High-intensity interval training and moderate-intensity continuous training versus usual care in adults with familial hypercholesterolaemia: protocol for the UPPA-FH three-arm randomised trial
BMJ Open, vol. 16, pp. e114501
Abstract
Introduction Familial hypercholesterolaemia (FH) is an inherited disorder associated with lifelong exposure to elevated low-density lipoprotein cholesterol (LDL-c) and substantially increased risk of premature atherosclerotic cardiovascular disease. Although intensive lipid-lowering therapy is the cornerstone of management, many individuals remain at elevated residual cardiovascular risk. Exercise training may improve cardiorespiratory fitness (CRF), vascular function and cardiometabolic health; however, randomised evidence comparing different exercise modalities in adults with FH is lacking. The UPPA-FH trial aims to evaluate the effects of high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT), compared with usual care, on CRF, subclinical atherosclerosis and cardiometabolic health in adults with FH. Methods and analysis The UPPA-FH is a single-centre, three-arm, parallel-group superiority randomised controlled trial. 75 adults with genetically confirmed FH will be randomly allocated (1:1:1) to 16 weeks of supervised HIIT, supervised MICT or usual care. The primary outcome is change in maximal oxygen uptake (VO₂max) from baseline to 16 weeks, measured by cardiopulmonary exercise testing. Key secondary outcomes include markers of subclinical atherosclerosis (vascular inflammation, carotid intima-media thickness), arterial stiffness, biomarkers of cardiometabolic health (inflammation, oxidative stress, endothelial dysfunction and lipid metabolism), as well as body composition, physical function and estimated cardiovascular risk. The primary analyses will be conducted in the intention-to-treat population using a mixed model for repeated measures, adjusted for baseline outcome values and prespecified covariates. Treatment effects will be presented as adjusted between-group differences with corresponding 95% CIs. Confirmatory treatment comparisons will follow a prespecified fixed-sequence hierarchical testing procedure: (1) HIIT versus usual care; (2) MICT versus usual care and (3) HIIT versus MICT. Each comparison will be tested using a two-sided significance level of 0.05. Ethics and dissemination The study has been approved by the Biomedical Research Ethics Committee of Granada (reference 1417 N-23). Results will be disseminated through peer-reviewed publications, scientific conferences and communication with healthcare professionals and patient organisations. Trial registration number NCT06833944. Version date and identifier Version 2.0 (12 July 2026).
Authors 39
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Affiliation as printed
Department of Education, University of Almeria, Almería, Spain
SPORT Research Group (CTS-1024), CIBIS (Centro de Investigación para el Bienestar y la Inclusión Social) Research Center, University of Almería, Almería, Spain
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Fundación para la Investigación Biosanitaria de Andalucía Oriental - Alejandro Otero · Universidad de Sevilla
Affiliation as printed
Departamento de Educación Física y Deporte, Universidad de Sevilla, Sevilla, Spain
FIBAO, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Affiliation as printed
Department of Physiology, University of Granada, Granada, Spain
Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
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Affiliation as printed
Department of Physiology, University of Granada, Granada, Spain
Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
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Andrés Baena‐Raya Aachen Department of Medicine Division of Endocrinology and Einthoven Laboratory for Experimental Vascular Medicine
Leiden University Medical Center
Affiliation as printed
Department of Medicine, Division of Endocrinology & Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, Netherlands
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Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública · Universidad Autónoma de Madrid
Affiliation as printed
CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain
Department of Preventive Medicine and Public Health, School of Medicine, Universidad Autónoma de Madrid, Madrid, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Nuclear Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Nuclear Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Nuclear Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Nuclear Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Nuclear Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Universidad de Granada · Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Human Anatomy and Embriology, University of Granada, Granada, Spain
Department of Radiology, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Radiology, Hospital Universitario Virgen de las Nieves, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Cardiology, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Cardiology, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Cardiology, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Clinical Analysis, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Clinical Analysis, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Universidad Internacional de La Rioja · Fundación para la Investigación Biosanitaria de Andalucía Oriental - Alejandro Otero
Affiliation as printed
Department of Educational Psychology and Psychobiology, International University of La Rioja, Logroño, Spain
FIBAO, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada
Affiliation as printed
Department of Internal Medicine, Hospital Universitario San Cecilio, Granada, Spain
ibs.GRANADA, Granada, Spain
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Complejo Hospitalario Torrecárdenas
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Torrecárdenas, Almería, Spain
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Complejo Hospitalario Torrecárdenas
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Torrecárdenas, Almería, Spain
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Complejo Hospitalario Torrecárdenas
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Torrecárdenas, Almería, Spain
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Affiliation as printed
Department of Nursing, Physiotherapy and Medicine, Chronic Complications of Diabetes Lab (ChroCoDiL), Biomedicine, Integrative Physiology and Therpeutics (BIT) CTS-1163, University of Almería, Almería, Spain
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Affiliation as printed
Department of Chemistry and Physics, Research Centre CIAIMBITAL, University of Almería, Almería, Spain
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Affiliation as printed
Department of Chemistry and Physics, Research Centre CIAIMBITAL, University of Almería, Almería, Spain
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Instituto de Investigación Biosanitaria de Granada
Affiliation as printed
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Instituto de Investigación Biosanitaria de Granada · Hospital Universitario Virgen de las Nieves
Affiliation as printed
Department of Internal Medicine, Hospital Universitario Virgen de las Nieves, Granada, Spain
ibs.GRANADA, Granada, Spain
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Frederiksberg Hospital · Copenhagen University Hospital
Affiliation as printed
The Parker Institute: MSU, Copenhagen University Hospital, Frederiksberg, Copenhagen, Denmark
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Blanca Gavilán‐Carrera corresponding
Affiliation as printed
Department of Physical Education and Sport, University of Granada, Granada, Spain
Sport and Health University Research Institute (iMUDS), University of Granada, Granada, Spain
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Affiliation as printed
Department of Education, Faculty of Education Sciences, University of Almería, Almería, Spain
SPORT Research Group (CTS-1024), CERNEP Research Center, University of Almería, Almería, Spain