Canagliflozin for HFpEF
While empagliflozin and dapagliflozin have Class 2a guideline recommendations for HFpEF, canagliflozin lacks robust evidence specifically for this indication and should not be considered first-line therapy for HFpEF.
Guideline-Directed SGLT2 Inhibitor Recommendations for HFpEF
The 2022 AHA/ACC/HFSA guidelines recommend SGLT2 inhibitors as a class for HFpEF (LVEF ≥50%) with a Class 2a recommendation, stating they "can be beneficial in decreasing HF hospitalizations and cardiovascular mortality." 1 However, this recommendation is based primarily on the EMPEROR-Preserved trial with empagliflozin and the DELIVER trial with dapagliflozin—not canagliflozin. 1
The 2023 ACC Expert Consensus specifically identifies dapagliflozin and empagliflozin as the SGLT2 inhibitors with demonstrated benefit in HFpEF, with recommended dosing of dapagliflozin 10 mg once daily or empagliflozin 10 mg once daily. 1 Canagliflozin is notably absent from these HFpEF-specific recommendations.
Evidence Base for Canagliflozin in HFpEF
Limited and Inconclusive Data
The CANONICAL study, a small randomized trial of 82 elderly patients (mean age 75.7 years) with HFpEF and type 2 diabetes, showed that canagliflozin 100 mg daily reduced body weight but did not significantly reduce plasma BNP concentrations compared with standard therapy after 24 weeks. 2 While BNP reductions at 4 weeks were greater with canagliflozin, this difference disappeared by 24 weeks. 2
A 2025 systematic review examining SGLT2 inhibitors in HFpEF included the CANDLE trial (Canagliflozin Anti-inflammatory and Metabolic Effects), which showed only modest NT-proBNP reductions of approximately -10.4% versus comparator. 3 This contrasts sharply with the robust cardiovascular outcomes demonstrated in EMPEROR-Preserved and DELIVER trials.
FDA-Approved Indications for Canagliflozin
The FDA label for canagliflozin does not include HFpEF as an approved indication. 4 The CREDENCE trial demonstrated canagliflozin's efficacy in diabetic nephropathy with albuminuria, reducing cardiovascular death and hospitalization for heart failure (HR 0.61; 95% CI 0.47-0.80), but this population had mixed ejection fractions and the primary focus was renal outcomes. 4
Preferred SGLT2 Inhibitors for HFpEF
Empagliflozin (First-Line Evidence)
EMPEROR-Preserved demonstrated a 21% reduction in the composite endpoint of HF hospitalization or cardiovascular death (HR 0.79; 95% CI 0.69-0.90), driven primarily by a 29% reduction in HF hospitalizations. 1 This benefit occurred in patients with LVEF >40% and elevated natriuretic peptides, regardless of diabetes status. 1
Dapagliflozin (First-Line Evidence)
The DELIVER trial showed dapagliflozin reduced the composite of worsening heart failure or cardiovascular death by 18% (HR 0.82; 95% CI 0.73-0.92) in patients with LVEF >40%. 5 Worsening heart failure events were reduced by 21% (HR 0.79; 95% CI 0.69-0.91). 5 Results were consistent across the ejection fraction spectrum, including patients with LVEF ≥60%. 5
Clinical Implementation Algorithm
For patients with HFpEF (LVEF ≥50%), symptomatic heart failure, and elevated natriuretic peptides:
Initiate empagliflozin 10 mg once daily OR dapagliflozin 10 mg once daily as guideline-directed medical therapy. 1
Do not substitute canagliflozin for empagliflozin or dapagliflozin in HFpEF, as it lacks equivalent evidence for this specific indication. 1
Continue SGLT2 inhibitor therapy even if initial eGFR decline occurs (expected decline of 3-4 mL/min/1.73 m² in first month), as this is not associated with adverse cardiovascular or kidney outcomes. 6
Monitor for genital infections (occurs in ~2.5% vs 0.5% with placebo) and symptomatic hypotension (7% vs 5%), though serious adverse event rates are comparable to placebo. 3, 7
Important Caveats
The benefit of SGLT2 inhibitors in HFpEF appears greater in patients with LVEF on the lower end of the spectrum (closer to 50% rather than >60%). 1 A subgroup analysis of EMPEROR-Preserved showed a signal for lower benefit at LVEFs >62.5%. 1
Safety profiles are similar across SGLT2 inhibitors for genitourinary infections in HFpEF populations, with no significant differences between canagliflozin, dapagliflozin, and empagliflozin. 7 However, this does not justify using canagliflozin when superior cardiovascular outcome data exist for the other agents.
Contraindications include eGFR <20 mL/min/1.73 m² and type 1 diabetes due to diabetic ketoacidosis risk. 1