An Expert Monograph on Repaglinide (DB00912)

1.0 Executive Summary

Repaglinide is a short-acting, oral insulin secretagogue belonging to the meglitinide class of antihyperglycemic agents. It is indicated as an adjunct to diet and exercise for the management of Type 2 Diabetes Mellitus (T2DM). As the first-in-class agent designed as a "prandial glucose regulator," its primary therapeutic value lies in its ability to specifically target post-meal hyperglycemia by mimicking the physiological first-phase insulin response, a mechanism that is deficient in individuals with T2DM. Its mechanism of action involves the closure of ATP-dependent potassium (KATP​) channels on pancreatic β-cells, an action that is critically glucose-dependent. This distinguishes it from the sulfonylurea class, theoretically conferring a lower risk of inter-meal and nocturnal hypoglycemia.

The clinical efficacy of repaglinide is well-established, with numerous trials demonstrating significant reductions in glycosylated hemoglobin (HbA1c​), fasting plasma glucose (FPG), and, most notably, postprandial glucose (PPG) excursions. Its pharmacokinetic profile is characterized by rapid oral absorption, a short time to peak concentration (approximately 1 hour), a brief plasma half-life (approximately 1 hour), and extensive hepatic metabolism with primary excretion into the feces. This metabolic profile makes repaglinide a particularly valuable therapeutic option for patients with varying degrees of renal impairment, a population in which many other oral antidiabetic agents require dose adjustments or are contraindicated.

Despite these advantages, the clinical utility of repaglinide is significantly tempered by several critical factors. Its metabolism via a complex interplay of Cytochrome P450 enzymes (CYP2C8 and CYP3A4) and the hepatic uptake transporter OATP1B1 creates a high potential for clinically significant drug-drug interactions, necessitating careful review of concomitant medications. This vulnerability is highlighted by an absolute contraindication for co-administration with gemfibrozil, a potent CYP2C8 inhibitor that can increase repaglinide exposure over eight-fold. The primary adverse effects include a notable risk of hypoglycemia and a tendency for weight gain, both of which are class effects of insulin secretagogues. Furthermore, its meal-based dosing regimen ("one meal, one dose"), while offering flexibility, results in a higher pill burden that can challenge patient adherence.

Critically, the cardiovascular safety profile of repaglinide remains a subject of concern. Unlike newer classes of antidiabetic agents, it lacks data from large-scale cardiovascular outcomes trials (CVOTs) to demonstrate benefit or confirm long-term safety. Some clinical data and regulatory labeling suggest a potential for increased risk of ischemic events, placing it at a disadvantage in the current therapeutic landscape, where preventing macrovascular complications is a primary goal of diabetes management. Consequently, repaglinide is no longer considered a first- or second-line agent in most major treatment guidelines. Its role has evolved into that of a niche therapeutic for specific patient populations, such as those with severe renal disease or significant postprandial hyperglycemia who are unable to use other agents.

2.0 Introduction and Drug Classification

2.1 Historical Context and Development

Repaglinide (CAS Number: 135062-02-1) represents a significant development in the oral treatment of T2DM, marking the introduction of a new class of insulin secretagogues. The drug was invented in 1983 by scientists at Dr Karl Thomae GmbH in Germany, a company later acquired by Boehringer Ingelheim.[1] The compound was subsequently licensed to the Danish pharmaceutical company Novo Nordisk, which spearheaded its clinical development.[1] Novo Nordisk filed an Investigational New Drug (IND) application with the U.S. Food and Drug Administration (FDA) in April 1992, followed by a New Drug Application (NDA) in July 1997.[1]

Repaglinide received FDA approval in December 1997, becoming the first drug approved in the meglitinide class.[1] This approval established the therapeutic concept of prandial glucose regulation, a strategy aimed at restoring the rapid, short-lived insulin release that normally follows a meal, which is characteristically blunted in T2DM.[2] The drug was marketed globally under various brand names, most notably Prandin in the United States, NovoNorm in Europe and other regions, Gluconorm in Canada, and Surepost in Japan.[1] Following its initial approval, Novo Nordisk also secured a patent for the combination therapy of repaglinide with metformin, extending its market presence.[1]

2.2 Chemical and Therapeutic Classification

Repaglinide is classified based on its mechanism and chemical structure:

• Therapeutic Class: It is an oral antihyperglycemic agent, also referred to as an antidiabetic drug.[3] It belongs to the specific pharmacological class of meglitinides, or "glinides".[3] Due to its mechanism, it is further described as a short-acting insulin secretagogue and a potassium channel antagonist.[3]
• Chemical Class: Repaglinide is a carbamoylmethyl benzoic acid derivative.[9] A crucial aspect of its identity is that it is chemically and structurally unrelated to the sulfonylurea class of insulin secretagogues, despite a superficially similar mechanism of action.[5] This structural distinction is fundamental to its unique binding properties at the pancreatic β-cell and its distinct pharmacokinetic profile.

2.3 Position in Diabetes Management

Repaglinide is positioned as an adjunct to diet and exercise for improving glycemic control in adults with T2DM.[1] It can be employed as monotherapy for patients who cannot tolerate other agents or as part of a combination therapy regimen, most commonly with metformin and also with thiazolidinediones.[8]

Its defining feature is the meal-based dosing strategy, often summarized as "one meal, one dose".[2] This approach provides patients with flexibility, allowing them to skip doses if meals are missed, thereby reducing the risk of hypoglycemia.[3] However, this same feature contrasts sharply with the simpler once-daily or even once-weekly regimens of many modern antidiabetic agents. The resulting high pill burden and complex dosing schedule can pose a significant challenge to patient adherence. This practical disadvantage, combined with the emergence of drug classes with proven cardiovascular and renal benefits, has led to a re-evaluation of its role in therapy. Major clinical practice guidelines, such as those from the American Diabetes Association (ADA) and the American Association of Clinical Endocrinology (AACE), have consequently de-emphasized the use of meglitinides like repaglinide, reserving them for specific clinical scenarios rather than as primary treatment options.[19]

3.0 Physicochemical Properties and Formulations

3.1 Chemical Identity

The precise chemical identity of repaglinide is defined by its structure and nomenclature:

• Systematic (IUPAC) Name: (S)-2-ethoxy-4-(2-((3-methyl-1-(2-(1-piperidinyl)-phenyl)butyl)amino)-2-oxoethyl)-benzoic acid.[1] The "(S)" designation refers to the specific stereochemistry at the chiral center, which is essential for its biological activity.
• Molecular Formula: C27​H36​N2​O4​.[1]
• Molar Mass / Molecular Weight: The calculated molar mass is 452.595 g·mol⁻¹, commonly rounded to 452.6 g/mol in pharmaceutical literature.[1]

3.2 Physical Characteristics

Repaglinide exhibits the following physical properties:

• Appearance: It is a white to off-white crystalline powder.[5]
• Melting Point: The melting point range is reported as 126 to 128 °C (259 to 262 °F).[1]
• Solubility: It demonstrates solubility in organic solvents such as dimethylformamide (DMF) at 30 mg/ml, dimethyl sulfoxide (DMSO) at 30 mg/ml, and ethanol at 25 mg/ml. Its solubility is poor in aqueous buffer systems, such as a 1:4 mixture of DMSO:PBS (pH 7.2), where it is soluble only up to 0.2 mg/ml.[12]

3.3 Formulations and Excipients

Repaglinide is marketed for oral administration in several tablet strengths to allow for flexible dose titration.

• Dosage Forms: It is available as immediate-release oral tablets in strengths of 0.5 mg, 1 mg, and 2 mg.[4]
• Inactive Ingredients (Excipients): The tablet formulation contains a number of excipients necessary for its manufacturing and performance. These include fillers and binders like calcium hydrogen phosphate (anhydrous), microcrystalline cellulose, and maize starch; a disintegrant (polacrilin potassium); a binder (povidone); a plasticizer (glycerol 85%); a lubricant (magnesium stearate); and solubilizers/stabilizers (meglumine and poloxamer).[9]
• Differentiation: To aid in identification and prevent medication errors, the 1 mg and 2 mg tablets are colored using iron oxides (yellow for 1 mg tablets and red for 2 mg tablets).[5]

Table 1: Key Drug and Chemical Identifiers for Repaglinide

To facilitate accurate identification and cross-referencing across diverse scientific and regulatory databases, the following table consolidates the key identifiers for repaglinide.

Identifier Type	Identifier Code	Source(s)
DrugBank ID	DB00912	1
CAS Number	135062-02-1	1
UNII (FDA)	668Z8C33LU	1
European Community (EC) Number	629-921-1	3
PubChem CID	65981	1
ChEMBL ID	CHEMBL1272	1
ChEBI ID	CHEBI:8805	3
KEGG ID	D00594, C07670	1
ATC Code (WHO)	A10BX02	1
RxCUI (RxNorm)	73044	3
HMDB ID	HMDB0015048	3
PharmGKB ID	PA451234	3

This comprehensive list of identifiers is essential for researchers, clinicians, and regulators, ensuring unambiguous communication and data retrieval regarding this specific small molecule drug.

4.0 Clinical Pharmacology

The clinical effects of repaglinide are a direct result of its distinct pharmacodynamic and pharmacokinetic properties. Its rapid, short-acting nature defines its therapeutic role and differentiates it from other oral antihyperglycemic agents.

4.1 Pharmacodynamics (Mechanism of Action)

The primary pharmacodynamic effect of repaglinide is the lowering of blood glucose concentrations through the stimulation of insulin secretion from the pancreas.[3] This process is contingent upon the presence of functional pancreatic β-cells.[9]

• Molecular Target and Binding: Repaglinide exerts its effect by binding to and blocking the ATP-dependent potassium (KATP​) channels located on the plasma membrane of pancreatic β-cells.[1] The KATP​ channel is a complex composed of an inwardly rectifying potassium channel pore (Kir6.2) and a regulatory subunit, the sulfonylurea receptor 1 (SUR1).[11] Repaglinide binds with high affinity to a unique site on the SUR1 subunit, a site that is structurally and functionally distinct from the binding site of sulfonylurea drugs.[8] This distinction underlies some of the differences in their clinical profiles.
• Cellular Cascade of Insulin Release: The binding of repaglinide to SUR1 closes the KATP​ channel. This action inhibits the outward flow of potassium ions (K+), which is the primary driver of the cell's negative resting membrane potential. The resulting accumulation of positive charge inside the cell leads to membrane depolarization.[1] This change in membrane voltage triggers the opening of voltage-dependent calcium channels. The subsequent influx of extracellular calcium ions ( Ca2+) into the β-cell raises intracellular calcium concentrations, which serves as the critical signal for the fusion of insulin-containing secretory granules with the cell membrane and the subsequent exocytosis (release) of insulin into the bloodstream.[1]
• Glucose-Dependency: A cornerstone of repaglinide's mechanism is its glucose-dependency. The insulin-releasing action of repaglinide is potent at intermediate glucose concentrations but diminishes significantly at low glucose levels.[9] It effectively potentiates the insulinotropic effect of glucose rather than causing insulin release in the absence of a glucose stimulus.[24] This is a key differentiator from sulfonylureas, which can stimulate insulin release irrespective of the ambient glucose concentration. This property is believed to contribute to a lower risk of severe or prolonged hypoglycemia with repaglinide, particularly during fasting periods between meals.[2]
• Tissue Selectivity: The ion channel mechanism is highly selective for the pancreatic β-cell. Repaglinide demonstrates low affinity for KATP​ channels found in other tissues, such as cardiac and skeletal muscle, contributing to a targeted pharmacological effect with fewer off-target actions.[9]

4.2 Pharmacokinetics (Absorption, Distribution, Metabolism, and Excretion)

The pharmacokinetic profile of repaglinide is defined by rapid absorption, a short duration of action, and extensive hepatic clearance, which collectively shape its clinical use.

• Absorption: Following oral administration, repaglinide is absorbed rapidly and completely from the gastrointestinal tract.[9] Peak plasma concentrations ( Cmax​) are typically achieved within 1 hour (Tmax​), facilitating a rapid onset of action that aligns with meal ingestion.[9] The mean absolute bioavailability is approximately 56%, indicating significant first-pass metabolism.[1] The presence of food does not delay the time to peak concentration but reduces the extent of absorption, with mean Cmax​ decreasing by 20% and the area under the curve (AUC) decreasing by approximately 12-15%.[1] This necessitates dosing immediately before a meal to ensure maximal effect on postprandial glucose.
• Distribution: Repaglinide has a relatively small volume of distribution at steady state (Vss​) of 31 L, suggesting its distribution is largely limited to the plasma and extracellular fluid compartments.[9] It is extensively bound to plasma proteins, with binding to human serum albumin exceeding 98%.[1] This high degree of protein binding creates a theoretical potential for displacement interactions with other highly protein-bound drugs.
• Metabolism: Repaglinide undergoes complete and extensive metabolism, primarily in the liver, with virtually no unchanged drug excreted renally.[3]
• Metabolic Pathways and Enzymes: Metabolism proceeds via two main pathways: oxidative biotransformation and direct conjugation with glucuronic acid.[9] The oxidative pathways are mediated by the cytochrome P450 (CYP) enzyme system. Specifically, CYP2C8 and CYP3A4 are the principal enzymes involved.[1] CYP2C8 is considered the most important enzyme for its clearance [16], while CYP3A4 also plays a significant role.
• Hepatic Transporters: The hepatic uptake of repaglinide from the blood into hepatocytes is an active process facilitated by the organic anion-transporting polypeptide OATP1B1 (encoded by the SLCO1B1 gene).[9] Inhibition of this transporter can significantly impair repaglinide clearance and increase plasma concentrations.
• Metabolites: The major identified metabolites are an oxidized dicarboxylic acid (M2), an aromatic amine (M1, formed via N-dealkylation), and an acyl glucuronide (M7).[9] Critically, these metabolites are pharmacologically inactive and do not contribute to the glucose-lowering effect of the drug.[3]
• Excretion: Elimination of repaglinide from the body is rapid, consistent with its short plasma half-life of approximately 1 hour.[1] Excretion occurs predominantly via the biliary route into the feces. Following an oral dose, approximately 90% is recovered in the feces, while only about 8% is recovered in the urine.[1] Unchanged parent drug accounts for less than 2% of the dose in feces and only 0.1% in urine, underscoring the completeness of its hepatic metabolism.[9] The major metabolite, M2, accounts for 60% of the administered dose found in the feces.[15]

The drug's defining pharmacokinetic characteristics—rapid absorption and a very short half-life—are the direct drivers of its pharmacodynamic role as a "prandial glucose regulator".[2] This profile is intentionally designed to mimic the body's natural first-phase insulin release, which is a rapid and transient surge in insulin following a meal.[2] This allows for targeted control of postprandial glucose excursions, a key challenge in T2DM management.[3] This pharmacokinetic profile also confers the clinical advantage of dosing flexibility; because the drug is cleared quickly, a dose can be skipped if a meal is missed, substantially reducing the risk of hypoglycemia that would occur with a longer-acting agent.[3]

However, this creates a clinical paradox. The very properties that provide physiological benefit also mandate a demanding, high-frequency dosing schedule of two to four times daily with meals.[29] This high pill burden can be a major impediment to patient adherence, particularly in an era where convenient once-daily oral agents and once-weekly injectables are available. The challenge of maintaining adherence to such a regimen is a significant practical limitation and is a contributing factor to why major clinical guidelines have largely moved away from recommending meglitinides as preferred agents, despite their unique and physiologically-mimetic mechanism.[19]

The reliance of repaglinide on a "trifecta" of clearance pathways—CYP2C8, CYP3A4, and the OATP1B1 transporter—represents its greatest clinical liability.[9] This multi-pathway dependence makes it highly susceptible to a wide range of drug-drug interactions. The clinical data supporting this vulnerability are not merely theoretical but demonstrate profound quantitative effects. For instance, co-administration with gemfibrozil, a potent CYP2C8 inhibitor, results in a staggering 8.1-fold increase in the repaglinide AUC, creating a severe and unacceptable risk of hypoglycemia that warrants an absolute contraindication.[9] Similarly, the OATP1B1 inhibitor cyclosporine can increase the AUC by 2.5-fold, another interaction of major clinical significance.[9] Conversely, potent enzyme inducers like rifampin can reduce the AUC by up to 80%, effectively negating the drug's therapeutic effect and risking severe hyperglycemia.[9] This complex vulnerability requires clinicians to be vigilant not just for inhibitors of a single CYP enzyme, but for modulators of multiple, distinct pathways. This metabolic complexity makes repaglinide a high-risk medication for patients on polypharmacy, a common scenario in the elderly and those with multiple comorbidities, and is a primary factor limiting its widespread application in modern diabetes care.

Table 2: Summary of Key Pharmacokinetic Parameters of Repaglinide

Pharmacokinetic Parameter	Value	Source(s)
Absolute Bioavailability	~56%	1
Time to Peak Plasma Concentration (Tmax​)	~1 hour	9
Plasma Half-life (t1/2​)	~1 hour	1
Volume of Distribution (Vss​)	31 L	9
Total Body Clearance (CL)	38 L/h	9
Plasma Protein Binding	>98%	1
Primary Route of Excretion	Fecal (~90%)	1
Renal Excretion	~8% (0.1% as parent drug)	3

5.0 Clinical Efficacy and Therapeutic Applications

5.1 Approved Indications and Usage

Repaglinide is officially indicated as an adjunct to diet and exercise to improve glycemic control in adult patients with type 2 diabetes mellitus.[3] Its use is flexible, allowing for:

• Monotherapy: For patients in whom diet and exercise alone are insufficient, or for those who cannot tolerate or have contraindications to other first-line agents like metformin.[8]
• Combination Therapy: Repaglinide is approved for use in combination with metformin or with thiazolidinediones (e.g., rosiglitazone, pioglitazone) in patients who are not adequately controlled on monotherapy with either agent.[9] Completed Phase 3 trials have also investigated its use with NPH insulin.[18]

Limitation of Use: Repaglinide is not indicated for the treatment of type 1 diabetes mellitus or for the management of diabetic ketoacidosis (DKA), as both conditions require insulin therapy.[1] Furthermore, due to their overlapping mechanisms of action, the concurrent use of repaglinide with sulfonylureas is considered duplicative and is contraindicated.[8]

5.2 Summary of Key Clinical Trials

The efficacy and safety of repaglinide have been established through a series of clinical trials comparing it to placebo, other oral agents, and in combination regimens.

• Efficacy versus Placebo: Placebo-controlled trials have robustly demonstrated the glucose-lowering efficacy of repaglinide. In a 24-week, multicenter, fixed-dose trial, patients receiving repaglinide at 1 mg or 4 mg doses experienced a mean decrease in FPG of approximately 47-49 mg/dL. In contrast, the placebo group saw an increase in FPG of 19 mg/dL. The resulting change in HbA1c​ was 1.8 to 1.9 percentage points lower in the repaglinide groups compared to placebo.[32] Another randomized trial confirmed these findings, showing that repaglinide treatment lowered mean HbA1c​ from a baseline of 8.5% to 7.8%, while the placebo group's HbA1c​ increased from 8.1% to 9.3%. This resulted in a statistically significant between-group difference of -1.7% in favor of repaglinide.[33]
• Efficacy versus Sulfonylureas (Glibenclamide/Glyburide): Comparative trials have generally shown that repaglinide provides glycemic control that is equivalent or non-inferior to that of second-generation sulfonylureas like glyburide.[19] However, these studies reveal nuances in their effects. Repaglinide tends to be more effective at reducing postprandial glucose peaks, consistent with its prandial regulator mechanism, whereas glyburide may exert a stronger effect on fasting glucose levels.[35] In elderly patients (≥65 years), a population particularly vulnerable to hypoglycemia, repaglinide demonstrated similar HbA1c​ reduction to glibenclamide but was associated with a significantly lower frequency of hypoglycemic episodes, with a reported 51% risk reduction.[37] Another study in elderly patients switching from a sulfonylurea to repaglinide found that while overall HbA1c​ changes were similar, repaglinide led to greater improvements in glycated albumin (GA) and the GA-to-HbA1c​ ratio, markers that are more sensitive to short-term glucose fluctuations. This suggests repaglinide provides better control over glycemic variability.[38]
• Efficacy in Combination Therapy:
• With Metformin: The combination of repaglinide and metformin is a cornerstone of its indicated use.[16] In patients inadequately controlled with metformin monotherapy, the addition of repaglinide resulted in a mean HbA1c​ reduction of 1.41%, compared to only a 0.33% reduction in those continuing metformin alone.[19] A fixed-dose combination (FDC) tablet of repaglinide and metformin has been developed and shown to be effective, with potential benefits for patient adherence and lipid profiles.[27]
• With Thiazolidinediones (TZDs): For patients with inadequate glycemic control on TZD monotherapy, adding repaglinide has been shown to be effective. One trial involving combination with rosiglitazone demonstrated an additional mean HbA1c​ reduction of 1.43%.[19]
• With Insulin: The role of repaglinide in combination with insulin is less well-defined. A comparative trial found that a regimen of metformin plus bedtime NPH insulin provided superior glycemic control and less weight gain than a regimen of repaglinide plus bedtime NPH insulin.[40] This suggests that for combination with basal insulin, metformin may be a more advantageous oral agent than repaglinide.

5.3 Use in Special Populations

Repaglinide's pharmacokinetic profile makes it suitable for certain patient populations where other agents may be problematic.

• Geriatric Population (≥65 years): Clinical studies support the use of repaglinide in the elderly, showing good efficacy and, importantly, a more favorable safety profile compared to longer-acting sulfonylureas due to a reduced risk of hypoglycemia.[8] While no dose adjustment is mandated based on age alone, a conservative approach with careful titration is recommended, particularly in frail or malnourished individuals.[9]
• Renal Impairment: The convergence of several key data points establishes a specific and important clinical niche for repaglinide. Its pharmacokinetic profile, dominated by hepatic metabolism and near-total fecal excretion, is the primary reason for its utility in patients with chronic kidney disease (CKD).[3] Clinical pharmacokinetic studies have confirmed that the AUC and Cmax​ of repaglinide are not significantly altered even in patients with severe renal impairment (creatinine clearance as low as 20–40 mL/min).[15] This makes it a favorable treatment choice in this population, where many other oral agents are limited by renal clearance.[16] However, it is important to note that insulin sensitivity can be increased in patients with renal failure, so cautious initiation and dose titration are still advised.[16]
• Hepatic Impairment: As repaglinide is extensively metabolized by the liver, its use in patients with hepatic impairment requires caution.[17] Impaired liver function can lead to higher plasma concentrations and diminished gluconeogenic capacity, both of which substantially increase the risk of severe hypoglycemia.[17] Consequently, repaglinide is contraindicated in patients with severe hepatic impairment.[16]
• Pregnancy and Lactation: Repaglinide is classified as FDA Pregnancy Category C. Its safety in pregnant women has not been established, and its use requires careful consideration of potential risks versus benefits.[8] It is generally recommended to be avoided during pregnancy and breastfeeding.[8]
• Pediatric Population: The safety and efficacy of repaglinide have not been established in children and adolescents under the age of 18, and its use is not recommended in this population.[8]

6.0 Safety and Tolerability Profile

The safety profile of repaglinide is well-characterized, with hypoglycemia being the most prominent risk. Its cardiovascular safety remains a key area of discussion.

6.1 Adverse Drug Reactions (ADRs)

• Hypoglycemia: As an insulin secretagogue, the most common and clinically significant adverse reaction associated with repaglinide is hypoglycemia.[1] In placebo-controlled clinical trials, mild or moderate hypoglycemia was reported in 31% of patients treated with repaglinide, compared to 7% in the placebo group.[9] In trials comparing it to sulfonylureas, the incidence of hypoglycemia with repaglinide was 16%.[9] While symptomatic episodes are relatively common, severe events that require third-party assistance or lead to hospitalization are rare.[9] The glucose-dependent nature of its action may contribute to this more favorable profile regarding severe hypoglycemia compared to sulfonylureas.
• Common ADRs (Incidence ≥2%): Data from pooled, placebo-controlled trials show a range of common adverse events.[1]
• Respiratory: Upper respiratory tract infection (16%), sinusitis (6%), rhinitis (3%), and bronchitis (2%).
• Neurological: Headache (11%) and paresthesia (3%).
• Gastrointestinal: Nausea (5%), diarrhea (5%), constipation (3%), and vomiting (3%).
• Musculoskeletal: Arthralgia (6%) and back pain (5%).
• Weight Gain: Consistent with its mechanism of stimulating insulin release, repaglinide therapy is associated with weight gain.[3] A clinical trial of repaglinide added to metformin showed a mean weight gain of 2.4 kg over 4 to 5 months, which was statistically significant compared to metformin monotherapy.[44]
• Cardiovascular Events: The cardiovascular safety of repaglinide is a critical consideration. The primary goal of modern diabetes management extends beyond glucose control to the prevention of long-term cardiovascular complications. While repaglinide effectively lowers glucose, its direct impact on cardiovascular outcomes is uncertain and potentially concerning. Data from 1-year comparator trials against sulfonylureas indicated a numerically higher incidence of total serious cardiovascular events for repaglinide (4% of 1228 patients) compared to sulfonylureas (3% of 498 patients).[5] The incidence of cardiac ischemic events was comparable at 2% for both groups.[5] However, in trials combining repaglinide with NPH-insulin, there was a signal of increased myocardial ischemia.[9] Further raising concern, the European product label includes a specific warning that the use of repaglinide might be associated with an increased incidence of acute coronary syndrome, such as myocardial infarction.[16]

Crucially, repaglinide predates the era of mandatory, large-scale cardiovascular outcomes trials (CVOTs) for new diabetes drugs. Therefore, unlike modern agents in the SGLT2 inhibitor and GLP-1 receptor agonist classes, there is no robust, long-term trial data establishing its cardiovascular benefit or confirming non-inferiority. This lack of proven cardiovascular benefit, coupled with a potential (though not definitively proven) signal for ischemic risk, places repaglinide at a significant disadvantage in the modern therapeutic landscape and is a key reason for its relegation from first- or second-line therapy in most major clinical guidelines.[19]

6.2 Contraindications, Warnings, and Precautions

Contraindications: Repaglinide is strictly contraindicated in patients with [1]:

• Known hypersensitivity to repaglinide or any of its inactive ingredients.
• Type 1 diabetes mellitus or diabetic ketoacidosis.
• Severe hepatic impairment.
• Concomitant use of gemfibrozil.
• Some regulatory bodies also list concomitant use of clopidogrel as a contraindication due to a significant interaction.[17]

Warnings and Precautions:

• Hypoglycemia: This is the primary warning. All patients and their families should be educated on the signs and symptoms of hypoglycemia (e.g., shakiness, dizziness, sweating, confusion), its treatment (e.g., oral carbohydrates), and conditions that predispose to it, such as deficient caloric intake, strenuous exercise, alcohol consumption, or the use of multiple glucose-lowering drugs.[9]
• Loss of Glycemic Control: During periods of physiological stress such as fever, trauma, infection, or surgery, patients stabilized on repaglinide may experience a loss of glycemic control. It may be necessary to temporarily discontinue the drug and administer insulin.[9] This also encompasses the phenomenon of "secondary failure," where the drug's effectiveness diminishes over time due to the progression of diabetes.[16]
• Macrovascular Outcomes: As previously noted, there are no clinical studies that have established conclusive evidence of a reduction in macrovascular risk with repaglinide therapy.[9]

6.3 Management of Overdose

An overdose of repaglinide can precipitate an exaggerated glucose-lowering effect, leading to hypoglycemia.[16]

• Mild Hypoglycemia: Symptoms such as dizziness, sweating, and tremor can be managed with the oral administration of carbohydrates (e.g., glucose tablets, fruit juice).
• Severe Hypoglycemia: An overdose leading to seizure, loss of consciousness, or coma constitutes a medical emergency. Treatment requires prompt administration of intravenous glucose. Glucagon injection (subcutaneous or intramuscular) may also be used.[43]
• Monitoring: Due to the potential for prolonged hypoglycemic effects even with a short-acting drug, patients should be closely monitored with repeated blood glucose measurements for at least 24 hours following a significant overdose.[43]

Table 3: Incidence of Adverse Reactions from Placebo-Controlled Trials*

Adverse Reaction	Repaglinide (N=352)	Placebo (N=108)
Hypoglycemia	31%	7%
Upper Respiratory Infection	16%	8%
Headache	11%	10%
Sinusitis	6%	2%
Arthralgia	6%	3%
Nausea	5%	5%
Diarrhea	5%	2%
Back Pain	5%	4%
Paresthesia	3%	3%
Constipation	3%	2%
Vomiting	3%	3%
Chest pain	3%	1%

*Data compiled from pooled 12- to 24-week placebo-controlled trials. Includes reactions occurring in ≥2% of repaglinide-treated patients. [5]

7.0 Drug-Drug Interactions

Repaglinide is highly susceptible to clinically significant drug-drug interactions (DDIs) due to its complex metabolic profile. These interactions can dramatically alter its plasma concentration, leading to either dangerous hypoglycemia or loss of therapeutic efficacy.

7.1 Pharmacokinetic Interactions (Metabolism- and Transporter-Mediated)

Repaglinide's clearance is a multi-step process involving hepatic uptake by the OATP1B1 transporter, followed by metabolism primarily via CYP2C8 and CYP3A4.[9] Inhibition or induction of any of these pathways can have profound clinical consequences.

• CYP2C8 Inhibitors:
• Gemfibrozil: Co-administration is CONTRAINDICATED. Gemfibrozil is a potent inhibitor of CYP2C8 and also appears to inhibit OATP1B1. This dual inhibition leads to a massive 8.1-fold increase in the repaglinide AUC and prolongs its half-life from 1.3 to 3.7 hours, creating an extreme risk of severe and prolonged hypoglycemia.[1]
• Clopidogrel: As a significant inhibitor of CYP2C8, clopidogrel can substantially increase repaglinide levels, leading to a risk of significant hypoglycemia. Concomitant use is considered contraindicated by some authorities and should be avoided.[1]
• Trimethoprim: This moderate CYP2C8 inhibitor increases repaglinide AUC by 61%. While not contraindicated, this is a clinically relevant interaction that requires caution, potential dose reduction of repaglinide, and enhanced glucose monitoring.[9]
• CYP3A4 Inhibitors:
• Strong inhibitors of CYP3A4 can increase repaglinide concentrations and the risk of hypoglycemia. This class includes azole antifungals (e.g., ketoconazole, itraconazole) and macrolide antibiotics (e.g., clarithromycin, erythromycin).[1] Clinical studies show that itraconazole increases repaglinide AUC by 1.4-fold, and clarithromycin increases it by 40%.[9]
• OATP1B1 Inhibitors:
• Cyclosporine: By inhibiting the OATP1B1 hepatic uptake transporter, cyclosporine blocks repaglinide from reaching its metabolizing enzymes in the liver. This results in a 2.5-fold increase in repaglinide AUC.[9] Concomitant use should be avoided if possible; if necessary, it requires extreme caution and significant dose reduction of repaglinide.[16]
• Dual CYP2C8 and CYP3A4 Inhibitors:
• The concurrent use of inhibitors of both major metabolic pathways is particularly hazardous. A study combining gemfibrozil (a CYP2C8 inhibitor) with itraconazole (a CYP3A4 inhibitor) resulted in a 19-fold increase in repaglinide AUC and a 70-fold increase in its plasma concentration at 7 hours.[9] This demonstrates the synergistic effect of blocking multiple clearance routes and underscores the critical need for vigilance.
• CYP Inducers:
• Rifampin: As a potent inducer of both CYP2C8 and CYP3A4, rifampin can dramatically accelerate the metabolism of repaglinide. Co-administration has been shown to decrease repaglinide AUC by as much as 80%, which can lead to a complete loss of glycemic control and treatment failure.[9] Other potent inducers, such as barbiturates and carbamazepine, are expected to have a similar effect and should be used with caution, likely requiring upward dose adjustments of repaglinide.[9]

7.2 Pharmacodynamic Interactions

• Increased Hypoglycemia Risk: The glucose-lowering effect of repaglinide can be potentiated by other drugs, increasing the risk of hypoglycemia. These include other antidiabetic agents, nonsteroidal anti-inflammatory drugs (NSAIDs), salicylates, sulfonamides, monoamine oxidase inhibitors (MAOIs), and non-selective beta-adrenergic blocking agents (which can also mask the adrenergic warning signs of hypoglycemia).[9] Alcohol consumption also increases this risk.[16]
• Decreased Efficacy (Hyperglycemia Risk): Certain drugs tend to produce hyperglycemia and may antagonize the effect of repaglinide, leading to a loss of glycemic control. These include thiazide and other diuretics, corticosteroids, phenothiazines, thyroid products, sympathomimetics, estrogens (including oral contraceptives), and isoniazid.[9]

Table 4: Clinically Significant Drug-Drug Interactions with Repaglinide

Interacting Drug/Class	Mechanism of Interaction	Clinical Consequence	Management Recommendation	Source(s)
Gemfibrozil	Potent CYP2C8 inhibitor	8.1-fold increase in repaglinide AUC; severe risk of prolonged hypoglycemia.	CONTRAINDICATED	1
Clopidogrel	Potent CYP2C8 inhibitor	Significant increase in repaglinide exposure and risk of hypoglycemia.	CONTRAINDICATED / AVOID	1
Cyclosporine	OATP1B1 transporter inhibitor	2.5-fold increase in repaglinide AUC; increased risk of hypoglycemia.	Avoid concomitant use. If necessary, use with extreme caution and dose reduction.	9
Rifampin	Potent inducer of CYP2C8 and CYP3A4	Up to 80% decrease in repaglinide AUC; risk of therapeutic failure and hyperglycemia.	Avoid concomitant use. If necessary, monitor glucose closely and significantly increase repaglinide dose.	9
Azole Antifungals (e.g., Ketoconazole, Itraconazole)	Strong CYP3A4 inhibitors	Moderate increase in repaglinide AUC (e.g., 1.4-fold with itraconazole); increased risk of hypoglycemia.	Use with caution. Monitor glucose closely and consider repaglinide dose reduction.	1
Macrolide Antibiotics (e.g., Clarithromycin)	Strong CYP3A4 inhibitors	Moderate increase in repaglinide AUC (40% with clarithromycin); increased risk of hypoglycemia.	Use with caution. Monitor glucose closely and consider repaglinide dose reduction.	1
Trimethoprim	Moderate CYP2C8 inhibitor	61% increase in repaglinide AUC; increased risk of hypoglycemia.	Use with caution. Monitor glucose closely and consider repaglinide dose reduction.	9
Beta-Blockers	Pharmacodynamic interaction	Increased risk of hypoglycemia; may mask adrenergic warning symptoms (tremor, tachycardia).	Use with caution. Counsel patient on alternative hypoglycemia symptoms (sweating, hunger, confusion).	9
Alcohol	Pharmacodynamic interaction	Increased risk of hypoglycemia.	Counsel patient to limit or avoid alcohol consumption.	16

8.0 Dosage, Administration, and Clinical Monitoring

The effective and safe use of repaglinide hinges on proper dosage, adherence to its unique meal-based administration schedule, and diligent clinical monitoring.

8.1 Dosing Regimen

• Administration: Repaglinide tablets are administered orally and must be taken preprandially (before meals). The dose is typically taken within 15 minutes of the start of a meal but can be taken up to 30 minutes before.[16] This timing is critical to align the drug's peak insulin-stimulating effect with the post-meal rise in blood glucose.
• The "One Meal, One Dose" Principle: This is the central concept of repaglinide therapy. The dosing is tied to the patient's meal pattern. If a patient skips a meal, the corresponding dose of repaglinide must also be skipped to prevent hypoglycemia. Conversely, if a patient adds an extra meal, an extra dose should be taken to cover the meal's glucose load.[3] This allows for greater lifestyle flexibility compared to fixed-dose, long-acting secretagogues.
• Starting Dose: The initial dose is determined by the patient's prior treatment history and baseline glycemic control:
• For patients who are treatment-naïve or whose baseline HbA1c​ is less than 8%, the recommended starting dose is 0.5 mg with each main meal.[29]
• For patients who have been previously treated with other oral hypoglycemic agents or whose baseline HbA1c​ is 8% or higher, the recommended initial dose is 1 mg or 2 mg with each main meal.[29]
• Dose Titration: Dosage adjustments should be based on the patient's glycemic response, which is typically assessed using self-monitored fasting blood glucose values.[16] To achieve the desired glucose target, the preprandial dose can be doubled. A minimum of one week should elapse between dose adjustments to allow for a full assessment of the response to the new dose.[16]
• Maintenance and Maximum Dose: The recommended maintenance dose range is 0.5 mg to 4 mg taken with each meal. The maximum recommended single dose is 4 mg, and the total maximum recommended daily dose is 16 mg.[16]

8.2 Combination Therapy Dosing

• When repaglinide is added to an existing regimen of metformin or a thiazolidinedione, the starting dose and titration schedule for repaglinide remain the same as for monotherapy.[31]
• If hypoglycemia occurs during combination therapy, it is the dose of repaglinide that should be reduced, as it is the agent directly stimulating insulin secretion.[29]

8.3 Clinical Monitoring

Continuous and comprehensive monitoring is essential for safe and effective repaglinide therapy.

• Patient Education: The cornerstone of monitoring is thorough patient education. Patients must understand the importance of adherence to their prescribed diet and exercise plan. They need to be proficient in the "one meal, one dose" rule and be able to recognize and manage the signs and symptoms of both hypoglycemia and hyperglycemia.[20]
• Blood Glucose Monitoring:
• Self-Monitoring of Blood Glucose (SMBG): Regular SMBG is critical. Fasting plasma glucose levels are the primary metric used to guide dose titration.[28]
• Postprandial Glucose (PPG) Monitoring: In patients whose fasting glucose levels are at target but whose overall glycemic control remains suboptimal (i.e., elevated HbA1c​), monitoring postprandial glucose levels can be clinically useful to assess the adequacy of the mealtime repaglinide dose.[19]
• Laboratory Tests:
• Glycosylated Hemoglobin (HbA1c​): This test provides an integrated measure of glycemic control over the preceding 2-3 months. It should be measured periodically (e.g., every 3 months) to assess the long-term efficacy of the therapeutic regimen and ensure the patient is meeting their glycemic goals.[19]

9.0 Comprehensive Analysis and Concluding Remarks

Repaglinide occupies a unique and evolving position in the therapeutic armamentarium for Type 2 Diabetes Mellitus. Its identity as a rapid-acting prandial glucose regulator, the first of its kind, represents its core conceptual strength. By more closely mimicking the physiological first-phase insulin response to a meal, it offers a targeted approach to controlling postprandial hyperglycemia, a key contributor to the overall glycemic burden in T2DM. This mechanism, combined with its favorable pharmacokinetic profile in the setting of renal impairment—a result of its extensive hepatic metabolism and predominantly fecal excretion—solidifies its value in a specific and often difficult-to-treat patient population.

However, a comprehensive analysis requires a critical balancing of these benefits against the drug's significant risks and limitations. The most formidable of these is its profound susceptibility to drug-drug interactions. Its reliance on a complex network of clearance pathways (CYP2C8, CYP3A4, and OATP1B1) makes it a metabolic "Achilles' heel," vulnerable to a wide array of commonly prescribed medications. The contraindication with gemfibrozil and the major interactions with drugs like clopidogrel, cyclosporine, and rifampin demand a high level of clinical vigilance and make it a challenging agent to use safely in patients on polypharmacy. Furthermore, the inherent risks of hypoglycemia and weight gain, while characteristic of all insulin secretagogues, remain important clinical considerations that can impact patient safety and quality of life. The practical challenge of a high pill burden associated with its meal-based dosing schedule can compromise patient adherence, potentially undermining its therapeutic efficacy.

Perhaps the most critical factor defining its modern role is the unresolved question of its long-term cardiovascular safety. In an era where the standard of care is shifting towards agents with proven cardiovascular and renal benefits, the absence of a dedicated cardiovascular outcomes trial for repaglinide is a glaring omission. The available data are neutral at best and include signals that raise concern about potential ischemic risk. This uncertainty places repaglinide at a distinct disadvantage compared to SGLT2 inhibitors and GLP-1 receptor agonists.

In conclusion, repaglinide is no longer a first- or second-line agent for the general T2DM population, a status reflected in the evolution of major international treatment guidelines. Its therapeutic role has transitioned from that of a mainstream option to a niche specialist drug. It remains a valuable, and at times essential, tool for carefully selected patient profiles. These include: (1) patients with severe postprandial hyperglycemia who are intolerant of, or have contraindications to, other oral agents; (2) patients with advanced chronic kidney disease, where its non-renal clearance provides a significant safety advantage; and (3) certain elderly patients in whom the short duration of action is desirable to minimize the risk of prolonged and severe hypoglycemia. For these specific individuals, when prescribed with a thorough understanding of its unique pharmacology and a meticulous approach to managing its drug interaction potential, repaglinide continues to be an important therapeutic option in the personalized management of Type 2 Diabetes Mellitus.

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