This retrospective cohort study linked whole-genome sequencing to electronic health records for 44,485 adult metoprolol users in All of Us. Discontinuation meant the last dispensed supply lapsing with no further fill for over 90 days. Discontinuation reached 67.4%; cause-specific hazard ratios versus normal metabolisers were 1.04 (0.99-1.09) poor, 1.01 (0.99-1.03) intermediate. Two alternative supply-gap definitions, with discontinuation rates of 70% and 98%, gave the same null. Poor and intermediate metabolisers had heart rate 1.85 and 0.84 bpm lower, with bradycardia odds ratios 1.19 and 1.16. Dispensing records miss fills obtained outside the linked system, and requiring two fills excluded single-fill stoppers.
Why it is interesting: A pharmacogenetic effect clearly present in measured physiology was not seen in rates of stopping the drug. The gap limits what genotype-informed dosing guidance can be expected to achieve.
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