Metformin + Rosiglitazone

Usage

• Medical Conditions: Metformin + Rosiglitazone is prescribed for type 2 diabetes mellitus in adults, particularly in overweight patients who are not adequately controlled on diet and exercise or on metformin or rosiglitazone alone. It improves glycemic control as an adjunct to diet and exercise. Rosiglitazone is no longer recommended for use with both metformin and a sulfonylurea due to an increased risk of adverse effects.
• Pharmacological Classification: Antidiabetic agent; combination of a biguanide (metformin) and a thiazolidinedione (rosiglitazone).
• Mechanism of Action: Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Rosiglitazone improves insulin sensitivity primarily in adipose tissue, muscle, and the liver. It acts as a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, increasing the transcription of insulin-responsive genes involved in glucose and lipid metabolism.

Alternate Names

• No widely recognized alternate generic names.
• Brand Names: Avandamet

How It Works

• Pharmacodynamics: Metformin reduces fasting and postprandial plasma glucose levels. It does not stimulate insulin secretion and, therefore, does not cause hypoglycemia when used alone. Rosiglitazone improves insulin sensitivity, leading to decreased insulin resistance and reduced plasma glucose levels. It may also modestly improve lipid profiles by increasing HDL cholesterol and decreasing triglycerides.
• Pharmacokinetics:
  • Absorption: Both metformin and rosiglitazone are well-absorbed orally, with bioavailability around 50-60% for metformin and nearly 100% for rosiglitazone. Food may enhance the absorption of rosiglitazone but decrease the extent of metformin absorption.
  • Metabolism: Metformin is not metabolized in the liver. Rosiglitazone is extensively metabolized by the liver, primarily by CYP2C8 and to a lesser extent by CYP2C9.
  • Elimination: Metformin is excreted unchanged by the kidneys. Rosiglitazone metabolites are excreted primarily in the feces and to a lesser extent in the urine.
• Mode of Action: Metformin’s exact mechanism is not fully understood but involves activation of AMP-activated protein kinase (AMPK), leading to downstream effects on glucose and lipid metabolism. Rosiglitazone activates PPAR-γ, which increases the transcription of genes involved in glucose and lipid metabolism.
• Receptor Binding/Enzyme Inhibition: Rosiglitazone binds to and activates PPAR-γ receptors. Metformin does not bind to receptors but affects cellular metabolism through AMPK activation.
• Elimination Pathways: Metformin: Renal excretion. Rosiglitazone: Hepatic metabolism (CYP2C8, CYP2C9) with primarily fecal excretion.

Dosage

Standard Dosage

Adults:

• Initial dose: 2 mg rosiglitazone/500 mg metformin once or twice daily with meals. If HbA1c is >11% or fasting plasma glucose (FPG) >270 mg/dL, consider a starting dose of 2 mg rosiglitazone/500 mg metformin twice daily.
• Titration: Increase in increments of 2 mg rosiglitazone/500 mg metformin daily, given in divided doses if not adequately controlled after 4 weeks. Monitor for fluid retention or heart failure, renal function, blood pressure, and liver enzymes.
• Maximum dose: 8 mg rosiglitazone/2000 mg metformin per day.

Children: Use is not recommended. Safety and efficacy not established.

Special Cases:

• Elderly Patients: Initiate with a low dose and titrate cautiously due to potential age-related decreased renal function. Monitor renal function regularly.
• Patients with Renal Impairment: Contraindicated in patients with an eGFR <30 mL/min/1.73 m². Not recommended to initiate in patients with an eGFR 30-45 mL/min/1.73 m².
• Patients with Hepatic Dysfunction: Contraindicated in patients with severe hepatic impairment or active liver disease. Use with caution in patients with mild to moderate hepatic impairment. Monitor liver function tests (LFTs) closely.
• Patients with Comorbid Conditions: Not recommended in patients with symptomatic heart failure. Use with caution in patients with edema, a history of myocardial ischemia, or other cardiovascular risk factors.

Clinical Use Cases

The combination of metformin and rosiglitazone is not specifically indicated for use in acute settings like intubation, surgical procedures, mechanical ventilation, ICU care, or emergency situations.

Dosage Adjustments

• Renal Dysfunction: See above.
• Hepatic Dysfunction: See above.
• Other Factors: Adjust dosage based on individual patient response and tolerability.

Side Effects

Common Side Effects:

• Upper respiratory tract infection, headache, edema, weight gain, nausea, diarrhea, muscle aches, anemia.

Rare but Serious Side Effects:

• Lactic acidosis (metformin), congestive heart failure (rosiglitazone), myocardial infarction, liver dysfunction, severe hypoglycemia (when used with sulfonylureas or insulin).

Long-Term Effects:

• Increased risk of fractures (especially in women), vitamin B12 deficiency (metformin), macular edema (rosiglitazone).

Adverse Drug Reactions (ADR):

• Lactic acidosis (metformin), angioedema, hepatotoxicity.

Contraindications

• Type 1 diabetes mellitus, known hypersensitivity to either drug, severe renal impairment (eGFR <30 mL/min/1.73 m²), active liver disease, acute or chronic metabolic acidosis (including diabetic ketoacidosis), congestive heart failure (NYHA Class III or IV), conditions predisposing to lactic acidosis (e.g., hypoxia), concomitant use with insulin, within 48 hours of radiographic procedures using iodinated contrast media.

Drug Interactions

• Clinically Significant Interactions: Concomitant use of rosiglitazone with gemfibrozil or other CYP2C8 inhibitors may increase rosiglitazone levels, increasing the risk of side effects. Concomitant use of metformin with cationic drugs eliminated by renal tubular secretion may increase metformin levels. Alcohol, iodinated contrast media, or other nephrotoxic drugs may increase the risk of lactic acidosis with metformin. Drugs that may affect blood glucose levels (e.g., corticosteroids, thiazide diuretics) may require dosage adjustment of metformin or rosiglitazone. Concurrent use with sulfonylureas or insulin may result in hypoglycemia. Beta blockers can make it hard to recognize signs and symptoms of hypoglycemia
• CYP450 Interactions: Rosiglitazone is primarily metabolized by CYP2C8, so CYP2C8 inhibitors (e.g., gemfibrozil) increase rosiglitazone levels. CYP2C8 inducers (e.g., rifampin) decrease rosiglitazone levels.
• Other Interactions: See above. The interaction checker provided on Drugs.com can be used to review the interactions of this combination product in detail (https://www.drugs.com/interactions-check.php?drug_list=1490-0,185-0).

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (FDA); both metformin and rosiglitazone cross the placenta. Use during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• Fetal Risks/Teratogenicity: May potentially increase the risk of congenital malformations. Use of insulin is usually recommended during pregnancy
• Breastfeeding: Both metformin and rosiglitazone are excreted in animal milk. Data for human milk are limited for rosiglitazone, so it is unknown how much may pass into human breast milk. Limited data for metformin in breast milk suggest the infant dose would likely be low, although monitoring infant blood sugar has been recommended. Weigh the benefits and risks for each individual case when making a recommendation.

Drug Profile Summary

• Mechanism of Action: Metformin: Reduces hepatic glucose production, decreases intestinal glucose absorption, improves insulin sensitivity. Rosiglitazone: PPAR-γ agonist, improves insulin sensitivity.
• Side Effects: See above.
• Contraindications: See above.
• Drug Interactions: See above.
• Pregnancy & Breastfeeding: See above.
• Dosage: See above.
• Monitoring Parameters: HbA1c, fasting plasma glucose, lipid profile, renal function (eGFR), liver function tests (LFTs), weight, blood pressure, signs and symptoms of heart failure.

Popular Combinations

Rosiglitazone and metformin are combined into a single pill, Avandamet, so it was previously popular to combine them. However, as the safety profile of rosiglitazone has been called into question over the years, the combination is less commonly used today. Sometimes metformin is combined with a sulfonylurea.

Precautions

• General Precautions: Before starting Metformin + Rosiglitazone, assess renal function (eGFR), liver function (LFTs), cardiovascular risk, and symptoms of heart failure. Monitor for signs and symptoms of lactic acidosis. Evaluate the patient’s risk factors for fractures.
• Specific Populations: See above under Dosage/Special Cases and Pregnancy and Breastfeeding.
• Lifestyle Considerations: Encourage lifestyle modifications, including diet and exercise, for optimal glycemic control. Counsel patients about the importance of medication adherence and regular monitoring. Avoid excessive alcohol intake due to the increased risk of lactic acidosis with metformin. Alcohol also can add calories to the diet, which may make weight loss and blood sugar control more difficult.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Metformin + Rosiglitazone?

A: See detailed Dosage guidelines above.

Q2: What are the most serious side effects of Metformin + Rosiglitazone?

A: Lactic acidosis (metformin), congestive heart failure (rosiglitazone), myocardial infarction, severe hypoglycemia (when used with a sulfonylurea or insulin), hepatotoxicity (rare).

Q3: What are the contraindications for Metformin + Rosiglitazone?

A: See Contraindications section above.

Q4: Can Metformin + Rosiglitazone be used during pregnancy?

A: It should only be used if the potential benefit justifies the potential risk to the fetus. Insulin is usually recommended during pregnancy, with close monitoring by both the obstetrician and the endocrinologist.

Q5: How does Metformin + Rosiglitazone interact with other medications?

A: See Drug Interactions section above.

Q6: What monitoring parameters are important for patients taking Metformin + Rosiglitazone?

A: HbA1c, fasting plasma glucose, lipid profile, renal function (eGFR), liver function tests (LFTs), weight, blood pressure, and signs and symptoms of heart failure.

Q7: What should I advise patients about lifestyle modifications while taking Metformin + Rosiglitazone?

A: Emphasize the importance of diet, exercise, weight management, and smoking cessation for improving glycemic control and overall health.

Q8: Can Metformin + Rosiglitazone be used with other antidiabetic agents?

A: It can be used with a sulfonylurea but is not recommended due to an increased risk of side effects. It should not be combined with insulin due to an increased risk of heart failure.

Q9: What are the signs and symptoms of lactic acidosis?

A: Early symptoms are often nonspecific and include malaise, myalgia, respiratory distress, somnolence, and abdominal discomfort. More severe symptoms include hypotension, hypothermia, and resistant bradyarrhythmias. Lactic acidosis is a medical emergency requiring immediate discontinuation of metformin and supportive treatment.