Usage
- Empagliflozin + Linagliptin is prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is specifically indicated for patients who are inadequately controlled on metformin and/or a sulfonylurea, and one of the individual components (empagliflozin or linagliptin). It is also indicated for patients already treated with a free combination of empagliflozin and linagliptin. Empagliflozin is also indicated to reduce the risk of cardiovascular death in adults with type 2 diabetes and established cardiovascular disease, however, the fixed combination has not been evaluated for this purpose.
- Pharmacological Classification: Combination antidiabetic agent; Sodium-Glucose Co-Transporter-2 (SGLT2) inhibitor + Dipeptidyl Peptidase-4 (DPP-4) inhibitor
- Mechanism of Action: Empagliflozin inhibits SGLT2 in the kidneys, reducing glucose reabsorption and increasing urinary glucose excretion. Linagliptin inhibits DPP-4, increasing incretin levels (GLP-1 and GIP), which enhance insulin secretion and suppress glucagon secretion, improving glycemic control.
Alternate Names
- International Nonproprietary Name (INN): Empagliflozin/Linagliptin
- Brand Names: Glyxambi
How It Works
- Pharmacodynamics: Empagliflozin lowers blood glucose levels by increasing urinary glucose excretion. Linagliptin enhances glucose-dependent insulin secretion and suppresses glucagon secretion, improving glycemic control. The combination has synergistic effects in improving glycemic parameters. Empagliflozin may also promote weight loss due to calorie loss through urinary glucose excretion.
- Pharmacokinetics:
- Absorption: Both drugs are orally administered and absorbed in the gastrointestinal tract. Food does not significantly impact the pharmacokinetics of either drug.
- Metabolism: Empagliflozin primarily undergoes glucuronidation via UGT enzymes, with minor metabolism via CYP3A4. Linagliptin undergoes metabolism primarily via CYP3A4, but it is also a weak inhibitor and substrate of P-glycoprotein (P-gp).
- Elimination: Empagliflozin is primarily eliminated renally, with some fecal excretion. Linagliptin is primarily eliminated via the biliary/fecal route, with a minor component of renal elimination.
- Mode of Action:
- Empagliflozin: Inhibits SGLT2 in the renal proximal tubules, reducing glucose reabsorption from the glomerular filtrate.
- Linagliptin: Inhibits DPP-4 enzyme, preventing degradation of incretin hormones GLP-1 and GIP.
- Receptor Binding: Empagliflozin targets SGLT2. Linagliptin targets DPP-4.
- Elimination Pathways: Empagliflozin predominantly via renal excretion; Linagliptin predominantly via hepatic/biliary excretion with some renal elimination.
Dosage
Standard Dosage
Adults:
- Initial dose: 10 mg empagliflozin/5 mg linagliptin orally once daily in the morning.
- For patients tolerating the initial dose and requiring additional glycemic control: May be increased to 25 mg empagliflozin/5 mg linagliptin once daily.
Children: Safety and efficacy not established in pediatric patients. Not recommended for use in patients under 18 years of age.
Special Cases:
- Elderly Patients: No dose adjustment based on age alone. However, consider more frequent renal function monitoring and careful attention to hydration status, particularly in patients ≥75 years of age due to increased risk of volume depletion. Glyxambi is not recommended in patients 75 years and older.
- Patients with Renal Impairment: No dose adjustment required for eGFR ≥ 30 mL/min/1.73 m2. Not recommended for patients with eGFR < 30 mL/min/1.73 m2 or end-stage renal disease.
- Patients with Hepatic Dysfunction: No dose adjustment necessary.
- Patients with Comorbid Conditions: Consider lower doses of insulin or sulfonylureas when Glyxambi is added to these therapies to reduce the risk of hypoglycemia. Monitor patients with a history of hypotension or volume depletion for worsening of these conditions.
Clinical Use Cases
- Dosage recommendations for the specified clinical settings have not been established for empagliflozin/linagliptin. Glyxambi is approved for the treatment of type 2 diabetes mellitus, in conjunction with diet and exercise, not for the conditions listed.
Dosage Adjustments
- Dosage adjustments may be needed based on renal function (see above). Consider holding therapy in settings of reduced oral intake or fluid loss.
Side Effects
Common Side Effects
- Urinary tract infection
- Nasopharyngitis (common cold)
- Upper respiratory tract infection
- Genital mycotic infections
- Increased urination
- Joint pain
- Nausea
- Runny or stuffy nose
- Diarrhea
- Cough
- Elevated blood cholesterol
Rare but Serious Side Effects
- Diabetic ketoacidosis (primarily in patients with type 1 diabetes)
- Pancreatitis
- Severe hypersensitivity reactions (angioedema, anaphylaxis)
- Serious urinary tract infections (pyelonephritis, urosepsis)
- Volume depletion
- Hypoglycemia (when used with insulin or sulfonylureas)
- Acute kidney injury
Long-Term Effects
- Potential for bone fractures has been observed with SGLT2 inhibitors, although this has not been specifically established with empagliflozin/linagliptin.
- Chronic kidney disease progression might be observed in patients with pre-existing renal impairment.
Adverse Drug Reactions (ADR)
- Angioedema
- Anaphylaxis
- Severe hypoglycemia
- Acute pancreatitis
- Stevens-Johnson syndrome (rare)
Contraindications
- Severe renal impairment (eGFR < 30 mL/min/1.73 m2), end-stage renal disease, or patients on dialysis
- History of hypersensitivity to empagliflozin, linagliptin, other SGLT2 inhibitors, other DPP-4 inhibitors, or any component of the formulation
- Type 1 diabetes mellitus
- Diabetic ketoacidosis
Drug Interactions
- Insulin or Sulfonylureas: Increased risk of hypoglycemia; dosage reductions may be required.
- Diuretics: May enhance the risk of volume depletion; monitor closely.
- Lithium: Empagliflozin may decrease serum lithium concentrations.
- Inducers of P-gp (e.g., rifampin) or CYP3A4 (e.g., rifampin, phenytoin, carbamazepine): May reduce the efficacy of linagliptin.
- Alcohol: May increase the risk of hypoglycemia and potentially diabetic ketoacidosis.
Pregnancy and Breastfeeding
- Pregnancy: Not recommended during the second and third trimesters due to potential adverse renal effects on the fetus observed in animal studies with empagliflozin. Use only if the potential benefit outweighs the potential risk to the fetus.
- Breastfeeding: Not recommended while breastfeeding due to the potential for infant exposure. The drug is excreted in animal milk. Limited human data.
Drug Profile Summary
- Mechanism of Action: SGLT2 inhibitor and DPP-4 inhibitor; reduces glucose reabsorption in the kidneys, increases glucose-dependent insulin release, and suppresses glucagon secretion.
- Side Effects: Urinary tract infections, nasopharyngitis, upper respiratory infections, genital mycotic infections, increased urination, hypercholesterolemia, and joint pain. Rare but serious side effects: DKA, pancreatitis, hypersensitivity, volume depletion.
- Contraindications: Severe renal impairment, ESRD, dialysis, type 1 diabetes, hypersensitivity.
- Drug Interactions: Insulin/sulfonylureas (hypoglycemia risk), diuretics (volume depletion), lithium (decreased levels), P-gp/CYP3A4 inducers (reduced linagliptin efficacy).
- Pregnancy & Breastfeeding: Not recommended during the second/third trimesters of pregnancy or during breastfeeding.
- Dosage: Adults: 10/5 mg once daily, may increase to 25/5 mg once daily. Not recommended for pediatric patients.
- Monitoring Parameters: Blood glucose, A1c, renal function (eGFR, creatinine), blood pressure, electrolytes (especially in patients at risk of volume depletion), signs/symptoms of urinary or genital infection, lipid profile.
Popular Combinations
- Metformin: Commonly used in combination with Glyxambi to further improve glycemic control.
Precautions
- General Precautions: Assess renal function prior to initiating and periodically thereafter. Monitor for signs and symptoms of volume depletion, especially in elderly patients and those on diuretics. Patients should maintain adequate hydration. Monitor for signs of urinary and genital infections. Screen for and manage cardiovascular risk factors.
- Specific Populations: See Dosage section for details regarding pregnant women, breastfeeding mothers, children, and the elderly.
- Lifestyle Considerations: Encourage patients to follow a healthy diet and exercise regularly. Caution patients about the risk of hypoglycemia when combined with insulin or sulfonylureas. Advise patients about the risk of volume depletion, especially during exercise or in hot weather. Limit alcohol intake.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Empagliflozin + Linagliptin?
A: The recommended starting dose is 10 mg empagliflozin/5 mg linagliptin once daily, taken in the morning. It can be increased to 25/5 mg once daily if needed.
Q2: Can Glyxambi be used in patients with type 1 diabetes?
A: No, Glyxambi is contraindicated in patients with type 1 diabetes due to an increased risk of diabetic ketoacidosis.
Q3: What are the most common side effects?
A: The most common side effects are urinary tract infections, upper respiratory tract infections, nasopharyngitis, and genital mycotic infections.
Q4: How does Glyxambi affect renal function?
A: Empagliflozin, a component of Glyxambi, can cause a transient decrease in eGFR and increase in serum creatinine upon initiation, which usually stabilizes. Glyxambi is not recommended for patients with severe renal impairment or end-stage renal disease.
Q5: Can Glyxambi be used during pregnancy or breastfeeding?
A: It is not recommended during the second and third trimesters of pregnancy or during breastfeeding.
Q6: Does Glyxambi interact with other diabetes medications?
A: Yes, Glyxambi can interact with insulin and sulfonylureas, increasing the risk of hypoglycemia. Dosage adjustments of these medications may be necessary.
Q7: What should be monitored in patients taking Glyxambi?
A: Blood glucose, A1c, renal function, blood pressure, signs of volume depletion and infection, lipid profile.
Q8: Should Glyxambi be discontinued if a patient experiences a urinary tract infection?
A: Not necessarily. Treat the UTI appropriately, but discontinuation of Glyxambi is typically not required unless it’s a severe or recurrent infection.
Q9: Can Glyxambi be used in patients with hepatic impairment?
A: Yes, no dose adjustment is necessary in patients with hepatic impairment.
Q10: What lifestyle advice should be given to patients taking Glyxambi?
A: Patients should maintain adequate hydration, especially during exercise or in hot weather. They should adhere to a healthy diet and exercise regularly. Alcohol intake should be limited. Patients should be educated on recognizing and managing hypoglycemia.
