Combined Effects of Statins and Exercise on Training Sensitive Health Markers
NCT ID: NCT06841536
Last Updated: 2025-12-29
Study Results
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Basic Information
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ACTIVE_NOT_RECRUITING
NA
120 participants
INTERVENTIONAL
2025-05-01
2025-12-31
Brief Summary
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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.
Detailed Description
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Among available therapies, statins are a cornerstone of dyslipidaemia management due to their efficacy in lowering LDL-C and consequent reduction in cardiovascular event rates. For instance, decreasing LDL-C by 1 mmol/L through statin therapy is associated with up to a 20% reduction in both cardiovascular events and all-cause mortality. While pharmacotherapy is central to risk management, exercise training is also strongly recommended to improve lipid profiles and enhance cardiovascular health. Even relatively modest increases in cardiorespiratory fitness (CRF), on the order of approximately 1 metabolic equivalent (MET), translate into significant survival benefits of 10-25%. As cardiovascular diseases remain a leading global health concern, understanding how statins may interact with exercise-based interventions is essential for developing optimized treatment strategies for patients with dyslipidaemia.
Recent evidence suggests that the concurrent use of statins and structured exercise training does not always produce additive benefits, as initially presumed. In particular, some studies have reported that statin therapy may attenuate improvements in CRF and skeletal muscle mitochondrial function typically observed with endurance training. For example, administration of simvastatin at 40 mg/day hindered the usual exercise-induced increase in citrate synthase (CS) activity and aerobic capacity following 12 weeks of endurance exercise training in overweight adults. Similarly, high-dose atorvastatin (80 mg/day) has been shown to impair mitochondrial oxidative capacity in skeletal muscle, even in individuals free from overt cardiometabolic disease. These results are consistent with a growing body of work linking statin use to mitochondrial perturbations within skeletal muscle tissue. However, the precise biological mechanisms responsible for these observations remain poorly characterized. Modern omics approaches, such as untargeted proteomic profiling, may help elucidate how statins impact the network of mitochondrial proteins and metabolic pathways involved in exercise adaptation.
In addition to mitochondrial dysregulation, statin therapy-particularly at high doses-has been associated with a heightened risk of incident type 2 diabetes mellitus (T2DM). The underlying mechanisms appear multifactorial, involving alterations in insulin sensitivity and secretory function. Statins may diminish Glucose transporter type 4 (GLUT4)-mediated glucose uptake, affect mitochondrial energy transduction in skeletal muscle and adipose tissue, and promote lipotoxicity in pancreatic beta cells, collectively increasing insulin resistance and impairing normal insulin secretion. Thus, while statins robustly lower LDL-C and cardiovascular risk, their influence on glycemic control and metabolic health parameters warrants careful patient selection and ongoing glucose monitoring, especially in individuals predisposed to diabetes.
Musculoskeletal side effects, referred to as statin-associated muscle symptoms (SAMS), are another important consideration. Affecting an estimated 5-30% of statin users, SAMS range from mild myalgias to more significant muscle weakness, potentially prompting discontinuation of therapy and reducing adherence. This issue may also discourage regular physical activity and thereby negate some of the positive lifestyle modifications critical for long-term health management. Physical exertion may exacerbate these muscle symptoms, promoting a more sedentary pattern in individuals on statins. Although the pathophysiology of SAMS is not fully delineated, mitochondrial dysfunction related to impaired complexes III and IV activity, as well as reduced coenzyme Q10 availability, has been implicated.
Moreover, genetic polymorphisms can modulate statin pharmacodynamics and pharmacokinetics, potentially altering muscle tissue statin exposure and influencing inter-individual variability in both therapeutic and adverse responses to these agents. To date, however, the extent to which genetic variation might modify the interaction between statin therapy and exercise adaptations (on parameters such as mitochondrial function and systemic fitness) remains unknown.
In summary, although statins effectively diminish ASCVD risk by lowering LDL-C, emerging data suggest statins can reduce the beneficial effects of exercise training on skeletal muscle mitochondria and CRF. In addition, high-dose statin therapy may increase susceptibility to T2DM and aggravate muscle-related symptoms, thereby influencing the overall therapeutic benefit-risk profile. Despite considerable investigation in related areas, the precise molecular mechanisms underlying these effects, as well as the influence of genetics on this interplay, remain unclear. Notably, previous research has not yet encompassed a comprehensive, randomized, double-blinded, placebo-controlled trial that examines the simultaneous impact of statin therapy and structured exercise training on cardiovascular, muscular, and metabolic endpoints in dyslipidaemic individuals aged 40-65 years, including in-depth molecular phenotyping and genetic analyses.
Objective The present study aims to determine how statin therapy and exercise training, alone and in combination, influence whole-body aerobic capacity and mitochondrial function in individuals with dyslipidaemia but without established ASCVD. By employing untargeted proteomic methods, the investigation will identify molecular signatures and pathways through which statins may modify exercise-induced alterations in mitochondrial protein composition and metabolic phenotypes. An embedded sub-analysis will evaluate the role of genetic polymorphisms influencing statin pharmacodynamics and pharmacokinetics, thereby assessing how these genetic factors might shape individual variability in responses at both the muscle tissue and systemic levels. This integrative approach is expected to advance our understanding of the complex interactions between pharmacological lipid-lowering strategies and lifestyle interventions, ultimately guiding personalized management plans for patients with dyslipidaemia.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
BASIC_SCIENCE
TRIPLE
Statistical analysis of primary outcome will be blinded to the assessor.
Study Groups
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Atorvastatin + exercise
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.
Atorvastatin 80mg
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.
Exercise
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.
Placebo + exercise
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.
Exercise
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 + non-exercise
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.
Atorvastatin 80mg
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.
Placebo + non-exercise
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.
No interventions assigned to this group
Interventions
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Atorvastatin 80mg
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.
Exercise
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.
Eligibility Criteria
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Inclusion Criteria
* LDL-C \> 4.0 mmol/L.
Exclusion Criteria
* 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.
40 Years
65 Years
ALL
No
Sponsors
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University of Copenhagen
OTHER
Research council Faroe Islands
UNKNOWN
National Hospital of the Faroe Islands
OTHER_GOV
Betri Stuðul
UNKNOWN
University of the Faroe Islands
OTHER
Responsible Party
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Locations
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University of the Faroe Islands
Tórshavn, , Faroe Islands
Countries
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References
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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.
Ryan TE, Torres MJ, Lin CT, Clark AH, Brophy PM, Smith CA, Smith CD, Morris EM, Thyfault JP, Neufer PD. High-dose atorvastatin therapy progressively decreases skeletal muscle mitochondrial respiratory capacity in humans. JCI Insight. 2024 Feb 22;9(4):e174125. doi: 10.1172/jci.insight.174125.
Allard NAE, Schirris TJJ, Verheggen RJ, Russel FGM, Rodenburg RJ, Smeitink JAM, Thompson PD, Hopman MTE, Timmers S. Statins Affect Skeletal Muscle Performance: Evidence for Disturbances in Energy Metabolism. J Clin Endocrinol Metab. 2018 Jan 1;103(1):75-84. doi: 10.1210/jc.2017-01561.
Paiva H, Thelen KM, Van Coster R, Smet J, De Paepe B, Mattila KM, Laakso J, Lehtimaki T, von Bergmann K, Lutjohann D, Laaksonen R. High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial. Clin Pharmacol Ther. 2005 Jul;78(1):60-8. doi: 10.1016/j.clpt.2005.03.006.
Schirris TJ, Renkema GH, Ritschel T, Voermans NC, Bilos A, van Engelen BG, Brandt U, Koopman WJ, Beyrath JD, Rodenburg RJ, Willems PH, Smeitink JA, Russel FG. Statin-Induced Myopathy Is Associated with Mitochondrial Complex III Inhibition. Cell Metab. 2015 Sep 1;22(3):399-407. doi: 10.1016/j.cmet.2015.08.002.
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.
Sirvent P, Mercier J, Vassort G, Lacampagne A. Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle. Biochem Biophys Res Commun. 2005 Apr 15;329(3):1067-75. doi: 10.1016/j.bbrc.2005.02.070.
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.
Muraki A, Miyashita K, Mitsuishi M, Tamaki M, Tanaka K, Itoh H. Coenzyme Q10 reverses mitochondrial dysfunction in atorvastatin-treated mice and increases exercise endurance. J Appl Physiol (1985). 2012 Aug;113(3):479-86. doi: 10.1152/japplphysiol.01362.2011. Epub 2012 May 31.
Bouitbir J, Charles AL, Rasseneur L, Dufour S, Piquard F, Geny B, Zoll J. Atorvastatin treatment reduces exercise capacities in rats: involvement of mitochondrial impairments and oxidative stress. J Appl Physiol (1985). 2011 Nov;111(5):1477-83. doi: 10.1152/japplphysiol.00107.2011. Epub 2011 Aug 18.
Kwak HB, Thalacker-Mercer A, Anderson EJ, Lin CT, Kane DA, Lee NS, Cortright RN, Bamman MM, Neufer PD. Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes. Free Radic Biol Med. 2012 Jan 1;52(1):198-207. doi: 10.1016/j.freeradbiomed.2011.10.449. Epub 2011 Oct 25.
Sirvent P, Fabre O, Bordenave S, Hillaire-Buys D, Raynaud De Mauverger E, Lacampagne A, Mercier J. Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins. Toxicol Appl Pharmacol. 2012 Mar 1;259(2):263-8. doi: 10.1016/j.taap.2012.01.008. Epub 2012 Jan 17.
Schick BA, Laaksonen R, Frohlich JJ, Paiva H, Lehtimaki T, Humphries KH, Cote HC. Decreased skeletal muscle mitochondrial DNA in patients treated with high-dose simvastatin. Clin Pharmacol Ther. 2007 May;81(5):650-3. doi: 10.1038/sj.clpt.6100124. Epub 2007 Feb 28.
Meador BM, Huey KA. Statin-associated changes in skeletal muscle function and stress response after novel or accustomed exercise. Muscle Nerve. 2011 Dec;44(6):882-9. doi: 10.1002/mus.22236.
Sjuretharson T, Larsen S, Jensen SBK, Bejder J, Rasmussen J, A Borg S, Kristiansen J, Meinhardsson JM, Olsen HW, Ellingsgaard H, Vigh-Larsen JF, Nordsborg NB, Mohr M. Investigating the combined effects of statins and exercise on skeletal muscle mitochondrial content and function, cardiorespiratory fitness and quality of life in individuals with dyslipidaemia: protocol for a randomised placebo-controlled trial. BMJ Open. 2025 Jun 5;15(6):e101425. doi: 10.1136/bmjopen-2025-101425.
Kopin L, Lowenstein C. Dyslipidemia. Ann Intern Med. 2017 Dec 5;167(11):ITC81-ITC96. doi: 10.7326/AITC201712050.
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.
Kokkinos PF, Faselis C, Myers J, Panagiotakos D, Doumas M. Interactive effects of fitness and statin treatment on mortality risk in veterans with dyslipidaemia: a cohort study. Lancet. 2013 Feb 2;381(9864):394-9. doi: 10.1016/S0140-6736(12)61426-3. Epub 2012 Nov 28.
Farrell SW, Finley CE, Grundy SM. Cardiorespiratory fitness, LDL cholesterol, and CHD mortality in men. Med Sci Sports Exerc. 2012 Nov;44(11):2132-7. doi: 10.1249/MSS.0b013e31826524be.
Mikus CR, Boyle LJ, Borengasser SJ, Oberlin DJ, Naples SP, Fletcher J, Meers GM, Ruebel M, Laughlin MH, Dellsperger KC, Fadel PJ, Thyfault JP. Simvastatin impairs exercise training adaptations. J Am Coll Cardiol. 2013 Aug 20;62(8):709-14. doi: 10.1016/j.jacc.2013.02.074. Epub 2013 Apr 10.
Provided Documents
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Document Type: Statistical Analysis Plan
Other Identifiers
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2024-10
Identifier Type: OTHER
Identifier Source: secondary_id
0360
Identifier Type: -
Identifier Source: org_study_id