Which pharmacogenomic factor determines whether a patient with type 2 diabetes will respond adequately to sulfonylurea monotherapy?

• A CYP2C9 polymorphism affecting sulfonylurea metabolism — poor metabolizers have hypoglycemia risk ✓
• B KCNJ11 (Kir6.2) and ABCC8 (SUR1) gene variants encoding the pancreatic KATP channel — certain gain-of-function mutations confer primary sulfonylurea failure
• C TCF7L2 polymorphism determines sulfonylurea efficacy by altering receptor affinity
• D HLA-DR4 genotype determines susceptibility to sulfonylurea-induced hepatotoxicity

Explanation

CYP2C9 metabolizes most sulfonylureas (glipizide, glibenclamide, glimepiride). Patients with CYP2C9*2 or CYP2C9*3 alleles (poor metabolizers) have reduced clearance of these drugs, leading to accumulation and severe prolonged hypoglycemia. This is the most clinically actionable pharmacogenomic interaction — dose reduction is recommended in poor metabolizers. KCNJ11/ABCC8 mutations (option B) cause neonatal diabetes responsive to sulfonylureas, not type 2 diabetes failure. TCF7L2 affects incretin response, not sulfonylurea efficacy directly.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.