HFpEF Treatment Revolution: SGLT2i, Finerenone, and GLP-1 Drugs Finally Deliver

HFpEF represents roughly half of all heart failure cases globally — an estimated 32 million people — yet 35–75% of patients who meet diagnostic criteria remain unrecognized in clinical practice. Annual mortality approaches 15%, five-year rehospitalization rates reach 80%, and five-year death rates hit 50%. Until recently, management was limited to diuretics for symptom relief and comorbidity control, with no drug demonstrably altering disease progression. This 2026 narrative review from Karolinska Institutet and the University Medical Center Hamburg-Eppendorf synthesizes the mechanistic understanding and pivotal trial evidence now reshaping HFpEF care.

The pathophysiology section moves well beyond the outdated 'stiff ventricle from hypertension' model, framing HFpEF as a multisystem syndrome driven by systemic inflammation, microvascular endothelial dysfunction, impaired calcium handling, RAAS overactivation, and metabolic inflammation ('metaflammation'). Obesity, present in 30–40% of HFpEF patients, is highlighted as a dominant phenotype, generating visceral fat-derived cytokines such as interleukin-6, epicardial fat accumulation, volume expansion, and neurohormonal activation — all converging to elevate left ventricular filling pressures and drive diastolic stiffness.

For SGLT2 inhibitors, the review details EMPEROR-Preserved (n=5,988), in which empagliflozin reduced the composite of cardiovascular death or first HF hospitalization by 21% (HR 0.79; 95% CI 0.69–0.90), driven primarily by a 29% reduction in HF hospitalizations (HR 0.71; 95% CI 0.60–0.83). Cardiovascular mortality was not significantly reduced (HR 0.91; 95% CI 0.76–1.09). The DELIVER trial with dapagliflozin produced strikingly consistent results. A meta-analysis of both trials in patients with EF ≥50% confirmed a 20% reduction in the composite primary endpoint (HR 0.80; 95% CI 0.73–0.87), with evidence of reduced all-cause mortality as well.

Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, was tested in FINEARTS-HF (n=6,001), enrolling patients with HFmrEF or HFpEF. The primary endpoint — total cardiovascular deaths and total HF events — was significantly reduced (rate ratio 0.84; 95% CI 0.74–0.95; p=0.007), marking the first non-SGLT2i drug to demonstrate outcome benefit in this population. Crucially, finerenone avoided the hyperkalemia and renal adverse effects that limited older steroidal MRAs such as spironolactone, which failed to reach primary endpoints in the TOPCAT trial.

For the obese HFpEF phenotype, GLP-1 receptor agonists semaglutide and the dual GIP/GLP-1 agonist tirzepatide showed compelling results. The STEP-HFpEF trial (semaglutide 2.4 mg) demonstrated an 8.4-point improvement in KCCQ clinical summary score versus 0.7 points for placebo (p<0.001) and a mean 13.3% body weight reduction versus 2.6% for placebo. SUMMIT (tirzepatide, n=731) showed significant reductions in the composite of cardiovascular death or worsening HF events (HR 0.62; 95% CI 0.41–0.95), though definitive mortality outcomes in larger cohorts are still awaited.

The review concludes by emphasizing that HFpEF now demands a phenotype-guided, multi-drug strategy — SGLT2i as foundational therapy across the EF spectrum, finerenone for additional neurohormonal blockade, and GLP-1/GIP agonists specifically for obese phenotypes. Diagnostic challenges including low natriuretic peptides in obese patients and the underperformance of scoring tools like HFA-PEFF relative to H2FPEF remain barriers to timely treatment initiation. Ongoing trials targeting inflammation, fibrosis, and mitochondrial dysfunction may yield further options.