Effect of Exercise Training on Apolipoproteins: Meta-analysis and Trial Sequence Analysis

Abstract

We conducted a systematic review and meta-analysis of the effect of exercise training on common lipid subunits. We systematically searched PubMed, Web of Science and the Cochrane Library of Controlled Trials for randomized, controlled trials of exercise training versus sedentary controls that reported lipid subunits including apolipoprotein-AI, apolipoprotein-AII, apolipoprotein-B, high density cholesterol-2, high density cholesterol-3 and lipoprotein (a) up until January 31, 2024. Our search identified 2,363 potential studies. We included 25 studies with 34 intervention groups, and a total of 1,429 participants, 775 exercise training and 654 control. We found significant favourable anti-atherogenic changes in apolipoprotein-AI with a mean difference of 8.17 mg/dL and a 95% confidence interval of 5.80–10.55, lipoprotein (a) with a mean difference of −2.52 mg/dL and a 95% confidence interval of −4.33 to −0.72), apolipoprotein-B with a mean difference of −0.11 mg/dL and a 95% confidence interval 0f −0.19 to −0.04, and high density cholesterol-2 with a mean difference of 1.28 mg/dL and a 95% CI of 0.28–2.28. Our trial sequence analysis showed that futility was achieved for apolipoprotein-AI, but not for lipoprotein (a), apolipoprotein-B and high density cholesterol-2. The minimal clinically important differences for apolipoprotein-AI, lipoprotein (a), apolipoprotein-B and high density cholesterol-2 were 0.76, 0.46, 0.02 and 0.26 mg/dL, respectively. Analyses of apolipoprotein-AII and high density cholesterol-3 were not significant and these trial sequence analyses failed to show futility. Exercise training produces significant improvements in apolipoprotein-AI, lipoprotein (a), apolipoprotein-B and high density cholesterol-2, with the minimal clinically important differences being achieved. The effect of exercise training on apolipoprotein-AII and high density cholesterol-3 is unclear.

Keywords

dyslipidaemia - physical activity - apolipoproteins - hypercholesterolaemia - exercise training - trial sequence analysis

Publication History

Received: 04 November 2024

Accepted: 09 April 2025

Accepted Manuscript online:
09 April 2025

Article published online:
20 May 2025

• References

• 1 Wu J, Mu Z, Jiang S. et al. Trends in all-cause mortality and leading causes of death from 2009 to 2019 among older adults in China. BMC Geriatr 2023; 23: 645
• 2 Du Z, Qin Y. Dyslipidemia and Cardiovascular Disease: Current Knowledge, Existing Challenges, and New Opportunities for Management Strategies. J Clin Med 2023; 12: 363
• 3 Katzke VA, Sookthai D, Johnson T, Kühn T, Kaaks R. Blood lipids and lipoproteins in relation to incidence and mortality risks for CVD and cancer in the prospective EPIC-Heidelberg cohort. BMC Med 2017; 15: 218
• 4 Sarzynski MA, Burton J, Rankinen T. et al. The effects of exercise on the lipoprotein subclass profile: A meta-analysis of 10 interventions. Atherosclerosis 2015; 243: 364-372
• 5 Reiner Ž, Tedeschi-Reiner E. Prevalence and types of persistent dyslipidemia in patients treated with statins. Croat Med J 2013; 54: 339-345
• 6 Ozdemir B, Selamoglu Z, Braidy N. Absolute Quantification of Plasma Apolipoproteins for Cardiovascular Disease Risk Prediction. Methods Mol Biol 2020; 2138: 373-379
• 7 Smart NA, Downes D, van der Touw T. et al. The Effect of Exercise Training on Blood Lipids: A Systematic Review and Meta-analysis. Sports Med 2025; 55: 67-78
• 8 Marshall DA, Vernalis MN, Remaley AT, Walizer EM, Scally JP, Taylor AJ. The role of exercise in modulating the impact of an ultralow-fat diet on serum lipids and apolipoproteins in patients with or at risk for coronary artery disease. Am Heart J 2006; 151: 484-491
• 9 Salmon J, Owen N, Crawford D, Bauman A, Sallis JF. Physical activity and sedentary behavior: a population-based study of barriers, enjoyment, and preference. Health Psychol 2003; 22: 178-188
• 10 Wood G, Taylor E, Ng V. et al. Estimating the Effect of Aerobic Exercise Training on Novel Lipid Biomarkers: A Systematic Review and Multivariate Meta-Analysis of Randomized Controlled Trials. Sports Med 2023; 53: 871-886
• 11 van der Vorst EPC. High-Density Lipoproteins and Apolipoprotein A1. Subcell Biochem 2020; 94: 399-420
• 12 Lappegård KT, Kjellmo CA, Hovland A. High-Density Lipoprotein Subfractions: Much Ado about Nothing or Clinically Important?. Biomedicines 2021; 9: 836
• 13 Mehta A, Shapiro MD. Apolipoproteins in vascular biology and atherosclerotic disease. Nat Rev Cardiol 2022; 19: 168-179
• 14 Rhainds D, Brodeur MR, Tardif JC. Lipids, Apolipoproteins, and Inflammatory Biomarkers of Cardiovascular Risk: What Have We Learned?. Clin Pharmacol Ther 2018; 104: 244-256
• 15 Wood G, Murrell A, van der Touw T, Smart N. HIIT is not superior to MICT in altering blood lipids: a systematic review and meta-analysis. BMJ Open Sport Exerc Med 2019; 5: e000647
• 16 Page MJ, McKenzie JE, Bossuyt PM. et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71
• 17 StataCorp. Stata Statistical Software: Release 18. College Station, TX: StataCorp LLC. 2023
• 18 Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135
• 19 Higgins JPT. Cochrane Handbook for Systematic Reviews of Interventions. http://www//Cochrane-handbook.org [Stand: March 29th 2012]
• 20 Partlett C, Riley RD. Random effects meta-analysis: Coverage performance of 95% confidence and prediction intervals following REML estimation. Stat Med 2017; 36: 301-317
• 21 Borenstein M. Avoiding common mistakes in meta-analysis: Understanding the distinct roles of Q, I-squared, tau-squared, and the prediction interval in reporting heterogeneity. Res Synth Methods 2024; 15: 354-368
• 22 Wendelberger B, Lewis RJ. Futility in Clinical Trials. JAMA 2023; 330: 764-765
• 23 Copenhagen Trial Unit CfCIR. Trial Sequence Anaysis Software. Copenhagen 2023
• 24 Franceschini M, Boffa A, Pignotti E, Andriolo L, Zaffagnini S, Filardo G. The Minimal Clinically Important Difference Changes Greatly Based on the Different Calculation Methods. Am J Sports Med 2023; 51: 1067-1073
• 25 Smart NA, Waldron M, Ismail H. et al. Validation of a new tool for the assessment of study quality and reporting in exercise training studies:TESTEX. Int J Evid Based Healthc 2015; 13: 9-18
• 26 Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. Br Med J 2003; 327: 557-560
• 27 Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. Br Med J 1997; 315: 629-634
• 28 Wood G, Taylor E, Ng V. et al. Determining the effect size of aerobic exercise training on the standard lipid profile in sedentary adults with three or more metabolic syndrome factors: a systematic review and meta-analysis of randomised controlled trials. Br J Sports Med 2021; 56: 1-13
• 29 Sterne JAC, Savović J, Page MJ. et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ 2019; 366: 4898
• 30 Aldred HE, Hardman AE, Taylor S. Influence of 12 weeks of training by brisk walking on postprandial lipemia and insulinemia in sedentary middle-aged women. Metabolism 1995; 44: 390-397
• 31 Babu AF, Csader S, Männistö V. et al. Effects of exercise on NAFLD using non-targeted metabolomics in adipose tissue, plasma, urine, and stool. Sci Rep 2022; 12: 6485
• 32 Busby J, Notelovitz M, Putney K, Grow T. Exercise, high-density lipoprotein-cholesterol, and cardiorespiratory function in climacteric women. South Med J 1985; 78: 769-773
• 33 Colado JC, Triplett NT, Tella V, Saucedo P, Abellán J. Effects of aquatic resistance training on health and fitness in postmenopausal women. Eur J Appl Physiol 2009; 106: 113-122
• 34 Ho SS, Dhaliwal SS, Hills AP, Pal S. The effect of 12 weeks of aerobic, resistance or combination exercise training on cardiovascular risk factors in the overweight and obese in a randomized trial. BMC Public Health 2012; 12: 704
• 35 Huttunen JK, Länsimies E, Voutilainen E. et al. Effect of moderate physical exercise on serum lipoproteins. A controlled clinical trial with special reference to serum high-density lipoproteins. Circulation 1979; 60: 1220-1229
• 36 Kiens B, Jörgensen I, Lewis S. et al. Increased plasma HDL-cholesterol and apo A-1 in sedentary middle-aged men after physical conditioning. Eur J Clin Invest 1980; 10: 203-209
• 37 Kukkonen-Harjula K, Laukkanen R. et al. Effects of walking training on health-related fitness in healthy middle-aged adults—a randomized controlled study. Scand J Med Sci Sports 1998; 8: 236-242
• 38 Laaksonen DE, Atalay M, Niskanen LK. et al. Aerobic exercise and the lipid profile in type 1 diabetic men: a randomized controlled trial. Med Sci Sports Exerc 2000; 32: 1541-1548
• 39 Liao HC, Zhong SG, Li P. et al. Effects and mechanism of moderate aerobic exercise on impaired fasting glucose improvement. Lipids Health Dis 2015; 14: 157
• 40 Manning JM, Dooly-Manning CR, White K. et al. Effects of a resistive training program on lipoprotein--lipid levels in obese women. Med Sci Sports Exerc 1991; 23: 1222-1226
• 41 Park S-K, Park J-H, Kwon Y-C, Kim HS, Yoon MS, Park HT. The effect of combined aerobic and resistance exercise training on abdominal fat in obese middle-aged women. J Physiol Anthropol Appl Human Sci 2003; 22: 129-135
• 42 Raz I, Rosenblit H, Kark JD. Effect of moderate exercise on serum lipids in young men with low high density lipoprotein cholesterol. Arteriosclerosis (Dallas, Tex.) 1988; 8: 245-251
• 43 Stensel DJ, Hardman AE, Brooke-Wavell K. et al. Brisk walking and serum lipoprotein variables in formerly sedentary men aged 42-59 years. Clin Sci (London, England: 1979) 1993; 85: 701-708
• 44 Stewart KJ, Bacher AC, Turner K. et al. Exercise and risk factors associated with metabolic syndrome in older adults. Am J Prev Med 2005; 28: 9-18
• 45 Sunami Y, Motoyama M, Kinoshita F. et al. Effects of low-intensity aerobic training on the high-density lipoprotein cholesterol concentration in healthy elderly subjects. Metabolism 1999; 48: 984-988
• 46 Suter E, Marti B. Little effect of long-term, self-monitored exercise on serum lipid levels in middle-aged women. J Sports Med Phys Fitness 1992; 32: 400-411
• 47 Suter E, Marti B, Gutzwiller F. Jogging or walking—comparison of health effects. Ann Epidemiol 1994; 4: 375-381
• 48 Veríssimo MT, Aragão A, Sousa A. et al. Effect of physical exercise on lipid metabolism in the elderly. Rev Port Cardiol 2002; 21: 1099-1112
• 49 Vesterbekkmo EK, Madssen E, Aamot Aksetøy IL. et al. CENIT (impact of cardiac exercise training on lipid content in coronary atheromatous plaques evaluated by near-infrared spectroscopy): a randomized trial. J Am Heart Assoc 2022; 11: e024705
• 50 Vincent HK, Bourguignon C, Vincent KR. Resistance training lowers exercise-induced oxidative stress and homocysteine levels in overweight and obese older adults. Obesity 2006; 14: 1921-1930
• 51 Williams PT, Stefanick ML, Vranizan KM, Wood PD. The effects of weight loss by exercise or by dieting on plasma high-density lipoprotein (HDL) levels in men with low, intermediate, and normal-to-high HDL at baseline. Metabolism 1994; 43: 917-924
• 52 Wilund KR, Colvin PL, Phares D, Goldberg AP, Hagberg JM. The effect of endurance exercise training on plasma lipoprotein AI and lipoprotein AI: AII concentrations in sedentary adults. Metabolism 2002; 51: 1053-1060
• 53 Woolf-May K, Kearney EM, Jones DW, Davison RC, Coleman D, Bird SR. The effect of two different 18-week walking programmes on aerobic fitness, selected blood lipids and factor XIIa. J Sports Sci 1998; 16: 701-710
• 54 Wooten JS, Phillips MD, Mitchell JB. et al. Resistance exercise and lipoproteins in postmenopausal women. Int J Sports Med 2011; 32: 7-13
• 55 Miyatani K, Fukui I. [Quantitative determination of serum apolipoprotein A-I and A-II using single radial immunodiffusion plate. Evaluation of determination methods and normal values]. Rinsho Byori 1983; 31: 409-413
• 56 Arneodo AL, Fassone R, Bini P. [Apo A and apo B values in childhood. A comparison between normal and obese subjects]. Minerva Pediatr 1986; 38: 553-557
• 57 Martin SS, Khokhar AA, May HT. et al. HDL cholesterol subclasses, myocardial infarction, and mortality in secondary prevention: the Lipoprotein Investigators Collaborative. Eur Heart J 2015; 36: 22-30
• 58 Vayá A, Sarnago A, Ricart JM, López V, Martínez-Triguero ML, Laiz B. Inflammatory markers and Lp(a) levels as cardiovascular risk factors in androgenetic alopecia. Clin Hemorheol Microcirc 2015; 61: 471-477
• 59 Boekholdt SM, Arsenault BJ, Hovingh GK. et al. Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis. Circulation 2013; 128: 1504-1512
• 60 Chen L, Zhao ZW, Zeng PH, Zhou YJ, Yin WJ. Molecular mechanisms for ABCA1-mediated cholesterol efflux. Cell Cycle 2022; 21: 1121-1139
• 61 Stanton KM, Kienzle V, Dinnes DLM. et al. Moderate- and High-Intensity Exercise Improves Lipoprotein Profile and Cholesterol Efflux Capacity in Healthy Young Men. J Am Heart Assoc 2022; 11: e023386
• 62 Enkhmaa B, Berglund L. Statins and Lp(a): The plot thickens. Atherosclerosis 2019; 289: 173-175
• 63 Khan SU, Khan MU, Valavoor S. et al. Association of lowering apolipoprotein B with cardiovascular outcomes across various lipid-lowering therapies: Systematic review and meta-analysis of trials. Eur J Prev Cardiol 2020; 27: 1255-1268
• 64 Devaraj S, Semaan JR, Jialal I. Biochemistry Apolipoprotein B. In: Stats Pearls Publishing, Hrsg. StatPearls. Treasure Island (FL) Ineligible Companies; 2024
• 65 Lamon-Fava S, Fisher EC, Nelson ME. et al. Effect of exercise and menstrual cycle status on plasma lipids, low density lipoprotein particle size, and apolipoproteins. J Clin Endocrinol Metab 1989; 68: 17-21
• 66 Thompson PD. What do muscles have to do with lipoproteins?. Circulation 1990; 81: 1428-1430
• 67 Casella-Filho A, Chagas AC, Maranhão RC. et al. Effect of exercise training on plasma levels and functional properties of high-density lipoprotein cholesterol in the metabolic syndrome. Am J Cardiol 2011; 107: 1168-1172
• 68 Degoricija V, Potočnjak I, Gastrager M. et al. HDL subclasses and mortality in acute heart failure patients. Clin Chim Acta 2019; 490: 81-87
• 69 Moholdt T, Parr EB, Devlin BL, Giskeødegård GF, Hawley JA. Effect of high-fat diet and morning or evening exercise on lipoprotein subfraction profiles: secondary analysis of a randomised trial. Sci Rep 2023; 13: 4008
• 70 Tamura S, Kaizu Y, Miyata K. The Minimal Clinically Important Difference Changes Greatly Based on the Different Calculation Methods: Letter to the Editor. Am J Sports Med 2023; 51: NP54-NP55