Table 2.

A comprehensive summary of the mainstay agents in the treatment of chronic HFpEF, evidenced by a conglomerate of landmark trials and current clinical practice guideline recommendation.

Drug class	Mechanism of action	Physiologic response	Indication	Pivotal evidence	2022 AHA/ACC/HFSA Class of Recommendation (COR) / Level of Evidence (LOE)
SGLT2i	Reversible inhibition of SGLT2 in the proximal tubule of the kidney	↑ Osmotic diuresis ↑ Natriuresis ↑ Glycosuria and polyuria ↓ BP Improve myocardial contractility	EMPEROR-Preserved26 DELIVER27	•Combined composite primary end point of CV death, HFH, or requiring IV treatment (HR, 0.77; 95% CI, 0.67-0.87)26 •HFH requiring intensive care (HR, 0.71; 95% CI, 0.52-0.96)26 •20-50% improvement in NYHA functional class26 Composite end point of HFH or CV death: •HR, 0.79; 95% CI, 0.69-0.90; P < .00127	COR 2b / LOE B-R
MRA	Competitively bind to aldosterone receptors in the late distal convoluted tubule and the collecting duct	↓ Aldosterone effects → ↓ Na+ reabsorption and K+ excretion ↑ Diuresis Prevent adverse cardiac remodeling	Aldo-DHF28 TOPCAT29	•↓ LV mass index (difference −6 g/m2; 95% CI, −10 to −1 g/m2)28 •Improved neuroendocrine activation (NT-proBNP geometric mean ratio 0.86; 95% CI, 0.75-0.99)28 •⇔ HF symptoms or QoL28 •↓ Incidence of HFH (HR 0.83 [95% CI 0.69-0.99])29 •⇔ Total deaths or hospitalization for any reason29	COR 2b / LOE B-R
ARNI	Inhibition of angiotensin II receptor type 1 (AT1 receptor) [ARB component] + Inhibition of breakdown of natriuretic peptides [Neprilysin inhibitor component]	↑ Natriuresis, diuresis, and vasodilation ↓ Extracellular fluid ↓ NT-proBNP concentration ARB effects as below	PARAMOUNT-HF30 PARAGON-HF31	Compared to ARB: •↓ NT-proBNP at 12 wk (ratio 0.77, 95% CI, 0.64-0.92; P = .005)30 •⇔ CV death or HFH31 •Improvement in NYHA class (OR, 1.45; 95% CI, 1.13-1.86)31	COR 2b / LOE B-R
ARB	Inhibition of angiotensin II receptor type 1 (AT1 receptor)	↓ Vasoconstriction ↓ Aldosterone secretion → ↓ reabsorption of Na+ and water ↓ BP ↑ renal plasma flow → ↓ GFR → ↓ filtration fraction ↓ Afterload ↓ Preload Promote cardiac reverse remodeling	CHARM-Preserved32	•⇔ Primary composite end point of CV death or HFH (HR, 0.89; 95% CI, 0.77-1.03)32 •↓ Total no. of HFH and total hospitalizations in ARB arm vs control32	COR 2b / LOE B-R

ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; AT1, angiotensin II receptor type 1; BP, blood pressure; CV, cardiovascular; GFR, glomerular filtration rate; HFH, heart failure hospitalization; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HR, hazard ratio; LV, left ventricular; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal pro-brain natriuretic peptide; OR, odds ratio; QoL, quality of life; SGLT2i, sodium-glucose cotransporter 2 inhibitor.