Can Canagliflozin (SGLT2 inhibitor) reduce mortality in an older adult patient with Heart Failure with preserved Ejection Fraction (HFpEF), hypertension, and diabetes?

Canagliflozin for Mortality Reduction in HFpEF

Canagliflozin has not been proven to reduce mortality in HFpEF patients, and you should use empagliflozin or dapagliflozin instead, as these are the only SGLT2 inhibitors with robust evidence for reducing cardiovascular death and heart failure hospitalizations in this population. 1, 2

Why Not Canagliflozin for HFpEF?

Canagliflozin lacks dedicated heart failure outcome trials in HFpEF patients. The CREDENCE trial studied canagliflozin in diabetic nephropathy patients and showed cardiovascular benefits (22% reduction in cardiovascular death or heart failure hospitalization), but this was a secondary endpoint in a renal-focused trial, not a primary heart failure study. 3 The small CANONICAL study (n=82) in elderly HFpEF patients with diabetes showed canagliflozin reduced body weight but failed to significantly reduce BNP levels at 24 weeks compared to standard therapy. 4

In contrast, empagliflozin and dapagliflozin have Class 2a guideline recommendations specifically for HFpEF based on large, dedicated heart failure trials. 1, 2

The Evidence-Based Choice: Empagliflozin or Dapagliflozin

Empagliflozin (Preferred for HFpEF)

Empagliflozin reduced the composite endpoint of cardiovascular death or heart failure hospitalization by 21% in EMPEROR-Preserved (5,792 patients with LVEF >40%, HR 0.79,95% CI 0.69-0.90), driven primarily by a 29% reduction in heart failure hospitalizations. 1 Cardiovascular death showed a non-significant trend toward reduction (HR 0.91,95% CI 0.76-1.0), and there was no benefit on all-cause mortality. 1

The benefit was consistent regardless of diabetes status, making empagliflozin appropriate for your older adult patient with diabetes and HFpEF. 1 The American Heart Association gives empagliflozin a Class 2a recommendation (moderate strength) for HFpEF to reduce heart failure hospitalizations and cardiovascular events. 2

Dapagliflozin (Alternative Option)

Dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 18% in the DELIVER trial (6,263 patients with LVEF >40%), with benefits seen across the ejection fraction spectrum. 5 The American Diabetes Association and American College of Cardiology strongly recommend dapagliflozin for symptomatic heart failure regardless of ejection fraction or diabetes status. 5

Clinical Implementation Algorithm

For your older adult patient with HFpEF, hypertension, and diabetes:

1. Choose empagliflozin 10 mg daily or dapagliflozin 10 mg daily as first-line SGLT2 inhibitor therapy. 2, 5

2. Verify eligibility: LVEF >40%, symptomatic heart failure (NYHA class II-IV), and eGFR ≥20-30 mL/min/1.73m² for dapagliflozin or ≥30 mL/min/1.73m² for empagliflozin. 5

3. Initiate therapy without dose titration - SGLT2 inhibitors require no up-titration and have minimal impact on blood pressure, heart rate, or potassium levels. 5

4. Add loop diuretics (furosemide or torsemide) as needed for symptom relief if overt congestion is present. 6

5. Monitor for mild, transient eGFR decline after initiation - this is expected and does not indicate kidney injury; do not discontinue therapy. 5

Important Caveats

The evidence hierarchy matters: Empagliflozin and dapagliflozin have dedicated HFpEF outcome trials (EMPEROR-Preserved, DELIVER), while canagliflozin does not. 1, 5 The CREDENCE trial showed canagliflozin reduced cardiovascular death by 22% and heart failure hospitalization by 39% in diabetic nephropathy patients, but these were secondary endpoints in a renal-focused population, not primary heart failure outcomes. 3

Benefits occur rapidly: Empagliflozin showed a 58% relative risk reduction at just 12 days after initiation in some analyses. 5 The treatment effect is consistent across age, sex, and background medical therapy. 5

Safety profile is favorable: Serious adverse events occur at rates comparable to placebo (~12% vs. 13%), with genital mycotic infections in ~2.5% and symptomatic hypotension in ~7% of patients. 7 Hypotension risk is approximately 5.7%, especially in volume-depleted patients. 5

Mortality reduction is modest to absent in HFpEF: Unlike HFrEF where SGLT2 inhibitors reduce cardiovascular death by 18%, the mortality benefit in HFpEF is less robust, with the primary benefit being reduction in heart failure hospitalizations. 1, 5, 6