Glimepiride + Metformin

Approved Indications:

• Type 2 Diabetes Mellitus:
• As an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus when monotherapy with either glimepiride or metformin alone does not provide adequate glycemic control.
• Useful in patients inadequately controlled on diet and exercise with a single oral hypoglycemic agent.

Off-label/Clinically Accepted Uses:

• Occasionally used early in type 2 diabetes management when dual therapy is considered appropriate.
• Sometimes combined with insulin or other antidiabetic agents for improved glycemic management.

• Adults:
• Initial dose typically combines low doses of each agent, e.g., glimepiride 1 mg plus metformin 500 mg orally twice daily with meals.
• Dose titrated based on glycemic response and tolerance, usually up to glimepiride 4 mg daily and metformin 2000 mg daily (divided doses).
• Adjustments should be made at intervals of 1–2 weeks.
• Elderly:
• Start at low doses due to increased risk of hypoglycemia and renal impairment; careful monitoring required.
• Pediatrics:
• Safety and efficacy not well established; not generally recommended.
• Renal Impairment:
• Contraindicated or used with caution depending on severity; metformin generally contraindicated if eGFR <30 mL/min/1.73m². Dose adjustment for glimepiride required.
• Hepatic Impairment:
• Use caution; metformin contraindicated in severe hepatic impairment due to risk of lactic acidosis.
• Administration Route:
• Oral tablets, usually taken with meals to reduce gastrointestinal side effects and risk of hypoglycemia.

This combination combines two complementary antihyperglycemic mechanisms:

• Glimepiride: A second-generation sulfonylurea that stimulates insulin release from pancreatic beta cells by binding to ATP-sensitive potassium channels, causing depolarization and calcium influx which triggers insulin secretion. This reduces blood glucose levels.
• Metformin: A biguanide that primarily decreases hepatic glucose production (gluconeogenesis), increases peripheral glucose uptake and utilization, and improves insulin sensitivity. It also decreases intestinal absorption of glucose, contributing to lowering blood glucose without stimulating insulin secretion.

Together, these effects enhance glycemic control through both increased insulin availability and improved insulin action.

• Glimepiride:
• Absorbed rapidly, peak plasma concentration in 2–3 hours, bioavailability nearly 100%.
• Highly protein-bound (~99.5%), metabolized mainly by CYP2C9 to inactive metabolites.
• Half-life approximately 5–9 hours; excreted via urine and feces.
• Metformin:
• Absorbed in the small intestine with bioavailability of 50–60%.
• Not metabolized; eliminated unchanged primarily by renal excretion.
• Half-life approximately 4–8.7 hours; steady-state achieved within 24–48 hours.

The combination does not significantly alter the pharmacokinetics of either drug.

• Pregnancy:
• Both drugs are FDA Category B (metformin) and C (glimepiride). Use only if benefits justify potential risks. Insulin preferred for glycemic control during pregnancy.
• Lactation:
• Both drugs are excreted in small amounts in breast milk. Caution is advised during breastfeeding.

• Primary Therapeutic Class: Antidiabetic agents
• Subclass:
• Glimepiride: Sulfonylurea (Second generation)
• Metformin: Biguanide

• Known hypersensitivity to glimepiride, metformin, or any excipients.
• Type 1 diabetes mellitus or diabetic ketoacidosis.
• Severe renal impairment (eGFR <30 mL/min/1.73 m²).
• Severe hepatic impairment or conditions predisposing to lactic acidosis.
• Acute or chronic metabolic acidosis including diabetic ketoacidosis.
• Conditions involving hypoxia or dehydration (e.g., severe infection, shock).
• Pregnancy and lactation unless benefits outweigh risks.

• Hypoglycemia: Increased risk due to sulfonylurea; more likely in elderly, renal/hepatic impairment, or with other hypoglycemics.
• Lactic Acidosis: Rare but serious risk associated with metformin, especially in renal impairment, hepatic disease, or hypoxic states.
• Renal Function: Monitor closely; metformin contraindicated or dose-adjusted according to renal function.
• Hepatic Function: Use cautiously due to risk of hypoglycemia and lactic acidosis.
• Cardiovascular Risk: Sulfonylureas may increase cardiovascular risk; monitor patients accordingly.
• Elderly: Higher susceptibility to adverse effects; cautious dosing and monitoring advised.

Common Adverse Effects:

• Hypoglycemia (due to glimepiride)
• Gastrointestinal disturbances: nausea, vomiting, diarrhea (due to metformin)
• Weight gain (glimepiride)
• Metallic taste (metformin)
• Dizziness, headache

Serious/Rare Side Effects:

• Severe hypoglycemia (life-threatening)
• Lactic acidosis (rare but potentially fatal with metformin)
• Allergic skin reactions
• Hematologic effects such as leukopenia or thrombocytopenia (rare)
• Hepatic dysfunction (rare)

• Increased hypoglycemia risk: Other antidiabetics, insulin, NSAIDs, warfarin, beta-blockers (mask hypoglycemia symptoms), sulfonamides.
• Drugs reducing efficacy: Rifampin, phenytoin, carbamazepine, corticosteroids.
• Metformin interactions: Contrast media (iodinated), alcohol (increases lactic acidosis risk).
• Enzyme systems: Glimepiride metabolized by CYP2C9; interactions with inhibitors or inducers may alter plasma levels. Metformin is not metabolized via CYP450.

• Emphasis on individualized therapy balancing efficacy and risk of hypoglycemia, especially in elderly and renal-impaired patients.
• Increasing preference for newer agents (SGLT2 inhibitors, GLP-1 receptor agonists) with better cardiovascular profiles and lower hypoglycemia risk as add-ons or alternatives.
• Continued warnings about lactic acidosis risk with metformin; renal function monitoring is standard practice.

• Store at 20°C to 25°C (68°F to 77°F).
• Protect from moisture, heat, and light.
• Keep tablets in original container tightly closed.
• Do not freeze.