Usage
- This triple combination therapy is prescribed for the treatment of Type 2 diabetes mellitus in adults when diet, exercise, and dual therapies fail to achieve adequate glycemic control. It is considered a third-line treatment.
- Pharmacological Classification: Antidiabetic combination, comprising a sulfonylurea (glimepiride), a biguanide (metformin), and a thiazolidinedione (pioglitazone).
- Mechanism of Action: This combination works by targeting multiple pathways involved in glucose regulation. Glimepiride stimulates insulin release from pancreatic beta cells. Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity. Pioglitazone enhances insulin sensitivity in peripheral tissues (liver, muscle, and fat).
Alternate Names
- While there isn’t a single international nonproprietary name for this combination, it is often referred to by the names of its components.
- Brand Names: This combination is available under various brand names such as Amaryl MP, Duetact (for the glimepiride/pioglitazone component), and various generic formulations. Some examples include Triopil, Triglimiprex, Ziglim Plus, Gluconorm PG, Triblend, Zoryl MP, Metride Plus, Tridart, Piopod GM2, Tripride, Pioz MF G2, Triobimet, Pioplus, Glimy MP2 and Trigulin.
How It Works
- Pharmacodynamics: Glimepiride binds to sulfonylurea receptors on pancreatic beta cells, closing ATP-sensitive potassium channels, depolarizing the cell, and triggering insulin release. Metformin activates AMP-activated protein kinase (AMPK), leading to reduced hepatic gluconeogenesis and increased peripheral glucose uptake. Pioglitazone activates peroxisome proliferator-activated receptor gamma (PPAR-γ), increasing insulin sensitivity in peripheral tissues and reducing hepatic glucose output.
- Pharmacokinetics: Glimepiride is well-absorbed orally, extensively metabolized by the liver (primarily CYP2C9), and excreted renally. Metformin is absorbed slowly and incompletely, not metabolized, and eliminated unchanged by the kidneys. Pioglitazone is well-absorbed, extensively metabolized by the liver (CYP2C8 and CYP3A4), and excreted primarily in bile and feces, with a small amount in urine.
- Elimination Pathways: Glimepiride is eliminated primarily through renal excretion of metabolites. Metformin is excreted unchanged renally. Pioglitazone is eliminated primarily in bile and feces following hepatic metabolism.
Dosage
Standard Dosage
Adults:
- The dosage is individualized based on patient response and prior therapy.
- A common starting dose is glimepiride 1 mg + metformin 500 mg + pioglitazone 15 mg once daily with the first meal.
- The dose may be titrated upwards as needed, based on blood glucose levels and tolerability. The maximum recommended daily dose of glimepiride is typically 1-4mg, metformin generally does not exceed 2000-2550mg (IR) and Pioglitazone usually not more than 45mg. The maximum number of tablets for combined formulas may be limited (e.g. a maximum of three tablets daily of Amaryl MP).
Children:
- This combination is not recommended for children as safety and efficacy have not been established.
Special Cases:
- Elderly Patients: Start with the lowest dose and titrate cautiously due to increased risk of hypoglycemia, heart failure, and bladder cancer, especially with pioglitazone. Renal function should be assessed.
- Patients with Renal Impairment: Metformin is contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²). Dose adjustments are necessary for moderate impairment. Glimepiride dosages may need modification in patients with creatinine clearance <22mL/min.
- Patients with Hepatic Dysfunction: Use with caution, especially with glimepiride and pioglitazone, as these drugs undergo hepatic metabolism. Combined metformin and pioglitazone is not recommended for patients with hepatic impairment.
- Patients with Comorbid Conditions: Use cautiously in patients with heart failure, as pioglitazone can exacerbate this condition. Monitor closely for signs and symptoms of fluid retention. Avoid in patients with bladder cancer.
Clinical Use Cases
- The provided sources do not give specific dosage recommendations for this combination in clinical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Standard diabetes management protocols should be followed.
Dosage Adjustments
- Dose adjustments are made based on renal function, hepatic function, age, and concomitant medications. Careful titration is essential to minimize the risk of hypoglycemia.
Side Effects
Common Side Effects
- Hypoglycemia, nausea, vomiting, diarrhea, stomach pain, flatulence, changes in taste (metallic taste), headache, dizziness, joint/muscle pain, upper respiratory infections, sinus infections, sore throat, weight gain, edema and impotence.
Rare but Serious Side Effects
- Lactic acidosis (with metformin), heart failure (with pioglitazone), severe hypoglycemia, liver problems (jaundice, dark urine, upper stomach pain), bladder cancer (with pioglitazone), vision changes, severe allergic reactions and fractures.
Long-Term Effects
- Long-term use may increase the risk of bladder cancer (pioglitazone), heart failure (pioglitazone), and vitamin B12 deficiency (metformin).
Adverse Drug Reactions (ADR)
- Hypoglycemia, lactic acidosis, angioedema, hepatotoxicity, and heart failure are potential ADRs requiring immediate medical attention.
Contraindications
- Type 1 diabetes, diabetic ketoacidosis, severe heart failure, active bladder cancer, severe renal impairment (eGFR < 30 ml/min/1.73 m²), hepatic impairment (especially for the combination containing both metformin and pioglitazone), hypersensitivity to sulfonylureas, sulfonamides, or any component of the formulation.
Drug Interactions
- CYP450 Interactions: Glimepiride is metabolized by CYP2C9, pioglitazone by CYP2C8 and CYP3A4. Drugs that inhibit or induce these enzymes can alter the concentrations of these drugs.
- Concomitant use of other antidiabetic agents (insulin, other oral hypoglycemics), certain antifungals (fluconazole), some antibiotics (rifampicin), and gemfibrozil can increase the risk of hypoglycemia.
- Alcohol can increase the risk of lactic acidosis with metformin and potentiate the hypoglycemic effects.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: This combination is contraindicated during pregnancy due to potential fetal harm. Insulin is generally recommended during pregnancy.
- Breastfeeding: This combination is contraindicated during breastfeeding as the drugs can be excreted in breast milk.
Drug Profile Summary
- Mechanism of Action: See “How It Works.”
- Side Effects: Hypoglycemia, gastrointestinal disturbances, weight gain, edema, heart failure, lactic acidosis, bladder cancer.
- Contraindications: Type 1 diabetes, ketoacidosis, severe heart or liver disease, bladder cancer, severe renal impairment, pregnancy, breastfeeding.
- Drug Interactions: See “Drug Interactions.”
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: See “Dosage.”
- Monitoring Parameters: Blood glucose, HbA1c, renal function, liver enzymes, weight, signs and symptoms of heart failure, and complete blood counts (especially for long term use).
Popular Combinations
- This triple combination itself represents a common and clinically relevant combination of antidiabetic agents targeting different mechanisms of glucose regulation. It’s often prescribed after dual therapies fail to achieve glycemic control.
Precautions
- General Precautions: Monitor for signs and symptoms of hypoglycemia and lactic acidosis. Periodically assess renal and liver function, especially in elderly patients. Assess risk factors for bladder cancer before and during pioglitazone therapy.
- Specific Populations: See “Dosage - Special Cases.”
- Lifestyle Considerations: Advise patients on lifestyle modifications including diet and exercise, to help manage diabetes and optimize the effectiveness of the medication.
FAQs (Frequently Asked Questions)
A: The dosage is individualized based on the patient’s current medication, their prior response, their blood glucose levels, and the presence of comorbidities or other risk factors. Starting doses are often low, usually 1mg Glimepiride + 500mg Metformin + 15mg Pioglitazone once daily. Maximum doses for Glimepiride are usually no more than 4mg daily. Metformin generally does not exceed 2000-2550mg (IR) daily, and Pioglitazone should not exceed 45mg daily.
Q2: How should this medication be taken?
A: The tablets should be taken orally once daily with the first meal of the day. Tablets in combined formulas should not be crushed or chewed.
Q3: What are the common side effects?
A: Common side effects include hypoglycemia, gastrointestinal problems (nausea, vomiting, diarrhea), weight gain, headache, metallic taste and edema.
A: Lactic acidosis (especially with metformin), heart failure (especially with pioglitazone), severe hypoglycemia, liver dysfunction, and signs of bladder cancer.
Q5: Can this medication be used during pregnancy or breastfeeding?
A: No, this medication is contraindicated in both pregnancy and breastfeeding due to the potential risks to the fetus or neonate.
Q6: What are the contraindications for this drug?
A: Contraindications include: type 1 diabetes, diabetic ketoacidosis, severe heart failure, active bladder cancer, severe renal impairment, and hypersensitivity to sulfonylureas, sulfonamides, or any components of the formulation. Hepatic impairement is often a contraindication, particularly for medications combining pioglitazone and metformin.
Q7: What if a patient misses a dose?
A: If a dose is missed, the patient should take it as soon as they remember. However, they should not double the dose if it is close to the next scheduled dose.
Q8: How does this combination interact with alcohol?
A: Alcohol can increase the risk of lactic acidosis with metformin and can interact with all three medications to potentially increase or decrease blood glucose levels. Therefore, alcohol should be avoided or consumed with caution in patients taking this medication.
Q9: Are there any dietary recommendations while taking this drug?
A: Patients should follow a healthy diet and exercise regimen as advised by their doctor or a registered dietitian. It’s crucial to maintain regular meal times and avoid prolonged fasting to manage blood sugar levels effectively and reduce the risk of hypoglycemia.
Q10: How should this triple combination be monitored?
A: Monitor blood glucose levels regularly, along with HbA1c levels every 3-6 months. Monitor renal and liver function, especially when initiating therapy and with any dose adjustments. Monitor weight and watch for signs of heart failure. Conduct regular complete blood count monitoring if patients are using the medication long term.
