Canagliflozin

1. Drug Name

• Generic Name: Canagliflozin

• Brand Names: Invokana, Sulvadi (varies by region)

2. Drug Classification

• Class: Antidiabetic Agent

• Subclass: Sodium-glucose co-transporter 2 (SGLT2) Inhibitor

3. Mechanism of Action

Canagliflozin is a selective inhibitor of the sodium-glucose co-transporter 2 (SGLT2) in the proximal renal tubules. SGLT2 is responsible for the reabsorption of glucose from the renal filtrate back into the bloodstream. By inhibiting SGLT2, canagliflozin reduces glucose reabsorption, resulting in increased urinary glucose excretion (glucosuria) and, consequently, a reduction in blood glucose levels.

Unlike insulin-based therapies, canagliflozin does not rely on insulin secretion or insulin sensitivity, which makes it useful for both insulin-sensitive and insulin-resistant individuals. In addition to its glucose-lowering effect, canagliflozin has been shown to reduce blood pressure and promote weight loss, beneficial in managing type 2 diabetes and associated cardiovascular conditions.

4. Pharmacokinetics

• Absorption: Canagliflozin is well absorbed following oral administration with a bioavailability of approximately 65%. Peak plasma concentrations occur within 1 to 2 hours after oral administration.

• Distribution: The volume of distribution (Vd) is 76.6 L, indicating significant distribution into body tissues. It is approximately 99% bound to plasma proteins.

• Metabolism: Canagliflozin is primarily metabolized in the liver by UDP-glucuronosyltransferase (UGT) enzymes to an inactive glucuronide metabolite. The metabolism via cytochrome P450 enzymes is minimal (mainly CYP3A4).

• Excretion: The elimination half-life of canagliflozin is about 13 hours. Approximately 65% of the drug is excreted unchanged in the urine, with the rest being excreted in the feces.

• Special Considerations:

  • Renal Impairment: In patients with renal impairment (eGFR <45 mL/min/1.73 m²), the pharmacokinetics of canagliflozin may be altered, and it is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²) or those on dialysis.

  • Hepatic Impairment: No dose adjustment is necessary for mild to moderate hepatic impairment. Use with caution in patients with severe hepatic impairment.

5. Indications

• Primary Indications:

  • Type 2 Diabetes Mellitus: Canagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. It can be used alone or in combination with other antidiabetic agents like metformin, sulfonylureas, and insulin.

  • Chronic Kidney Disease (CKD): Canagliflozin is indicated for the treatment of chronic kidney disease to reduce the progression of kidney function decline, cardiovascular events, and hospitalization due to heart failure in patients with diabetic nephropathy and albuminuria.

  • Cardiovascular Risk Reduction in Type 2 Diabetes: Canagliflozin has been shown to reduce the risk of major cardiovascular events in patients with type 2 diabetes and a history of cardiovascular disease or high cardiovascular risk.

• Off-label Uses: Canagliflozin may be considered for off-label use in weight loss due to its glucosuria-promoting effect and potential to reduce body fat.

• Specific Populations: Canagliflozin is most beneficial in patients with type 2 diabetes and concomitant cardiovascular disease, chronic kidney disease, or other comorbidities.

6. Dosage and Administration

• Adult Dosing:

  • For Type 2 Diabetes Mellitus: The recommended starting dose is 100 mg once daily, preferably taken before the first meal of the day. The dose may be increased to 300 mg once daily depending on the patient’s blood glucose response and tolerability.

  • For Chronic Kidney Disease (CKD): 100 mg once daily, with dose adjustment based on kidney function.

  • For Cardiovascular Risk Reduction: 100 mg once daily, with the option to increase to 300 mg depending on patient response and tolerability.

• Renal Impairment Dosing:

  • eGFR <45 mL/min/1.73 m²: Contraindicated.

  • eGFR ≥45 mL/min/1.73 m²: No dose adjustment needed.

• Administration: Can be taken with or without food. It should be taken at approximately the same time each day to maintain consistent drug levels.

7. Contraindications

• Absolute Contraindications:

  • Severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or dialysis.

  • Hypersensitivity to canagliflozin or any of its components.

• Relative Contraindications:

  • History of diabetic ketoacidosis (DKA).

  • Use with caution in patients who have a history of frequent urinary tract infections (UTIs) or genital infections.

8. Warnings and Precautions

• Diabetic Ketoacidosis (DKA): Use caution in patients at risk for DKA, including insulin-dependent diabetic patients. Symptoms to monitor for include nausea, vomiting, abdominal pain, and difficulty breathing.

• Volume Depletion and Hypotension: Canagliflozin can cause dehydration, especially in patients with low blood pressure, the elderly, or those on diuretics. Patients should be adequately hydrated, and blood pressure should be monitored.

• Acute Kidney Injury (AKI): Monitor renal function regularly, especially in patients with pre-existing renal conditions. Canagliflozin may cause or worsen kidney function decline.

• Infections: Increased risk of urinary tract infections (UTIs) and genital infections (e.g., yeast infections) has been reported. Patients should be monitored for symptoms of infection and seek early treatment.

• Bone Fractures: Long-term use of canagliflozin has been associated with an increased risk of bone fractures. Bone health should be monitored, particularly in elderly patients.

• Amputations: A warning regarding an increased risk of lower-limb amputations (especially at the toe) has been added, based on clinical trial data. Proper foot care and regular monitoring are essential.

9. Adverse Effects

• Common Adverse Effects (≥10%):

  • Urinary tract infections.

  • Genital infections (e.g., candidiasis).

  • Increased urination.

  • Thirst, dehydration.

• Less Common but Clinically Significant Side Effects:

  • Diabetic ketoacidosis (DKA), especially in insulin-treated patients.

  • Acute kidney injury.

  • Hypotension and dehydration, especially in volume-depleted patients.

• Rare/Serious Adverse Reactions:

  • Necrotizing fasciitis of the perineum (Fournier’s gangrene).

  • Severe allergic reactions, including anaphylaxis and angioedema.

  • Bone fractures with long-term use.

10. Drug Interactions

• Major Drug Interactions:

  • Diuretics (e.g., furosemide, hydrochlorothiazide): Increased risk of dehydration, hypotension, and kidney injury. Careful monitoring is required.

  • ACE inhibitors/Angiotensin II Receptor Blockers (ARBs): Co-administration may increase the risk of hypotension and kidney impairment. Monitor renal function and blood pressure.

  • Insulin and Insulin Secretagogues: May increase the risk of hypoglycemia. Blood glucose levels should be monitored, and insulin doses may require adjustments.

• Food Interactions: Can be taken with or without food. No significant food-drug interactions are known.

• Lab Test Interactions: Canagliflozin may cause an increase in serum creatinine and uric acid levels. It can also interfere with the interpretation of blood glucose levels in some laboratory tests.

11. Clinical Pharmacology

• Pharmacodynamics: By inhibiting SGLT2, canagliflozin reduces the renal reabsorption of glucose, leading to increased urinary glucose excretion and a reduction in blood glucose levels. Additionally, it lowers blood pressure, induces modest weight loss, and has beneficial effects on kidney function.

• Additional Pharmacological Effects: Canagliflozin has been shown to reduce the risk of major cardiovascular events, including myocardial infarction, stroke, and cardiovascular death in patients with type 2 diabetes and established cardiovascular disease.

12. Special Populations

• Pregnancy: Category C. Canagliflozin should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Insulin is the preferred treatment for gestational diabetes.

• Lactation: Canagliflozin is excreted in breast milk, and its effects on the nursing infant are unknown. Caution should be exercised when using canagliflozin in breastfeeding women.

• Geriatrics: Elderly patients may be more susceptible to adverse effects such as volume depletion, hypotension, and kidney impairment. Dose adjustments and careful monitoring are required.

• Renal and Hepatic Dysfunction: Contraindicated in severe renal impairment (eGFR <30 mL/min/1.73 m²). Caution is required in moderate renal dysfunction and no dose adjustment is necessary for hepatic impairment.

13. Therapeutic Uses

• Type 2 Diabetes Mellitus: As an adjunct to diet and exercise, canagliflozin helps improve blood glucose control, either as monotherapy or in combination with other agents.

• Chronic Kidney Disease: Used to slow the progression of kidney disease in patients with type 2 diabetes and proteinuria.

• Cardiovascular Risk Reduction: Reduces the risk of cardiovascular events, including death, in patients with type 2 diabetes at high cardiovascular risk.

14. Monitoring and Follow-Up

• Lab Tests: Renal function (serum creatinine, eGFR), blood glucose levels, HbA1c, blood pressure.

• Patient-Reported Symptoms: Watch for signs of dehydration, urinary tract infections, genital infections, and DKA.

• Monitoring Therapeutic and Toxic Levels: Regular monitoring of kidney function, blood glucose levels, and vital signs is essential for optimal therapy.

15. Overdose Management

• Symptoms of Overdose: Symptoms may include dehydration, hypotension, and hypoglycemia.

• Treatment Protocols: There is no specific antidote for canagliflozin overdose. Treatment should be symptomatic, with intravenous fluids for dehydration and glucose administration if hypoglycemia occurs.

• Supportive Measures: Monitoring of kidney function and blood glucose is essential in overdose situations.

16. Patient Counseling Information

• Key Points:

  • Take canagliflozin as prescribed, with or without food.

  • Be aware of signs of dehydration (e.g., dizziness, fainting) and genital infections (e.g., yeast infections).

  • Seek immediate medical attention if you experience symptoms of DKA (e.g., nausea, vomiting, abdominal pain).

  • Maintain a healthy diet and regular exercise to improve blood sugar control.