Functional impairment is a hallmark of heart failure (HF) and a strong prognostic factor. Cardiopulmonary exercise testing (CPET) provides a robust and objective assessment of exercise capacity; however, the impact of new pharmacotherapies on CPET parameters remains largely uncharacterized systematically. This review examines the influence of contemporary HF therapies on functional capacity, with particular focus on CPET-derived metrics, such as peak oxygen uptake (VO2 peak), ventilatory efficiency (VE/VCO2 slope), and oxygen uptake efficiency slope (OUES). A critical synthesis of randomized trials, observational studies, and meta-analyses was performed to assess the effects of both conventional (angiotensin-converting enzyme (ACE) inhibitors, beta-blockers, mineralocorticoid receptor antagonists (MRAs)) and novel agents (angiotensin receptor neprilysin inhibitor (ARNIs), sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP)-1 receptor agonists, vericiguat, finerenone) on CPET outcomes. Conventional therapies provide modest improvements in CPET indices, whereas sacubitril/valsartan and SGLT2 inhibitors show more consistent and clinically meaningful benefits across different HF phenotypes. Vericiguat provided preliminary promise in improving VO2 peak and ventilatory parameters. Meanwhile, evidence for GLP-1 receptor agonists and finerenone remains limited or inconclusive. Heterogeneity across studies, in terms of the timing of CPET follow-up and baseline functional status, emerged as important modulators of the observed outcomes. Novel HF therapies can potentially improve exercise capacity beyond symptomatic relief, supporting a shift toward CPET-based endpoints in HF clinical trials. Personalized CPET monitoring may optimize therapeutic strategies and better reflect meaningful functional gains in HF populations.
