Adverse Effects of Nateglinide
The main adverse effects of nateglinide include hypoglycemia and weight gain, though the risk of hypoglycemia is lower than with sulfonylureas. 1, 2
Common Adverse Effects
Metabolic Effects
Hypoglycemia: The most clinically significant adverse effect, though less severe and less frequent than with sulfonylureas 1, 2
- Severe hypoglycemia (plasma glucose <36 mg/dL) reported in only 2 patients in clinical trials 2
- Non-severe hypoglycemia occurred in 2.4% of nateglinide-treated patients vs. 0.4% of placebo-treated patients 2
- Risk factors for hypoglycemia include:
- Changes in meal patterns
- Increased physical activity
- Concomitant use of other antidiabetic agents
- Renal or hepatic impairment 2
Weight gain: Statistically significant compared to placebo 2
- Mean weight increase of 1-1.6 kg with nateglinide 60-120 mg three times daily 2
Gastrointestinal Effects
- Diarrhea (3.2% of patients) 2
Other Common Effects (≥2% incidence)
- Upper respiratory tract infection (10.5%) 2
- Back pain (4%) 2
- Flu symptoms (3.6%) 2
- Dizziness (3.6%) 2
- Arthropathy (3.3%) 2
- Accidental trauma (2.9%) 2
- Bronchitis (2.7%) 2
- Coughing (2.4%) 2
Laboratory Abnormalities
- Increased uric acid levels (mean increase of 0.29 mg/dL compared to placebo) 2
Rare Adverse Effects (Post-Marketing)
- Hypersensitivity reactions: Rash, itching, and urticaria 2
- Hepatobiliary disorders: Jaundice, cholestatic hepatitis, and elevated liver enzymes 2
Special Considerations for Specific Populations
Elderly Patients
- Higher risk of hypoglycemia in elderly patients 1
- Should be used with caution in elderly patients, especially those with cognitive or functional impairment 1
Patients with Renal Impairment
- Can be used in patients with renal insufficiency, but requires careful monitoring 1
- Increased risk of hypoglycemia in patients with renal impairment 2
Patients with Hepatic Impairment
- Higher risk of hypoglycemia in patients with hepatic impairment 2
- Use with caution in patients with liver disease 2
Drug Interactions
Medications That May Increase Hypoglycemia Risk
- NSAIDs, salicylates
- Monoamine oxidase inhibitors
- Non-selective beta-blockers
- CYP2C9 inhibitors (e.g., amiodarone, fluconazole, voriconazole)
- Alcohol 2
Medications That May Reduce Efficacy
- Thiazides
- Corticosteroids
- Thyroid products
- Sympathomimetics
- CYP inducers (e.g., rifampin, phenytoin, St. John's Wort) 2
Risk Mitigation Strategies
- Proper administration: Take 1-30 minutes before meals 2
- Skip dose if meal is skipped: Critical to avoid hypoglycemia 2
- Patient education: Recognize and manage hypoglycemia symptoms 2
- Blood glucose monitoring: Essential for prevention and management of hypoglycemia, especially in high-risk patients 2
- Dose adjustment: Consider lower doses in patients at risk for hypoglycemia 2
Unique Pharmacological Properties
Nateglinide has a rapid onset and short duration of action ("fast on-fast off" effect) 3, which:
- Stimulates and restores normal physiological first-phase insulin secretion 3
- Reduces postprandial hyperglycemia when taken immediately before meals 3
- Avoids delayed hyperinsulinemia after meals 3
This pharmacological profile contributes to its relatively lower risk of hypoglycemia compared to sulfonylureas, while still providing effective postprandial glucose control 3, 4.