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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
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article
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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.
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.
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.
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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
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.
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).
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doi:10.1111/dom.12122 3
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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.
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.
Acknowledgements
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
References
1. Sullivan PW, Morrato EH, Ghushchyan V, Wyatt HR, Hill JO. Obesity,
inactivity, and the prevalence of diabetes and diabetes-related
cardiovascular comorbidities in the U.S., 2000-2002. Diabetes Care 2005;
28: 15991603.
original article
10. Study rationale and design of ADVANCE: action in diabetes and vascular
diseasepreterax and diamicron MR controlled evaluation. Diabetologia
2001; 44: 11181120.
11. Patel A, MacMahon S, Chalmers J et al. Intensive blood glucose control
and vascular outcomes in patients with type 2 diabetes. N Engl J Med
2008; 358: 25602572.
12. Patel A, MacMahon S, Chalmers J et al. Effects of a xed combination of
perindopril and indapamide on macrovascular and microvascular outcomes
in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised
controlled trial. Lancet 2007; 370: 829840.
13. Church TS, Cheng YJ, Earnest CP et al. Exercise capacity and body
composition as predictors of mortality among men with diabetes. Diabetes
Care 2004; 27: 8388.
14. Church TS, LaMonte MJ, Barlow CE, Blair SN. Cardiorespiratory tness and
body mass index as predictors of cardiovascular disease mortality among
men with diabetes. Arch Intern Med 2005; 165: 21142120.
15. Gregg EW, Gerzoff RB, Caspersen CJ, Williamson DF, Narayan KM.
Relationship of walking to mortality among US adults with diabetes.
Arch Intern Med 2003; 163: 14401447.
2. Chan JC, Malik V, Jia W et al. Diabetes in Asia: epidemiology, risk factors,
and pathophysiology. JAMA 2009; 301: 21292140.
3. Pate RR, Pratt M, Blair SN et al. Physical activity and public health. A
recommendation from the Centers for Disease Control and Prevention and
the American College of Sports Medicine. JAMA 1995; 273: 402407.
17. Church TS, Blair SN, Cocreham S et al. Effects of aerobic and resistance
training on hemoglobin A1c levels in patients with type 2 diabetes: a
randomized controlled trial. JAMA 2010; 304: 22532262.
4. Sayer AA, Dennison EM, Syddall HE, Gilbody HJ, Phillips DI, Cooper C. Type
2 diabetes, muscle strength, and impaired physical function: the tip of the
iceberg? Diabetes Care 2005; 28: 25412542.
18. Knudtson MD, Klein R, Klein BE. Physical activity and the 15-year
cumulative incidence of age-related macular degeneration: the Beaver
Dam Eye Study. Br J Ophthalmol 2006; 90: 14611463.
19. Cruickshanks KJ, Moss SE, Klein R, Klein BE. Physical activity and proliferative
retinopathy in people diagnosed with diabetes before age 30 yr. Diabetes
Care 1992; 15: 12671272.
2013
20. Cruickshanks KJ, Moss SE, Klein R, Klein BE. Physical activity and the
risk of progression of retinopathy or the development of proliferative
retinopathy. Ophthalmology 1995; 102: 11771182.
21. Ward KM, Mahan JD, Sherman WM. Aerobic training and diabetic
nephropathy in the obese Zucker rat. Ann Clin Lab Sci 1994; 24: 266277.
22. Ghosh S, Khazaei M, Moien-Afshari F et al. Moderate exercise attenuates
caspase-3 activity, oxidative stress, and inhibits progression of diabetic
renal disease in db/db mice. Am J Physiol Renal Physiol 2009; 296:
F700708.
23. Tufescu A, Kanazawa M, Ishida A et al. Combination of exercise and
losartan enhances renoprotective and peripheral effects in spontaneously
type 2 diabetes mellitus rats with nephropathy. J Hypertens 2008; 26:
312321.
doi:10.1111/dom.12122 5