Nateglinide

Nateglinide, marketed under the brand name Starlix, is an oral antidiabetic agent in the meglitinide class designed to help control blood sugar in patients with type 2 diabetes.

It is prescribed to improve postprandial glucose levels by stimulating insulin release as part of a comprehensive treatment plan including diet and exercise.

Mechanistically, nateglinide closes ATP-sensitive potassium channels in pancreatic beta cells, enhancing insulin secretion and reducing blood glucose spikes after meals.

The CYP2C9 gene encodes a hepatic enzyme responsible for metabolizing nateglinide. This enzyme helps clear the drug from the bloodstream by chemically transforming it in the liver.

Genetic variations (alleles) in CYP2C9 can produce enzymes with reduced or normal activity. These differences are classified into metabolizer phenotypes—poor, intermediate, or normal—that affect how quickly nateglinide is processed.

CYP2C9 metabolizer status directly influences nateglinide levels: poor metabolizers clear the drug more slowly and have higher systemic exposure (increasing hypoglycemia risk), intermediate metabolizers have moderately elevated levels, and normal metabolizers achieve expected drug concentrations; indeterminate genotypes require standard dosing with close monitoring.

Normal Metabolizer

• Effect on drug levels: Typical clearance maintains expected blood concentrations.
• Clinical consequence: Standard glycemic control as anticipated.
• Side effects: Baseline risk of hypoglycemia, mild to moderate, occurs occasionally.

Intermediate Metabolizer

• Effect on drug levels: Moderately increased blood concentrations due to slower metabolism.
• Clinical consequence: Slightly heightened risk of hypoglycemia.
• Side effects: Hypoglycemia episodes may be more frequent, severity mild to moderate.

Poor Metabolizer

• Effect on drug levels: Significantly elevated blood concentrations from reduced clearance.
• Clinical consequence: High risk of hypoglycemia requiring dose adjustment and close monitoring.
• Side effects: Severe hypoglycemia risk increased; may occur frequently without dose reduction.

Indeterminate/Not Available

• Effect on drug levels: Unknown due to unclear genotype information.
• Clinical consequence: No specific guidance; standard dosing with clinical monitoring.
• Side effects: Risk based on general population; monitor for hypoglycemia.

CYP2C9 Dosing Guideline

The FDA labeling does not provide specific alternative pharmacogenomic-guided treatment options for CYP2C9 variants; clinicians may consider other mealtime insulin secretagogues (e.g., repaglinide) or adjust the therapeutic regimen based on individual patient factors. These are examples only and not medical advice.

• FDA – Table of Pharmacogenetic Associations