Genotype-Drug-Diet Interactions in Metabolic Regulation: CYP1A2 rs762551 Modulates the Effect of Caffeine on Lipid and Glucose Profiles in the Context of Pharmacotherapy.

: Inter-individual metabolic responses to caffeine are shaped by CYP1A2 clearance rate and by concurrent lipid- or glucose-lowering drugs. We investigated how habitual caffeine intake relates to serum cholesterol and fasting glucose under different CYP1A2 rs762551 genotypes and statin or oral antidiabetic (OAD) use. : A prospective cross-sectional analysis was performed on 358 adults (AA = 65, AC = 163, CC = 130) with recorded genotype, daily caffeine intake, total cholesterol, fasting glucose, and medication status. Multivariable linear regression tested the main and interaction effects of caffeine (mg day), genotype, and therapy. Caffeine intake was positively associated with cholesterol levels (β = 0.30; < 0.001). A significant genotype × caffeine interaction (β = 0.27; < 0.001) revealed the steepest rise in fast metabolisers (AA) not on statins, an effect largely blunted by statin therapy. For glucose, the genotype × caffeine term was also significant (β = 0.30; < 0.001). Among slow metabolisers (CC) without OADs, caffeine correlated positively with glycaemia (r = 0.34; = 0.028), whereas in fast metabolisers on OADs the association reversed (r = -0.36; = 0.015). No meaningful associations occurred in AC carriers. : Caffeine's metabolic impact depends jointly on CYP1A2 genotype and medication. It raises cholesterol in fast metabolisers lacking statins and elevates glucose in slow metabolisers without OADs, yet may lower glucose when rapid metabolisation coincides with antidiabetic therapy. Accounting for this gene-diet-drug interplay could refine caffeine guidance within precision nutrition frameworks.