What are the considerations and potential risks for using Invokana (canagliflozin) to treat type 2 diabetes?

Considerations and Potential Risks of Invokana (Canagliflozin) for Type 2 Diabetes

Invokana (canagliflozin) offers cardiovascular and renal benefits for type 2 diabetes patients but carries significant risks including increased lower-limb amputation risk, fractures, diabetic ketoacidosis, and genital mycotic infections that require careful patient selection and monitoring.

Mechanism and Benefits

• Canagliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor that reduces renal glucose reabsorption, thereby increasing urinary glucose excretion and reducing blood glucose levels 1
• Provides high glucose-lowering efficacy with minimal risk for hypoglycemia when used as monotherapy 2
• Associated with weight loss and blood pressure reduction benefits 2, 3
• Reduces risk of major adverse cardiovascular events in adults with type 2 diabetes and established cardiovascular disease 4
• Reduces 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 4

Major Safety Concerns

Amputation Risk

• FDA Black Box Warning: Canagliflozin has been associated with increased risk for lower-limb amputation (6.3 vs. 3.4 per 1,000 patient-years with placebo; HR 1.97 [95% CI 1.41,2.75]) 2
• Higher risk in patients with history of amputation, heart disease, blocked or narrowed blood vessels, neuropathy, or diabetic foot ulcers 4
• Requires careful monitoring for new pain, tenderness, sores, ulcers, or infections in leg or foot 4

Fracture Risk

• Increased fracture risk reported with canagliflozin (15.4 vs. 11.9 participants with fracture per 1,000 patient-years; HR 1.26 [95% CI 1.04,1.52]) 2
• Use with caution in patients with history of osteoporosis 2

Diabetic Ketoacidosis (DKA)

• Case reports of diabetic ketoacidosis with SGLT2 inhibitors in type 2 diabetes continue to raise concern 2
• Can present as euglycemic DKA (ketoacidosis with relatively normal blood glucose levels) 5
• Risk factors include insulin deficiency, reduced caloric intake, acute illness, surgical procedures, and alcohol consumption 6
• Patients should be educated about symptoms (nausea, vomiting, abdominal pain, weakness) and instructed to seek urgent medical attention if these occur 2

Volume Depletion and Kidney Effects

• Can cause dehydration leading to dizziness, fainting, lightheadedness, or weakness, especially upon standing (orthostatic hypotension) 4
• Associated with increased risk of acute kidney injury 2
• Higher risk in patients taking diuretics, on low sodium diets, with kidney problems, or aged ≥65 years 4
• Contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), end-stage renal disease, or on dialysis 4

Genital and Urinary Tract Infections

• Increased risk of genital mycotic infections in both women and men 4, 7
• Women may experience vaginal odor, white/yellowish discharge, and vaginal itching 4
• Men may experience redness, itching, swelling of the penis, foul-smelling discharge, rash, or pain 4
• Increased risk of urinary tract infections 1

Dosing and Renal Considerations

• Recommended starting dose is 100 mg orally once daily 2
• For patients with eGFR 30-59 mL/min/1.73 m², maximum dose is 100 mg daily 2
• Not recommended for use in patients with eGFR <30 mL/min/1.73 m² for glycemic control 2, 4
• Pharmacodynamic response declines with increasing severity of renal impairment 1

Special Precautions

Perioperative Management

• Discontinue at least 3 days before scheduled surgery to prevent postoperative ketoacidosis 2, 4

Drug Interactions and Monitoring

• May increase hypoglycemic potential when combined with insulin or sulfonylureas; consider reducing doses of these medications 2
• Monitor for symptoms of dehydration and hypotension, especially when used with diuretics and/or ACE inhibitors/ARBs 2
• May increase LDL cholesterol levels 2

High-Risk Populations

• Use with caution in elderly patients due to increased risk of volume depletion and adverse effects 6
• Patients with reduced renal function, on diuretics, or with low systolic blood pressure are at higher risk of adverse effects 6

Patient Education and Monitoring

• Educate patients about proper foot care and monitoring for signs of infection or injury 2
• Instruct patients to monitor glucose more closely during the first 4 weeks of therapy, especially if on insulin or sulfonylureas 2
• Advise patients to maintain adequate hydration and report symptoms of volume depletion 4
• Inform patients about the risk and symptoms of genital mycotic infections and appropriate management 2
• Instruct patients to hold medication during periods of reduced oral intake or illness 2

By carefully selecting appropriate patients and implementing proper monitoring strategies, the benefits of canagliflozin may outweigh its risks for many patients with type 2 diabetes.