What are benefits of increasing cardiorespiratory fitness through exercise?

Xiaochen Lin, MS,1 Xi Zhang, PhD,3 Jianjun Guo, MD,4 Christian K Roberts, PhD,5 Steve McKenzie, PhD,6 Wen-Chih Wu, MD,1,2 Simin Liu, MD, ScD,1,2,7 and Yiqing Song, MD, ScD3

Xiaochen Lin

1Department of Epidemiology, School of Public Health, Brown University, Providence, RI

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Xi Zhang

3Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN

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Jianjun Guo

4Center for the Youth Sport Research and Development, China Institute of Sport Science, Beijing, China

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Christian K Roberts

5Geriatrics, Research, Education and Clinical Centers, VA Greater Los Angeles Healthcare System, Los Angeles, CA

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Steve McKenzie

6Department of Kinesiology, Center for Physical Activity in Wellness and Prevention, Indiana University-Purdue University at Indianapolis, IN

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Wen-Chih Wu

1Department of Epidemiology, School of Public Health, Brown University, Providence, RI

2Division of Cardiology and Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School, Brown University, Providence, RI

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Simin Liu

1Department of Epidemiology, School of Public Health, Brown University, Providence, RI

2Division of Cardiology and Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School, Brown University, Providence, RI

7Division of Endocrinology, Department of Medicine, Rhode Island Hospital, Providence, RI

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Yiqing Song

3Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN

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Author information Article notes Copyright and License information Disclaimer

1Department of Epidemiology, School of Public Health, Brown University, Providence, RI

2Division of Cardiology and Veterans Affairs Medical Center, Department of Medicine, Alpert Medical School, Brown University, Providence, RI

3Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana University, Indianapolis, IN

4Center for the Youth Sport Research and Development, China Institute of Sport Science, Beijing, China

5Geriatrics, Research, Education and Clinical Centers, VA Greater Los Angeles Healthcare System, Los Angeles, CA

6Department of Kinesiology, Center for Physical Activity in Wellness and Prevention, Indiana University-Purdue University at Indianapolis, IN

7Division of Endocrinology, Department of Medicine, Rhode Island Hospital, Providence, RI

Correspondence to: Simin Liu, MD, ScD, Department of Epidemiology and Medicine, Brown University, 121 South Main St, Providence, RI 02903. E-mail: ude.nworb@uil_nimiS and Yiqing Song, MD, ScD, Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, 714 North Senate Avenue, Indianapolis, IN 46202. E-mail: ude.ui@gnosqiy

Received 2015 Apr 2; Accepted 2015 Apr 30.

Copyright © 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Abstract

Background

Guidelines recommend exercise for cardiovascular health, although evidence from trials linking exercise to cardiovascular health through intermediate biomarkers remains inconsistent. We performed a meta-analysis of randomized controlled trials to quantify the impact of exercise on cardiorespiratory fitness and a variety of conventional and novel cardiometabolic biomarkers in adults without cardiovascular disease.

Methods and Results

Two researchers selected 160 randomized controlled trials (7487 participants) based on literature searches of Medline, Embase, and Cochrane Central (January 1965 to March 2014). Data were extracted using a standardized protocol. A random-effects meta-analysis and systematic review was conducted to evaluate the effects of exercise interventions on cardiorespiratory fitness and circulating biomarkers. Exercise significantly raised absolute and relative cardiorespiratory fitness. Lipid profiles were improved in exercise groups, with lower levels of triglycerides and higher levels of high-density lipoprotein cholesterol and apolipoprotein A1. Lower levels of fasting insulin, homeostatic model assessment–insulin resistance, and glycosylated hemoglobin A1c were found in exercise groups. Compared with controls, exercise groups had higher levels of interleukin-18 and lower levels of leptin, fibrinogen, and angiotensin II. In addition, we found that the exercise effects were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, dyslipidemia, or metabolic syndrome appeared to benefit more.

Conclusions

This meta-analysis showed that exercise significantly improved cardiorespiratory fitness and some cardiometabolic biomarkers. The effects of exercise were modified by age, sex, and health status. Findings from this study have significant implications for future design of targeted lifestyle interventions.

Keywords: biomarker, cardiometabolic health, cardiovascular disease prevention, exercise training

Cardiovascular disease (CVD) remains a leading cause of morbidity and mortality affecting ≈84 million people in the United States.1–3 Current guidelines recommend exercise for both primary and secondary prevention of CVD.4–6 Observational studies have associated exercise with lower CVD risk in populations free of preexisting CVD.7–9 Substantial evidence from secondary prevention studies also confirms better survival and reduced CVD recurrence after exercise interventions.10,11 Because of apparent ethical and feasibility issues, however, no long-term randomized controlled trials (RCTs) have directly investigated the benefits and risks of exercise training in relation to CVD incidence.12 Consequently, exercise interventions among healthy populations have focused on intermediate CVD biomarkers. Changes in circulating CVD biomarkers and cardiorespiratory fitness (CRF) are reasonable indicators for the favorable effects of exercise training on cardiovascular health.

An important component of health-related fitness, CRF refers to the capacity of respiratory and cardiovascular systems to provide muscles with oxygen during sustained and/or intense exercise. Available evidence has shown that CRF can significantly improve the predictive ability of both short- and long-term CVD risk when added to traditional risk factors.13 In addition to serving as a diagnostic and prognostic health indicator in clinical settings, CRF has been used as an indicator of habitual exercise.14,15

Traditional CVD biomarkers, such as non–high-density lipoprotein cholesterol and high-sensitivity C-reactive protein, may also have the potential to be used in CVD risk prediction.16–19 Although most previous studies examining the relationship between exercise and circulating biomarkers focus on commonly measured CVD biomarkers, an increasing number of studies are evaluating novel biomarkers.20,21 Evidence has implicated, for example, relevant biomarkers in insulin resistance and inflammation that contribute to CVD development.22–26

Nevertheless, much remains uncertain concerning the effects of exercise on both traditional and novel CVD biomarkers for targeted interventions and clinical evaluations.20,21,27 The primary objective of this meta-analysis was to assess the effects of exercise training on CRF and a variety of both traditional and novel circulating CVD biomarkers. Furthermore, we aimed to investigate the sources of heterogeneity, especially by potential effect modifiers such as age, sex, obesity, lifestyle, preexisting conditions (type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome), and intervention duration and intensity.

Methods

Data Sources and Searches

We developed and followed a standardized protocol to do this meta-analysis in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.28 Two investigators (X.L., X.Z.) independently conducted literature searches of Medline, Embase, and the Cochrane Central Register of Controlled Trials published from January 1965 (index date) to March 2014, using keywords and Medical Subject Headings (Table​(Table1).1). All relevant studies and review articles (including meta-analysis) and the reference lists of the identified articles were checked manually. Any disagreements between 2 investigators were resolved by consensus. Institutional review board approval is not applicable because the current study is a systematic review and meta-analysis, which is not considered research involving human subjects.

Table 1

Search Strategy for Medline

1.exp Exercise/2.physical activity.ab.3.aerobic*.ab.4.or/1 to 35.exp Biological Markers/6.Exercise Tolerance/7.Exercise Test/8.exp Oxygen Consumption/9.Physical Fitness/10.or/5 to 911.randomized controlled trial.pt.12.controlled clinical trial.pt.13.Randomized Controlled Trials/14.Random Allocation/15.Intervention Studies/16.or/11 to 1517.4 and 1018.17 and 1619.limit 18 to English language20.limit 19 to humans

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Study Selection

Articles were included (1) if the study was an RCT that assigned at least 1 group of participants to exercise training and 1 group to control and (2) if CRF (absolute and relative maximal oxygen uptake) or circulating CVD biomarkers of lipid and lipoprotein metabolism, glucose intolerance and insulin resistance, systemic inflammation, or hemostasis were measured at baseline and at the end of the trial.

All abstracts about RCTs reporting the effect of exercise training on CVD-related biomarkers or CRF were included for screening. We excluded studies (1) if the study design was not a RCT; (2) if the exercise intervention was acute (≤1 week), because we are interested in the effects of exercise interventions of moderate to long duration; (3) if interventions were based on education or counseling rather than a structured exercise training assignment; (4) if maximal oxygen consumption, or VO2max, was indirectly calculated through heart rate or fixed time testing and no other biomarkers of interest to this study were reported; (5) if levels of circulating biomarkers were not directly measured; (6) if values of outcome measures at the end of trials were not reported; (7) if participants had severe chronic diseases (preexisting CVD, liver or kidney diseases, or cancers), any other conditions that could potentially compromise participants’ capacity to exercise (disability, frailty, declined activities of daily living, or wheelchair dependency), or any mental conditions (depression, anxiety, schizophrenia, bipolar disorder, Parkinson’s disease, or Alzheimer’s disease); (8) if participants were identified as trained professionals, athletes, or soldiers; (9) if participants were infants, children, or adolescents; or (10) if participants were pregnant, postpartum, nursing, had recent surgery, or were undergoing rehabilitation exercise. If multiple articles were published based on the same trial, data were retrieved as 1 independent trial. If there were duplicate results from the same trial, the most updated and comprehensive ones were extracted.

Data Extraction and Quality Assessment

In total, 6135 articles were retrieved from the literature search. We excluded 5796 articles after abstract review and 170 after full-text examination. Data extraction was conducted independently by 2 investigators (X.L., X.Z.), and discrepancies were resolved through consensus. The following information was extracted from all eligible studies: general information (first author’s name, article title, and country of origin), study characteristics (study design, eligibility criteria, randomization, blinding, cointervention, dropout rate, and reason for dropping out), participant characteristics (age, sex, ethnicity, body mass index, life style, health status, and number of participants in each group), intervention and setting (exercise type, duration, intensity, and supervision), and outcome measures (definition of outcomes, statistical techniques, pre- and postintervention means, standard deviation, sample size of each arm, and adverse events). Maximal oxygen uptake VO2max was measured directly and determined based on the highest VO2 obtained prior to volitional fatigue. In this meta-analysis, we focused on biomarkers in blood samples, including plasma, serum, and whole blood. All samples for fasting glucose and insulin measurement in the studies were collected after >10 hours of fasting.

Data Synthesis and Analysis

Methodological quality was assessed by 2 investigators (X.L., X.Z.) using the Cochrane Collaboration’s tool for assessing risk of bias.29 This included random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. For each trial, the risk of bias was reported as low risk, unclear risk, or high risk. Disagreement was resolved by discussion. All eligible comparisons from each trial were extracted separately according to exercise intensity. The criteria for classifying exercise interventions as moderate exercise or vigorous exercise are summarized in Table​Table2.2. If the intensity measures were not reported in individual studies, maximum heart rate, maximum heart rate percentage, speed of running, metabolic equivalent, oxygen uptake, or relative metabolic rate were used to classify exercise intensity. To maintain independence, the most vigorous intervention and the control group in each trial were included in the primary analysis if multiple training groups of different intensities were compared with a single control group. Sensitivity analyses were performed by conducting separate analyses of all eligible comparisons for moderate and vigorous exercise interventions, respectively.

Table 2

Criteria Used for Exercise Intensity Classification

ModerateVigorousMaximum heart rate, beats/min<140≥140Maximum heart rate, %<75≥75Speed of running, m/s<6.8≥6.8Metabolic equivalentsWomen: <6Women: ≥6Men: <8Men: ≥8Oxygen uptake (% of VO2max)<70≥70Relative metabolic rate<8≥8

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Mean levels and standard deviations of CRF and CVD biomarkers after the exercise interventions from individual trials were used to calculate weighted mean differences (WMDs) and 95% CIs using DerSimonian and Laird random-effects models.30 Between-study heterogeneity was examined using Q statistics and I2 statistics.31,32 I2 ≈25%, 50%, and 75% is suggestive, respectively, of low, medium, and high heterogeneity. Egger’s tests were used to formally test publication bias.33 If there was any evidence of publication bias, the trim and fill method was used to evaluate the impact of publication bias.34

All eligible trials were analyzed in subgroup analyses conducted within the strata of the predetermined potential modifiers, including age (mean or median <50 versus ≥50 years), sex (women versus men), body mass index (obese versus nonobese), lifestyle (active versus sedentary), health status (having at least 1 of the following comorbidities: type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome versus none), and trial duration (≥16 versus <16 weeks). Obesity was defined as body mass index ≥30 kg/m2. Active lifestyle was defined according to the report of individual trials. Health status was confirmed by clinical diagnosis or reported medication use. Metaregressions were performed to evaluate the overall impact of potential modifiers.

Two-sided P≤0.05 was used as the significance level except for the Q statistic and the Egger’s tests (P=0.10).35 All statistical analyses were performed with Stata statistical software version 12 (Stata Corp).

Results

Figure​Figure11 shows the number of trials included in the analysis for each outcome. A total of 7487 participants aged between 18 and 90 years, from 169 articles based on 160 RCTs, were included in the meta-analysis. Characteristics of eligible studies are summarized in Table​Table3.3. Among all participants, 4276 (57.1%) were women; 3211 (42.9%) were men; 5845 (78.1%) were free of type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome; and 1640 (21.9%) had at least 1 of those conditions. The median duration of trials was 12 weeks (range: 2 weeks to 2 years).

Table 3

Characteristics of the Trials Included in the Meta-Analysis

StudyAge, ySexBMI, kg/m2Duration, wkActivity/Medical ConditionExercise Type, Intensity and CointerventionsNT/NCMarkerAbderrahman, 201336Mean: 20.6Male onlyMean: 22.87NR/HealthRunning/Vigorous/No9/6Absolute CRF, Relative CRFAhmaidi, 19983753 to 74NRNR12Sedentary/HealthWalking/Jogging/Vigorous/No11/11Absolute CRF, Relative CRFAldred, 19953841 to 55Female onlyT: 24.8±1.0 C: 26.8±0.812Sedentary/HealthWalking/Moderate/No11/11TC, HDL-C2 LDL-C, FFAAshutosh, 19973920 to 60Female onlyOverweight or obesity46NR/HealthAerobic exercise/NR/Dietary intervention9/6Absolute CRF, Relative CRFAsikainen, 20024048 to 63Female onlyMean: 26.224Sedentary/HealthWalking/Vigorous/No20/38Relative CRFBaker, 198641Mean: 58.2Male onlyNR20Sedentary/HealthAerobic training/Vigorous/No20/14Absolute CRF, Relative CRF, TC, HDL-C, LDL-C, VLDL-CBalducci, 2010, 201242C: 58.8±8.6 T: 58.8±8.5NRC: 31.9±4.6 T: 31.2±4.652Sedentary/Diabetes mellitusAerobic and resistance training/Moderate/No288/275Relative CRF, TC, TG, HDL-C, LDL-C, CRP, Fasting glucose, Insulin, HOMA-IR HbA1cBeavers, 20104360 to 79Female: 67%>28.078Active/HealthWalking and interactive, health education in control97/93LeptinBell, 201044Male: 49±11 Female: 50±9NRMean: 3024Sedentary/HealthWalking/Moderate/No43/45Absolute CRF, Relative CRF, TC, TG, HDL-C, LDL-C, Fasting glucoseBermon, 19994567 to 80Male: 16T: 24.9±0.5 C: 25.9±0.68Sedentary/HealthStrength training/Vigorous/No16/16IGF-1, IGF-BPBiddle, 201146Mean: 34.8±12.6Female 13Mean: 36.3±6.74Sedentary/HealthSmall-sided games-based exercise/NR/No9/7Absolute CRF, Relative CRF, TC, TG, HDL-C, LDL-C, CRP, Fasting glucose, HbA1cBlumenthal, 19914760 to 83Female: 50%NR60Sedentary/HealthAerobic exercise or yoga/Vigorous/No15/15Absolute CRF, Relative CRFBlumenthal, 19914829 to 59Male: 62%Mean: 26.916NR/untreated mild hypertensionAerobic exercise training/Joging39/22Absolute CRF, Relative CRFBoardley, 200749≥65Male: 27%NR16Sedentary/HealthResistance training and aerobic walking/Moderate/No33/35TC, TG, HDL-C, LDL-CBobeuf, 20115059 to 73Female: 52.6%Mean: 26.2±2.624Sedentary/HealthResistance training/Vigorous/Vitamins C/E supplementation17/12TC, TG, HDL-C, LDL-CBoreham, 20005118 to 22Female onlyNR7Sedentary/HealthStair climbing/Moderate/No12/10TC, HDL-CBoudou, 200352Mean: 45.4±7.2Male onlyMean: 29.6±4.68NR/Diabetes mellitusEndurance exercise/Vigorous/No8/8Adiponectin, Leptin, InsulinBourque, 19975323 to 43Female onlyMean: 23.1±4.912Sedentary/HealthEndurance exercise/Vigorous/No6/7Relative CRFBraith, 19945460 to 79Female: 54.5%NR24Sedentary/HealthWalking/Vigorous/No14/11Relative CRFBroeder, 19925518 to 35Male onlyMean: 25.312NR/HealthWalk or jog/Vigorous/No15/19Relative CRFBroman, 20065669±4Female onlyNR8NR/HealthIn deep water running/Walking/Vigorous/No15/9Absolute CRF, Relative CRFBurr, 201157Mean: 26NRNR6Sedentary/HealthVehicle riding/Vigorous/No34/12Relative CRF, Fasting glucoseCamargo, 200858Mean: 29Male onlyMean: 27.312Sedentary/HealthAerobic training/Moderate/No7/7Relative CRFCampbell, 20075940 to 75Female only29.9 to 28.752Sedentary/HealthAerobic Exercise/Moderate/No17/15Absolute CRF, Relative CRF, CRPCanuto, 20126018 to 64Female onlyMean: 34.812NR/HealthResistance training/Moderate/Education29/30TC, TG, HDL-C, LDL-C, CRP, Fasting glucose, Insulin, HbA1cCarroll, 201261T: 39.3±7.8 C: 41.0±7.7Female onlyT: 39.9±7.4 C: 41.0±7.712Sedentary/HealthTreadmill walking/Moderate/Lifestyle intervention22/22Absolute CRF, Relative CRFChan, 201362Mean: 54±11Female onlyMean: 31±710Sedentary/HypertensionTreadmill walking/Vigorous/Education10/13Relative CRF,Chandler, 19966360 to 79Female: 38.6%NR24NR/HealthEndurance training/Moderate/No16/11Relative CRF, PAI-1Cho, 20116434 to 60Female onlyMean: 25.612Sedentary/HealthWalking/Moderate/No13/10Relative CRF,TG, HDL-C FFA, Fasting glucose, Insulin, HOMA-IRChristiansen, 20106518 to 45Female: 3830 to 4012Sedentary/HealthAerobic exercise/Vigorous/Dietary intervention21/19Absolute CRF,TC, TG, HDL-C, FFA, IL-6, IL-18, Adiponectin, Fasting glucose, Insulin, HOMA-IRChurch, 20076645 to 75Female only25 to 4324Sedentary/HealthAerobic exercise/Moderate/No103/102Absolute CRF, relative CRF, TG, HDL-C, LDL-C, Fasting glucoseCiolac, 20116720 to 30Female onlyMean: 23.7816Sedentary/HealthEndurance exercise/Vigorous/No11/12Relative CRF,TC, TG, HDL-C, LDL-C, Fasting glucose, Insulin, HOMA-IRCoker, 20096865 to 90Female: 50%26 to 3712NR/HealthCycle ergometer/Moderate/No6/6Absolute CRFCortez-Cooper, 20086940 to 80Female: 73.8%<3013Sedentary/HealthAerobic exercise strength training vs stretching/Moderate/No12/12Relative CRF,TC, TG, HDL-C, LDL-C, Endothelin-1, Fasting glucoseCox, 19937020 to 45Male onlyMean: 26.3 (25.7 to 26.9)4Sedentary/HealthNot report/Vigorous/Drink low-alcohol beer or continue their normal drinking habits19/16TC, TG, HDL-C, HDL-C2, HDL-C3, LDL-C, Apo AI, Apo AII, Apo BCox, 200371Mean: 42.4±5.0Male onlyOverweight or obesity16Sedentary/HypertensionNR/Moderate & vigorous/Dietary intervention and usual dietary13/17Absolute CRFDalleck, 20097245 to 75 yearFemale onlyNormal12Sedentary/HealthNR/Moderate/No8/10Absolute CRF, Relative CRF,TC, TG, HDL-C, LDL-C, Fasting glucoseDe Vito, 19997360 to 70Female onlyNR12Sedentary/HealthWalking/Moderate/No11/9Absolute CRF, Relative CRFDimeo, 20127442 to 78Female: 58%Mean: 29.412NR/HyperlipidemiaWalking on a treadmill/NR/No22/25Relative CRFDipietro, 20067562 to 84Female onlyMean: 27.336Sedentary/HealthAerobic training/Moderate/No9/7Relative CRF,FFA, Fasting glucose, InsulinDuncan, 19917620 to 40Female onlyNR24Sedentary/HealthWalk/Moderate/No12/13Relative CRF,TC, TG, HDL-C, LDL-CDuscha, 20057740 to 65NR25 to 3536NR/HyperlipidemiaWalking/Moderate/No25/37Absolute CRF, Relative CRFEguchi, 20127820 to 65Female onlyMean: 25.1±3.912NR/HealthEndurance training using bicycle ergometers/Moderate/No8/10Absolute CRF, Relative CRF,TC, TG, HDL-C, LDL-C, Fasting glucose, HbA1cFatouros, 20057965 to 78Male only28.7 to 30.224Sedentary/HealthResistance exercises/Moderate/No12/10Relative CRF, Adiponectin, Leptin, Fasting glucose, HOMA-IRFinucane, 20108067.4 to 76.3Female: 44%Mean: 27.212NR/HealthCycle ergometer/Moderate/No48/48TC, TG, HDL-C, LDL-C, Fasting glucose, HbA1cFriedenreich, 20118150 to 74Female only22 to 4052Sedentary/HealthAerobic exercise/Vigorous/No154/154Adiponectin, Leptin, Fasting glucose, Insulin, HOMA-IR, IGF-1, IGF-BPGarber, 19928224 to 50Female: 75%NR8Sedentary/HealthWalk-jog/Moderate/No13/9Relative CRFGeogiades, 200083≥29Female: 44%25 to 3724Sedentary/HypertensionAerobic exercise/Vigorous/No36/19Relative CRFGormley, 20088418 to 31Female: 65.5%Mean: 24.36Sedentary/HealthAerobic/Moderate/No14/13Relative CRFGram, 20108525 to 80Female: 45.6%NR52NR/Diabetes mellitusStrength training and aerobic exercise/Moderate/No21/20Absolute CRF,TC, HDL-C, LDL-C, HbA1cGrandjean, 199686NRFemale onlyNR24Sedentary/HealthWalking and jog and cycling/Vigorous/No20/17Absolute CRF,TC, TG, HDL-C, LDL-C, VLDL-CGray, 20098718 to 65Female: 77%Mean: 28.612Sedentary/HealthPedometer-based walking/Moderate/No24/24CRP, IL-6, TNF-α, Fasting glucose, Insulin, HOMA-IRGuadalupe-Grau, 200988Mean: 23.9±2.4Female: 34.8%C: 24.0±3.6 T: 22.8±2.09Active/HealthStrength combined with plyometric jumps training/Vigorous/No8/15LeptinHagan, 198689Mean: 36.6Female: 50%Normal12Sedentary/HealthAerobic training/Moderate/Dietary training12/12Absolute CRF, Relative CRF,TC, TG, HDL-C, LDL-C, VLDL-CHass, 20019035 to 55Female: 50%NR12Sedentary/HealthNR/Moderate/No17/9Absolute CRF, Relative CRFHendrickson, 20109118 to 26Female onlyNR12Active/HealthAerobic endurance and strength training/Vigorous/No13/10Relative CRFHeydari, 201392Mean: 24.9±4.3Male onlyMean: 28.7±3.112Sedentary/HealthHigh-intensity intermittent exercise/Vigorous/No20/18Absolute CRF, Relative CRFHeydari, 201392Mean: 24.9±4.3Male onlyMean: 28.712Active/HealthHigh-intensity intermittent exercise/Vigorous/No25/21Absolute CRF, Relative CRFHilberg, 201393T: 49±6 C: 48±6Male onlyNR12NR/HealthNR/Vigorous/No22/22Relative CRFHiruntrakul, 20109418 to 25Male onlyC: 21.35±3.54 T: 20.99±3.3512Sedentary/HealthAerobic exercise/Moderate/No19/18Relative CRF, HDL-CHo, 20129540 to 66Female: 83.5%25 to 4012Sedentary/HealthAerobic resistance training/Moderate/No15/16Relative CRF, TC, TG, HDL-C, LDL-C, Fasting glucose, InsulinHu, 20099620 to 45Male onlyNR10Sedentary/HealthProgressive strength training/Moderate/No48/21Absolute CRF, Relative CRF,Huttunen, 19799740 to 45Male onlyNR16Sedentary/HealthWalking, Jogging, Swimming, Skiing, or Cycling/Moderate/No44/46Relative CRF, HDL-C, Apo AI, Apo AIITsuji, 20009860 to 81Female: 53%NR25Active/HealthEndurance session with a bicycle ergometer, and a resistance exercise training session using rubber films/Moderate/Education31/33Relative CRFIrwin, 20129959 to 86Female: 61%NR9Sedentary/HealthTai Chi Chih vs health education/Moderate/No46/37CRP, IL-6, IL-18Larose, 201110039 to 70Female 36.2%Mean: 34.924Sedentary/Diabetes mellitusAerobic or resistance training/Vigorous/No60/63Relative CRF, HbA1cJessup, 199810161 to 77Female: 52%NR16Sedentary/HealthTreadmills and stair-climbers/Vigorous/No11/10Relative CRFKadoglou, 2012102Mean: 61.3±2.1Female: 67.6%T: 32.74±4.05 C: 31.58±5.7112NR/Diabetes mellitusResistance Exercise/Vigorous/No23/24Relative CRF, TC, TG, HDL-C, LDL-C, Fasting glucose, Insulin, HOMA-IR, HbA1c, FibrinogenKarstoft, 2013103C: 57.1±3.0 T: 60.8±2.2Female: 31%NR16NR/Diabetes mellitusWalking/Moderate/No12/8Absolute CRF, Relative CRF,TC, TG, HDL-C, LDL-C, Fasting glucose, Insulin, HbA1cKing, 1989104Male 49±6 Female 47±5Female: 50%NR24Sedentary/HealthAerobic/Exercise/Training/Moderate/No29/28Relative CRFKirk, 200310519 to 30Male only27 to 3236Sedentary/HealthAerobic exercise/Moderate/No16/15Absolute CRF, Relative CRFKirk, 200310519 to 30Female only27 to 3236Sedentary/HealthAerobic Exercise/Moderate/No25/18Absolute CRF, Relative CRFKiviniemi, 2007106T: 31±6 C 35±8Male onlyT: 24±2 C: 25±14Active/HealthRunning/Vigorous/No9/10Absolute CRF, Relative CRFKokkinos, 199810735 to 76Male onlyT: 30±4 C: 31±516Sedentary/HypertensionAerobic/Exercise/Moderate/No15/19TC, TG, HDL-C, HDL-C2, HDL-C3, LDL-C, Apo AI, Apo BKraemer, 1997,108 1999109Mean: 35.4±8.5Female onlyC: 28.2±4.0 T: 28.3±4.212NR/HealthAerobic endurance exercise/Vigorous/Dietary intervention9/8Absolute CRF, Relative CRF, TG, Fasting glucoseKrogh, 201211018 to 60Female: 67%NR12NR/HealthAerobic exercise/Vigorous/No56/59Relative CRF, TC, TG, HDL-C, Fasting glucose, InsulinKrustrup, 200911120 to 43Male onlyMean: 25.712Sedentary/HealthRecreational soccer/Vigorous/No12/10Relative CRF, TC, HDL-C, LDL-C,Absolute CRF, CRP, Fasting glucose, InsulinKukkonen-Harjula, 199811231 to 52Female: 53%18.5 to 32.715Sedentary/HealthWalking/Training/Moderate/No58/58Absolute CRF, Relative CRF, FibrinogenKurban, 2011113T: 53.77±8.2 C: 53.57±6.6Female: 51.7%T: 30.90±4.64 C: 30.23±4.7412Sedentary/Diabetes MellitusWalking/Moderate/No30/30Fasting glucose, HbA1cLaaksonen, 200011420 to 40Male onlyMean: 24.416Active/Diabetes mellitusSustained running/Moderate/No20/22Relative CRF, TC, TG, HDL-C, LDL-C, Apo AI, Apo B, HbA1cLabrunee, 2012115Mean: 52.7±8.2Female: 82.6%Mean: 38.5±7.612NR/Diabetes mellitusCyclergometer training/NR/No11/12Relative CRF, TC, TG, HDL-C, LDL-C, Fasting glucose, HOMA-IR, HbA1cLake, 199611618 to 28Male onlyNR6Active/HealthRunning training/Moderate/No8/7Relative CRFLaPerriere, 199411718 to 40Male onlyNR10Sedentary/HealthAerobic exercise/Vigorous/No7/7Relative CRFLee, 200311818 to 30Male onlyNR2Sedentary/HealthCycle ergometer/Vigorous/No12/12Relative CRFLee, 201211930 to 50Female only≥2514NR/HealthNR/Moderate/No8/7Relative CRF, TC, TG, HDL-C, LDL-C, CRP, IL-6, TNF-αLeMura, 2000120Mean: 20.4±1Female onlyT: 20.8±2.1 C: 21.8±2.316Sedentary/HealthResistance training and aerobic training/Vigorous/No10/12Relative CRF,TC, TG, HDL-C, LDL-CLibardi, 2012121T 48.6+5.0 C 49.1+5.5Male onlyT: 27.5+4.1 C: 24.7+3.324Sedentary/HealthResistance training/Moderate/No12/13Relative CRF, TC, TG, HDL-C, LDL-C, CRP, IL-6, TNF-α, Fasting glucosede Lima, 201212220 to 35Female onlyC: 23.0±2.4 T: 22.8±3.612Sedentary/HealthMuscular endurance/Moderate/No10/8Relative CRFLovell, 201112370 to 80Male onlyNR20Active/HealthCycle ergometer and stretching/Vigorous/No12/12Absolute CRF, Relative CRFMartin, 1990124T: 58.6±4.6 C 60.6±7.4Female onlyNR12Sedentary/HealthCycle ergometer training/Vigorous/No14/14Absolute CRF, Relative CRFMcAuley, 200212525 to 70Female: 67%<2716NR/HealthNR/Moderate/Dietary intervention29/23TC, TG, HDL-C, LDL-C, Fasting glucose, InsulinMeckling, 200712620 to 62Female only25 to 3012NR/HealthResistance training and endurance training/Moderate and vigorous/Dietary intervention or high protein11/8TC, TG, HDL-C, Fasting glucose, InsulinMeyer, 200612730 to 60Female: 47%NR12Sedentary/HealthWalking or running/Vigorous/No12/13Relative CRFMiyaki, 2012128Mean: 60±6Female onlyNR8Sedentary/HealthWalking and cycling/Moderate/No11/11Relative CRF, TC, TG, HDL-C, LDL-C, Fasting glucoseMorey, 201212960 to 89Female: 3%25 to 45 kg/m252NR/HealthEnhanced fitness intervention/NR/No180/122TC, TG, HDL-C, LDL-C, Fasting glucose, Insulin, HOMA-IR HbA1cMorgan, 201013050 to 70Females: 73.3%NR15Sedentary/HealthWalk/Moderate/No14/15TC, HDL-CMorton, 2010131T: 61+10 C: 63+9Females: 22.2%T: 32+7 C: 30.9+7.07Sedentary/Diabetes mellitusWalking/Vigorous/No15/12Absolute CRF, Relative CRF, Fasting glucose, HbA1cMurphy, 2006132Mean: 41.5±9.3Female: 64.9%T: 26.8±5.6 C: 24.4±3.68Sedentary/HealthWalking/Moderate/No21/12TC, TG, HDL-C, LDL-C, CRPMurtagh, 2005133Mean: 45.7±9.4Female: 64.6%<3012Sedentary/HealthWalking/Vigorous/No18/11Relative CRF, TC, TG, HDL-C, LDL-CMusa, 200913421 to 36Male onlyNormal8Sedentary/HealthInterval running/Moderate/No20/16TC, HDL-CNemoto, 2007135Mean: 63±6Female: 75.6%C: 22.8 T moderate: 22.8 vigorous: 22.920NR/HealthWalking/Moderate/No43/37Absolute CRFNicklas, 200913650 to 70Female only25 to 4020Sedentary/HealthCalorie restriction and aerobic exercise/Moderate/dietary intervention36/29TG, HDL-C, LDL-C, Fasting glucose, InsulinNiederseer, 2011137T: 66.6±2.1 C: 67.3±4.4Female: 47.6%T: 27.1±3.3 C: 25.4±2.812Active/HealthSkiing/Moderate/No22/20Relative CRF, TC, TG, HDL-C, LDL-C, CRP VCAM-1, ICAM-1, Endothelin-1, e_selectinNieman, 199313867 to 85Female onlyMean: 23.712Sedentary/HealthWalk/Moderate/No14/16Relative CRF, TC, TG, HDL-C, LDL-C,Nieman, 1998139Mean: 45.6±1.1Female onlyMean: 33.1±0.612Active/HealthWalking/Moderate and vigorous/dietary intervention22/26Absolute CRF, TC, Fasting glucoseNordby, 201214020 to 40Male only25 to 3012Sedentary/HealthEndurance training (cycling, running, cross-training, or rowing)/Moderate/Dietary intervention12/12Absolute CRF, Relative CRF, Fasting glucose, Insulin, HbA1cO’donovan, 200514130 to 45Male onlyNR24Sedentary/HealthNR/Moderate/No14/15Absolute CRF, Relative CRF, TC, TG, HDL-C, LDL-C, FibrinogenPanton, 1990142 Pollock, 199114370 to 79Female: 53.1%NR24Sedentary/HealthAerobic and resistance training/NR/No13/15Relative CRFPhillips, 201214462 to 67Female onlyOverweight or Obesity12Active/HealthAerobic training/Vigorous/No11/12LeptinPoehlman, 200014518 to 35Female onlyC: 22±2 T: 22±224Sedentary/HealthEndurance training (N=14), resistance training/Vigorous/No14/20Absolute CRFPosner, 199214660 to 86Female: 61.9%NR16Sedentary/HealthCycle ergometer/Moderate/No166/81Absolute CRF, Relative CRFProbart, 1991147≥70Female onlyMean: 24.626NR/HealthWalking on a treadmill/Vigorous/No10/6Absolute CRF, Relative CRFPyka, 199414864 to 78Female: 60%NR104NR/HealthResistance exercise (walking and stretching)/Moderate/No8/6IGF-1Chow, 198714950 to 62Female onlyNR52NR/HealthAerobic exercise or aerobic and strengthening exercises/Vigorous/No17/15Relative CRFRaz, 198815024 to 26Male onlyMean: 22.89Sedentary/HealthAerobic exercise/Vigorous/No28/27Relative CRF, TC, TG, HDL-C, HDL-C2, HDL-C3, LDL-C, HbA1cReady, 1996151≥50Female onlyNR24Sedentary/HealthWalk/Moderate/No17/18Absolute CRF, Relative CRF, TC, TG, HDL-C, LDL-CRomero-Arenas, 201315255 to 75NRMean: 29.912Active/HealthResistance training/Moderate/No16/10Relative CRFSanta-Clara, 2003,153 200615445 to 70Female onlyCaucasian-American T: 25±3 C: 27±5 African-American T: 29±7 C: 29±624Sedentary/HealthTreadmill walking/Jogging, stationary cycling, and rowing/Vigorous/No17/16Relative CRF, IGF ISantiago, 199515522 to 40Female only≥3140Sedentary/HyperlipidemiaWalking/Vigorous/No16/11Relative CRF, TC, TG, HDL-C, LDL-CScanga, 1998156Mean: 38±7Female onlyC: 35.2±3.9 T: 36.6±4.38NR/HealthAerobic and resistance training/Moderate/Dietary intervention10/12Absolute CRF, Relative CRFSeifert, 2009157C: 30±5 T: 32±6Male only25 to 3012Sedentary/HealthEndurance training/Moderate/Endurance training10/7Fasting glucoseLamina, 201115850 to 70Male only20 to 308Sedentary/HypertensionBicycle ergometer/Vigorous/No112/105Relative CRFSillanpaa, 2009,159 201016039 to 64Female onlyNormal21NR/HealthNR/Vigorous/15/12TC, TG, HDL-C, LDL-C, Fasting glucose, InsulinSloan, 2013161T: 54.1±5.8 C: 54.1±4.9Female onlyT: 29.2±4.9 C: 27.1±5.916Sedentary/HealthWalking/Moderate/No16/16Relative CRFSpence, 2013162NRMale onlyT: 73.0±16.9 C: 81.7±15.2324Active/HealthEndurance vs resistance/Moderate/No10/13Absolute CRF, Relative CRFStachenfeld, 1998163> 65Female onlyNR24Active/HealthAerobic training/Vigorous/No9/8Relative CRFStein, 1992164T: 46.2±6.1 C: 45.0±6.1Male onlyNR8Sedentary/HealthAerobic exercise training/Moderate/No19/14Absolute CRFStensel, 199316542 to 59Male onlyNormal52Sedentary/HealthBrisk/Walking/Moderate/No24/24TC, TG, HDL-C, LDL-C, VLDL-C, Apo AI, Apo B, Lp-AStensvold, 2010166Mean: 50.2±9.5Female: 39.5%C: 31.9±4.1 T: 32.2±4.212Sedentary/HealthStrength training vs aerobic interval training/Vigorous/No11/10Relative CRF, TC, TG, HDL-C, Fasting glucose, C-peptide, HbA1cStrasser, 2009167>70Females: 55.6%Mean: 26.924Sedentary/HealthEndurance training or–and resistance training/Vigorous/No13/14Relative CRFSung, 2012168>70Female: 65%NR24NR/Diabetes mellitusWalking/Moderate/No22/18TC, TG, HDL-C, LDL-C, Fasting glucose, HbA1cTakeshima, 200216960 to 75Female onlyNR7Sedentary/HealthStretching, endurance-type exercise (walking and dancing, 30 min), Resistance exercise/Vigorous/No15/15TC, TG, HDL-C, LDL-CTakeshima, 200417060 to 838 Males and 10 FemalesNR12Sedentary/HealthProgressive accommodating circuit exercise/Vigorous/No18/17Absolute CRF, TC, TG, HDL-C, LDL-CThomas, 198417118 to 32Female onlyNR12Active/HealthRunning/Vigorous/No9/6Absolute CRF, Relative CRF, TC, TG, HDL-CThompson, 201017245 to 64Male onlyC: 28.0±2.7 T: 28.5±2.924Sedentary/HealthNR/Moderate/Dietary intervention20/21Relative CRF,TC, TG, HDL-C, CRP, IL-6, Fasting glucose, Insulin, HOMA-IRTjonna, 2008173Mean: 52.3±3.7Female: 53.6%C: 32.1±3.3 T: 29.4±4.916NR/HealthAerobic interval training/Vigorous/No8/9Relative CRF, TG, HDL-C, Adiponectin, Fasting glucose, Insulin, HOMA-BToledo, 2008174>30Female: 62.5%T: 34.8±1.1 C: 33.4±1.216Sedentary/HealthWalking/Moderate/Dietary training9/7FFA, Fasting glucose, InsulinTseng, 201317518 to 29Male only12NR/HealthAerobic, resistance or combined aerobic and resistance training/Moderate/10/10TG, HDL-C, Fasting glucoseTulppo, 200317635±10Male onlyModerate: 25±3 Vigorous: 25±2 C: 25±38Sedentary/HealthWalking and Jogging/Vigorous/No16/11Absolute CRF, Relative CRFUtter, 199817725 to 75Female only25 to 6512Sedentary/HealthWalk/Moderate and vigorous/Dietary intervention21/22Absolute CRF, Relative CRFVan Aggel-Leijssen, 2001,178 2001179C: 38.6±6.5 T: 39.3±7.7Male onlyC: 32.6±2.5 T: 32.0±2.112Sedentary/HealthCycling on an ergometer, walking, and aqua-jogging/Moderate/Energy restriction and dietary intervention20/17Absolute CRF, FFA, Fasting glucose, InsulinVan Den Berg, 201018018 to 30Male onlyNR7Sedentary/HealthMotor-driven treadmill/Moderate/No9/13Absolute CRF, Relative CRFVicente-Campos, 201218162 to 67Female: 60%NR28Sedentary/HealthAerobic training/Vigorous/No22/21TC, TG, HDL-C, LDL-CVincent, 200218260 to 83Female and MaleNR24Sedentary/HealthResistance training/Moderate/No24/16Relative CRFVissers, 2010183C: 44.8±11.4 T: 44.7±13.0Female: 74.7%C: 29.8±2.6 T: 33.1±3.452Active/HealthBicycle ergometer/Vigorous/No20/20TG, HDL-CVitiello, 1997184Male: 66.9±1.0 Female: 67.1±1.7Female: 40.3%NR24Sedentary/HealthEndurance or stretching/Flexibility/Moderate/No30/22Relative CRF, IGF-1Volpe, 2008185Mean: 44.2±7.2Female onlyMean: 30.5±2.752Sedentary/HealthSkiing/NR/Dietary intervention14/14TC, TG, HDL-C, LDL-CWaib, 201118647 to 56Training: 60.8%T: 30.0 (28.8 to 31.2) C: 29.6 (27.8 to 31.5)15Sedentary/HypertensionAerobic training jogging on an electronic treadmill/Moderate/No55/24Relative CRF, HOMA-IR, C-peptideWallman, 200918718 to 64Female: 75%Mean: 30±28Sedentary/HealthAerobic Exercise/Vigorous/Dietary education6/8TC, TG, HDL-C, LDL-CWang, 2005188C: 24.7±2.3 T: 23.5±1.6Male onlyC: 22.7±1.7 T: 23.1±0.68Sedentary/HealthBicycle ergometer/Moderate/No15/15Relative CRFWang, 2011189T: 21.5±0.7 C: 22.9±0.4Male onlyT: 22.9±0.4 C: 23.3±0.74Sedentary/HealthBicycle ergometer/Moderate/No10/10Relative CRFWarner, 198919027 to 63Female: 35.3%NR12Sedentary/HyperlipidemiaAerobic training/Vigorous/Fish oil intervention7/7Relative CRF, LDL-C, Apo BWarren, 1993191Mean: 73.6±0.7Female onlyNormal12Sedentary/HealthWalking or calisthenics control/Moderate/No14/16Relative CRFWatkins, 2003192NRNRT: 33.4±4.5 C: 34.0±5.224Sedentary/HealthAerobic training/Vigorous/Weight lost14/9Relative CRF,TC, TG, HDL-C, LDL-C, Fasting glucose, InsulinWong, 1990193Mean: 62.7±3.1Male onlyNormal52NR/HealthTreadmill walking/Moderate/No69/69Absolute CRF,Woods, 1999194Mean: 65±0.8NRNR24Sedentary/HealthAerobic exercise/Moderate/No14/15Absolute CRF, Relative CRFWu, 201119545 to 64Female: 71.9%16.0 to 33.336NR/HealthAerobic exercise, stretching exercise/Vigorous/No68/67TG, Adiponectin, Fasting glucose, Insulin, HOMA-IRYoshizawa, 200919650 to 65Female onlyMean: 23.78Sedentary/HealthResistance training/Moderate/No12/13Relative CRF, TC, TG, HDL-C, LDL-CYoshizawa, 200919732 to 59Female onlyT: 24.6±1.1 C: 21.8±1.012Sedentary/HealthAerobic exercise training/Moderate/No12/12Relative CRF, TC, HDL-C, LDL-CYou, 200619850 to 70Female only25 to 4020Sedentary/HealthTreadmill/Moderate/Dietary intervention13/14Absolute CRF, Relative CRFZiemann, 2011199T: 21.6±1.1 C: 21.0±0.9Male onlyT: 24.5±1.8 C: 23.0±1.96Active/HealthNR/Vigorous/Physical education10/11Absolute CRF, Relative CRF

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Apo AI indicates apolipoprotein A1; Apo AII, apolipoprotein A2; Apo B, apolipoprotein B; BMI, body mass index; C, control group; CRF, cardiorespiratory fitness; CRP, C-reactive protein; FFA, free fatty acid; HbA1c, glycosylated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment–insulin resistance; ICAM-1, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor 1; IGF-BP, insulin-like growth factor binding protein; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; NR, not reported; PAI-1, plasminogen activator inhibitor-1; T, training group; TC, total cholesterol; TNF, tumor necrosis factor; VCAM-1, vascular cell adhesion molecule 1; VLDL-C, very low-density lipoprotein cholesterol.

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Figure 1

Summary of study selection process. In total, 6135 articles were retrieved from the literature search that evaluated the effect of exercise interventions on CRF or cardiometabolic biomarkers. We excluded 5796 articles after abstract review and 170 after full text examination. After exclusion, 160 RCTs reported in 169 articles were included in the meta-analysis. Apo AI indicates apolipoprotein A1; Apo AII, apolipoprotein A2; Apo B, apolipoprotein B; CRF, cardiorespiratory fitness; CRP, C-reactive protein; FFA, free fatty acid; HbA1c, glycosylated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOME-B, homeostatic model assessment-beta cell function; HOMA-IR, homeostatic model assessment–insulin resistance; HOMA-S, homeostatic model assessment-insulin sensitivity; ICAM-1, intercellular adhesion molecule 1; IGF-1, insulin-like growth factor 1; IGF-BP, insulin-like growth factor binding protein; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; Lp(a), lipoprotein(a); PAI-1, plasminogen activator inhibitor-1; RCTs, randomized controlled trials; TC, total cholesterol; TG, triglycerides; TNF-α, tumor necrosis factor α; VCAM-1, vascular cell adhesion molecule 1; VLDL-C, very low-density lipoprotein cholesterol.

Description of Study Quality

The quality of studies included was heterogeneous (Figure​(Figure2).2). Random sequence generation was reported in 50 trials, and allocation concealment was reported in 20 trials; only 1 of these trials showed a high probability of selection bias because the random allocation was not concealed. The risk of potential performance bias was high in all trials because it was not possible to blind participants and trainers in exercise interventions. Among 26 trials reporting the blinding of outcome assessment, the risk of detection bias was high in only 1 trial. The risk of other bias was high in 46 trials because of poor compliance, the use of intention-to-treat analysis, limited sample sizes, or limitations discussed in individual articles.

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Figure 2

Assessment of risk of bias: summary for items of bias.

Cardiorespiratory Fitness

A total of 67 and 123 independent comparisons were included in the primary analysis for absolute and relative CRF, respectively (Table​(Table4).4). Both measures were significantly raised by exercise interventions (both P<0.001). The WMDs comparing exercise groups and control groups were 0.28 L/min (95% CI 0.23 to 0.33; I2=93.7%; P<0.001 for heterogeneity) for absolute CRF and 3.90 mL/kg per minute (95% CI 3.45 to 4.35; I2=91.4%; P<0.001 for heterogeneity) for relative CRF. The Egger’s tests showed evidence of publication bias in both instances (P<0.05). When applying the trim and fill method, the conclusion regarding the associations between exercise training and CRF did not change (filled analysis for absolute CRF: WMD 0.14 L/min, 95% CI 0.20 to 5.28, P<0.001; filled analysis for relative CRF: WMD 2.56 mL/kg per minute, 95% CI 3.06 to 10.16, P<0.001).

Table 4

WMDs in Cardiorespiratory Fitness and Circulating Concentrations of Biomarkers Between Exercise Groups and Control Groups

OutcomeNo.*Number of ParticipantsWMD95% CIP WMDExerciseControlCardiorespiratory fitness Absolute, L/min67144812720.280.23 to 0.33<0.001 Relative, mL/kg per minute122254322493.943.48 to 4.39<0.001Lipid and lipoprotein markers TC, mg/dL68175416041.16−9.28 to 11.990.82 TG, mg/dL6618511703−5.31−10.63 to −0.890.02 HDL-C, mg/dL74196718002.321.16 to 3.87<0.001 HDL2-C, mg/dL591920.39−1.93 to 2.320.8 HDL3-C, mg/dL36262−0.08−1.55 to 1.550.94 LDL-C, mg/dL59168115253.87−8.12 to 0.390.08 VLDL-C, mg/dL7130102−3.09−8.51 to 2.320.29 Apo AI, g/L563620.030.02 to 0.04<0.001 Apo AII, g/L21401260.01−0.01 to 0.030.2 Apo B, g/L5103870.01−0.01 to 0.030.4 FFA, mmol/L67062−0.06−0.14 to 0.030.21Adipokine and inflammatory markers CRP, mg/L13598554−0.22−0.78 to 0.340.44 IL-6, pg/mL6130121−0.05−0.27 to 0.170.66 IL-18, pg/mL2675618.30.10 to 36.60.05 TNF-α, pg/mL343440.21−0.37 to 0.790.48 Adiponectin, μg/mL62732670.52−0.20 to 1.230.16 Leptin, ng/mL7312315−2.72−4.03 to −1.42<0.001Glucose/insulin metabolism markers Glucose, mmol/L4917201569−0.07−0.13 to 0.0040.06 Insulin, μIU/mL2912721149−1.03−1.69 to −0.370.002 HOMA-IR141033912−0.3−0.49 to −0.110.002 HbA1c, %19972878−0.28−0.42 to −0.14<0.001 C-peptide, nmol/L26634−0.08−0.29 to 0.460.67 IGF-1, ng/mL52302073.16−2.98 to 9.310.31 IGF-BP3, μg/mL2170164−0.002−0.23 to 0.230.99Hemostatic factors Fibrinogen, g/L23639−0.39−0.75 to −0.030.04 Endothelin-1, pg/mL23432−0.22−0.62 to 0.190.29 Angiotensin II, pg/mL22425−1.32−2.11 to −0.540.001

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Apo AI indicates apolipoprotein A1; Apo AII, apolipoprotein A2; Apo B, apolipoprotein B; CRP, C-reactive protein; FFA, free fatty acid; HbA1c, glycosylated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment–insulin resistance; IGF-1, insulin-like growth factor 1; IGF-BP3, insulin-like growth factor binding protein 3; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglycerides; TNF-α, tumor necrosis factor α; VLDL-C, very low-density lipoprotein cholesterol; WMDs, weighted mean differences.

*Number of eligible independent comparisons.

Lipid and Lipoprotein Markers

The number of comparisons for each lipid and lipoprotein marker is shown in Table​Table4.4. Exercise training significantly lowered the levels of triglycerides (P=0.02) and increased the levels of high-density lipoprotein cholesterol (HDL-C; P<0.001) and apolipoprotein A1 (P<0.001). The WMDs were −5.31 mg/dL (95% CI −10.63 to −0.89; I2=71.8%; P<0.001 for heterogeneity) for triglycerides, 2.32 mg/dL (95% CI 1.16 to 3.87; I2=87.5%; P<0.001 for heterogeneity) for HDL-C, and 0.03 g/L (95% CI 0.02 to 0.04; I2=0.0%; P=0.81 for heterogeneity) for apolipoprotein A1. The P value of the Egger’s test for HDL-C was 0.03, suggesting possible publication bias; however, the results from the trim and fill analysis did not show substantial impact of publication bias on the estimates or the statistics (filled analysis: WMD 2.32 mg/dL, 95% CI 1.16 to 3.87, P<0.001).

Adipokine and Inflammatory Markers

Significant associations were found for interleukin-18 (WMD 18.3 pg/mL; 95% CI 0.10 to 36.6; I2=0.0%; P=0.95 for heterogeneity) but not for C-reactive protein, interleukin-6, or tumor necrosis factor α in the primary analysis (Table​(Table4).4). Although there was no effect on adiponectin, exercise training was significantly associated with reduced levels of leptin (WMD −2.72 ng/mL; 95% CI −4.03 to −1.42; I2=82.10%; P<0.001 for heterogeneity) (Table​(Table44).

Markers of Glucose Intolerance and Insulin Resistance

Table​Table44 also shows the effects of exercise training on markers of glucose intolerance and insulin resistance. Fasting insulin levels; homeostatic model assessment–insulin resistance, or HOMA-IR; and glycosylated hemoglobin A1c were significantly lowered in exercise groups compared with control groups (P=0.002, P=0.002, and P<0.001) (Table​(Table4).4). The WMDs between exercise groups and control groups were −1.03 μIU/mL (95% CI −1.69 to −0.37; I2=79.8%; P<0.001 for heterogeneity) for fasting insulin. The WMD for HOMA-IR was −0.30 (95% CI −0.49 to −0.11; I2=77.5%; P<0.001 for heterogeneity), whereas the WMD for hemoglobin A1c was −0.28% (95% CI −0.42 to −0.14; I2=80.1%; P<0.001 for heterogeneity). The Egger’s tests for fasting glucose and insulin were not suggestive of substantial publication bias (P=0.18 and P=0.24, respectively). The results from the trim and fill analysis suggested that there was no substantial impact of publication bias on the results for HOMA-IR or hemoglobin A1c (filled analysis for HOMA-IR: WMD −0.30, 95% CI −0.49 to −0.11, P=0.002; filled analysis for hemoglobin A1c: WMD −0.28%, 95% CI −0.42 to −0.14, P<0.001).

Hemostatic Factors

The primary analysis examined 3 hemostatic factors: fibrinogen, endothelin-1, and angiotensin II (Table​(Table4).4). On average, the levels of fibrinogen and angiotensin II were 0.39 g/L (95% CI 0.03 to 0.75; I2=45.00%; P=0.18 for heterogeneity) and 1.32 pg/mL (95% CI 0.54 to 2.11; I2=0.00%; P=0.71 for heterogeneity) lower in exercise groups than in control groups. No significant association was found for endothelin-1.

Subgroup Analyses

Our metaregression results suggest that the differences in CRF between exercise and control groups were modified by age and sex (absolute CRF: P=0.008 and P<0.001 for age and sex, respectively; relative CRF: P=0.003 and P=0.001 for age and sex, respectively) (Table​(Table5,5, Figure​Figure3).3). In addition, the effects of exercise on levels of total cholesterol (P=0.04), low-density lipoprotein cholesterol (LDL-C; P=0.06), and fasting insulin (P=0.05) were modified by the presence of at least 1 of the following comorbidities: type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome (Tables​(Tables66 and ​and7,7, Figure​Figure3).3). Sex differences in the effects of exercise were also found for fasting insulin (P=0.04).

Table 5

WMDs in Absolute and Relative Cardiorespiratory Fitness Comparing Exercise Intervention Groups to Control Groups by Specific Modifiers

ModifierAbsolute CRF (L/min)Relative CRF (mL/kg per minute)nWMD95% CII2, %P interaction *nWMD95% CII2, %P interactionAge, y <50160.470.34 to 0.6093.40.008285.604.56 to 6.6585.10.003 ≥50120.210.11 to 0.3284.0303.312.46 to 4.1591.0Sex Women250.190.13 to 0.2492.3<0.001483.242.61 to 3.8788.70.001 Men270.420.32 to 0.5390.4375.434.32 to 6.5390.2Lifestyle Active90.330.15 to 0.5197.00.89143.621.39 to 5.8596.50.83 Sedentary430.310.25 to 0.3788.4883.853.36 to 4.3390.5BMI† Obese190.280.20 to 0.3693.30.65193.852.83 to 4.8794.90.96 Nonobese200.260.17 to 0.3689.1464.013.22 to 4.7985.7Health status‡ Yes80.330.07 to 0.6088.20.84163.342.63 to 4.0474.80.46 None530.270.22 to 0.3394.6944.103.51 to 4.7192.7Duration, wk <16390.330.25 to 0.4091.30.09693.833.12 to 4.5490.70.72 ≥16280.210.15 to 0.2892.3543.903.34 to 4.3590.4

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BMI indicates body mass index; CRF, cardiorespiratory fitness; WMDs, weighted mean differences,

*P values for the impact of potential modifiers on the exercise effects.

†BMI in kg/m2: obese ≥30; nonobese <30.

‡Health status: participants having at least 1 of type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome (yes) vs those with none of them (none).

Table 6

WMDs in Lipid Biomarkers Comparing Exercise Intervention and Control Groups by Specific Modifiers

ModifierTotal Cholesterol (mg/dL)Total Triglycerides (mg/dL)nWMD95% CII2, %P interaction *nWMD95% CII2, %P interactionAge, y <5012−4.25−10.1 to 1.550.00.4312−6.20−14.2 to 2.6634.30.21 ≥50150.77−5.41 to 7.3572.5131.77−8.86 to 13.375.5Sex Women281.16−5.41 to 7.7391.60.6127−1.77−9.74 to 5.3176.10.25 Men15−0.39−5.80 to 5.0354.313−8.86−14.2 to −4.4312.8Lifestyle Active68.12−7.73 to 24.092.50.715−8.86−30.1 to 12.461.20.64 Sedentary471.93−13.9 to 17.499.143−3.54−9.74 to 2.6675.1BMI† Obese1612.8−22.4 to 47.699.70.2019−7.97−14.2 to −1.7753.00.70 Nonobese29−1.55−7.73 to 4.2583.628−5.31−14.2 to 4.4380.7Health status‡ Yes10−11.2−19.3 to −3.4875.20.049−9.74−26.6 to 6.2063.90.48 None47−1.55−5.41 to 2.3281.644−4.43−11.5 to 2.6675.2Duration, wk <16393.87−15.5 to 22.882.90.3435−6.20−13.3 to 0.8971.10.76 ≥1629−3.09−7.73 to 1.5599.231−5.31−11.5 to 1.7772.7

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ModifierHDL-C (mg/dL)LDL-C (mg/dL)NWMD95% CII2, %P interaction *NWMD95% CII2, %P interactionAge, y <50164.252.32 to 6.1973.90.949−3.87−10.8 to 3.0949.30.38 ≥50153.870.77 to 6.9684.5140.39−5.03 to 6.1973.0Sex Women282.320.08 to 4.6484.80.8024−1.93−9.67 to 5.8095.00.93 Men192.710.39 to 5.0392.513−2.32−8.89 to 4.2579.7Lifestyle Active54.250.39 to 8.5186.90.5228.12−10.4 to 27.154.90.21 Sedentary522.320.77 to 3.8718.645−3.87−8.12 to 0.3988.3BMI‡ Obese194.251.93 to 6.9688.10.1314−0.08−4.64 to 4.2562.00.33 Nonobese301.16−1.16 to 3.8783.025−4.25−10.4 to 2.3291.4Health status‡ Yes112.71−2.32 to 7.7391.20.8912−11.6−19.7 to −3.0980.80.06 None502.320.77 to 3.8787.339−3.09−7.73 to 1.5589.3Duration, wk <16392.711.16 to 4.6483.00.5529−3.09−9.28 to 3.4889.60.63 ≥16351.930.15 to 0.2890.430−4.64−10.4 to 1.1692.2

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BMI indicates body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; WMDs, weighted mean differences.

*P values for the impact of potential modifiers on the exercise effects.

†BMI in kg/m2: obese ≥30; nonobese <30.

‡Health status: participants having at least 1 of type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome (yes) vs those with none of them (none).

Table 7

WMDs in Biomarkers of Glucose Intolerance and Insulin Resistance Comparing Exercise Intervention Groups to Control Groups by Specific Modifiers

ModifierFasting Glucose (mmol/L)Fasting Insulin (μIU/mL)nWMD95% CII2, %P interaction *nWMD95% CII2, %P interactionAge, y <5050.09−0.11 to 0.2991.30.574−1.34−3.44 to 0.7676.90.22 ≥5070.01−0.06 to 0.0736.930.45−1.23 to 2.1375.6Sex Women16−0.06−0.19 to 0.0891.40.939−0.27−1.12 to 0.5768.70.04 Men9−0.07−0.25 to 0.1284.36−2.86−3.55 to −2.170.0Lifestyle Active2−0.20−0.74 to 0.3499.00.630NANANANA Sedentary29−0.06−0.16 to 0.0380.217−0.94−1.75 to −0.1378.5BMI† Obese20−0.06−0.20 to 0.0790.70.9013−0.93−2.18 to 0.3282.00.88 Nonobese18−0.05−0.17 to 0.0780.710−0.86−1.52 to −0.1932.8Health status‡ Yes9−0.18−0.40 to 0.050.00.406−2.68−4.67 to −0.7075.20.05 None27−0.03−0.11 to 0.0687.214−0.70−1.60 to 0.2177.5Duration, wk <1630−0.10−0.22 to 0.0390.00.7013−1.35−2.50 to −0.2079.30.58 ≥1619−0.02−0.09 to 0.0647.516−0.83−1.83 to 0.1778.7

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BMI indicates body mass index; NA, not available due to the lack of comparisons reported for active participants; WMDs, weighted mean differences.

*P-values for the impact of potential modifiers on the exercise effects.

†BMI in kg/m2: obese ≥30; nonobese <30.

‡Health status: participants having at least 1 of type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome (yes) vs those with none of them (none).

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Figure 3

Forest plot of effects of exercise interventions on cardiorespiratory fitness, TC, TG, HDL-C, LDL-C, Fasting glucose, and fasting insulin within subgroups. The WMDs (diamonds) and corresponding CIs (extended line) between exercise groups and control groups are shown for each subgroup. Abs. CRF indicates absolute cardiorespiratory fitness; BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; Rel. CRF, relative cardiorespiratory fitness; TC, total cholesterol; TG, triglycerides; WMDs, weighted mean differences.

After conducting metaregressions, analyses within subgroups were performed. Compared with older people, those aged <50 years appeared to have larger changes in CRF. Consistent with the metaregression results, men seemed to have greater exercise-related improvement in CRF, LDL-C, and fasting insulin than women did (Figure​(Figure3).3). Exercise interventions appreciably improved the levels of total cholesterol, LDL-C, and fasting insulin (P=0.004, P=0.01, and P=0.01, respectively) in people having at least 1 of type 2 diabetes, hypertension, hyperlipidemia, and metabolic syndrome (Tables​(Tables66 and ​and7,7, Figure​Figure3);3); no such improvements were observed among people without any of those health conditions (P=0.44, P=0.19, and P=0.13, respectively) (Tables​(Tables66 and ​and7,7, Figure​Figure33).

Sensitivity Analyses

In light of the potential impact of exercise intensity, we conducted separate analyses of all eligible comparisons for moderate and vigorous exercise interventions, respectively. The 95% CIs for moderate and vigorous interventions overlapped for both CRF measures and for all biomarkers (Table​(Table88).

Table 8

WMDs in Cardiorespiratory Fitness and Circulating Concentrations of Biomarkers Comparing Moderate and Vigorous Exercise Intervention Groups to Control Groups

OutcomeModerateVigorousNo.*WMD95% CINo.*WMD95% CICardiorespiratory fitness Absolute, L/min390.220.16 to 0.29330.310.22 to 0.40 Relative, mL/kg per minute643.222.61 to 4.18683.262.63 to 3.89Lipids markers TC, mg/dL414.25−7.73 to 16.6283.87−31.7 to 39.8 TG, mg/dL37−5.31−12.4 to 1.7732−5.31−11.5 to 0.09 HDL-C, mg/dL441.16−0.39 to 2.71332.710.39 to 5.03 HDL2-C, mg/dL21.16−0.77 to 3.4821.55−1.16 to 4.25 HDL3-C, mg/dL1−1.16−5.80 to 3.8720.04−1.55 to 1.55 LDL-C, mg/dL35−3.09−8.12 to 2.3226−4.64−12.0 to 2.32 VLDL-C, mg/dL5−1.93−5.41 to 1.932−7.35−22.9 to 6.19 Apo AI, g/L40.030.02 to 0.0410.00−0.12 to 0.12 Apo AII, g/L1−0.001−0.24 to 0.2410.01−0.01 to 0.03 Apo B, g/L30.01−0.01 to 0.032−0.02−0.21 to 0.18 FFA, mmol/L5−0.06−0.16 to 0.033−0.04−0.17 to 0.10Inflammatory markers CRP, mg/L9−0.23−1.01 to 0.5540.04−0.24 to 0.31 IL-6, pg/mL50.02−0.22 to 0.252−0.39−0.83 to 0.06 IL-18, pg/mL114.0−128 to 156118.40.02 to 36.8 TNF-α, pg/mL30.06−0.48 to 0.601−0.01−0.93 to 0.91 Adiponectin, μg/mL13.521.17 to 5.8760.52−0.20 to 1.23 Leptin, ng/mL1−0.70−1.19 to −0.216−2.56−4.04 to −1.08Insulin resistance markers Glucose, mmol/L31−0.04−0.24 to 0.17220.03−0.08 to 0.12 Insulin, μIU/mL17−0.91−2.08 to 0.2617−1.32−2.15 to −0.50 HOMA-IR7−0.30−0.66 to 0.067−0.47−0.82 to −0.12 HbA1c, %11−0.28−0.46 to −0.117−2.71−0.54 to −0.002 C-peptide, nmol/L10.220.19 to 0.251−0.18−0.62 to 0.26 IGF-1, ng/mL2−4.64−29.58 to 20.3033.91−2.87 to 10.69 IGF-BP3, μg/mL0NANA2−0.002−0.23 to 0.23Hemostatic factors Fibrinogen, g/L0NANA2−0.39−0.75 to −0.03 Endothelin-1, pg/mL2−0.22−0.62 to 0.190NANA Angiotensin II, pg/mL2−1.32−2.11 to −0.540NANA

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Apo AI indicates apolipoprotein A1; Apo AII, apolipoprotein A2; Apo B, apolipoprotein B; CRP, C-reactive protein; FFA, free fatty acid; HbA1c, glycosylated hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment–insulin resistance; IGF-1, insulin-like growth factor 1; IGF-BP3, insulin-like growth factor binding protein 3; IL, interleukin; LDL-C, low-density lipoprotein cholesterol; NA, not available due to the lack of comparisons reported; TC, total cholesterol; TG, triglycerides; TNF-α, tumor necrosis factor α; VLDL-C, very low-density lipoprotein cholesterol; WMDs, weighted mean differences.

*Number of eligible independent comparisons.

Discussion

This systematic review and meta-analysis of 160 RCTs involving 7487 participants indicates that exercise training may significantly improve CRF and CVD biomarkers of lipid and lipoprotein metabolism, glucose intolerance and insulin resistance, systemic inflammation, and hemostasis (Figure​(Figure4).4). In addition, we identified several important modifiers, including age, sex, and health status, that may partially modify the exercise effects on cardiovascular health.

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Figure 4

Mechanisms by which exercise training may improve cardiovascular health.

The current meta-analysis shows that exercise, with relatively low risk of side effects compared with medications, may be an effective way to prevent CVD through impact on various biomarkers. Our results from the meta-analysis showed that exercise training significantly raised CRF, which has been demonstrated to be an independent predictor of CVD risk, CVD mortality, and total mortality.200,201 Lower levels of triglycerides and higher levels of HDL-C were observed in exercise groups. Aside from conventional CVD biomarkers, our meta-analysis also examined the effects on biomarkers that have not been well studied in previous studies, including biomarkers of insulin resistance and hemostasis, adipokines, and novel lipid and inflammatory biomarkers. We found evidence supporting the favorable effects of exercise on apolipoprotein A1, interleukin-18, fasting insulin, HOMA-IR, and hemoglobin A1c. Although the exact biological mechanisms are not clear, our findings indicate that exercise may exert cardioprotective effects by altering dyslipidemia, inflammation, insulin resistance, and hemostasis.19

As a major component of HDL, apolipoprotein A1 plays an important role in the cardioprotective effects of HDL-C.202–204 Our findings on apolipoprotein A1 strengthen the hypothesis that exercise may accelerate reverse cholesterol transport. Another plausible mechanism by which exercise improves the lipid profile is by regulation of lipoprotein lipase. Various studies have suggested that exercise may decrease the levels of triglycerides and increase the levels of HDL-C through its impact on lipoprotein lipase expression and activity, which were consistent with the results from our meta-analysis.205–207 In addition, our analysis also confirmed that the proportion of CVD risk that could have been reduced by exercise via effects on total cholesterol and LDL-C is much lower than what has been observed previously.208,209 Consequently, the results from our meta-analysis provide additional evidence in support of the notion that, in addition to modifying total cholesterol and LDL-C, exercise training may also affect cardiovascular health through other pathways. We found that people in exercise groups also had significantly lower levels of IL-18 and several biomarkers of insulin resistance and hemostatic factors, indicating that exercise may exert its effects via pathways of inflammation-characterized atherothrombosis and insulin resistance. A recent review suggested that exercise training may regulate white adipose tissue mass and the expression of adipokines.210 Obesity has become widely regarded as a chronic proinflammatory state, and substantial evidence indicates that chronic inflammation in adipose tissues, especially in white adipose tissue, could lead to insulin resistance.211,212 Consequently, it is biologically plausible that by reducing the white adipose tissue mass and regulating the expression of adipokines, exercise could mitigate the chronic inflammation in adipose tissues, resulting in improved insulin sensitivity. Nevertheless, the exact mechanism remains to be elucidated.

The results from the subgroup analyses also may have important clinical implications. Consistent with previous evidence,213 both moderate and vigorous exercise training appeared to have favorable effects on cardiorespiratory fitness and cardiometabolic health. We found that the differences in CVD risk between exercise groups and control groups were not significantly modified by lifestyle, body mass index, or intervention duration. These findings suggest that exercise interventions may have similar effects on cardiovascular health in populations regardless of these factors. Alternatively, the effectiveness of exercise training appeared to be different across strata of age, sex, and health status. The effects of exercise interventions on CRF measures were modified by age, sex, and health status such that people aged <50 years, men, and people with type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndrome appeared to benefit more from exercise interventions. We also observed significant modification of the effects on total cholesterol and LDL-C by preexisting medical conditions (type 2 diabetes, hypertension, hyperlipidemia, or metabolic syndromes), and that may explain why we did not find significant effects of exercise on total cholesterol and LDL-C. This finding also suggests that exercise interventions may provide significant benefits for people with those preexisting conditions by lowering total cholesterol and LDL-C.

Strengths of this meta-analysis include the comprehensive and systematic review of both conventional and novel CVD biomarkers, detailed subgroup analyses for potential effect modifiers that have not been conducted previously, assessment of robustness with regard to exercise intensity, and evaluation of the risk of different bias. The 2008 Physical Activity Guidelines Advisory Committee Report included a number of comprehensively systematic reviews and meta-analyses based mostly on observational studies.214 The evidence from RCTs has been relatively scarce, especially for novel cardiometabolic biomarkers. Our study is the first that synthesized evidence from the RCT setting and covered a comprehensive set of both traditional and novel biomarkers. Our findings are corroborated by several previous meta-analyses of RCTs,20,215 but the inclusion of both sexes, more studies, subgroup analyses, and sensitivity analyses allowed us to achieve higher precision in the estimates and to determine the effect modification in subgroups.

This meta-analysis had some limitations. First, the evidence for hemostatic factors is based on a limited number of available trials, and we were not able to synthesize evidence for some novel biomarkers, such as plasminogen activator inhibitor 1, lipoprotein(a), and homocysteine due to sparse available data. Second, subgroup analyses were restricted to outcomes with >20 studies included, and cutoff points used for categorizing modifiers were arbitrarily selected. Third, due to the heterogeneity of exercise training programs and the limited number of RCTs that provided separate data, this meta-analysis can neither perform a dose-response analysis nor distinguish exercise types. We maximized the utility of data regarding exercise duration and intensity available from original RCTs and found that exercise effects were not significantly different across subgroups defined by duration and intensity. Our findings are consistent with previous evidence showing that both moderate and vigorous exercise training has similarly favorable effects on cardiometabolic health.213 The duration threshold at which exercise exerts its effects needs further investigation. Fourth, to maintain independence, we selected 1 comparison from each trial with exercise groups of different intensities compared with 1 single control group. The results may potentially be subject to bias by excluding several eligible intervention groups with moderate intensity; however, we found that the direction and magnitude of the effects on most of the outcome measures were quite similar between moderate and vigorous interventions (Table​(Table8).8). Finally, like any meta-analysis, our results may be prone to publication bias and inherent weaknesses of individual studies.

In conclusion, this large meta-analysis of RCTs clearly shows that exercise training significantly improved CRF and some traditional and novel CVD biomarkers in adults without CVD, indicating the causal role of exercise in the primary prevention of CVD morbidity and mortality.

Acknowledgments

Author contributions: Lin, Liu, and Song designed research; Lin and Zhang were involved in data collection; Lin analyzed data; Guo, Roberts, McKenzie, Wu, and Liu participated in interpretation of findings; Lin and Song wrote the first draft. All authors read, edited, and approved the final manuscript.

Sources of Funding

The study was supported by the Indiana University Health–Indiana University School of Medicine Strategic Research Initiative Grant (Zhang and Song), R01DK09406 (Roberts) and P50HL105188 (Roberts) from the National Institutes of Health (NIH), and Brown University. The NIH, Brown University, or Indiana University had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript.