original article

The inuence of physical activity on vascular complications

and mortality in patients with type 2 diabetes mellitus
J. I. Blomster1,2 , C. K. Chow1 , S. Zoungas1,3 , M. Woodward1,4 , A. Patel1 , N. R. Poulter5 , M. Marre6 ,
S. Harrap7 , J. Chalmers1 & G. S. Hillis1
1 The George Institute for Global Health and University of Sydney, Sydney, Australia
2 University of Turku, Turku, Finland
3 School of Public Health, Monash University, Melbourne, Australia
4 Department of Epidemiology, Johns Hopkins University, Baltimore, USA
5 The Imperial College, London, UK
6 Service dEndocrinologie Diabetologie

Nutrition, Groupe Hospitalier BichatClaude Bernard, Paris, France

7 University of Melbourne and Royal Melbourne Hospital, Melbourne, Australia

Aims: There is limited evidence regarding the association between physical activity and vascular complications, particularly microvascular
disease, in patients with type 2 diabetes.

Methods: From the 11 140 patients in the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron modied release
Controlled Evaluation) trial, the effect of physical activity, categorized as none, mild, moderate or vigorous, and the number of sessions within
a week, was examined in multivariable regression models adjusted for potential confounders. The study end-points were major cardiovascular
events, microvascular complications and all-cause mortality.
Results: Forty-six percent of participants reported undertaking moderate to vigorous physical activity for >15 min at least once in the previous
week. During a median of 5 years of follow-up, 1031 patients died, 1147 experienced a major cardiovascular event and 1136 a microvascular
event. Compared to patients who undertook no or mild physical activity, those reporting moderate to vigorous activity had a decreased risk of
cardiovascular events (HR: 0.78, 95% CI: 0.690.88, p < 0.0001), microvascular events (HR: 0.85, 95% CI: 0.760.96, p = 0.010) and all-cause
mortality (HR: 0.83, 95% CI: 0.730.94, p = 0.0044).
Conclusions: Moderate to vigorous, but not mild, physical activity is associated with a reduced incidence of cardiovascular events,
microvascular complications and all-cause mortality in patients with type 2 diabetes.
Keywords: cardiovascular disease, diabetes complications, exercise
Date submitted 4 February 2013; date of first decision 24 March 2013; date of final acceptance 23 April 2013

Introduction
The global burden of type 2 diabetes is increasing due to the
consumption of high energy diets, reduced levels of physical
activity and a resultant increase in the incidence of excess
weight and obesity [1,2]. Studies suggest that few individuals
participate in adequate physical activity and that only one in
five adults participate in physical activity to the extent necessary
to obtain health benefits [3]. Patients with diabetes frequently
experience muscle weakness and exercise intolerance [4] and
are thus likely to be even less active than others.
In general, physical activity is associated with an up to 50%
reduction in cardiovascular and all-cause mortality [5] and
an improved survival after an acute coronary syndrome [6].
In patients with type 2 diabetes, two previous observational
studies have suggested that weekly moderate or vigorous
Correspondence to: Dr Juuso I. Blomster, MD, Ph.D., The George Institute for Global Health,
Level 10, King George V Building, 83-117 Missenden Road, Sydney, NSW 2050, Australia.
E-mail: jmakinen@georgeinstitute.org.au

exercise is associated with a reduced incidence of cardiovascular

events (fatal coronary heart disease, myocardial infarction or
stroke) [7] and that physical inactivity is associated with an
increased risk of premature death [8]. Altogether, a recent
prospective meta-analysis concluded a hazard ratio of 0.62
for total mortality in moderately active individuals with type
2 diabetes [9]. However, no studies have reported on the
association between regular physical activity and microvascular
complications in patients with type 2 diabetes. The aim
of this study is, therefore, to evaluate whether physical
activity is associated with changes in the incidences of major
cardiovascular events, microvascular complications and allcause mortality in a large cohort of patients with type 2 diabetes.

Materials and Methods

The Action in Diabetes and Vascular Disease: Preterax
and Diamicron modified release Controlled Evaluation (ADVANCE) study (ClinicalTrials.gov number
NCT00145925) was a factorial, randomized, controlled trial

original
article

Diabetes, Obesity and Metabolism 2013.

2013 John Wiley & Sons Ltd

original article
conducted in 20 countries which recruited 11 140 patients with
type 2 diabetes mellitus [10]. Participants were eligible for the
study if they were at least 55 years old, had been diagnosed
with type 2 diabetes after the age of 30 years, and had a history
of major macro- or micro-vascular disease or had at least
one additional cardiovascular risk factor. The study had two
treatment arms. In one arm, patients were randomized to either
intensive or standard glucose control groups. In the other
arm patients were randomized to either active blood pressure
treatment or matching placebo. The outcomes included major
cardiovascular events (death from cardiovascular disease,
non-fatal stroke or non-fatal myocardial infarction), major
microvascular events (new or worsening renal disease or diabetic eye disease) and all-cause mortality. All of these outcomes
were independently adjudicated. Participants in the study
provided written informed consent, and approval was obtained
from the local ethics committee in all participating centres.
Detailed study eligibility criteria and study methods [10] as
well as the main results [11,12], have been previously reported.

Assessment and Analyses of Physical Activity

Participants in the ADVANCE study were asked, at their
baseline visit, to report the number of times they had
participated in mild, moderate or vigorous physical activity for
greater than 15 min within the prior week. Mild physical activity
was described as activity of minimal effort, for example easy
walking or bowling, moderate physical activities included fast
walking, tennis or dancing and vigorous activities encompassed
exercise such as jogging or vigorous swimming. For each
participant the number of sessions (regardless of duration, but
>15 min) of each intensity was recorded. For our primary
analyses, we divided the cohort into participants who were
sedentary or undertook only mild physical activity in the prior
week and those who participated in at least one session of
moderate or vigorous physical activity >15 min. In subsequent
analyses we sought to clarify whether participation in mild
physical activity was beneficial. We, therefore, compared the
outcomes of patients who undertook only mild exertion
with those who were entirely sedentary and those who
undertook moderate or vigorous exercise at the week prior
to randomization. All study data excluding outcomes were
collected in the beginning of the study.

Statistical Analyses
Baseline variables were summarized as means with standard
deviations for continuous variables. Categorical variables were
reported as percentages. The differences between exercise
groups were tested by Students t-test for normally distributed continuous variables, by Wilcoxon signed rank-test
for skewed continuous variables and by chi-square test for categorical variables. Cox regression models were derived and
the final model included age, sex, allocation to randomized treatments, body mass index (BMI), HbA1c, duration
of diabetes, known macrovascular disease (diagnosed myocardial infarction, unstable angina, coronary revascularization,
transient ischaemic attack, stroke, peripheral revascularization and amputation secondary to peripheral vascular disease),

2 Blomster et al.

DIABETES, OBESITY AND METABOLISM

high-density lipoprotein cholesterol, low-density lipoprotein

cholesterol, triglycerides, creatinine clearance, systolic blood
pressure, heart rate, any blood pressure medication, any lipid
lowering medication, use of acetyl salicylic acid or thienopyridines, smoking, physical activity, alcohol use and higher
education (age >19 years at the time of finishing highest level
of education). A sensitivity analysis included Cox models of all
three outcomes in subgroups of prior cardiovascular disease
(yes/no). Risk reduction was presented as a percentage [(1hazard ratio) 100]. All analyses were performed using SAS
version 9.3 (SAS Institute, Cary, NC, USA).

Results
Physical Activity
Estimates regarding frequency and intensity of physical activity
at baseline were available for all 11 140 participants in the
ADVANCE trial (Table 1). Individuals who participated
in moderate to vigorous intensity activity (n = 5113, 46%)
undertook over twice as many exercise sessions in the prior
week compared to those who undertook no or only mild
activity (n = 6027, 54%; 13 times/week vs. 5 times/week on
average). More men than women participated in moderate to
vigorous activity than no or mild activity (p < 0.0001). In the
moderate to vigorous activity group HbA1c, BMI, low-density
lipoprotein cholesterol and triglycerides were significantly
lower (p < 0.001) than in the group who undertook no or
only mild activity (Table 1). However, systolic blood pressure
and high-density lipoprotein cholesterol levels were similar.

Outcomes
During a median of 5 years of follow-up 1147 (10%)
participants experienced a major cardiovascular event, 1136
(10%) a major microvascular complication and 1031 (9%)
died.

Association Between Physical Activity and Outcomes

Participation in moderate or vigorous physical activity was
associated with a marked reduction in cardiovascular events,
microvascular complications and all-cause mortality (figure 1).
In further analyses, patients undertaking mild intensity
of activity (n = 4418) were compared to those who were
entirely sedentary (n = 1609). These analyses demonstrated
that participation in mild physical activity was not associated
with a lower incidence of adverse events, although an apparent
trend towards reduced all-cause mortality was observed
(figure 2). In contrast, moderate or vigorous physical activity
was associated with a lower incidence of all outcomes, including
a 26% reduction in mortality.
In sensitivity analyses the outcomes were assessed in Cox
models by subgroups of prior cardiovascular disease. There
were 3518 (32%) individuals with prior cardiovascular disease.
In this group, participation in moderate or vigorous activity
was associated with cardiovascular events (hazard ratio,
HR: 0.77, 95% CI: 0.640.92, p = 0.0038), microvascular
complications (HR: 0.79, 95% CI; 0.640.98, p = 0.036) but in

2013

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DIABETES, OBESITY AND METABOLISM

Table 1. Patient characteristics in general and by physical activity groups: mean (standard deviation) unless otherwise stated.

No of individuals
Age (years)
Female (%)
Body mass index (kg/m2 )
Current smoking (%)
Never smoking (%)
Any regular weekly alcohol consumption (%)
History of macrovascular disease (%)
History of microvascular disease (%)
History of stroke (%)
Age at completion of highest level of education (years)
Systolic blood pressure (mmHg)
Diastolic blood pressure (mmHg)
Resting heart rate (beats/min)
Total cholesterol (mmol/l)
HDL-cholesterol (mmol/l)
LDL-cholesterol (mmol/l)
Triglycerides (mmol/l)
HbA1c (%)
Creatinine clearance (ml/min)
ACEi/ARB medication (%)
Beta blocker (%)
Any blood pressure lowering medications (%)
Lipid lowering medication (%)
Aspirin or thienopyridines (%)
Duration of diabetes (years)

Total

Sedentary or mild physical activity

Moderate to vigorous activity

11 140
65.8 (6.4)
42.4
28.3 (5.2)
15.2
58.0
30.4
32.2
10.4
9.2
18.4 (7.3)
145.0 (21.5)
80.6 (10.9)
74(12)
5.20 (1.19)
1.26 (0.35)
3.11 (1.03)
1.95 (1.29)
7.51 (1.57)
82.3 (28.6)
47.7
24.5
75.1
35.3
46.7
7.9 (6.4)

6027 (54.1%)
66.1 (6.4)
47.0
28.5 (5.5)
15.2
61.0
25.0
33.2
11.4
10.3
18.0 (7.1)
145.1 (22.0)
80.3 (11.1)
75(12)
5.24 (1.20)
1.25 (0.35)
3.15 (1.04)
1.99 (1.32)
7.58 (1.62)
81.2 (29.3)
47.5
25.0
76.3
32.9
46.5
8.0 (6.4)

5113 (45.9%)
65.4 (6.3)
37.1
28.1 (4.8)
15.0
45.4
36.8
31.0
9.1
7.9
18.9 (7.4)
144.9 (20.9)
81.1 (10.7)
73(12)
5.15 (1.18)
1.26 (0.35)
3.07 (1.02)
1.91 (1.25)
7.44 (1.47)
83.6 (27.5)
47.8
24.0
73.7
38.2
46.9
7.8 (6.3)

p
<0.0001
<0.0001
0.020
0.79
<0.0001
<0.0001
0.014
<0.0001
<0.0001
<0.0001
0.78
<0.0001
<0.0001
<0.0001
0.59
<0.0001
<0.0001
<0.0001
<0.0001
0.61
0.22
0.0015
<0.0001
0.68
<0.0001

HDL, high density lipoprotein; LDL, low density lipoprotein; ACEi, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker.

Discussion

Figure 1. Major cardiovascular and microvascular outcomes and allcause mortality grouped according to participation in moderate and
vigorous physical activity. The Cox model is adjusted for age, sex, allocation
to randomized treatments, body mass index, HbA1c, duration of diabetes,
known macrovascular disease, high-density lipoprotein cholesterol, lowdensity lipoprotein cholesterol, triglycerides, creatinine clearance, systolic
blood pressure, heart rate, any blood pressure medication, any lipid
lowering medication, use of acetyl salicylic acid or thienopyridines,
smoking, physical activity, alcohol use and higher education.

This study demonstrates that patients with type 2 diabetes who

undertake moderate or vigorous physical activity for at least
15 min per week have a lower incidence of major cardiovascular
events, microvascular complications and death within 5 years
than patients who undertake no or only mild physical activity.
Notably, patients who participated in moderate or vigorous
exercise had a better risk profile than those who were more
sedentary, with slightly lower diastolic blood pressure, BMI and
triglyceride levels, better renal function and shorter duration
of diagnosed diabetes. Even after correction for these potential
confounding factors, those patients who undertook more than
just mild physical activity had an approximately 20% or greater
reduction in their risk of vascular complications or death within
5 years. In contrast, patients who undertook only mild physical
activity did not have a better outcome than those who reported
being sedentary.

Prior Studies
all-cause mortality the association was borderline (HR: 0.84,
95% CI: 0.691.02, p = 0.077). In individuals without prior
cardiovascular disease, participation in moderate or vigorous
activity was associated with cardiovascular events (HR: 0.78,
95% CI: 0.660.93, p = 0.0053) and all-cause mortality (HR;
0.82, 95% CI; 0.690.98, p = 0.025) but only a trend was
observed in microvascular complications (HR: 0.89, 95% CI:
0.771.03, p = 0.12).

2013

Patients with type 2 diabetes who exhibit higher levels of

physical fitness experience fewer cardiovascular complications
and live longer [13,14]. While this association has been clearly
established, it is important to recognize that it does not
necessarily indicate a beneficial effect of physical activity on
outcome. There are several other components that influence
physical fitness and pre-existing complications of diabetes
and/or co-morbid conditions will also affect measures of
exercise capacity and confound any observed association.

doi:10.1111/dom.12122 3

original article

DIABETES, OBESITY AND METABOLISM

Figure 2. Outcomes and the intensity of physical activity. Physical activity was analysed in three categories: sedentary, mild physical activity and moderate
to vigorous physical activity groups, where the sedentary group serves as the reference. Cox model adjusted as in figure 1.

Estimates of physical activity share similar limitations, but

also suggest that patients with diabetes who undertake regular
moderate to vigorous exercise experience a reduced incidence of
cardiovascular events [7] and mortality [8,15]. The evidence is
not, however, uniform, as other large prospective studies have
failed to confirm similar benefits in patients with impaired
glucose tolerance [16,17].
The evidence that physical activity levels are associated with
the risk of microvascular complications in type 2 diabetes
is even more limited. Physical activity may reduce the risk
of age-related macular degeneration [18] but there are few
prior data exploring its relationship to diabetic retinopathy. In
the Wisconsin Epidemiological Study of Diabetic Retinopathy
women who participated in strenuous exertion and/or gave a
history of participation in team sports at school or in college had
a lower prevalence of proliferative diabetic retinopathy [19].
No such associations were, however, observed in men [19] and
in a subsequent analysis of patients who had no retinopathy
at baseline none of the measures of physical activity were
associated with incident or progressive diabetic eye disease [20].
Similarly, although regular exercise reduces the development
and progression of diabetic nephropathy in animal models
[2123], this study provides the first evidence of a beneficial
effect in humans.

during follow-up. Only the number of times that study

individuals participated in leisure time physical activity in the
prior week was documented, without recording the duration
beyond 15 min. No interventions to alter physical activity
habits were examined and dietary factors were not recorded.
The partial dilution of findings in sensitivity analyses reflects
the smaller populations in the subgroups. In addition, it
is impossible to exclude the possibility that the association
between greater physical activity and better outcomes was due
to these patients being generally fitter, having less comorbidity
and fewer diabetic complications at baseline: what has been
termed the healthy exerciser effect.

Conclusions
This study provides evidence that greater physical activity
is associated with a reduced risk of major cardiovascular
events and improved survival in patients with type 2 diabetes.
Importantly, it also demonstrates, for the first time that
moderate to vigorous physical activity is associated with a
reduced risk of major microvascular complications. Further
scientifically rigorous, prospective and randomized studies
are required to clearly determine whether exercise-based
interventions can reduce major diabetic complications.

Strengths and Limitations

Acknowledgements

This study is one of the largest to explore the relationship

between physical activity and vascular outcomes and mortality
in patients with type 2 diabetes to date. The study cohort is
well characterized and all outcomes were pre-specified and
independently adjudicated. This study also has limitations. The
physical activity variables were self-reported and reflect the
activity levels of participants at the time of randomization,
consequently they do not necessarily reflect their behaviour

The ADVANCE study was funded by grants from Servier (the

major financial sponsor) and the National Health and Medical
Research Council of Australia (211086 and 358395).

4 Blomster et al.

Conict of Interest
S. Z. holds a Career Development Fellowship from the
Heart Foundation of Australia (CR 10S 5330). J. C. has

2013

DIABETES, OBESITY AND METABOLISM

received research grants from Servier, administered through the

University of Sydney. J. C., A. P., M. W. and S. Z. have received
honoraria from Servier for speaking at scientific meetings. J. I.
B. has received research grants from the Academy of Finland,
the Finnish Medical Foundation and Finnish Foundation for
Cardiovascular Research. The other authors report no conflict
of interest.
J. I. B. analysed the data. J. I. B. and G. S. H. wrote the
manuscript. J. I. B., C. K. C., S. Z., M. W., A. P., N. R. P., M.
M., S. H., J. C. and G. S. H. all contributed to study design,
revised the manuscript and approved the final version of the
manuscript.

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