberg C, Kovacs P, Kraja AT, Kumari M, Kuusisto J, Lakka TA, Langenberg C, Marchand LL, Lehtimaki T, Lyssenko V, Mannisto S, Marette A, Matise TC, McKenzie CA, McKnight B, Moll FL, Morris AD, Morris AP, Murray JC, Nelis M, Ohlsson C, Oldehinkel AJ, Ong KK, Madden PAF, Pasterkamp G, Peden JF, Peters A, Postma DS, Pramstaller PP, Price JF, Qi L, Raitakari OT, Rankinen T, Rao DC, Rice TK, Ridker PM, Rioux JD, Ritchie MD, Rudan I, Salomaa V, Samani NJ, Saramies J, Sarzynski MA, Schunkert H, Schwarz PEH, Sever P, Shuldiner AR, Sinisalo J, Stolk RP, Strauch K, Tonjes A, Tregouet DA, Tremblay A, Tremoli E, Virtamo J, Vohl MC, Volker U, Waeber G, Willemsen G, Witteman JC, Zillikens MC, Adair LS, Amouyel P, Asselbergs FW, Assimes TL, Bochud M, Boehm BO, Boerwinkle E, Bornstein SR, Bottinger EP, Bouchard C, Cauchi S, Chambers JC, Chanock SJ, Cooper RS, de Bakker PIW, Dedoussis G, Ferrucci L, Franks PW, Froguel P, Groop LC, Haiman CA, Hamsten A, Hui J, Hunter DJ, Hveem K, Kaplan RC, Kivimaki M, Kuh D, Laakso M, Liu Y, Martin NG, Marz W, Melbye M, Metspalu A, Moebus S, Munroe PB, Njolstad I, Oostra BA, Palmer CNA, Pedersen NL, Perola M, Perusse L, Peters U, Power C, Quertermous T, Rauramaa R, Rivadeneira F, Saaristo TE, Saleheen D, Sattar N, Schadt EE, Schlessinger D, Slagboom PE, Snieder H, Spector TD, Thorsteinsdottir U, Stumvoll M, Tuomilehto J, Uitterlinden AG, Uusitupa M, van der Harst P, Walker M, Wallaschofski H, Wareham NJ, Watkins H, Weir DR, Wichmann HE, Wilson JF, Zanen P, Borecki IB, Deloukas P, Fox CS, Heid IM, O'Connell JR, Strachan DP, Stefansson K, van Duijn CM, Abecasis GR, Franke L, Frayling TM, McCarthy MI, Visscher PM, Scherag A, Willer CJ, Boehnke M, Mohlke KL, Lindgren CM, Beckmann JS, Barroso I, North KE, Ingelsson E, Hirschhorn JN, Loos RJF, Speliotes EK. Genetic studies of body mass index yield new insights for obesity biology. Nature. 2015 Feb 12;518(7538):197-206. doi: 10.1038/nature14177.
• Jastreboff AM, Aronne LJ, Ahmad NN, Wharton S, Connery L, Alves B, Kiyosue A, Zhang S, Liu B, Bunck MC, Stefanski A; SURMOUNT-1 Investigators. Tirzepatide Once Weekly for the Treatment of Obesity. N Engl J Med. 2022 Jul 21;387(3):205-216. doi: 10.1056/NEJMoa2206038. Epub 2022 Jun 4.
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Study record dates

Study Major Dates

• Study Start (Actual): April 22, 2026
• Primary Completion (Estimated): January 30, 2027
• Study Completion (Estimated): June 30, 2027

Study Registration Dates

• First Submitted: June 12, 2026
• First Submitted That Met QC Criteria: June 12, 2026
• First Posted (Actual): June 17, 2026

Study Record Updates

• Last Update Posted (Actual): June 17, 2026
• Last Update Submitted That Met QC Criteria: June 12, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Obesity; Precision Medicine; Genetic Risk Score; GLP-1 Receptor Agonist; GIP/GLP-1 Receptor Agonist
• Additional Relevant MeSH Terms: Pathologic Processes; Nutrition Disorders; Disease Attributes; Overnutrition; Body Weight; Overweight; Disease Susceptibility; Genetic Predisposition to Disease; Pathological Conditions, Signs and Symptoms; Nutritional and Metabolic Diseases; Signs and Symptoms; Genetic Risk Score; 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; semaglutide
• Other Study ID Numbers: 5002

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data (IPD) will not be shared due to privacy considerations, the inclusion of genetic data, and restrictions related to participant consent and data protection regulations.

Drug and device information, study documents

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