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 .
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 ( table1 ) .
all relevant studies and review articles ( including meta - analysis ) and the reference lists of the identified articles were checked manually .
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 .
search strategy for medline 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
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 . in total
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 .
) 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 .
the criteria for classifying exercise interventions as moderate exercise or vigorous exercise are summarized in table2 . 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 .
criteria used for exercise intensity classification 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 i statistics.31,32 i 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 / m .
two - sided p0.05 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 ) .
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 .
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 ( table1 ) .
all relevant studies and review articles ( including meta - analysis ) and the reference lists of the identified articles were checked manually .
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 .
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
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 .
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 .
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 .
the criteria for classifying exercise interventions as moderate exercise or vigorous exercise are summarized in table2 . 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 .
criteria used for exercise intensity classification 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 i statistics.31,32 i 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 ) .
two - sided p0.05 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 ) .
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 table3 . 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 ) .
characteristics of the trials included in the meta - analysis 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 . 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 .
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- , tumor necrosis factor  ; vcam-1 , vascular cell adhesion molecule 1 ; vldl - c , very low - density lipoprotein cholesterol .
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 .
a total of 67 and 123 independent comparisons were included in the primary analysis for absolute and relative crf , respectively ( table4 ) . 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 ; i=93.7% ; p<0.001 for heterogeneity ) for absolute crf and 3.90  ml / kg per minute ( 95% ci 3.45 to 4.35 ; i=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 ) .
wmds in cardiorespiratory fitness and circulating concentrations of biomarkers between exercise groups and control groups 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- , tumor necrosis factor  ; vldl - c , very low - density lipoprotein cholesterol ; wmds , weighted mean differences . number of eligible independent comparisons .
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 ; i=71.8% ; p<0.001 for heterogeneity ) for triglycerides , 2.32  mg / dl ( 95% ci 1.16 to 3.87 ; i=87.5% ; p<0.001 for heterogeneity ) for hdl - c , and 0.03  g / l ( 95% ci 0.02 to 0.04 ; i=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 ) .
significant associations were found for interleukin-18 ( wmd 18.3  pg / ml ; 95% ci 0.10 to 36.6 ; i=0.0% ; p=0.95 for heterogeneity ) but not for c - reactive protein , interleukin-6 , or tumor necrosis factor  in the primary analysis ( table4 ) .
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 ; i=82.10% ; p<0.001 for heterogeneity ) ( table4 ) .
table4 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 ) ( table4 ) .
the wmds between exercise groups and control groups were 1.03  iu / ml ( 95% ci 1.69 to 0.37 ; i=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 ; i=77.5% ; p<0.001 for heterogeneity ) , whereas the wmd for hemoglobin a1c was 0.28% ( 95% ci 0.42 to 0.14 ; i=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 ) .
the primary analysis examined 3 hemostatic factors : fibrinogen , endothelin-1 , and angiotensin ii ( table4 ) . on average ,
the levels of fibrinogen and angiotensin ii were 0.39  g / l ( 95% ci 0.03 to 0.75 ; i=45.00% ; p=0.18 for heterogeneity ) and 1.32  pg / ml ( 95% ci 0.54 to 2.11 ; i=0.00% ; p=0.71 for heterogeneity ) lower in exercise groups than in control groups .
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 ) ( table5 , figure3 ) .
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 ( tables6 and 7 , figure3 ) .
sex differences in the effects of exercise were also found for fasting insulin ( p=0.04 ) .
wmds in absolute and relative cardiorespiratory fitness comparing exercise intervention groups to control groups by specific modifiers bmi indicates body mass index ; crf , cardiorespiratory fitness ; wmds , weighted mean differences , p values for the impact of potential modifiers on the exercise effects .
health status : participants having at least 1 of type 2 diabetes , hypertension , hyperlipidemia , or metabolic syndrome ( yes ) vs those with none of them ( none ) .
wmds in lipid biomarkers comparing exercise intervention and control groups by specific modifiers bmi indicates body mass index ; hdl - c , high - density lipoprotein cholesterol ; ldl - c , low - density lipoprotein cholesterol ; wmds , weighted mean differences .
health status : participants having at least 1 of type 2 diabetes , hypertension , hyperlipidemia , or metabolic syndrome ( yes ) vs those with none of them ( none ) .
wmds in biomarkers of glucose intolerance and insulin resistance comparing exercise intervention groups to control groups by specific modifiers bmi indicates body mass index ; na , not available due to the lack of comparisons reported for active participants ; wmds , weighted mean differences .
health status : participants having at least 1 of type 2 diabetes , hypertension , hyperlipidemia , or metabolic syndrome ( yes ) vs those with none of them ( none ) .
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 .
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 .
consistent with the metaregression results , men seemed to have greater exercise - related improvement in crf , ldl - c , and fasting insulin than women did ( figure3 ) .
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 ( tables6 and 7 , figure3 ) ; no such improvements were observed among people without any of those health conditions ( p=0.44 , p=0.19 , and p=0.13 , respectively ) ( tables6 and 7 , figure3 ) . 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 ( table8 ) .
wmds in cardiorespiratory fitness and circulating concentrations of biomarkers comparing moderate and vigorous exercise intervention groups to control groups 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- , tumor necrosis factor  ; vldl - c , very low - density lipoprotein cholesterol ; wmds , weighted mean differences .
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 .
a total of 67 and 123 independent comparisons were included in the primary analysis for absolute and relative crf , respectively ( table4 ) . both measures
the wmds comparing exercise groups and control groups were 0.28  l / min ( 95% ci 0.23 to 0.33 ; i=93.7% ; p<0.001 for heterogeneity ) for absolute crf and 3.90  ml / kg per minute ( 95% ci 3.45 to 4.35 ; i=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 ) .
wmds in cardiorespiratory fitness and circulating concentrations of biomarkers between exercise groups and control groups 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- , tumor necrosis factor  ; vldl - c , very low - density lipoprotein cholesterol ; wmds , weighted mean differences .
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 ; i=71.8% ; p<0.001 for heterogeneity ) for triglycerides , 2.32  mg / dl ( 95% ci 1.16 to 3.87 ; i=87.5% ; p<0.001 for heterogeneity ) for hdl - c , and 0.03  g / l ( 95% ci 0.02 to 0.04 ; i=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 ) .
significant associations were found for interleukin-18 ( wmd 18.3  pg / ml ; 95% ci 0.10 to 36.6 ; i=0.0% ; p=0.95 for heterogeneity ) but not for c - reactive protein , interleukin-6 , or tumor necrosis factor  in the primary analysis ( table4 ) .
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 ; i=82.10% ; p<0.001 for heterogeneity ) ( table4 ) .
table4 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 ) ( table4 ) .
the wmds between exercise groups and control groups were 1.03  iu / ml ( 95% ci 1.69 to 0.37 ; i=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 ; i=77.5% ; p<0.001 for heterogeneity ) , whereas the wmd for hemoglobin a1c was 0.28% ( 95% ci 0.42 to 0.14 ; i=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 ) .
the primary analysis examined 3 hemostatic factors : fibrinogen , endothelin-1 , and angiotensin ii ( table4 ) . on average , the levels of fibrinogen and angiotensin ii were 0.39  g / l ( 95% ci 0.03 to 0.75 ; i=45.00% ; p=0.18 for heterogeneity ) and 1.32  pg / ml ( 95% ci 0.54 to 2.11 ; i=0.00% ; p=0.71 for heterogeneity ) lower in exercise groups than in control groups .
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 ) ( table5 , figure3 ) .
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 ( tables6 and 7 , figure3 ) .
sex differences in the effects of exercise were also found for fasting insulin ( p=0.04 ) .
wmds in absolute and relative cardiorespiratory fitness comparing exercise intervention groups to control groups by specific modifiers bmi indicates body mass index ; crf , cardiorespiratory fitness ; wmds , weighted mean differences , p values for the impact of potential modifiers on the exercise effects .
health status : participants having at least 1 of type 2 diabetes , hypertension , hyperlipidemia , or metabolic syndrome ( yes ) vs those with none of them ( none ) .
wmds in lipid biomarkers comparing exercise intervention and control groups by specific modifiers bmi indicates body mass index ; hdl - c , high - density lipoprotein cholesterol ; ldl - c , low - density lipoprotein cholesterol ; wmds , weighted mean differences .
health status : participants having at least 1 of type 2 diabetes , hypertension , hyperlipidemia , or metabolic syndrome ( yes ) vs those with none of them ( none ) .
wmds in biomarkers of glucose intolerance and insulin resistance comparing exercise intervention groups to control groups by specific modifiers bmi indicates body mass index ; na , not available due to the lack of comparisons reported for active participants ; wmds , weighted mean differences .
health status : participants having at least 1 of type 2 diabetes , hypertension , hyperlipidemia , or metabolic syndrome ( yes ) vs those with none of them ( none ) .
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 .
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 <
consistent with the metaregression results , men seemed to have greater exercise - related improvement in crf , ldl - c , and fasting insulin than women did ( figure3 ) .
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 ( tables6 and 7 , figure3 ) ; no such improvements were observed among people without any of those health conditions ( p=0.44 , p=0.19 , and p=0.13 , respectively ) ( tables6 and 7 , figure3 ) .
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 ( table8 ) .
wmds in cardiorespiratory fitness and circulating concentrations of biomarkers comparing moderate and vigorous exercise intervention groups to control groups 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- , tumor necrosis factor  ; vldl - c , very low - density lipoprotein cholesterol ; wmds , weighted mean differences .
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 ( figure4 ) .
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 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.202204 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.205207 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 .
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 .
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 ( table8 ) .
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 .
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 .
 backgroundguidelines 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 resultstwo 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.conclusionsthis 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 . 
Methods
Data Sources and Searches
Study Selection
Data Extraction and Quality Assessment
Data Synthesis and Analysis
Results
Description of Study Quality
Cardiorespiratory Fitness
Lipid and Lipoprotein Markers
Adipokine and Inflammatory Markers
Markers of Glucose Intolerance and Insulin Resistance
Hemostatic Factors
Subgroup Analyses
Sensitivity Analyses
Discussion
Sources of Funding
Disclosures