Nateglinide (DB00731): A Comprehensive Pharmacological and Clinical Monograph

Executive Summary

Nateglinide is an orally administered, short-acting insulin secretagogue belonging to the meglitinide (or glinide) class of antidiabetic agents. Chemically, it is a D-phenylalanine derivative, distinguishing it structurally from the sulfonylurea class of drugs.[1] Its primary therapeutic application is as an adjunct to diet and exercise for the management of type 2 diabetes mellitus, specifically targeting postprandial hyperglycemia.[3] The pharmacological action of nateglinide is characterized by a unique "fast on-fast off" kinetic profile at its molecular target, the pancreatic β-cell ATP-sensitive potassium channel.[5] This property enables it to mimic the physiological first-phase insulin secretion that occurs in response to a meal, leading to rapid but transient insulin release that effectively controls post-meal glucose excursions.

The clinical use of nateglinide is governed by its rapid and short-lived action. A strict, meal-dependent dosing regimen is essential for both efficacy and safety, encapsulated by the critical patient counseling point: "skip a meal, skip a dose".[3] This approach mitigates the principal adverse effect of hypoglycemia. Pharmacokinetically, nateglinide is characterized by rapid absorption, a short half-life of approximately 1.5 hours, and extensive hepatic metabolism. Its clearance is predominantly mediated by the cytochrome P450 isozyme CYP2C9, a fact that introduces significant considerations for pharmacogenomics and drug-drug interactions, particularly in individuals who are genetically poor metabolizers of the enzyme.[7] While approved by major regulatory bodies, including the U.S. Food and Drug Administration (FDA), its marketing authorization in the European Union was withdrawn in 2022 for commercial reasons, reflecting a shift in the therapeutic landscape toward newer antidiabetic agents with more convenient dosing and broader metabolic benefits.[9]

Introduction and Drug Classification

Nateglinide represents a targeted approach to the management of type 2 diabetes mellitus, a complex metabolic disorder characterized by insulin resistance and progressive β-cell dysfunction. It is classified as an oral antihyperglycemic agent within the meglitinide (glinide) class, a group of non-sulfonylurea insulin secretagogues known for their rapid onset and short duration of action.[1]

Structurally, nateglinide is an N-acylated derivative of the amino acid D-phenylalanine, specifically (2R)-3-phenyl-2-({[trans-4-(1-methylethyl)cyclohexyl]carbonyl}amino)-3-phenylpropanoic acid.[2] This chemical identity distinguishes it fundamentally from the sulfonylurea and biguanide classes of antidiabetic drugs. This structural uniqueness is directly responsible for its distinct pharmacokinetic and pharmacodynamic properties, which define its therapeutic niche.

The primary role of nateglinide in diabetes management is that of a prandial glucose regulator. Its mechanism is finely tuned to restore the deficient first-phase insulin response, a key pathophysiological defect in type 2 diabetes that leads to exaggerated postprandial glucose excursions.[1] By stimulating a rapid, short-lived pulse of insulin secretion timed with meal ingestion, nateglinide addresses this specific defect. This targeted action contrasts sharply with longer-acting secretagogues like sulfonylureas, which provide a more sustained, meal-independent insulin release, or agents like metformin, which primarily target basal hepatic glucose production. This positions nateglinide not as a foundational, broad-spectrum glucose-lowering agent, but as a specialist drug for patients whose primary glycemic challenge is the control of blood sugar after meals.

Physicochemical Properties and Identification

A precise understanding of nateglinide's chemical and physical properties is fundamental to its formulation, pharmacology, and biopharmaceutical behavior.

Chemical Identity

• IUPAC Name: (2R)-3-phenyl-2-({[trans-4-(1-methylethyl)cyclohexyl]carbonyl}amino)-3-phenylpropanoic acid [2]
• Molecular Formula: C19​H27​NO3​ [14]
• Molecular Weight: Approximately 317.43 g/mol [16]
• Stereochemistry: As a derivative of D-phenylalanine, nateglinide possesses a specific stereochemical configuration, denoted by the (R) designator in its chemical name, which is critical for its biological activity. The enantiomer, derived from L-phenylalanine, is a related substance but not the active pharmaceutical ingredient.[19]
• Computational Identifiers:
• SMILES: CC(C)C1CCC(CC1)C(=O)N[C@H](CC2=CC=CC=C2)C(=O)O [2]
• InChI: InChI=1S/C19H27NO3/c1-13(2)15-8-10-16(11-9-15)18(21)20-17(19(22)23)12-14-6-4-3-5-7-14/h3-7,13,15-17H,8-12H2,1-2H3,(H,20,21)(H,22,23)/t17-/m1/s1 (stereochemistry varies slightly by source) [2]
• InChIKey: OELFLUMRDSZNSF-BRWVUGGUSA-N (or similar, depending on stereochemical definition) [1]

Physical Properties

Nateglinide is a white to off-white crystalline powder.[8] Its solubility profile reflects a lipophilic character, which is consistent with its oral absorption and extensive hepatic metabolism. It is practically insoluble in water but exhibits good solubility in organic solvents: freely soluble in methanol, ethanol, and chloroform; soluble in ether; and sparingly soluble in acetonitrile and octanol.[8] The melting point is reported to be in the range of 137–141 °C.[20]

For unambiguous identification across various scientific and regulatory databases, a comprehensive list of identifiers is provided in Table 1.

Table 1: Comprehensive Drug Identifiers for Nateglinide

Identifier Type	Identifier Value	Source/Database
DrugBank ID	DB00731	DrugBank 1
CAS Number	105816-04-4	ChemIDplus, DrugBank 1
UNII	41X3PWK4O2	FDA Global Substance Registration System (GSRS) 1
PubChem CID	5311309	PubChem 2
ChEBI ID	CHEBI:31897	Chemical Entities of Biological Interest 1
KEGG ID	D01111	Kyoto Encyclopedia of Genes and Genomes 1
European Community (EC) Number	642-283-9	European Chemicals Agency (ECHA) 1
ATC Code	A10BX03	WHO Collaborating Centre for Drug Statistics Methodology 20
RxCUI	274332	NLM RxNorm Terminology 1

Pharmacology: Mechanism of Action and Pharmacodynamic Profile

The therapeutic effect of nateglinide is derived from a precise and well-characterized pharmacological mechanism that modulates pancreatic insulin secretion in a manner that closely mimics the body's natural response to a meal.

Molecular Target and Mechanism

Nateglinide's primary pharmacological action is the stimulation of insulin secretion from pancreatic β-cells, an effect that is contingent upon the presence of functioning β-cells.[3] The molecular target for this action is the ATP-sensitive potassium (

KATP​) channel on the β-cell membrane.[8] Nateglinide binds to the sulfonylurea receptor 1 (SUR1) subunit of this channel, a protein also identified as the ATP-binding cassette sub-family C member 8 (ABCC8).[5]

The binding of nateglinide to the SUR1 subunit closes the KATP​ channel, inhibiting the outward flow of potassium ions. This leads to a depolarization of the β-cell membrane. The change in membrane potential triggers the opening of voltage-gated calcium channels, resulting in an influx of extracellular calcium (Ca2+). The subsequent rise in intracellular calcium concentration is the final signal that initiates the exocytosis of pre-formed, insulin-containing secretory granules, releasing insulin into the bloodstream.[8]

Unique Pharmacodynamic Properties

While the general mechanism of closing KATP​ channels is shared with sulfonylureas, nateglinide's pharmacodynamic profile is distinguished by several unique features that define its clinical utility.

The most critical of these is its binding kinetics, often described as a "fast on-fast off" effect.[5] Nateglinide associates with the SUR1 receptor rapidly but with a relatively low affinity, and, most importantly, it dissociates from the receptor extremely quickly, on the order of seconds.[5] This kinetic profile is the molecular basis for its rapid onset of action (stimulating insulin secretion within 20 minutes) and very short duration of action (insulin levels return to baseline within approximately 4 hours).[11]

This rapid, transient action allows nateglinide to preferentially stimulate and restore the physiological first-phase of insulin secretion, the initial, sharp peak of insulin release that occurs within minutes of nutrient ingestion.[5] In type 2 diabetes, this first phase is characteristically blunted or absent, leading to poor initial control of meal-derived glucose. By restoring this early insulin peak, nateglinide effectively attenuates the subsequent postprandial glucose spike.[5]

Furthermore, the insulinotropic effect of nateglinide is glucose-dependent. Its ability to stimulate insulin release diminishes as blood glucose levels fall.[8] Unlike sulfonylureas, which can continue to promote insulin secretion even at hypoglycemic levels, nateglinide has little to no effect on insulin release in the absence of glucose.[24] This glucose-sensing mechanism is a key safety feature, reducing the risk of interprandial (between-meal) and fasting hypoglycemia.

Comparative Pharmacology

When compared to other insulin secretagogues, nateglinide's profile is distinct. Its action is more rapid and of shorter duration than that of both traditional sulfonylureas (e.g., glyburide) and the fellow meglitinide repaglinide.[5] This leads to superior control of postprandial glucose excursions and a lower risk of delayed hyperinsulinemia, which can cause hypoglycemia hours after a meal.[5] However, this specialization in prandial control comes with a trade-off. Clinical studies have demonstrated that nateglinide is generally less effective than metformin or glyburide at lowering integrated measures of long-term glycemic control, such as glycosylated hemoglobin (

HbA1c​) and fasting plasma glucose (FPG).[13] The entire clinical utility and safety profile of nateglinide can thus be understood as a direct consequence of its unique binding kinetics at the SUR1 receptor. The rapid "on" rate necessitates its administration just before a meal to align insulin release with glucose absorption. The rapid "off" rate and short half-life ensure its effect is transient, covering only the mealtime glucose load and minimizing the risk of delayed hypoglycemia, which in turn dictates the "skip a meal, skip a dose" rule. Finally, its glucose-dependent action provides an intrinsic safety mechanism against severe hypoglycemia, distinguishing it from older secretagogues.

Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The pharmacokinetic profile of nateglinide is characterized by rapid absorption, extensive protein binding, efficient hepatic metabolism, and swift elimination, all of which are consistent with its role as a short-acting prandial glucose regulator.

Absorption

Following oral administration, nateglinide is rapidly and completely absorbed from the gastrointestinal tract, with an estimated absolute bioavailability of approximately 73%.[8] Peak plasma concentrations (

Cmax​) are typically achieved within one hour after dosing, allowing for a rapid onset of its pharmacodynamic effect.[8]

The timing of administration relative to food intake is a critical factor. When nateglinide is taken with or after a meal, the rate of its absorption is delayed, as evidenced by a decrease in Cmax​ and a prolonged time to peak concentration (Tmax​); however, the overall extent of absorption (AUC) is not significantly affected.[8] Studies have shown that administration just prior to food consumption (e.g., 10 to 30 minutes before) results in optimal pharmacodynamic effects, with a more rapid insulin response and better control of the postprandial glucose peak.[27]

Distribution

Nateglinide has a relatively small steady-state volume of distribution (Vd​), estimated to be approximately 10 liters in healthy subjects.[8] It is extensively bound (98%) to plasma proteins, primarily serum albumin and, to a lesser extent,

α1​-acid glycoprotein.[8] This high degree of protein binding suggests a low potential for displacement interactions with other highly protein-bound drugs, as confirmed in in vitro studies.[13]

Metabolism

Nateglinide undergoes extensive metabolism in the liver via the cytochrome P450 (CYP) mixed-function oxidase system prior to elimination.[1] The primary metabolic pathways involve hydroxylation of the isopropyl group or the cyclohexyl ring, followed by glucuronide conjugation.[8]

The key enzymes responsible for its metabolism are well-defined: nateglinide is predominantly metabolized by CYP2C9 (approximately 70%) and to a lesser extent by CYP3A4 (approximately 30%).[7] This heavy reliance on CYP2C9 is a critical aspect of its clinical pharmacology, forming the basis for significant drug interactions and pharmacogenomic variability.

The major metabolites produced are less potent hypoglycemic agents than the parent compound. However, a minor metabolite, the isoprene metabolite, possesses a potency similar to that of nateglinide itself.[1]

Excretion

Nateglinide and its metabolites are rapidly and completely eliminated from the body. Following an oral dose, approximately 83% is recovered in the urine and 10% in the feces.[1] The majority of the renally excreted portion consists of metabolites; only about 16% of the dose is excreted in the urine as unchanged parent drug.[8]

The elimination half-life (t1/2​) of nateglinide is very short, averaging approximately 1.5 hours.[8] This rapid elimination prevents drug accumulation with multiple daily doses and reinforces its short duration of action, ensuring that its glucose-lowering effect is confined to the postprandial period.

Table 2: Key Pharmacokinetic Parameters of Nateglinide

Parameter	Value	Reference(s)
Absolute Bioavailability (F)	~73%	8
Time to Peak (Tmax​)	<1 hour	8
Plasma Protein Binding	98%	8
Volume of Distribution (Vd​)	~10 L	8
Elimination Half-life (t1/2​)	~1.5 hours	8
Primary Metabolic Pathway	Hepatic (CYP2C9: 70%, CYP3A4: 30%)	7
Primary Excretion Route	Renal (83% of dose, primarily as metabolites)	1

Clinical Efficacy and Therapeutic Applications

The clinical utility of nateglinide is precisely defined by its pharmacological profile, positioning it as a targeted therapy for postprandial hyperglycemia in type 2 diabetes.

Approved Indication

Nateglinide is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.[3] It can be used as monotherapy or in combination with other oral antidiabetic agents, most notably metformin.[11]

Limitations of Use

The drug's mechanism of action dictates its limitations. Nateglinide is explicitly contraindicated and not for use in patients with type 1 diabetes or for the treatment of diabetic ketoacidosis (DKA).[3] These conditions are characterized by an absolute or near-absolute deficiency of insulin, and since nateglinide requires functioning pancreatic β-cells to exert its effect, it would be ineffective. Insulin therapy is required for these conditions.

Efficacy as Monotherapy

In clinical trials involving patients with type 2 diabetes previously treated with diet alone (treatment-naïve), nateglinide monotherapy demonstrated statistically significant reductions in mean HbA1c​ and fasting plasma glucose (FPG) levels compared to placebo.[8] However, its potency in this regard is modest compared to other established agents. Head-to-head comparisons have shown nateglinide to be less effective than either metformin or the second-generation sulfonylurea glyburide at lowering these overall measures of glycemic control.[13]

Efficacy in Combination Therapy

Nateglinide's role is often more pronounced in combination therapy. When added to metformin in patients inadequately controlled on metformin alone, nateglinide provides a significant additive effect, leading to greater reductions in both HbA1c​ and FPG than could be achieved with either agent as monotherapy.[5] This synergy arises from their complementary mechanisms of action: metformin primarily reduces hepatic glucose production and improves insulin sensitivity, while nateglinide directly addresses prandial insulin secretion.

Conversely, a clinical trial examining the addition of nateglinide to a regimen of a patient inadequately controlled on glyburide found no additional clinical benefit.[13] This finding suggests a mechanistic redundancy; since both drugs are insulin secretagogues acting on the

KATP​ channel, adding nateglinide to a maximally effective dose of a sulfonylurea does not further enhance insulin release.

This body of clinical evidence paints a clear picture of nateglinide's role. It is not a first-line, "generalist" agent for achieving powerful, broad-spectrum glucose lowering. Its relative weakness in reducing FPG and overall HbA1c​ compared to workhorse drugs like metformin makes it less suitable as a foundational monotherapy. Instead, its strength as a "specialist" in targeting postprandial hyperglycemia defines its place in therapy. It is a logical add-on for a patient who is on metformin but continues to experience significant glucose spikes after meals. This targeted application leverages its unique pharmacodynamic profile without relying on it for 24-hour glycemic control.

Dosage, Administration, and Patient Counseling

Effective and safe use of nateglinide is highly dependent on strict adherence to its specific dosing and administration schedule, which requires thorough patient education.

Dosage Forms and Strengths

Nateglinide is available for oral administration as tablets in two strengths: 60 mg and 120 mg.[18]

Standard Dosing

• Monotherapy or Combination Therapy: The standard recommended dose is 120 mg taken orally three times daily.[3]
• Patients Near Glycemic Goal: For patients who are already close to their target HbA1c​ level when treatment is initiated, a lower starting dose of 60 mg three times daily may be appropriate to minimize the risk of hypoglycemia.[6]

Administration

The timing of nateglinide administration is critical to its mechanism and safety.

• Timing with Meals: The dose must be taken 1 to 30 minutes before the start of a main meal.[3] This timing is designed to ensure that the peak insulin secretion stimulated by the drug coincides with the peak glucose absorption from the meal.
• The "Skip a Meal, Skip a Dose" Rule: This is the most important principle of nateglinide administration. Patients must be explicitly and repeatedly instructed to skip their scheduled dose of nateglinide if they skip a meal.[3] Taking the drug without a subsequent meal will lead to insulin release without a corresponding glucose load, creating a high risk of hypoglycemia. Conversely, if an extra meal is added, an extra dose should be taken.[4]

Patient Counseling

Comprehensive patient counseling is paramount for the safe and effective use of nateglinide. Key counseling points include:

• Role of Lifestyle: Patients should understand that nateglinide is an adjunct to, and not a substitute for, a healthy diet, regular physical exercise, and weight management.[3]
• Hypoglycemia Management: Patients and their family members or caregivers must be thoroughly educated on the signs and symptoms of hypoglycemia (e.g., shakiness, dizziness, sweating, anxiety, confusion, rapid heartbeat).[4] They should be instructed on how to treat it promptly with a fast-acting source of sugar (such as glucose tablets, fruit juice, or hard candy) and to always carry such a source with them.[10]
• Alcohol Consumption: Patients must be strongly cautioned about the consumption of alcoholic beverages. Alcohol can potentiate the glucose-lowering effect of nateglinide and may cause severe or delayed hypoglycemia. This topic should be discussed in detail with their healthcare provider.[3]
• Self-Monitoring of Blood Glucose (SMBG): Regular SMBG is essential to assess the drug's effectiveness, guide any dose adjustments, and, most importantly, detect and prevent hypoglycemia.[3]
• Polypharmacy and OTC Medications: Patients should be advised to inform their doctor or pharmacist of all other medications they are taking, including nonprescription (over-the-counter) drugs for conditions like colds, coughs, allergies, or pain, as many of these can contain ingredients that affect blood sugar levels.[3]
• Missed Doses: If a dose is missed but the patient is about to eat, it can be taken. However, if it is almost time for the next meal and dose, the missed dose should be skipped entirely. Patients should never double the dose to make up for a missed one.[3]

Safety Profile, Contraindications, and Warnings

While generally well-tolerated when used appropriately, nateglinide has a distinct safety profile dominated by the risk of hypoglycemia.

Adverse Effects

• Most Common Adverse Effects: In clinical trials, the most frequently reported adverse effects (occurring in ≥3% of patients) include upper respiratory tract infections, back pain, flu-like symptoms, dizziness, arthropathy (joint disease), and diarrhea.[3]
• Less Common Adverse Effects: Other reported side effects include cough, chest tightness, muscle aches, and joint pain.[3]
• Weight Gain: Nateglinide monotherapy has been associated with a modest increase in body weight when compared to placebo or metformin monotherapy.[13]

Primary Safety Concern: Hypoglycemia

The principal and most serious risk associated with nateglinide therapy is hypoglycemia (low blood sugar).[3]

• Risk and Severity: As with all insulin secretagogues, nateglinide can cause hypoglycemia, which may be severe and, in rare cases, life-threatening or fatal. Severe hypoglycemia can lead to seizures and loss of consciousness.[11]
• Risk Factors: The risk of hypoglycemia is increased by factors such as strenuous physical exercise, insufficient caloric intake (or skipped meals), ingestion of alcohol, and concomitant use of other glucose-lowering medications.[18]
• Blunted Awareness: Symptomatic awareness of hypoglycemia can be less pronounced in certain individuals, including those with long-standing diabetes, diabetic autonomic neuropathy, or those concurrently using medications that block the sympathetic nervous system, such as non-selective beta-blockers. This blunted awareness increases the risk of severe hypoglycemic events.[11]

Contraindications

Nateglinide is strictly contraindicated in the following patient populations:

• Patients with a known hypersensitivity to nateglinide or any of its inactive ingredients.[14]
• Patients with Type 1 diabetes mellitus.[3]
• Patients with diabetic ketoacidosis.[3]

Warnings and Precautions

• Hepatic Impairment: Nateglinide should be used with caution in patients with moderate-to-severe liver disease. Such patients have not been extensively studied, and impaired hepatic function could potentially alter drug metabolism, increasing exposure and the risk of hypoglycemia.[6]
• Macrovascular Outcomes: There have been no dedicated clinical trials establishing conclusive evidence of a reduction in macrovascular risk (e.g., heart attack, stroke) with nateglinide or any other antidiabetic drug.[18] This is a notable point of differentiation from some newer classes of antidiabetic agents.
• Hepatotoxicity: While rare, postmarketing surveillance has linked nateglinide to instances of clinically apparent acute liver injury.[1]

Clinically Significant Interactions

The potential for drug interactions with nateglinide is significant, arising from both pharmacokinetic (metabolism-based) and pharmacodynamic (effect-based) mechanisms. The central role of CYP2C9 in its clearance makes it particularly vulnerable to interactions with inhibitors and inducers of this enzyme.

Pharmacokinetic Interactions (Metabolism-Based)

• CYP2C9 Inhibitors: Co-administration of nateglinide with potent inhibitors of CYP2C9 can substantially increase its plasma concentration and duration of effect, thereby elevating the risk of hypoglycemia. Clinically significant inhibitors include azole antifungals (e.g., fluconazole, voriconazole), amiodarone, and sulfinpyrazone. When such combinations are necessary, dose reductions of nateglinide and more frequent blood glucose monitoring are required.[7]
• CYP2C9 Inducers: Conversely, co-administration with strong inducers of CYP2C9 can accelerate the metabolism of nateglinide, leading to lower plasma concentrations and a potential loss of glycemic control. Important inducers include rifampin, barbiturates (e.g., phenobarbital), and carbamazepine. Patients on these combinations should be monitored for reduced efficacy of nateglinide.[31]
• Dual CYP2C9/CYP3A4 Interactions: Some drugs affect both of nateglinide's metabolic pathways. For instance, efavirenz (an inhibitor) can increase nateglinide levels, while ivosidenib (an inducer) can decrease them. These are considered serious interactions, and avoidance or use of an alternative drug is recommended.[31]

Pharmacodynamic Interactions (Effect-Based)

• Drugs Increasing Hypoglycemic Risk: The glucose-lowering effect of nateglinide can be potentiated by other drugs, leading to an additive risk of hypoglycemia. This includes other antidiabetic agents (e.g., metformin, SGLT2 inhibitors, GLP-1 receptor agonists), nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, monoamine oxidase (MAO) inhibitors, and non-selective beta-adrenergic blocking agents. Careful monitoring and potential dose adjustments are necessary when these drugs are used concomitantly.[7]
• Drugs Decreasing Hypoglycemic Effect: Certain medications can antagonize the effect of nateglinide and cause hyperglycemia, potentially leading to a loss of glycemic control. These include thiazide diuretics, corticosteroids, sympathomimetic agents (e.g., pseudoephedrine), and some atypical antipsychotics.[11]
• Drugs Masking Hypoglycemia Symptoms: Non-selective beta-blockers (e.g., propranolol), clonidine, and reserpine can blunt the adrenergic warning signs and symptoms of hypoglycemia (e.g., tremor, tachycardia). This can make it difficult for patients to recognize a developing hypoglycemic episode, increasing the danger. Patients on these combinations require more vigilant blood glucose monitoring.[11]

Drug-Food/Lifestyle Interactions

• Alcohol: This represents a major and potentially dangerous interaction. Alcohol can potentiate the hypoglycemic effect of nateglinide, and excessive or acute consumption, particularly on an empty stomach, can lead to severe and prolonged hypoglycemia. Patients should be strongly advised to avoid or limit alcohol intake.[3]
• Grapefruit Juice: Consumption of grapefruit or grapefruit juice should be avoided during nateglinide treatment. Grapefruit juice is an inhibitor of CYP enzymes (primarily CYP3A4, but also noted as a CYP2C9 inhibitor in some sources) and can increase nateglinide exposure, elevating the risk of adverse effects, including hypoglycemia.[33]

Table 3: Clinically Significant Drug Interactions with Nateglinide

Interacting Drug/Class	Mechanism of Interaction	Potential Clinical Effect	Clinical Recommendation
Fluconazole, Amiodarone	Strong CYP2C9 Inhibition	Increased nateglinide levels; high risk of severe hypoglycemia	Monitor closely; consider dose reduction 7
Rifampin, Carbamazepine, Barbiturates	CYP2C9 Induction	Decreased nateglinide levels; loss of glycemic control	Monitor for efficacy; may require dose increase 31
Efavirenz, Ivosidenib	CYP2C9 Inhibition/Induction	Significant alteration of nateglinide levels	Avoid or use alternate drug 31
Other Antidiabetics (e.g., Metformin, SGLT2i)	Pharmacodynamic Synergism	Additive hypoglycemic effect	Monitor closely; may require dose reduction of one agent 31
NSAIDs, Salicylates, MAOIs	Potentiation of Hypoglycemia	Increased risk of hypoglycemia	Monitor closely 7
Thiazides, Corticosteroids	Pharmacodynamic Antagonism	Decreased hypoglycemic effect; hyperglycemia	Monitor for loss of glycemic control 11
Non-selective Beta-Blockers	Masks adrenergic symptoms of hypoglycemia	Unawareness of developing hypoglycemia	Counsel patient; increase frequency of glucose monitoring 11
Alcohol	Potentiation of Hypoglycemia	Severe, potentially prolonged hypoglycemia	Avoid or limit consumption; contraindicated with excessive use 31
Grapefruit Juice	CYP Enzyme Inhibition	Increased nateglinide levels; increased risk of adverse effects	Avoid consumption 33

Use in Special Populations and Pharmacogenomics

The use of nateglinide requires careful consideration in specific patient populations and in those with certain genetic predispositions.

Special Populations

• Geriatric Patients: No specific dose adjustment is recommended based on age alone. However, caution is advised, as elderly individuals may exhibit greater sensitivity to the glucose-lowering effects of the drug and are generally more susceptible to hypoglycemia.[6]
• Renal Impairment: No dose adjustment is required for patients with renal impairment.[6]
• Hepatic Impairment: For patients with mild hepatic impairment, no dose adjustment is necessary. In patients with moderate-to-severe hepatic impairment, nateglinide should be used with caution due to a lack of comprehensive studies and the increased theoretical risk of hypoglycemia from altered drug metabolism.[6]
• Pregnancy: Nateglinide is classified as US FDA Pregnancy Category C and Australian TGA Pregnancy Category C.[37] There are no adequate and well-controlled studies in pregnant women. While animal studies did not show teratogenicity in rats, adverse effects on embryonic development were seen in rabbits at high doses. Because poorly controlled diabetes during pregnancy poses significant risks to both mother and fetus, nateglinide should be used during pregnancy only if the potential benefit clearly justifies the potential risk to the fetus.[11]
• Lactation: Use of nateglinide during breastfeeding is not recommended. It is not known whether the drug is excreted in human milk, but it is distributed into the milk of lactating rats. Due to the potential risk of causing hypoglycemia in a nursing infant, an alternative medication is generally preferred, especially when nursing a newborn or preterm infant.[11]
• Pediatric Use: The safety and efficacy of nateglinide have not been established in patients younger than 18 years of age, and it is not approved for pediatric use.[3]

Pharmacogenomics

The metabolism of nateglinide presents a clinically significant example of a gene-drug interaction.

• CYP2C9 Poor Metabolizers: A subset of the population carries genetic variants of the CYP2C9 gene that result in reduced or absent enzyme function. These individuals are known as "poor metabolizers." Because nateglinide is predominantly (70%) cleared by this enzyme, poor metabolizers will have significantly higher systemic concentrations and prolonged exposure to the drug following a standard dose.[7]
• Clinical Implications: This impaired metabolism directly translates to a substantially increased risk of adverse reactions, most notably severe and prolonged hypoglycemia.[7]
• Regulatory Recommendations: Recognizing this risk, regulatory bodies have issued specific guidance. The U.S. FDA label recommends dosage reduction and an increased frequency of blood glucose monitoring for patients known to be CYP2C9 poor metabolizers.[7] Similarly, the former European Medicines Agency (EMA) label also advised caution in this patient subgroup.[34]

This pharmacogenomic consideration elevates the discussion of nateglinide's safety beyond general warnings. It identifies a specific, genetically defined patient subpopulation at high risk for its primary dose-limiting toxicity. This is not merely a theoretical concern but a practical clinical issue that underscores the importance of personalized medicine. The heavy reliance of nateglinide on a single, highly polymorphic enzyme for its clearance makes it a candidate for preemptive pharmacogenetic testing to enhance prescribing safety.

Regulatory Status and Commercial History

Nateglinide was developed by the Japanese company Ajinomoto and marketed globally by Novartis under various brand names, most notably Starlix.[14] Other brand names include Starsis, Trazec, and Fastic.[1]

United States (FDA)

The U.S. Food and Drug Administration (FDA) granted approval for nateglinide (Starlix) in December 2000 for the management of type 2 diabetes.[13] While the original brand name product, Starlix, has since been discontinued, generic versions of nateglinide remain available on the U.S. market.[1]

Europe (EMA)

The European Medicines Agency (EMA) granted marketing authorization for nateglinide under the brand names Starlix and Trazec on April 3, 2001.[1] The indication in Europe was specifically for combination therapy with metformin in patients inadequately controlled on metformin alone.[9] However, on April 29, 2022, the marketing authorization for Starlix was withdrawn from the European Union at the request of the manufacturer, Novartis, which cited

commercial reasons for the decision.[9] The authorization for Trazec had previously lapsed under the "sunset clause" due to it never being marketed in Europe.[41]

Australia (TGA)

While specific approval dates from Australia's Therapeutic Goods Administration (TGA) are not detailed in the available materials, the drug's approval and availability in that market are confirmed by the assignment of an AU TGA Pregnancy Category C.[37]

The commercial withdrawal of nateglinide from the competitive European market, despite its established efficacy in a specific clinical niche, is telling. This decision was likely a consequence of its clinical profile when compared to the newer classes of antidiabetic agents that have emerged since its launch. Nateglinide's demanding thrice-daily dosing regimen, which is strictly tied to meals, represents a significant burden on patient adherence. Furthermore, its primary adverse effects of hypoglycemia and weight gain are precisely the liabilities that newer drug classes—such as DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists—have sought to minimize or even reverse. Most critically, nateglinide has no proven benefit on macrovascular outcomes, whereas several newer agents have demonstrated cardiovascular risk reduction, a paramount goal in modern diabetes care.[18] In a crowded therapeutic landscape, a drug with a higher treatment burden, a less favorable side-effect profile, and no demonstrated cardiovascular benefit becomes commercially less viable, even if it remains mechanistically effective. Its clinical profile, therefore, appears to have directly influenced its market longevity.

Conclusion and Expert Clinical Perspective

Nateglinide is a pharmacologically elegant drug, representing a second generation of insulin secretagogues designed with a specific therapeutic goal: to address postprandial hyperglycemia by restoring the deficient first-phase insulin secretion characteristic of type 2 diabetes. Its unique "fast on-fast off" binding kinetics at the pancreatic KATP​ channel and its glucose-dependent action are significant refinements over older, long-acting sulfonylureas, offering a more physiological approach to mealtime glucose control with a theoretically lower risk of interprandial hypoglycemia.

However, the very properties that define its specialized role also impose its clinical limitations. The short half-life and rapid action necessitate a demanding and relatively inflexible thrice-daily, meal-dependent dosing regimen, which can be a barrier to long-term patient adherence. Despite its more refined mechanism, its use still carries an inherent and clinically significant risk of hypoglycemia, as well as a tendency for weight gain.

From a contemporary clinical perspective, while nateglinide remains an effective tool for a specific patient profile—namely, an individual on metformin with isolated postprandial hyperglycemia—its place in the broader diabetes treatment algorithm has been largely superseded. The advent of newer drug classes, including DPP-4 inhibitors, SGLT-2 inhibitors, and GLP-1 receptor agonists, has shifted the paradigm of diabetes management. These modern agents offer the convenience of once-daily or even weekly dosing, are associated with a much lower risk of hypoglycemia, have neutral or beneficial effects on body weight, and, in the case of SGLT-2 inhibitors and GLP-1 receptor agonists, have demonstrated robust cardiovascular and renal benefits.

Ultimately, the story of nateglinide serves as an important case study in drug development and the evolution of therapeutic standards. It highlights how a clinically effective medication can become less relevant as the treatment landscape evolves to prioritize not only glycemic efficacy but also patient convenience, safety from hypoglycemia, and the reduction of long-term cardiovascular complications. The most enduring clinical lesson from nateglinide may be the critical importance of understanding its CYP2C9-mediated metabolism and the associated pharmacogenomic variability, which stands as a clear and actionable principle for ensuring patient safety in an era of personalized medicine.

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