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Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study)

Research output: Contribution to journal › Article › Research › peer review

Authors

  • Daniel Sedding
  • Tim M. Schmidt
  • Heike Bähre
  • Udo Bavendiek
  • Andreas Hahn

Research Organisations

External Research Organisations

  • Martin Luther University Halle-Wittenberg
  • Hannover Medical School (MHH)
  • Maastricht University
  • Monash University
  • Zagazig University
  • Sapienza Università di Roma
  • HM Pharma Consultancy

Details

Original languageEnglish
Article number101590
JournalJACC: Advances
Volume4
Issue number3
Publication statusPublished - Mar 2025

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.

Keywords

    ADMA, arginine, citrulline, nitric oxide synthase, peripheral artery disease, tetrahydrobiopterin

ASJC Scopus subject areas

Sustainable Development Goals

Cite this

Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). / Sedding, Daniel; Schmidt, Tim M.; Bähre, Heike et al.
In: JACC: Advances, Vol. 4, No. 3, 101590, 03.2025.

Research output: Contribution to journal › Article › Research › peer review

Sedding, D, Schmidt, TM, Bähre, H, Bavendiek, U, Casas, AI, Chen, S, Thao-Vi Dao, V, Elbatreek, MH, Gutzki, F, Hahn, A, Kleikers, P, Krahn, T, Macchiusi, C, Martin, C, Mucke, H, Nogales, C, Schmidt, BML, Seifert, R, Sonnenschein, K, Tongers, J, Thol, J, van der Arend, I, van Kuijk, SMJ, Wingler, K, Wu, M, Bauersachs, J, McGrath, B & Schmidt, HHHW 2025, 'Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study)', JACC: Advances, vol. 4, no. 3, 101590. https://doi.org/10.1016/j.jacadv.2025.101590
Sedding, D., Schmidt, T. M., Bähre, H., Bavendiek, U., Casas, A. I., Chen, S., Thao-Vi Dao, V., Elbatreek, M. H., Gutzki, F., Hahn, A., Kleikers, P., Krahn, T., Macchiusi, C., Martin, C., Mucke, H., Nogales, C., Schmidt, B. M. L., Seifert, R., Sonnenschein, K., ... Schmidt, H. H. H. W. (2025). Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). JACC: Advances, 4(3), Article 101590. https://doi.org/10.1016/j.jacadv.2025.101590
Sedding D, Schmidt TM, Bähre H, Bavendiek U, Casas AI, Chen S et al. Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study). JACC: Advances. 2025 Mar;4(3):101590. doi: 10.1016/j.jacadv.2025.101590
Sedding, Daniel ; Schmidt, Tim M. ; Bähre, Heike et al. / Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease : A Phase II Randomized Trial (CIPER Study). In: JACC: Advances. 2025 ; Vol. 4, No. 3.
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title = "Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease: A Phase II Randomized Trial (CIPER Study)",
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.",
keywords = "ADMA, arginine, citrulline, nitric oxide synthase, peripheral artery disease, tetrahydrobiopterin",
author = "Daniel Sedding and Schmidt, {Tim M.} and Heike B{\"a}hre and Udo Bavendiek and Casas, {Ana I.} and Suzi Chen and {Thao-Vi Dao}, Vu and Elbatreek, {Mahmoud H.} and Frank Gutzki and Andreas Hahn and Pamela Kleikers and Thomas Krahn and Cecilia Macchiusi and Catherine Martin and Hermann Mucke and Cristian Nogales and Schmidt, {Beate M.L.} and Roland Seifert and Kristina Sonnenschein and J{\"o}rn Tongers and Jens Thol and {van der Arend}, In{\'e}s and {van Kuijk}, {Sander M.J.} and Kirstin Wingler and Michael Wu and Johann Bauersachs and Barry McGrath and Schmidt, {Harald H.H.W.}",
note = "Publisher Copyright: {\textcopyright} 2025",
year = "2025",
month = mar,
doi = "10.1016/j.jacadv.2025.101590",
language = "English",
volume = "4",
number = "3",

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TY - JOUR

T1 - Nutritional L-Citrulline and Tetrahydrobiopterin in Peripheral Artery Disease

T2 - A Phase II Randomized Trial (CIPER Study)

AU - Sedding, Daniel

AU - Schmidt, Tim M.

AU - Bähre, Heike

AU - Bavendiek, Udo

AU - Casas, Ana I.

AU - Chen, Suzi

AU - Thao-Vi Dao, Vu

AU - Elbatreek, Mahmoud H.

AU - Gutzki, Frank

AU - Hahn, Andreas

AU - Kleikers, Pamela

AU - Krahn, Thomas

AU - Macchiusi, Cecilia

AU - Martin, Catherine

AU - Mucke, Hermann

AU - Nogales, Cristian

AU - Schmidt, Beate M.L.

AU - Seifert, Roland

AU - Sonnenschein, Kristina

AU - Tongers, Jörn

AU - Thol, Jens

AU - van der Arend, Inés

AU - van Kuijk, Sander M.J.

AU - Wingler, Kirstin

AU - Wu, Michael

AU - Bauersachs, Johann

AU - McGrath, Barry

AU - Schmidt, Harald H.H.W.

N1 - Publisher Copyright: © 2025

PY - 2025/3

Y1 - 2025/3

N2 - 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.

AB - 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.

KW - ADMA

KW - arginine

KW - citrulline

KW - nitric oxide synthase

KW - peripheral artery disease

KW - tetrahydrobiopterin

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U2 - 10.1016/j.jacadv.2025.101590

DO - 10.1016/j.jacadv.2025.101590

M3 - Article

AN - SCOPUS:85218783224

VL - 4

JO - JACC: Advances

JF - JACC: Advances

IS - 3

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ER -

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