Metformin + Sitagliptin

Usage

• Metformin + Sitagliptin is prescribed for type 2 diabetes mellitus in adults. It is used as an adjunct to diet and exercise to improve glycemic control when metformin alone or sitagliptin alone does not provide adequate glycemic control. It is not indicated for type 1 diabetes or diabetic ketoacidosis.
• Pharmacological Classification: Antidiabetic combination; Biguanide (Metformin) and Dipeptidyl Peptidase-4 (DPP-4) inhibitor (Sitagliptin).
• Mechanism of Action: Metformin decreases hepatic glucose production and intestinal glucose absorption and improves insulin sensitivity. Sitagliptin increases incretin levels, which in turn increase insulin secretion and decrease glucagon secretion.

Alternate Names

• Sitagliptin Phosphate/Metformin Hydrochloride
• Brand Names: Janumet, Janumet XR, Zituvimet, Zituvimet XR

How It Works

• Pharmacodynamics: Metformin reduces hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity (peripheral glucose uptake and utilization). Sitagliptin inhibits the DPP-4 enzyme, which prolongs the action of incretin hormones (like GLP-1 and GIP). These hormones increase insulin release and suppress glucagon secretion, particularly after meals.
• Pharmacokinetics:
  • Metformin: Absorbed from the gastrointestinal tract, not metabolized, and excreted primarily by the kidneys.
  • Sitagliptin: Absorbed from the gastrointestinal tract, primarily metabolized by CYP3A4 with minor contribution by CYP2C8, and eliminated primarily through renal excretion.
• Mode of Action: Metformin’s precise mechanism is not fully understood, but it involves activation of AMP-activated protein kinase (AMPK). Sitagliptin’s mode of action involves competitive and reversible inhibition of DPP-4, preventing the inactivation of incretin hormones.
• Receptor binding, enzyme inhibition, or neurotransmitter modulation: Metformin activates AMPK. Sitagliptin inhibits DPP-4.
• Elimination pathways: Metformin is renally excreted. Sitagliptin undergoes some hepatic metabolism via CYP3A4 (primarily) and CYP2C8 (minor), with primarily renal elimination of the parent compound and metabolites.

Dosage

Standard Dosage

Adults:

• Immediate-release:
  • For patients not currently on Metformin: Initial dose is 50 mg Sitagliptin/500 mg Metformin twice daily.
  • For patients currently on Metformin: Initial dose is 50 mg Sitagliptin twice daily plus the current Metformin dose. For patients already taking 850 mg Metformin twice daily, the starting dose is 50 mg Sitagliptin/1000 mg Metformin twice daily.
• Extended-release:
  • For patients not currently on Metformin: Initial dose is 100 mg Sitagliptin/1000 mg Metformin once daily.
  • For patients currently on Metformin: Initial dose is 100 mg Sitagliptin once daily plus the current Metformin dose. For patients currently on 850 mg or 1000 mg Metformin twice daily, initial dose is 100 mg Sitagliptin/1000 mg Metformin HCl once daily.
• The maximum daily dose is 100 mg Sitagliptin and 2000 mg Metformin.

Children:

• Not recommended for use in children under 18.

Special Cases:

• Elderly Patients: Dose adjustment may be required based on renal function.
• Patients with Renal Impairment: Use with caution; contraindicated in patients with eGFR <30 mL/min/1.73 m². Dose reduction is required for moderate renal impairment (eGFR 30-45 mL/min/1.73 m²).
• Patients with Hepatic Dysfunction: Not recommended.
• Patients with Comorbid Conditions: Use with caution in CHF patients and those at risk of lactic acidosis.

Clinical Use Cases The listed clinical scenarios are generally not applicable for the use of Metformin + Sitagliptin. This medication is used for the long-term management of type 2 diabetes. The use in emergency or acute care situations is not relevant.

Dosage Adjustments Dosage adjustments are based on renal function, as described in the Special Cases section.

Side Effects

Common Side Effects

• Nausea, vomiting, diarrhea, flatulence, abdominal discomfort
• Headache
• Upper respiratory tract infection
• Metallic taste
• Peripheral edema
• Vitamin B12 deficiency (long-term use)

Rare but Serious Side Effects

• Lactic acidosis (Metformin)
• Pancreatitis (Sitagliptin)
• Bullous pemphigoid
• Hypoglycemia
• Severe hypersensitivity reactions (e.g., angioedema, anaphylaxis)

Long-Term Effects

• Vitamin B12 deficiency

Adverse Drug Reactions (ADR)

• Lactic acidosis
• Pancreatitis
• Bullous pemphigoid
• Severe hypersensitivity reactions (e.g., angioedema, anaphylaxis)

Contraindications

• Hypersensitivity to sitagliptin or metformin.
• Severe renal impairment (eGFR < 30 mL/min/1.73 m²).
• Acute or chronic metabolic acidosis, including diabetic ketoacidosis.
• Conditions that predispose to tissue hypoxia or may acutely alter renal function (e.g., dehydration, severe infection, shock, acute or chronic heart failure).

Drug Interactions

• Sulfonylureas and Insulin: Increased risk of hypoglycemia.
• Carbonic Anhydrase Inhibitors (e.g., topiramate): Increased risk of lactic acidosis.
• Cationic Drugs: Increased Metformin levels (e.g., cimetidine, ranolazine, vandetanib, dolutegravir)
• Alcohol: Increases risk of lactic acidosis.

Pregnancy and Breastfeeding

• Pregnancy: Not recommended during pregnancy.
• Breastfeeding: Not recommended during breastfeeding.

Drug Profile Summary

• Mechanism of Action: Metformin reduces hepatic glucose production and intestinal absorption; enhances insulin sensitivity. Sitagliptin enhances incretin activity by inhibiting DPP-4.
• Side Effects: Nausea, vomiting, diarrhea, headache, upper respiratory infection, lactic acidosis (rare), pancreatitis (rare).
• Contraindications: Renal impairment, metabolic acidosis, hypersensitivity.
• Drug Interactions: Sulfonylureas, insulin, carbonic anhydrase inhibitors, cationic drugs.
• Pregnancy & Breastfeeding: Not recommended.
• Dosage: See detailed dosage guidelines above.
• Monitoring Parameters: HbA1c, fasting plasma glucose, renal function, vitamin B12 levels.

Popular Combinations

• Often combined with other antidiabetic agents like sulfonylureas, thiazolidinediones, or insulin when dual therapy is insufficient.

Precautions

• Renal function monitoring is essential.
• Patients at increased risk for lactic acidosis should be carefully monitored.
• Patients should be educated on signs and symptoms of hypoglycemia and lactic acidosis.
• Alcohol should be avoided.

FAQs (Frequently Asked Questions)

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

A: See the detailed dosage guidelines above.

Q2: What are the common side effects?

A: Common side effects include gastrointestinal issues like nausea, vomiting, and diarrhea, as well as headache and upper respiratory tract infections.

Q3: What are the serious side effects?

A: Rare but serious side effects include lactic acidosis and pancreatitis.

Q4: Can this medicine be used during pregnancy?

A: It is generally not recommended during pregnancy.

Q5: Can this medicine be used during breastfeeding?

A: It is generally not recommended during breastfeeding.

Q6: What should I do if a patient develops lactic acidosis?

A: Stop the medication immediately and provide supportive care. Lactic acidosis is a medical emergency.

Q7: How does Metformin + Sitagliptin differ from other antidiabetic medications?

A: It combines two different mechanisms of action to control blood sugar, offering synergistic effects.

Q8: What monitoring parameters are important?

A: Regularly monitor HbA1c, fasting blood glucose, renal function, and vitamin B12 levels.

Q9: What is the mechanism of action of Metformin?

A: Metformin decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity.

Q10: What is the mechanism of action of Sitagliptin?

A: Sitagliptin inhibits DPP-4, which prolongs the action of incretin hormones, increasing insulin secretion and decreasing glucagon secretion.