Canagliflozin: A Renal and Cardiac Protective Medication
Canagliflozin is definitively a renal and cardiac protective medication for patients with type 2 diabetes, particularly those with chronic kidney disease and/or cardiovascular disease, as demonstrated by multiple high-quality clinical trials. 1
Cardiovascular Protection
Canagliflozin provides significant cardiovascular protection through several mechanisms:
- Reduces major adverse cardiovascular events (MACE) by 14% in patients with type 2 diabetes and established cardiovascular disease 1
- Decreases risk of hospitalization for heart failure by 31% 1
- Lowers cardiovascular mortality by 20% in patients with type 2 diabetes and CKD 1
- Provides cardiovascular benefits regardless of baseline HbA1c levels 1
The CANVAS Program demonstrated that canagliflozin significantly reduced the composite outcome of cardiovascular death, MI, or stroke versus placebo (HR 0.86 [95% CI 0.75–0.97]) 1.
Renal Protection
Canagliflozin offers substantial renal protective effects:
- Reduces risk of end-stage kidney disease by 32% 1
- Decreases risk of doubling of serum creatinine as part of composite renal outcomes 1
- Slows annual eGFR decline compared to placebo 1
- Reduces albuminuria significantly 1
The CREDENCE trial was the first renal outcome trial of a diabetes medication with a primary composite endpoint of end-stage kidney disease, doubling of serum creatinine, or death from renal or cardiovascular causes. This landmark trial demonstrated a clear benefit of canagliflozin (100 mg) on multiple renal endpoints, including progression to end-stage kidney disease 1.
FDA Indications
The FDA has approved canagliflozin for:
- Reducing the risk of MI, stroke, or CV death in adults with T2D and CV disease
- Reducing the risk of end-stage kidney disease, doubling of serum creatinine, CV death, and hospitalization for heart failure in patients with T2D and diabetic nephropathy with albuminuria 1
Patient Selection and Dosing
- Recommended dose: 100 mg PO daily 1
- Renal dosing adjustments:
- eGFR 30-59 ml/min/1.73 m²: max dose 100 mg daily
- eGFR <30 ml/min/1.73 m²: use is not recommended for glycemic control, though the FDA label allows use specifically for patients with diabetic kidney disease down to an eGFR of 30 ml/min/1.73 m² 1
Mechanism of Protection
Canagliflozin provides cardiorenal protection through multiple mechanisms:
- Diuretic and natriuretic effects
- Blood pressure reduction
- Weight loss
- Effects on the sympathetic nervous system
- Inhibition of the sodium-hydrogen exchanger
- Reduction of cardiac injury, hypertrophy, fibrosis, and remodeling 1
Important Considerations and Cautions
Potential adverse effects:
- Genital mycotic infections (educate patients on genital hygiene)
- Volume depletion (may need to reduce diuretic doses)
- Diabetic ketoacidosis (can occur even with normal blood glucose levels)
- Increased risk of lower limb amputation (particularly with canagliflozin)
- Bone fractures (reported with canagliflozin) 1
Contraindications:
- History of serious hypersensitivity reaction to the drug
- eGFR <30 mL/min/1.73 m² (for glycemic control) 1
Clinical Application
For patients with type 2 diabetes and either established cardiovascular disease or CKD (especially with UACR >300 mg/g and eGFR 30-90 mL/min/1.73 m²), canagliflozin should be considered independently of baseline HbA1c or individualized HbA1c target for its cardiorenal protective effects 1.
The CREDENCE results demonstrated that the benefits of canagliflozin in reducing MACE, heart failure hospitalization, cardiovascular mortality, and renal endpoints were similar regardless of baseline cardiovascular status or CKD grade 2-3 1.
In summary, canagliflozin provides significant and clinically meaningful renal and cardiovascular protection in patients with type 2 diabetes, particularly those with established cardiovascular disease or chronic kidney disease.