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Repaglinide side effects: Side Effects of Prandin (Repaglinide), Warnings, Uses


Repaglinide (Oral Route) Side Effects

Side Effects

Drug information provided by: IBM Micromedex

Along with its needed effects, a medicine may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur:

More common

  1. Anxiety

  2. blurred vision

  3. chills

  4. cold sweats

  5. coma

  6. confusion

  7. cool, pale skin

  8. depression

  9. dizziness

  10. fast heartbeat

  11. headache

  12. increased hunger

  13. nausea

  14. nightmares

  15. seizures

  16. shakiness

  17. slurred speech

  18. unusual tiredness or weakness
Less common

  1. Bladder pain

  2. bloody or cloudy urine

  3. difficult, burning, or painful urination

  4. frequent urge to urinate

  5. lower back or side pain
Incidence not known

  1. Back, leg, or stomach pains

  2. bleeding gums

  3. blistering, peeling, or loosening of the skin

  4. bloating

  5. clay-colored stools

  6. constipation

  7. cough

  8. darkened urine

  9. diarrhea

  10. difficulty with breathing

  11. fever

  12. general body swelling

  13. general tiredness and weakness

  14. indigestion

  15. itching or rash

  16. joint or muscle pain

  17. light-colored stools

  18. loss of appetite

  19. nosebleeds

  20. pains in the side, or abdomen, possibly radiating to the back

  21. pale skin

  22. red skin lesions, often with a purple center

  23. red, irritated eyes

  24. sore throat

  25. sores, ulcers, or white spots in the mouth or on the lips

  26. unpleasant breath odor

  27. upper right abdominal or stomach pain

  28. vomiting

  29. vomiting of blood

  30. yellow eyes or skin

Some side effects may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

More common

  1. Body aches or pain

  2. difficulty with moving

  3. ear congestion

  4. loss of voice

  5. muscle stiffness

  6. pain in the joints

  7. pain or tenderness around the eyes and cheekbones

  8. sneezing

  9. sore throat

  10. stuffy or runny nose

  11. tightness of the chest
Less common

  1. Acid or sour stomach

  2. belching

  3. burning, crawling, itching, numbness, prickling, “pins and needles”, or tingling feelings

  4. cough producing mucus

  5. heartburn

  6. indigestion

  7. weight gain
Incidence not known

  1. Hair loss or thinning of the hair

Other side effects not listed may also occur in some patients. If you notice any other effects, check with your healthcare professional.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Portions of this document last updated: March 01, 2021

Copyright © 2021 IBM Watson Health. All rights reserved. Information is for End User’s use only and may not be sold, redistributed or otherwise used for commercial purposes.


Repaglinide for diabetes – Enyglid, Prandin. Side effects; dosage

About repaglinide

Type of medicine An antidiabetic medicine
Used for Type 2 diabetes mellitus
Also called Enyglid®; Prandin®
Available as Tablets

Insulin is a hormone which is made naturally in your body, in the pancreas. It helps to control the levels of sugar (glucose) in your blood. If your body does not make enough insulin, or if it does not use the insulin it makes effectively, this results in the condition called diabetes (diabetes mellitus).

People with diabetes need treatment to control the amount of sugar in their blood. This is because good control of blood sugar levels reduces the risk of complications later on. Some people can control the sugar in their blood by making changes to the food they eat but, for other people, medicines like repaglinide are given alongside the changes in diet.

Repaglinide lowers blood glucose by encouraging your pancreas to produce more insulin. It starts to work quickly so it is particularly helpful in controlling blood sugar levels straight after a meal.

Before taking repaglinide

Some medicines are not suitable for people with certain conditions, and sometimes a medicine may only be used if extra care is taken. For these reasons, before you start taking repaglinide it is important that your doctor knows:

  • If you are under 18 or over 75 years of age.
  • If you are pregnant, trying for a baby or breastfeeding.
  • If you have any problems with the way your liver works, or with the way your kidneys work.
  • If you have a severe illness or infection.
  • If you have ever had an allergic reaction to a medicine.
  • If you are taking any other medicines. This includes any medicines you are taking which are available to buy without a prescription, as well as herbal and complementary medicines. 

How to take repaglinide

  • Before you start the treatment, read the manufacturer’s printed information leaflet from inside the pack. It will give you more information about repaglinide tablets and will provide you with a full list of the side-effects which you may experience from taking them.
  • Take repaglinide exactly as your doctor tells you to. Take a dose before each of your main meals (usually breakfast, lunch and dinner). The best time to take repaglinide is 15 minutes before your meal, but you can take it at any time within the 30-minute period before your meal. If you miss a meal, do not take a tablet.
  • There are three strengths of tablet – 500 micrograms, 1 mg, and 2 mg. It is likely you will be prescribed the lower-strength tablet to begin with. If it becomes necessary, your doctor may later increase the strength of the tablet you are prescribed.
  • Take the tablets with a drink of water to help you swallow.
  • If you forget to take a dose, do not worry, just take your next dose at the next mealtime as normal. Do not take two doses together to make up for a forgotten dose, and do not take the tablets between meals. 

Getting the most from your treatment

  • It is important that you keep your regular doctor’s and clinic appointments. This is so that your progress can be monitored. You will need regular check-ups with an eye clinic and a foot clinic as well as with your doctor and diabetes clinic.
  • Your doctor may recommend that you test for sugar (glucose) in your blood or urine regularly to check that your diabetes is being controlled. Your doctor or diabetes nurse will show you how to do this.
  • If you have been given advice by your doctor about changes to your diet, stopping smoking or taking regular exercise, it is important for you to follow the advice you have been given.
  • Repaglinide can cause low blood sugar. Make sure you know what it feels like if your blood sugar is too low. This is known as hypoglycaemia, or a ‘hypo’. The first signs of hypoglycaemia are feeling shaky or anxious, sweating, looking pale, feeling hungry, having a feeling that your heart is pounding (palpitations), and feeling dizzy. If this happens, eat something containing sugar, such as dextrose tablets, jelly babies or a sugary drink (non-diet), and then follow this up with a snack such as a sandwich or a banana.
  • If you are a driver you should take special care, as your ability to concentrate may be affected if your diabetes is not well controlled. You may be advised to check your blood sugar levels before you travel and to have a snack with you on long journeys.
  • Do not drink alcohol, as it can affect the control of your blood sugar. Ask your doctor if you need further advice about this.
  • If you get unusually thirsty, pass urine more frequently than normal, or feel very tired, you should let your doctor know. These are signs that there is too much sugar in your blood and your treatment may need adjusting.
  • Check with your doctor before taking up any new physical exercise, as this will have an effect on your blood sugar levels and you may need to check your blood or urine levels more regularly.
  • If you are due to have an operation or dental treatment, you should tell the person carrying out the treatment that you have diabetes and give them a list of the medicines you are taking. This is because if you are not able to eat for a time, you will be advised to skip your doses of repaglinide until you are eating normally again.
  • If you buy any medicines, always check with a pharmacist that they are suitable for you to take.
  • Treatment for diabetes is usually lifelong. Continue to take the tablets unless you are advised otherwise by your doctor.

Can repaglinide cause problems?

Along with their useful effects, most medicines can cause unwanted side-effects although not everyone experiences them. The table below contains some of the most common ones associated with repaglinide. You will find a full list in the manufacturer’s information leaflet supplied with your medicine. The unwanted effects often improve as your body adjusts to the new medicine, but speak with your doctor or pharmacist if any of the following continue or become troublesome.

Common repaglinide side-effects (these affect fewer than 1 in 10 people)
What can I do if I experience this?
Diarrhoea, stomach pain Drink plenty of water to replace any lost fluids
Low blood sugar (hypoglycaemia): symptoms include feeling shaky or anxious, sweating, looking pale, feeling hungry, feeling that your heart is pounding (palpitations), feeling dizzy Eat something containing sugar, such as dextrose tablets, jelly babies or a sugary drink (non-diet), then follow this up with a snack such as a sandwich or a banana. Tell your doctor if you notice these symptoms

If you experience any other symptoms which you think may be due to the tablets, speak with your doctor or pharmacist for further advice.

How to store repaglinide

  • Keep all medicines out of the reach and sight of children.
  • Store in a cool, dry place, away from direct heat and light.

Important information about all medicines

Never take more than the prescribed dose. If you suspect that you or someone else might have taken an overdose of this medicine, go to the accident and emergency department of your local hospital. Take the container with you, even if it is empty.

This medicine is for you. Never give it to other people even if their condition appears to be the same as yours.

Do not keep out-of-date or unwanted medicines. Take them to your local pharmacy which will dispose of them for you.

If you have any questions about this medicine ask your pharmacist.

Repaglinide Uses, Side Effects & Warnings

Generic Name: repaglinide (oral) (re PAG li nide)
Brand Name: Prandin
Dosage Forms: oral tablet (0.5 mg; 1 mg; 2 mg)

Medically reviewed by Drugs.com on May 21, 2020. Written by Cerner Multum.

What is repaglinide?

Repaglinide is used together with diet and exercise to improve blood sugar control in adults with type 2 diabetes mellitus. repaglinide is not for treating type 1 diabetes.

Repaglinide may also be used for purposes not listed in this medication guide.


You should not use repaglinide if you have type 1 diabetes, severe liver disease, or diabetic ketoacidosis.

You should not use repaglinide together with gemfibrozil or NPH insulin (such as isophane insulin).

Before taking this medicine

You should not use repaglinide if you are allergic to it, or if you have:

Many drugs can interact with repaglinide and some drugs should not be used at the same time. Your doctor may change your treatment plan if you also use:

Tell your doctor if you have ever had:

Follow your doctor’s instructions about using repaglinide if you are pregnant or you become pregnant. Controlling diabetes is very important during pregnancy, and having high blood sugar may cause complications in both the mother and the baby.

You should not breastfeed while using repaglinide.

Repaglinide is not approved for use by anyone younger than 18 years old.

How should I take repaglinide?

Follow all directions on your prescription label and read all medication guides or instruction sheets. Your doctor may occasionally change your dose. Use the medicine exactly as directed.

Repaglinide is usually taken 2 to 4 times daily, within 30 minutes before eating a meal. Follow your doctor’s instructions. If you skip a meal, do not take your dose of repaglinide. Wait until your next meal.

Your blood sugar will need to be checked often, and you may need other blood tests at your doctor’s office.

You may have low blood sugar (hypoglycemia) and feel very hungry, dizzy, irritable, confused, anxious, or shaky. To quickly treat hypoglycemia, eat or drink a fast-acting source of sugar (fruit juice, hard candy, crackers, raisins, or non-diet soda).

Your doctor may prescribe a glucagon injection kit in case you have severe hypoglycemia. Be sure your family or close friends know how to give you this injection in an emergency.

Also watch for signs of high blood sugar (hyperglycemia) such as increased thirst or urination.

Blood sugar levels can be affected by stress, illness, surgery, exercise, alcohol use, or skipping meals. Ask your doctor before changing your dose or medication schedule.

Repaglinide is only part of a treatment program that may also include diet, exercise, weight control, blood sugar testing, and special medical care. Follow your doctor’s instructions very closely.

Store repaglinide at room temperature away from moisture and heat.

What happens if I miss a dose?

Take your dose as soon as you can, but only if you are getting ready to eat a meal. If you skip a meal, skip the missed dose and wait until your next meal.

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222. A repaglinide overdose can cause life-threatening hypoglycemia.

Symptoms of severe hypoglycemia include extreme weakness, blurred vision, sweating, trouble speaking, tremors, stomach pain, confusion, and seizure (convulsions).

What should I avoid while taking repaglinide?

Avoid drinking alcohol. It lowers blood sugar and may interfere with your diabetes treatment.

Repaglinide side effects

Get emergency medical help if you have signs of an allergic reaction (hives, difficult breathing, swelling in your face or throat) or a severe skin reaction (fever, sore throat, burning eyes, skin pain, red or purple skin rash with blistering and peeling).

Call your doctor at once if you have:

  • pale or yellowed skin, dark colored urine, fever, confusion or weakness; or

  • pancreatitis–severe pain in your upper stomach spreading to your back, nausea and vomiting.

Common side effects may include:

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Repaglinide dosing information

Usual Adult Dose for Diabetes Type 2:

Individualize therapy:
Dose preprandially 2, 3, or 4 times a day
-For patients not previously treated with antidiabetic agents or whose glycosylated hemoglobin (HbA1c) is less than 8%:
Initial dose: 0.5 mg orally with each meal
-For patients previously treated with antidiabetic agents or whose HbA1c is 8% or higher:
Initial dose: 1 or 2 mg orally with each meal

Dose Adjustments: Based upon blood glucose response, double the preprandial dose up to a maximum meal time dose of 4 mg until satisfactory glycemic response is achieved; allow at least 1 week to assess response after each dose adjustment.
Recommended Dose Range: 0.5 to 4 mg orally with each meal
Maximum Daily Dose: 16 mg per day

-Fasting blood glucose concentrations are generally used to adjust doses, however, postprandial glucose levels may be used in patients whose pre-meal blood glucose levels are satisfactory but whose overall glycemic control (HbA1c) is inadequate.
-When hypoglycemia occurs in patients taking this drug in combination with a thiazolidinedione or metformin, the dose of this drug should be reduced.

Use: As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

What other drugs will affect repaglinide?

Many other medicines that can increase or decrease the effects of repaglinide on lowering your blood sugar. Some drugs can also cause you to have fewer symptoms of hypoglycemia, making it harder to tell when your blood sugar is low. This includes prescription and over-the-counter medicines, vitamins, and herbal products. Tell each of your health care providers about all medicines you use now and any medicine you start or stop using.

More about repaglinide

Consumer resources

Other brands

Professional resources

Related treatment guides

Further information

Remember, keep this and all other medicines out of the reach of children, never share your medicines with others, and use this medication only for the indication prescribed.

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

Copyright 1996-2021 Cerner Multum, Inc. Version: 9.02.

Memorial Sloan Kettering Cancer Center

This information from Lexicomp® explains what you need to know about this medication, including what it’s used for, how to take it, its side effects, and when to call your healthcare provider.

Brand Names: US

Prandin [DSC]

Brand Names: Canada

ACT Repaglinide; APO-Repaglinide; Auro-Repaglinide; GlucoNorm; JAMP Repaglinide; SANDOZ Repaglinide

What is this drug used for?

  • It is used to lower blood sugar in patients with high blood sugar (diabetes).

What do I need to tell my doctor BEFORE I take this drug?

  • If you have an allergy to repaglinide or any other part of this drug.
  • If you are allergic to this drug; any part of this drug; or any other drugs, foods, or substances. Tell your doctor about the allergy and what signs you had.
  • If you have any of these health problems: Acidic blood problem or type 1 diabetes.
  • If you are taking any of these drugs: Clopidogrel, gemfibrozil, or insulin NPH.
  • If you are breast-feeding. Do not breast-feed while you take this drug.

This is not a list of all drugs or health problems that interact with this drug.

Tell your doctor and pharmacist about all of your drugs (prescription or OTC, natural products, vitamins) and health problems. You must check to make sure that it is safe for you to take this drug with all of your drugs and health problems. Do not start, stop, or change the dose of any drug without checking with your doctor.

What are some things I need to know or do while I take this drug?

  • Tell all of your health care providers that you take this drug. This includes your doctors, nurses, pharmacists, and dentists.
  • Do not drive if your blood sugar has been low. There is a greater chance of you having a crash.
  • Check your blood sugar as you have been told by your doctor.
  • Have blood work checked as you have been told by the doctor. Talk with the doctor.
  • Talk with your doctor before you drink alcohol.
  • Follow the diet and workout plan that your doctor told you about.
  • It may be harder to control blood sugar during times of stress such as fever, infection, injury, or surgery. A change in physical activity, exercise, or diet may also affect blood sugar.
  • Low blood sugar may happen with this drug. Very low blood sugar can lead to seizures, passing out, long lasting brain damage, and sometimes death. Talk with the doctor.
  • If you are 65 or older, use this drug with care. You could have more side effects.
  • Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this drug while you are pregnant.

What are some side effects that I need to call my doctor about right away?

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

  • Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.
  • Low blood sugar can happen. The chance may be raised when this drug is used with other drugs for diabetes. Signs may be dizziness, headache, feeling sleepy or weak, shaking, fast heartbeat, confusion, hunger, or sweating. Call your doctor right away if you have any of these signs. Follow what you have been told to do for low blood sugar. This may include taking glucose tablets, liquid glucose, or some fruit juices.

What are some other side effects of this drug?

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

  • Headache.
  • Signs of a common cold.
  • Diarrhea.
  • Joint pain.
  • Back pain.

These are not all of the side effects that may occur. If you have questions about side effects, call your doctor. Call your doctor for medical advice about side effects.

You may report side effects to your national health agency.

You may report side effects to the FDA at 1-800-332-1088. You may also report side effects at https://www.fda.gov/medwatch.

How is this drug best taken?

Use this drug as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take within 30 minutes before meals.
  • If a meal is skipped, skip the dose. If a meal is added, add a dose for that meal.

What do I do if I miss a dose?

  • Take a missed dose as soon as you think about it, with a meal.
  • If it is close to the time for your next dose, skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

How do I store and/or throw out this drug?

  • Store at room temperature.
  • Store in a dry place. Do not store in a bathroom.
  • Keep lid tightly closed.
  • Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
  • Throw away unused or expired drugs. Do not flush down a toilet or pour down a drain unless you are told to do so. Check with your pharmacist if you have questions about the best way to throw out drugs. There may be drug take-back programs in your area.

General drug facts

  • If your symptoms or health problems do not get better or if they become worse, call your doctor.
  • Do not share your drugs with others and do not take anyone else’s drugs.
  • Some drugs may have another patient information leaflet. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about this drug, please talk with your doctor, nurse, pharmacist, or other health care provider.
  • If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

Consumer Information Use and Disclaimer

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.

Last Reviewed Date



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ACT Repaglinide – Uses, Side Effects, Interactions

How does this medication work? What will it do for me?

Repaglinide belongs to the class of medications called antidiabetes agents. It is an oral hypoglycemic (lowering of blood sugar) medication used by people with type 2 diabetes, along with proper diet and exercise, for the control of blood sugar. It is used when diet, exercise, and weight reduction alone have not been found to control blood sugar well enough.

Repaglinide may also be used in combination with metformin or rosiglitazone, two other medications that lower blood sugar, when medication (in addition to diet, exercise, and weight reduction) does not control blood sugar well enough on its own. Repaglinide helps to control blood sugar by increasing the amount of insulin released by the pancreas.

This medication may be available under multiple brand names and/or in several different forms. Any specific brand name of this medication may not be available in all of the forms or approved for all of the conditions discussed here. As well, some forms of this medication may not be used for all of the conditions discussed here.

Your doctor may have suggested this medication for conditions other than those listed in these drug information articles. If you have not discussed this with your doctor or are not sure why you are taking this medication, speak to your doctor. Do not stop taking this medication without consulting your doctor.

Do not give this medication to anyone else, even if they have the same symptoms as you do. It can be harmful for people to take this medication if their doctor has not prescribed it.

What form(s) does this medication come in?

0.5 mg
Each white-to-off-white, round biconvex tablet with “RA05” on one side and a symbol on the other, contains repaglinide 0.5 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, croscarmellose sodium, glycerol, iron oxide yellow, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, poloxamer, and povidone.

1 mg
Each yellow, round, biconvex tablet with “RA1” on one side and a symbol on the other, contains repaglinide 1 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, croscarmellose sodium, glycerol, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, poloxamer, and povidone.

2 mg
Each pink, round, biconvex tablet with “RA2” on one side and a symbol on the other, contains repaglinide 2 mg. Nonmedicinal ingredients: calcium hydrogen phosphate, croscarmellose sodium, glycerol, iron oxide red, magnesium stearate, maize starch, meglumine, microcrystalline cellulose, poloxamer, and povidone.

How should I use this medication?

The usual dose of repaglinide is based on response to the medication, but is usually started at 0.5 mg. It can be taken either immediately before a meal or up to 30 minutes before a meal. The dose is increased by your doctor based on your response to the medication. The maximum daily dose is 16 mg. Repaglinide may be used along with other medications that reduce blood sugar if one medication is not enough to reduce blood sugar levels to the desired range.

Many things can affect the dose of medication that a person needs, such as body weight, other medical conditions, and other medications. If your doctor has recommended a dose different from the ones given here, do not change the way that you are taking the medication without consulting your doctor.

It is important to take this medication exactly as prescribed by your doctor. If you miss a dose of this medication, skip the missed dose and continue with your regular schedule. Do not take a double dose to make up for a missed one. If you are not sure what to do after missing a dose, contact your doctor or pharmacist for advice.

Store this medication at room temperature, protect it from light and moisture, and keep it out of the reach of children.

Do not dispose of medications in wastewater (e.g. down the sink or in the toilet) or in household garbage. Ask your pharmacist how to dispose of medications that are no longer needed or have expired.

Who should NOT take this medication?

Do not take this medication if you:

  • are allergic to repaglinide or any ingredients of this medication
  • are taking the medication gemfibrozil
  • are taking the medication clopidogrel
  • have diabetic ketoacidosis with or without coma (this condition should be treated with insulin)
  • have severe liver disease
  • have type 1 diabetes

What side effects are possible with this medication?

Many medications can cause side effects. A side effect is an unwanted response to a medication when it is taken in normal doses. Side effects can be mild or severe, temporary or permanent.

The side effects listed below are not experienced by everyone who takes this medication. If you are concerned about side effects, discuss the risks and benefits of this medication with your doctor.

The following side effects have been reported by at least 1% of people taking this medication. Many of these side effects can be managed, and some may go away on their own over time.

Contact your doctor if you experience these side effects and they are severe or bothersome. Your pharmacist may be able to advise you on managing side effects.

  • abdominal pain
  • back pain
  • constipation
  • diarrhea
  • dizziness
  • fatigue
  • headache
  • joint pain
  • nausea
  • vomiting

Although most of the side effects listed below don’t happen very often, they could lead to serious problems if you do not seek medical attention.

Check with your doctor as soon as possible if any of the following side effects occur:

  • bloody or cloudy urine
  • burning, painful, or difficult urination
  • chills
  • cough
  • fever
  • low blood sugar, including:
    • anxious feeling
    • behavioural change similar to being drunk
    • blurred vision
    • cold sweats
    • confusion
    • cool pale skin
    • difficulty thinking
    • drowsiness
    • excessive hunger
    • fast heartbeat
    • headache
    • nausea
    • nervousness
    • nightmares
    • restless sleep
    • shakiness
    • slurred speech
    • unusual tiredness or weakness
  • runny or stuffy nose
  • shortness of breath
  • signs of liver damage:
    • abdominal pain
    • dark urine
    • fatigue
    • fever
    • loss of appetite
    • yellow skin or eyes
  • sinus congestion with pain
  • sneezing
  • sore throat
  • vision changes
  • wheezing

Stop taking the medication and seek immediate medical attention if any of the following occur:

  • chest pain
  • convulsions (seizures)
  • fast or irregular heartbeat
  • signs of an allergic reaction, e.g.:
    • difficulty breathing
    • hives
    • swelling of the face or throat
  • signs of bleeding, e.g.:
    • bleeding gums
    • blood in the urine
    • dark tarry stools
    • easy bruising
    • nosebleeds
    • vomiting blood
  • unconsciousness

Some people may experience side effects other than those listed. Check with your doctor if you notice any symptom that worries you while you are taking this medication.

Are there any other precautions or warnings for this medication?

Before you begin using a medication, be sure to inform your doctor of any medical conditions or allergies you may have, any medications you are taking, whether you are pregnant or breast-feeding, and any other significant facts about your health. These factors may affect how you should use this medication.


July 31, 2015

Health Canada has issued new restrictions concerning the use of gluconorm (repaglinide). To read the full Health Canada Advisory, visit Health Canada’s web site at www.hc-sc.gc.ca.

Blood sugar control: If you are exposed to extra stress such as fever, trauma, infection, or surgery, your blood sugar control may vary. Monitor your blood sugar carefully and call the doctor if any important changes occur in your control.

Hypoglycemia (low blood sugar): Hypoglycemia (low blood sugar) can occur when taking repaglinide. If you experience low blood sugar (e.g., headache, drowsiness, weakness, dizziness, confusion, irritability, hunger, fast heartbeat, sweating, and feeling jittery) while taking this medication, contact your doctor.

Kidney function: If you have decreased kidney function, discuss with your doctor how this medication may affect your medical condition, how your medical condition may affect the dosing and effectiveness of this medication, and whether any special monitoring is needed.

Liver function: Reduced liver function may cause higher levels of repaglinide in the body and increase the risk for low blood sugar levels (hypoglycemia). Make sure you report all your medical conditions to your doctor(s). People with severe liver disease should not take repaglinide.

Missed or delayed meals: This medication acts by promoting the secretion of insulin and should be taken before meals. If a meal is skipped or delayed, the dosing of repaglinide should be skipped or delayed as well.

Pregnancy: This medication should not be used during pregnancy. If you become pregnant while taking this medication, contact your doctor immediately.

Breast-feeding: It is not known whether repaglinide passes into breast milk.  If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breast-feeding.

Children: This safety and effectiveness of using this medication have not been established for children.

What other drugs could interact with this medication?

There may be an interaction between repaglinide and any of the following:

  • abiraterone
  • ACE inhibitors (e.g., ramipril, lisinopril)
  • anti-psychotics (e.g., chlorpromazine, clozapine, haloperidol, olanzepine, quetiapine, risperidone)
  • barbiturates (e.g., phenobarbital)
  • beta-blockers (e.g., propranolol, metoprolol)
  • birth control pills
  • boceprevir
  • bosentan
  • calcium channel blockers (e.g., nifedipine, verapamil)
  • carbamazepine
  • celecoxib
  • clopidogrel
  • corticosteroids (e.g., dexamethasone, prednisone)
  • cyclosporine
  • dabrafenib
  • danazol
  • deferasirox
  • other diabetes medications (e.g., chlorpropamide, glipizide, glyburide, insulin, metformin, nateglinide, rosiglitazone, sitagliptin)
  • diuretics (e.g., furosemide, hydrochlorothiazide)
  • eltrombopag
  • enzalutamide
  • estrogens
  • gemfibrozil
  • HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delaviridine, efavirenz, etravirine, nevirapine)
  • HIV protease inhibitors (e.g., darunavir, indinavir, lopinavir, saquinavir, tipranavir)
  • irbesartan
  • isoniazid
  • itraconazole
  • ketoconazole
  • losartan
  • macrolide antibiotics (e.g., clarithromycin, erythromycin)
  • monoamine oxidase inhibitors (MAOIs; e.g., moclobemide, phenelzine, rasagiline, selegiline, tranylcypromine)
  • nefazodone
  • nicotinic acid
  • nonsteroidal anti-inflammatory drugs (e.g., ibuprofen, naproxen)
  • octreotide
  • phenytoin
  • primidone
  • progesterone
  • quinine
  • quinolone antibiotics (e.g., ciprofloxacin, norfloxacin, ofloxacin)
  • rifabutin
  • rifampin
  • rifapentine
  • ritonavir
  • St. John’s wort
  • salicylates (e.g., ASA)
  • selective serotonin reuptake inhibitors (SSRI; e.g., fluoxetine, paroxetine, sertraline)
  • stiripentol
  • sulfonamides (e.g., sulfamethoxazole)
  • tacrolimus
  • tamoxifen
  • testosterone
  • trimethoprim

If you are taking any of these medications, speak with your doctor or pharmacist. Depending on your specific circumstances, your doctor may want you to:

  • stop taking one of the medications,
  • change one of the medications to another,
  • change how you are taking one or both of the medications, or
  • leave everything as is.

An interaction between two medications does not always mean that you must stop taking one of them. Speak to your doctor about how any drug interactions are being managed or should be managed.

Medications other than the ones listed above may interact with this medication. Tell your doctor or prescriber about all prescription, over-the-counter (non-prescription), and herbal medications that you are taking. Also tell them about any supplements you take. Since caffeine, alcohol, the nicotine from cigarettes, or street drugs can affect the action of many medications, you should let your prescriber know if you use them.

All material copyright MediResource Inc. 1996 – 2021. Terms and conditions of use. The contents herein are for informational purposes only. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Source: www.medbroadcast.com/drug/getdrug/ACT-Repaglinide

Repaglinide Side Effects, Adverse Reactions | Healthgrades

The following serious adverse reaction is also described elsewhere in the labeling:

The most common adverse reactions (5% or greater incidence) among patients treated with repaglinide tablets were: hypoglycemia, upper respiratory infection, headache, sinusitis, arthralgia, nausea, diarrhea, and back pain. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

clinical trials experience

Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

Repaglinide tablets have been administered to 2931 individuals during clinical trials. Approximately 1500 of these individuals with type 2 diabetes have been treated for at least 3 months, 1000 for at least 6 months, and 800 for at least 1 year. The majority of these individuals (1228) received repaglinide tablets in one of five 1-year, active-controlled trials. Over one year, 13% of repaglinide tablets patients were discontinued due to adverse reactions. The most common adverse reactions leading to withdrawal were hyperglycemia, hypoglycemia, and related symptoms.

Table 1 lists the common adverse reactions for repaglinide tablets patients compared to placebo in trials 12 to 24 weeks duration.

* See trial descriptions in Clinical Trials (14)


In clinical trials with repaglinide tablets, hypoglycemia is the most commonly observed adverse reaction. Mild or moderate hypoglycemia occurred in 31% of repaglinide tablets treated patients and 7% of placebo treated patients [see Warnings and Precautions (5.1)].


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Hypoglycemia was reported in 16% of 1228 repaglinide tablets patients, 20% of 417 glyburide patients, and 19% of 81 glipizide patients in 1-year controlled trials. Of repaglinide tablets-treated patients with symptomatic hypoglycemia, none developed coma or required hospitalization.

In a 24-week placebo controlled trial, patients who were naïve to oral hypoglycemic agent therapy and patients with a HbA1c below 8% at baseline had a higher frequency of hypoglycemia.

Weight Gain

There was no average gain in body weight when patients previously treated with oral hypoglycemic agents were switched to repaglinide tablets. The average weight gain in patients treated with repaglinide tablets and not previously treated with sulfonylurea drugs was 3.3%.

Cardiovascular Events

The incidence of total serious cardiovascular adverse events, including ischemia, was higher for repaglinide tablets (51/1228 or 4%) than for sulfonylurea drugs (13/498 or 3%) in controlled comparator clinical trials.

Table 2: Summary of Serious Cardiovascular Events in Trials Comparing Repaglinide Tablets to Sulfonylureas (% of total patients with events)

Repaglinide tablets


Total Exposed



Serious CV Events



Cardiac Ischemic Events



Deaths due to CV Events



*: glyburide and glipizide

Seven controlled clinical trials included repaglinide tablets combination therapy with NPH-insulin (n=431), insulin formulations alone (n=388) or other combinations (sulfonylurea plus NPH-insulin or repaglinide tablets plus metformin) (n=120). There were six serious adverse events of myocardial ischemia in patients treated with repaglinide tablets plus NPH-insulin from two studies, and one event in patients using insulin formulations alone from another study [see Warnings and Precautions (5.3)].

Combination Therapy with Thiazolidinediones


During 24-week treatment clinical trials of repaglinide tablets-rosiglitazone or repaglinide tablets-pioglitazone combination therapy (a total of 250 patients in combination therapy), hypoglycemia (blood glucose < 50 mg/dL) occurred in 7% of patients in combination therapy compared to 7% for repaglinide tablets monotherapy, and 2% for thiazolidinedione monotherapy.

Peripheral Edema and Heart Failure

Peripheral edema was reported in 12 out of 250 (4.8%) repaglinide tablets-thiazolidinedione combination therapy patients and 3 out of 124 (2.4%) thiazolidinedione monotherapy patients, with no cases reported in these trials for repaglinide tablets monotherapy. There were reports in 2 of 250 patients (0.8%) treated with repaglinide tablets-thiazolidinedione therapy of episodes of edema with congestive heart failure. Both patients had a prior history of coronary artery disease and recovered after treatment with diuretic agents. No comparable cases in the monotherapy treatment groups were reported.

Weight Gain

Mean weight increases associated with combination, repaglinide tablets and pioglitazone therapy were 5.5 kg, 0.3 kg, and 2.0 kg respectively. Mean weight increases associated with combination, repaglinide tablets and rosiglitazone therapy were 4.5 kg, 1.3 kg, and 3.3 kg respectively.

Infrequent Adverse Events (<1% of Patients)

Less common adverse clinical or laboratory events observed in clinical trials included elevated liver enzymes, thrombocytopenia, leukopenia, and anaphylactoid reactions.

The following additional adverse reactions have been identified during post approval use of repaglinide tablets. Because these reactions are reported voluntarily from a population of uncertain size, it is generally not possible to reliably estimate their frequency or a causal relationship to drug exposure.

Repaglinide – an overview | ScienceDirect Topics

General information

The meglitinides bind with high affinity to a site, distinct from the sulfonylurea receptor site, on the ATP-sensitive potassium channels in pancreatic beta cells and stimulate insulin secretion. After binding, the ATP-dependent potassium channels are closed, reducing potassium efflux and depolarizing the cell membrane. The meglitinides do not have to be internalized in the membrane, in contrast to the sulfonylureas. This may explain their rapid onset of the action and the end of that action when glucose concentrations are falling. MgADP potentiates the effect in beta cells but not in cardiac cells [1], which may explain the reduced cardiovascular adverse effects of repaglinide in vivo. Meglitinide-stimulated insulin secretion depends on the glucose concentration; insulin secretion is not stimulated in vitro or in fasted animals. Nateglinide (and perhaps repaglinide) reduces the secretion of glycated insulin, which has poor activity, from islet cells; this may contribute to its hypoglycemic action [2].

Repaglinide is a carbamoylmethyl benzoic acid derivative, which contains the non-sulfonylurea moiety of glibenclamide, and nateglinide is a phenylalanine derivative. Nateglinide acts more quickly than repaglinide, and both act more quickly than sulfonylureas, which stimulate insulin secretion independent of blood glucose concentrations [3]. It has been stated [4] that earlier studies [5] showed that the efficacy in lowering HbA1c is almost equivalent for sulfonylureas and repaglinide and is slightly lower for nateglinide. When a lunch-time meal was omitted [6] patients taking glibenclamide had the lowest blood glucose concentrations, often within the hypoglycemic range, in contrast to patients taking repaglinide. Both drugs can cause hypoglycemia.

Repaglinide has been reviewed [7–9]. It stimulates glucose-dependent insulin secretion, amplifying insulin bursts without changing burst frequency, but it does not restore disrupted pulsatile secretion in type 2 diabetes [10]. It is rapidly absorbed. It is metabolized by CYP3A4 in the liver and is 90% excreted in the feces. It has a half-life of 32 minutes. Its pharmacokinetics do not differ in young or older healthy persons [11]. It can be given as monotherapy [12], and the effective dose is 0.5–8 mg/day, starting with 0.5 mg/day. It has to be given before each meal and can be adapted to irregular food intake or missed meals [13]. When given preprandially it improves glucose control without increasing the risk of adverse effects [14]. There were no differences in action in healthy younger or older volunteers [15]. Repaglinide is short-acting and seems to be associated with significantly fewer episodes of serious hypoglycemia [16]. In a short review of a number of clinical studies the following contraindications were reported [17]:

known hypersensitivity to repaglinide or one of the constituents of Novonorm®;

type 1 diabetes;

renal or hepatic impairment.

Nateglinide (and perhaps repaglinide) reduces the excretion of glycated insulin, which has impaired biological activity, from the islets [2]. This may contribute to the antihyperglycemic action of nateglinide.

General adverse effects and adverse reactions

The most frequent adverse effect of meglitinides is hypoglycemia. The overall incidence of hypoglycemia with repaglinide is similar to that reported with sulfonylureas, but the incidence of serious hypoglycemia is lower. Other adverse effects are respiratory tract infections and headache. Cardiovascular events and cardiovascular mortality are not different from those in users of sulfonylureas. In Europe, repaglinide is contraindicated in patients with severe liver dysfunction and it is not recommended in people over 75 years old; in America the advice is to use repaglinide cautiously in patients with impaired liver function and there is no restriction on its use in elderly patients. In renal impairment, the half-life of repaglinide is prolonged. Reasons for withdrawal are hyperglycemia, hypoglycemia, and myocardial infarction [18].

Active substance REPAGLINIDUM (REPAGLINIDUM) | Compendium

Medicinal preparations containing the active substance REPAGLINIDE


Novo Nordisk

tablets 1 mg blister, No. 30, 90

tablets 2 mg blister, No. 30, 90

hypoglycemic drugs, excluding insulin

hypoglycemic drugs, excluding insulin

repaglinide – oral fast-acting hypoglycemic agent.Repaglinide lowers blood glucose levels by stimulating the release of insulin by the β-cells of the pancreas. Repaglinide, interacting with specific receptors, blocks ATP-dependent channels in the membranes of β-cells; this leads to depolarization of the outer membranes and the opening of calcium channels. As a result, the increased intracellular entry of calcium ions induces the secretion of insulin by the β-cells of the pancreas.

The hypoglycemic effect of repaglinide develops within 30 minutes after ingestion; when using repaglinide before meals, its action prevents the development of postprandial hyperglycemia in patients with type II diabetes mellitus; there is no increase in insulin secretion between meals.Repaglinide is rapidly absorbed in the digestive tract, which leads to a rapid increase in its concentration in blood plasma; C max repaglinide is noted 1 hour after oral administration. The content of repaglinide in the blood plasma decreases rapidly, and after 4–6 hours, only trace concentrations of it are noted in the blood plasma. T ½ – about 1 hour Dose-dependent hypoglycemic effect is observed when used in the dose range of 0.5-4 mg. Absolute bioavailability – 63%; distribution volume – 30 liters.Clinical trials have revealed a high interindividual variability (60%) in plasma concentrations of repaglinide. More than 98% of repaglinide binds to blood plasma proteins. There were no clinically significant differences in the pharmacokinetics of repaglinide when taken on an empty stomach, 15 or 30 minutes, or immediately before meals. Repaglinide is almost completely metabolized in the liver to form inactive metabolites. Repaglinide and its metabolites are excreted mainly in the bile (less than 1% is excreted unchanged in the feces), a small amount (up to 8%) in the urine, also mainly in the form of metabolites.Elimination of repaglinide is slowed down in patients with renal and hepatic insufficiency, as well as in elderly patients with type II diabetes.

non-insulin dependent diabetes mellitus with insufficient effectiveness of diet therapy, to normalize body weight and increase physical activity; combination therapy in combination with metformin in case of insufficient effectiveness of the latter.

repaglinide is taken before meals; the dose is set individually. In addition to the usual self-monitoring of blood and urine glucose levels, the patient should periodically undergo a medical examination with monitoring of the glycemic level to determine the minimum effective dose of repaglinide and control the level of glycosylated hemoglobin.Periodic repeated examinations are required to determine primary resistance to repaglinide (repaglinide at the maximum dose does not have an adequate hypoglycemic effect), as well as the development of secondary resistance to treatment (the moment when adequate hypoglycemic activity of repaglinide is lost after an initial period of satisfactory efficacy). In some cases, repaglinide is prescribed for a short time to compensate for the condition in patients with type II diabetes mellitus, in whom the normalization of carbohydrate metabolism is achieved by following a diet.

The recommended starting dose is 0.5 mg. Increasing the dose is carried out at intervals of at least 1-2 weeks, depending on the level of glycemia. If the patient has previously taken another oral hypoglycemic agent, the recommended starting dose is 1 mg.

The maximum maintenance single dose is 4 mg with the main meal. The maximum daily maintenance dose should not exceed 16 mg.

hypersensitivity to repaglinide, insulin-dependent diabetes mellitus, diabetic ketoacidosis, age up to 12 years, severe renal or liver dysfunction.

hypoglycemic reactions, temporary decrease in visual acuity, abdominal pain, diarrhea, nausea, vomiting and constipation, moderately pronounced transient changes in the activity of liver enzymes, hypersensitivity reactions (pruritus, erythema, urticaria).

repaglinide should be prescribed only if adherence to an adequate diet, physical activity and normalization of body weight are ineffective, but the use of the drug does not exclude the need to perform these measures.

Repaglinide, like other oral hypoglycemic agents, is capable of causing the development of a hypoglycemic state (usually of moderate severity), which can be easily eliminated by taking carbohydrates. In severe hypoglycemia, there may be a need for intravenous glucose administration. The development and severity of such reactions depend on many factors, including the dose of repaglinide, dietary habits, the degree of physical exertion and stress. Treatment with metformin is associated with an increased risk of hypoglycemia.

During treatment with repaglinide, some stressful influences (trauma, surgery, fever, infectious diseases) can cause decompensation of the state; in such cases, it is necessary to stop taking repaglinide and temporarily transfer the patient to insulin.

It is not recommended to prescribe repaglinide to children and adolescents under the age of 18 years, elderly people (over 75 years old), as well as during pregnancy and lactation.

Patients should be warned about precautions to avoid hypoglycemia while driving.This is especially important at the beginning of therapy, as well as in patients with frequent hypoglycemic reactions.

The hypoglycemic effect of repaglinide can be enhanced by MAO inhibitors, non-selective β-adrenoreceptor blockers, ACE inhibitors, salicylates and other NSAIDs, octreotide, alcohol and anabolic steroids. The severity of the hypoglycemic effect of repaglinide can be reduced by oral contraceptives, thiazide diuretics, GCS, danazol, thyroid hormones and sympathomimetics. When prescribing or canceling the listed drugs in patients receiving repaglinide, it is necessary to carefully monitor the blood glucose level.Repaglinide has no clinically significant effect on the pharmacokinetic properties of digoxin, theophylline or warfarin at equilibrium when used in healthy volunteers. Cimetidine, with simultaneous use, practically does not affect the pharmacokinetics of repaglinide. Β-adrenergic receptor blockers can mask the symptoms of hypoglycemia. Alcohol can potentiate and prolong the hypoglycemic effect of repaglinide. The results of studies in vitro indicate that repaglinide is mainly metabolized by the CYP 3A4 enzyme.Although in vivo studies have not been conducted, CYP 3A4 inhibitors such as ketoconazole, itraconazole, erythromycin, fluconazole and mibefradil are thought to increase plasma repaglinide levels. Compounds that induce CYP 3A4, such as rifampicin or phenytoin, can reduce plasma levels of repaglinide. Since the magnitude of the degree of inducing or inhibitory effect is unknown, combinations of repaglinide with these drugs are contraindicated. With the combined use of repaglinide with drugs that are mainly excreted in the bile, the potential interaction between them should be considered.

in clinical trials, repaglinide was prescribed with a weekly dose increase from 4 to 20 mg 4 times a day for 6 weeks without the development of serious side effects. Since in these studies, hypoglycemic reactions were prevented by increasing the caloric content of food, a relative overdose can cause an excessive hypoglycemic effect with the development of corresponding symptoms (nausea, increased sweating, tremors, headache). When these symptoms appear, oral carbohydrate intake is recommended.The development of severe hypoglycemia with loss of consciousness, seizures, or the development of coma requires intravenous administration of dextrose.

90,000 composition, indications, dosage, side effects

The drug is prescribed for the treatment of type II diabetes mellitus.

Form of issue, composition

The drug is produced in the form of white or yellow, biconvex, round tablets, which are sealed in blisters, 10 tablets each, blisters are packed in a cardboard box, 3 blisters each.

Ingredients: corn starch, magnesium stearate, calcium phosphate anhydrous, 0.5-2 mg repaglinide, yellow iron oxide, povidone, microcrystalline cellulose, glycerin, meglumine, palacrilin, 85% ethanol, poloxamer.

Indications for use

Doctors advise to use the drug for: type II diabetes mellitus, is an addition to physical activity or diet.


Do not use the drug for those patients who have: impaired liver function, type I diabetes (insulin-dependent diabetes mellitus, IDDM), sensitivity to the composition of the drug, diabetic ketoacidosis, C-peptide-negative diabetes.

Period of pregnancy and breastfeeding

Before using the drug, without fail, you must go to the doctor and pay attention to the composition of this drug. If its ingredients do not harm the health of your baby and your health, then you can use the medication.

Method of application

In order to exclude the occurrence of side reactions of the body to the drug, your attending specialist, after consultation and diagnosis, prescribes the dosage according to which you should use this drug.

Doctors advise using the medicine for treatment in exactly this dosage: preprandially, that is, before each meal, 0.5-1 mg for each meal, but for 1 day the maximum dosage should not exceed 16 mg.

The duration of use depends on the effectiveness of the drug on the patient’s body.


Patients inadvertently used this drug to a greater extent than recommended by the attending physician and, at the same time, they had the following symptoms of the body’s response to the drug: increased side effects, tremors, convulsions, dizziness, headache, sweating …

Adverse reactions

Situations with patients who had adverse reactions were recorded and the following symptoms were observed: impaired visual acuity, metabolic disorders, liver dysfunction, gastrointestinal disorders, diseases of the subcutaneous tissue and skin … If these reactions appear, you need to go to your doctor.

Storage conditions

It is recommended to store this medicinal product in a place that is dark, preferably very dry, to which children under the age of 18 do not have access, and at the same time, the temperature of this place, without fail, should not exceed +25 ° C.

In all pharmacies, you can purchase this medication only with a prescription from your treating specialist.

The shelf life of the medicine lasts 24 months from the date indicated on each package of the medicine.

Glibenclamide – Efficacy and Safety Profile | Nedosugova

Type 2 diabetes mellitus (DM2) is one of the most common diseases in the world, affecting the population of both economically developed and developing countries.At the same time, according to Reaven’s definition [1], T2DM is “a chronic, incurable, progressive disease,” the course of which is complicated by the development of specific vascular complications, the so-called microangiopathies, and the rapid progression of atherosclerosis, leading to cardiovascular mortality in patients with T2DM in 4– 5 times more often compared to the general population [2]. A series of large randomized trials [3–7] have proven the importance of tight glycemic control in reducing the risk of progression of diabetic vascular complications, which requires aggressive treatment of T2DM using effective and safe antihyperglycemic drugs and their combinations to achieve the target glycemic level.Among all the variety of existing antihyperglycemic agents, sulfonylurea derivatives (PSMs), used for more than 50 years, and today remain the leaders among oral antihyperglycemic drugs. Their popularity is based not only on good popularity and ease of use (in most cases, no more than once a day), but also on proven efficacy, the absence of clinically significant (except for hypoglycemia) side effects and low cost. Among PSM, the most widely used drug in the USA and Germany is glibenclamide (one of its drugs on the Russian market is Maninil® by Berlin-Chemie / Menarini, Germany).

Glibenclamide has been used in clinical practice since 1969 and remains, nevertheless, the “gold standard” in terms of the strength of its hypoglycemic effect, with which all new oral hypoglycemic agents that appear on the market are compared. The effectiveness of the drug, providing a decrease in HbA1c by 1.2-1.9%, depending on its initial level, is due to the maximum affinity for SUR 1 (ATP-dependent K + (K + ATP) channels) on the β-cells of the pancreas due to compounds with benzamide and sulfonylurea binding sites on SUR 1, on the one hand, and the ability to complex with SUR 2A and SUR 2B, which are part of the structure of K + ATP channels in peripheral tissues, on the other [8, 9, 10].Thus, due to its chemical structure, which contains not only a sulfonylurea group common to all PSMs, but also a benzamide ring in the side chain, glibenclamide is able to work not only at the level of pancreatic β-cells, stimulating insulin secretion most actively of all PSMs, but also at the level of peripheral tissues, increasing insulin sensitivity. There are many publications indicating that glibenclamide in the culture of adipose and muscle tissues stimulates glucose utilization, potentiates lipogenesis and glycogen synthesis, increasing insulin sensitivity [11–17].An increase in the activity of the tyrosine kinase of the insulin receptor substrate-1 (IRS-1), glycogen synthase, phospho-inositol-3-phosphate kinase (PIP-3-kinase) against the background of glibenclamide was also shown [18, 19, 20].

In 2010, the sulfonylurea drug Maninil® (glibenclamide) was awarded the G.G. Creutzfeldt. This renowned award is presented by an independent panel of experts from clinical, institutional and research institutions. By presenting this award, the Institute.G.G. Creutzfeldt in Kiel aims to pay tribute to a drug that, thanks to its mode of action, played a central role in the optimization of pharmacotherapy. The efficacy of the drug, its safety profile and possible long-term beneficial effects are of particular importance.

The independent expert group consists of leading renowned German professors: prof. W.-D. Gerber, Keel; prof. R. Lucius, Keel; PD Dr. H.-L. Poser, Zizebi; prof.W.-D Möller, Kiel; prof. Dr. Müller, Hamburg; prof. B. Weisser, Kiel.

In 2010, the G.G. Creutzfeldt was awarded based on the following key factors.

Effectiveness confirmed by long-term research in practical health care

More than 40 years of practical use of the drug has proven its clinical efficacy in maintaining glycemic control, which is confirmed by a huge number of randomized studies, the most authoritative of which is the UK Prospective Diabetes Study (UKPDS), which included 4279 patients with newly diagnosed type 2 diabetes.Depending on the baseline glycemic level, patients were prescribed either drug therapy (chlorpropamide, metformin, glibenclamide, or insulin) or diet therapy in combination with lifestyle changes. The effect of long-term monotherapy was assessed after 3, 6, 9 years of treatment. This study showed the efficacy of glibenclamide comparable to insulin: after 3 years of therapy, target levels of glycemic control (glycemia <7.8 mmol / L and HbA1c <7.0%) were achieved in 47% of patients treated with glibenclamide and insulin therapy, and in 44% of patients treated with metformin.In the UKPDS study [3], it was also shown that over time after 6 and 9 years of therapy, there is a decrease in the effectiveness of antihyperglycemic therapy in all observed groups. The results of a meta-analysis of 20 comparative studies of glibenclamide with other PSM and secretagogues conducted by A.S. Gangji et al. [21], indicate a greater efficacy of the drug in relation to glycemic control, which was also manifested in an increase in the incidence of hypoglycemic reactions. The A Diabetes Outcome Progression Trial (ADOPT) [5], concluded in 2006.and including 4127 patients, of whom 1393 received rosiglitazone, 1397 - metformin and 1337 - glibenclamide for 4 years, demonstrated the highest glucose-lowering activity of glibenclamide during the first year of therapy. Although in subsequent years of observation, as in the UKPDS study, there was a decrease in the hypoglycemic effect against the background of monotherapy, in the group of patients receiving glibenclamide, the most significant reduction in the risk of cardiovascular complications was noted.

The drug reduces the risk of developing long-term complications

Not only the achievement and maintenance of adequate glycemic control, but also the ability of the drug to prevent macro- and microvascular complications of diabetes, from which most patients die, is a criterion of effectiveness.In this regard, glibenclamide can be considered the most studied second-generation PSM, since all large multicenter studies devoted to the treatment of type 2 diabetes and the assessment of the long-term consequences of the disease involved groups of patients who took glibenclamide as the most popular and affordable antihyperglycemic drug in many countries.

As mentioned above, in the ADOPT study, there was a 2.2-fold reduction in cardiovascular complications in the glibenclamide group (p <0.05) compared with rosiglitazone.The UKPDS showed that each 1% decrease in HbA1c was associated with a 21% reduction in the risk of diabetes-related death, a 14% reduction in the risk of myocardial infarction (MI), and a 37% reduction in the risk of microangiopathy progression. The effectiveness of glibenclamide in the prevention of vascular complications of diabetes is also confirmed by the results of follow-up over 10 years for patients who participated in the UKPDS study, which demonstrated a 24% reduction in the risk of microvascular complications (p = 0.001), the risk of MI by 15% (p = 0 , 01) and death from any cause by 13% (p = 0.007) in the group of patients who continued receiving PSM and insulin therapy [22].

Proven efficacy and safety in long term trials

In the mid 70s of the last century, the results of the University Group for the Study of Diabetes (UGDP) were published, which showed an excess of cardiovascular mortality when using first generation sulfonylurea derivatives, in particular tolbutamide [23]. In the same years, studies began to study the safety profile of glibenclamide, the results of which were contradictory.Some authors refuted the assumptions about a high risk of vascular catastrophes when taking glibenclamide, others pointed to its cardiotoxicity. This was most likely due to differences in research methodology. In those of them where the negative effect of glibenclamide on the cardiovascular system was shown, the drug was administered in high doses intracoronary or intravenously, which, of course, cannot be compared with oral administration in T2DM. This question was closed only with the publication of the UKPDS results [3], which showed no significant difference in cardiovascular morbidity and mortality between groups of patients treated with insulin, glibenclamide or chlorpropamide after about 10 years of treatment.

The discovery of the heterogeneity of the SCM receptors (SUR) and the presence of SUR2A and SUR2B in cardiomyocytes and smooth muscle cells of the vascular wall, as well as the heterogeneity of the interaction of various SCMs with these receptors in the heart and their effect on the vascular bed in animal models renewed the discussion of the potential cardiotoxicity of SCM when appointing some of them. Theoretically, the potential cardiotoxic effect of glibenclamide can be expected based on the peculiarity of its chemical structure, which contains a benzamide group, which is able to bind not only to SUR 1 K + ATP channel of the β-cell, but also to SUR 2A K + ATP on cardiomyocyte containing only benzamide binding sites.It is natural to assume the possibility of a negative effect of the closure of KATP channels and an increase in the concentration of intracellular Ca on the state of the myocardium, caused by glibenclamide, especially under ischemic conditions. Many authors have studied the role of K + ATP channels in the adaptation of the heart muscle to ischemia [24, 25]. At a high concentration of ATP in cardiac myocytes, the K + ATP channels are closed. They open in various situations: a decrease in ATP concentration, accumulation of lactate, activation of the A1 adenosine receptor. Under conditions of hypoxia or myocardial ischemia, a decrease in the intracellular ATP content leads to the opening of K + ATP channels.The release of K + ions from myocardial cells initiates repolarization of the cell membrane, preventing the entry of Ca2 + ions, shortening the action potential and the amplitude of myocardiocyte contractions, which effectively reduces myocardial oxygen demand and the risk of its subsequent damage. The opening of K + ATP channels induces the phenomenon of the so-called ischemic preconditioning (IPC), which is a mechanism of endogenous protection of the myocardium from ischemic damage. The phenomenon was first described more than 20 years ago, when it was found that exposure of the myocardium to a brief episode of myocardial ischemia significantly reduced the effect of subsequent long-term ischemia [26], leading to a significant reduction in the size of the emerging acute MI.In addition, the opening of K + ATP channels reduces vascular resistance, increases coronary blood flow and myocardial oxygen supply [27]. Thus, K + ATP channels play a protective role against myocardial damage during ischemia, and the likelihood of a negative effect of glibenclamide, which contributes to their closure, on the state of the myocardium is quite high. In theory, this could increase the death rate of patients from myocardial infarction. Does this pattern take place in real clinical practice?

In a prospective study LAMBDA (The LAngendreer Myocardial infarction and Blood glucose in Diabetic patients Assessment) [28], it was shown that previous administration of glibenclamide, like all other PSMs, does not have a negative effect on the survival rate of patients with T2DM after MI.

In a retrospective analysis, the mortality rates from MI in 409 patients with T2DM who took oral hypoglycemic drugs (PSS) before heart attack were estimated. After excluding patients who received first-generation PSM, biguanides, or thiazolidinediones, mortality was analyzed in the remaining 386 patients who received second-generation PSM (n = 120), insulin (n = 180), or non-drug diabetes treatment (n = 86). After statistically excluding factors such as age, gender, heart failure, duration of diabetes mellitus, renal dysfunction, reperfusion or myocardial revascularization, it turned out that the mortality from MI was significantly lower than in the insulin group (relative risk 0.41 ; 95% confidence interval 0.21-0.80; p = 0.009) [29].

In a recent retrospective meta-analysis of the study of the effect of monotherapy with various SCIs on mortality of 11141 patients with type 2 diabetes (4279 on glibenclamide monotherapy, 4325 on glipizide monotherapy, and 2537 on glimepiride monotherapy) over 18 years of age who did not receive insulin therapy, suffered from heart disease, did not have coronary artery disease a significant difference in the risk of overall mortality between patients who received these drugs [30].

On the other hand, if we assume that glibenclamide really interacts with the K + ATP channels of cardiomyocytes, then this mechanism explains well the pronounced antiarrhythmic effect of the drug in acute myocardial infarction.Glibenclamide has the most pronounced antiarrhythmic effect compared to other PSMs, including gliclazide, as the most arrhythmogenic drug, and glimepiride, which practically does not bind to sulfonylurea receptors in the myocardium. The antiarrhythmic effect of glibenclamide is associated with its ability to close ATP-dependent K + channels (the blockade affects about 10% of the channels) and to prevent excessive loss of K + ions by myocardial cells in severe ischemia. In some clinical studies, evidence has been obtained that in patients with T2DM who took glibenclamide, in conditions of developed ischemia, the likelihood of developing ventricular arrhythmias and fibrillation, which are common causes of death in patients with acute MI, decreases [31].

According to Lomuscio A. et al. [32], who assessed the incidence of ventricular fibrillation in 232 patients with T2DM in the acute stage of myocardial infarction and in 830 patients with MI without diabetes, their lowest frequency (1.9%) was observed in the group of patients (106 people) who received glibenclamide before myocardial infarction, then as in the group of patients receiving other therapy (126 people), it was 7.9%, in the group of patients without diabetes, fibrillation was observed in 9.9% of cases. This is confirmed by the results of a retrospective analysis of mortality in acute myocardial infarction, conducted in Australia based on an assessment of 56,715 case histories [33].The mortality rate was 12% in patients without diabetes and 28.1% in patients with diabetes (p <0.001), while there was no evidence of side effects depending on the concomitant therapy received. The incidence of ventricular fibrillation, which caused death in patients with diabetes and receiving glibenclamide, was similar to that in patients without diabetes (11.8% and 11.0%, respectively), but was less than in patients taking gliclazide (18% , p <0.05) and insulin (22.8%, p <0.05).

It can be concluded that the drug has rather a cardioprotective effect in conditions of myocardial ischemia, since its mild effect on the ATP-dependent K + -channels of myocardiocytes prevents excessive loss of potassium and, consequently, rhythm disturbances in MI.

The already mentioned meta-analysis of A.S. Gangji, T. et al. [21], published in 2007. One of its goals was to compare the safety of monotherapy with glibenclamide, other secretagogues and insulin in relation to the risk of hypoglycemia and cardiovascular events.The meta-analysis included 21 randomized clinical trials conducted between 1966 and 2005. The authors of the meta-analysis concluded that the use of glibenclamide is associated with a higher incidence of hypoglycemic conditions, but is not accompanied by an increased risk of cardiovascular events, death, and weight gain by the end of the observation period.

The high incidence of hypoglycemic conditions with the use of glibenclamide, shown in many clinical studies, can be explained by its maximum affinity for SUR 1 β-cells.However, firstly, in most of these studies, non-micronized glibenclamide was used, which really has an unsafe pharmacokinetic profile: slow absorption and the onset of action of the drug lead to the fact that its maximum plasma concentration (Cmax) and, accordingly, maximum insulin secretion are achieved in the range from 1 , 5 to 4 hours from the moment of taking the pill, i.e. fall predominantly in the postabsorption period, characterized by a gradually decreasing level of glycemia.This explains the increased risk of delayed hypoglycemia occurring 4–6 hours after taking the drug. Secondly, in the studies mentioned, there is no information on the correctness of patient compliance with the drug intake regimen, which, obviously, is also of great importance. The micronized form of glibenclamide (Maninil®, Berlin-Chemie / Menarini), having 100% bioavailability (as opposed to 70% in its non-micronized precursor), begins to act quickly – the Cmax of the drug in plasma is reached within 30 minutes after its administration, which to a greater extent corresponds to the postprandial rise in glycemia, restores such a significant acute phase of the insulin response, and, on the other hand, can significantly reduce the risk of delayed hypoglycemia [34].The development of hypoglycemic conditions is caused not so much by excessive stimulation of insulin secretion in patients while taking the drug, but by overeating as a result of an overdose of Maninil®, which leads to increased appetite, weight gain and aggravation of insulin resistance, since, as already noted, the drug increases the sensitivity of the β-cell to GIP and stimulates insulin secretion according to glycemic levels. Only a gradual, slow increase in the dose can be achieved in this situation, the maximum effect with a minimum risk of complications.An indispensable condition for the correct selection of the dose is the patient’s strict adherence to a low-calorie (with T2DM with obesity) or isocaloric (with normal body weight) diet. Correctly selected dose of Maninil® against the background of correct diet therapy with prolonged use provides a decrease in circulating insulin relative to its level before treatment, if, due to the restoration of insulin sensitivity of peripheral tissues, the level of glycemia decreases.

From the foregoing, it follows that the widespread use of the “old” version of glibenclamide is really not justified from the standpoint of safety and should be discontinued, while the use of its “new” form, if the therapy is carried out correctly, provides a favorable combination of efficacy and safety.

The incidence of hypoglycemia during treatment with glibenclamide in real clinical practice remains low. In a prospective study on a large sample of T2DM patients, the incidence of severe hypoglycemia that required intravenous glucose or glucagon was 5.6 per 1000 patient-years of glibenclamide use, although it was higher than in patients taking glimepiride [35]. However, all cases of hypoglycemia occurred in the elderly (mean age 79; 95% confidence interval (CI) 75.2–82.6), well compensated (mean HbA1c level 5.4% (95% CI 5 , 1-5,7)) patients with severe concomitant pathology (decreased renal function, heart failure, coronary heart disease – coronary artery disease, tumors, cerebral ischemia, alcoholism, dementia) [9].A systematic review comparing the safety parameters of PSI and other secretagogues [36] assessed the incidence of hypoglycemia in patients receiving glibenclamide monotherapy versus chlorpropamide, glipizide, glimepiride, gliclazide, repaglinide, and nateglinide monotherapy. In 3 of 11 randomized controlled trials selected for analysis, involving a total of 4713 patients and a follow-up period of 8 weeks to 5 years, it was shown that the incidence of hypoglycemia during therapy with glibenclamide is indeed higher than with other antihyperglycemic drugs.However, it should be noted that in these studies, non-micronized glibenclamide was prescribed at a maximum dose of 10 mg / day. In the remaining 8 prospective studies, there were no statistically significant differences in the incidence of hypoglycemia between glibenclamide and other secretagogues, despite the fact that 5 studies also used non-micronized glibenclamide. Two studies compared micronized glibenclamide with repaglinide. The relative risk of hypoglycemia in the glibenclamide and repaglinide groups was comparable and amounted to 0.93 (95% CI 0.39–2.24) and 0.97 (95% CI 0.51–1.83), respectively.

Thus, when comparing monotherapy with glibenclamide and other secretagogues in studies performed independently by different authors, there was no evidence of an increased risk of hypoglycemic episodes during glibenclamide therapy. The use of micronized forms of glibenclamide can reduce the risk of this common complication of hypoglycemic therapy.

Acute stroke is the second manifestation of atherosclerosis due to lethality, the risk of which in T2DM increases by 4-5 times.Under conditions of damage or ischemia of the nervous tissue, the so-called NCCa-ATP channels are expressed on the neuronal membrane, when opened under ischemic conditions, with a decrease in ATP, the membrane permeability to Na + and water ions increases, leading to cerebral edema and increased mortality. Like the K + ATP channels in the β-cell, NCCa-ATP channels are regulated via SUR1 and can be blocked by glibenclamide. In a rodent model of ischemic stroke, glibenclamide infusions actually prevented the expansion of the cerebral infarction zone and reduced mortality by a factor of 2 [37].

The hypothesis of improved outcomes of ischemic stroke in T2DM patients who took PSI was tested in a retrospective study by H. Kunte et al. [38]. We analyzed the data of 90 patients with stroke developing on the background of T2DM, 36 of whom took glibenclamide, glimepiride or glibornuride before stroke and during hospitalization. Patients who received PSM before stroke, but due to the severity of the condition and swallowing disorders, stopped taking them after hospitalization were excluded from the analysis.After all the exclusions, the data of 33 patients in the SCM group and 28 in the control group were analyzed. As a result, patients taking PSM at the time of discharge had significantly better neurological outcomes of stroke compared with the control group (improvement on the NIHSS scale by more than 4 points or zero score; p = 0.007) and were functionally more independent (assessment on the modified Rankine scale ≤2 points; p = 0.035). The dynamics of glycemia during the period of inpatient treatment did not affect the outcomes of stroke.The prognosis depended on the subtype of stroke: the best treatment results were observed in patients with atherosclerotic occlusion of large cerebral arteries or cardioembolic stroke, while the course of lacunar (small-focal) strokes was practically unaffected by PSM after excluding all other factors. Despite the retrospectiveness of the study and the small sample size, the authors concluded that the use of PSM before and during the acute phase of ischemic stroke in patients with T2DM may improve neurological outcomes.However, for a definitive answer to the question of whether PSM has a neuroprotective effect, it is necessary to conduct prospective randomized studies.

The problem of gestational diabetes mellitus (GDM) is becoming increasingly important due to the increase in the prevalence of this pathology and unfavorable perinatal outcomes. In most countries, only insulin therapy is used to treat GDM. Pregnancy is a contraindication to the prescription of most oral glucose-lowering drugs, including PSM, but there is more and more evidence in the literature in favor of their use in GDM as a safe, convenient and pharmacoeconomically beneficial alternative.The drug of choice was glibenclamide, which does not penetrate the blood-placental barrier and, therefore, does not enter the fetal bloodstream [39]. According to most authors who have conducted clinical studies of oral glucose-lowering therapy in pregnant women, the effectiveness of glibenclamide in achieving target glycemic levels is 80–85%, which is comparable to the results of insulin administration. At the same time, the appointment of an oral drug has undeniable advantages: non-invasiveness and the ability for patients to independently carry out treatment under the supervision of a physician.

The safety aspects of PSM in GDM have been studied in sufficient detail in clinical trials. Their pooled analysis (4 randomized clinical trials involving a total of 1229 pregnant women) found no differences in the efficacy of glycemic control, maternal and neonatal outcomes in the treatment of GDM with oral glucose-lowering drugs compared with the traditional strategy of insulin therapy. There was no difference between the glibenclamide and insulin groups in the frequency of caesarean section, the mean body weight of newborns, and the incidence of congenital malformations [40].

Some clinical guidelines already include glibenclamide as the drug of choice for the treatment of GDM. For example, the UK’s National Institute for Health and Clinical Excellence recommends the use of human short-acting insulins, insulin analogs and / or oral hypoglycemic agents metformin and glibenclamide to control glycemia in GDM. For the treatment of T2DM in pregnant women, SCIs, as before, are contraindicated.

Criterion: the drug is potent and easy to combine

It is known that T2DM is a chronic, incurable and progressive disease in which insulin deficiency progresses and insulin resistance increases, which leads to the development of secondary resistance to SCI and the need to prescribe combined antihyperglycaemic therapy, or to transfer to insulin therapy.A number of studies have shown the efficacy of glibenclamide in combination with background insulin therapy [41], metformin [42] and thiazolinediones (pioglitazone, rosiglitazone) in the development of secondary resistance to PSI [43].

Glibenclamide most effectively prolongs the period from initial metabolic disturbances to the need to prescribe insulin replacement therapy due to secondary resistance to PSS. The combination of glibenclamide with insulin therapy allows you to reduce the dose of insulin administered and avoid significant weight gain compared to insulin monotherapy.The combined use of a nighttime insulin background to suppress excessive glucose production by the liver with the intake of Maninil® in the daytime is currently considered the most effective treatment regimen for patients with developing secondary resistance to PSS. Maninil® is effective in small doses (no more than 2.5–5 mg) in combination with metformin and glucobay. In any case, with the combination of these PSS, it is possible to achieve better metabolic control when using significantly lower doses of glibenclamide.The emergence of insulin sensitizers, that is, drugs that increase insulin sensitivity, in particular thiazolidinediones (Aktos, Avandia), made it possible to cope with secondary resistance to PSS by combining glibenclamide with these agents. According to the T2DM treatment algorithm based on the 2008 EASD / ADA consensus, a triple combination of glibenclamide, metformin, and pioglitazone is not excluded in order to improve glycemic control [44].

The emergence of a new group of incretin drugs – mimetics and analogues of glucagon-like peptide (GLP-1) and dipeptyl-peptidase-4 inhibitors (DPP-4), gave rise to a new wave of publications demonstrating the effectiveness and safety of the combination of glibenclamide with GLP- 1 and DPP-4 inhibitors.A double-blind, placebo-controlled 24-week study compared the efficacy and safety of a combination of liraglutide / placebo at doses of 0.6 and 0.9 mg with glibenclamide, gliclazide or glimepiride in 264 patients with T2DM, with a mean HbA1c level of 8.4%. A significant decrease in fasting glycemia was achieved – 1.47 mmol / l and HbA1c from 8.60 to 7.14% at a dose of 0.6 mg and a decrease in glycemia – 1.80 mmol / l and HbA1c from 8.23 ​​to 6.67 % at a dose of 0.9 mg without episodes of significant hypoglycemia and weight gain [45].

In an acute experiment with constant intravenous administration of GLP-1 for 240 minutes in patients with diabetes mellitus, suffering from obesity and secondary resistance to PSS, its potentiating effect on the stimulating insulin secretion effect of glibenclamide, slowing down gastric emptying and lowering the basal glucagon level was demonstrated. which allowed the authors to suggest the possibility of its use in situations of development of secondary resistance to SCI in patients with T2DM and obesity [46].

In a double-blind, placebo-controlled 6-month study of the addition of saxagliptin / placebo at a dose of 2.5 or 5 mg to 7.5 or 10 mg glibenclamide in 768 patients with type 2 diabetes, inadequately compensated for monotherapy with glibenclamide, a significant decrease in HbA1c ( by -0.6% versus + 1% on placebo p <0.0001), while there was no significant increase in body weight. The incidence of confirmed hypoglycemia was 0.8% in the 5 mg saxagliptin group in combination with glibenclamide and 0.7% in the placebo group in combination with glibenclamide [47].

A randomized open crossover study of the efficacy and safety of combination therapy with glibenclamide and vildagliptin in patients with type 2 diabetes was also conducted, which demonstrated improved glycemic control and the absence of hypoglycemic conditions [48]. Thus, glibenclamide can be combined with any of the currently known hypoglycemic agents (with the exception of secretagogues and prandial insulin), which improves glycemic control, without increasing the risk of hypoglycemic conditions, due to the possibility of reducing the dose of the drug when combined with other PSS.

The drug can also be prescribed for elderly and multimorbid patients

T2DM is one of the components of the metabolic syndrome characterized by insulin resistance, hyperinsulinemia, dyslipidemia leading to the progression of atherosclerosis, and arterial hypertension. Patients with T2DM are mainly overweight elderly people with ischemic heart disease, hypertension, who are at risk of developing acute myocardial infarction and stroke. Hyperglycemia, as shown by the results of a meta-analysis of 20 different studies, including 95,783 patients followed for 12 years, is the same risk factor for the development of atherosclerosis and acute cardiovascular mortality as the level of total cholesterol and blood pressure [49].It is possible to reduce the risk of cardiovascular mortality by using tight glycemic control, while avoiding the risk of developing hypoglycemic conditions. In this regard, the use of glibenclamide in micronized form is the most effective and safe, as evidenced by the results of the studies presented in our review.

This fact explains the inclusion of glibenclamide in the WHO list of Vital Medicines (16th edition of the list dated March 2010.) and RF. Glibenclamide is the only member of the PSM group included in the list of Essential Medicines of the World Health Organization.

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48. Serra D., He Y.L., Bullock J., Riviere G.J., Balez S., Schwartz S., Wang Y., Ligueros-Saylan M., Jarugula V., Dole W.P. Evaluation of pharmacokinetic and pharmacodynamic interaction between the dipeptidyl peptidase IV inhibitor vildagliptin, glyburide and pioglitazone in patients with Type 2 diabetes // Int. J. Clin. Pharmacol Ther. – 2008. – No. 46. – R.349-364.

49. Coutinho M., Gerstein H.C., Wang Y. Yusuf S. The relationship between glucose and incident cardiovascular events: a metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years // Diabetes Care. – 1999 .– 22 .– P. 233-240.

Repaglinide – properties, preparation and use

Repaglinide, an antidiabetic drug, was invented in 1983.Repaglinide is an oral medication used in addition to diet and exercise to control blood sugar levels in type 2 diabetes. The mechanism of action of Repaglinide is to increase the release of insulin from the β-islet cells of the pancreas; As with other antidiabetic drugs, hypoglycemia is the main side effect. The drug is marketed by Novo Nordisk under the names Prandin in the US, GlucoNorm in Canada, Surepost in Japan, Repaglinide in Egypt by Iifi, and NovoNorm elsewhere.It is produced in Japan by Dainippon Sumitomo Pharma.

IUPAC (S) – (+) – 2-ethoxy-4- [2- (3-methyl-1- [2- (piperidin-1-yl) phenyl] butylamino) -2-oxoethyl] benzoic acid
Gross formula C 27 H 36 N 2 O 4
Molar mass 452.586 g / mol
CAS 135062-02-1
PubChem 65981
DrugBank DB00912
Bioavailable. 56% (oral)
Plasma protein binding > 98%
Metabolism Hepatic oxidation and glucuronidation (CYP3A4-mediated)
Half-life. 1 hour
Excretion Fecal (90%) and renal (8%)

Medical use

Repaglinide is an oral medication used in addition to diet and exercise to control blood sugar levels in type 2 diabetes.


Repaglinide is contraindicated in people with:

  1. Diabetic ketoacidosis
  2. Type 1 diabetes mellitus
  3. Simultaneous use with gemfibrozil
  4. With hypersensitivity to the drug or inactive ingredients

Side effects

Common side effects include:

Metabolic –

  • Hypoglycemia (31%)

Respiratory –

  • Upper respiratory tract infection (16%)
  • Sinusitis (6%)
  • Rhinitis (3%)

Gastrointestinal –

  • Nausea (5%)
  • Diarrhea (5%)
  • Constipation (3%)
  • Vomiting (3%)

Musculoskeletal system –

  • Arthralgia (6%)
  • Back pain (5%)

Others –

  • Headache (11%)
  • Paresthesias (3%)

Serious side effects include:

  • Myocardial ischemia (2%)
  • Angina (1.8%)
  • Death due to cardiovascular events (0.5%)

For special population groups

Pregnancy Category C: Safety for pregnant women has not been established. Data are limited and there is only one case, the report notes that no complications were observed with repaglinide during pregnancy.

Caution should be exercised in people with liver disease and decreased kidney function when using this drug.

Drug interactions

Repaglinide is the main substrate of CYP3A4 and should not be administered concomitantly with Gemfibrozil, Clarithromycin, or azole antifungal drugs such as Itraconazole and Ketoconazole. Taking repaglinide with one or more of these drugs will increase the plasma concentration of repaglinide and may lead to hypoglycemia. Co-administration of clopidogrel and repaglinide (a cyp2c8 inhibitor) can lead to significant decreases in blood glucose levels due to drug interactions.in fact, using these drugs together for at least one day can lead to severe hypoglycemia. Repaglinide should not be taken in combination with sulfonylureas because they have the same mechanism of action.

Mechanism of action

Repaglinide lowers blood glucose levels by stimulating the release of insulin from the beta cells of the islet of the pancreas. It does this by closing the ATP-dependent potassium channels in the beta cell membrane. This depolarizes beta cells by opening up cellular calcium channels, and as a result, calcium influx induces insulin secretion.


Absorption: Repaglinide has 56% bioavailability when absorbed from the gastrointestinal tract. Bioavailability decreases when taken with food; the maximum concentration is reduced by 20%.

Distribution: Repalglinide protein binding to albumin is more than 98%.

Metabolism: Repaglinide is metabolized primarily in the liver, in particular CYP450 2C8 and 3A4 and to a lesser extent through glucuronidation. Repaglinide metabolites are inactive and do not display hypoglycemic effects.

Excretion: Repaglinide is excreted 90% in feces and 8% in urine. 0.1% is removed unchanged in the urine. Less than 2% unchanged in feces.


The precursors of the repaglinide drug were invented at the end of 1983 in Biberach an der Rice in southern Germany.

Intellectual property

Patent protected in the United States in March 1990, which eventually became US Patents 5,216,167 (June 1993), 5,312,924 (May 1994) and 6,143,769 (November 2000).After

Repaglinide – instructions for use


Repaglinide is rapidly absorbed from the gastrointestinal tract, which is accompanied by a rapid increase in its plasma concentration. The maximum plasma concentration of repaglinide is reached within 1 hour after administration. After reaching the maximum concentration (C max ), the plasma content decreases rapidly.

There were no clinically significant differences between the pharmacokinetics of repaglinide when taken immediately before meals, 15 minutes or 30 minutes before meals, or on an empty stomach.

The pharmacokinetics of repaglinide is characterized by an average absolute bioavailability of 63% (coefficient of variation (CV) is 11%).

Clinical studies have shown high interindividual variability (60%) in plasma repaglinide concentration.

Intraindividual variability ranges from low to moderate (35%). Since titration of the repaglinide dose is performed depending on the patient’s clinical response to therapy, interindividual variability does not affect the effectiveness of therapy.


Pharmacokinetics of repaglinide is characterized by a low volume of distribution of 30 liters (in accordance with the distribution in the intracellular fluid), as well as a high degree of binding to human plasma proteins (more than 98%).


The half-life (T ½ ) is approximately one hour. Repaglinide is completely eliminated from the body within 4-6 hours. Repaglinide is completely metabolized, mainly by the CYP2C8 isoenzyme, but also, albeit to a lesser extent, by the CYP3A4 isoenzyme, and no metabolites have been identified that have a clinically significant hypoglycemic effect.

Repaglinide metabolites are excreted mainly by the intestines, while less than 2% of the drug is found unchanged in the feces. A small part (approximately 8%) of the administered dose is found in urine, mainly in the form of metabolites.

Special groups of patients

Renal failure

The pharmacokinetic parameters of repaglinide with a single dose and at equilibrium were assessed in patients with type 2 diabetes mellitus and impaired renal function of varying severity.AUC ( Area under the plasma drug concentration-time curve ) and C max were similar in patients with normal renal function and in patients with mild to moderate renal impairment (mean the values ​​were 56.7 ng / ml × h versus 57.2 ng / ml × h, and 37.5 ng / ml versus 37.7 ng / ml, respectively). In patients with severe renal impairment, increased AUC and C max values ​​(98.0 ng / ml × hour and 50.7 ng / ml, respectively) were noted, but this study revealed only a weak correlation between the concentration of repaglinide and creatinine clearance …It seems that patients with impaired renal function do not need to adjust the initial dose. However, the subsequent dose increase in patients with type 2 diabetes mellitus in combination with severe renal impairment, which requires hemodialysis, should be carried out with caution.

Liver failure

An open-label study was conducted that included a single dose of repaglinide in 12 healthy volunteers, as well as 12 patients with chronic liver disease (CKD), which was classified on the Child-Pugh scale, as well as the value of caffeine clearance.Patients with moderate or severe hepatic impairment showed higher and persistent serum concentrations of total and unbound repaglinide than in healthy volunteers (AUC in healthy volunteers = 91.6 ng / ml × h; AUC in patients with CKD = 368.9 ng / ml × hour; C max in healthy volunteers = 46.7 ng / ml, C max in patients with CKD = 105.4 ng / ml). AUC was statistically correlated with caffeine clearance. There were no differences in glucose concentration between these groups.Thus, with conventional doses of repaglinide, patients with impaired liver function will achieve higher concentrations of repaglinide and its metabolites than patients with normal liver function. Therefore, in patients with impaired liver function, repaglinide should be used with caution. The intervals between dose adjustments should also be increased in order to more accurately assess the response to therapy.

Preclinical safety data

Preclinical data based on studies of pharmacological safety, repeated dose toxicity, genotoxicity and carcinogenic potential did not reveal any danger to humans.Animal studies have shown that repaglinide is not teratogenic. Anomalies of non-teratogenic limb development were observed in embryos and newborn rats born to female rats receiving high doses of repaglinide in the last third of pregnancy and during lactation. Repaglinide has been found in animal milk.

Can hypoglycemic agents – stimulants of insulin secretion – prevent or delay the development of type 2 diabetes and its complications in individuals at increased risk of developing this disease?

Review Question

Can a group of hypoglycemic agents, so-called “insulin secretion stimulants”, prevent or delay the development of type 2 diabetes and its complications in individuals at increased risk of developing type 2 diabetes?


Insulin secretion stimulants are widely used to treat people with type 2 diabetes.Insulin secretion stimulants can be divided into two main classes of hypoglycemic agents – sulfonylurea derivatives (eg glibenclamide / glyburide, glipizide and gliclazide) and meglitinides (nateglinide and repaglinide). Insulin secretion stimulants lower blood glucose by stimulating insulin secretion in the body, thereby increasing blood insulin levels. It is believed that people with moderately high glucose levels are often at increased risk of developing type 2 diabetes (often referred to as “prediabetes”).As such, people with mildly high glucose are often advised to increase their physical activity and reduce their calorie intake (behavior changes or lifestyle interventions) to prevent type 2 diabetes. It is currently not known whether stimulants of insulin secretion should be prescribed for people with elevated blood glucose levels who do not meet the diagnostic criteria for type 2 diabetes. We wanted to find out if stimulants of insulin secretion can prevent or delay the development of type 2 diabetes in people with moderately high glucose levels.Moreover, we wanted to analyze the effect of insulin secretion stimulants on such important patient outcomes as complications of diabetes (eg, kidney and eye disease, heart attacks, strokes), death from any cause, health-related quality of life, and drug side effects.

Characteristics of research

We searched the medical literature and ongoing trials registries for randomized controlled trials of at least 12 weeks in duration comparing insulin stimulants with other antidiabetic drugs, placebo, or no intervention.Randomized controlled trials are clinical trials in which people are randomly assigned to one of two or more groups to directly compare the effects of different interventions. Participants in the studies were required to have glucose levels above normal, but below what is used to diagnose type 2 diabetes. We pooled the results of several studies to answer the question in our review. We found 6 randomized controlled trials.A total of 10,018 people took part in the tests. The duration of the interventions ranged from 6 months to 5 years.

This evidence is current to April 2016.

Main results

Several participants died after being treated with sulfonylureas. Sulfonylureas (most of the evidence was for glimepiride) did not reduce the risk of type 2 diabetes compared with placebo. None of the sulfonylurea studies reported serious side effects, nonfatal heart attacks and strokes, heart failure, health-related quality of life, and socioeconomic effects.

Only one study reported data on a meglitinide analog (nateglinide). This large study included 95% of all participants in our review. We were unable to find conclusive evidence regarding deaths from any cause, the risk of developing type 2 diabetes, or serious side effects. This study did not report health-related quality of life or socioeconomic effects.

Future research should focus on patient outcomes and, in particular, drug side effects, since we do not know for sure if “prediabetes” is just a laboratory sign or a real risk factor for type 2 diabetes, for which it is possible to influence the treatment.

Quality of evidence

All of the trials included in the review had deficiencies in their design or presentation of highlights. For individual comparisons, the number of participants was small, resulting in a high risk of random errors (accidents).

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