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. 2023 Aug 25:10:1242108.
doi: 10.3389/fcvm.2023.1242108. eCollection 2023.

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

Carmen Mora-Fernández #  1 , Adora Pérez #  2 , Anna Mollar  2   3 , Patricia Palau  2 , Martina Amiguet  4 , Rafael de la Espriella  2 , Juan Sanchis  2   3 , Jose Luis Górriz  5 , María José Soler  6 , Juan F Navarro-González  1   7 , Julio Núñez  2   3 ; DAPA-VO2 Investigators; DAPA-VO Investigators
Collaborators, Affiliations

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

Carmen Mora-Fernández et al. Front Cardiovasc Med. .

Abstract

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-VO2 (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 m2 (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); p = 0.009] and a non-significant decrease of FGF-23 [Δ-4.6, (-1.7 to -5.4); p = 0.051]. A significant increase in log-klotho (p = 0.011) and a decrease in log-FGF-23 (p = 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.

Keywords: dapagliflozin; fibroblast growth factor 23; functional capacity; heart failure with reduced ejection fraction; klotho; peak oxygen consumption.

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Conflict of interest statement

JG has received consultancy fees from Astellas, GSK, CSL VIFOR, and speaker fees from AstraZeneca, Boehringer Ingelheim, Esteve, Bayer, Lilly, Astellas, and Novonordisk. JN-G has served as a consultant and has received speaker fees or travel support from AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Esteve, Eli Lilly, MSD, Mundipharma, Novartis, Novonordisk, Sanofi-Genzyme, Servier, Shire, and Vifor Pharma. JN has received speaker fees from Astra Zeneca, Alleviant, Amgen, Bayer, Boehringer Ingelheim, CSL VIFOR, Daiichi Sankyo, GSK, Lilly, Pfizer, Novartis, Novonordisk, and Rovi. MS reports honorarium for conferences, consulting fees and advisory boards from AstraZeneca, NovoNordisk, Esteve, Vifor, Bayer, Mundipharma, Ingelheim Lilly, Jansen, ICU Medical, Travere Therapeutics, GE Healthcare, and Boehringer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
(A) Raw data. Changes in the median of klotho across treatment arms. (B) Raw data. Changes in the median of FGF-23 across treatment arms. (C) Raw data. Changes in the median of klotho/FGF-23 ratio across treatment arms. Values are presented as median (percentile 25% to percentile 75%). FGF-23, fibroblast growth factor 23.
Figure 2
Figure 2
(A) Between-treatment changes in logKlotho at 1-month. logKlotho, logarithm of klotho. (B) Between-treatment changes in logFGF-23 at 1-month. logFGF-23, logarithm of fibroblast growth factor 23. (C) Between-treatment changes in the ratio logKlotho and logFGF-23 at 1-month. logFGF-23, logarithm of fibroblast growth factor 23.
Figure 3
Figure 3
(A) Between-treatment changes in peakVO2 across baseline values of klotho. peakVO2, peak oxygen consumption. (B) Between-treatment changes in peakVO2 across baseline values of FGF-23. FGF-23, fibroblast growth factor 23; peak VO2, peak oxygen consumption.
See this image and copyright information in PMC

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