Usage
- Glimepiride + Metformin is prescribed for type 2 diabetes mellitus as an adjunct to diet and exercise to improve glycemic control. It is particularly useful in patients not adequately controlled with metformin monotherapy or those who initially responded to glimepiride alone and require additional glycemic control.
- Pharmacological classification: Oral antihyperglycemic, Sulfonylurea (glimepiride) and Biguanide (metformin) combination.
- Mechanism of Action: Glimepiride stimulates insulin release from pancreatic beta cells, while metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity.
Alternate Names
This combination medication doesn’t have an international nonproprietary name (INN). It is known by various brand names depending on the manufacturer.
- Brand Names: Amaryl M, Amaryl M Forte, Glimitab M, Diapride Plus, and various other brand names.
How It Works
- Pharmacodynamics: Glimepiride binds to sulfonylurea receptors on pancreatic beta cells, closing ATP-sensitive potassium channels. This depolarizes the cell membrane, opening voltage-gated calcium channels. The influx of calcium triggers insulin granule exocytosis, increasing insulin secretion. Metformin primarily works by activating AMP-activated protein kinase (AMPK), which suppresses hepatic gluconeogenesis. It also enhances peripheral glucose uptake and utilization.
- Pharmacokinetics:
- Glimepiride: Rapidly and completely absorbed from the GI tract. Metabolized primarily by CYP2C9 in the liver. Excreted in urine and feces.
- Metformin: Absorbed from the small intestine. Not metabolized by the liver. Excreted unchanged in the urine.
- Mode of Action: See Pharmacodynamics.
- Receptor binding/Enzyme inhibition: Glimepiride: Sulfonylurea receptor binding; Metformin: AMPK activation.
- Elimination pathways: Glimepiride: Renal and hepatic (CYP2C9); Metformin: Renal excretion.
Dosage
Standard Dosage
Adults:
- Initial: 1 mg glimepiride / 500 mg metformin once daily with breakfast or the first main meal.
- Maintenance: Titrate dose upwards in 1 mg glimepiride/ 500 mg metformin increments every 1-2 weeks, as needed, based on glycemic control.
- Maximum: 8 mg glimepiride / 2000 mg metformin per day. (Daily doses of glimepiride > 6 mg are only more effective in a minority of patients.)
Children:
- Not recommended due to potential adverse effects on body weight and hypoglycemia.
Special Cases:
- Elderly Patients: Start with 1 mg glimepiride/500 mg metformin once daily and titrate cautiously. Monitor closely for hypoglycemia.
- Patients with Renal Impairment: Initiate cautiously with 1 mg glimepiride/500 mg metformin and titrate slowly with close monitoring. Contraindicated in moderate to severe renal impairment (GFR < 45 mL/min/1.73m²).
- Patients with Hepatic Dysfunction: Use with caution. Initiate at a low dose and titrate carefully. Not recommended in severe hepatic impairment.
- Patients with Comorbid Conditions: Individualize dosage based on specific comorbidity and patient factors.
Clinical Use Cases
The combination of glimepiride and metformin is specifically indicated for long-term management of type 2 diabetes mellitus. It is not typically used in acute settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Short-term or acute hyperglycemia in these settings is usually managed with insulin.
Dosage Adjustments:
Individualize dose adjustment based on patient-specific factors like renal function, hepatic function, age, other medications, and comorbidities.
Side Effects
Common Side Effects
- Hypoglycemia
- Nausea
- Diarrhea
- Headache
- Dizziness
- Weight gain
Rare but Serious Side Effects
- Lactic acidosis (metformin)
- Hepatic dysfunction (glimepiride)
- Hemolytic anemia (glimepiride)
- Stevens-Johnson syndrome (glimepiride)
Long-Term Effects
- Vitamin B12 deficiency (metformin)
Adverse Drug Reactions (ADR)
- Severe hypoglycemia
- Lactic acidosis
Contraindications
- Hypersensitivity to glimepiride, metformin, sulfonylureas, or sulfonamides
- Type 1 diabetes
- Diabetic ketoacidosis
- Severe renal impairment (GFR <30 mL/min)
- Acute or chronic conditions causing tissue hypoxia
- Hepatic insufficiency
- Acute alcohol intoxication
- Pregnancy
Drug Interactions
- Alcohol (increases risk of lactic acidosis with metformin)
- Cationic drugs (e.g., cimetidine) (reduce metformin clearance)
- CYP2C9 inducers/inhibitors (alter glimepiride metabolism)
- Beta-blockers (mask symptoms of hypoglycemia)
- Other antidiabetic agents (additive hypoglycemic effects)
Pregnancy and Breastfeeding
- Pregnancy: Contraindicated. Insulin is recommended for managing diabetes during pregnancy.
- Breastfeeding: Not recommended. Glimepiride is excreted in breast milk, and metformin can potentially affect the infant’s glucose metabolism. If medication is needed, insulin may be a safer option.
Drug Profile Summary
- Mechanism of Action: Glimepiride stimulates insulin secretion; metformin decreases hepatic glucose production and improves insulin sensitivity.
- Side Effects: Hypoglycemia, nausea, diarrhea, lactic acidosis (rare), hepatic dysfunction (rare).
- Contraindications: Type 1 diabetes, diabetic ketoacidosis, severe renal or hepatic impairment, pregnancy.
- Drug Interactions: Alcohol, cationic drugs, CYP2C9 inducers/inhibitors, beta-blockers.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy; not recommended while breastfeeding.
- Dosage: See above for standard dosage.
- Monitoring Parameters: Blood glucose, HbA1c, renal function (especially in the elderly), Vitamin B12 levels.
Popular Combinations
- Often used as a single combination tablet. May be combined with other antidiabetic agents (e.g., DPP-4 inhibitors, SGLT2 inhibitors, or insulin) if dual therapy is inadequate.
Precautions
- General Precautions: Renal function assessment prior to initiation and periodic monitoring.
- Specific Populations: See section on Special Cases under Dosage.
- Lifestyle Considerations: Adherence to diet and exercise is crucial for optimal glycemic control. Alcohol should be consumed in moderation due to the risk of lactic acidosis with metformin.
FAQs (Frequently Asked Questions)
A: See section on Standard Dosage above.
Q2: What are the common side effects of this combination?
A: Hypoglycemia, nausea, diarrhea, and headache.
A: Glimepiride increases insulin secretion by acting on pancreatic beta cells, while metformin decreases hepatic glucose production and improves insulin sensitivity peripherally.
Q4: Can this combination be used during pregnancy?
A: No, it’s contraindicated during pregnancy. Insulin is the preferred agent for managing diabetes in pregnant women.
Q5: What monitoring parameters are important for patients on this medication?
A: Blood glucose levels, HbA1c, renal function (especially in elderly patients), and Vitamin B12 levels.
Q6: Are there any specific precautions for elderly patients?
A: Yes, start with a lower dose and titrate cautiously due to the increased risk of hypoglycemia and reduced renal function in older adults. Close monitoring of renal function is essential.
Q7: What should I do if a patient experiences hypoglycemia?
A: For mild hypoglycemia, administer oral glucose (e.g., glucose tablets, juice). For severe hypoglycemia or if the patient is unconscious, administer glucagon or intravenous dextrose.
Q8: What is the significance of CYP2C9 interactions with Glimepiride?
A: CYP2C9 is the primary enzyme involved in glimepiride metabolism. Drugs that inhibit CYP2C9 can increase glimepiride levels and the risk of hypoglycemia, while CYP2C9 inducers can decrease glimepiride levels and reduce its efficacy.
Q9: Can this combination be used in patients with type 1 diabetes?
A: No, it is contraindicated in patients with type 1 diabetes. Glimepiride works by stimulating insulin release, and type 1 diabetes is characterized by a lack of insulin production.
