Canagliflozin (Invokana) — SGLT2 Inhibitor — Weight & Metabolism

Overview

Canagliflozin (Invokana) was the first SGLT2 inhibitor approved by the FDA (2013) for type 2 diabetes. The CANVAS trial program demonstrated a 14% reduction in major adverse cardiovascular events (MACE) but also identified a concerning signal: approximately doubled risk of lower limb amputations (primarily toe and midfoot) compared to placebo. This amputation risk, not seen with empagliflozin or dapagliflozin, led to an FDA boxed warning in 2017 (later removed in 2020 after additional data suggested the risk may have been overestimated). The CREDENCE trial subsequently demonstrated significant renal benefits: 30% reduction in the primary composite of end-stage kidney disease, doubling of serum creatinine, or renal/cardiovascular death in patients with T2DM and diabetic kidney disease. Canagliflozin also inhibits SGLT1 (intestinal glucose transporter) at higher doses, which may contribute to additional postprandial glucose lowering but also increases GI side effects. As with all SGLT2 inhibitors, canagliflozin produces modest weight loss, blood pressure reduction, and carries risks of genital infections, UTIs, and rare euglycemic DKA.

Indications

• FDA-approved: Type 2 diabetes mellitus
• FDA-approved: Risk reduction of MACE in T2DM with established CVD
• FDA-approved: Risk reduction of ESKD in T2DM with diabetic nephropathy

Mechanism of Action

Primarily inhibits SGLT2 in the proximal tubule; at 300 mg also partially inhibits intestinal SGLT1, providing additional postprandial glucose lowering

Dosing

Evidence Grade

GRADE A

Safety & Contraindications

• Amputation risk signal (CANVAS trial) — primarily toe/midfoot; boxed warning removed 2020
• Genital mycotic infections
• Euglycemic DKA (rare but serious)
• Volume depletion and hypotension
• Fracture risk (slight increase observed in CANVAS)
• Fournier's gangrene (very rare)
• Reduced glycemic efficacy below eGFR 30 mL/min