Pharmacogenomics of GLP-1 Receptor Agonists: Precision Medicine in the Age of Ozempic and Mounjaro
This narrative review examines the pharmacogenomics of GLP-1 receptor agonists — principally semaglutide (Ozempic®/Wegovy®) and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro®/Zepbound®) — with a focus on explaining the wide inter-individual variability in efficacy and tolerability observed in clinical practice. The authors synthesise evidence around key genetic loci, including GLP1R, GIPR, ARRB1, TCF7L2, and MC4R, and highlight a purported April 2026 genome-wide association study (GWAS) conducted by 23andMe (n=27,885) as the largest pharmacogenomic study of GLP-1 therapies to date. The review also surveys the competitive landscape among Novo Nordisk, Eli Lilly, 23andMe Research Institute, and PGxAI, and dedicates substantial attention to South Asian and Indian populations, arguing that their large diabetes burden and undercharacterised pharmacogenomic profiles represent a critical gap. The authors conclude that GLP-1 pharmacogenomics has advanced from exploratory science toward actionable clinical discovery. Limitations include the narrative (non-systematic) design, reliance on a preprint-stage GWAS of uncertain peer-review status, and the absence of prospective clinical validation data for genotype-guided prescribing.
Why this grade: This is a narrative review available only as a preprint, synthesising largely preclinical and early genomic association data without a systematic methodology, meta-analysis, or prospective human clinical validation of genotype-guided GLP-1 prescribing.
Glucagon-like peptide-1 (GLP-1) receptor agonists — including semaglutide (Ozempic®, Wegovy®) and the dual GIP/GLP-1 agonist tirzepatide (Mounjaro®, Zepbound®) — have transformed the management of type 2 diabetes, obesity, and cardiovascular disease. Yet a clinically significant and underappreciated challenge persists: profound inter-individual variability in both efficacy and tolerability. Some patients lose more than 20% of body weight; others less than 5%. Some experience debilitating nausea; others experience none at all.This narrative review synthesises the rapidly evolving evidence in pharmacogenomics as it applies to GLP-1 therapies, with a focus on: (1) the genetic architecture of drug-response variability across GLP1R, GIPR, ARRB1, TCF7L2, MC4R, and related loci; (2) landmark genomic research including the April 2026 23andMe GWAS published in Nature (n=27,885) — the largest pharmacogenomic study of GLP-1 drugs to date; (3) the strategic positioning of leading biopharma companies (Novo Nordisk, Eli Lilly, 23andMe Research Institute, PGxAI) in this space; (4) the emerging research landscape in India and South Asia, where the world's largest diabetes burden intersects with a distinct and undercharacterised pharmacogenomic profile; and (5) a roadmap toward clinically actionable precision prescribing. We argue that GLP-1 pharmacogenomics has moved from exploratory science to actionable discovery, and that its translation into clinical practice — particularly for the 1.3 billion people of South Asia — is the defining precision medicine challenge of the next decade in metabolic disease.
Educational summary of published research — not medical advice. License: cc by. Full text is shown only where licensing permits.