ORIGINAL RESEARCH

Effects of Exercise Training on Cardiorespiratory Fitness and
Biomarkers of Cardiometabolic Health: A Systematic Review and
Meta-Analysis of Randomized Controlled Trials
Xiaochen Lin, MS; Xi Zhang, PhD; Jianjun Guo, MD; Christian K. Roberts, PhD; Steve McKenzie, PhD; Wen-Chih Wu, MD;
Simin Liu, MD, ScD; Yiqing Song, MD, ScD

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. ( J Am Heart Assoc. 2015;4:e002014 doi: 10.1161/
JAHA.115.002014)
Key Words: biomarker • cardiometabolic health • cardiovascular disease prevention • exercise training

C

ardiovascular 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

From the Department of Epidemiology, School of Public Health (X.L., W.-C.W., S.L.) and Division of Cardiology and Veterans Affairs Medical Center, Department of
Medicine, Alpert Medical School (W.-C.W., S.L.), Brown University, Providence, RI; Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indiana
University, Indianapolis, IN (X.Z., Y.S.); Center for the Youth Sport Research and Development, China Institute of Sport Science, Beijing, China (J.G.); Geriatrics,
Research, Education and Clinical Centers, VA Greater Los Angeles Healthcare System, Los Angeles, CA (C.K.R.); Department of Kinesiology, Center for Physical Activity
in Wellness and Prevention, Indiana University-Purdue University at Indianapolis, IN (S.M.); Division of Endocrinology, Department of Medicine, Rhode Island Hospital,
Providence, RI (S.L.).
Correspondence to: Simin Liu, MD, ScD, Department of Epidemiology and Medicine, Brown University, 121 South Main St, Providence, RI 02903. E-mail:
Simin_liu@brown.edu 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: yiqsong@iu.edu
Received April 2, 2015; accepted April 30, 2015.
ª 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.

DOI: 10.1161/JAHA.115.002014

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Exercise and Biomarkers of Cardiometabolic Health

Lin et al

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 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
DOI: 10.1161/JAHA.115.002014

ORIGINAL RESEARCH

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.

Table 1. Search Strategy for Medline
1.

exp Exercise/

2.

physical activity.ab.

3.

aerobic*.ab.

4.

or/1 to 3

5.

exp Biological Markers/

6.

Exercise Tolerance/

7.

Exercise Test/

8.

exp Oxygen Consumption/

9.

Physical Fitness/

10.

or/5 to 9

11.

randomized controlled trial.pt.

12.

controlled clinical trial.pt.

13.

Randomized Controlled Trials/

14.

Random Allocation/

15.

Intervention Studies/

16.

or/11 to 15

17.

4 and 10

18.

17 and 16

19.

limit 18 to English language

20.

limit 19 to humans

current study is a systematic review and meta-analysis, which is
not considered research involving human subjects.

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,
Journal of the American Heart Association

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Exercise and Biomarkers of Cardiometabolic Health

Lin et al

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
DOI: 10.1161/JAHA.115.002014

ORIGINAL RESEARCH

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.

Table 2. Criteria Used for Exercise Intensity Classification
Moderate

Vigorous

Maximum heart rate, beats/min

<140

≥140

Maximum heart rate, %

<75

≥75

Speed of running, m/s

<6.8

≥6.8

Metabolic equivalents

Women: <6

Women: ≥6

Men: <8

Men: ≥8

Oxygen uptake (% of VO2max)

<70

≥70

Relative metabolic rate

<8

≥8

exercise interventions as moderate exercise or vigorous
exercise are summarized in Table 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.
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 randomeffects 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).
Journal of the American Heart Association

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Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Figure 1 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

Records idenfied through database
searching
(n = 5998, 5734 from Medline, 236
from EMBASE, 28 from CENTRAL)

eligible studies are summarized in Table 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).

Addional records idenfied
through other sources
(n = 201)

Records Total for screening
(n = 6199)

Records aer duplicates removed
(n = 6135)

Records excluded by
abstract review
(n = 5796)
Full-text arcles excluded (n =170)

Full-text arcles assessed
for eligibility
(n = 339)

Trials finally included in
the meta-analysis
(n = 160 trials/169 arcles)

Cardiorespiratory
fitness
Absolute CRF
(N=67)
Relave CRF
(N=122)

Lipid/lipoprotein
markers
TC (N=68)

Adipokine/inflammatory
markers
CRP (N=13)

N=106 Data not available/not extractable
Lack of SD, values of post-treatment or baseline
Lack of exact data only provided the figures
Lack of the outcomes of relave biomarkers
N=20 Not RCTs (not complete random/no control)
N=22 Wrong intervenons
Combined with other intervenons or not real
assigned exercises (educaon)

Glucose/insulin metabolism
markers
Glucose (N=49)

Haemostac/thrombotic
factors
Endothelin-1 (N=2)

IL-6 (N=6)

Insulin (N=29)

HDL-C (N=74)

IL-18 (N=2)

HOMA-IR (N=14)

Angiotensin II (N=2)

HDL-C2 (N=5)

TNF-α (N=3)

C-pepde (N=2)

Fibrinogen (N=2)

HDL-C3 (N=3)

ICAM-1 (N=1)

HbA1c (N=19)

PAI-1 (N=1)

LDL-C (N=59)

VCAM-1 (N=1)

HOMA-S (N=1)

VLDL-C (N=7)

Lepn (N=7)

HOMA-B (N=1)

Homocysteine
(N=1)

Apo A I (N=5)

Adiponecn
(N=6)

IGF-BP (N=2)

TG (N=66)

Apo A II (N=2)

Angiotensin I (N=1)

E-selecn (N=1)

IGF-I (N=5)

Apo B (N=5)
FFA (N=6)
Lp(a) (N=1)

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-a, tumor necrosis
factor a; VCAM-1, vascular cell adhesion molecule 1; VLDL-C, very low-density lipoprotein cholesterol.
DOI: 10.1161/JAHA.115.002014

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ORIGINAL RESEARCH

Results

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

5

Female only
Female only
Female only

Male: 62%
Male: 27%

53 to 74

41 to 55

20 to 60

48 to 63

Mean: 58.2

C: 58.88.6
T: 58.88.5

60 to 79

Male: 4911
Female: 509

67 to 80

Mean: 34.812.6

60 to 83

29 to 59

≥65

59 to 73

18 to 22

Ahmaidi, 199837

Aldred, 199538

Ashutosh,
199739

Asikainen,
200240

Baker, 198641

Balducci, 2010,
201242

Beavers, 201043

Bell, 201044

Bermon, 199945

Biddle, 201146

Blumenthal,
199147

Blumenthal,
199148

Boardley,
200749

Bobeuf, 201150

Boreham, 200051

Female only

Female: 52.6%

Female: 50%

Female 13

Male: 16

NR

Female: 67%

NR

Male only

NR

Male only

Mean: 20.6

Abderrahman,
201336

Sex

Age, y

Study

NR

Mean: 26.22.6

NR

Mean: 26.9

NR

Mean: 36.36.7

T: 24.90.5
C: 25.90.6

7

24

16

16

60

4

8

24

78

>28.0
Mean: 30

52

20

24

46

12

12

7

Duration,
wk

C: 31.94.6
T: 31.24.6

NR

Mean: 26.2

Overweight or
obesity

T: 24.81.0
C: 26.80.8

NR

Mean: 22.8

BMI, kg/m2

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/untreated mild
hypertension

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Active/Health

Sedentary/Diabetes
mellitus

Sedentary/Health

Sedentary/Health

NR/Health

Sedentary/Health

Sedentary/Health

NR/Health

Activity/Medical
Condition

Stair climbing/Moderate/No

Resistance training/Vigorous/
Vitamins C/E
supplementation

Resistance training and
aerobic walking/Moderate/
No

Aerobic exercise training/
Joging

Aerobic exercise or yoga/
Vigorous/No

Small-sided games-based
exercise/NR/No

Strength training/Vigorous/
No

Walking/Moderate/No

Walking and interactive,
health education in control

Aerobic and resistance
training/Moderate/No

Aerobic training/Vigorous/No

Walking/Vigorous/No

Aerobic exercise/NR/Dietary
intervention

Walking/Moderate/No

Walking/Jogging/Vigorous/
No

Running/Vigorous/No

Exercise Type, Intensity and
Cointerventions

12/10

17/12

33/35

39/22

15/15

9/7

16/16

43/45

97/93

288/275

20/14

20/38

9/6

11/11

11/11

9/6

NT/NC

TC, HDL-C

TC, TG, HDL-C, LDL-C

TC, TG, HDL-C, LDL-C

Continued

Absolute CRF, Relative CRF

Absolute CRF, Relative
CRF

Absolute CRF, Relative
CRF, TC, TG, HDL-C,
LDL-C, CRP, Fasting
glucose, HbA1c

IGF-1, IGF-BP

Absolute CRF, Relative
CRF, TC, TG, HDL-C,
LDL-C, Fasting glucose

Leptin

Relative CRF, TC, TG,
HDL-C, LDL-C, CRP,
Fasting glucose, Insulin,
HOMA-IR HbA1c

Absolute CRF, Relative CRF,
TC, HDL-C, LDL-C, VLDL-C

Relative CRF

Absolute CRF, Relative CRF

TC, HDL-C2 LDL-C, FFA

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

Marker

ORIGINAL RESEARCH

Table 3. Characteristics of the Trials Included in the Meta-Analysis

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

6

60 to 79

Braith, 199454

34 to 60

18 to 45

Cho, 201164

Christiansen,
201065

65 to 90

60 to 79

Chandler,
199663

Coker, 200968

Mean: 5411

Chan, 201362

20 to 30

Female: 38.6%

T: 39.37.8
C: 41.07.7

Carroll, 201261

Ciolac, 201167

Female only

18 to 64

Canuto, 201260

45 to 75

Female only

40 to 75

Campbell,
200759

Church, 200766

Male only

Mean: 29

Camargo,
200858

Female: 50%

Female only

Female only

Female: 38

Female only

Female only

Female only

NR

Mean: 26

Burr, 201157

Female only

694

Male only

Female: 54.5%

Female only

Male only

Sex

Broman, 200656

18 to 35

23 to 43

Bourque, 199753

Broeder, 1992

Mean: 45.47.2

Boudou, 200352

55

Age, y

Study

26 to 37

Mean: 23.78

25 to 43

30 to 40

Mean: 25.6

NR

Mean: 317

T: 39.97.4
C: 41.07.7

Mean: 34.8

29.9 to 28.7

Mean: 27.3

NR

NR

Mean: 25.3

NR

Mean: 23.14.9

Mean: 29.64.6

BMI, kg/m2

12

16

24

12

12

24

10

12

12

52

12

6

8

12

24

12

8

Duration,
wk

NR/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Health

Sedentary/
Hypertension

Sedentary/Health

NR/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Health

NR/Health

Sedentary/Health

Sedentary/Health

NR/Diabetes mellitus

Activity/Medical
Condition

Cycle ergometer/Moderate/
No

Endurance exercise/
Vigorous/No

Aerobic exercise/Moderate/
No

Aerobic exercise/Vigorous/
Dietary intervention

Walking/Moderate/No

Endurance training/
Moderate/No

Treadmill walking/
Vigorous/Education

Treadmill walking/Moderate/
Lifestyle intervention

Resistance training/
Moderate/Education

Aerobic Exercise/Moderate/
No

Aerobic training/Moderate/
No

Vehicle riding/Vigorous/No

In deep water running/
Walking/Vigorous/No

Walk or jog/Vigorous/No

Walking/Vigorous/No

Endurance exercise/
Vigorous/No

Endurance exercise/
Vigorous/No

Exercise Type, Intensity and
Cointerventions
NT/NC

6/6

11/12

103/102

21/19

13/10

16/11

10/13

22/22

29/30

17/15

7/7

34/12

15/9

15/19

14/11

6/7

8/8

Marker

Absolute CRF

Continued

Relative CRF,TC, TG, HDL-C,
LDL-C, Fasting glucose,
Insulin, HOMA-IR

Absolute CRF, relative
CRF, TG, HDL-C, LDL-C,
Fasting glucose

Absolute CRF,TC, TG, HDL-C,
FFA, IL-6, IL-18,
Adiponectin, Fasting
glucose, Insulin, HOMA-IR

Relative CRF,TG, HDL-C
FFA, Fasting glucose,
Insulin, HOMA-IR

Relative CRF, PAI-1

Relative CRF,

Absolute CRF, Relative CRF

TC, TG, HDL-C, LDL-C,
CRP, Fasting glucose,
Insulin, HbA1c

Absolute CRF, Relative
CRF, CRP

Relative CRF

Relative CRF, Fasting glucose

Absolute CRF, Relative
CRF

Relative CRF

Relative CRF

Relative CRF

Adiponectin, Leptin, Insulin

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

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7

20 to 45

Mean: 42.45.0

45 to 75 year

60 to 70

42 to 78

62 to 84

20 to 40

40 to 65

Cox, 199370

Cox, 200371

Dalleck, 200972

De Vito, 199973

Dimeo, 201274

Dipietro, 200675

Duncan, 199176

Duscha, 200577

Female: 75%
Female: 44%

24 to 50

≥29

18 to 31

Garber, 199282

Geogiades,
200083

Gormley, 200884

Female: 65.5%

Female only

50 to 74

Friedenreich,
201181

Female: 44%

Male only

67.4 to 76.3

65 to 78

Female only

NR

Female only

Female only

Female: 58%

Female only

Female only

Male only

Male only

Female: 73.8%

Sex

Finucane,
201080

Fatouros,
200579

Eguchi, 2012

20 to 65

40 to 80

Cortez-Cooper,
200869

78

Age, y

Study

Mean: 24.3

25 to 37

NR

22 to 40

Mean: 27.2

28.7 to 30.2

Mean: 25.13.9

25 to 35

NR

Mean: 27.3

Mean: 29.4

NR

Normal

Overweight or
obesity

6

24

8

52

12

24

12

36

24

36

12

12

12

16

4

13

<30

Mean: 26.3 (25.7
to 26.9)

Duration,
wk

BMI, kg/m2

Sedentary/Health

Sedentary/
Hypertension

Sedentary/Health

Sedentary/Health

NR/Health

Sedentary/Health

NR/Health

NR/Hyperlipidemia

Sedentary/Health

Sedentary/Health

NR/Hyperlipidemia

Sedentary/Health

Sedentary/Health

Sedentary/
Hypertension

Sedentary/Health

Sedentary/Health

Activity/Medical
Condition

Aerobic/Moderate/No

Aerobic exercise/Vigorous/
No

Walk-jog/Moderate/No

Aerobic exercise/Vigorous/
No

Cycle ergometer/Moderate/
No

Resistance exercises/
Moderate/No

Endurance training using
bicycle ergometers/
Moderate/No

Walking/Moderate/No

Walk/Moderate/No

Aerobic training/Moderate/
No

Walking on a treadmill/NR/
No

Walking/Moderate/No

NR/Moderate/No

NR/Moderate & vigorous/
Dietary intervention and
usual dietary

Not report/Vigorous/Drink
low-alcohol beer or
continue their normal
drinking habits

Aerobic exercise strength
training vs stretching/
Moderate/No

Exercise Type, Intensity and
Cointerventions
NT/NC

14/13

36/19

13/9

154/154

48/48

12/10

8/10

25/37

12/13

9/7

22/25

11/9

8/10

13/17

19/16

12/12

Marker

Relative CRF

Relative CRF

Relative CRF

Continued

Adiponectin, Leptin,
Fasting glucose, Insulin,
HOMA-IR, IGF-1, IGF-BP

TC, TG, HDL-C, LDL-C,
Fasting glucose, HbA1c

Relative CRF, Adiponectin,
Leptin, Fasting glucose,
HOMA-IR

Absolute CRF, Relative
CRF,TC, TG, HDL-C, LDL-C,
Fasting glucose, HbA1c

Absolute CRF, Relative CRF

Relative CRF,TC, TG,
HDL-C, LDL-C

Relative CRF,FFA, Fasting
glucose, Insulin

Relative CRF

Absolute CRF, Relative
CRF

Absolute CRF, Relative
CRF,TC, TG, HDL-C,
LDL-C, Fasting glucose

Absolute CRF

TC, TG, HDL-C, HDL-C2,
HDL-C3, LDL-C, Apo AI,
Apo AII, Apo B

Relative CRF,TC, TG, HDL-C,
LDL-C, Endothelin-1,
Fasting glucose

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

8

85

18 to 65

Mean: 23.92.4

Gray, 200987

Guadalupe-Grau,

Male only
Male only

35 to 55

18 to 26

Mean: 24.94.3

Mean: 24.94.3

T: 496
C: 486

18 to 25

40 to 66

Hass, 200190

Hendrickson,
201091

Heydari, 201392

Heydari, 201392

Hilberg, 201393

Hiruntrakul,
201094

Ho, 201295

Male only

40 to 45

60 to 81

Huttunen,
197997

Tsuji, 200098
Female: 53%

Male only

20 to 45

Hu, 200996

Female: 83.5%

Male only

Male only

Female only

Female: 50%

Mean: 36.6

Female: 50%

Female: 34.8%

Female: 77%

Female only

Female: 45.6%

Sex

Hagan, 198689

200988

NR

25 to 80

Age, y

Grandjean,
199686

Gram, 2010

Study

NR

NR

NR

25 to 40

C: 21.353.54
T: 20.993.35

NR

Mean: 28.7

Mean: 28.73.1

NR

NR

Normal

C: 24.03.6
T: 22.82.0

Mean: 28.6

NR

NR

BMI, kg/m2

25

16

10

12

12

12

12

12

12

12

12

9

12

24

52

Duration,
wk

Active/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Health

Active/Health

Sedentary/Health

Active/Health

Sedentary/Health

Sedentary/Health

Active/Health

Sedentary/Health

Sedentary/Health

NR/Diabetes mellitus

Activity/Medical
Condition

Endurance session with a
bicycle ergometer, and a
resistance exercise training
session using rubber films/
Moderate/Education

Walking, Jogging,
Swimming, Skiing, or
Cycling/Moderate/No

Progressive strength
training/Moderate/No

Aerobic resistance training/
Moderate/No

Aerobic exercise/Moderate/
No

NR/Vigorous/No

High-intensity intermittent
exercise/Vigorous/No

High-intensity intermittent
exercise/Vigorous/No

Aerobic endurance and
strength training/Vigorous/
No

NR/Moderate/No

Aerobic training/Moderate/
Dietary training

Strength combined with
plyometric jumps training/
Vigorous/No

Pedometer-based walking/
Moderate/No

Walking and jog and
cycling/Vigorous/No

Strength training and
aerobic exercise/Moderate/
No

Exercise Type, Intensity and
Cointerventions

Relative CRF

Continued

Relative CRF, HDL-C,
Apo AI, Apo AII

44/46

31/33

Absolute CRF, Relative CRF,

Relative CRF, TC, TG,
HDL-C, LDL-C, Fasting
glucose, Insulin

Relative CRF, HDL-C

Relative CRF

Absolute CRF, Relative CRF

48/21

15/16

19/18

22/22

25/21

Absolute CRF, Relative CRF

Relative CRF

13/10

20/18

Absolute CRF, Relative CRF

17/9

Absolute CRF, Relative CRF,
TC, TG, HDL-C, LDL-C,
VLDL-C

Leptin

8/15

12/12

CRP, IL-6, TNF-a, Fasting
glucose, Insulin, HOMA-IR

Absolute CRF,TC, TG,
HDL-C, LDL-C, VLDL-C

Absolute CRF,TC, HDL-C,
LDL-C, HbA1c

Marker

24/24

20/17

21/20

NT/NC

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

9

35 to 76

Mean: 35.48.5

Kokkinos,
1998107

Kraemer,
1997,108
1999109

T: 53.778.2
C: 53.576.6

T: 316
C 358

Kiviniemi,
2007106

Kurban, 2011113

19 to 30

Kirk, 2003105

31 to 52

19 to 30

Kirk, 2003105

KukkonenHarjula,
1998112

Male only

Male 496
Female 475

King, 1989104

20 to 43

Male only

C: 57.13.0
T: 60.82.2

Karstoft,
2013103

Krustrup,
2009111

Female only

Mean: 61.32.1

Kadoglou,
2012102

18 to 60

Female: 67.6%

61 to 77

Jessup, 1998101

Krogh, 2012110

Female: 52%

39 to 70

Larose, 2011100

Female: 51.7%

Female: 53%

Male only

Female: 67%

Female only

Male only

Female: 50%

Female: 31%

Female 36.2%

Female: 61%

59 to 86

Irwin, 201299

Sex

Age, y

Study

T: 30.904.64
C: 30.234.74

18.5 to 32.7

Mean: 25.7

NR

C: 28.24.0
T: 28.34.2

T: 304
C: 315

T: 242
C: 251

27 to 32

27 to 32

NR

NR

T: 32.744.05
C: 31.585.71

NR

Mean: 34.9

NR

BMI, kg/m2

12

15

12

12

12

16

4

36

36

24

16

12

16

24

9

Duration,
wk

Sedentary/Diabetes
Mellitus

Sedentary/Health

Sedentary/Health

NR/Health

NR/Health

Sedentary/
Hypertension

Active/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Diabetes mellitus

NR/Diabetes mellitus

Sedentary/Health

Sedentary/Diabetes
mellitus

Sedentary/Health

Activity/Medical
Condition

Walking/Moderate/No

Walking/Training/Moderate/
No

Recreational soccer/
Vigorous/No

Aerobic exercise/Vigorous/
No

Aerobic endurance exercise/
Vigorous/Dietary
intervention

Aerobic/Exercise/Moderate/
No

Running/Vigorous/No

Aerobic Exercise/Moderate/
No

Aerobic exercise/Moderate/
No

Aerobic/Exercise/Training/
Moderate/No

Walking/Moderate/No

Resistance Exercise/
Vigorous/No

Treadmills and stairclimbers/Vigorous/No

Aerobic or resistance
training/Vigorous/No

Tai Chi Chih vs health
education/Moderate/No

Exercise Type, Intensity and
Cointerventions
NT/NC

30/30

58/58

12/10

56/59

9/8

15/19

9/10

25/18

16/15

29/28

12/8

23/24

11/10

60/63

46/37

Marker

Fasting glucose, HbA1c

Continued

Absolute CRF, Relative CRF,
Fibrinogen

Relative CRF, TC, HDL-C,
LDL-C,Absolute CRF, CRP,
Fasting glucose, Insulin

Relative CRF, TC, TG, HDL-C,
Fasting glucose, Insulin

Absolute CRF, Relative CRF,
TG, Fasting glucose

TC, TG, HDL-C, HDL-C2,
HDL-C3, LDL-C, Apo AI,
Apo B

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

Relative CRF

Absolute CRF, Relative CRF,
TC, TG, HDL-C, LDL-C,
Fasting glucose, Insulin,
HbA1c

Relative CRF, TC, TG, HDL-C,
LDL-C, Fasting glucose,
Insulin, HOMA-IR, HbA1c,
Fibrinogen

Relative CRF

Relative CRF, HbA1c

CRP, IL-6, IL-18

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

10

T 48.6+5.0
C 49.1+5.5

20 to 35

70 to 80

T: 58.64.6
C 60.67.4

25 to 70

Libardi,
2012121

de Lima,
2012122

Lovell, 2011123

Martin, 1990124

McAuley,
2002125

Mean: 606

Mean: 20.41

LeMura,
2000120

Miyaki, 2012128

30 to 50

Lee, 2012119

30 to 60

Female: 67%

18 to 30

Lee, 2003118

Meyer, 2006127

Female only

18 to 40

LaPerriere,
1994117

20 to 62

Male only

18 to 28

Lake, 1996116

Meckling,
2007126

Male only

Mean: 52.78.2

Labrunee,
2012115

Female only

Female: 47%

Female only

Male only

Female only

Male only

Female only

Female only

Male only

Female: 82.6%

Male only

20 to 40

Laaksonen,
2000114

Sex

Age, y

Study

NR

NR

8

12

12

16

<27
25 to 30

12

20

12

24

NR

NR

C: 23.02.4
T: 22.83.6

T: 27.5+4.1
C: 24.7+3.3

16

14

≥25
T: 20.82.1
C: 21.82.3

2

10

6

12

16

Duration,
wk

NR

NR

NR

Mean: 38.57.6

Mean: 24.4

BMI, kg/m2

Sedentary/Health

Sedentary/Health

NR/Health

NR/Health

Sedentary/Health

Active/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Health

Sedentary/Health

Sedentary/Health

Active/Health

NR/Diabetes mellitus

Active/Diabetes
mellitus

Activity/Medical
Condition

Walking and cycling/
Moderate/No

Walking or running/
Vigorous/No

Resistance training and
endurance training/
Moderate and vigorous/
Dietary intervention or
high protein

NR/Moderate/Dietary
intervention

Cycle ergometer training/
Vigorous/No

Cycle ergometer and
stretching/Vigorous/No

Muscular endurance/
Moderate/No

Resistance training/
Moderate/No

Resistance training and
aerobic training/
Vigorous/No

NR/Moderate/No

Cycle ergometer/Vigorous/
No

Aerobic exercise/Vigorous/
No

Running training/Moderate/
No

Cyclergometer training/NR/
No

Sustained running/
Moderate/No

Exercise Type, Intensity and
Cointerventions

11/11

Continued

Relative CRF, TC, TG,
HDL-C, LDL-C, Fasting
glucose

Relative CRF

TC, TG, HDL-C, Fasting
glucose, Insulin

11/8

12/13

TC, TG, HDL-C, LDL-C,
Fasting glucose, Insulin

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

Relative CRF

29/23

14/14

12/12

10/8

Relative CRF, TC, TG, HDL-C,
LDL-C, CRP, IL-6, TNF-a,
Fasting glucose

Relative CRF,TC, TG, HDL-C,
LDL-C

10/12

12/13

Relative CRF, TC, TG, HDL-C,
LDL-C, CRP, IL-6, TNF-a

Relative CRF

Relative CRF

Relative CRF

Relative CRF, TC, TG, HDL-C,
LDL-C, Fasting glucose,
HOMA-IR, HbA1c

Relative CRF, TC, TG, HDL-C,
LDL-C, Apo AI, Apo B,
HbA1c

Marker

8/7

12/12

7/7

8/7

11/12

20/22

NT/NC

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

11

50 to 70

T: 66.62.1
C: 67.34.4

67 to 85

Mean: 45.61.1

Nicklas, 2009136

Niederseer,
2011137

Nieman,
1993138

Nieman,
1998139

70 to 79

Mean: 636

Nemoto,
2007135

Panton, 1990142
Pollock,
1991143

21 to 36

Musa, 2009134

30 to 45

Female: 75.6%

Mean: 45.79.4

Murtagh,
2005133

O’donovan,
2005141

Male only

Mean: 41.59.3

Murphy,
2006132

20 to 40

Female: 64.6%

T: 61+10
C: 63+9

Morton, 2010131

Nordby, 2012140

Female: 64.9%

50 to 70

Morgan,
2010130

Female: 53.1%

Male only

Male only

Female only

Female only

Female: 47.6%

Female only

Females: 22.2%

Females: 73.3%

Female: 3%

60 to 89

Morey, 2012129

Sex

Age, y

Study

NR

NR

25 to 30

Mean: 33.10.6

Mean: 23.7

T: 27.13.3
C: 25.42.8

25 to 40

C: 22.8
T moderate: 22.8
vigorous: 22.9

24

24

12

12

12

12

Sedentary/Health

Sedentary/Health

Sedentary/Health

Active/Health

Sedentary/Health

Active/Health

Sedentary/Health

NR/Health

20

20

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Diabetes
mellitus

Sedentary/Health

NR/Health

Activity/Medical
Condition

8

12

<30
Normal

8

7

15

52

Duration,
wk

T: 26.85.6
C: 24.43.6

T: 32+7
C: 30.9+7.0

NR

25 to 45 kg/m2

BMI, kg/m2

Aerobic and resistance
training/NR/No

NR/Moderate/No

Endurance training (cycling,
running, cross-training, or
rowing)/Moderate/Dietary
intervention

Walking/Moderate and
vigorous/dietary
intervention

Walk/Moderate/No

Skiing/Moderate/No

Calorie restriction and
aerobic exercise/
Moderate/dietary
intervention

Walking/Moderate/No

Interval running/Moderate/
No

Walking/Vigorous/No

Walking/Moderate/No

Walking/Vigorous/No

Walk/Moderate/No

Enhanced fitness
intervention/NR/No

Exercise Type, Intensity and
Cointerventions
NT/NC

Marker

13/15

14/15

Relative CRF

Continued

Absolute CRF, Relative CRF,
TC, TG, HDL-C, LDL-C,
Fibrinogen

Absolute CRF, Relative CRF,
Fasting glucose, Insulin,
HbA1c

Absolute CRF, TC, Fasting
glucose

22/26

12/12

Relative CRF, TC, TG,
HDL-C, LDL-C,

Relative CRF, TC, TG, HDL-C,
LDL-C, CRP VCAM-1,
ICAM-1, Endothelin-1,
e_selectin

TG, HDL-C, LDL-C, Fasting
glucose, Insulin

Absolute CRF

TC, HDL-C

Relative CRF, TC, TG, HDL-C,
LDL-C

TC, TG, HDL-C, LDL-C, CRP

Absolute CRF, Relative CRF,
Fasting glucose, HbA1c

TC, HDL-C

TC, TG, HDL-C, LDL-C,
Fasting glucose, Insulin,
HOMA-IR HbA1c

14/16

22/20

36/29

43/37

20/16

18/11

21/12

15/12

14/15

180/122

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

12

Female only

≥50

55 to 75

45 to 70

Ready, 1996151

Romero-Arenas,
2013152

Santa-Clara,
2003,153
2006154

C: 305
T: 326

NR

24 to 26

Raz, 1988150

Seifert, 2009157

Female only

50 to 62

Chow, 1987149

Mean: 387

Male only

64 to 78

Pyka, 1994148

Scanga, 1998156

Female only

≥70

Probart, 1991147

22 to 40

Female: 61.9%

60 to 86

Posner, 1992146

Santiago,
1995155

Female only

18 to 35

Poehlman,
2000145

Male only

Female only

Female only

Female only

Female: 60%

Female only

62 to 67

Phillips, 2012144

Sex

Age, y

Study

25 to 30

C: 35.23.9
T: 36.64.3

≥31

CaucasianAmerican T:
253
C: 275
African-American
T: 297
C: 296

Mean: 29.9

NR

Mean: 22.8

NR

NR

Mean: 24.6

NR

C: 222
T: 222

Overweight or
Obesity

BMI, kg/m2

12

8

Sedentary/Health

NR/Health

Sedentary/
Hyperlipidemia

Sedentary/Health

24

40

Active/Health

Sedentary/Health

Sedentary/Health

NR/Health

NR/Health

NR/Health

Sedentary/Health

Sedentary/Health

Active/Health

Activity/Medical
Condition

12

24

9

52

104

26

16

24

12

Duration,
wk

Endurance training/
Moderate/Endurance
training

Aerobic and resistance
training/Moderate/Dietary
intervention

Walking/Vigorous/No

Treadmill walking/Jogging,
stationary cycling, and
rowing/Vigorous/No

Resistance training/
Moderate/No

Walk/Moderate/No

Aerobic exercise/Vigorous/
No

Aerobic exercise or aerobic
and strengthening
exercises/Vigorous/No

Resistance exercise
(walking and stretching)/
Moderate/No

Walking on a treadmill/
Vigorous/No

Cycle ergometer/Moderate/
No

Endurance training (N=14),
resistance training/
Vigorous/No

Aerobic training/Vigorous/
No

Exercise Type, Intensity and
Cointerventions

10/7

10/12

Fasting glucose

Continued

Absolute CRF, Relative CRF

Relative CRF, TC, TG, HDL-C,
LDL-C

Relative CRF, IGF I

17/16

16/11

Relative CRF

Absolute CRF, Relative CRF,
TC, TG, HDL-C, LDL-C

Relative CRF, TC, TG, HDL-C,
HDL-C2, HDL-C3, LDL-C,
HbA1c

Relative CRF

IGF-1

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

16/10

17/18

28/27

17/15

8/6

10/6

166/81

Absolute CRF

14/20

Marker

Leptin

NT/NC

11/12

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

13

Mean: 50.29.5

>70

>70

60 to 75

Stensvold,
2010166

Strasser,
2009167

Sung, 2012168

Takeshima,
2002169

45 to 64

Female: 65%

42 to 59

Stensel, 1993165

Thompson,
2010172

Females: 55.6%

T: 46.26.1
C: 45.06.1

Stein, 1992164

18 to 32

Female: 39.5%

> 65

Stachenfeld,
1998163

Thomas,
1984171

Female only

NR

Spence, 2013162

60 to 83

Male only

T: 54.15.8
C: 54.14.9

Sloan, 2013161

Takeshima,
2004170

Female only

39 to 64

Sillanpaa,
2009,159
2010160

Male only

Female only

8 Males and 10
Females

Female only

Male only

Male only

Female only

Male only

50 to 70

Lamina, 2011158

Sex

Age, y

Study

C: 28.02.7
T: 28.52.9

NR

NR

NR

NR

Mean: 26.9

C: 31.94.1
T: 32.24.2

Normal

NR

NR

T: 73.016.9
C: 81.715.23

T: 29.24.9
C: 27.15.9

Normal

20 to 30

BMI, kg/m2

24

12

12

7

24

24

12

52

8

24

24

16

21

8

Duration,
wk

Sedentary/Health

Active/Health

Sedentary/Health

Sedentary/Health

NR/Diabetes mellitus

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Active/Health

Active/Health

Sedentary/Health

NR/Health

Sedentary/
Hypertension

Activity/Medical
Condition

NR/Moderate/Dietary
intervention

Running/Vigorous/No

Progressive accommodating
circuit exercise/Vigorous/
No

Stretching, endurance-type
exercise (walking and
dancing, 30 min),
Resistance exercise/
Vigorous/No

Walking/Moderate/No

Endurance training or–and
resistance training/
Vigorous/No

Strength training vs aerobic
interval training/Vigorous/
No

Brisk/Walking/Moderate/
No

Aerobic exercise training/
Moderate/No

Aerobic training/Vigorous/
No

Endurance vs resistance/
Moderate/No

Walking/Moderate/No

NR/Vigorous/

Bicycle ergometer/
Vigorous/No

Exercise Type, Intensity and
Cointerventions
NT/NC
Marker

20/21

9/6

Continued

Relative CRF,TC, TG, HDL-C,
CRP, IL-6, Fasting glucose,
Insulin, HOMA-IR

Absolute CRF, Relative CRF,
TC, TG, HDL-C

Absolute CRF, TC, TG,
HDL-C, LDL-C

TC, TG, HDL-C, LDL-C

15/15

18/17

TC, TG, HDL-C, LDL-C,
Fasting glucose, HbA1c

Relative CRF

Relative CRF, TC, TG, HDL-C,
Fasting glucose, C-peptide,
HbA1c

TC, TG, HDL-C, LDL-C,
VLDL-C, Apo AI, Apo B,
Lp-A

Absolute CRF

Relative CRF

Absolute CRF, Relative CRF

Relative CRF

TC, TG, HDL-C, LDL-C,
Fasting glucose, Insulin

Relative CRF

22/18

13/14

11/10

24/24

19/14

9/8

10/13

16/16

15/12

112/105

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

14

Female: 62.5%

Male only
Female: 60%

>30

18 to 29

3510

25 to 75

C: 38.66.5
T: 39.37.7

18 to 30

62 to 67

60 to 83

C: 44.811.4
T: 44.713.0

Male: 66.91.0
Female:
67.11.7

Mean: 44.27.2

47 to 56

Toledo, 2008174

Tseng, 2013175

Tulppo, 2003176

Utter, 1998177

Van AggelLeijssen,
2001,178
2001179

Van Den Berg,
2010180

Vicente-Campos,
2012181

Vincent, 2002182

Vissers, 2010183

Vitiello, 1997184

Volpe, 2008185

Waib, 2011186
Training: 60.8%

Female only

Female: 40.3%

Female: 74.7%

Female and Male

Male only

Female only

Male only

Male only

Female: 53.6%

Mean: 52.33.7

Tjonna, 2008173

Sex

Age, y

Study

T: 30.0 (28.8 to
31.2)
C: 29.6 (27.8 to
31.5)

Mean: 30.52.7

NR

C: 29.82.6
T: 33.13.4

NR

NR

NR

C: 32.62.5
T: 32.02.1

25 to 65

Moderate: 253
Vigorous: 252
C: 253

T: 34.81.1
C: 33.41.2

C: 32.13.3
T: 29.44.9

BMI, kg/m2

15

52

24

52

24

28

7

12

12

8

12

16

16

Duration,
wk

Sedentary/
Hypertension

Sedentary/Health

Sedentary/Health

Active/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Health

Sedentary/Health

NR/Health

Activity/Medical
Condition

Aerobic training jogging
on an electronic treadmill/
Moderate/No

Skiing/NR/Dietary
intervention

Endurance or stretching/
Flexibility/Moderate/No

Bicycle ergometer/
Vigorous/No

Resistance training/
Moderate/No

Aerobic training/Vigorous/
No

Motor-driven treadmill/
Moderate/No

Cycling on an ergometer,
walking, and aquajogging/Moderate/Energy
restriction and dietary
intervention

Walk/Moderate and
vigorous/Dietary
intervention

Walking and Jogging/
Vigorous/No

Aerobic, resistance or
combined aerobic and
resistance training/
Moderate/

Walking/Moderate/Dietary
training

Aerobic interval training/
Vigorous/No

Exercise Type, Intensity and
Cointerventions
NT/NC
Marker

55/24

14/14

30/22

20/20

24/16

22/21

Continued

Relative CRF, HOMA-IR,
C-peptide

TC, TG, HDL-C, LDL-C

Relative CRF, IGF-1

TG, HDL-C

Relative CRF

TC, TG, HDL-C, LDL-C

Absolute CRF, Relative CRF

Absolute CRF, FFA, Fasting
glucose, Insulin

20/17

9/13

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

TG, HDL-C, Fasting glucose

FFA, Fasting glucose, Insulin

Relative CRF, TG, HDL-C,
Adiponectin, Fasting
glucose, Insulin, HOMA-B

21/22

16/11

10/10

9/7

8/9

ORIGINAL RESEARCH

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

Female only
NR

Female only
Male only

C: 24.72.3
T: 23.51.6

T: 21.50.7
C: 22.90.4

27 to 63

Mean: 73.60.7

NR

Mean: 62.73.1

Mean: 650.8

45 to 64

50 to 65

32 to 59

50 to 70

T: 21.61.1
C: 21.00.9

Wang, 2005188

Journal of the American Heart Association

Wang, 2011189

Warner, 1989190

Warren, 1993191

Watkins,
2003192

Wong, 1990193

Woods, 1999194

Wu, 2011195

Yoshizawa,
2009196

Yoshizawa,
2009197

You, 2006198

Ziemann,
2011199

T: 24.51.8
C: 23.01.9

25 to 40

T: 24.61.1
C: 21.81.0

Mean: 23.7

16.0 to 33.3

NR

Normal

T: 33.44.5
C: 34.05.2

Normal

NR

T: 22.90.4
C: 23.30.7

6

20

12

8

36

24

52

24

12

12

4

8

8

Duration,
wk

Active/Health

Sedentary/Health

Sedentary/Health

Sedentary/Health

NR/Health

Sedentary/Health

NR/Health

Sedentary/Health

Sedentary/Health

Sedentary/
Hyperlipidemia

Sedentary/Health

Sedentary/Health

Sedentary/Health

Activity/Medical
Condition

NR/Vigorous/Physical
education

Treadmill/Moderate/Dietary
intervention

Aerobic exercise training/
Moderate/No

Resistance training/
Moderate/No

Aerobic exercise, stretching
exercise/Vigorous/No

Aerobic exercise/
Moderate/No

Treadmill walking/
Moderate/No

Aerobic training/Vigorous/
Weight lost

Walking or calisthenics
control/Moderate/No

Aerobic training/Vigorous/
Fish oil intervention

Bicycle ergometer/
Moderate/No

Bicycle ergometer/
Moderate/No

Aerobic Exercise/Vigorous/
Dietary education

Exercise Type, Intensity and
Cointerventions
NT/NC

10/11

13/14

12/12

12/13

68/67

14/15

69/69

14/9

14/16

7/7

10/10

15/15

6/8

Marker

Absolute CRF, Relative CRF

Absolute CRF, Relative CRF

Relative CRF, TC, HDL-C,
LDL-C

Relative CRF, TC, TG, HDL-C,
LDL-C

TG, Adiponectin, Fasting
glucose, Insulin, HOMA-IR

Absolute CRF, Relative CRF

Absolute CRF,

Relative CRF,TC, TG, HDL-C,
LDL-C, Fasting glucose,
Insulin

Relative CRF

Relative CRF, LDL-C, Apo B

Relative CRF

Relative CRF

TC, TG, HDL-C, LDL-C

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.

Female only

Female only

Female: 71.9%

NR

Male only

Female: 35.3%

Male only

C: 22.71.7
T: 23.10.6

Mean: 302

BMI, kg/m2

ORIGINAL RESEARCH

DOI: 10.1161/JAHA.115.002014

Male only

Female: 75%

18 to 64

Wallman,
2009187

Sex

Age, y

Study

Table 3. Continued

Exercise and Biomarkers of Cardiometabolic Health
Lin et al

15

Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Lipid and Lipoprotein Markers

The quality of studies included was heterogeneous (Figure 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.

The number of comparisons for each lipid and lipoprotein
marker is shown in Table 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).

Cardiorespiratory Fitness
A total of 67 and 123 independent comparisons were
included in the primary analysis for absolute and relative
CRF, respectively (Table 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).

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 a in the primary analysis (Table 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 4).

Markers of Glucose Intolerance and Insulin
Resistance
Table 4 also shows the effects of exercise training on markers
of glucose intolerance and insulin resistance. Fasting insulin

Figure 2. Assessment of risk of bias: summary for items of bias.
DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

16

ORIGINAL RESEARCH

Description of Study Quality

Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Number of Participants
Outcome

No.*

Exercise

Control

WMD

95% CI

PWMD

Cardiorespiratory fitness
Absolute, L/min

67

1448

1272

0.28

0.23 to 0.33

<0.001

Relative, mL/kg per minute

122

2543

2249

3.94

3.48 to 4.39

<0.001

TC, mg/dL

68

1754

1604

1.16

TG, mg/dL

66

1851

1703

HDL-C, mg/dL

74

1967

1800

2.32

HDL2-C, mg/dL

5

91

92

0.39

Lipid and lipoprotein markers

5.31

9.28 to 11.99

0.82

10.63 to

0.02

0.89

1.16 to 3.87

<0.001

1.93 to 2.32

0.8

1.55 to 1.55

0.94

8.12 to 0.39

0.08

8.51 to 2.32

0.29

HDL3-C, mg/dL

3

62

62

LDL-C, mg/dL

59

1681

1525

VLDL-C, mg/dL

7

130

102

Apo AI, g/L

5

63

62

0.03

Apo AII, g/L

2

140

126

0.01

0.01 to 0.03

0.2

Apo B, g/L

5

103

87

0.01

0.01 to 0.03

0.4

FFA, mmol/L

6

70

62

0.06

0.14 to 0.03

0.21

CRP, mg/L

13

598

554

0.22

0.78 to 0.34

0.44

IL-6, pg/mL

6

130

121

0.05

0.27 to 0.17

0.66

IL-18, pg/mL

2

67

56

18.3

TNF-a, pg/mL

3

43

44

0.21

0.37 to 0.79

0.48

Adiponectin, lg/mL

6

273

267

0.52

0.20 to 1.23

0.16

Leptin, ng/mL

7

312

315

2.72

4.03 to

<0.001

49

1720

1569

0.07

0.13 to 0.004

0.06

0.08
3.87
3.09

0.02 to 0.04

<0.001

Adipokine and inflammatory markers

0.10 to 36.6

1.42

0.05

Glucose/insulin metabolism markers
Glucose, mmol/L
Insulin, lIU/mL

29

1272

1149

1.03

1.69 to

0.37

0.002

HOMA-IR

14

1033

912

0.3

0.49 to

0.11

0.002

HbA1c, %

19

972

878

0.28

0.42 to

0.14

<0.001

C-peptide, nmol/L

2

66

34

0.08

0.29 to 0.46

IGF-1, ng/mL

5

230

207

2.98 to 9.31

0.31

IGF-BP3, lg/mL

2

170

164

0.002

0.23 to 0.23

0.99

Fibrinogen, g/L

2

36

39

0.39

0.75 to

0.04

Endothelin-1, pg/mL

2

34

32

0.22

0.62 to 0.19

0.29

Angiotensin II, pg/mL

2

24

25

1.32

2.11 to

0.001

3.16

0.67

Hemostatic factors
0.03

0.54

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, highdensity 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-a, tumor necrosis factor a; VLDL-C, very low-density lipoprotein cholesterol; WMDs,
weighted mean differences.
*Number of eligible independent comparisons.

levels; homeostatic model assessment–insulin resistance,
or HOMA-IR; and glycosylated hemoglobin A1c were significantly lowered in exercise groups compared with control
DOI: 10.1161/JAHA.115.002014

groups (P=0.002, P=0.002, and P<0.001) (Table 4). The
WMDs between exercise groups and control groups were
1.03 lIU/mL (95% CI 1.69 to 0.37; I2=79.8%; P<0.001
Journal of the American Heart Association

17

ORIGINAL RESEARCH

Table 4. WMDs in Cardiorespiratory Fitness and Circulating Concentrations of Biomarkers Between Exercise Groups and Control
Groups

Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Hemostatic Factors
The primary analysis examined 3 hemostatic factors: fibrinogen, endothelin-1, and angiotensin II (Table 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 5, Figure 3). In addition, the
effects of exercise on levels of total cholesterol (P=0.04), lowdensity 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 6 and 7,
Figure 3). Sex differences in the effects of exercise were also
found for fasting insulin (P=0.04).
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 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,

Table 5. WMDs in Absolute and Relative Cardiorespiratory Fitness Comparing Exercise Intervention Groups to Control Groups by
Specific Modifiers
Absolute CRF (L/min)

Relative CRF (mL/kg per minute)

n

WMD

95% CI

I ,%

Pinteraction*

n

WMD

95% CI

I2, %

Pinteraction

<50

16

0.47

0.34 to 0.60

93.4

0.008

28

5.60

4.56 to 6.65

85.1

0.003

≥50

12

0.21

0.11 to 0.32

84.0

30

3.31

2.46 to 4.15

91.0

Women

25

0.19

0.13 to 0.24

92.3

48

3.24

2.61 to 3.87

88.7

Men

27

0.42

0.32 to 0.53

90.4

37

5.43

4.32 to 6.53

90.2

Active

9

0.33

0.15 to 0.51

97.0

14

3.62

1.39 to 5.85

96.5

Sedentary

43

0.31

0.25 to 0.37

88.4

88

3.85

3.36 to 4.33

90.5

Obese

19

0.28

0.20 to 0.36

93.3

19

3.85

2.83 to 4.87

94.9

Nonobese

20

0.26

0.17 to 0.36

89.1

46

4.01

3.22 to 4.79

85.7

Yes

8

0.33

0.07 to 0.60

88.2

16

3.34

2.63 to 4.04

74.8

None

53

0.27

0.22 to 0.33

94.6

94

4.10

3.51 to 4.71

92.7

<16

39

0.33

0.25 to 0.40

91.3

69

3.83

3.12 to 4.54

90.7

≥16

28

0.21

0.15 to 0.28

92.3

54

3.90

3.34 to 4.35

90.4

Modifier

2

Age, y

Sex
<0.001

0.001

Lifestyle
0.89

0.83

BMI†
0.65

0.96

Health status‡
0.84

0.46

Duration, wk
0.09

0.72

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).

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

18

ORIGINAL RESEARCH

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).

Exercise and Biomarkers of Cardiometabolic Health

Rel. CRF (mL/kg/min)

TC (mg/dL)

TG (mg/dL)

HDL−C (mg/dL)

LDL−C (mg/dL)

Glucose (mmol/L)

ORIGINAL RESEARCH

Abs. CRF (L/min)
Age

Lin et al

Insulin (uIU/mL)

<50 yr
=/> 50 yr

Gender

Women
Men

Lifestyle

Active
Sedentary

BMI

Obese
Non−obese

Condition Yes
No
Duration

<16 wk
=/>16 wk

Intensity

Moderate
Vigorous
0.1 0.2 0.3 0.4 0.5

WMD

2

3

4

WMD

5

6

−20

0

20

40

−30

−20

WMD

−10

WMD

0

10

−1

1

3

WMD

5

7

−20 −10

0

10

WMD

20

−0.6 −0.4 −0.2

WMD

0

0.2

−5 −4 −3 −2 −1 0

1

2

WMD

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.

respectively) in people having at least 1 of type 2 diabetes,
hypertension, hyperlipidemia, and metabolic syndrome
(Tables 6 and 7, Figure 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 6 and 7, Figure 3).

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 8).

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 4).
In addition, we identified several important modifiers, including age, sex, and health status, that may partially modify the
exercise effects on 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
DOI: 10.1161/JAHA.115.002014

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
Journal of the American Heart Association

19

Lin et al

Exercise and Biomarkers of Cardiometabolic Health

ORIGINAL RESEARCH

Table 6. WMDs in Lipid Biomarkers Comparing Exercise Intervention and Control Groups by Specific Modifiers
Total Cholesterol (mg/dL)
Modifier

n

WMD

Total Triglycerides (mg/dL)
2

95% CI

I,%

Pinteraction*

10.1 to 1.55

0.0

0.43

5.41 to 7.35

72.5

n

WMD

95% CI

I 2, %

Pinteraction

0.21

Age, y
<50

12

≥50

15

0.77

Women

28

1.16

Men

15

4.25

12
13

6.20
1.77

14.2 to 2.66

34.3

8.86 to 13.3

75.5

Sex

0.39

5.41 to 7.73

91.6

5.80 to 5.03

54.3

0.61

27

1.77

9.74 to 5.31

76.1

13

8.86

14.2 to

12.8

5

8.86

30.1 to 12.4

61.2

43

3.54

9.74 to 2.66

75.1

19

7.97

14.2 to

53.0

28

5.31

14.2 to 4.43

80.7

9

9.74

26.6 to 6.20

63.9

44

4.43

11.5 to 2.66

75.2

35

6.20

13.3 to 0.89

71.1

31

5.31

11.5 to 1.77

72.7

4.43

0.25

Lifestyle
Active

6

8.12

7.73 to 24.0

92.5

Sedentary

47

1.93

13.9 to 17.4

99.1

Obese

16

12.8

22.4 to 47.6

99.7

Nonobese

29

1.55

7.73 to 4.25

83.6

Yes

10

11.2

19.3 to

75.2

None

47

1.55

5.41 to 2.32

81.6

15.5 to 22.8

82.9

7.73 to 1.55

99.2

0.71

0.64

BMI†
0.20

1.77

0.70

Health status‡
3.48

0.04

0.48

Duration, wk
<16

39

≥16

29

3.87
3.09

0.34

HDL-C (mg/dL)
Modifier

0.76

LDL-C (mg/dL)
2

N

WMD

95% CI

I,%

Pinteraction*

N

<50

16

4.25

2.32 to 6.19

73.9

0.94

9

≥50

15

3.87

0.77 to 6.96

84.5

Women

28

2.32

0.08 to 4.64

84.8

Men

19

2.71

0.39 to 5.03

92.5

Active

5

4.25

0.39 to 8.51

86.9

Sedentary

52

2.32

0.77 to 3.87

18.6

19

4.25

1.93 to 6.96

88.1

30

1.16

1.16 to 3.87

83.0

Yes

11

2.71

2.32 to 7.73

91.2

None

50

2.32

0.77 to 3.87

87.3

<16

39

2.71

1.16 to 4.64

83.0

≥16

35

1.93

0.15 to 0.28

90.4

WMD

I 2, %

Pinteraction

10.8 to 3.09

49.3

0.38

5.03 to 6.19

73.0

95% CI

Age, y

14

3.87
0.39

Sex
0.80

24

1.93

9.67 to 5.80

95.0

13

2.32

8.89 to 4.25

79.7

10.4 to 27.1

54.9

0.93

Lifestyle

BMI

0.52

2

8.12

45

3.87

8.12 to 0.39

88.3

14

0.08

4.64 to 4.25

62.0

25

4.25

10.4 to 2.32

91.4

12

11.6

19.7 to

80.8

39

3.09

7.73 to 1.55

89.3

29

3.09

9.28 to 3.48

89.6

30

4.64

10.4 to 1.16

92.2

0.21

†

Obese
Nonobese
Health status

0.13

0.33

‡

0.89

3.09

0.06

Duration, wk
0.55

0.63

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).

DOI: 10.1161/JAHA.115.002014

Journal of the American Heart Association

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Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Table 7. WMDs in Biomarkers of Glucose Intolerance and Insulin Resistance Comparing Exercise Intervention Groups to Control
Groups by Specific Modifiers
Fasting Glucose (mmol/L)
Modifier

n

WMD

<50

5

0.09

≥50

7

0.01

Fasting Insulin (lIU/mL)
I 2, %

Pinteraction*

n

0.11 to 0.29

91.3

0.57

4

0.06 to 0.07

36.9

95% CI

WMD

I2, %

Pinteraction

3.44 to 0.76

76.9

0.22

1.23 to 2.13

75.6

95% CI

Age, y

3

1.34
0.45

Sex
Women

16

0.06

0.19 to 0.08

91.4

Men

9

0.07

0.25 to 0.12

84.3

Active

2

0.20

0.74 to 0.34

99.0

Sedentary

29

0.06

0.16 to 0.03

80.2

Obese

20

0.06

0.20 to 0.07

90.7

Nonobese

18

0.05

0.17 to 0.07

80.7

Yes

9

0.18

0.40 to 0.05

0.0

None

27

0.03

0.11 to 0.06

87.2

<16

30

0.10

0.22 to 0.03

90.0

≥16

19

0.02

0.09 to 0.06

47.5

0.93

9

0.27

1.12 to 0.57

68.7

6

2.86

3.55 to

0.0

2.17

0.04

Lifestyle
0.63

0

NA

NA

NA

17

0.94

1.75 to

0.13

13

0.93

2.18 to 0.32

82.0

10

0.86

1.52 to

0.19

32.8

6

2.68

4.67 to

0.70

75.2

14

0.70

1.60 to 0.21

77.5

13

1.35

2.50 to

79.3

16

0.83

1.83 to 0.17

NA

78.5

BMI†
0.90

0.88

Health status‡
0.40

0.05

Duration, wk
0.70

0.20

0.58

78.7

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).

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
DOI: 10.1161/JAHA.115.002014

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.
Journal of the American Heart Association

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Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Moderate
Outcome

Vigorous

No.*

WMD

95% CI

No.*

WMD

95% CI

Absolute, L/min

39

0.22

0.16 to 0.29

33

0.31

0.22 to 0.40

Relative, mL/kg per minute

64

3.22

2.61 to 4.18

68

3.26

2.63 to 3.89

4.25

3.87

Cardiorespiratory fitness

Lipids markers
TC, mg/dL

41

TG, mg/dL

37

HDL-C, mg/dL

44

HDL2-C, mg/dL

2

7.73 to 16.6

28

12.4 to 1.77

32

1.16

0.39 to 2.71

33

2.71

1.16

0.77 to 3.48

2

1.55
0.04

5.31

5.31

31.7 to 39.8
11.5 to 0.09
0.39 to 5.03
1.16 to 4.25

HDL3-C, mg/dL

1

1.16

5.80 to 3.87

2

LDL-C, mg/dL

35

3.09

8.12 to 2.32

26

4.64

12.0 to 2.32

VLDL-C, mg/dL

5

1.93

5.41 to 1.93

2

7.35

22.9 to 6.19

Apo AI, g/L

4

Apo AII, g/L

1

Apo B, g/L

3

FFA, mmol/L

5

CRP, mg/L

9

IL-6, pg/mL

5

0.03

1

0.00

0.12 to 0.12

0.24 to 0.24

1

0.01

0.01 to 0.03

0.01 to 0.03

2

0.02

0.21 to 0.18

0.06

0.16 to 0.03

3

0.04

0.17 to 0.10

0.23

1.01 to 0.55

4

0.22 to 0.25

2

0.001
0.01

0.02 to 0.04

1.55 to 1.55

Inflammatory markers

0.02

IL-18, pg/mL

1

14.0

128 to 156

1

TNF-a, pg/mL

3

0.06

0.48 to 0.60

1

Adiponectin, lg/mL

1

3.52

Leptin, ng/mL

1

31

1.17 to 5.87

6

0.70

1.19 to

6

0.04

0.24 to 0.17

0.21

0.04
0.39
18.4
0.01
0.52
2.56

0.24 to 0.31
0.83 to 0.06
0.02 to 36.8
0.93 to 0.91
0.20 to 1.23
4.04 to

1.08

Insulin resistance markers
Glucose, mmol/L

22

0.03

0.08 to 0.12

Insulin, lIU/mL

17

0.91

2.08 to 0.26

17

1.32

2.15 to

0.50

HOMA-IR

7

0.30

0.66 to 0.06

7

0.47

0.82 to

0.12

HbA1c, %

11

0.28

0.46 to

7

2.71

0.54 to

0.002

C-peptide, nmol/L

1

1

0.18

0.62 to 0.26

0.22
4.64

0.11

0.19 to 0.25

IGF-1, ng/mL

2

IGF-BP3, lg/mL

0

NA

NA

29.58 to 20.30

NA

NA

3
2

3.91
0.002

2.87 to 10.69
0.23 to 0.23

Hemostatic factors
Fibrinogen, g/L

0

Endothelin-1, pg/mL

2

0.22

0.62 to 0.19

0

2

NA

NA

Angiotensin II, pg/mL

2

1.32

2.11 to

0

NA

NA

0.54

0.39

0.75 to

0.03

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, highdensity 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-a, tumor necrosis factor a;
VLDL-C, very low-density lipoprotein cholesterol; WMDs, weighted mean differences.
*Number of eligible independent comparisons.

Strengths of this meta-analysis include the comprehensive
and systematic review of both conventional and novel CVD
biomarkers, detailed subgroup analyses for potential effect
DOI: 10.1161/JAHA.115.002014

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
Journal of the American Heart Association

22

ORIGINAL RESEARCH

Table 8. WMDs in Cardiorespiratory Fitness and Circulating Concentrations of Biomarkers Comparing Moderate and Vigorous
Exercise Intervention Groups to Control Groups

Exercise and Biomarkers of Cardiometabolic Health

Lin et al

Figure 4. Mechanisms by which exercise training may improve
cardiovascular health.

Activity Guidelines Advisory Committee Report included a
number of comprehensively systematic reviews and metaanalyses 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 metaanalyses 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
DOI: 10.1161/JAHA.115.002014

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.

Disclosures
None.

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