The paper looks at how your DNA might change the way you respond to tirzepatide, a new drug that helps lower blood sugar, cut weight, and protect the heart. It gathers what we know so far about genetic differences that can make the drug work better or cause more side‑effects, and talks about how this could someday let you tailor the dose to your own genes.

Type 2 diabetes mellitus (T2DM) is frequently complicated by atherosclerosis (AS), with substantial overlap in their underlying pathophysiological mechanisms, posing serious threats to patient health. Tirzepatide, a novel dual agonist of glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors, has demonstrated remarkable efficacy in glycemic control, weight reduction, and cardiometabolic improvement, making it a promising candidate for managing T2DM comorbid with AS. However, substantial interindividual variability in treatment response suggests a role for genetic determinants. This review systematically summarises current evidence on pharmacogenomic variants influencing the efficacy and toxicity of tirzepatide, explores the interplay between drug response genes and genetic susceptibilities to T2DM and AS, and highlights the potential of pharmacogenomics in guiding precision subtyping and individualised therapy. Finally, we highlight key challenges and future directions in the clinical translation of tirzepatide pharmacogenomics, aiming to inform personalized, genomics-guided therapy for cardiometabolic disease.