Imagin

Approved Indications:

• Type 2 Diabetes Mellitus (T2DM):
  Imeglimin Hydrochloride is indicated as an adjunct to diet and exercise for improving glycemic control in adults with type 2 diabetes. It may be used:
• As monotherapy, or
• In combination with other antidiabetic agents such as:
• Metformin
• Sulfonylureas
• DPP-4 inhibitors
• SGLT2 inhibitors
• GLP-1 receptor agonists
• Insulin

Off-Label or Investigational Uses:

• Prediabetes: Studied for delaying progression to type 2 diabetes by improving insulin sensitivity.
• Type 2 Diabetes with Chronic Kidney Disease (CKD Stage 3-4): Considered safe in patients with moderate renal impairment, making it a suitable alternative to metformin in some cases.

Adult Dosage:

• Recommended dose: 1000 mg orally twice daily (total daily dose: 2000 mg)
• Tablets should be taken with meals to minimize gastrointestinal discomfort.

Pediatric Use:

• Not recommended for individuals under 18 years of age. Safety and efficacy not established.

Elderly Patients:

• No routine dose adjustment required based on age alone. Monitor renal function periodically.

Renal Impairment:

• Mild to moderate impairment (eGFR ≥30 mL/min/1.73m²): No dose adjustment required.
• Severe impairment (eGFR <30 mL/min/1.73m²): Use is not recommended due to insufficient safety data.

Hepatic Impairment:

• Use with caution. Clinical data are limited; no specific dosage recommendations exist.

Administration Route:

• Oral. Swallow tablets whole with water. Do not crush or chew.

Duration of Therapy:

• Chronic, long-term use depending on glycemic targets and patient response.

Imeglimin acts through a dual mechanism to improve glycemic control in type 2 diabetes. It enhances glucose-stimulated insulin secretion from pancreatic beta cells and improves insulin sensitivity in muscle and liver tissues. At the cellular level, Imeglimin works by optimizing mitochondrial function, reducing oxidative stress, and modulating the respiratory chain to improve ATP production. These actions collectively reduce hepatic glucose output, increase peripheral glucose uptake, and improve overall mitochondrial bioenergetics, leading to better glycemic control without increasing the risk of hypoglycemia.

• Absorption: Rapidly absorbed; peak plasma concentration occurs approximately 1–2 hours after administration.
• Bioavailability: Approximately 90%.
• Distribution: Low plasma protein binding (20–30%); widely distributed in body tissues.
• Metabolism: Minimally metabolized. Not a substrate of major CYP450 enzymes.
• Elimination: Primarily excreted unchanged via renal excretion through active tubular secretion.
• Half-life: Approximately 4.5–5 hours. No accumulation with multiple doses.

• Pregnancy:
  Not assigned an FDA pregnancy category. Animal studies have shown no fetal harm, but there are no adequate human studies. Use only if the potential benefit justifies the potential risk.
• Lactation:
  It is unknown whether Imeglimin is excreted in human breast milk. Use with caution in breastfeeding mothers. Decision should consider the benefit to the mother and potential risk to the infant.
• General Advice:
  Avoid use during pregnancy and lactation unless clearly necessary. Close medical supervision is advised.

• Primary Class: Oral Antidiabetic Agent
• Subclass: First-in-class Mitochondrial Bioenergetics Modulator
• Category: Insulin sensitizer and glucose-dependent insulin enhancer

• Known hypersensitivity to Imeglimin or any component of the formulation
• Type 1 diabetes mellitus
• Diabetic ketoacidosis
• Severe renal impairment (eGFR <30 mL/min/1.73m²)
• Severe hepatic impairment
• Pregnancy or lactation without specialist evaluation

• Lactic Acidosis Risk: Although lower than metformin, caution advised in renal impairment. Monitor renal function regularly.
• Hypoglycemia: Risk increases when used with insulin or sulfonylureas. Dose adjustment may be needed.
• Hepatic Impairment: Use with caution; insufficient clinical data available.
• Pediatric Use: Not approved for use under 18 years.
• Monitoring: Baseline and periodic assessment of renal and liver function are recommended during prolonged use.

Common Side Effects:

• Gastrointestinal: Nausea, diarrhea, abdominal pain, bloating
• Neurological: Headache, dizziness
• General: Fatigue, decreased appetite

Serious or Rare Side Effects:

• Lactic acidosis (very rare)
• Hypersensitivity reactions: rash, pruritus, or urticaria
• Liver enzyme elevations (uncommon and reversible)

Timing & Severity:

• Most side effects occur early in therapy and are mild to moderate. GI disturbances tend to resolve within 1–2 weeks. Hypoglycemia is rare unless combined with insulin or sulfonylureas.

Major Drug-Drug Interactions:

• Insulin and Sulfonylureas: Increased risk of hypoglycemia. Consider dose reduction of these agents.
• Renally Eliminated Drugs (e.g., cimetidine, probenecid): May interfere with Imeglimin’s renal clearance. Monitor closely.

CYP450 Interactions:

• Not a substrate, inducer, or inhibitor of major CYP enzymes. Low risk of CYP-mediated interactions.

Food Interactions:

• No significant interaction. Recommended to take with food to improve GI tolerability.

Alcohol:

• Excessive alcohol intake may increase the risk of lactic acidosis. Use with caution or avoid.

• Japan Approval (2021): Marketed as Twymeeg®, approved as first-in-class for type 2 diabetes.
• Ongoing Global Trials: Phase 3 studies in Europe and North America are evaluating broader use.
• Renal Safety: Emerging evidence supports its use in patients with moderate renal impairment, offering an alternative to metformin in this population.

• Storage Temperature: Store at below 30°C (86°F).
• Humidity/Light: Keep in a dry place, away from moisture and direct sunlight.
• Container: Store in original blister or bottle.
• Handling: No special reconstitution needed. Do not crush or split tablets. Keep out of reach of children.