What is the comparison of Dapagliflozin (Dapa) and Empagliflozin (Empa) in terms of risk of fracture and cardiovascular benefits?

Comparison of Dapagliflozin, Empagliflozin, and Canagliflozin: Fracture Risk and Cardiovascular Benefits

Empagliflozin offers superior cardiovascular mortality benefits compared to dapagliflozin and canagliflozin, while dapagliflozin and empagliflozin have lower fracture risk than canagliflozin. 1

Cardiovascular Benefits Comparison

Empagliflozin

• Demonstrated the strongest cardiovascular mortality reduction with 38% relative risk reduction (3.7% vs 5.9%) in the EMPA-REG OUTCOME trial 1
• Reduced all-cause mortality by 32% (5.7% vs 8.3%) 1
• Reduced heart failure hospitalizations by 35% (2.7% vs 4.1%) 1
• Reduced progression of chronic kidney disease by 39% (12.7% vs 18.8%) 1
• Benefits appeared early in the treatment course, suggesting hemodynamic effects rather than atherosclerosis reduction 1

Dapagliflozin

• Did not significantly reduce major adverse cardiovascular events (MACE) in the DECLARE-TIMI 58 trial 1
• Reduced the composite of cardiovascular death or heart failure hospitalization by 17% (4.9% vs 5.8%) 1
• Reduced heart failure hospitalizations by 27% (HR 0.73; 95% CI 0.61-0.88) 1
• Reduced progression of chronic kidney disease 1
• In a real-world Korean cohort study, dapagliflozin showed lower risks of heart failure-related events (HR 0.84,95% CI 0.714-0.989) and cardiovascular death (HR 0.76,95% CI 0.618-0.921) compared to empagliflozin 2

Canagliflozin

• Reduced MACE by 14% (26.9 vs 31.5 per 1000 person-years) in the CANVAS program 1
• Reduced heart failure hospitalization by 33% (5.5 vs 8.7 per 1000 person-years) 1
• Reduced progression of chronic kidney disease by 40% (6.6 vs 9.0 per 1000 person-years) 1
• Did not show significant reduction in cardiovascular death 1

Fracture Risk Comparison

Canagliflozin

• Doubled the rate of bone fractures in the CANVAS trial 1
• Listed as a specific caution in the American College of Cardiology guidelines 1
• History of osteoporosis is a specific caution for canagliflozin use 1

Dapagliflozin and Empagliflozin

• No increased risk of bone fractures reported in major clinical trials 1
• No specific warnings regarding fracture risk in guidelines 1
• In a patient-level meta-analysis of DAPA-HF and DELIVER trials, dapagliflozin did not increase amputation risk even in patients with peripheral artery disease 3

Clinical Decision Algorithm

1. For patients with established cardiovascular disease and low fracture risk:

   • Empagliflozin is preferred due to superior cardiovascular mortality benefits 1

2. For patients with high fracture risk (osteoporosis, history of fractures):

   • Choose either dapagliflozin or empagliflozin 1
   • Avoid canagliflozin due to increased fracture risk 1

3. For patients with heart failure with reduced ejection fraction:

   • Both dapagliflozin and empagliflozin are effective 1, 4
   • Some evidence suggests empagliflozin may have greater improvements in left ventricular ejection fraction compared to dapagliflozin 5

4. For patients with chronic kidney disease:

   • Both dapagliflozin and empagliflozin provide renal protection 1, 6
   • Dapagliflozin has been specifically studied in non-diabetic CKD patients with positive outcomes 4

Important Considerations and Caveats

• Patient population differences exist between major trials: DECLARE-TIMI 58 (dapagliflozin) enrolled more primary prevention patients (59%) compared to CANVAS (34%) and EMPA-REG OUTCOME (0%) 1
• SGLT2 inhibitors generally do not require dose adjustment or up-titration and have minimal impact on blood pressure, heart rate, or potassium levels 1
• All three agents can be used with eGFR as low as 30 mL/min/1.73m², with dapagliflozin studied down to 20 mL/min/1.73m² 1, 4
• Common adverse effects across all agents include genital mycotic infections and urinary tract infections 1, 4
• A mild, transient decrease in eGFR may occur after initiating SGLT2 inhibitors but does not indicate kidney injury and should not prompt discontinuation 4
• Canagliflozin also carries an increased risk of lower limb amputations (6.3 vs 3.4 per 1000 person-years) 1