Diabetes mellitus, type 2, treatment:
Note: May be used as an adjunctive agent or alternative monotherapy for patients in whom initial therapy with lifestyle intervention and metformin failed or who cannot take metformin. Meglitinides are associated with a greater risk of hypoglycemia than other noninsulin antidiabetic agents (AACE/ACE [Garber 2020]; ADA 2021).
Oral: Initial: 60 to 120 mg before meals (up to 3 times daily); in patients whose glycemic levels are close to goal, initiate at 60 mg before meals (up to 3 times daily). After ≥1 week, may increase dose if needed based on response up to 120 mg/dose (360 mg/day) (Raskin 2003; Rosenstock 2004; manufacturer’s labeling).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild to moderate impairment: No dosage adjustment necessary.
Severe impairment: Initiate conservatively at 60 mg 3 times daily with meals if eGFR <30 mL/minute/1.73 m2 (ADA [Tuttle 2014]). Use with caution (especially if eGFR <15 mL/minute/1.73m2) due to potential accumulation of a metabolite with hypoglycemic activity (Inoue 2003).
Mild impairment (Child-Pugh class A): No dosage adjustment necessary.
Moderate to severe impairment (Child-Pugh class B or C): There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use with caution due to potential for hypoglycemia.
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Starlix: 60 mg [DSC], 120 mg [DSC]
Generic: 60 mg, 120 mg
Yes
Oral: Administer 1 to 30 minutes prior to meals. Scheduled dose should not be administered if a meal is missed to avoid hypoglycemia.
Diabetes mellitus, type 2, treatment: Treatment of adults with type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. As reported with nateglinide monotherapy:
>10%: Respiratory: Upper respiratory infection (11%)
1% to 10%:
Central nervous system: Dizziness (4%)
Endocrine & metabolic: Hypoglycemia (2%), increased uric acid, weight gain
Neuromuscular & skeletal: Arthropathy (3%)
Respiratory: Flu-like symptoms (4%)
Miscellaneous: Accidental injury (3%)
Postmarketing and/or case reports: Cholestatic hepatitis, hypersensitivity reaction (including pruritus, rash, urticaria), increased liver enzymes, jaundice
Hypersensitivity to nateglinide or any component of the formulation
Concerns related to adverse effects:
• Hypoglycemia: May cause hypoglycemia; risk factors include inconsistent nutrition, physical activity changes, concomitant use with other antidiabetic therapy, ethanol use, renal impairment, and hepatic impairment. Appropriate patient selection, dosage, and patient education are important to avoid hypoglycemic episodes.
Disease-related concerns:
• Adrenal/pituitary impairment: Use with caution in patients with adrenal and/or pituitary impairment; may be more susceptible to glucose-lowering effects.
• Bariatric surgery:
– Altered absorption: Absorption may be altered given the anatomic and transit changes created by gastric bypass and sleeve gastrectomy surgery (Mechanick 2020; Mingrone 2016).
– Hypoglycemia: May increase the risk of hypoglycemia after gastric bypass, sleeve gastrectomy, and gastric band (Mechanick 2020). Insulin secretion and sensitivity may be partially or completely restored after these procedures (gastric bypass is most effective, followed by sleeve, and finally band) (Korner 2009; Peterli 2012). First-phase insulin secretion and hepatic insulin sensitivity have been shown to be significantly improved in the immediate days after gastric bypass and sleeve gastrectomy. The restorative effects of these procedures on peripheral insulin sensitivity may occur later in the 3- to 12-month period after surgery. Where possible, the selection of antidiabetic agents without the potential for hypoglycemia is advised.
• Hepatic impairment: Use with caution in patients with moderate-to-severe hepatic impairment due to risk of hypoglycemia.
• Renal impairment: Use with caution in patients with severe renal impairment; use may result in prolonged hypoglycemia due to accumulation of a metabolite with hypoglycemic activity (Inoue 2003).
• Stress-related states: It may be necessary to discontinue nateglinide and administer insulin if the patient is exposed to stress (eg, fever, trauma, infection, surgery).
Other warnings/precautions:
• Appropriate use: Not for use in patients with diabetic ketoacidosis (DKA) or patients with type 1 diabetes mellitus.
• Hospitalized patients: Consider temporary discontinuation of noninsulin antidiabetic agents and initiation or continuation of insulin therapy during hospitalization (ADA 2021). In noncritically ill hospitalized patients, continued use of nateglinide may be considered if there are no contraindications, regular nutritional intake is expected, and blood glucose is well controlled; close monitoring and subsequent dosage adjustments are recommended (ADA/AACE [Moghissi 2009]; Bogun 2013; Inzucchi 2006).
Special populations:
• Malnourished patients: Use with caution in malnourished patients; may be more susceptible to glucose-lowering effects.
Substrate of CYP2C9 (major), CYP3A4 (major), OATP1B1/1B3 (SLCO1B1/1B3); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alpha-Lipoic Acid: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Androgens: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Antidiabetic Agents: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Beta-Blockers (Beta1 Selective): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Beta-Blockers (Nonselective): May enhance the hypoglycemic effect of Antidiabetic Agents. Beta-Blockers (Nonselective) may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Bortezomib: May enhance the therapeutic effect of Antidiabetic Agents. Bortezomib may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
CYP2C9 Inhibitors (Moderate): May increase the serum concentration of Nateglinide. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Nateglinide. Risk C: Monitor therapy
Direct Acting Antiviral Agents (HCV): May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Etilefrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Glucagon-Like Peptide-1 Agonists: May enhance the hypoglycemic effect of Meglitinides. Management: Consider meglitinide dose reductions when used in combination with glucagon-like peptide-1 agonists, particularly when also used with basal insulin. Risk D: Consider therapy modification
Guanethidine: May enhance the hypoglycemic effect of Antidiabetic Agents. Risk C: Monitor therapy
Herbal Products with Glucose Lowering Effects: May enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hyperglycemia-Associated Agents: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: May enhance the hypoglycemic effect of other Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Hypoglycemia-Associated Agents: Antidiabetic Agents may enhance the hypoglycemic effect of Hypoglycemia-Associated Agents. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Lumacaftor and Ivacaftor may increase the serum concentration of CYP2C9 Substrates (High Risk with Inhibitors or Inducers). Risk C: Monitor therapy
Maitake: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Pegvisomant: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Prothionamide: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Quinolones: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Quinolones may diminish the therapeutic effect of Agents with Blood Glucose Lowering Effects. Specifically, if an agent is being used to treat diabetes, loss of blood sugar control may occur with quinolone use. Risk C: Monitor therapy
Ritodrine: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Salicylates: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Selective Serotonin Reuptake Inhibitors: May enhance the hypoglycemic effect of Agents with Blood Glucose Lowering Effects. Risk C: Monitor therapy
Thiazide and Thiazide-Like Diuretics: May diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Rate of absorption is decreased and Tmax is delayed when taken with food. Food does not affect AUC. Multiple peak plasma concentrations may be observed if fasting. Not affected by composition of meal. Management: Administer 1-30 minutes prior to meals.
Information describing the effects of nateglinide on pregnancy outcomes is limited (Twaites 2007).
Poorly controlled diabetes during pregnancy can be associated with an increased risk of adverse maternal and fetal outcomes, including diabetic ketoacidosis, preeclampsia, spontaneous abortion, preterm delivery, delivery complications, major malformations, stillbirth, and macrosomia (ACOG 201 2018). To prevent adverse outcomes, prior to conception and throughout pregnancy, maternal blood glucose and HbA1c should be kept as close to target goals as possible but without causing significant hypoglycemia (ADA 2021; Blumer 2013).
Agents other than nateglinide are currently recommended to treat diabetes mellitus in pregnancy (ADA 2021).
It is not known if nateglinide is present in breast milk.
Due to the potential for hypoglycemia in the breastfeeding infant, breastfeeding is not recommended by the manufacturer.
Individualized medical nutrition therapy based on American Diabetes Association recommendations is an integral part of therapy.
Weight, lipid profile, fasting blood glucose (periodically and during dosage titration).
HbA1c: Monitor at least twice yearly in patients who have stable glycemic control and are meeting treatment goals; monitor quarterly in patients in whom treatment goals have not been met, or with therapy change. Note: In patients prone to glycemic variability (eg, patients with insulin deficiency), or in patients whose HbA1c is discordant with serum glucose levels or symptoms, consider evaluating HbA1c in combination with blood glucose levels and/or a glucose management indicator (ADA 2021; KDIGO 2020).
Recommendations for glycemic control in patients with diabetes:
Nonpregnant adults with diabetes (ADA 2021):
HbA1c: <7% (a more aggressive [<6.5%] or less aggressive [<8%] HbA1c goal may be targeted based on patient-specific characteristics). Note: In patients using a continuous glucose monitoring system, a goal of time in range >70% with time below range <4% is recommended and is similar to a goal HbA1c <7%.
Preprandial capillary blood glucose: 80 to 130 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Peak postprandial capillary blood glucose (~1 to 2 hours after a meal): <180 mg/dL (more or less stringent goals may be appropriate based on patient-specific characteristics).
Older adults (≥65 years of age) (ADA 2021):
Note: Consider less strict targets in patients who are using insulin and/or insulin secretagogues (sulfonylureas, meglitinides) (ES [LeRoith 2019]).
HbA1c: <7% to 7.5% (healthy); <8% to 8.5% (complex/intermediate health). Note: Individualization may be appropriate based on patient and caregiver preferences and/or presence of cognitive impairment. In patients with very complex or poor health (ie, limited remaining life expectancy), consider making therapy decisions based on avoidance of hypoglycemia and symptomatic hyperglycemia rather than HbA1c level.
Preprandial capillary blood glucose: 80 to 130 mg/dL (healthy); 90 to 150 mg/dL (complex/intermediate health); 100 to 180 mg/dL (very complex/poor health).
Bedtime capillary blood glucose: 80 to 180 mg/dL (healthy); 100 to 180 mg/dL (complex/intermediate health); 110 to 200 mg/dL (very complex/poor health).
Classification of hypoglycemia (ADA 2021):
Level 1: 54 to 70 mg/dL; hypoglycemia alert value; initiate fast-acting carbohydrate (eg, glucose) treatment.
Level 2: <54 mg/dL; threshold for neuroglycopenic symptoms; requires immediate action.
Level 3: Hypoglycemia associated with a severe event characterized by altered mental and/or physical status requiring assistance.
Nonsulfonylurea hypoglycemic agent which blocks ATP-dependent potassium channels, depolarizing the membrane and facilitating calcium entry through calcium channels. Increased intracellular calcium stimulates insulin release from the pancreatic beta cells. Nateglinide-induced insulin release is glucose-dependent.
Onset of action: Insulin secretion: ~20 minutes
Peak effect: 1 hour
Duration: 4 hours
Absorption: Rapid
Distribution: 10 L
Protein binding: 98%, primarily to albumin
Metabolism: Hepatic via hydroxylation followed by glucuronide conjugation via CYP2C9 (70%) and CYP3A4 (30%) to metabolites, including M1 (a major metabolite)
Bioavailability: 73%
Half-life elimination: 1.5 hours
Time to peak: ≤1 hour
Excretion: Urine (83%, 16% as unchanged drug); feces (10%)
Altered kidney function: Accumulation of M1, a major metabolite with modest hypoglycemic activity, was observed following repeated administration in patients with severe renal impairment (CrCl <17 mL/minute/1.73 m2). Hemodialysis sessions did significantly reduce M1 levels in these patients (Inoue 2003).
Hepatic function impairment: Cmax increased 37% and AUC increased 30% in patients with mild hepatic insufficiency.
Tablets (Nateglinide Oral)
60 mg (per each): $1.66
120 mg (per each): $1.73
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
