What are the differences between Canagliflozin (SGLT2 inhibitor) and Dapagliflozin (SGLT2 inhibitor) in terms of efficacy and safety for a patient with type 2 diabetes and impaired renal function?

Canagliflozin vs Dapagliflozin in Type 2 Diabetes with Impaired Renal Function

Direct Recommendation

For patients with type 2 diabetes and impaired renal function, dapagliflozin is the preferred SGLT2 inhibitor due to superior renal protection evidence, absence of amputation and fracture risks, and proven efficacy down to eGFR 25 mL/min/1.73 m², whereas canagliflozin carries FDA Black Box Warnings for amputation risk and should be avoided in patients with osteoporosis or peripheral vascular disease. 1, 2, 3

Renal Protection Efficacy

Dapagliflozin Evidence

• The DAPA-CKD trial demonstrated a 44% reduction in renal-specific outcomes (sustained eGFR decline ≥50%, ESRD, or renal death) with HR 0.56 (95% CI 0.45-0.68) in patients with CKD and eGFR 25-75 mL/min/1.73 m². 1, 2
• Dapagliflozin reduced the composite outcome of sustained eGFR decline ≥50%, ESRD, or cardiovascular/renal death by 39% (HR 0.61,95% CI 0.51-0.72). 1, 2
• All-cause mortality was reduced by 31% (HR 0.69,95% CI 0.53-0.88) in the DAPA-CKD trial. 2
• The American Diabetes Association recommends SGLT2 inhibitors for kidney protection with strongest evidence for UACR >300 mg/g and eGFR 30-90 mL/min/1.73 m². 2

Canagliflozin Evidence

• The CREDENCE trial showed canagliflozin reduced worsening nephropathy (persistent macroalbuminuria, doubling of serum creatinine, ESRD, or death from ESRD) by 22%. 1
• Canagliflozin is approved for initiation down to eGFR 30 mL/min/1.73 m², but current guidelines recommend use down to eGFR 20 mL/min/1.73 m² for CKD progression reduction. 1

Key Difference: Dapagliflozin has more robust renal protection data (44% vs 22% risk reduction) and can be used at lower eGFR thresholds (25 vs 30 mL/min/1.73 m²). 1, 2

Critical Safety Differences

Canagliflozin-Specific Risks

• FDA Black Box Warning 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). 3
• Increased fracture risk: 15.4 vs 11.9 per 1,000 patient-years (HR 1.26,95% CI 1.04-1.52). 3
• Must be discontinued at least 3 days before scheduled surgery to prevent postoperative ketoacidosis. 3
• May increase LDL cholesterol levels. 3

Dapagliflozin Safety Profile

• No amputation or fracture warnings. 2
• Similar DKA risk to other SGLT2 inhibitors but without the additional amputation/fracture concerns. 3
• Volume depletion monitoring recommended, particularly with eGFR 30-60 mL/min/1.73 m². 2

Clinical Pitfall: Canagliflozin should be avoided in patients with peripheral vascular disease, history of amputation, neuropathy, or osteoporosis due to these specific safety concerns. 3

Cardiovascular Outcomes

Dapagliflozin

• Reduced cardiovascular death or heart failure hospitalization by 29% (HR 0.71,95% CI 0.55-0.92) in DAPA-CKD. 2
• DECLARE-TIMI 58 showed 27% reduction in heart failure hospitalization (HR 0.73,95% CI 0.61-0.88). 2
• Did not show MACE superiority in DECLARE-TIMI 58 (HR 0.93,95% CI 0.84-1.03). 2

Canagliflozin

• CANVAS program demonstrated cardiovascular event reduction as a primary outcome. 1
• Both agents show cardiovascular benefits, but dapagliflozin has more extensive heart failure-specific data. 1, 2

Dosing in Renal Impairment

Dapagliflozin

• Standard dose: 10 mg once daily for eGFR ≥25 mL/min/1.73 m². 2
• Should not be used with eGFR <25 mL/min/1.73 m² as it is unlikely to be effective. 2
• Renal benefits are independent of glucose-lowering effects and baseline HbA1c. 2

Canagliflozin

• Starting dose: 100 mg once daily, with maximum of 100 mg daily for eGFR 30-59 mL/min/1.73 m². 3
• Glucose-lowering effects are blunted with declining eGFR. 1

Head-to-Head Comparison Data

• A 2022 observational study found no significant differences in clinical outcomes between dapagliflozin and empagliflozin, supporting an SGLT2 inhibitor class effect for cardiovascular and renal outcomes. 4
• A 2019 prospective study comparing empagliflozin and dapagliflozin showed greater HbA1c reduction with empagliflozin but similar safety profiles. 5
• No direct head-to-head trials exist comparing canagliflozin and dapagliflozin specifically in patients with impaired renal function. 4, 5

Clinical Algorithm for Selection

Choose Dapagliflozin if:

• eGFR 25-30 mL/min/1.73 m² (canagliflozin not approved at this level) 1, 2
• History of peripheral vascular disease, amputation, or neuropathy 3
• Osteoporosis or high fracture risk 3
• Primary goal is renal protection with robust mortality benefit 2

Avoid Canagliflozin if:

• Any history of lower extremity amputation 3
• Active foot ulcers or peripheral vascular disease 3
• Osteoporosis or prior fragility fractures 3
• Upcoming scheduled surgery within 3 days 3

Monitoring Requirements

For Both Agents

• Monitor for genital mycotic infections (more common mechanism-based adverse event). 3
• Educate on DKA symptoms (nausea, vomiting, abdominal pain, weakness) and seek urgent care if present. 3
• Monitor volume status, particularly with baseline eGFR 30-60 mL/min/1.73 m². 2

Canagliflozin-Specific

• Intensive foot care education and regular foot examinations for infection or injury signs. 3
• Monitor for bone health and fracture risk. 3
• Consider reducing insulin or sulfonylurea doses to prevent hypoglycemia. 3