Combined Effects of Statins and Exercise on Training Sensitive Health Markers

NCT06841536 | Completed DMC

• 2 other identifiers: 03602024-10
• Study Type: interventional
• Target: 120
• Locations: 1 country
• Sites: 1

Brief Summary

Around the world, about 4 in 10 adults have abnormal blood fat levels-known as dyslipidaemia-which raises their chances of getting heart disease. Many people with this condition are prescribed statins, medications that help lower the "bad" Low-density lipoprotein cholesterol (LDL-C) in the blood and, in doing so, help prevent serious heart-related problems. While statins do lower these harmful cholesterol levels, recent research suggests that statins might interfere with some of the positive effects that exercise typically has on muscle cells' energy centers (the mitochondria) and on a person's aerobic capacity. It is not yet fully understood how statins might influence these exercise benefits at the molecular level. To address this gap, the present study will look closely at how taking statins combined with a structured exercise program affects both the muscle cells and the whole-body fitness of people with dyslipidaemia. By using a wide-ranging protein analysis, the research aims to identify changes in muscle proteins and other metabolism-related factors that could explain why statins might alter the expected improvements from exercise. Methods and Analysis In this 12-week study, we aim to enrol between 100 and 125 adults (aged 40-65 years, with dyslipidaemia without established heart disease); the trial is powered for the first 100, and recruitment will stay open up to 125 to offset potential drop-outs. Participants will be randomly split into one of four groups: (1) exercise plus a placebo (an inactive pill), (2) exercise plus a daily high-dose statin (atorvastatin, 80 mg), (3) a daily high-dose statin without exercise, or (4) a placebo without exercise. More participants will be placed in the exercise groups to better understand the combined effects of exercise and statins. The main measurement will be how well the muscle's mitochondria work, assessed by changes in an enzyme called citrate synthase (CS) from before the program to after. Other important measures will include overall fitness (using a peak oxygen uptake (VO2peak) test) and detailed protein analyses. The study will also look at genetic variations to see if they influence how each participant responds to the treatment. Ethics and Sharing of Results The study has received approval from the Faroe Islands Ethical Committee (2024-10) and follows international guidelines to protect participants' rights and data. Once the research is complete, the findings will be shared in leading scientific journals for the broader public and medical community to learn from.

Conditions

Dyslipidemias

Keywords

Dyslipidemia; Exercise training; Mitochondria; Aerobic capacity; Statins; Adaptation, Physiological; proteomics; genetics; quality of life

Outcome Measures

Primary Outcomes (1)

• Citrate synthase maximal activity (µmol/g/min)

  Maximal enzyme activity of citrate synthase will be determined from muscle homogenate using fluorometry

  Change from baseline to end-of-treatment (12 weeks)

Secondary Outcomes (49)

• Maximal oxygen uptake (ml/min)

  Change from baseline to end-of-treatment (12 weeks)

• Targeted skeletal muscle proteomics

  Change from baseline to end-of-treatment (12 weeks)

• Lipid profile (mmol/L)

  Change from baseline to end-of-treatment (12 weeks)

• Concentration of lipoprotein (a) (nmol/L)

  Change from baseline to end-of-treatment (12 weeks)

• Concentration of apolipoprotein B (nmol/L)

  Change from baseline to end-of-treatment (12 weeks)

Other Outcomes (11)

• Anaerobic capacity

  Change from baseline to end-of-treatment (12 weeks)

• Concentration of systemic coenzyme Q10

  Change from baseline to end-of-treatment (12 weeks)

• Total hemoglobin mass (g)

  Change from baseline to end-of-treatment (12 weeks)

Study Arms (4)

Atorvastatin + exercise

ACTIVE COMPARATOR

Atorvastatin (80 mg) will be ingested once daily as oral tablets (80 mg/day). The starting dosage is 40 mg per day with a weekly increment of 40 mg reaching the maintenance dosage of 80 mg per day on week two. The titration protocol may be extended for participants with intolerable side-effects, and participants with intolerable side-effects at 80 mg may stay at a lower dosage (40 mg) Exercise: The exercise will be performed as supervised aerobic interval training sessions on cycling ergometers lasting \~45 min, four times weekly for 12 weeks. The exercise training will be conducted as a combination of high- and moderate-intensity interval training to ensure optimal adaptations of the primary outcomes.

Drug: Atorvastatin 80mg; Behavioral: Exercise

Placebo + exercise

OTHER

Placebo (CaCO3) will be ingested once daily as oral tablets (volume-matched to atorvastatin group). Exercise: The exercise will be performed as supervised aerobic interval training sessions on cycling ergometers lasting \~45 min, four times weekly for 12 weeks. The exercise training will be conducted as a combination of high- and moderate-intensity interval training to ensure optimal adaptations of the primary outcomes.

Behavioral: Exercise

Atorvastatin + non-exercise

OTHER

Atorvastatin (80 mg) will be ingested once daily as oral tablets (80 mg/day). The starting dosage is 40 mg per day with a weekly increment of 40 mg reaching the maintenance dosage of 80 mg per day on week two. The titration protocol may be extended for participants with intolerable side-effects, and participants with intolerable side-effects at 80 mg may stay at a lower dosage (40 mg) non-exercise: Participants are instructed to maintain habitual activity levels at the same level as when the participant was enrolled in the study.

Drug: Atorvastatin 80mg

Placebo + non-exercise

NO INTERVENTION

Placebo (CaCO3) will be ingested once daily as oral tablets (volume-matched to atorvastatin group). Non-exercise: Participants are instructed to maintain habitual activity levels at the same level as when the participant was enrolled in the study.

Interventions

Exercise BEHAVIORAL

Exercise will be performed as aerobic interval training sessions on cycling ergometers lasting \~45 min, four times weekly for 12 weeks. All exercise sessions will be supervised. Participants will wear HR monitor system during all sessions (Polar Electro Oy, Kempele, Finland) and the Borg 6-to-20 scale will also be used to assess the rate of perceived exertion during exercise sessions. A 4-week ramp-up phase will be applied, consisting of two sessions in weeks 1 and 2, three sessions in weeks 3 and 4 after which participants will complete 4 sessions a week from weeks 5 to 12.

Atorvastatin + exercise; Placebo + exercise

Atorvastatin 80mg DRUG

Daily intake of 80 mg of the approved drug Atorvastatin. Starting at dose 40 mg with 40 mg weekly increment reaching the maintenance dosage of 80 mg on week two, which is the approved maximum dosage of Atorvastatin. Participants who don't tolerate this fast up-titration may have prolonged tritation protocol (up to four weeks). Under special circumstances, participants with intolerable side-effects may stay at a lower dose (40 mg/day). The dosage and applied up-tritation is based on recommendations from trained cardiologists at the National Hospital of the Faroe Islands.

Atorvastatin + exercise; Atorvastatin + non-exercise

Eligibility Criteria

• Age: 40 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age: 40-65 years
• LDL-C \> 4.0 mmol/L.

You may not qualify if:

• Diagnosed with serious chronic disease including type 1 or 2 diabetes.
• Cancer.
• A history of atherosclerotic cardiovascular disease.
• A history of major depression or other severe psychiatric disorders.
• Severe renal dysfunction (creatinine clearance \<30 mL/min).
• Severe hepatic impairment.
• Active pregnancy or breast feeding.
• Active cigarette or e-cigarette smoker.
• Regular (\>2 hours pr week) aerobic high-intensity exercise training.

Sponsors & Collaborators

• University of the Faroe Islands: lead
• University of Copenhagen: collaborator
• Research council Faroe Islands: collaborator
• National Hospital of the Faroe Islands: collaborator
• Betri Stuðul: collaborator

Study Sites (1)

University of the Faroe Islands

Tórshavn, 100, Faroe Islands

Location

Related Publications (20)

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  PMID: 29204622 BACKGROUND

• Boren J, Chapman MJ, Krauss RM, Packard CJ, Bentzon JF, Binder CJ, Daemen MJ, Demer LL, Hegele RA, Nicholls SJ, Nordestgaard BG, Watts GF, Bruckert E, Fazio S, Ference BA, Graham I, Horton JD, Landmesser U, Laufs U, Masana L, Pasterkamp G, Raal FJ, Ray KK, Schunkert H, Taskinen MR, van de Sluis B, Wiklund O, Tokgozoglu L, Catapano AL, Ginsberg HN. Low-density lipoproteins cause atherosclerotic cardiovascular disease: pathophysiological, genetic, and therapeutic insights: a consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2020 Jun 21;41(24):2313-2330. doi: 10.1093/eurheartj/ehz962. No abstract available.

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• Morales-Palomo F, Ramirez-Jimenez M, Ortega JF, Moreno-Cabanas A, Mora-Rodriguez R. Exercise Training Adaptations in Metabolic Syndrome Individuals on Chronic Statin Treatment. J Clin Endocrinol Metab. 2020 Apr 1;105(4):dgz304. doi: 10.1210/clinem/dgz304.

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• Sirvent P, Bordenave S, Vermaelen M, Roels B, Vassort G, Mercier J, Raynaud E, Lacampagne A. Simvastatin induces impairment in skeletal muscle while heart is protected. Biochem Biophys Res Commun. 2005 Dec 23;338(3):1426-34. doi: 10.1016/j.bbrc.2005.10.108. Epub 2005 Oct 26.

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• Dirks AJ, Jones KM. Statin-induced apoptosis and skeletal myopathy. Am J Physiol Cell Physiol. 2006 Dec;291(6):C1208-12. doi: 10.1152/ajpcell.00226.2006. Epub 2006 Aug 2.

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  PMID: 40473295 DERIVED

MeSH Terms

Conditions

Dyslipidemias

Interventions

Atorvastatin; Exercise

Condition Hierarchy (Ancestors)

Lipid Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Pyrroles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Heptanoic Acids; Fatty Acids; Lipids; Motor Activity; Movement; Musculoskeletal Physiological Phenomena; Musculoskeletal and Neural Physiological Phenomena

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: The above-mentioned are masked with regards to atorvastatin/placebo and not exercise/non-exercise Statistical analysis of primary outcome will be blinded to the assessor.
• Purpose: BASIC SCIENCE
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Participants will be randomized by block to achieve a 60 : 40 allocation between exercise and non-exercise conditions, stratified by (1) sex (male/female) and (2) prior statin use (yes/no). The four 12-week treatment arms are: 1) exercise + placebo, 2) exercise + atorvastatin (80 mg/day), 3) atorvastatin (80 mg/day) and 4) placebo for 12 weeks

Study Record Dates

• First Submitted: February 8, 2025
• First Posted: February 24, 2025
• Study Start: May 1, 2025
• Primary Completion: December 16, 2025
• Study Completion: January 30, 2026
• Last Updated: February 25, 2026

Record last verified: 2026-02

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF

Locations

FA (1)