Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease

A Phase II Randomized Trial (CIPER Study)

authored by: Daniel Sedding, Tim M. Schmidt, Heike Bähre, Udo Bavendiek, Ana I. Casas, Suzi Chen, Vu Thao-Vi Dao, Mahmoud H. Elbatreek, Frank Gutzki, Andreas Hahn, Pamela Kleikers, Thomas Krahn, Cecilia Macchiusi, Catherine Martin, Hermann Mucke, Cristian Nogales, Beate M.L. Schmidt, Roland Seifert, Kristina Sonnenschein, Jörn Tongers, Jens Thol, Inés van der Arend, Sander M.J. van Kuijk, Kirstin Wingler, Michael Wu, Johann Bauersachs, Barry McGrath, Harald H.H.W. Schmidt
Abstract: Background: Peripheral artery disease (PAD) is a major public health concern due to its high prevalence, severe impact on individuals' health and quality of life, and substantial economic burden. Pharmacological interventions are still limited with numbers needed-to-treat ranging from 6 (cilostazol) to 50 (aspirin, statins, and vorapaxar). Objectives: This randomized, placebo-controlled, double-blinded crossover interventional trial aims to measure the effect of L-citrulline and tetrahydrobiopterin (H₄Bip) on walking distance in patients with PAD, stratified by plasma levels of asymmetric dimethyl L-arginine (ADMA), the endogenous inhibitor of endothelial nitric oxide (NO) synthase. Methods: We measured preinterventional ADMA levels in 51 patients with PAD in Australia and Germany with mean changes in absolute claudication distance (dACD) as the primary outcome upon orally supplementing the L-arginine precursor, L-citrulline (3 g) twice daily for 12 weeks, and, in one arm, additionally H₄Bip (0.45 g) once per day for a further 2 weeks. Results: Preinterventional ADMA levels were pathological (>0.4 μM) in 34 patients. Supplementation with L-citrulline significantly increased the mean plasma levels of both L-citrulline and L-arginine, from 41.8 ± 2.7 μmol/l to 246.3 ± 67.3 μmol/l (P = 0.004) and from 75.2 ± 4.2 μmol/l to 119.2 ± 6.9 μmol/l (P < 0.0001) respectively, when compared with placebo. dACD in % of control was significantly improved by L-citrulline vs placebo (20.11% ± 4.50% vs 5.73% ± 2.74%, respectively; P = 0.011). Further addition of H₄Bip increased the mean percentage dACD to 28.15% ± 6.84% (P = 0.021), but only in patients with preinterventional pathological ADMA levels. Conclusions: L-citrulline and, when ADMA levels are pathological, H₄Bip are effective nutritional interventions in patients with PAD warranting further confirmatory trials.
Organisation(s): Institute of Food Science and Human Nutrition
Nutrition Physiology and Human Nutrition Section
Institute of Food and One Health
External Organisation(s): Martin Luther University Halle-Wittenberg
Hannover Medical School (MHH)
Maastricht University
Monash University
Zagazig University
Sapienza Università di Roma
HM Pharma Consultancy
Type: Article
Journal: JACC: Advances
Volume: 4
Publication date: 03.2025
Publication status: Published
Peer reviewed: Yes
ASJC Scopus subject areas: Cardiology and Cardiovascular Medicine
Sustainable Development Goals: SDG 3 - Good Health and Well-being
Electronic version(s): https://doi.org/10.1016/j.jacadv.2025.101590 (Access: Open)