Canagliflozin: A Comprehensive Monograph on a Foundational SGLT2 Inhibitor from Glycemic Control to Cardiorenal Protection

Abstract

Canagliflozin is a small molecule drug belonging to the sodium-glucose co-transporter 2 (SGLT2) inhibitor class, representing a significant advancement in the management of type 2 diabetes mellitus (T2DM) and related cardiorenal complications. As the first SGLT2 inhibitor approved in the United States, its primary mechanism of action involves the inhibition of glucose reabsorption in the proximal renal tubules, leading to increased urinary glucose excretion and a subsequent reduction in plasma glucose levels, independent of insulin pathways. Initially indicated as an adjunct to diet and exercise for glycemic control, the therapeutic role of canagliflozin has been profoundly expanded by the findings of landmark clinical trials. The Canagliflozin Cardiovascular Assessment Study (CANVAS) Program demonstrated its efficacy in reducing the risk of major adverse cardiovascular events (MACE) in patients with T2DM and high cardiovascular risk. Subsequently, the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) trial established its potent renoprotective effects, showing a significant reduction in the progression of diabetic kidney disease. More recent evidence from trials like CHIEF-HF suggests emerging benefits in improving symptoms of heart failure, even in patients without diabetes. This comprehensive monograph details the chemical profile, pharmacology, pharmacokinetics, and extensive clinical evidence supporting canagliflozin's efficacy across its approved indications. It provides a thorough analysis of its safety and tolerability profile, including notable risks such as genital mycotic infections, diabetic ketoacidosis, and a historically important concern regarding lower limb amputations, which has since been contextualized by further data. Dosing guidelines, drug interactio