Introduction
Canagliflozin is an oral antihyperglycemic agent belonging to the sodium-glucose cotransporter 2 (SGLT2) inhibitor class. Approved by the FDA in 2013, it represents a novel approach to diabetes management by targeting renal glucose reabsorption. Canagliflozin has since demonstrated benefits beyond glycemic control, including cardiovascular and renal protective effects in specific patient populations.
Mechanism of Action
Canagliflozin selectively inhibits SGLT2 receptors in the proximal renal tubules, reducing glucose reabsorption and increasing urinary glucose excretion. This insulin-independent mechanism lowers plasma glucose concentrations by promoting glucosuria. Additionally, canagliflozin induces mild osmotic diuresis and natriuresis, contributing to blood pressure reduction and modest weight loss.
Indications
- Type 2 diabetes mellitus as an adjunct to diet and exercise
- Reduction of cardiovascular risk in adults with type 2 diabetes and established cardiovascular disease
- Reduction of risk of end-stage kidney disease, doubling of serum creatinine, cardiovascular death, and hospitalization for heart failure in adults with type 2 diabetes and diabetic nephropathy with albuminuria
Dosage and Administration
Standard dosing: 100 mg orally once daily, taken before the first meal of the day Dose escalation: May increase to 300 mg daily if needed for additional glycemic control Renal impairment: Not recommended when eGFR <30 mL/min/1.73m²; dose adjustment required when eGFR 30-45 mL/min/1.73m² Hepatic impairment: No dosage adjustment necessary for mild to moderate impairmentPharmacokinetics
Absorption: Rapidly absorbed with Tmax of 1-2 hours; bioavailability ~65% Distribution: Protein binding ~99%, primarily to albumin; steady state reached in 4-5 days Metabolism: Primarily via UGT1A9 and UGT2B4 glucuronidation; minor CYP3A4 metabolism Elimination: Half-life ~10.6 hours; excreted primarily in feces (41.5%) and urine (32.5%)Contraindications
- Severe renal impairment (eGFR <30 mL/min/1.73m²)
- End-stage renal disease
- Dialysis patients
- History of serious hypersensitivity reaction to canagliflozin
- Type 1 diabetes mellitus
Warnings and Precautions
Ketoacidosis: Increased risk of diabetic ketoacidosis, including in patients with type 2 diabetes Acute kidney injury: Cases reported; consider temporary discontinuation during reduced oral intake Volume depletion: May cause symptomatic hypotension; assess volume status before initiation Genital mycotic infections: Increased risk of fungal infections Lower limb amputations: Increased risk observed in clinical trials UTIs: Serious urinary tract infections including urosepsis and pyelonephritis Hypoglycemia: Risk increased when used with insulin or insulin secretagoguesDrug Interactions
Diuretics: Increased risk of volume depletion Insulin/insulin secretagogues: Increased risk of hypoglycemia (dose reduction may be needed) UGT inducers: Rifampin may decrease canagliflozin concentrations Digoxin: Moderate increase in digoxin exposure observedAdverse Effects
Common (>10%): Female genital mycotic infections, urinary tract infections, increased urination Less common (1-10%): Male genital mycotic infections, thirst, constipation, nausea Serious: Ketoacidosis, acute kidney injury, volume depletion, hypersensitivity reactions, lower limb amputationsMonitoring Parameters
- HbA1c every 3 months until stable, then every 6 months
- Renal function (eGFR) at baseline and periodically thereafter
- Volume status and blood pressure
- Signs/symptoms of genital infections and urinary tract infections
- Lower limb examinations regularly
- Ketone levels during acute illness or when symptoms suggest ketoacidosis
Patient Education
- Take medication before the first meal of the day
- Maintain adequate hydration to prevent volume depletion
- Monitor for symptoms of genital infections (itching, discharge) and report promptly
- Be aware of symptoms of ketoacidosis (nausea, vomiting, abdominal pain, fatigue)
- Practice regular foot care and report any foot sores or infections
- Understand potential for increased urination
- Carry identification indicating diabetes status
- Report any signs of urinary tract infections promptly
References
1. FDA Prescribing Information: Invokana (canagliflozin) 2. Neal B, et al. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N Engl J Med. 2017;377(7):644-657 3. Perkovic V, et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N Engl J Med. 2019;380(24):2295-2306 4. American Diabetes Association. Standards of Medical Care in Diabetes - 2023. Diabetes Care. 2023;46(Suppl 1) 5. Inzucchi SE, et al. Management of Hyperglycemia in Type 2 Diabetes, 2022. Diabetes Care. 2022;45(11):2753-2786