Imeglimin

Usage

• Imeglimin is prescribed for Type 2 Diabetes Mellitus as an adjunct to diet and exercise. It can be used as monotherapy or in combination with other antidiabetic medications, including insulin.
• Pharmacological Classification: Antidiabetic agent; Glimin (a novel class of glucose-lowering agents).
• Mechanism of Action: Imeglimin has a multimodal mechanism of action targeting mitochondrial bioenergetics. It enhances glucose-stimulated insulin secretion, improves insulin action (including reduction of hepatic glucose output and improvement in insulin signaling in liver and skeletal muscle), and decreases oxidative stress.

Alternate Names

• Imeglimin Hydrochloride
• Brand Names: Twymeeg, Zuglimin, Imegli, Imeg CKD

How It Works

• Pharmacodynamics: Imeglimin improves glycemic control by increasing glucose-stimulated insulin secretion (GSIS), improving insulin sensitivity in peripheral tissues, and inhibiting hepatic gluconeogenesis. It achieves these effects by improving mitochondrial function. It may also preserve β-cell mass. Imeglimin is glucose-dependent, minimizing the risk of hypoglycemia.

• Pharmacokinetics:

  • Absorption: Intermediate intestinal permeability with both active transport and passive paracellular absorption. Absorption can decrease with increasing doses, likely due to saturation of active transport. Bioavailability is estimated between 50-80%. Food may improve absorption.
  • Distribution: Rapid and wide distribution to internal organs, with low plasma protein binding.
  • Metabolism: Primarily excreted unchanged in the urine, with minimal hepatic metabolism. Does not inhibit or induce CYP450 enzymes.
  • Elimination: Primarily renal excretion, with minimal hepatic involvement. It is a substrate of OCT1, OCT2, MATE1, and MATE2-K transporters, and an inhibitor of OCT1, OCT2, and MATE1. However, no clinically significant drug-drug interactions are seen with substrates or inhibitors of these transporters.

• Mode of Action: Imeglimin targets mitochondrial dysfunction, a key factor in the pathogenesis of Type 2 diabetes. It acts by:

  • Increasing glucose-stimulated ATP generation.
  • Increasing the synthesis of nicotinamide adenine dinucleotide (NAD+) via the salvage pathway, which enhances GSIS and decreases oxidative stress.
  • Preventing mitochondrial permeability transition pore opening, which may protect against cell death.

Dosage

Standard Dosage

Adults:

• 1000 mg orally twice daily (with morning and evening meals). Starting dose can be 500 mg twice daily.

Children:

• Not recommended for use in patients under 18 years of age.

Special Cases:

• Elderly Patients: Start with a lower dose and titrate upwards based on tolerability and efficacy. Monitor renal function closely.
• Patients with Renal Impairment: Dose adjustment is required. For patients with an eGFR between 15-45 mL/min/1.73m², the recommended dose is 500 mg twice daily. Use is not recommended for patients with an eGFR <15 mL/min/1.73m².
• Patients with Hepatic Dysfunction: Use with caution, as imeglimin’s blood concentration may increase. Clinical trials have not been conducted in patients with severe hepatic dysfunction (Child-Pugh C).
• Patients with Comorbid Conditions: Use with caution in patients with heart failure. Close monitoring is advised.

Clinical Use Cases

• Imeglimin’s usage is specifically indicated for type 2 diabetes management in conjunction with diet and exercise. It is not currently indicated for acute settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.

Dosage Adjustments

Adjustments are based on renal function and individual patient response.

Side Effects

Common Side Effects

• Nausea
• Vomiting
• Diarrhea
• Constipation
• Abdominal pain
• Headache

Rare but Serious Side Effects

• Hypoglycemia (especially when combined with insulin or other antidiabetic drugs)
• Vitamin B12 deficiency
• Lactic acidosis (although risk is considered lower than with metformin)

Long-Term Effects

Long-term effects are still being investigated, but vitamin B12 deficiency may develop with chronic use.

Adverse Drug Reactions (ADR)

• Severe hypoglycemia
• Lactic acidosis
• Allergic reactions (rash, itching)

Contraindications

• Hypersensitivity to imeglimin or any of its components.
• Type 1 diabetes
• Diabetic ketoacidosis
• Severe ketosis, diabetic coma, or pre-coma
• Severe renal impairment (eGFR <15 mL/min/1.73m²)
• Severe hepatic dysfunction (Child-Pugh C)
• Pregnancy and breastfeeding
• Perioperative period, severe trauma, or severe infection

Drug Interactions

• Other Antidiabetic Drugs: Increased risk of hypoglycemia when combined with insulin, sulfonylureas, or glinides.
• Drugs Affecting Renal Function: NSAIDs, certain antibiotics, diuretics, and cimetidine can alter imeglimin clearance.
• Alcohol: Increases the risk of lactic acidosis and hypoglycemia.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: Contraindicated. Animal studies show potential fetal harm.
• Breastfeeding: Contraindicated. Imeglimin is excreted in breast milk.

Drug Profile Summary

• Mechanism of Action: Improves mitochondrial function, enhancing GSIS, improving insulin action, and decreasing oxidative stress.
• Side Effects: Nausea, vomiting, diarrhea, constipation, abdominal pain, headache. Rarely, hypoglycemia, vitamin B12 deficiency, and lactic acidosis.
• Contraindications: Hypersensitivity, Type 1 diabetes, diabetic ketoacidosis, severe renal/hepatic impairment, pregnancy, breastfeeding.
• Drug Interactions: Insulin, sulfonylureas, glinides, drugs affecting renal function, alcohol.
• Pregnancy & Breastfeeding: Contraindicated.
• Dosage: 1000 mg twice daily (with meals). Adjust for renal impairment.
• Monitoring Parameters: HbA1c, fasting blood glucose, renal function (eGFR), vitamin B12 levels.

Popular Combinations

• Metformin
• DPP-4 inhibitors
• SGLT2 inhibitors
• Insulin
• Glinides

Precautions

• Monitor renal function, especially in elderly patients and those with renal impairment.
• Monitor vitamin B12 levels.
• Educate patients about signs and symptoms of hypoglycemia and lactic acidosis.
• Advise patients to avoid excessive alcohol intake.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Imeglimin?

A: The standard adult dosage is 1000 mg twice daily, taken orally with meals. Dose adjustment is needed for renal impairment.

Q2: How does Imeglimin differ from other antidiabetic drugs?

A: Imeglimin has a unique mechanism of action targeting mitochondrial dysfunction. It improves both insulin secretion and insulin action, with a lower risk of hypoglycemia compared to some other agents.

Q3: What are the most common side effects of Imeglimin?

A: Gastrointestinal side effects like nausea, vomiting, diarrhea, and constipation are common.

Q4: Is Imeglimin safe for patients with kidney disease?

A: Imeglimin requires dose adjustment for patients with renal impairment. It is contraindicated in severe renal impairment (eGFR <15 mL/min/1.73m²). Regular monitoring of renal function is necessary.

Q5: Can Imeglimin be used during pregnancy or breastfeeding?

A: No, Imeglimin is contraindicated during pregnancy and breastfeeding due to potential risks to the fetus/infant.

Q6: Does Imeglimin interact with other medications?

A: Yes, Imeglimin can interact with insulin, sulfonylureas, glinides, drugs affecting renal function (like NSAIDs and some antibiotics), and alcohol.

Q7: How should Imeglimin be taken?

A: Imeglimin should be taken orally twice daily, with morning and evening meals, to improve absorption and minimize gastrointestinal side effects.

Q8: What should I do if I miss a dose of Imeglimin?

A: Take the missed dose as soon as possible. If it’s close to the next dose, skip the missed dose and resume your regular schedule. Do not double the dose.

Q9: Can Imeglimin cause hypoglycemia?

A: Yes, although the risk is lower compared to some other antidiabetic drugs, hypoglycemia can occur, especially when combined with insulin or other glucose-lowering medications.

Q10: What are the long-term safety concerns associated with Imeglimin?

A: One potential long-term side effect is vitamin B12 deficiency. Regular monitoring of B12 levels is recommended.