Is empagliflozin (Empagliflozin) or canagliflozin (Canagliflozin) more effective for reducing cardiovascular events in patients with established cardiovascular disease and impaired renal function?

Empagliflozin is Superior to Canagliflozin for Patients with Established Cardiovascular Disease and Impaired Renal Function

Empagliflozin should be the preferred SGLT2 inhibitor in this population due to its proven 38% reduction in cardiovascular mortality and superior safety profile, particularly the absence of amputation risk that significantly complicates canagliflozin therapy. 1

Cardiovascular Mortality: The Critical Difference

The most important distinction between these agents is their impact on cardiovascular death, which directly affects mortality:

• Empagliflozin reduced cardiovascular death by 38% (3.7% vs 5.9%; HR 0.62,95% CI 0.49-0.77) in the EMPA-REG OUTCOME trial, which enrolled 7,020 patients with 99% having established cardiovascular disease 1

• Canagliflozin showed no significant reduction in cardiovascular death in the CANVAS Program despite similar MACE reduction rates 1

• Empagliflozin also reduced all-cause mortality by 32% (5.7% vs 8.3%), a benefit not demonstrated with canagliflozin 1

Comparable Benefits on Other Cardiovascular Outcomes

Both agents show similar efficacy for composite cardiovascular endpoints:

• MACE reduction: Both reduced major adverse cardiovascular events by 14% (HR 0.86) 1

• Heart failure hospitalization: Empagliflozin reduced by 35% (2.7% vs 4.1%) 1, while canagliflozin reduced by 33% (5.5 vs 8.7 per 1000 patient-years) 1

• Chronic kidney disease progression: Empagliflozin reduced by 39% (12.7% vs 18.8%) 1, while canagliflozin reduced by 40% (6.6 vs 9.0 per 1000 patient-years) 1

Critical Safety Advantage: Amputation Risk

The most concerning safety difference is canagliflozin's doubling of lower-limb amputation rates:

• Canagliflozin increased amputations with HR 1.97 (95% CI 1.41-2.75), occurring in 6.3 vs 3.4 participants per 1000 patient-years 1

• This amputation risk was observed in the CANVAS Program but notably was not seen in the subsequent CREDENCE trial, which enrolled patients with more advanced kidney disease 1

• Empagliflozin has not shown increased amputation risk in any trial to date 1

• Canagliflozin also showed more bone fractures in CANVAS 1

Performance in Impaired Renal Function

Both agents demonstrate efficacy in patients with chronic kidney disease, but with important nuances:

Empagliflozin in CKD:

• In patients with prevalent kidney disease (eGFR <60 mL/min/1.73 m² and/or UACR >300 mg/g), empagliflozin reduced cardiovascular death by 29% (HR 0.71,95% CI 0.52-0.98) 2

• Effects were consistent across eGFR categories including patients with eGFR as low as 30-45 mL/min/1.73 m² 2, 3

• The adverse event profile in patients with eGFR <60 mL/min/1.73 m² was consistent with the overall trial population 2

Canagliflozin in CKD:

• The CREDENCE trial specifically enrolled patients with diabetic nephropathy (eGFR 30-90 mL/min/1.73 m² and UACR >300 mg/g) 1

• Canagliflozin 100 mg reduced the primary composite renal outcome by 30% (HR 0.70,95% CI 0.59-0.82) 1

• Importantly, no significant increase in amputations was noted in CREDENCE, unlike CANVAS 1

• Canagliflozin increased diabetic ketoacidosis risk (HR 10.80,95% CI 1.39-83.65) 1

Practical Implementation Algorithm

For patients with established cardiovascular disease and impaired renal function:

1. First-line choice: Empagliflozin 10 mg daily 4

   • Provides optimal cardiovascular and renal benefits
   • No dose titration needed for cardiovascular protection 4
   • Can be used down to eGFR ≥30 mL/min/1.73 m² (though not recommended for glycemic control if eGFR <45 mL/min/1.73 m²) 4

2. Consider canagliflozin only if:

   • Empagliflozin is unavailable or contraindicated
   • Patient has diabetic nephropathy with UACR >300 mg/g and eGFR 30-90 mL/min/1.73 m² (CREDENCE population) 1
   • Mandatory screening: Assess for peripheral vascular disease, prior amputation, neuropathy, or foot ulcers before initiating 1

3. When initiating either agent:

   • Reduce sulfonylureas/glinides or decrease insulin dose by approximately 20% to prevent hypoglycemia 4
   • Discontinue at least 3 days before planned surgery to prevent ketoacidosis 4
   • Monitor for genital infections (common with both agents) 3

Common Pitfalls to Avoid

• Do not use canagliflozin in patients with peripheral vascular disease risk factors without careful consideration of amputation risk, particularly based on CANVAS data 1

• Do not assume equivalent mortality benefits between SGLT2 inhibitors—only empagliflozin has demonstrated cardiovascular and all-cause mortality reduction 1

• Do not initiate either agent in severe renal impairment (eGFR <30 mL/min/1.73 m²) 4, 5

• Do not overlook the FDA indication: Empagliflozin has an FDA indication to reduce cardiovascular death in adults with type 2 diabetes and cardiovascular disease 1