AUTHOR=Mora-Fernández Carmen , Pérez Adora , Mollar Anna , Palau Patricia , Amiguet Martina , de la Espriella Rafael , Sanchis Juan , Górriz Jose Luis , Soler María José , Navarro-González Juan F. , Núñez Julio ,  DAPA-VO2 Investigators , Palau Patricia , Amiguet Martina , Domínguez Eloy , Sastre Clara , Mollar Anna , Seller Julia , Pinilla Jose Manuel Garcia , Larumbe Ainoha , Valle Alfonso , Doblas Juan Jose Gómez , de la Espriella Rafael , Miñana Gema , Mezcua Ainhoa Robles , Santas Enrique , Bodí Vicent , Sanchis Juan , Pascual-Figal Domingo , Górriz Jose Luis , Baýes-Genís Antonio , Civera Jose , Conesa Adriana , Zakarne Rim , Rubio Clara Jiménez , Cabeza Alejandro I. Pérez , Expósito Arancha Díaz , Carmona José David Martínez , Morales Manuel Luna , Sánchez Francisco J. Zafra , Trujillo Ángel Montiel , Climent Herminio Morillas , Núñez Julio 

TITLE=Short-term changes in klotho and FGF23 in heart failure with reduced ejection fraction—a substudy of the DAPA-VO2 study

JOURNAL=Frontiers in Cardiovascular Medicine

VOLUME=10

YEAR=2023

URL=https://www.frontiersin.org/journals/cardiovascular-medicine/articles/10.3389/fcvm.2023.1242108

DOI=10.3389/fcvm.2023.1242108

ISSN=2297-055X

ABSTRACT=<p>The klotho and fibroblast growth factor 23 (FGF-23) pathway is implicated in cardiovascular pathophysiology. This substudy aimed to assess the changes in klotho and FGF-23 levels 1-month after dapagliflozin in patients with stable heart failure and reduced ejection fraction (HFrEF). The study included 29 patients (32.2% of the total), with 14 assigned to the placebo group and 15 to the dapagliflozin, as part of the double-blind, randomized clinical trial [DAPA-VO<sub>2</sub> (NCT04197635)]. Blood samples were collected at baseline and after 30 days, and Klotho and FGF-23 levels were measured using ELISA Kits. Between-treatment changes (raw data) were analyzed by using the Mann-Whitney test and expressed as median (p25%–p75%). Linear regression models were utilized to analyze changes in the logarithm (log) of klotho and FGF-23. The median age was 68.3 years (60.8–72.1), with 79.3% male and 81.5% classified as NYHA II. The baseline medians of left ventricular ejection fraction, glomerular filtration rate, NT-proBNP, klotho, and FGF-23 were 35.8% (30.5–37.8), 67.4 ml/min/1.73 m<sup>2</sup> (50.7–82.8), 1,285 pg/ml (898–2,305), 623.4 pg/ml (533.5–736.6), and 72.6 RU/ml (62.6–96.1), respectively. The baseline mean peak oxygen uptake was 13.1 ± 4.0 ml/kg/min. Compared to placebo, patients on dapagliflozin showed a significant median increase of klotho [Δ+29.5, (12.9–37.2); <italic>p</italic> = 0.009] and a non-significant decrease of FGF-23 [Δ−4.6, (−1.7 to −5.4); <italic>p</italic> = 0.051]. A significant increase in log-klotho (<italic>p</italic> = 0.011) and a decrease in log-FGF-23 (<italic>p</italic> = 0.040) were found in the inferential analysis. In conclusion, in patients with stable HFrEF, dapagliflozin led to a short-term increase in klotho and a decrease in FGF-23.</p>