Nateglinide

Nateglinide is an Anti-diabetic Agent belonging to the pharmacological class of Meglitinides Derivatives.

Nateglinide is approved for treating type 2 diabetes mellitus, particularly for individuals who experience post-meal elevations in blood glucose levels. It helps reduce blood sugar levels by increasing insulin release from the pancreas in response to meals.

After oral administration, Nateglinide is quickly absorbed, and peak blood concentrations occur within an hour. The drug is predominantly eliminated in the urine after being metabolized by the liver.

Nateglinide's most common side effects include upper respiratory tract infection, joint pain, back discomfort, diarrhoea, flu-like symptoms, and disorientation.

Nateglinide is available in the form of oral tablets.

The molecule is available in the United States, Canada, the United Kingdom, Australia, Germany, India and Japan.

Nateglinide is an Anti-diabetic Agent belonging to the pharmacological class of Meglitinides Derivatives.

Glucose and functional cells are necessary for nateglinide to exert its effects. Unlike sulfonylurea insulin secretagogues, nateglide does not impact insulin release without glucose. Instead, it enhances extracellular glucose's effects on ATP-sensitive potassium channels without affecting insulin levels during the day and nighttime. As a result, Nateglinide is more successful in lowering postprandial blood glucose levels than fasting blood glucose levels and needs to be taken for a more extended period (about one month) before fasting blood glucose levels are reduced. Nateglinide has the most potent insulinotropic effects at intermediate glucose concentrations (3 to 10 mmol/L). Still, it has no further impact on insulin release that has already been stimulated by high glucose concentrations (more than 15 mmol/L). Nateglinide does not affect thyroid tissue, skeletal or cardiac muscle, or other body tissues. Instead, it appears to be selective for pancreatic cells.

Data duration of Nateglinide action lasting about 4 hr after each dose.

The onset of Nateglinide action is shown at the Initial effect of 15 min and max effect lasting 1-2 hr

The Data of Tmax of Nateglinide is typically within 1-2 hours after oral administration.

The Data of Cmax of Nateglinide typically achieved within 1- 2 hours after oral administration

Nateglinide is available in the form of oral tablets.

Tablets: To be swallowed whole with water/liquid. Do not chew, crush or break it.

As the physician recommends, take the medication orally once daily; it is best taken before meals.

Treatment of Type 2 diabetes mellitus

With a healthy diet and exercise routine, nateglinide treats high blood sugar, particularly in people with type 2 diabetes use it.

Maintaining blood sugar levels under control helps avoid kidney disease, blindness, nerve damage, limb loss, and issues with sexual function. The risk of having a heart attack or stroke may be lowered if the diabetes is well-managed. It functions by encouraging the body to create more insulin. The body uses insulin, a naturally occurring molecule, to use the sugar in the food.

In Treatment of Type 2 diabetes mellitus

Nateglinide increases the amount of insulin your body produces (in the pancreas). Insulin lowers blood glucose levels and prevents them from rising after meals.

To effectively manage diabetes, the blood glucose levels must be reduced. Controlling blood sugar levels will lower the likelihood of any of the severe complications of diabetes, including kidney damage, eye damage, nerve problems, and amputation of limbs. The risk of cardiac disease and stroke can be reduced with proper diabetes management. Individuals can live longer if they take this medication consistently and follow a healthy diet and exercise routine.

It is indicated as an adjunct to exercise and diet to help individuals with type 2 diabetes mellitus (T2DM) in adults improve their glycemic control.

Orally: Nateglinide is available as a tablet that can be taken orally. Nateglinide should be taken on an empty stomach or with food, usually 15 to 30 minutes before eating. It is best to take it regularly at a fixed time each day following the physician's prescribed schedule for regular and evenly spaced intervals because the dose and duration of therapy are individualized per specific conditions to achieve the most effective and successful treatment outcome. If a meal is skipped, the corresponding amount of Nateglinide should also be skipped to avoid the risk of hypoglycemia (low blood sugar).

The dosage and duration of treatment should be as per the treating physician's clinical judgment.

Tablets: 60mg or 120mg

Nateglinide is available in the form of oral tablets.

Dose Adjustment in Adult Patients:

Monotherapy for type 2 diabetes, or metformin 120 mg PO every 8 hours

60 mg PO every 8hr if patient near goal HbA1C

Take a dose 1 to 30 minutes before a meal.

Nateglinide should be used in treating Type 2 Diabetes Mellitus, along with appropriate nutritional limits.

While taking Nateglinide, maintain regular meal schedules with balanced macronutrient content to help stabilize blood sugar levels.

Taking Nateglinide just before or up to 30 minutes before a meal is advised. Skipping meals or delaying meals while on this medication can lead to low blood sugar (hypoglycemia).

Reduce the intake of high-sugar foods and beverages, as high-carb meals can lead to higher post-meal blood sugar levels.

Avoid excessive consumption of grapefruit or its juice, as it may interact with Nateglinide.

Limit or avoid the intake of alcohol, as it can interfere with blood sugar regulation.

Staying hydrated and maintaining a rich, balanced diet with appropriate fibre-rich foods like fruits, vegetables, whole grains, and lean proteins are advised to help manage your overall health and blood sugar levels effectively.

The dietary restriction should be individualized as per patient requirements.

Nateglinide may be contraindicated in the following conditions:-

• Hypersensitivity reaction to Nateglinide or any inactive ingredients
• Diabetic ketoacidosis
• Type I diabetes mellitus

• Hypoglycemia: Nateglinide is one of the glinides that can result in hypoglycemia. Seizures, a threat to one's life, or even death can be caused by severe hypoglycemia. When these skills are crucial (such as when driving or operating other machinery), hypoglycemia can decrease focus and response time, putting the person and others in danger.

Hypoglycemia can occur abruptly, and the signs for every individual will be different and vary over time. Patients with long-term diabetes, those with diabetic neuropathy (nerve disease), those taking drugs that block the sympathetic nervous system, such as beta-blockers, patients with recurrent hypoglycemia, or patients with long-term diabetes may have less pronounced symptomatic awareness of hypoglycemia. Changes in physical activity level, changes to coadministered medications, changes in meal pattern (e.g., macronutrient composition), and concurrent usage with other antidiabetic medicines are all factors that may raise the risk of hypoglycemia. Patients who have liver or renal disease may be more susceptible to hypoglycemia.

• Patients should take Nateglinide before meals and only take Nateglinide if a meal is included. The ability to identify and treat hypoglycemia must be taught to patients and carers. Self-blood-glucose monitoring is crucial for both preventing and treating hypoglycemia. An increased frequency of blood glucose monitoring is advised in individuals more likely to have hypoglycemia and those with less symptomatic awareness of the condition.
• An insulin secretagogue, such as glyburide, should not be taken with this medication. Not to be taken as a substitute for metformin monotherapy but as an adjunctive. Clinical research has not provided conclusive evidence that treatment can lower the risk of macrovascular disease.

It is unsafe to consume Nateglinide with alcohol.

Not recommended for use during breastfeeding.

Safe to use during pregnancy only if the possible benefit outweighs the potential risk to the foetus.

Limit alcohol or grapefruit consumption and reduce intake of high-carb foods and beverages.

The adverse reactions related to Nateglinide can be categorized as

• Common Adverse Effects: Hypoglycemia (low blood sugar), upper respiratory tract infection, headache, and back pain.
• Less Common Adverse Effects: Gastrointestinal issues like diarrhoea and abdominal pain.
• Rare Adverse Effects: Allergic reactions, elevated liver enzymes, and severe hypoglycemia

Reports on Postmarketing

Rash, itching, and urticaria are signs of hypersensitivity reactions.

Jaundice, cholestatic hepatitis, and elevated liver enzyme levels are hepatobiliary disorders.

The clinically relevant drug interactions of Nateglinide are briefly summarized here.

• Beta-Blockers: Concurrent use with beta-blockers like propranolol can mask the symptoms of hypoglycemia, making it challenging for patients to recognize and treat low blood sugar levels.
• Gemfibrozil: Co-administration with gemfibrozil can substantially increase Nateglinide levels in the blood, increasing the risk of hypoglycemia. This combination is generally not recommended.
• Other Anti-diabetic Agents: Using Nateglinide with other antidiabetic medications, like sulfonylureas or insulin, may increase the risk of hypoglycemia. Dose adjustments and close monitoring are essential.
• CYP2C9 Inhibitors: Drugs that inhibit the enzyme CYP2C9 (e.g., fluconazole) may affect Nateglinide metabolism, potentially leading to altered blood glucose levels.

The most common side effects of Nateglinide include:

• An upper respiratory infection
• Back pain
• Diarrhoea
• Flu-like symptoms
• Dizziness
• Pain in the joints

• Pregnancy

Pregnancy Category C; Use with caution if the benefits outweigh the risks.

For Nateglinide in pregnant women, there is no sufficient and well-monitored research. Nateglinide may damage a developing foetus if given to a pregnant woman. However, this is not known. If only the possible benefit outweighs the potential risk to the foetus, Nateglinide should only be administered during pregnancy.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

Pregnant women with poorly managed diabetes have an increased risk of developing diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm birth, stillbirth, and delivery complications. Significant birth abnormalities, stillbirths, and macrosomia-related morbidity are more likely in foetuses with poorly managed diabetes.

Animal Data

In animal reproduction studies, oral Nateglinide at doses of around 27 and 8 times the maximum recommended human dosage (MRHD), based on body surface area (BSA), respectively, did not cause teratogenicity in rats or rabbits during organogenesis.

• Nursing Mothers

There is no information on Nateglinide's presence in human milk, its effects on nursing infants, or its impact on milk production.

The medication is found in animal milk, and it is likely it will also be found in human milk if found in animal milk.

Informing mothers that using the medication while nursing is not advised due to the possibility of hypoglycemia in breastfed infants

Data

Nateglinide and its metabolite are excreted in milk after oral administration (300 mg/kg) in rat reproductive tests. Based on AUC0-48 results, the total radioactivity's milk: plasma (M/P) concentration ratio was about 1.4. Unchanged Nateglinide had an M/P ratio of about 2.2.

• Pediatric Use

As per the FDA, safety and effectiveness in the pediatric population have not been established.

• Geriatric Use

In clinical investigations, Nateglinide was administered to 80 individuals 75 or older and 436 people 65 or older. Between individuals 65 and older and those under 65, there were no variations in Nateglinide's safety or effectiveness. Nevertheless, certain elderly people may be more sensitive to nateglinide treatment.

Dose Adjustment in Kidney Impairment Patients:

No dosage adjustment is recommended in patients with mild to severe renal impairment

Dose adjustment in Hepatic Impairment Patients:

Patients with moderate hepatic impairment are advised not to change their dosage. Due to the lack of research, Nateglinide should be taken cautiously in individuals with moderate to severe hepatic impairment.

Signs and Symptoms

The physician should be vigilant about the knowledge pertaining to the identification and treatment of overdosage of Nateglinide.

Overconsumption of Nateglinide may include hypoglycemia (low blood sugar), gastrointestinal symptoms (nausea, vomiting, diarrhoea), headache, fatigue, irritability and, in severe cases, unconsciousness or seizures.

Management

There is no specific antidote or treatment for excessive intake of Nateglinide. However, immediate medical attention is essential. Nateglinide should be terminated immediately when an overdose is suspected or if any unusual symptoms occur after intake. In severe cases, when the patient is unconscious or experiencing seizures, intravenous glucagon may be considered to raise blood sugar rapidly.

Management typically involves administering oral glucose or intravenous dextrose to increase blood sugar levels. Continuous blood glucose and vital signs should be monitored until the patient stabilizes.

Maintain a healthy lifestyle through proper nutritional diet, regular physical activity, and stress management. These factors can help improve blood sugar control and reduce the risk of hypoglycemia.

Pharmacodynamics:

Cellular membrane potential influences the release of insulin by pancreatic cells. Membrane potential is controlled by an inverse connection between extracellular glucose concentrations and the activity of ATP-sensitive potassium channels (ABCC8) in cell membranes. Through GLUT2

(SLC2A2) transporters, extracellular glucose enters the cell. Once within the cell, glucose is metabolized to create ATP. High ATP concentrations block ATP-sensitive potassium channels, which depolarize the membrane. ATP-sensitive potassium channels activate and cause membrane repolarization when extracellular glucose contents are low. High glucose levels induce ATP-sensitive potassium channels to shut, depolarizing the membrane and opening L-type calcium channels. The increase in calcium ions increases the calcium-dependent exocytosis of insulin granules. Nateglinide enhances insulin release by blocking. ATP-sensitive potassium channels in a glucose-dependent manner.

Pharmacokinetics:

Absorption

Absolute bioavailability is estimated to be around 73% after an oral dose before a meal, and it is quickly absorbed. Within an hour of oral treatment, peak plasma concentrations often happen. The action begins at twenty minutes in and lasts for approximately four hours.

Peak Plasma Time: < 1hr

Bioavailability: 72-75%

Distribution

Nateglinide's steady-state volume of distribution is thought to be around 10 L in healthy persons after intravenous (IV) treatment. Most of the serum proteins, mainly albumin and the 1 acid glycoprotein, are highly (98%) bound to Nateglinide. Over the test range of 0.1 to 10 mcg/mL, serum protein binding intensity is unrelated to drug concentration.

Vd: 10 L

Protein Bound: 97-99%

Metabolism

Hepatic, via the cytochrome P450 isoenzymes CYP2C9 (70%) and CYP3A4 (30%). The first step in metabolism is hydroxylation; next follows glucuronidation. The isoprene minor metabolite has a comparable antidiabetic effect to Nateglinide, but the larger metabolites have less antidiabetic action than Nateglinide.

Metabolism: by hepatic cytochrome P450 CYP2C9 (70%) & CYP3A4 (30%)

Metabolites: major metabolite M1 (20% potency of parent drug), & many other metabolites

Elimination

Following oral administration, Nateglinide and its metabolites are entirely and quickly excreted from the body. 83% of the 14C-nateglinide was excreted in the urine, and 10% was removed in the faeces. In urine, almost 16% of the parent molecule 14C-nateglinide was eliminated.

Urine:83%

Feces: 10%

• Tentolouris, Nicholas et al. "A review of nateglinide in the management of patients with type 2 diabetes." Vascular health and risk management vol. 3,6 (2007): 797-807.
• NAVIGATOR Study Group et al. "Effect of the nateglinideon the incidence of diabetes and cardiovascular events." The New England journal of Medicine vol. 362,16 (2010): 1463-76. doi:10.1056/NEJMoa1001122
• Mita, Tomoya et al. "Nateglinide reduces the carotid intima-media thickening in type 2 diabetic patients under good glycemiccontrol." Arteriosclerosis, thrombosis, and vascular biology vol. 27,11 (2007): 2456-62. doi:10.1161/ATVBAHA.107.152835
• Tostes, G.C.U., et al. Effects of Nateglinide and rosiglitazone on the pancreatic alpha- and beta-cells, GLP-1 secretion and inflammatory markers in the patients with type 2 diabetes: The randomized crossover clinical study. Diabetol Metab Syndr 8, 1 (2016). https://doi.org/10.1186/s13098-015-0120-6
• Tentolouris, Nicholas & Voulgari, Christina & Katsilambros, Nicholas. (2007). A review of Nateglinide in the management of patients with type 2 diabetes. Vascular health and risk management. 3. 797-807.
• Carola Saloranta, Kenneth Hershon, Michele Ball, Sheila Dickinson, David Holmes, Efficacy and Safety of Nateglinide in Type 2 Diabetic Patients with the Modest Fasting Hyperglycemia, The Journal of Clinical Endocrinology & Metabolism, Volume 87, Issue 9, 1 September 2002, Pages 4171–4176

• Patients should be advised to take Nateglinide up to 30 minutes before meals. Inform patients to forgo their nateglinide dosage if they skip meals.
• Inform patients and their caregivers about self-management techniques, such as glucose monitoring and managing hypoglycemia, let them know that Nateglinide can induce hypoglycemia. Let patients know that hypoglycemia may make it difficult to focus and react. It is advised to monitor blood sugar levels more often in individuals at higher risk for hypoglycemia and those whose symptoms make hypoglycemia less apparent.
• Inform patients that taking Nateglinide while breastfeeding is not advised.

• https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm
• https://www.ema.europa.eu/en/documents/scientific-discussion/starlix-epar-scientific-discussion_en.pdf
• https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/077467s000lbl.pdf
• https://pubmed.ncbi.nlm.nih.gov/11449877/
• https://www.ncbi.nlm.nih.gov/books/NBK548227/