Usage
Empagliflozin + Metformin is prescribed for type 2 diabetes mellitus in conjunction with diet and exercise. It improves glycemic control in adults and children 10 years and older. Additionally, it is indicated to reduce the risk of cardiovascular death in patients with type 2 diabetes and established cardiovascular disease. It is also used to lower the risk of cardiovascular death and hospitalization in patients with heart failure. It does not treat type 1 diabetes.
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Pharmacological Classification: Combination drug containing a sodium-glucose cotransporter 2 (SGLT2) inhibitor (empagliflozin) and a biguanide (metformin).
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Mechanism of Action: Empagliflozin lowers blood glucose by increasing glucose excretion through the urine. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Alternate Names
- International Nonproprietary Name (INN): Empagliflozin/Metformin Hydrochloride
- Brand Names: Synjardy, Synjardy XR, Jardiamet
How It Works
- Pharmacodynamics: Empagliflozin acts on SGLT2 in the kidneys to prevent glucose reabsorption, thus increasing urinary glucose excretion. Metformin works through multiple mechanisms to improve glycemic control without stimulating insulin secretion.
- Pharmacokinetics:
- Empagliflozin: Rapidly absorbed after oral administration. Peak plasma concentration occurs about 1.5 hours post-dose. Primarily metabolized by glucuronidation. Excreted via urine and feces.
- Metformin: Absorbed slowly and incompletely from the gastrointestinal tract. Not metabolized in the liver. Excreted unchanged primarily by the kidneys.
- Mode of Action: Empagliflozin inhibits SGLT2 in the renal proximal tubule. Metformin’s precise mechanism of action is not fully understood, but it is known to activate AMP-activated protein kinase (AMPK).
- Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Empagliflozin specifically inhibits SGLT2. Metformin does not bind to receptors but acts through intracellular pathways.
- Elimination Pathways: Empagliflozin is eliminated via renal and hepatic routes (urine and feces). Metformin undergoes renal excretion unchanged in the urine.
Dosage
Standard Dosage
Adults:
- Immediate-Release: The starting dose is typically 5 mg empagliflozin/500 mg metformin twice daily or 5 mg empagliflozin/1000 mg metformin twice daily, taken with food. The dose can be titrated up as needed and tolerated to a maximum of 12.5 mg empagliflozin/1000 mg metformin twice daily (25 mg empagliflozin/ 2000 mg metformin total daily dose).
- Extended-Release: The starting dose is typically 10 mg empagliflozin/1000 mg metformin once daily, taken with food. The dose can be titrated up to a maximum of 25 mg empagliflozin/ 2000 mg metformin once daily.
Children (10 years and older):
Dosage must be individualized based on the patient’s current regimen, effectiveness, and tolerability, not to exceed the maximum daily dosage of 25 mg empagliflozin and 2000 mg metformin. Administer twice daily with meals. Gradually escalate the dose to reduce gastrointestinal side effects.
Special Cases:
- Elderly Patients: Begin with a lower dose and titrate cautiously due to age-related decline in renal function and increased risk of volume depletion.
- Patients with Renal Impairment: Contraindicated in patients with moderate to severe renal impairment (eGFR < 45 mL/min/1.73 m²). Use with caution in mild renal impairment. Dose adjustments or discontinuation may be necessary.
- Patients with Hepatic Dysfunction: Use with caution as metformin accumulation can occur. Empagliflozin is primarily metabolized by glucuronidation, so hepatic impairment may not significantly affect its pharmacokinetics, but close monitoring is still recommended.
- Patients with Comorbid Conditions: Careful assessment and dose adjustments are necessary for patients with heart failure, recent myocardial infarction, or other conditions that may predispose to volume depletion or lactic acidosis.
Clinical Use Cases
The use of empagliflozin + metformin in specific medical settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations should be determined on a case-by-case basis, taking into consideration patient-specific factors and potential risks and benefits. Dose adjustments or temporary discontinuation may be necessary depending on the clinical situation and renal function.
Dosage Adjustments
Dose adjustments are necessary based on renal function, tolerability, and glycemic control. Temporarily discontinue before procedures involving iodinated contrast media.
Side Effects
Common Side Effects
- Urinary tract infections (UTIs)
- Genital mycotic infections (yeast infections)
- Diarrhea, nausea, vomiting, flatulence
- Increased urination
- Headache
- Fatigue
Rare but Serious Side Effects
- Diabetic ketoacidosis (DKA)
- Lactic acidosis (especially in patients with renal impairment)
- Hypoglycemia (low blood sugar) with concomitant use of insulin or insulin secretagogues
- Acute kidney injury
- Serious hypersensitivity reactions (e.g., angioedema)
- Volume depletion
Long-Term Effects
- Vitamin B12 deficiency (with metformin)
- Increased Low-Density Lipoprotein Cholesterol (LDL-C) (with empagliflozin)
Adverse Drug Reactions (ADR)
- Angioedema
- Severe hypoglycemia
- Lactic acidosis
Contraindications
- Hypersensitivity to empagliflozin or metformin
- Type 1 diabetes
- Severe renal impairment (eGFR <30 mL/min/1.73 m²) or end-stage renal disease
- Diabetic ketoacidosis
- Acute or chronic metabolic acidosis
- Conditions that may predispose to lactic acidosis (e.g., severe infection, dehydration, shock, acute heart failure)
Drug Interactions
- Diuretics: May increase the risk of volume depletion.
- Insulin or Insulin Secretagogues: May increase the risk of hypoglycemia.
- Cationic Drugs (e.g., cimetidine): May increase metformin exposure and risk of lactic acidosis.
- Alcohol: May increase the risk of lactic acidosis.
- Iodinated Contrast Media: May cause acute kidney injury and should be temporarily discontinued before or at the time of the procedure.
Pregnancy and Breastfeeding
- Pregnancy: Not recommended during the second and third trimesters. Insufficient data during the first trimester. Insulin is recommended to manage diabetes during pregnancy.
- Breastfeeding: Metformin is excreted in breast milk. Empagliflozin may also be excreted. Not recommended during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Empagliflozin inhibits SGLT2, increasing urinary glucose excretion. Metformin reduces hepatic glucose production, decreases intestinal glucose absorption, and improves insulin sensitivity.
- Side Effects: UTIs, genital mycotic infections, diarrhea, nausea, increased urination, headache, fatigue. Rarely: DKA, lactic acidosis, hypoglycemia, acute kidney injury, hypersensitivity reactions.
- Contraindications: Hypersensitivity, type 1 diabetes, severe renal impairment, DKA, metabolic acidosis.
- Drug Interactions: Diuretics, insulin, cationic drugs, alcohol, iodinated contrast media.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Individualized based on patient factors and formulation. See dosage section for details.
- Monitoring Parameters: Renal function (eGFR), blood glucose, HbA1c, electrolytes, lipid panel, vitamin B12.
Popular Combinations
Empagliflozin + Metformin is often combined with other antidiabetic agents, such as:
- Sulfonylureas (e.g., glipizide): Provides additional glucose-lowering effects by stimulating insulin secretion.
- DPP-4 inhibitors (e.g., linagliptin): Increases incretin levels, which enhance insulin secretion and suppress glucagon secretion.
- Insulin: Provides exogenous insulin for patients not adequately controlled with oral medications.
Precautions
- General Precautions: Assess renal function before and during treatment. Monitor for signs and symptoms of UTIs, genital mycotic infections, and volume depletion. Educate patients about the risk of DKA and lactic acidosis.
- Pregnant Women: Not recommended during the second and third trimesters.
- Breastfeeding Mothers: Not recommended.
- Children & Elderly: Use with caution. Dose adjustments based on renal function and other factors are necessary.
- Lifestyle Considerations: Encourage diet and exercise. Advise patients to limit alcohol intake.
FAQs (Frequently Asked Questions)
A: See detailed dosage guidelines above in the “Dosage” section, as it varies based on formulation, renal function, tolerability, and other factors.
A: Take with food to reduce gastrointestinal side effects. The immediate-release formulation is typically taken twice daily, while the extended-release formulation is taken once daily.
Q3: What are the most common side effects?
A: The most common side effects are UTIs, genital mycotic infections, diarrhea, nausea, increased urination, headache, and fatigue.
A: Contraindicated in patients with type 1 diabetes, severe renal impairment, DKA, or metabolic acidosis.
Q5: What are the signs of lactic acidosis?
A: Lactic acidosis is a rare but serious side effect. Symptoms include muscle pain or cramps, stomach pain, unusual sleepiness, trouble breathing, feeling cold, dizziness, and weakness. Seek immediate medical attention if these symptoms occur.
A: It is generally not recommended during the second and third trimesters. Consult a healthcare professional for guidance.
Q7: Can this medication be used with other diabetes medications?
A: Yes, it can be combined with other antidiabetic agents such as sulfonylureas, DPP-4 inhibitors, and insulin.
Q8: What should patients be monitored for during treatment?
A: Renal function (eGFR), blood glucose levels, HbA1c, signs and symptoms of UTIs and genital infections, volume status, and electrolytes should be monitored regularly. Vitamin B12 levels may need to be checked periodically, especially in patients at risk of deficiency.
Q9: What should I do if a dose is missed?
A: If a dose is missed, take it as soon as remembered. However, if it is close to the time for the next dose, skip the missed dose and take the next dose at the regular time. Do not double the dose.
Q10: What precautions are necessary regarding alcohol consumption?
A: Patients should limit alcohol intake while taking Empagliflozin + Metformin as alcohol can increase the risk of lactic acidosis, particularly in patients with risk factors such as renal impairment.
