Download Role of exercise training on cardiovascular disease in persons who

Cardiol Clin 22 (2004) 569–586
Role of exercise training on cardiovascular disease in
persons who have type 2 diabetes and hypertension
Kerry J. Stewart, EdD, FAACVPR, FACSM, FSGC
Division of Cardiology, Johns Hopkins Bayview Medical Center, 4940 Eastern Avenue, Baltimore, MD 21224, USA
Regular exercise is an important modality in
the treatment of type 2 diabetes. Most studies of
exercise training in patients who had diabetes
were concerned with glycemic and weight control
and less on its affect on cardiovascular health.
Hypertension is a common comorbid condition in
patients who have type 2 diabetes. Although it is
well-established that exercise reduces blood pressure in persons who do not have diabetes, the
effects of exercise on blood pressure and parameters of cardiovascular structure and function in
patients who have type 2 diabetes and hypertension has not been examined fully. This article
identifies the cardiovascular consequences of these
conditions, discusses the potential mechanisms by
which exercise training may improve cardiovascular health, and provides practical guidelines for
exercise prescription.
Type 2 diabetes and cardiovascular health
Type 2 diabetes is associated with dysfunction
and failure of various organs, especially the heart
and peripheral blood vessels. The molecular basis
for type 2 diabetes is poorly understood but
insulin resistance and b-cell dysfunction are welldocumented [1,2]. Environmental influences and
genetic factors [3,4], and in particular, the increasing prevalence of obesity [5] and a sedentary
lifestyle [6] are likely contributors to the increasing
prevalence of type 2 diabetes.
Two other metabolic conditions that precede
the development of overt diabetes also have
adverse effects on cardiovascular health.
E-mail address: [email protected]
Prediabetes is a metabolic condition that is
between normal glucose homeostasis and diabetes
[7]; its prevalence in 2000 was estimated at nearly
12 million adults in the United States [8]. The risk
of progressing from prediabetes to overt diabetes
is about 10% over 6.5 years [9]. There also is
a 40% increased risk of mortality, independent of
other risk factors, in persons who have impaired
glucose tolerance [10]. The metabolic syndrome
also stems from an underlying abnormality in
insulin resistance [11–13]. The Third Report of the
National Cholesterol Education Program Adult
Treatment Panel (ATP III) [14] included clinical
criteria for diagnosis of the metabolic syndrome.
Its estimated prevalence is greater than 20% of the
United States adult population [15] and approaches 50% in older groups [16].
Although type 2 diabetes increases the risk of
microvascular complications, such as retinopathy
and nephropathy [17,18], most diabetic patients
die of macrovascular complications, including
coronary artery disease and stroke. Type 2 diabetes increases the risk of cardiovascular disease
by 200% to 400% [19]. The burden of cardiovascular disease is pronounced, especially in women
who have diabetes [20]. The risk of macrovascular
disease is increased before glucose levels reach the
diagnostic threshold for diabetes; 25% of newly
diagnosed patients already have overt cardiovascular disease [21].
The coexistence of type 2 diabetes and hypertension
Hypertension is associated with diabetes,
largely independent of age and obesity [22], although abdominal visceral obesity is an especially
strong risk factor for the development of both conditions [23]. Hypertension is part of the metabolic
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K.J. Stewart / Cardiol Clin 22 (2004) 569–586
syndrome [24], with a prevalence as high as 60% in
patients who have type 2 diabetes [25]. According
to The Seventh Report Of The Joint National
Committee On Prevention, Detection, Evaluation,
and Treatment Of High Blood Pressure [26],
diabetes is a compelling indication for treating
hypertension aggressively in affected patients.
There is an estimated doubling of cardiovascular
events when hypertension and diabetes coexist
[27]. These patients have abnormalities in central
and peripheral parameters of cardiovascular structure and function that precede the clinical manifestation of cardiovascular disease, including
increased left ventricular mass and wall thickness,
left ventricular diastolic filling abnormalities, impaired endothelial function, increased arterial
stiffness, and systemic inflammation. In the Strong
Heart study [28], clinically-relevant findings were
that left ventricular mass was 6% to 14% greater,
left ventricular function was 5% less, and arterial
stiffness was 12% greater among patients with
diabetes. Although glycemic control is essential for
preventing microvascular disease [29], intensive
blood pressure control is required for reducing
cardiovascular events in diabetic patients who
have hypertension [27,29]. Low-dosage diuretics,
b-blockers, angiotensin-converting enzyme inhibitors, or calcium antagonists are used as first-line
therapy [30]. In the Hypertension Optimal Treatment Study [31], intensive diastolic blood pressure
lowering was associated with a 49% reduction in
cardiovascular events in patients who had diabetes. The blood pressure goal in patients who have
type 2 diabetes is less than 130/80 mm Hg [26].
Because of the harmful effects of these diseases,
there is a need for therapies, above and beyond
pharmacologic measures, that may help to attenuate the cardiovascular consequences of diabetes
and hypertension.
Exercise training for diabetes and hypertension
The American College of Sports Medicine
Position Stand on ‘‘Exercise and Type 2 Diabetes’’
[25] says, ‘‘physical activity, including appropriate
endurance and resistance training, is a major
therapeutic modality for type 2 diabetes.’’ The
American Diabetes Association Clinical Practice
Recommendations 2002 [32] says ‘‘the possible
benefits of exercise in type 2 diabetes are substantial.’’ Data from the National Health Interview Survey [33] demonstrated that among
a diverse spectrum of adults who had diabetes,
walking was associated with a 39% lower all-
cause mortality and a 34% lower cardiovascular
disease mortality. It was further estimated that 1
death per year could be prevented for every 61
people who would walk at least 2 hours per week.
Well-established adaptive responses to exercise
training in conditions of insulin resistance are
improved glucose tolerance and enhanced skeletal
muscle insulin sensitivity of glucose transport [34].
A meta-analysis of 14 trials reported that exercise
training reduced hemoglobin A1c (HbA1c) by
0.66%—a clinically important reduction [35]. An
evidence-based review found that the effect of
aerobic or resistance training on glycemic control
in type 2 diabetes is positive, although evidence
for a dose-response relationship is lacking [36].
Increased participation in exercise also plays
a role in the prevention of type 2 diabetes and
related metabolic conditions. Laaksonen and colleagues [37] found that men who engaged in more
than 3 hours per week of moderate or vigorous
leisure time physical activity were half as likely as
their sedentary counterparts to develop the metabolic syndrome over a follow-up period of 4 years.
In the multicultural Insulin Resistance Atherosclerosis Study [38], increased levels of nonvigorous
and vigorous physical activity were associated with
higher insulin sensitivity. Among women in the
Nurse’s Health Study [39], sedentary behaviors,
especially television watching, were associated
with an elevated risk of obesity and type 2
diabetes, whereas even light to moderate activity
was associated with a decreased risk of developing
these conditions. In the Diabetes Prevention Program Research Group Study [40], which enrolled
subjects who had impaired glucose tolerance, the
intensive lifestyle intervention reduced the incidence of developing type 2 diabetes by 58%,
whereas pharmacologic therapy with metformin
reduced the incidence by 31% as compared with
placebo. The lifestyle intervention, which included
at least 30 minutes of moderate physical activity
every day, was significantly more effective than
metformin. The risk of developing diabetes after 4
years also was reduced by 58% after participation
in a diet and exercise program in older, obese
Finnish men and women [41].
The efficacy of exercise training to lower blood
pressure is well-established in patients who do not
have diabetes [42]. A meta-analysis of 54 randomized trials found that aerobic exercise was associated with an average reduction in blood pressure
of 3.9/2.6 mm Hg across all initial blood pressure
levels and was independent of body weight and
race. Subgroup analysis showed an average
K.J. Stewart / Cardiol Clin 22 (2004) 569–586
reduction of 4.9/3.7 mm Hg in hypertensive
persons [43]. The degree of blood pressure reduction did not differ by frequency or intensity of
exercise; this suggests that all forms are effective.
This notion is supported by a recent study [44]
that reported a decrease in blood pressure of
about 6/6 mm Hg with 30 to 60 minutes of
physical activity per week in previously sedentary
hypertensive subjects. The magnitude of reduction
in systolic blood pressure was about 11 mm Hg
with 61 to 90 minutes of activity; however, there
were no further reductions in blood pressure with
further increases in amount of time spent in
exercise. There did not seem to be any doseresponse relation for diastolic blood pressure.
These results suggest that the volume of exercise
that is required to reduce blood pressure may be
modest and should be attainable by a sedentary
hypertensive population. Another meta-analysis
of 47 trials [45] estimated decreases in blood pressure of 6/5 mm Hg (about 4/5%) in hypertensive
patients and decreases of 2/3 mm Hg (about 2/
1%) in normotensive persons [47]. In another
meta-analysis of 16 studies with walking as the
intervention, normotensive and hypertensive patients decreased their blood pressure by 3/2 mm
Hg (about 2%) after an average of 25 weeks [46].
In older persons who had mild or moderate
hypertension who performed endurance exercise
for 7 months, the reduction in systolic blood
pressure was accompanied by regression of left
ventricular mass and concentric left ventricular
remodeling [47]. Because of differences among
studies in the type, intensity, and duration of
exercise; baseline blood pressure; and concomitant use of antihypertensive medications, there is
wide variation in the magnitude of blood pressure
reduction across studies and meta-analyses. Nonetheless, exercise training seems to reduce blood
pressure to some degree.
Exercise can play an important role in glycemic
and blood pressure control; however, few studies
have investigated the effect of physical activity on
cardiovascular disease outcomes among patients
who had type 2 diabetes. In the Health Professionals’ Follow-up Study [48], a large-scale epidemiologic trial, physical activity was associated
with reduced risk of cardiovascular disease, cardiovascular death, and total mortality in men who
had type 2 diabetes after 14 years of follow-up.
Although no randomized exercise trials have
examined the efficacy of exercise on the cardiovascular consequences of diabetes and hypertension, studies in patients who had diabetes,
571
hypertension, cardiovascular disease, or related
conditions, and animal data suggest that exercise
training also is a potentially efficacious treatment
for improving cardiovascular health in patients
who have these conditions.
Left ventricular diastolic dysfunction: a precursor
to heart failure
Heart failure is a frequent consequence of type
2 diabetes, independent of coronary artery disease
[49,50]. The most common feature of the diabetic
heart is abnormal early left ventricular diastolic
filling which suggests reduced compliance or
prolonged relaxation [51]. Several mechanisms
for diabetic cardiomyopathy have been proposed,
including small and microvascular disease, autonomic dysfunction, metabolic derangements, and
interstitial fibrosis [50]. Hypertension also is associated with impaired diastolic filling. [52] Several
studies have demonstrated left ventricular diastolic
dysfunction (LVDD) in patients who had wellcontrolled type 2 diabetes without cardiovascular
complications [53–56]. Two similar studies evaluated patients who had type 2 diabetes who did not
have clinical heart disease or hypertension [57,58].
Each used the Valsalva maneuver and pulmonary
venous echocardiographic recordings to reveal
a pseudonormal mitral flow pattern of left ventricular diastolic filling. Pseudonormalization refers to the masking of impaired left ventricular
filling that is caused by a compensatory increase in
left atrial pressure. Poirier et al [57] found LVDD
in 28 subjects (60%), 13 of whom (28%) had
a pseudonormal pattern of diastolic filling and 15
(32%) had impaired relaxation. Zabalgoitia et al
[58] found LVDD in 41 subjects (47%), of which
15 (17%) had a pseudonormal-filling pattern and
26 (30%) had impaired relaxation. Thus, LVDD in
patients who have type 2 diabetes may be more
prevalent than the previously reported estimate of
32% [53]. Although the clinical relevance of
pseudonormalization remains uncertain, this pattern denotes an advanced stage of LVDD which is
a robust prognostic marker for heart failure [59]. A
recent study reported an association of LVDD
with cardiac autonomic neuropathy in patients
who had type 2 diabetes who were free of clinically
overt heart disease [60]. This association was seen
with the impaired relaxation or pseudonormalfilling pattern of LVDD and was independent of
metabolic control.
LVDD is associated with reduced exercise
performance in patients who have type 2 diabetes
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K.J. Stewart / Cardiol Clin 22 (2004) 569–586
and normal systolic function [61,62]. The left
ventricular ejection fraction response to exercise
may also be impaired although resting systolic
function is normal [56]. Possible causes of left
ventricular dysfunction are latent global myocardial ischemia [63,64] or metabolic myocardial
disturbances [51,65]. Animal data suggest that
impaired myocycte handling of calcium contributes to LVDD [66]. Scheuermann-Freestone et al
[67] reported that patients who have type 2
diabetes and apparently normal cardiac function
at rest have impaired myocardial and skeletal
muscle energy metabolism during exercise. The
abnormalities in circulating metabolic substrates
correlated negatively with exercise tolerance.
Some studies showed a correlation of glycemic
control and LVDD with treatment [68,69],
whereas others did not [53,70,71]. Differences in
medications, treatment duration, duration of diabetes, techniques for measuring left ventricular
diastolic function, and small sample sizes contribute to the lack of agreement among studies on
the efficacy of glycemic control on cardiac
function.
Generally, it is accepted that diabetes affects
diastolic function before systolic function. Fang
et al [72] used newer tissue Doppler imaging techniques to demonstrate subtle abnormalities in
systolic function, in addition to diastolic function,
in patients who had diabetes but not coronary
disease. The same investigators also examined
myocardial reflectivity—an echocardiographic
finding that is indicative of collagen accumulation—and reduced myocardial strain rate—a fundamental quality of tissue that reflects its ability to
shorten [73]. Patients who had diabetes but did
not have left ventricular hypertrophy demonstrated evidence of abnormalities in these indices
of systolic structure and function that were similar
to those that were attributed to left ventricular
hypertrophy alone; these were incrementally
worse in patients who had both conditions.
Exercise and left ventricular diastolic dysfunction
The age-related decline in early diastolic filling
is less pronounced in healthy, older persons who
have a long history of endurance exercise compared with their sedentary peers [74,75]. Moderate-intensity aerobic and resistance exercise for 10
weeks improved LVDD in men who had mild
hypertension [76]. In healthy normotensive men,
60 to 82 years of age and 24 to 32 years of age [77],
aerobic training for 6 months increased early
diastolic filling at rest and during acute exercise
by 14%, increased left ventricular mass by 8%,
and increased maximal oxygen uptake by 19%.
Training also reduced elevated resting atrial filling
rate in the older men by 27%. The increased left
ventricular mass and improved diastolic filling
represent a desirable physiologic, rather than
a pathologic, hypertrophy.
The mechanisms by which exercise training
enhance early diastolic filling have not been
elucidated fully. Twelve weeks of treadmill running reversed the age-associated decline in early
diastolic filling in older rats, whereas controls did
not improve [78]. Relevant to patients who have
type 2 diabetes and hypertension who are at a high
risk for atherosclerotic disease, the increased degree of diastolic stiffening that is due to ischemia
in isolated rat hearts was not seen in the exercisetrained group. Abete et al [79] found that exercise
training may restore ischemia preconditioning,
a powerful endogenous cardioprotective mechanism, in the senescent rat heart through an
increase of norepinephrine release. Exercise training in these animals was performed at an intensity
of 70% to 85% of maximal oxygen uptake,
whereas the recommended starting intensity is
40% to 70% for most patients who have type 2
diabetes [25]. Although some patients may perform a higher intensity of exercise gradually [80],
it is unknown if less intensive exercise produces
comparable enhancements in diastolic filling in
humans.
Impairment of endothelial vasodilator function
Impaired endothelium-dependent vasodilator
function in the micro- and macrocirculation,
which is mediated primarily by nitric oxide, is
well-established in type 2 diabetes [81–87]. An
attenuation of leg blood flow secondary to impaired endothelium-dependent vasodilation was
demonstrated in patients who had type 2 diabetes
[88]. This mechanism may be of importance in
determining the leg ischemic threshold in diabetic
individuals who have peripheral arterial disease.
Impairment of endothelial function also is found
in patients who have hypertension [89] and was
related independently to left ventricular mass in
patients who had mild hypertension but who did
not have left ventricular hypertrophy [90]. Endothelial dysfunction seems to be part of the
metabolic syndrome, independent of hyperglycemia [91]. Some data suggest that sustained
K.J. Stewart / Cardiol Clin 22 (2004) 569–586
hyperinsulinemia impairs nitric oxide synthesis,
which may contribute to the development of
insulin resistance and hypertension [92,93].
Exercise and endothelial vasodilator function
Exercise increases blood flow to active muscles;
the elevated shear stress on the vessel walls could
be a mechanism for the increased production of
endothelium-derived nitric oxide that leads to
smooth muscle relaxation and vasodilation [94].
In a rat model of noninsulin-dependent diabetes
[95], 16 weeks of running, but not food restriction
or a sedentary condition, improved endothelial
vasodilator function in the aorta—presumably
because of an increase in nitric oxide—as suggested by increased urinary nitrite excretion.
Regular physical activity improved endotheliumdependent vasodilation in patients who had type 1
diabetes [96], coronary artery disease [97], heart
failure [98], and peripheral arterial disease [99]. In
a randomized, crossover study, patients who had
type 2 diabetes who performed 8 weeks of aerobic
and resistance training had improved reactive
hyperemic brachial artery vasodilation and forearm blood flow [100]. Because the exercise regimen avoided hand and forearm exercises, the
improvements in endothelial vasodilator function
can be attributed to systemic effect of exercise,
rather than a local response in the exercise-trained
arm. In contrast, nondiabetic subjects who also
exercised had no improvement in endothelial
function, despite increases in fitness [101]. In
a randomized, controlled trial, exercise training
improved brachial artery endothelial vasodilator
function in patients who had the metabolic
syndrome [102]. The 12-week program, which
consisted of three weekly sessions of stationary
cycling at 80% of maximal heart rate for 30
minutes, induced an increase of 18% in fitness,
but no change in the baseline blood pressure of
148/95 mm Hg, BMI, insulin resistance, lipids,
and big endothelin-1. The improved vasodilator
function was not explained by any known atherosclerosis risk factors; this suggests that chronic
exercise hyperemia may upregulate endothelial
release of nitric oxide directly. In other studies,
12 weeks of brisk walking in patients who had
mild to moderate hypertension improved endothelial vasodilator function through increased
nitric oxide release [103,104]. Blood pressure decreased by a mean 8/4 mm Hg but the improvements in endothelial function did not correlate
with blood pressure changes.
573
Besides vasomotor tone, the endothelium also
regulates fibrinolysis and thrombosis, the inflammatory response, and growth of vascular smooth
muscle [105]. Exercise training seems to improve
endothelial function; it may be through this
mechanism that exercise may improve the cardiovascular health of patients who have type 2
diabetes and hypertension.
Increased arterial stiffness
With aging and hypertension, the arteries
stiffen from progressive degeneration of the arterial media, increased collagen and calcium content, and large artery dilation and hypertrophy
[106]. Aortic stiffening is a stronger predictor of
cardiovascular events and recently was shown to
be an independent predictor of fatal stroke in
patients who had essential hypertension [107]. The
process of artery stiffening is accelerated by
diabetes [28,108] and insulin resistance [109]. The
Atherosclerosis Risk in Communities Study [110],
a large sample of middle-aged men and women,
found that several indices of common carotid
artery stiffness were greater in patients who had
type 2 diabetes or impaired glucose tolerance
compared with persons who had normal glucose
tolerance. Elevated glucose, insulin, and triglycerides levels contributed to increased artery stiffness.
Glycation-induced cross-linking formation in interstitial collagen seemed to contribute to arterial
stiffness in aging and diabetes [111]. Structural
changes, like medial degeneration, reduce arterial
compliance and cause more stiffening. These
factors increase the systolic blood pressure and
the risk of atherosclerosis and adverse cardiovascular events.
Exercise and arterial stiffness
It was suggested that growth factors that are
released during repeated bouts of exercise may
mediate stiffness or that increases in heart rate and
blood pressure during exercise condition artery
walls [112]. In rats that ran on exercise wheels for
16 weeks, aortic cross-sectional compliance was
higher than in sedentary animals; this indicated
favorable structural adaptations to exercise
[113,114]. In the Baltimore Longitudinal Study of
Aging [115], higher maximal oxygen uptake was
associated with less arterial stiffness at any age and
in both genders. Moreover, pulse wave velocity was
decreased by 26% and carotid arterial pressure
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K.J. Stewart / Cardiol Clin 22 (2004) 569–586
pulse augmentation index was decreased by 36%
in men, ages 54 to 75 years who had a history of
endurance training, when compared with their
sedentary peers. In a similar cross-sectional study
of men with a mean age of 75 years, a history of lifelong regular strenuous exercise was associated with
less stiffness by the carotid arterial pressure pulse
augmentation index [116].
These cross-sectional data suggest, but do not
establish, cause and effect between increased
fitness and reduced arterial stiffening. Conversely,
in a small, randomized, crossover study of 10
patients who had isolated systolic hypertension
who were aged 64 7 years, 8 weeks of cycling at
65% of maximal heart rate had no effect on large
artery stiffness [117]. Although aerobic capacity
and workload increased, the baseline systolic
blood pressure of 154 7 mm Hg did not
decrease with training. It is unknown whether
established isolated systolic hypertension, a clinical manifestation of larger artery stiffening, is
particularly resistant to exercise training compared with essential hypertension or whether
exercise of longer than 8 weeks or of greater
intensity is needed to reduce arterial stiffness.
Longer-term exercise training in older men has
been associated with reduced arterial stiffness
[115,116]. Thus, although exercise-induced mechanisms that reduce arterial stiffness may be
a potential benefit of the training response,
randomized studies are needed to establish this
benefit definitively.
Systemic inflammation: does it underlie the
development of diabetes and hypertension?
In The Women’s Health Study [118], elevated
C-reactive protein and interleukin-6 levels predicted the development of type 2 diabetes. This
association was independent of BMI, family
history of diabetes, smoking, exercise, alcohol
use, and hormone replacement therapy. The
Atherosclerosis Risk in Communities Study [119]
reported that inflammation markers and endothelial dysfunction predicted the development of
diabetes and obesity. In the Monitoring of Trends
and Determinants in Cardiovascular Disease
study [120], men who had C-reactive protein levels
that were in the highest quartile ($2.91 mg/L) had
a 2.7 times higher risk of developing diabetes. This
association was not statistically significant after
adjustment for BMI, smoking, and systolic blood
pressure; this suggested that inflammation could
be a mechanism by which known risk factors,
such as obesity, smoking, and hypertension promote the development of diabetes mellitus. Creactive protein levels also are associated with
many components of the metabolic syndrome
[121]. In a cross-sectional study that involved
508 healthy men, elevated blood pressure was
associated with inflammation markers [122]. Data
from the Third National Health and Nutrition
Examination Survey [123] suggest that increases in
pulse pressure are associated with elevated Creactive protein levels among healthy adults,
independent of blood pressure. Thus, the chronic
activation of the immune system may be a common adverse mechanism among cardiovascular
and metabolic disease.
Exercise and inflammation
In the Cardiovascular Health Study [124],
higher self-reported physical activity was associated with lower concentrations of several inflammation markers, independent of gender,
cardiovascular disease, age, race, smoking, BMI,
diabetes, and hypertension. In recent data from
the National Health and Nutrition Examination
Survey III [125], regular participants in jogging
and aerobic dancing were less likely to have
elevated cardiovascular markers, independent of
age, race, sex, BMI, smoking, and health status.
C-reactive protein levels were reduced after 9
months in distance runners but not in sedentary
controls, which suggested that exercise has a systemic anti-inflammatory effect [126]. In patients
who had chronic heart failure, 12 weeks of
moderate-intensity cycling for 30 minutes, 5 days
per week, improved exercise tolerance and attenuated peripheral inflammatory markers reflecting
monocyte/macrophage–endothelial cell interactions [127]. In a recent study, exercise training
significantly reduced the local expression of tumor
necrosis factor-a, interleukin-1b, and interleukin6 in the skeletal muscle of patients who had
chronic heart failure who exercised for 6 months;
measurements in controls did not change [128].
There also was a reduction in the inducible
isoform of nitric oxide synthase and intracellular
accumulation of nitric oxide which was suggestive
of less oxidative stress. Inflammatory markers
also were reduced in patients who had peripheral
arterial disease after 6 months of walking; this
also improved claudication symptoms [129]. In
a randomized, controlled trial program that
K.J. Stewart / Cardiol Clin 22 (2004) 569–586
aimed to reduce body weight in premenopausal
obese women, the intervention, which consisted of
a low calorie diet and increased physical activity,
was associated with a reduction in markers of
vascular inflammation and insulin resistance [130].
Although direct data about the effects of exercise
training on the inflammatory process in patients
who have diabetes and hypertension are lacking,
the available evidence suggests that a reduction in
systemic inflammation is an important feature of
the training response.
Exercise and lipoproteins
Patients who have type 2 diabetes have a dyslipidemia that is characterized by increases in
atherogenic small, dense, low-density lipoprotein
(LDL) subfractions and serum triglycerides and
decreases in high-density lipoprotein (HDL)-2
cholesterol [131]. After a 4-week program of
exercise training and reduced calorie diet in
patients who had type 2 diabetes, reductions in
body weight and improvements in glycemic control were associated with reductions in serum
cholesterol and apolipoprotein B concentrations
in very low-density lipoprotein, intermediate-density lipoprotein, and small, dense (>1.040 g/mL)
LDL particles [132]. Thus, lifestyle interventions,
including exercise, seem to improve the LDL
subfraction profile with a decrease in small, dense
LDL particles and may protect against cardiovascular disease, despite a lack of reduction of total or
LDL cholesterol. Because the amount of exercise
training, rather than the intensity of exercise, may
be a more important determinant of lipoprotein
particle size, it is important for patients to engage
in frequent and regular exercise [133].
The role of body composition and fat distribution
The increasing prevalence of type 2 diabetes is
correlated highly with the prevalence of obesity
[134]. Based on data from Behavioral Risk Factor
Surveillance System [135], the prevalence of obesity
(BMI $30) 19.8% in 2000 and was 20.9% in 2001
(an increase of 5.6%), whereas the prevalence of
diabetes increased to 7.9% from 7.3% (an increase
of 8.2%). The prevalence of BMI of 40 or higher in
2001 was 2.3%. Overweight and obesity were
associated significantly with diabetes, high blood
pressure, high cholesterol, asthma, arthritis, and
poor health status. In the Nurse’s Health Study
[39], during 6 years of follow-up, sedentary
575
behaviors, especially TV watching, were associated
with significantly elevated risk of obesity and type 2
diabetes, whereas even light to moderate activity
was associated with substantially lower risk. Besides total fat, abdominal obesity is an independent
predictor of diabetes and hypertension [136–139]
and may play a role in the development of
cardiovascular abnormalities. A recent study
found that intra-abdominal adiposity predicted
coronary artery calcium scores in persons who
had insulin resistance, independent of blood pressure, HDL, triglycerides, glucose, insulin, insulin
resistance, or b-cell function [140]. In another
study, impaired endothelial vasodilator function
was predicted by abdominal obesity, independent
of total body weight, blood pressure, and metabolic parameters [141]. Because visceral and subcutaneous adipose tissues are the major sources of
cytokines (adipokines), increased adipose tissue is
associated with alteration in adipokine production,
such as overexpression of tumor necrosis factor-a,
interleukin-6, plasminogen activator inhibitor-1,
and underexpression of adiponectin in adipose
tissue [87]. The proinflammatory status that is
associated with these changes also provides a potential link between insulin resistance, endothelial
dysfunction, and type 2 diabetes.
Exercise and body composition
The exercise training–induced improvements in
glycemic control can occur independent of changes
in total body weight. Because few studies report
body mass in terms of lean and fat mass, or visceral
fat, it is uncertain if glycemic changes are independent of reductions in fat mass or increases in lean
tissue. Studies in persons who did not have diabetes
showed that increased fitness and activity may
reduce abdominal fat [137,142,143]; limited data
suggest a preferential loss of abdominal visceral fat
with exercise training [143,144]. A recent randomized trial in sedentary, overweight, postmenopausal
women, a group who is at high risk for diabetes,
showed that exercise training without diet for 12
months resulted in a 4.2% loss in total body fat and
a 6.9% loss of intra-abdominal visceral fat [145]. A
significant dose response for greater body fat loss
was observed with increasing duration of exercise.
Walking was the activity that was reported most
frequently. In a randomized trial of patients who
had type 2 diabetes, patients who performed highintensity aerobic exercise three times per week for 2
months increased aerobic capacity by 41% and
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insulin sensitivity by 46% [80]. Although there was
no change in total body weight with exercise
training, there was a 48% loss of abdominal visceral
fat and an 18% loss of abdominal subcutaneous fat.
The change in visceral fat correlated highly with
improved insulin sensitivity. Obese women who did
not have diabetes who performed moderate-intensity aerobic exercise four to five times a week
for 14 months increased fitness and decreased body
fat mass, with a greater loss of abdominal fat
compared with midthigh fat [146]. A key finding
was that the reduction in the insulinogenic index
correlated with reductions in total fat mass and
deep abdominal fat, but not with changes in fitness.
Thus, the reduction of abdominal obesity,
either independently or in combination with
changes in total fat, is an important benefit of
exercise training. These changes in body composition and fat distribution are associated with
decreases in blood pressure and improvements in
glycemic control and they may play a role in
improving the cardiovascular consequences of
type 2 diabetes and hypertension.
Guidelines for exercise training
Generally, exercise is considered to be a standard of care for glycemic control and blood
pressure reduction. Based on scientific evidence
and expert opinion, exercise guidelines have been
published by the American College of Sports
Medicine for type 2 diabetes [25] and for hypertension [147]. Guidelines from the American
Diabetes Association can be found in their Handbook of Exercise in Diabetes [148]. The key
recommendations that are applicable to patients
without significant health complications or limitations are summarized in Box 1.
Because patients who have diabetes and hypertension often have concomitant clinical or
occult coronary artery disease, adverse cardiovascular and physiologic responses during exercise
training are possible. The American Diabetes
Association [149] and ATP III guidelines [150]
consider diabetes as a coronary artery disease risk
equivalent. The prevalence of silent myocardial
ischemia in patients who have type 2 diabetes can
be as high as 20% to 25%, especially in patients
who are older than 60 years [151] or when the
duration of diabetes is more than 10 years and
there is the presence of other cardiovascular risk
factors [152]. Thus, patients should undergo
exercise stress testing before initiating a moderate-
intensity exercise program or greater to identify
ischemia, arrhythmias, anginal thresholds, and patients who have asymptomatic ischemia [153–155].
Exercise testing also provides data about heart rate
and blood pressure responses for establishing an
appropriate exercise prescription.
Patients should expend a minimum cumulative
1000 Kcal per week in aerobic exercise and participate in resistance training for improving fitness
and body composition, reducing blood pressure,
and controlling blood glucose levels [156,157].
Most patients can meet this level by exercising
3 days per week, whereas more frequent sessions
are recommended when weight loss is a goal. Each
exercise session should include 5 to 10 minutes
of warm-up and 5 to 10 minutes of cool-down
activities. Appropriate activities for these phases
are calisthenics, range of motion, and low intensity
aerobic exercise that allow for gradual transition to
and from the higher metabolic demands of the main
aerobic phase of the exercise session. Walking,
cycling, and swimming are examples of aerobic
activity; they should be increased gradually in
duration to last for 30 to 45 minutes to reach energy
expenditure recommendations [155].
Heart rate is the primary guide for aerobic
exercise intensity and can be monitored by manually counting the pulse or with a heart rate
monitor. The target heart rate for exercise is
typically set at 60% to 90% of the maximum
heart rate for healthy adults [155]. For patients
who have diabetes and hypertension and other
risk factors, such as smoking, hyperlipidemia, and
obesity that further increase their cardiovascular
disease risk, a target heart rate that corresponds to
55% to 79% of maximum heart rate is used
instead [155]. The maximal heart rate can be
obtained from exercise testing [153]. In the absence of exercise testing and for patients whose
heart rate response is not limited by medications
or autonomic neuropathy [154] or a cardiac
pacemaker, the maximal heart rate can be estimated from age using the formula:
220age ¼ maximum heart beats per minute ðbpmÞ
For example, the age-predicted maximal heart
rate for a 60-year old is calculated as 220 60 ¼
160 bpm. If the individual has uncomplicated
diabetes, the target heart rate range would be
55% to 79% of 160 bpm, or 88 to 126 bpm.
In patients who have a low initial level of fitness,
the target heart rate can be set at 50% to 60% of
maximum and increased as tolerated. A lower heart
K.J. Stewart / Cardiol Clin 22 (2004) 569–586
577
Box 1. Guidelines for exercise training in persons who have diabetes
and hypertension
Warm-up and cool down period of 5 to 10 minutes each
Stretching, calisthenics, low-level aerobic exercise (eg, walking or cycling)
Types of exercise
Aerobic exercise consists of activities like walking, cycling, swimming, rowing.
Resistance exercise consists of weight lifting. Machines are preferred for safety and ease
of use; hand-held weights, barbells, and elastic bands also can be used.
Intensity
Aerobic exercise at 55% to 79% of maximal heart rate for most patients who have
type 2 diabetes; 50% to 60% of maximal heart rate for patients who have low initial
level of fitness.
Resistance (weight) training, 8 to 10 exercises at 30% to 50% of 1-repetition maximum.
A minimum of 1 set of 12 to 15 repetitions; increase workload when 15 repetitions can
be done without difficulty.
Duration
Aerobic exercise for 30 to 45 minutes.
Resistance training takes about 20 minutes for 1 set each for 8 to 10 exercises.
Frequency
Aerobic exercise should be done three to four times per week.
Resistance exercise should be done at least twice per week.
It is recommended that individualized exercise prescriptions be based on the results
of exercise stress testing. See text, ACSM Position Stand on Exercise and Type 2
Diabetes [25], and the American Diabetes Association Handbook of Exercise in
Diabetes [148] for exercise precautions.
rate range also may be necessary for patients who
have autonomic neuropathy, which limits the heart
rate response during exercise. The use of b-blockers
and abnormal exercise stress test findings, such as
ischemic ECG changes, require individualized
adjustment of the target heart rate because the
general guidelines do not apply. Although b-blockers attenuated the heart rate response during
exercise, they did not generally preclude an improvement in aerobic and muscle fitness [158].
The American College of Sports Medicine [25]
and the American Heart Association, in its
Scientific Advisory on Resistance Training in
Individuals With and Without Cardiovascular
Disease [159], recommend resistance training,
when appropriately prescribed and supervised.
Resistance training produces beneficial effects on
muscular strength and endurance, cardiovascular
function, metabolism, coronary risk factors, and
psychosocial well-being. The American Diabetes
Association advises the use of light to moderate
weights and high repetitions for maintaining or
enhancing upper body strength in nearly all
patients who have diabetes [160]. For the elderly
patient who has diabetes, light-intensity resistance
training has positive effects on bone density,
osteoarthritic symptoms, mobility impairment,
and self-efficacy [161]. It also alleviates symptoms
of anxiety, depression, and insomnia in individuals who have clinical depression [161]. Resistance
training should be performed at least twice per
week, with a typical workout consisting of a minimum of 1 set of 8 to 10 exercises to cover the
large muscle groups of the upper and lower body
[162]. If maximal muscle strength testing is available, 1-repetition maximum evaluation can be
performed to determine the patient’s initial level
of strength [163]. The weight intensity for subsequent workouts are set at a moderate level,
which corresponds to a load of 30% to 50% of
maximum strength. At a moderate intensity, the
patient should be able to perform 12 to 15
repetitions. For example, if the 1-repetition maximum for a given exercise is 100 pounds, the
weight lifted during the workout is 30 pounds to
50 pounds and it should be lifted 12 to 15 times.
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K.J. Stewart / Cardiol Clin 22 (2004) 569–586
When 15 repetitions of an exercise can be completed without difficulty, the weight should be
increased by 5 pounds to 10 pounds to assure
a progressive muscle overload [162]. If muscle
strength testing is not done, the individual can
select an initial weight that can be lifted with
moderate difficulty approximately 10 to 15 times
[159,164]. Weight machines are recommended for
their ease of use and safety. Alternatively, if the
initial load on a particular machine is too heavy or
machines are not available, hand weights, barbells, or elastic bands can be used instead. Studies
in patients who have type 2 diabetes are needed to
determine if they should be performing more
intense or frequent resistance training than the
current recommendations because of the potential
benefit of resistance training for increasing muscle
mass and reducing fat mass [35].
Exercise precautions
The risk-benefit of exercise is highly favorable
for most patients who have diabetes and hypertension; however, some precautions are warranted
(Table 1). Moderate or severe hypertension (systolic blood pressure $160 mm Hg or diastolic
blood pressure $100 mm Hg) should be controlled to lower levels before starting an exercise
program [165]. An exercise stress test should be
performed to rule out ischemia, complex arrhythmias, and symptoms. Although contraindications
to exercise based on glycemic control have been
established for type 1 diabetes [148], guidelines for
type 2 diabetes are less definitive. Badenhop et al
[166] evaluated exercising patients who had type 2
diabetes and baseline glucose levels that ranged
from 60 mg/dL to 400 mg/dL. Patients who used
insulin were excluded. In more than 550 cases,
there was no episode of ketosis or hypoglycemia
in the 24 hours after exercise and the occurrence
of hypoglycemia (blood glucose <60 mg/dL)
during exercise was 2%. Thus, patients who have
type 2 diabetes who do not use insulin may not
need to have their blood glucose checked routinely
when exercising. Supplementary food should be
available, but it usually is not required unless the
exercise session is exceptionally vigorous and of
long duration [25]. Patients who use insulin
should be encouraged to exercise and be given
Table 1
Diabetic complications and comorbidities and precautions for exercise
Complication
Pathophysiology
Clinical signs/symptoms
Exercise precaution
Myocardial ischemia, acute
coronary syndrome,
cardiac arrhythmias
Macrovascular and
microvascular
atherosclerosis, endothelial
dysfunction
Retinopathy, background
or active proliferative
retinopathy
Angina, dyspnea, silent
ischemia is common
Consider graded exercise
test
Ophthalmic examination
Foot injury
Neuropathy and peripheral
artery disease
Degenerative joint disease,
foot ulcers, poor
peripheral pulses
Orthostatic hypotension
Autonomic dysfunction
Peripheral artery disease
Macrovascular disease
Nephropathy
Vascular disease,
glomerulorsclerosis
Depressed blood pressure
and heart rate response
to exercise, low heart
rate variability
Intermittent claudication,
resting claudication,
diminished peripheral
pulses
Proteinuria, hypertension
Avoid high-intensity
exercises, rapid head
movements, head down
maneuvers, and Valsalva
maneuvers, especially
during resistance training
Wear proper footwear,
engage in low-impact
exercise, perform daily
examination of feet
Longer warm-up periods,
lower intensity activities
Retinal hemorrhage
Walk to pain
tolerance, intersperse
exercise with periods of
rest
Avoid increasing systolic
blood pressure
>180 mm Hg during
exercise
K.J. Stewart / Cardiol Clin 22 (2004) 569–586
instructions about blood glucose monitoring, insulin dosing, and supplementary foods. Guidelines for exercise training in patients who use
insulin can be found elsewhere [167]. To minimize
excessive blood pressure responses, patients
should be told to maintain normal controlled
breathing while performing resistance training.
Although short periods of breath holding are
unavoidable at higher exercise intensities, extended
breath holding should be avoided. Precautions for
patients who have diabetic peripheral and autonomic neuropathy [25,148] and peripheral arterial
disease [168] are discussed elsewhere. There is no
evidence that properly prescribed exercise worsens
diabetic retinopathy and it may reduce or delay
the risk of eye complications by reducing blood
pressure, increasing HDL cholesterol [169], and
increasing fitness [170]. Because of a concern for
579
vitreous hemorrhage or traction retinal detachment retinopathy, exercise that involves straining,
such as heavy resistance training, should be
avoided in patients who have active proliferative
diabetic retinopathy or moderate or worse nonproliferative diabetic retinopathy. The exact
threshold for this risk is unknown [169]. Whether
patients who have had laser or surgical procedures
for diabetic retinopathy can undertake more
vigorous resistive exercise is unknown.
Summary
Exercise training is an essential component in
the medical management of patients who have
type 2 diabetes and hypertension. Regular exercise
improves the cardiovascular health of individuals
who have these conditions through multiple
Decreases blood glucose
Increases insulin sensitivity
Decreases blood pressure
Decreases total body fat
and abdominal obesity
Increases lean body mass
Increases aerobic capacity
and muscle strength
Exercise Training
Improves endothelial
vasodilator function
Improves left ventricular
diastolic function
Decreases arterial stiffness
Decreases systemic inflammation
Fig. 1. Overview of the potential beneficial effects of exercise training in diabetes and hypertension. In addition to the
well-established improvements in glycemic control, blood pressure levels, and fitness, exercise training also contributes to
improvements in the cardiovascular consequences of type 2 diabetes and hypertension.
580
K.J. Stewart / Cardiol Clin 22 (2004) 569–586
mechanisms (Fig. 1). These mechanisms include
improvements in endothelial vasodilator function,
left ventricular diastolic function, arterial stiffness,
systematic inflammation, and reducing left ventricular mass. Exercise training also reduces total
and abdominal fat, which mediate improvements
in insulin sensitivity and blood pressure, and
possibly, endothelial function.
Persons who are in a prediabetic stage or those
who have the metabolic syndrome may be able to
prevent or delay the progression to overt diabetes
by adopting a healthier lifestyle, of which increasing habitual levels of physical activity is
a vital component. Most persons who have diabetes and hypertension or are at risk for these
conditions should be able to initiate an exercise
program safely after appropriate medical screening and the establishment of an individualized
exercise prescription.
Despite the increasing amount of evidence that
shows the benefits of exercise training, this modality of prevention and treatment continues to be
underused. Although patients’ lack of knowledge
of the benefits of exercise or lack of motivation
contributes to this underuse, a lack of clear and
specific guidelines from health care professionals
also is an important factor. Clinicians need to
educate patients about the benefits of exercise for
managing their type 2 diabetes and assist in
formulating specific advice for increasing physical
activity. Specific instructions should be given to
patients, rather than general advice, such as ‘‘you
should exercise more often.’’ Many cardiac rehabilitation and clinical exercise programs can
accommodate patients who have type 2 diabetes
and hypertension. Such programs can establish
individualized exercise prescriptions and provide
an environment that is conducive for ‘‘lifestyle
change’’ that underlies long-term compliance to
exercise and risk factor modification.
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