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

Official title

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

Overview

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.

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.

Interventions

• 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.

Primary outcome measures

• Percentage weight loss at 6 months [Time frame: 6 months]

Eligibility criteria

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

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

Greece · 1 center

• Laiko General Hospital, Athens — Athens

Publications

• Khera AV, Chaffin M, Aragam KG, Haas ME, Roselli C, Choi SH, Natarajan P, Lander ES, Lubitz SA, Ellinor PT, Kathiresan S. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat Genet. 2018 Sep;50(9):1219-1224. doi: 10.1038/s41588-018-0183-z. Epub 2018 Aug 13. PMID 30104762
• 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. PMID 35658024
• 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. PMID 33567185
• Grant SF, Thorleifsson G, Reynisdottir I, Benediktsson R, Manolescu A, Sainz J, Helgason A, Stefansson H, Emilsson V, Helgadottir A, Styrkarsdottir U, Magnusson KP, Walters GB, Palsdottir E, Jonsdottir T, Gudmundsdottir T, Gylfason A, Saemundsdottir J, Wilensky RL, Reilly MP, Rader DJ, Bagger Y, Christiansen C, Gudnason V, Sigurdsson G, Thorsteinsdottir U, Gulcher JR, Kong A, Stefansson K. Variant PMID 16415884
• Hruby A, Hu FB. The Epidemiology of Obesity: A Big Picture. Pharmacoeconomics. 2015 Jul;33(7):673-89. doi: 10.1007/s40273-014-0243-x. PMID 25471927
• Frayling TM, Timpson NJ, Weedon MN, Zeggini E, Freathy RM, Lindgren CM, Perry JR, Elliott KS, Lango H, Rayner NW, Shields B, Harries LW, Barrett JC, Ellard S, Groves CJ, Knight B, Patch AM, Ness AR, Ebrahim S, Lawlor DA, Ring SM, Ben-Shlomo Y, Jarvelin MR, Sovio U, Bennett AJ, Melzer D, Ferrucci L, Loos RJ, Barroso I, Wareham NJ, Karpe F, Owen KR, Cardon LR, Walker M, Hitman GA, Palmer CN, Doney A PMID 17434869
• Yengo L, Sidorenko J, Kemper KE, Zheng Z, Wood AR, Weedon MN, Frayling TM, Hirschhorn J, Yang J, Visscher PM; GIANT Consortium. Meta-analysis of genome-wide association studies for height and body mass index in approximately 700000 individuals of European ancestry. Hum Mol Genet. 2018 Oct 15;27(20):3641-3649. doi: 10.1093/hmg/ddy271. PMID 30124842
• Locke AE, Kahali B, Berndt SI, Justice AE, Pers TH, Day FR, Powell C, Vedantam S, Buchkovich ML, Yang J, Croteau-Chonka DC, Esko T, Fall T, Ferreira T, Gustafsson S, Kutalik Z, Luan J, Magi R, Randall JC, Winkler TW, Wood AR, Workalemahu T, Faul JD, Smith JA, Zhao JH, Zhao W, Chen J, Fehrmann R, Hedman AK, Karjalainen J, Schmidt EM, Absher D, Amin N, Anderson D, Beekman M, Bolton JL, Bragg-Gresham PMID 25673413

Identifiers

NCT: NCT07653412 · 5002

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗