Metformin + Pioglitazone + Teneligliptin

Usage

• This triple combination therapy is prescribed for type 2 diabetes mellitus, specifically in adults whose blood sugar levels are inadequately controlled by diet, exercise, and other antidiabetic medications, either alone or in combination. It may be used as a second-line treatment following insufficient glycemic control with lifestyle changes and single antidiabetic drugs.
• Pharmacological Classification: Antidiabetic combination therapy comprising a biguanide (Metformin), a thiazolidinedione (Pioglitazone), and a dipeptidyl peptidase-4 (DPP-4) inhibitor (Teneligliptin).
• Mechanism of Action: This combination targets multiple pathways involved in glucose regulation. Metformin reduces hepatic glucose production and enhances insulin sensitivity, Pioglitazone increases insulin sensitivity in peripheral tissues, and Teneligliptin increases incretin levels which stimulate insulin secretion and decrease glucagon release.

Alternate Names

• No widely recognized alternate generic names exist for this specific triple combination.
• Several brand names may exist depending on the manufacturer and region. Examples include Teneligold-PM 500. It is crucial to confirm the active ingredients listed on the packaging.

How It Works

• Pharmacodynamics:

  • Metformin: Reduces hepatic glucose production, improves peripheral insulin sensitivity, and decreases intestinal glucose absorption.
  • Pioglitazone: Acts as a peroxisome proliferator-activated receptor gamma (PPAR-γ) agonist, increasing insulin sensitivity in liver, muscle, and adipose tissue.
  • Teneligliptin: Inhibits DPP-4, the enzyme that degrades incretin hormones. This increases levels of glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), leading to enhanced glucose-dependent insulin secretion and suppressed glucagon release.

• Pharmacokinetics:

  • Metformin: Absorbed from the gastrointestinal tract, not metabolized, and excreted renally.
  • Pioglitazone: Extensively metabolized by the liver (primarily CYP2C8 and CYP3A4) and excreted in bile and urine.
  • Teneligliptin: Rapidly absorbed, partially metabolized, and eliminated through both renal and hepatic routes.

• Mode of Action:

  • Metformin: Although the exact mechanism remains unclear, it is thought to activate AMP-activated protein kinase (AMPK), leading to decreased hepatic gluconeogenesis.
  • Pioglitazone: PPAR-γ activation modulates gene expression, enhancing insulin signaling and glucose uptake.
  • Teneligliptin: By preventing DPP-4-mediated degradation of incretins, it enhances the incretin effect, promoting insulin secretion and lowering glucagon levels.

• Elimination Pathways:

  • Metformin: Renal excretion.
  • Pioglitazone: Hepatic metabolism (CYP2C8, CYP3A4) followed by biliary and urinary excretion.
  • Teneligliptin: Both renal and hepatic elimination.

Dosage

Standard Dosage

Adults:

• Initial dose: Metformin 500mg + Pioglitazone 15mg + Teneligliptin 20mg once daily with food.
• Dosage can be titrated up based on efficacy and tolerability, up to a maximum of Metformin 2000mg + Pioglitazone 45mg + Teneligliptin 40mg per day. Individual components may be adjusted separately based on patient response and tolerability.

Children:

• Not recommended for patients under 18 years of age. Safety and efficacy have not been established.

Special Cases:

• Elderly Patients: Close monitoring of renal function and dose adjustment as needed.
• Patients with Renal Impairment: Contraindicated in moderate to severe renal impairment (eGFR < 60 mL/min/1.73 m²). Dose reduction may be required for mild renal impairment.
• Patients with Hepatic Dysfunction: Use with caution due to the risk of Pioglitazone-induced liver toxicity. Liver function tests should be monitored regularly.
• Patients with Comorbid Conditions: Use cautiously in heart failure, as Pioglitazone can cause fluid retention and exacerbate symptoms. Consider specific drug interactions and adjust doses accordingly.

Clinical Use Cases

• This combination is not specifically indicated for use in intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations.

Dosage Adjustments

• Dose adjustments should be individualized based on patient response, renal/hepatic function, and other relevant factors.

Side Effects

Common Side Effects

• Nausea, vomiting, diarrhea, abdominal pain
• Headache
• Upper respiratory tract infection
• Hypoglycemia (especially when combined with other antidiabetic agents)
• Weight gain (primarily due to Pioglitazone)

Rare but Serious Side Effects

• Lactic acidosis (Metformin)
• Liver dysfunction (Pioglitazone)
• Fluid retention and edema (Pioglitazone)
• Bladder cancer (Pioglitazone)
• Fractures (Pioglitazone)
• Pancreatitis

Long-Term Effects

• Potential for chronic complications such as worsening of renal or hepatic function, development of cardiovascular complications, and increased risk of bladder cancer with long-term Pioglitazone use.

Adverse Drug Reactions (ADR)

• Lactic acidosis, severe hypoglycemia, angioedema, and symptomatic hepatotoxicity.

Contraindications

• Hypersensitivity to any component of the combination
• Type 1 diabetes, diabetic ketoacidosis
• Severe renal impairment (eGFR < 30 mL/min/1.73 m²)
• Acute conditions affecting renal function
• History of bladder cancer, uninvestigated macroscopic hematuria
• Active or history of heart failure (NYHA Class III or IV)

Drug Interactions

• Drugs that affect glucose control (e.g., corticosteroids, thiazide diuretics)
• CYP2C8 inhibitors (e.g., gemfibrozil) and inducers (e.g., rifampin) may alter Pioglitazone metabolism
• Alcohol may increase the risk of lactic acidosis with Metformin and may affect glucose control.

Pregnancy and Breastfeeding

• Not recommended for use during pregnancy or breastfeeding. Teneligliptin and Pioglitazone can be excreted in breastmilk and may have unknown effects on the fetus or neonate. Metformin is generally considered safe during pregnancy but should be used with caution.

Drug Profile Summary

• Mechanism of Action: Metformin decreases hepatic glucose production; Pioglitazone increases insulin sensitivity; Teneligliptin enhances incretin activity.
• Side Effects: Nausea, vomiting, diarrhea, headache, hypoglycemia, weight gain, lactic acidosis, liver damage, fluid retention, bladder cancer.
• Contraindications: Hypersensitivity, type 1 diabetes, severe renal impairment, bladder cancer, heart failure NYHA Class III or IV.
• Drug Interactions: Drugs affecting glucose control, CYP2C8 inhibitors/inducers, alcohol.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: Start with Metformin 500mg + Pioglitazone 15mg + Teneligliptin 20mg once daily, titrate as needed.
• Monitoring Parameters: HbA1c, fasting and postprandial glucose, renal function tests, liver function tests, weight, signs of fluid retention.

Popular Combinations

• This triple combination itself is a popular combination used when dual therapy is not sufficient to achieve desired glycemic control.

Precautions

• General Precautions: Assess renal function, hepatic function, and cardiac status before initiation.
• Specific Populations: Avoid in pregnancy, breastfeeding, and children.
• Lifestyle Considerations: Encourage regular exercise, healthy diet, and avoidance of alcohol.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Metformin + Pioglitazone + Teneligliptin?

A: The initial dose is typically Metformin 500mg + Pioglitazone 15mg + Teneligliptin 20mg once daily with food. The dosage may be gradually titrated up based on individual patient response and tolerability, with a maximum of Metformin 2000mg + Pioglitazone 45mg + Teneligliptin 40mg daily.

Q2: What are the most common side effects?

A: Common side effects include gastrointestinal issues like nausea, diarrhea, and abdominal pain, headache, upper respiratory tract infections, hypoglycemia, and weight gain.

Q3: When is this combination contraindicated?

A: This combination is contraindicated in patients with type 1 diabetes, severe renal impairment, heart failure NYHA Class III or IV, history of bladder cancer, and hypersensitivity to any component.

Q4: How does this combination compare to other antidiabetic therapies?

A: This triple therapy offers the advantage of targeting multiple mechanisms of glucose regulation, potentially leading to more effective glycemic control compared to individual agents or dual therapies in some patients.

Q5: What patient education is essential?

A: Educate patients on lifestyle modifications (diet and exercise), regular blood glucose monitoring, potential side effects, and the importance of medication adherence.

Q6: What are the monitoring parameters for this combination?

A: Monitor HbA1c, fasting and postprandial glucose, renal and liver function, weight, and signs of fluid retention or heart failure.

Q7: Are there any specific dietary restrictions with this combination?

A: While no specific restrictions exist, patients should follow a healthy, balanced diet as recommended for diabetes management.

Q8: Can this combination be used in patients with impaired liver function?

A: Use with caution in patients with hepatic impairment. Monitor liver function tests and adjust the dosage as needed. Pioglitazone can cause liver damage, though rare, and pre-existing liver conditions require careful consideration.

Q9: What should be done if a patient misses a dose?

A: Patients should take the missed dose as soon as they remember, unless it is almost time for the next dose. Do not double the dose.

Q10: Is this combination safe during pregnancy and breastfeeding?

A: This combination is not recommended during pregnancy and breastfeeding due to potential risks to the fetus and neonate. Consult a specialist for appropriate management of diabetes during these periods.