A patient is started on glimepiride and develops recurrent hypoglycemia during Ramadan fasting. The sulfonylurea's pharmacogenomic risk in this patient is most related to:

• A CYP2C9*3 poor metabolizer status — reduced glimepiride clearance leads to drug accumulation and prolonged hypoglycemia ✓
• B ABCC8 (SUR1) gain-of-function variant causing exaggerated KATP channel closure
• C KCNJ11 (Kir6.2) loss-of-function variant reducing channel sensitivity to sulfonylureas
• D UGT1A9 polymorphism causing glimepiride glucuronidation to an active hypoglycemic metabolite

Explanation

Glimepiride is primarily metabolized by CYP2C9 to its M1 and M2 metabolites. Patients carrying CYP2C9*2 or *3 alleles (poor metabolizers, particularly *3/*3 homozygotes) have significantly reduced glimepiride clearance, resulting in 2–4-fold higher AUC and risk of prolonged severe hypoglycemia. This is especially dangerous during fasting (Ramadan), requiring dose reduction or switching to a sulfonylurea less dependent on CYP2C9 (e.g., gliclazide, which has alternative metabolic pathways). ABCC8 and KCNJ11 variants are relevant to neonatal diabetes and familial hyperinsulinism, not standard sulfonylurea pharmacogenomics.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.