Usage
Canagliflozin + Metformin is prescribed as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It is also indicated to reduce the risk of end-stage renal disease (ESRD), doubling of serum creatinine, cardiovascular (CV) death, and hospitalization for heart failure in adults with type 2 diabetes mellitus (T2DM) and diabetic nephropathy with albuminuria >300 mg/day. It is not indicated for type 1 diabetes or diabetic ketoacidosis.
It belongs to the pharmacological classes of:
- Sodium-glucose co-transporter 2 (SGLT2) inhibitor (Canagliflozin)
- Biguanide (Metformin)
Canagliflozin works by inhibiting SGLT2 in the kidneys, thereby increasing glucose excretion in urine and lowering blood glucose levels. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.
Alternate Names
Canagliflozin + Metformin is available as fixed-dose combinations under various brand names, including Invokamet and Invokamet XR.
How It Works
Pharmacodynamics: Canagliflozin increases urinary glucose excretion. Metformin reduces hepatic glucose production, increases peripheral glucose uptake, and decreases intestinal glucose absorption. The combination leads to improved glycemic control.
Pharmacokinetics:
- Absorption: Both drugs are orally administered and absorbed in the gastrointestinal tract. Food may delay and slightly reduce canagliflozin absorption. Metformin’s absorption can be affected by gastrointestinal motility.
- Metabolism: Canagliflozin is primarily metabolized via glucuronidation by UGT enzymes (mainly UGT1A9 and UGT2B4), with minor oxidative metabolism by CYP3A4 (less than 7%). Metformin is not hepatically metabolized.
- Elimination: Canagliflozin is primarily excreted in urine (42%) and feces (33%). Metformin is eliminated primarily through renal excretion as the unchanged drug with negligible metabolism.
Mode of Action: Canagliflozin inhibits SGLT2, the main transporter of glucose in the renal proximal tubules, preventing glucose reabsorption into the bloodstream. Metformin’s exact mechanism is not fully understood, but it activates AMP-activated protein kinase (AMPK), which regulates multiple metabolic pathways. This leads to a decrease in gluconeogenesis and increase in insulin sensitivity.
Receptor Binding/Enzyme Inhibition: Canagliflozin selectively inhibits SGLT2 receptors. Metformin activates AMPK.
Elimination Pathways: Canagliflozin undergoes renal and hepatic excretion. Metformin is eliminated by renal excretion.
Dosage
Standard Dosage
Adults:
- Invokamet (immediate-release): Initial dose is typically canagliflozin 50 mg/metformin 500 mg twice daily with meals. The dose may be increased based on efficacy and tolerability to a maximum of canagliflozin 300 mg and metformin 2000 mg per day.
- Invokamet XR (extended-release): Initial dose is usually canagliflozin 100 mg/metformin 1000 mg once daily with the morning meal. This may be increased to a maximum of canagliflozin 300 mg/metformin 2000 mg daily based on individual response.
Children: Not recommended for patients under 18 years of age.
Special Cases:
- Elderly Patients: Initiate with lower doses and monitor renal function closely. Dose adjustment may be required.
- Patients with Renal Impairment: Contraindicated if eGFR <30 mL/min/1.73 m². Dose reductions are necessary for patients with eGFR between 30 and 60 mL/min/1.73 m².
- Patients with Hepatic Dysfunction: Contraindicated in patients with hepatic impairment.
- Patients with Comorbid Conditions: Dose adjustments may be required. Patients with heart failure are at higher risk for adverse events.
Clinical Use Cases
Canagliflozin + Metformin is not indicated for use in intubation, surgical procedures, mechanical ventilation, ICU, or emergency situations.
Dosage Adjustments
Dose adjustment may be required based on eGFR, concomitant UGT enzyme inducers, and individual tolerability.
Side Effects
Common Side Effects
Genital mycotic infections (female), urinary tract infections, increased urination, nausea, vomiting, diarrhea, flatulence, abdominal discomfort, and headache.
Rare but Serious Side Effects
Lactic acidosis (especially in patients with renal impairment), serious urinary tract infections, Fournier’s gangrene, ketoacidosis, lower limb amputation, hypoglycemia (when used with sulfonylureas or insulin).
Long-Term Effects
Potential long-term effects include bone fractures and changes in bone mineral density.
Adverse Drug Reactions (ADR)
Lactic acidosis, severe hypoglycemia, acute kidney injury, angioedema.
Contraindications
Hypersensitivity to either drug, severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, dialysis, hepatic impairment, and history of or risk for lactic acidosis.
Drug Interactions
Cationic drugs, UGT inducers (e.g., rifampin), digoxin, insulin or insulin secretagogues.
Pregnancy and Breastfeeding
Not recommended during pregnancy, particularly the second and third trimesters, or during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Canagliflozin: SGLT2 inhibitor, increases urinary glucose excretion; Metformin: Decreases hepatic glucose production, increases peripheral glucose uptake, and decreases intestinal glucose absorption.
- Side Effects: Female genital mycotic infections, UTIs, increased urination, nausea, vomiting, diarrhea. Serious: Lactic acidosis, lower limb amputation.
- Contraindications: eGFR <30 ml/min/1.73 m², dialysis, hepatic impairment.
- Drug Interactions: Cationic drugs, UGT inducers, digoxin.
- Pregnancy & Breastfeeding: Not recommended.
- Dosage: Individualized based on renal function and current regimen. Max: canagliflozin 300 mg, metformin 2000 mg daily.
- Monitoring Parameters: Blood glucose, eGFR, serum creatinine, HbA1c, signs and symptoms of lactic acidosis, and lower limb complications.
Popular Combinations
Often used in combination with sulfonylureas or insulin.
Precautions
Assess renal function before initiating and periodically thereafter. Monitor volume status and correct volume depletion before starting therapy, especially in elderly patients and patients with renal impairment or receiving diuretics. Assess for and counsel about lower limb complications. Monitor for signs and symptoms of UTIs and genital mycotic infections.
FAQs (Frequently Asked Questions)
A: The dosage is individualized based on the patient’s current regimen and renal function. For immediate release, the initial dose is 50/500mg BID and max of 300/2000 mg total daily dose. For extended release, 100/1000 mg once daily or max 300/2000 mg once daily total. It is essential to consider renal function when adjusting the dose.
Q2: What are the common side effects?
A: Common side effects include female genital mycotic infections, urinary tract infections, increased urination, nausea, vomiting, and diarrhea.
A: Contraindications include severe renal impairment (eGFR < 30 mL/min/1.73 m²), end-stage renal disease, patients on dialysis, and hepatic impairment.
A: Canagliflozin inhibits SGLT2, increasing urinary glucose excretion. Metformin reduces hepatic glucose production and enhances peripheral glucose uptake.
Q5: Can this combination be used in patients with type 1 diabetes?
A: No, Canagliflozin + Metformin is not indicated for use in patients with type 1 diabetes. It is specifically for type 2 diabetes.
Q6: Are there any drug interactions I should be aware of?
A: Yes, significant drug interactions can occur with cationic drugs, UGT inducers (e.g., rifampin), and digoxin. Concomitant use with insulin or insulin secretagogues increases the risk of hypoglycemia.
Q7: What monitoring parameters are important for patients on this medication?
A: Monitor blood glucose, renal function (eGFR and serum creatinine), HbA1c, signs and symptoms of lactic acidosis and lower limb complications.
Q8: Can I prescribe this medication to pregnant or breastfeeding women?
A: No, Canagliflozin + Metformin is generally not recommended during pregnancy or breastfeeding due to potential risks to the fetus or infant.
Q9: What should I do in case of an overdose?
A: Contact the Poison Control Center and employ usual supportive measures.
Q10: What are the advantages of using the combination versus individual components?
A: The fixed-dose combination improves patient compliance by simplifying the dosing regimen. It can also offer cost benefits compared to taking two separate medications.
