Usage
- Metformin + Vildagliptin is prescribed for the treatment of type 2 diabetes mellitus in adults when diet, exercise, and metformin or vildagliptin alone do not adequately control blood sugar levels. It is also used as initial combination therapy in drug-naïve patients.
- Pharmacological classification: Antidiabetic agent, specifically a combination of a biguanide (metformin) and a dipeptidyl peptidase-4 (DPP-4) inhibitor (vildagliptin).
- Mechanism of action: Metformin decreases hepatic glucose production, reduces intestinal glucose absorption, and improves insulin sensitivity. Vildagliptin increases insulin release and decreases glucagon levels, primarily in a glucose-dependent manner, by inhibiting DPP-4, thereby increasing incretin levels (GLP-1 and GIP).
Alternate Names
- No widely recognized alternate names for the combination exist.
- Brand names: Galvus Met.
How It Works
- Pharmacodynamics: Metformin primarily works by suppressing hepatic glucose production. It also enhances peripheral glucose uptake and utilization. Vildagliptin, by inhibiting DPP-4, prolongs the action of incretins GLP-1 and GIP, resulting in increased glucose-dependent insulin secretion and decreased glucagon secretion. The combined effect leads to improved glycemic control.
- Pharmacokinetics:
- Absorption: Both drugs are orally administered and well-absorbed. Food may slightly delay the absorption of metformin.
- Metabolism: Vildagliptin is primarily metabolized by hydrolysis, with a small fraction undergoing CYP-mediated metabolism. Metformin is not metabolized.
- Elimination: Metformin is excreted unchanged in the urine. Vildagliptin and its metabolites are primarily eliminated through renal excretion.
- Mode of action: Metformin acts through multiple mechanisms, including activation of AMP-activated protein kinase (AMPK), inhibition of mitochondrial respiratory chain complex I, and modulation of gut microbiota. Vildagliptin selectively and reversibly inhibits DPP-4, the enzyme responsible for the degradation of incretin hormones.
- Receptor binding, enzyme inhibition, or neurotransmitter modulation: Vildagliptin selectively inhibits DPP-4. Metformin’s mechanism doesn’t primarily involve receptor binding or neurotransmitter modulation.
- Elimination pathways: Metformin is renally excreted. Vildagliptin and its metabolites are primarily excreted via the kidneys, with a minor fraction in the feces.
Dosage
Standard Dosage
Adults:
- Initial dose: 50mg/500mg or 50mg/850mg or 50 mg/1000 mg twice daily (one tablet in the morning and one in the evening).
- Maximum dose: 100 mg vildagliptin and 2000 mg metformin hydrochloride daily. The maximum daily dose of vildagliptin is 100 mg.
- Dosage adjustment may be needed based on individual response and tolerability.
Children: Not recommended for use in patients under 18 years of age due to lack of sufficient data.
Special Cases:
- Elderly Patients: Dosage should be initiated cautiously, considering renal function.
- Patients with Renal Impairment: Dosage adjustment is necessary based on estimated glomerular filtration rate (eGFR). Contraindicated in severe renal impairment (eGFR <30 ml/min).
- Patients with Hepatic Dysfunction: Contraindicated in patients with hepatic impairment or pre-treatment ALT or AST > 3x ULN.
- Patients with Comorbid Conditions: Dosage adjustments may be required for various comorbid conditions, including heart failure and other cardiovascular diseases. Close monitoring is recommended.
Clinical Use Cases Dosage recommendations for specific medical settings are not specifically defined for this combination. Dosage is adjusted according to the general principles of diabetes management in these settings, with consideration of the patient’s renal function and overall clinical status.
- Intubation
- Surgical Procedures
- Mechanical Ventilation
- Intensive Care Unit (ICU) Use
- Emergency Situations
Dosage Adjustments
- Dose modifications are necessary based on renal function, hepatic function, and potential drug interactions. Dosage individualization based on glycemic control, tolerability, and patient-specific factors is essential.
Side Effects
Common Side Effects
- Nausea, vomiting, diarrhea, abdominal pain
- Headache, dizziness, tremor
- Fatigue
- Upper respiratory tract infections
Rare but Serious Side Effects
- Lactic acidosis (especially in patients with renal impairment)
- Pancreatitis
- Hepatitis
- Angioedema
- Bullous pemphigoid
Long-Term Effects
- Vitamin B12 deficiency (with long-term metformin use)
Adverse Drug Reactions (ADR)
- Lactic acidosis
- Pancreatitis
- Hepatic dysfunction
- Angioedema
Contraindications
- Hypersensitivity to vildagliptin, metformin, or any component of the formulation.
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
- Severe renal impairment (eGFR < 30 ml/min)
- Acute conditions with the potential to alter renal function (e.g., dehydration, severe infection, shock)
- Hepatic impairment
- Congestive heart failure requiring pharmacological treatment
- Acute or chronic metabolic acidosis
- Conditions associated with hypoxia
Drug Interactions
- Cationic drugs (e.g., cimetidine) can compete with metformin for renal tubular secretion, potentially increasing metformin levels.
- Alcohol increases the risk of lactic acidosis with metformin.
- Concomitant use with iodinated contrast media can cause acute renal failure and lactic acidosis. Metformin must be discontinued before or at the time of imaging studies using such agents and restarted after 48 hours, provided renal function is stable.
- Medications that affect renal function (e.g., diuretics, NSAIDs, ACE inhibitors) should be used with caution.
- Corticosteroids, thiazides, thyroid products may reduce the hypoglycemic effect.
Pregnancy and Breastfeeding
- Vildagliptin/metformin is not recommended during pregnancy due to limited human data and potential risks to the fetus. Metformin has been shown to cross the placental barrier and studies in animals have shown excretion of both metformin and vildagliptin in milk. While the safety of metformin during breastfeeding has been established, the effects of vildagliptin in breastfeeding infants are unknown. Thus, it is generally not recommended. Insulin is often the preferred glucose-lowering agent during pregnancy and lactation.
Drug Profile Summary
- Mechanism of Action: Improves glycemic control through decreased hepatic glucose production, increased insulin secretion, and reduced glucagon secretion.
- Side Effects: Nausea, diarrhea, abdominal pain, headache, dizziness, tremor. Rare but serious side effects include lactic acidosis, pancreatitis, hepatitis.
- Contraindications: Type 1 diabetes, renal impairment, hepatic impairment, heart failure, metabolic acidosis.
- Drug Interactions: Cationic drugs, alcohol, iodinated contrast media, medications affecting renal function.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Initial: 50mg/500mg or 50mg/850mg or 50mg/1000mg twice daily. Maximum: 100mg vildagliptin/2000mg metformin daily. Adjustments based on renal function.
- Monitoring Parameters: Blood glucose, HbA1c, renal function (eGFR, creatinine), liver function tests (ALT, AST), vitamin B12 levels (with long-term metformin use).
Popular Combinations
- While Metformin + Vildagliptin is itself a combination, it can be used with other antidiabetic agents, such as insulin, sulfonylureas, or thiazolidinediones, when dual therapy is insufficient to achieve glycemic control. However, triple oral therapy with vildagliptin/metformin and a thiazolidinedione hasn’t been studied fully for safety and efficacy.
Precautions
- General Precautions: Assess renal function before initiating therapy and periodically thereafter. Monitor liver function tests before starting treatment, at three-month intervals for the first year, and periodically afterward. Evaluate for signs and symptoms of lactic acidosis. Monitor vitamin B12 levels with long-term metformin use.
- Specific Populations: Use with caution in the elderly. Avoid in pregnancy and breastfeeding. Not for pediatric use.
- Lifestyle Considerations: Patients should continue lifestyle modifications, including diet and exercise, to optimize glycemic control. Alcohol should be consumed in moderation due to the increased risk of lactic acidosis with metformin.
FAQs (Frequently Asked Questions)
A: The standard initial dose is 50mg/500mg or 50mg/850mg or 50mg/1000mg twice daily. The dose is titrated based on glycemic control, tolerability, and renal function. The maximum daily dose is 100 mg vildagliptin and 2000 mg metformin hydrochloride.
A: Common side effects include nausea, vomiting, diarrhea, abdominal pain, headache, dizziness, tremor, and fatigue.
A: It is contraindicated in patients with type 1 diabetes, severe renal impairment, hepatic dysfunction, congestive heart failure requiring pharmacological treatment, metabolic acidosis, and hypersensitivity to either drug.
A: Metformin reduces hepatic glucose production and improves insulin sensitivity. Vildagliptin increases insulin release and decreases glucagon secretion by inhibiting DPP-4, thus increasing incretin levels.
A: It’s generally not recommended. Limited human data exist on vildagliptin’s safety in pregnancy. Insulin is often preferred during pregnancy and lactation.
A: Clinically significant interactions can occur with cationic drugs, alcohol, iodinated contrast media, and medications affecting renal function.
A: Monitor blood glucose, HbA1c, renal function, liver function tests, and vitamin B12 levels (with long-term metformin use).
A: Take the missed dose as soon as remembered, unless it is almost time for the next dose. Do not double the dose.
Q9: What should be done in case of a suspected overdose?
A: Seek immediate medical attention. Lactic acidosis is a serious potential consequence of metformin overdose.
A: Yes, it can be combined with other agents, such as insulin or sulfonylureas, if dual therapy is insufficient. However, assess for potential drug interactions and adjust doses accordingly. Triple therapy with metformin, vildagliptin, and thiazolidinediones is not recommended since efficacy and safety hasn’t been established.
