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Physical Activity and Mortality in Individuals

With Diabetes Mellitus
A Prospective Study and Meta-analysis
Diewertje Sluik, MSc; Brian Buijsse, PhD; Rebecca Muckelbauer, PhD; Rudolf Kaaks, PhD; Birgit Teucher, PhD;
Nina Fns Johnsen, PhD; Anne Tjnneland, PhD; Kim Overvad, PhD; Jane Nautrup stergaard, PhD;
Pilar Amiano, MSc; Eva Ardanaz, PhD; Benedetta Bendinelli, PharmD; Valeria Pala, PhD; Rosario Tumino, MD;
Fulvio Ricceri, MSc; Amalia Mattiello, MD; Annemieke M. W. Spijkerman, PhD; Evelyn M. Monninkhof, PhD;
Anne M. May, PhD; Paul W. Franks, PhD; Peter M. Nilsson, MD, PhD; Patrik Wennberg, PhD;
Olov Rolandsson, MD, PhD; Guy Fagherazzi, PhD; Marie-Christine Boutron-Ruault, MD, PhD;
Francoise Clavel-Chapelon, PhD; Jose Mara Huerta Castano, PhD; Valentina Gallo, PhD;
Heiner Boeing, PhD; Ute Nothlings, DrPH
Background: Physical activity (PA) is considered a cornerstone of diabetes mellitus management to prevent complications, but conclusive evidence is lacking.
Methods: This prospective cohort study and metaanalysis of existing studies investigated the association
between PA and mortality in individuals with diabetes.
In the EPIC study (European Prospective Investigation
Into Cancer and Nutrition), a cohort was defined of 5859
individuals with diabetes at baseline. Associations of leisure-time and total PA and walking with cardiovascular
disease (CVD) and total mortality were studied using multivariable Cox proportional hazards regression models.
Fixed- and random-effects meta-analyses of prospective
studies published up to December 2010 were pooled with
inverse variance weighting.
Results: In the prospective analysis, total PA was associated with lower risk of CVD and total mortality. Compared with physically inactive persons, the lowest mortality risk was observed in moderately active persons:
hazard ratios were 0.62 (95% CI, 0.49-0.78) for total mortality and 0.51 (95% CI, 0.32-0.81) for CVD mortality.
Leisure-time PA was associated with lower total mortality risk, and walking was associated with lower CVD mortality risk. In the meta-analysis, the pooled randomeffects hazard ratio from 5 studies for high vs low total
PA and all-cause mortality was 0.60 (95% CI, 0.490.73).
Conclusions: Higher levels of PA were associated with
lower mortality risk in individuals with diabetes. Even
those undertaking moderate amounts of activity were at
appreciably lower risk for early death compared with inactive persons. These findings provide empirical evidence supporting the widely shared view that persons with
diabetes should engage in regular PA.
Arch Intern Med.

Published online August 6, 2012.
doi:10.1001/archinternmed.2012.3130
IABETES MELLITUS IS A MA-
jor cause of illness and

premature death in most
countries.1 Efforts to reduce the impact of diabetes complications have been predominantly aimed at controlling hyperglycemia,
See related articles
Author Affiliations are listed at

the end of this article.
hypertension, and dyslipidemia by using

medication strategies, despite the lack of
evidence of long-term benefits.2,3 However, diabetes management should extend to an overall intervention strategy that
includes lifestyle modification to reduce
the risk of complications.4
ARCH INTERN MED
PUBLISHED ONLINE AUGUST 6, 2012

E1
Lifestyle measures, including physical

activity (PA), are key factors for selfmanagement in patients with diabetes to
prevent macrovascular complications and
premature mortality.5 Increased PA has long
been considered a cornerstone of diabetes
management. Persons with diabetes are recommended to engage in at least 150 minutes per week of moderate-intensity aerobic PA.5,6 Walking has been of particular
interest because it requires no specific facilities, can be easily implemented in the
daily routine, and is relatively safe.7
In the general population, being physically active has been associated with a
lower risk of overall and cardiovascular disease (CVD) mortality compared with being
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Author Affil
the end of th
inactive.8 Because persons with diabetes are at higher risk for CVD and
premature death, it is important to
determine whether PA can produce similar beneficial effects in this
high-risk population. Indeed, a metaanalysis9 of 14 controlled trials in
diabetic persons showed that exercise programs had beneficial effects
on glycemic control. Several prospective cohort studies 10-21 have
found that higher PA levels were associated with reduced CVD and total
mortality rates, but conclusive highlevel evidence is lacking.
The objective was to investigate
whether PAtotal, leisure time, and
walkingwas associated with CVD
and total mortality in a large cohort of individuals with diabetes. A
meta-analysis summarizing evidence from prospective studies was
performed to put the present findings in context and to provide a
higher level of evidence.
METHODS
STUDY DESIGN AND

POPULATION
The EPIC study (European Prospective Investigation Into Cancer and Nutrition) is an ongoing prospective study
of 519 978 men and women aged 35 to
70 years from 23 study centers in 10 European countries.22 Within the EPIC
study, a cohort was established of participants with a confirmed diagnosis of
diabetes mellitus at baseline between
1992 and 2000. As described previously,23,24 15 study centers from 6 countries provided additional data on diabetes diagnosis and medications. No
information was available to distinguish type 1 and 2 diabetes mellitus. To
be considered diabetic, a self-reported
diagnosis at baseline had to be confirmed by at least 1 additional information source. Depending on the available options in the study centers, these
sources included contact with a physician, self-reported use of diabetes medication, confirmation of self-reported diabetes status during follow-up, linkage to
diabetes registries, and a baseline glycated hemoglobin (HbA1c) level greater
than 6%. The cohort comprised 6412 individuals with confirmed diabetes at
study enrollment. After the exclusion of
participants without follow-up information on vital status (n = 27), participants with extreme or implausible energy intakes (n=177), and participants
ARCH INTERN MED
with missing PA data (n=349, including the cohort in Umea, Sweden), the
analytical sample included 5859 individuals.
PA ASSESSMENT
At baseline, participants received a lifestyle questionnaire by mail, which they
completed at home. This questionnaire
asked about occupational activity and
duration and frequency of walking, cycling, gardening (average values of summer and winter), household work, doit-yourself activities, and sports during
the past year.
Total PA was investigated using the
Cambridge Physical Activity Index,25
which combines self-reported occupational activity with time participating in
cycling and sports. Occupational activity was categorized as sedentary, standing, manual, or heavy manual. The sum
of hours per week spent on cycling and
sports was categorized into 4 levels.
Based on a 4 4 matrix, participants
were divided into 4 categories, that is,
inactive (sedentary job and no recreational activity), moderately inactive,
moderately active, and active (sedentary job with 1 hour of recreational activity per day, standing or physical job
with some recreational activity, or a
heavy manual job). The index has been
shown to have acceptable repeatability,
and it was positively associated with objective measures of the ratio of daytime
expenditure to resting metabolic rate and
cardiorespiratory fitness.25
Leisure-time PA included walking,
cycling, gardening, sports, household
work, and do-it-yourself activities. Duration and frequency were directly assessed, and intensity, that is, energy expenditure, was estimated by assigning
metabolic equivalents (METs), ranging
from 3 for walking and household activities to 6 for sports.26 A MET is defined as the ratio of work metabolic rate
to a standard metabolic rate of 1.0 kcal
(4.184 kJ)kg1h1. One MET is
the energy expended by a person while
sitting quietly.
COVARIATE ASSESSMENT
Diabetes duration was calculated by subtracting the self-reported year of diagnosis or, when available, the exact date
of diagnosis supplied by the physician
from the year of baseline examination.
Insulin therapy or use of oral hypoglycemic agents was either self-reported
during the visit at the study center or was
obtained through medical verification;
this information was not collected in
Spain and Denmark. Moreover, the lifePUBLISHED ONLINE AUGUST 6, 2012
E2
style questionnaire included a question

about insulin therapy. When a participant did not report the use of diabetes
medication during the visit or reported
insulin therapy in the questionnaire, we
assumed that the participant did not take
medication.
Dietary intake, including alcohol consumption during the past year, was assessed using country-specific instruments. 2 2 Weight and height were
measured with participants not wearing shoes. Systolic and diastolic blood
pressures were measured by trained personnel at baseline except in Navarra,
Spain. The HbA1c level was measured in
erythrocytes of blood collected at baseline except in Denmark. Smoking behavior, educational level, and prevalence of myocardial infarction, stroke,
and cancer were assessed using questionnaires.
OUTCOME ASCERTAINMENT
Sixty-one participants (1%) were lost to
follow-up. For those completely followed up, causes and dates of deaths
were ascertained using record linkages
with local, regional, or central cancer registries, boards of health, or death indices. An exception was Germany, where
deceased participants were identified
with follow-up mailings and subsequent inquiries to municipality registries, regional health departments, physicians, or hospitals. Mortality data were
coded according to the International
Classification of Diseases, Injuries, and
Causes of Death, Tenth Revision, using the
codes I00-I99 for CVD mortality.
STATISTICAL ANALYSIS
Hazard ratios (HRs) and 95% CIs of total
and CVD mortality were calculated using
Cox proportional hazards regression and
a commercially available software program (SAS, version 9.2; SAS Institute,
Inc).27 Total PA was analyzed in 4 categories, and leisure-time PA (METhours per week) and walking (hours per
week) were analyzed in quartiles. The
lowest category or quartile was the reference. Center and age at recruitment in
1-year categories were entered as stratum variables.28 Age was used as the underlying time scale, with entry time defined as the participants age (in years)
at recruitment and exit time defined as
the participants age (in years) at death
or censoring.
The HRs were adjusted for sex
(model 1); disease duration (years); use
of diabetes-related medication (none, insulin, oral hypoglycemic agents, or
both); self-reported myocardial infarc-
tion, stroke, or cancer; alcohol consumption (grams per day); smoking status
(never, former [quit 10, 11-20, or 20
years ago], or current), smoking duration (10, 11-20, 21-30, 31-40, or 41
years), and number of cigarettes currently smoked (15, 15-24, or 25 per
day); education (5 categories); energy intake (kilocalories per day); and factor
scores for the first 3 patterns derived
from factor analysis on 16 food groups
(model 2).
Among the covariates, proportions of
missing data were 31% for diabetes medication, 8% for disease duration, 5% for
prevalence of cancer, 1% for prevalence of myocardial infarction or stroke,
and less than 1% for diet and education. These missing values were imputed using the multiple imputation
technique.29 All the variables included
in the multivariable adjustment model
were included in the imputation procedure, and 20 duplicate data sets were
sampled.30
In sensitivity analyses, it was checked
whether additional adjustment for HbA1c
level, BMI, and systolic blood pressure
affected the risk estimates. Prevalent
cases of myocardial infarction, stroke,
and cancer and participants with follow-up of less than 2 years (n = 5039)
were excluded. Statistical interaction by
sex, body mass index (BMI), and insulin therapy was tested by adding a product term to the multivariable adjustment model. Finally, results were
compared with analyses without multiple imputation (n = 5376), in which
participants with missing values for continuous variables were excluded, and
missing values for categorical variables
were modeled as a separate indicator
variable.
META-ANALYSIS
A systematic literature search in
MEDLINE and ISI Web of Knowledge for
prospective studies on PA published up
to December 2010 yielded 4344 publications, of which 12 were included in the
meta-analysis (eFigure 1; http://www
.archinternmed.com). Study quality
scores were assigned using the NewcastleOttawa Scale (eTable); quality criteria included representativeness, exposure and
outcome ascertainment, adjustment, follow-up, and attrition.31 The most complete adjusted HRs and 95% CIs of the
highest vs the lowest activity category
were extracted. Study selection, quality
assessment, and data extraction was performed by 2 of us (D.S. and B.B.) independently; any discrepancies between the
2 were resolved by discussion. Fixed- and
random-effects meta-analyses with inARCH INTERN MED
verse variance weighting were performed using R package meta (version 2.12.2). Heterogeneity was assessed
by the Q statistic and the I2 index.
RESULTS
BASELINE CHARACTERISTICS
Individuals who were more physically active were younger, were
more likely to be male, had a lower
BMI and a lower HbA1c level, and
had a shorter diabetes duration
than did those who were inactive
(Table 1). They were also more
likely to use insulin and to report
fewer comorbidities.
PROSPECTIVE ANALYSIS
After median follow-up of 9.4 years,
755 participants had died (13%).
Death due to CVD accounted for
28% of all deaths (n = 212). Total PA
was inversely associated with total
and CVD mortality (Table 2). The
lowest HR was observed in persons
categorized as moderately active: the
HR in the multivariable adjustment model was 0.62 (95% CI, 0.490.78) for total mortality. When excluding heavy manual workers and
nonworkers from the analyses, the
lowest risk was still observed in the
moderately active group. Leisuretime PA was also associated with a
lower risk of CVD and total mortality: the HR in the highest category
was 0.73 (95% CI, 0.57-0.93) for
total mortality. The association with
CVD mortality was weaker in magnitude and nonsignificant but
showed the same trend. Participants who walked more than 2 hours
per week had lower CVD mortality
risk compared with those in the lowest activity group: the HR in the category of 2 to 4.5 hours per week was
0.54 (95% CI, 0.36-0.82). The relationship of walking with total mortality was less pronounced. Additional adjustment for vigorous PA
did not alter the association.
Adjustment for intermediate factors did not affect the risk estimates. For total PA, the HR in moderately active persons was 0.62 (95%
CI, 0.50-0.79) after additional adjustment for HbA1c and 0.62 (95%
CI, 0.49-0.78) after additional adPUBLISHED ONLINE AUGUST 6, 2012
E3
justment for BMI or systolic blood

pressure. Excluding participants
with comorbidities at baseline led to
lower HRs: for total PA, the HR in
moderately active persons was 0.58
(95% CI, 0.43-0.77) for total mortality and 0.31 (95% CI, 0.15-0.60)
for CVD mortality. Sex seemed to
modify the association between total
PA and total mortality (P for interaction = .04, multivariable model).
Women had a lower HR across quartiles than did men, but the trend
showed the same direction (the HR
in the highest category was 0.79
[95% CI, 0.59-1.05] in men and 0.59
[95% CI, 0.36-0.96] in women). The
analyses without multiple imputation showed similar results (the HR
for total mortality in the highest category of total PA was 0.70 [95% CI,
0.54-0.90]), indicating that missing observations did not influence
the effect estimates.
META-ANALYSIS
In the 12 cohort studies10,13-15,17-21,32-34
included in the meta-analyses, verification criteria of diabetes status
ranged from self-report to an oral
glucose tolerance test; 4 studies used
official diagnostic criteria (Table 3).
Sample sizes ranged from 29221 to
5859 (the present study), and mean
follow-up was 12.5 years. Physical
activity was assessed by questionnaire in 8 studies10,14,17,19,20,32-34 and
by interview in 4.13,15,18,21 Participants were divided into PA categories ranging from inactive to active.
All but 1 study13 adjusted for a wide
range of multiple risk factors. Study
quality ranged from 613,14,19,34 to 918
stars of a maximum of 9. Three studies19,20,33 reported on total PA but
measured only leisure-time activities and were, therefore, classified as
such.
The meta-analyses of prospective studies showed that the highest levels of total and leisure-time PA
and walking were associated with a
lower risk of total and CVD mortality compared with a low activity level
( Figures 1 , 2 , and 3 ). Magnitudes of associations were similar for
total and CVD mortality.
Significant heterogeneity was
found for total PA and total mortality (I2 = 69%, P = .01) and for walking and total mortality (I2 = 71%;
Table 1. Baseline Characteristics of 5859 Individuals With Diabetes Mellitus Across Categories of Total Physical Activity
Total Physical Activity a
Variable
Men, %
Age, mean (SD), y
HbA1c, mean (SD), %
Disease duration, median (IQR), y
Medication use, %
None
Insulin and OHA
Insulin only
OHA only
Types of physical activity, MET-h/wk, median (IQR)
Cycling
Sports
Gardening
Do-it-yourself activities
Housework activity
Walking
Stair climbing
Vigorous physical activity
Physical activity at work, %
Sedentary occupation
Standing occupation
Manual work
Heavy manual work
Nonworker
Unknown
BMI, mean (SD)
Men
Women
Waist-height ratio, mean (SD)
Men
Women
Energy intake, mean (SD), kcal/d
Alcohol consumption, median (IQR), g/d
Factor scores, mean (SD) b
Healthy pattern
Traditional pattern
Modern pattern
Smoking status, %
Never
Former
Current
Educational level, %
None
Primary school
Technical/professional school
Secondary school
Higher, including university degree
Comorbidities, %
Hypertension
Myocardial infarction
Stroke
Cancer
Inactive
(n = 1793)
Moderately Inactive
(n = 1897)
Moderately Active
(n = 1171)
Active
(n = 998)
47
58.5 (6.6)
8.3 (2.0)
5.2 (2.3-11.0)
53
58.0 (6.4)
8.2 (1.9)
5.1 (2.1-10.6)
61
56.6 (6.6)
8.1 (1.9)
4.6 (1.9-9.9)
61
56.6 (6.3)
8.1 (2.0)
4.2 (2.0-8.2)
24
8
24
43
27
11
25
38
0 (0-0)
0 (0-0)
0 (0-8)
0 (0-4.5)
27 (6-63)
13.5 (4.5-27)
0.5 (0-1.6)
2 (1-5)
26
10
29
36
3 (0-9)
0 (0-6)
3 (0-12)
0 (0-9)
18 (6-48)
13.5 (6-25.5)
1 (0-2.3)
2 (1-3)
28
0
0
0
69
3
9 (0-24)
0 (0-12)
4 (0-14)
0 (0-9)
15 (3-42)
13.5 (6-25.5)
1.0 (0-2.6)
2 (1-3)
26
17
0
0
54
3
16
31
16
0
35
2
22
13
36
29
23.3 (6-45)
6 (0-21)
4 (0-12)
0 (0-9)
15 (3-36)
15 (7.5-27)
1.2 (0-2.6)
3 (1-4)
9
21
32
12
25
1
28.8 (4.4)
30.0 (5.7)
28.4 (4.1)
29.1 (5.5)
28.4 (4.4)
28.7 (5.1)
28.0 (4.1)
28.7 (5.6)
0.59 (0.07)
0.59 (0.09)
2007 (606)
3.2 (0-17.0)
0.58 (0.07)
0.57 (0.08)
2073 (613)
6.9 (0.9-21.6)
0.58 (0.07)
0.56 (0.08)
2138 (648)
8.2 (1.5-25.5)
0.57 (0.06)
0.56 (0.09)
2229 (676)
9.3 (1.7-25.6)
0.01 (0.98)
0.13 (0.99)
0.04 (0.98)
0.07 (0.98)
0.04 (0.95)
0.01 (1.01)
0.004 (1.04)
0.05 (1.00)
0.01 (0.99)
0.13 (1.02)
0.27 (1.05)
0.03 (1.03)
41
33
26
38
38
24
37
38
25
37
37
26
6
43
22
12
16
3
40
27
11
18
4
40
28
11
17
3
43
31
9
14
59
8
5
4
57
7
4
5
52
6
3
4
52
6
2
2
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); HbA1c, glycated hemoglobin; IQR, interquartile
range; MET, metabolic equivalent; OHA, oral hypoglycemic agent.
a Classification of total physical activity level according to the Cambridge Physical Activity Index based on occupational activity and duration of cycling and
sports.
b Derived from factor analysis of 16 food groups, the healthy pattern (eigenvalue, 2.16) was characterized by high intake of fruit, vegetables, legumes, and
fish; the traditional pattern (eigenvalue, 2.00) by high intake of potatoes, dairy, eggs, meat, and sugar; and the modern pattern (eigenvalue, 1.76) by high
intake of cereals, fats, cakes, and biscuits.
P = .01). For walking, an influential meta-analysis revealed that the

present study contributed most
ARCH INTERN MED
heterogeneity, although excluding

the present study from the metaanalyses did not substantially influPUBLISHED ONLINE AUGUST 6, 2012
E4
ence the pooled HR. Visual inspection of funnel plots did not indicate
publication bias (eFigure 2).
Table 2. HRs (95% CIs) for Associations Between Total Physical Activity, Leisure-Time Physical Activity, and Walking and Total
and CVD Mortality in 5859 Individuals With Diabetes Mellitus
Variable
Inactive
Moderately Inactive
Moderately Active
Active
P Trend
Total Physical Activity a

Total mortality
Cases/PY
Incidence rate per 1000 PY
Sex-adjusted HR (95% CI) b
Multivariable HR (95% CI) c
Multivariable HR (95% CI) d
CVD mortality
Cases/PY
304/15 941
19.1
1 [Reference]
1 [Reference]
1 [Reference]
271/17 230
15.7
0.64 (0.53-0.76)
0.69 (0.57-0.83)
0.68 (0.54-0.66)
115/10 768
10.7
0.53 (0.42-0.66)
0.62 (0.49-0.78)
0.58 (0.43-0.77)
119/9253
12.9
0.62 (0.50-0.78)
0.74 (0.59-0.94)
0.81 (0.61-1.08)
.001
.001
.03
99/15 941
6.2
1 [Reference]
1 [Reference]
1 [Reference]
61/17 230
3.5
0.59 (0.43-0.82)
0.65 (0.46-0.91)
0.46 (0.28-0.74)
27/10 768
2.5
0.40 (0.26-0.63)
0.51 (0.32-0.81)
0.31 (0.15-0.60)
25/9253
2.7
0.53 (0.34-0.85)
0.62 (0.38-1.01)
0.48 (0.25-0.94)
.001
.004
.001
45
Total mortality
Cases/PY
CVD mortality
Cases/PY
Total mortality
Cases/PY
CVD mortality
Cases/PY
Leisure-Time Physical Activity, MET-h/wk e

45-74
75-113
113
269/14 809
18.2
1 [Reference]
1 [Reference]
1 [Reference]
191/11 976
15.9
0.80 (0.66-0.98)
0.85 (0.70-1.04)
0.77 (0.60-0.99)
174/12 864
13.5
0.74 (0.60-0.91)
0.80 (0.64-0.99)
0.79 (0.60-1.03)
121/13 544
8.9
0.64 (0.50-0.81)
0.73 (0.57-0.93)
0.62 (0.46-0.85)
.001
.007
.003
67/14 809
4.5
1 [Reference]
1 [Reference]
1 [Reference]
66/11 976
5.5
1.09 (0.76-1.57)
1.18 (0.81-1.73)
0.91 (0.54-1.52)
50/12 864
3.9
0.83 (0.56-1.24)
0.90 (0.60-1.37)
0.69 (0.39-1.24)
29/13 544
2.1
0.57 (0.35-0.93)
0.63 (0.38-1.04)
0.30 (0.14-0.64)
.02
.06
.002
2.0
Walking, h/wk
2.0-4.5
4.6-9.0
269/15 930
16.9
1 [Reference]
1 [Reference]
1 [Reference]
159/11 778
13.5
0.83 (0.67-1.02)
0.88 (0.71-1.09)
0.87 (0.67-1.12)
166/13 302
12.5
0.83 (0.67-1.02)
0.86 (0.70-1.07)
0.76 (0.58-1.00)
161/12 183
13.2
0.95 (0.75-1.19)
0.95 (0.75-1.20)
0.90 (0.67-1.21)
.80
.70
.24
90/15 930
5.6
1 [Reference]
1 [Reference]
1 [Reference]
37/11 778
3.1
0.52 (0.35-0.78)
0.54 (0.36-0.82)
0.40 (0.22-0.74)
37/13 302
2.8
0.49 (0.32-0.75)
0.50 (0.32-0.77)
0.44 (0.24-0.79)
48/12 183
3.9
0.69 (0.46-1.06)
0.64 (0.41-0.98)
0.65 (0.35-1.19)
.21
.10
.06
9.0
Abbreviations: CVD, cardiovascular disease; HR, hazard ratio; MET, metabolic equivalent; PY, person-years.
a Classification of total physical activity level according to the Cambridge Physical Activity Index based on occupational activity and duration of cycling and
sports.
b Model 1: age and center stratified and adjusted for sex.
c Model 2: model 1 additionally adjusted for diabetes medication (no medication, insulin, oral hypoglycemic agents, or both); disease duration; self-reported
myocardial infarction, stroke, or cancer; alcohol consumption; smoking behavior; educational attainment; energy; and scores for the first 3 dietary patterns derived
from a factor analysis of 16 food groups.
d Model 3: excluding participants with self-reported myocardial infarction, stroke, or cancer or follow-up of less than 2 years (n = 5039).
e Leisure-time physical activity included walking, cycling, gardening, sports, and household and do-it-yourself activities.
COMMENT
In this prospective analysis and

meta-analysis of individuals with
diabetes, higher levels of total PA, leisure-time PA, and walking were associated with a lower risk of total and
CVD mortality. In the prospective
analysis, people who reported being
moderately physically active had
lower mortality risk compared with
ARCH INTERN MED
those who reported being physically inactive.

In persons with diabetes, an increase in PA has been shown to reduce
HbA1c levels9,35 and improve insulin
sensitivity.36 Moreover, PA has been
shown to have beneficial effects on inflammation, hypertension, dyslipidemia, endothelial function, and abdominal adiposity in persons with and
without diabetes.37-40
E5
PROSPECTIVE ANALYSIS
The association between total PA
and mortality was slightly Jshaped. This could have been due to
misclassification of activity levels,
which may be higher in the most
physically active group owing to labeling bias. This result is in contrast to the other studies15,19,21,32,34 included in the meta-analysis, which
Table 3. Identified Published Prospective Cohort Studies on PA and Mortality in Individuals With Diabetes Mellitus
Patients,
No./Sex/
Age, y
Source
10
Diabetes
Verification
Follow-up,
Mean, y
Type 2 diabetes
or IGT: oral
glucose
tolerance test
25.0
Batty et al, 2002,

Whitehall II
Study, United
Kingdom
352/M/
40-64
Ford and
DeStefano,13
1991, National
Health and
Nutrition
Examination
Survey I
Epidemiologic
Follow-up Study
(1982-1984),
United States
Gaziano et al,14
2002, Physicians
Health Study
enrollment
cohort, United
States
Gregg et al,15 2003,
National Health
Interview Survey,
United States
602/M-F/
40-77
Self-reported
diabetes
10.0
2838/M/
40-84
Self-reported
diabetes
5.2
2896/MF/18
Self-reported
diabetes
Hu et al,17 2004, six

independent
population
surveys
(1972-1997),
Finland
3316/M-F/ Type 2 diabetes

25-74
confirmed by
WHO criteria
18.4
18.7
Hu et al,32 2005, six 3708/M-F/ Type 2 diabetes
independent
25-74
confirmed by
population
WHO criteria
surveys
(1972-1997),
Finland
Jonker et al,21 2006, 292/M-F/ Random blood 12.0 (3
Framingham
28-62
glucose 200
Pooled
Heart Study,
mg/dL or
follow-up
United States
treatment with periods)
hypoglycemic
agent
Exposure
Outcome,
No. of Cases
Outcome
Ascertainment
Stars a
Adjustments
Walking pace:
215 Total
National Health
Age, employment
mortality,
Service Register
grade, systolic
slower/same/faster
Leisure-time activity:
79 CHD
blood pressure,
inactive/moderately mortality,
cholesterol level,
active/active
39 other CVD
smoking, BMI,
(questionnaire)
mortality
forced expiratory
volume in 1
second, disease at
study entry
Leisure-time PA:
233 Total
National Death
None
most
mortality,
Index and other
active/moderately
92 CHD
tracing methods
mortality
active/inactive
(interview)
Vigorous exercise:
1-3 times per mo,
1 time/wk,
2-4 times/wk,
5 times/wk
(questionnaire)
Walking: 0, 0-1.9,
2 h/wk
Total PA: 0, 0-1.9,
2 h/wk
(interview)
356 Total
mortality
Death certificate, Age, smoking,

medical records, alcohol, history of
next of kin
angina or transient
ischemic attack
Age, sex, race, BMI,

self-rated health,
smoking status,
weight loss
approaches,
hospitalizations,
hypertension,
physician visits,
limitations due to
CVD and cancer,
level of functional
limitation
Age, sex, study year,
BMI, systolic blood
pressure,
cholesterol level,
smoking status
Age, sex, study year,

educational level,
BMI, systolic blood
pressure, total
cholesterol level,
smoking status
Office and
Age, sex, educational
level, marital
hospitalization
status, smoking,
records,
laboratory test
baseline diseases
results, death
(CVD, cancer, left
certificates, and
ventricular
autopsy reports
hypertrophy,
arthritis, ankle
edema, pulmonary
disease),
examination at start
of follow-up
671 Total
National Death
mortality, 316 Index
CVD mortality
Occupational:
1410 Total
Statistics Finland
light/moderate/
mortality, 903
active; commuting: CVD mortality
0, 1-29, 30
min/d; leisure-time
activity:
low/moderate/high
(questionnaire)
Total PA:
1423 Total
Statistics Finland
low/moderate/high
mortality, 906
(questionnaire)
CVD mortality
Total PA:
292 Total
low/moderate/high
mortality
(interview)
(continued)
ARCH INTERN MED

E6
Table 3. Identified Published Prospective Cohort Studies on PA and Mortality in Individuals With Diabetes Mellitus (continued)
Patients,
No./Sex/
Age, y
Source
33
Nelson et al, 2010,

Third National
Health and
Nutrition
Examination
Survey, United
States
Smith et al,18 2007,
Rancho Bernardo
Study, United
States
Diabetes
Verification
Follow-up,
Mean, y
1507/MF/17
Self-report
347/M-F/
50-90
Type 2 diabetes
confirmed by
WHO criteria
10
Tanasescu et al,19
2003, Health
Professionals
Follow-up Study
(1986-1998),
United States
2803/M/
40-75
14
Trichopoulou et al,34
2006, European
Prospective
Investigation Into
Cancer and
Nutrition, Greece
1013/MF/35
Self-reported
diagnosis at
30 y
confirmed
with 1
classic
symptoms
plus raised
plasma
glucose or
OHA use
Self-reported
diagnosis and
use of
diabetes
medication
Wei et al,20 2000,

Aerobics Center
Longitudinal
Study, United
States
1188/M/50 Type 2 diabetes

defined
according to
ADA criteria
7.6
4.5
11.7
Exposure
Leisure-time PA:
inactive,
insufficient,
recommended
levels
(questionnaire)
Outcome,
No. of Cases
642 Total
mortality
Outcome
Ascertainment
Adjustments
National Death
Index
Age, sex,
race/ethnicity,
educational level,
HbA1c level, HDL
cholesterol level,
BMI, and smoking
status
Walking: nonwalker, 538 Total
Annual mailings
Sex, age, smoking
and telephone
status, BMI,
1-mile walker,
mortality,
1-mile walker
143 CHD
calls, death
average drinks per
(interview)
mortality,
certificates
day, exercise,
138 other
obtained
hypertension,
CVD mortality
triglyceride levels,
HDL cholesterol
level, history of
CHD
Walking: 0-1.4,
355 Total
Reported in or by Alcohol use, smoking
1.5-4.1, 4.2-7.9,
mortality, 96
linkage with the
status, family MI
8.0-16.0, 16.1
CVD mortality National Death
history, vitamin E
MET-h/wk
Index, CVD
use, disease
Leisure-time PA:
confirmed by
duration, OHAs,
review of
dietary intake of
0-5.1, 5.2-12.0,
trans and saturated
12.1-21.7,
medical records
21.8-37.1, 37.2
or autopsy
fat, fiber and folic
MET-h/wk
report
acid, history of
CVD, hypertension,
(questionnaire)
cholesterol level
80 Total
Active follow-up
Sex, age, educational
Total (occupational
and leisure-time)
mortality
by qualified
level, smoking
PA: 30, 30-32,
physicians
status, waist-height
32-34, 34-37,
ratio, hip
37 MET-h/d
circumference,
(questionnaire)
insulin use,
hypertension, or
hyperlipidemia
treatment
Leisure-time PA:
180 Total
National Health
Age, examination
active/inactive
mortality
Index. Death
year, CVD history,
(questionnaire)
certificates
cholesterol level,
smoking status,
obtained
diabetes status,
glucose level,
alcohol use,
hypertension,
overweight
Stars a
8
Abbreviations: ADA, American Diabetes Association; BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); CHD,
coronary heart disease; CVD, cardiovascular disease; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IGT, impaired glucose tolerance; MET, metabolic
equivalent; MI, myocardial infarction; OHA, oral hypoglycemic agents; PA, physical activity; WHO, World Health Organization.
a Stars (maximum = 9) indicate the quality of the studies assessed using the Newcastle-Ottawa Scale.31
showed linear inverse associations,

with the lowest observed HR in the
highest quartile. In the present study,
participants with heavy manual work
occupations were automatically assigned to the active category. Because such people are more frequently exposed to occupational risk
factors and more often have a lower
socioeconomic status, they may have
a more unfavorable risk profile.41
However, excluding heavy manual
workers and nonworkers from the
analyses did not change the findARCH INTERN MED
ings. Thus, diabetic individuals who

are physically inactive seem to have
a higher risk of early death, and already being moderately active may
improve survival.
Walking may reduce the risk of
CVD in people with diabetes by improving glycemic control and other
risk factors.7 In the present study and
meta-analysis, persons in the highest quartiles of walking duration had
a lower risk of CVD mortality compared with those in the lowest quartile. In contrast, walking was not rePUBLISHED ONLINE AUGUST 6, 2012
E7
lated to significantly lower total

mortality risk in this study, whereas
other studies10,15,18,19 in the metaanalysis reported strong inverse relationships. In the present study, persons in the highest category reported
walking more than 9 hours per week.
Walking levels were lower in the
other studies included: in comparison, persons in the active category
in the study by Tanasescu et al19
walked more than 16 MET-hours per
week. It is known that Europeans are
more active than North American
A
Source
Gregg et al,15 2003
Hu et al,32 2005
Jonker et al,21 2006
Trichopoulou et al,34 2006
Present study
Population
HR (95% CI)
National Health Interview Survey, United States

Population surveys, Finland
Framingham Heart Study, United States
EPIC, Greece
EPIC, Europe
0.71 (0.58-0.86)
0.52 (0.45-0.60)
0.53 (0.39-0.72)
0.33 (0.16-0.71)
0.74 (0.59-0.93)
Combined fixed-effects model

Combined random-effects model
Heterogeneity: I 2 = 69% (95% CI, 19%-88%), Q = 12.71; (P = .01)
0.59 (0.54-0.66)
0.60 (0.49-0.73)
0.25
0.5
1.0
2.0
Hazard Ratio
B
Source
Gregg et al,15 2003
Hu et al,32 2005
Present study
Population
HR (95% CI)

EPIC, Europe
0.76 (0.57-1.02)
0.52 (0.44-0.62)
0.62 (0.38-1.01)

0.58 (0.50-0.66)
0.61 (0.47-0.80)
0.25
0.5
1.0
2.0
Hazard Ratio
Figure 1. Hazard ratios (HRs) and 95% CIs for associations between total physical activity (highest vs lowest category) and total (A) and cardiovascular (B)
mortality for individual cohort studies, including the present study, and all the cohort studies combined. EPIC indicates European Prospective Investigation Into
Cancer and Nutrition; black squares, estimates for the individual studies; solid horizontal lines, 95% CIs; and white diamonds and dashed vertical lines, combined
estimates for the analysis (the width of the diamond represents the 95% CI).
A
Source
Batty et al,10 2002
Ford and DeStefano,13 1991
Gaziano et al,14 2002
Hu et al,17 2004
Nelson et al,33 2010
Tanasescu et al,19 2003
Wei et al,20 2000
Present study
Population
HR (95% CI)
Whitehall Study, United Kingdom

NHANES, United States
Physicians Health Study, United States
NHANES III, United States
Health Professionals Follow-up Study, United States
Aerobics Center Longitudinal Study, United States
EPIC, Europe
0.61 (0.40-0.92)
0.84 (0.48-1.47)
0.45 (0.31-0.66)
0.73 (0.57-0.94)
0.63 (0.49-0.80)
0.58 (0.41-0.83)
0.56 (0.40-0.78)
0.73 (0.57-0.93)

0.64 (0.57-0.72)
0.64 (0.57-0.72)
0.25
0.5
1.0
2.0
Hazard Ratio
B
Source
Batty et al,10 2002
Ford and DeStefano,13 1991
Hu et al,17 2004
Present study
Population
HR (95% CI)

NHANES, United States
EPIC, Europe
0.39 (0.21-0.72)
1.35 (0.49-3.71)
0.70 (0.51-0.96)
0.55 (0.28-1.08)
0.63 (0.38-1.04)

0.64 (0.51-0.80)
0.63 (0.48-0.83)
0.25
0.5
1.0
2.0
Hazard Ratio
Figure 2. Hazard ratios (HRs) and 95% CIs for associations between leisure-time physical activity (highest vs lowest category) and total (A) and cardiovascular
(B) mortality for individual cohort studies, including the present study, and all the cohort studies combined. EPIC indicates European Prospective Investigation
Into Cancer and Nutrition; NHANES, National Health and Nutrition Examination Survey; black squares, estimates for the individual studies; solid horizontal lines,
95% CIs; and white diamonds and dashed vertical lines, combined estimates for the analysis (the width of the diamond represents the 95% CI).
populations,42 and it has been observed in a Dutch population that activities of at least moderate intensity, but not lower intensity, such as
walking, were related to reduced
CVD incidence.43 This seems to be
ARCH INTERN MED
in contrast to our findings on walking and CVD mortality. However, because no information on walking
pace was available, we cannot draw
conclusions about walking intensity. In conclusion, although these
E8
results did not reach statistical significance, from the meta-analysis the
potential benefits of walking on mortality are well established.
Reverse causality could have overestimated the mortality risks if dia-
A
Source
Population
Batty et al,10 2002

Gregg et al,15 2003
Smith et al,18 2007
Present study

Rancho Bernardo Study, United States
EPIC, Europe

HR (95% CI)
0.42 (0.25-0.69)
0.61 (0.48-0.78)
0.54 (0.33-0.88)
0.57 (0.39-0.83)
0.95 (0.75-1.20)
0.68 (0.59-0.78)
0.62 (0.47-0.83)
0.25
0.5
1.0
2.0
Hazard Ratio
B
Source
Batty et al,10 2002
Gregg et al,15 2003
Smith et al,18 2007
Present study
Population
HR (95% CI)

Rancho Bernardo Study, United States
EPIC, Europe
0.29 (0.14-0.60)
0.66 (0.45-0.96)
0.66 (0.33-1.32)
0.64 (0.41-0.99)

0.59 (0.46-0.76)
0.58 (0.42-0.79)
0.25
0.5
1.0
2.0
Hazard Ratio
Figure 3. Hazard ratios (HRs) and 95% CIs for associations between walking (highest vs lowest category) and total (A) and cardiovascular (B) mortality for
individual cohort studies, including the present study, and all the cohort studies combined. EPIC indicates European Prospective Investigation Into Cancer and
Nutrition; black squares, estimates for the individual studies; solid horizontal lines, 95% CIs; and white diamonds and dashed vertical lines, combined estimates
for the analysis (the width of the diamond represents the 95% CI).
betes or comorbidities at baseline led

to inactivity. Excluding participants
with comorbidities at baseline or the
first 2 years of follow-up strengthened the risk estimates, indicating that
reverse causality is unlikely to explain the results. However, residual
confounding or misclassification cannot be excluded because measures of
disease severity and comorbidities
were self-reported.
Adjustment for factors on the
causal pathway may underestimate
the magnitude of the true association between PA and mortality.11,12
However, risk estimates were not affected by additional adjustment for
the intermediate factors HbA1c level,
BMI, and systolic blood pressure.
META-ANALYSIS
Physical activity was associated with
a lower total mortality risk in diabetic individuals. These associations are in line with those found in
the general population, where PA relates to a 33% lower risk of overall
mortality and a 35% lower risk of
CVD mortality compared with inactivity.8 The present meta-analysis
was a high vs low comparison. This
is a common practice for metaanalyses of observational studies, but
results can be difficult to interpret
ARCH INTERN MED
because absolute levels of PA will

vary between studies and are unknown.44 However, this was the best
option based on the available data.
Statistically significant heterogeneity was found for the associations
between total PA and walking and
total mortality. Because statistical
heterogeneity is based only on the effect estimates and their precision, it
is important to consider clinical
heterogeneity. All the studies included in the meta-analysis were comparable in terms of study design, diabetes population, and outcome.
However, an important issue when
performing meta-analyses of PA is
comparability of the exposure assessment, which was heterogeneous
across the included studies. Physical activity was assessed by questionnaire or interview, with varying questions, categories, and classifications.
Questionnaires, including interviews, are the most common tools for
PA assessment in large epidemiologic studies because they are inexpensive and feasible. In general, PA
questionnaires have a low reliability
and low validity but can be adequately used to rank individuals.45
It was considered appropriate to combine the studies by meta-analyses because all measured common perceptions of PA levels.
E9
In conclusion, evidence from the

present study and from previous
studies summarized by metaanalyses supports the widely held
view that PA is beneficially associated with lower mortality in people
with diabetes. Although these findings highlight that persons with diabetes should engage in regular PA,5
they need to be confirmed in a longterm randomized controlled trial.
Also, because not many patients with
diabetes adhere to this advice,46 future research should elucidate the
determinants of physical inactivity
and design successful strategies to
promote active lifestyles.
Accepted for Publication: May 12,
2012.
Published Online: August 6, 2012.
doi:10.1001/archinternmed.2012
.3130
Author Affiliations: Department of
Epidemiology, German Institute
of Human Nutrition PotsdamRehbrucke, Nuthetal, Germany (Ms
Sluik and Drs Buijsse, Boeing, and
Nothlings); Berlin School of Public
Health, Charite University Medical
Center, Berlin, Germany (Dr Muckelbauer); Division of Cancer Epidemiology, German Cancer Research
Center, Heidelberg, Germany
(Drs Kaaks and Teucher); Danish
Cancer Society, Copenhagen, Denmark (Drs Johnsen and Tjnneland); Department of Epidemiology, School of Public Health (Drs
Overvad and stergaard), and Department of Cardiology, Aalborg
Hospital (Dr stergaard), Aarhus
University Hospital, Aalborg, Denmark; Public Health Division of
Gipuzkoa, IIS Institute BioDonostia, Health Department Basque Region, San Sebastian, Spain (Ms
Amiano); Consortium for Biomedical Research in Epidemiology and
Public Health, Spain (Ms Amiano
and Drs Ardanaz and Huerta
Castano); Navarre Public Health Institute, Pamplona, Spain (Dr Ardanaz); Molecular and Nutritional
Epidemiology Unit, Cancer Research and Prevention Institute,
Florence, Italy (Dr Bendinelli); Department of Preventive and Predictive Medicine, Nutritional Epidemiology Unit, National Cancer
Institute, Milan, Italy (Dr Pala); Cancer Registry and Histopathology
Unit, CivileM.P. Arezzo Hospital, Ragusa, Italy (Dr Tumino); Human Genetics Foundation, Turin,
Italy (Mr Ricceri); Department of
Clinical and Experimental Medicine, Federico II University, Naples,
Italy (Dr Mattiello); National Institute for Public Health and the Environment, Centre for Prevention
and Health Services Research,
Bilthoven, the Netherlands (Dr Spijkerman); Julius Centre for Health
Sciences and Primary Care, University Medical Centre Utrecht, Utrecht,
the Netherlands (Drs Monninkhof
and May); Department of Clinical
Sciences, Genetic and Molecular Epidemiology Unit, Skane University
Hospital, Lund University, Malmo,
Sweden (Dr Franks); Department of
Nutrition, Harvard School of Public Health, Boston, Massachusetts
(Dr Franks); Department of Clinical Sciences, Internal Medicine,
Lund University, Skane University
Hospital, Malmo (Dr Nilsson); Department of Public Health and Clinical Medicine, Family Medicine,
Umea University, Umea, Sweden
(Drs Wennberg and Rolandsson);
Institut National de la Sante et de la
Recherche Medicale, Center for Research in Epidemiology and Population Health, and Paris-South University, Villejuif, France (Drs
ARCH INTERN MED
Fagherazzi, Boutron-Ruault, and

Clavel-Chapelon); Department of
Epidemiology, Murcia Regional
Health Authority, Murcia, Spain (Dr
Huerta Castano); School of Public
Health, Imperial College London,
London and London School of Hygiene and Tropical Medicine, London (Dr Gallo); and Epidemiology
Section, Institute for Experimental
Medicine, Christian-AlbrechtsUniversity of Kiel, Kiel, Germany
(Dr Nothlings).
Correspondence: Diewertje Sluik,
MSc, German Institute of Human
Nutrition Potsdam-Rehbrucke, Epidemiology Arthur-ScheunertAllee, 114-116 Nuthetal 14558, Germany (Diewertje.Sluik@dife.de).
Author Contributions: Ms Sluik had
full access to all the data in the study
and takes responsibility for the integrity of the data and the accuracy
of the data analyses. Study concept and
design: Sluik, Amiano, Ardanaz, Tumino, Boeing, and Nothlings. Acquisition of data: Sluik, Kaaks,
Teucher, Tjnneland, Overvad,
Amiano, Ardanaz, Bendinelli, Pala,
Tumino, Ricceri, Mattiello, Nilsson, Wennberg, Rolandsson,
Boutron-Ruault, Clavel-Chapelon,
Boeing, and Nothlings. Analysis and
interpretation of data: Sluik, Buijsse,
Muckelbauer, Overvad, stergaard, Pala, Spijkerman, Monninkhof, May, Franks, Nilsson, Rolandsson, Fagherazzi, Huerta Castano,
Gallo, and Nothlings. Drafting of the
manuscript: Sluik. Critical revision of
the manuscript for important intellectual content: Buijsse, Muckelbauer,
Kaaks, Teucher, Johnsen, Tjnneland, Overvad, stergaard,
Amiano, Ardanaz, Bendinelli, Pala,
Tumino, Ricceri, Mattiello, Spijkerman, Monninkhof, May, Franks,
Nilsson, Wennberg, Rolandsson,
Fagherazzi, Boutron-Ruault, ClavelChapelon, Huerta Castano, Gallo,
Boeing, and Nothlings. Statistical
analysis: Sluik and Buijsse. Obtained funding: Overvad, Tumino,
and Nothlings. Administrative, technical, and material support: Teucher,
Tjnneland, stergaard, Ardanaz,
Nilsson, Rolandsson, Gallo, and Boeing. Study supervision: Buijsse, Muckelbauer, Kaaks, Overvad, Amiano,
Ardanaz, Boeing, and Nothlings.
Financial Disclosure: None reported.
E10
Funding/Support: This study was

supported by a European Foundation for the Study of Diabetes/sanofiaventis grant (Dr Nothlings).
Role of the Sponsor: The European Foundation for the Study of
Diabetes and sanofi-aventis had no
role in the design or conduct of the
study, collection or analysis of the
data, or preparation or approval of
the manuscript and did not have any
influence on the contents.
Online-Only Material: The eFigures and eTable are available at http:
//www.archinternmed.com.
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REVIEW ARTICLE

Physical Activity and Mortality in Individuals

Arch Intern Med.

IABETES MELLITUS IS A MA-

jor cause of illness and

See related articles

Author Affiliations are listed at

hypertension, and dyslipidemia by using

ARCH INTERN MED

PUBLISHED ONLINE AUGUST 6, 2012

Lifestyle measures, including physical

2012 American Medical Association. All rights reserved.

STUDY DESIGN AND

style questionnaire included a question

2012 American Medical Association. All rights reserved.

justment for BMI or systolic blood

2012 American Medical Association. All rights reserved.

P = .01). For walking, an influential meta-analysis revealed that the

heterogeneity, although excluding

2012 American Medical Association. All rights reserved.

Total Physical Activity a

Leisure-Time Physical Activity, MET-h/wk e

In this prospective analysis and

those who reported being physically inactive.

2012 American Medical Association. All rights reserved.

Batty et al, 2002,

Hu et al,17 2004, six

3316/M-F/ Type 2 diabetes

Death certificate, Age, smoking,

Age, sex, race, BMI,

Age, sex, study year,

ARCH INTERN MED

PUBLISHED ONLINE AUGUST 6, 2012

2012 American Medical Association. All rights reserved.

Nelson et al, 2010,

Wei et al,20 2000,

1188/M/50 Type 2 diabetes

showed linear inverse associations,

ings. Thus, diabetic individuals who

lated to significantly lower total

2012 American Medical Association. All rights reserved.

National Health Interview Survey, United States

Combined fixed-effects model

National Health Interview Survey, United States

Combined fixed-effects model

Whitehall Study, United Kingdom

Combined fixed-effects model

Whitehall Study, United Kingdom

Combined fixed-effects model

2012 American Medical Association. All rights reserved.

Batty et al,10 2002

Whitehall Study, United Kingdom

Combined fixed-effects model

Whitehall Study, United Kingdom

Combined fixed-effects model

betes or comorbidities at baseline led

because absolute levels of PA will

In conclusion, evidence from the

2012 American Medical Association. All rights reserved.

Fagherazzi, Boutron-Ruault, and

Funding/Support: This study was

2012 American Medical Association. All rights reserved.

persons with diabetes: findings from the National