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(Circulation. 1999;100:1134-1146.)
© 1999 American Heart Association, Inc.
AHA Scientific Statement |
Diabetes and Cardiovascular Disease
A Statement for Healthcare Professionals From the American Heart Association
Key Words: AHA Scientific Statements • diabetes mellitus • risk factors • cardiovascular diseases
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Introduction |
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Top
Introduction
Clinical Presentations of...This statement examines the cardiovascular complications of diabetes mellitus and considers opportunities for their prevention. These complications include coronary heart disease (CHD), stroke, peripheral arterial disease, nephropathy, retinopathy, and possibly neuropathy and cardiomyopathy. Because of the aging of the population and an increasing prevalence of obesity and sedentary life habits in the United States, the prevalence of diabetes is increasing. Thus, diabetes must take its place alongside the other major risk factors as important causes of cardiovascular disease (CVD). In fact, from the point of view of cardiovascular medicine, it may be appropriate to say, "diabetes is a cardiovascular disease."
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Clinical Presentations of Diabetes Mellitus |
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The most prevalent form of diabetes mellitus is type 2 diabetes. This disorder typically makes its appearance later in life. The underlying metabolic causes of type 2 diabetes are the combination of impairment in insulin-mediated glucose disposal (insulin resistance) and defective secretion of insulin by pancreatic ß-cells. Insulin resistance develops from obesity and physical inactivity, acting on a substrate of genetic susceptibility.1 2 Insulin secretion declines with advancing age,3 4 and this decline may be accelerated by genetic factors.5 6 Insulin resistance typically precedes the onset of type 2 diabetes and is commonly accompanied by other cardiovascular risk factors: dyslipidemia, hypertension, and prothrombotic factors.7 8 The common clustering of these risk factors in a single individual has been called the metabolic syndrome. Many patients with the metabolic syndrome manifest impaired fasting glucose (IFG)9 even when they do not have overt diabetes mellitus.10 The metabolic syndrome commonly precedes the development of type 2 diabetes by many years11 ; of great importance, the risk factors that constitute this syndrome contribute independently to CVD risk.
Recently, new criteria have been accepted for the diagnosis of
diabetes.9 The upper threshold of fasting plasma glucose
for the diagnosis of diabetes has been lowered from 
140 mg/dL to
126 mg/dL. The upper threshold for normoglycemia likewise has been
reduced from <115 to <110 mg/dL. A fasting plasma glucose of 110 to
125 mg/dL is now designated IGF. These changes removed the need for
oral glucose tolerance testing for diagnosis of diabetes; a diagnosis
rests entirely on confirmed elevations of fasting plasma glucose.
Furthermore, the terms insulin-dependent diabetes mellitus and
non–insulin-dependent diabetes mellitus have been replaced by type 1
diabetes and type 2 diabetes, respectively.
The other form of diabetes mellitus is type 1 diabetes, which follows immunologic destruction of pancreatic ß-cells.12 Type 1 diabetes usually begins early in life and is often called juvenile diabetes. This form of diabetes frequently produces microvascular complications, nephropathy, and retinopathy,12 but it also predisposes to CHD.13 Because type 2 diabetes occurs much more commonly than type 1 diabetes, the present statement will emphasize type 2 diabetes. Nonetheless, type 1 diabetes will be integrated into the overall strategy of cardiovascular risk reduction.
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Scope of the Problem |
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At least 10.3 million Americans carry a diagnosis of diabetes mellitus.14 Another 5.4 million are estimated to have undiagnosed diabetes.14 Approximately 90% of patients with diabetes have the type 2 variety.14 The onset of type 2 diabetes usually precedes clinical diagnosis by several years.14 An increasing prevalence of type 2 diabetes cannot be divorced from the rising prevalence of obesity and physical inactivity in our society. An estimated 97 million adults in the United States are overweight or obese.15 Furthermore,
75% of
adult Americans have minimal physical activity or daily
exercise.16 Both excess body fat and physical inactivity
predispose to type 2 diabetes. Several ethnic groups are particularly
susceptible to type 2 diabetes: Hispanics, blacks, Native
Americans, and Asians (especially South Asians).17 18 19 20 The
growing ethnic diversity, including these groups, contributes to the
increasing prevalence of type 2 diabetes in the United States. |
Diabetes as a Major Risk Factor |
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A large body of epidemiological and pathological data documents that diabetes is an independent risk factor for CVD in both men and women.21 22 23 Women with diabetes seem to lose most of their inherent protection against developing CVD.21 24 CVDs are listed as the cause of death in
65% of persons with
diabetes.25 Diabetes acts as an independent risk factor
for several forms of CVD. To make matters worse, when patients with
diabetes develop clinical CVD, they sustain a worse prognosis for
survival than do CVD patients without diabetes.26 27 28
These considerations have convinced the Scientific Advisory and
Coordinating Committee of the American Heart Association (AHA) that
diabetes mellitus deserves to be designated a major risk factor for
CVD. This formal designation commits the AHA to a greater emphasis on
diabetes as a risk factor in its scientific and educational programs.
This statement provides the scientific rationale for the decision to
classify diabetes as a major risk factor for CVD. |
Diabetes and Specific CVD |
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Atherosclerotic CHD
Both type 1 diabetes and type 2 diabetes are independent risk factors for CHD.21 22 23 Moreover, myocardial ischemia due to coronary atherosclerosis commonly occurs without symptoms in patients with diabetes.29 As a result, multivessel atherosclerosis often is present before ischemic symptoms occur and before treatment is instituted. A delayed recognition of various forms of CHD undoubtedly worsens the prognosis for survival for many diabetic patients.
Diabetic Cardiomyopathy
One reason for the poor prognosis in patients with both diabetes
and ischemic heart disease seems to be an enhanced myocardial
dysfunction leading to accelerated heart failure (diabetic
cardiomyopathy).30 31 32 33 34 35 36 37 Thus, patients
with diabetes are unusually prone to congestive heart failure. Several
factors probably underlie diabetic cardiomyopathy:
severe coronary atherosclerosis, prolonged
hypertension, chronic hyperglycemia, microvascular disease,
glycosylation of myocardial proteins, and autonomic
neuropathy. Improved glycemic control, better control of
hypertension, and prevention of atherosclerosis with
cholesterol-lowering therapy may prevent or mitigate
diabetic cardiomyopathy. An early clinical
trial38 suggested that sulfonyl ureas used for control of
hyperglycemia are cardiotoxic and may exacerbate diabetic
cardiomyopathy. This side effect, however, was not
confirmed in a recent large clinical trial.39
Stroke
Mortality from stroke is increased almost 3-fold when patients
with diabetes are matched to those without diabetes.40 The
most common site of cerebrovascular disease in patients with diabetes
is occlusion of small paramedial penetrating arteries.41
Diabetes also increases the likelihood of severe carotid
atherosclerosis.42 43 Patients with
diabetes, moreover, are likely to suffer irreversible brain damage with
carotid emboli that otherwise would produce only transient
ischemic attacks in persons without diabetes. Approximately
13% of patients with diabetes >65 years old have had a
stroke.44
Renal Disease
Renal disease is a common and often severe complication of
diabetes.45 Approximately 35% of patients with type 1
diabetes of 18 years' duration will have signs of diabetic renal
involvement.46 Up to 35% of new patients beginning
dialysis therapy have type 2 diabetes.47 End-stage renal
disease (ESRD) appears to be especially common among Hispanics, blacks,
and Native Americans with diabetes.48 49 50 51 52 For patients
with diabetes who are on renal dialysis, mortality rates probably
exceed 20% per year.47 When diabetes is present, CVD
is the leading cause of death among patients with
ESRD.53 54 55
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Covariate Risk Factors |
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Prospective studies22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 indicate that all of the major cardiovascular risk factors—cigarette smoking, hypertension, and high serum cholesterol—continue to act as independent contributors to CVD in patients with diabetes. As already mentioned, clustering of metabolic risk factors, called the metabolic syndrome, occurs commonly in type 2 diabetes.56 The onset of hyperglycemia in patients with the metabolic syndrome appears to accelerate atherogenesis, possibly by enhanced formation of glycosylated proteins and advanced glycation products57 58 and/or by increasing endothelial dysfunction.59 These direct consequences of hyperglycemia probably contribute to the microvascular disease underlying nephropathy and retinopathy, and they may promote macrovascular disease as well.
Predisposing Risk Factors
Several predisposing factors simultaneously affect the
development of CVD and diabetes mellitus. Among these concomitant
factors are obesity, physical inactivity, heredity, sex, and advancing
age. The mechanisms whereby they predispose to chronic diseases are
complex and often overlapping. To some extent, these predisposing
factors exacerbate the major risk factors: dyslipidemia,
hypertension, and glucose tolerance; and they may cause CVD and
diabetes mellitus through other pathways as well. To a large extent,
both CVD and diabetes must be prevented through control of the
predisposing risk factors. Modification of life habits is at the heart
of the public health strategy for prevention of CVD and diabetes
mellitus. High priorities are the prevention (or treatment) of obesity
and promotion of physical activity. Drug therapy nonetheless may be
required to control the metabolic risk factors,
particularly when they arise from genetic aberration and aging.
Effective drugs are currently available for treatment of hypertension
and dyslipidemia. Hypoglycemic agents also are available
for treatment of type 2 diabetes, but new pharmacological strategies
are under investigation for more effective treatment and
prevention.
Insulin Resistance and the Metabolic Syndrome
Most patients with type 2 diabetes have insulin resistance.
Indeed, insulin resistance seems to predispose to both CVD and
diabetes.60 Research suggests that insulin resistance is a
multisystem disorder that induces multiple metabolic
alterations. Factors that contribute to insulin resistance are
genetics,61 obesity,62 physical
inactivity,63 and advancing age.64 Patients
with insulin resistance often have abdominal obesity.65
Metabolic risk factors that occur commonly in patients with
insulin resistance are atherogenic dyslipidemia,
hypertension, glucose intolerance, and a prothrombotic
state.60 Each of these risk factors can be reviewed
briefly.
Atherogenic Dyslipidemia
Atherogenic dyslipidemia is characterized by 3
lipoprotein abnormalities: elevated very-low-density lipoproteins
(VLDL), small LDL particles, and low high-density-lipoprotein (HDL)
cholesterol (the lipid triad). The lipid triad occurs
frequently in patients with premature CHD and appears to be an
atherogenic lipoprotein phenotype independent of elevated LDL
cholesterol.66 67 68 69 Most patients with
atherogenic dyslipidemia are insulin
resistant.69 70 71 Atherogenic
dyslipidemia in diabetic patients often is called diabetic
dyslipidemia. Many patients with atherogenic
dyslipidemia also have an elevated serum total
apolipoprotein B.72 Growing evidence suggests that all of
the components of the lipid triad are independently atherogenic.
Together they represent a set of lipoprotein abnormalities
besides elevated LDL cholesterol that promote
atherosclerosis.
Hypertension
Hypertension is a well-established major risk factor for
CVD.22 It increases risk for both CHD and stroke and
contributes to diabetic nephropathy.73 Several
investigators74 75 report a positive association between
insulin resistance and hypertension; this finding suggests that
elevated blood pressure deserves to be listed among the components of
the metabolic syndrome. Hypertension nonetheless is a
multifactorial disorder, and the mechanistic connections between
insulin resistance and hypertension are largely conjectural; even so,
evidence for a causal link is growing.76 When hypertension
coexists with overt diabetes, which it commonly does, the risk for CVD,
including nephropathy, is doubly increased.
Elevated Plasma Glucose
For several years after onset of insulin resistance, fasting and
postprandial glucose levels typically are normal. During this period,
pancreatic ß-cells are able to increase insulin secretion in response
to insulin resistance and thereby maintain normal plasma glucose
levels. In some people, however, insulin secretion declines with aging,
and elevated glucose concentrations appear. The first abnormality in
plasma glucose in patients with insulin resistance is IFG (or impaired
glucose tolerance).9 The presence of IFG usually
accompanies long-standing insulin resistance. It is currently estimated
that 13.4 million adults, 7.0% of the US population, have
IFG.14 Many prospective studies77 78 show
that IFG (or impaired glucose tolerance) is a risk factor for CVD; the
degree of independence as a risk factor, however, is uncertain, because
IGF commonly coexists with other components of the
metabolic syndrome.11 A patient with IFG
nonetheless must be considered at risk for both CVD and type 2
diabetes. As already indicated, once categorical hyperglycemia
develops, it counts as an independent risk factor for
CVD.22
Prothrombotic State
A newly recognized component of the metabolic
syndrome is a prothrombotic state.76 Patients with insulin
resistance frequently manifest several alterations in coagulation
mechanisms that predispose them to arterial thrombosis.
These alterations include increased fibrinogen levels,79
increased plasminogen activator
inhibitor-1,80 and various platelet
abnormalities.81
LDL Cholesterol and Atherogenesis in Diabetic
Patients
An elevated concentration of serum LDL cholesterol is
a major risk factor for CHD.82 In fact, some elevation of
LDL cholesterol appears to be necessary for the initiation
and progression of atherosclerosis. In populations
having very low LDL cholesterol levels, clinical CHD is
relatively rare, even when other risk factors—hypertension, cigarette
smoking, and diabetes—are common.83 In contrast, severe
elevations in LDL cholesterol can produce full-blown
atherosclerosis and premature CHD in the complete
absence of other risk factors.84
The view has been expressed that most patients with diabetes do not have an elevated serum LDL cholesterol; if not, a high LDL serum cholesterol would not be a common risk factor in patients with diabetes. It is true that most patients who have diabetes do not have marked elevations of LDL cholesterol, but these patients nonetheless carry high enough levels to support the development of atherosclerosis.85 A role for LDL in hyperglycemic patients became apparent in recent clinical trials, eg, the Scandinavian Simvastatin Survival Study (4S),86 87 the Cholesterol and Recurrent Events (CARE) trial,88 89 and the Long-Term Intervention with Pravastatin in Ischemic Disease (LIPID).90 In all of these trials, aggressive LDL-lowering therapy reduced recurrent CHD events in patients with diabetes.
Cigarette Smoking
Cigarette smoking is a leading risk factor for CVD. Patients with
diabetes who are smokers are doubly at risk. Unfortunately, many
patients continue to smoke despite having diabetes; for these patients,
the benefits that can be derived from modifying other risk factors are
mitigated.
Diabetic Nephropathy
Diabetic nephropathy can be divided into 4 phases:
microalbuminuria, macroalbuminuria, the
nephrotic syndrome, and chronic renal failure.45
Microalbuminuria (urine albumin 30 to 300 mg/d or
<300 mg/g creatinine) is the first clinical sign of
diabetic damage to the kidney.91 92 Not only is
microalbuminuria a harbinger of progressive kidney damage,
but its presence also reflects a higher risk for
CVD.92 93 94 95 Macroalbuminuria (urine
albumin >300 mg/d or >300 mg/g creatinine)
usually denotes significant diabetic nephropathy and will
be followed by a decline in glomerular filtration rate
(GFR). The majority of patients with diabetes who have
macroalbuminuria also have hypertension96 97 ;
in these patients, control of hypertension slows the decline in
GFR.98 99 100 Some patients with diabetes develop the
nephrotic syndrome (urine protein >3 g/d); diabetic
dyslipidemia in such patients often is compounded by
nephrotic dyslipidemia, most notably by higher
cholesterol levels. The nephrotic syndrome usually heralds
progressive renal insufficiency; thereafter, ESRD ensues and dialysis
and/or transplantation become necessary to sustain life.
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Risk Assessment in the Diabetic Patient |
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Risk assessment must take into account the major risk factors (cigarette smoking, elevated blood pressure, abnormal serum lipids and lipoproteins, and hyperglycemia) and predisposing risk factors (excess body weight and abdominal obesity, physical inactivity, and family history of CVD). Identification of risk factors is a major first step for developing a plan for risk reduction in persons with diabetes. Specific steps in the evaluation of the major risk factors in such persons are presented in Table 1
. These steps include a thorough
medical history, careful physical examination, and appropriate
laboratory measurements. Specialized testing may be particularly
useful, eg, 24-hour monitoring of ambulatory blood pressure by
automated techniques. Lipoprotein analysis should draw a clear
distinction between elevated LDL cholesterol concentrations
and atherogenic dyslipidemia (or diabetic
dyslipidemia) as manifested by elevated
triglycerides and small LDL and low HDL
cholesterol levels. Even borderline-high-risk LDL
cholesterol levels (130 to 159 mg/dL) are of concern in
patients with diabetes and call for aggressive intervention. The
quality of glycemic control can best be assessed by periodic
measurement of hemoglobin A1c. Furthermore, because hyperglycemia per
se confers increased risk for CVD, the presence of other risk
factors—smoking, hypertension, even borderline-high-risk LDL
cholesterol, and atherogenic
dyslipidemia—signifies enhanced risk and signals the need
for more aggressive intervention on all risk factors.
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Risk assessment in the diabetic patient is not complete until
predisposing risk factors—obesity, physical inactivity, and family
history of premature CVD—have been evaluated (Table 2). Identification of predisposing risk
factors will provide insight into the causation of the major risk
factors. The finding of abdominal obesity, as evidenced by an increased
waist circumference, usually indicates the presence of insulin
resistance. A careful assessment of the status of the predisposing risk
factor sets the stage for therapeutic modification of life habits. A
genetic basis for risk, as revealed by a positive family history of CVD
or diabetes, may point to the need for pharmacological control of risk
factors. Moreover, a positive family history often uncovers family
members who also need risk-factor intervention.
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Clinical Evaluation |
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Detection of Clinical and Subclinical CVD
Prospective studies101 document an increased likelihood of sudden cardiac death and unrecognized myocardial infarctions in patients with diabetes. Moreover, acute ischemic syndromes, peripheral arterial disease, and advanced CVD complications occur more commonly in patients with diabetes than in those without.101 Because the typical cardiac symptoms often are masked in patients with diabetes, the diagnosis of myocardial infarction commonly is missed or delayed. Effective strategies for earlier detection of clinical CVD could reduce morbidity and mortality in patients with diabetes. In addition, detection of subclinical atherosclerosis and early clinical manifestation of CVD could lead to more effective primary prevention in some patients with diabetes.
Table 3 outlines a general approach to
the detection of clinical and subclinical CVD in the hyperglycemic
patient. Stress testing for myocardial ischemia and dysfunction
should be performed in accord with general American College of
Cardiology (ACC)/AHA guidelines102 ; Table 3 lists further special considerations for exercise testing in
patients with diabetes. Noninvasive evaluation of cardiac function in
hyperglycemic patients suspected of having myocardial dysfunction may
be a useful guide to cardiovascular management in some
of these patients. Many patients with diabetes suffer from an autonomic
dysfunction that impairs quality of life and predisposes to
life-threatening cardiovascular complications. Finally,
the finding of subclinical CVD signals the need for institution of more
aggressive preventive measures.
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Evaluation of Renal Status
Chronic renal failure is a major clinical outcome in patients with
diabetes. It is more likely to develop in type 1 diabetes than in type
2 diabetes. However, the high prevalence of type 2 diabetes makes it a
major cause of ESRD. The renal status of patients with diabetes
therefore must be appropriately monitored so that effective
intervention can be introduced early in the course of renal disease.
Table 4 outlines the steps in evaluation.
Testing for urine albumin and protein is the first step.
Microalbuminuria is indicative of early diabetic
nephropathy. In patients with type 1 diabetes, it is a
harbinger of ongoing renal damage; in type 2 diabetes, it signifies
enhanced risk for CVD. Macroalbuminuria and/or
nephrotic-range proteinuria predicts a decline in renal function.
Patients with macroalbuminuria should be referred to a
nephrologist who can rule out another kidney disease and who can help
to plan a strategy for preventing progression to ESRD. This strategy
should include aggressive management of hypertension to blood pressure
levels of <130/85 mm Hg. Although the serum
creatinine is not a sensitive indicator of the degree of
loss of GFR, a rising serum creatinine plotted as changes
in the reciprocal of serum creatinine versus time provides
a means of determining the rate of decline in renal function. Direct
measurement of GFR is the most reliable estimate of the amount of
residual kidney function but is more expensive and technically
demanding.
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Cardiovascular Clinical Management |
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Medical (Noninvasive) Management of Diabetic Patients With Clinical CVD
Compelling evidence, including data from recent clinical trials, demonstrates that comprehensive medical intervention in patients with established atherosclerotic CVD has thefollowing benefits: it extends overall survival; improves quality of life; decreases the need for intervention procedures, such as angioplasty and coronary artery bypass graft surgery; and reduces the incidence of subsequent myocardial infarction.103 In many patients with CHD, aggressive risk reduction with medical therapy will delay or eliminate the need for revascularization procedures. Treatment of risk factors in patients with established CHD or other clinical atherosclerotic disease has been called secondary prevention. Although the number of patients with diabetes included in clinical trials has been limited, the available results suggest that these patients respond to secondary prevention interventions at least as well as those without diabetes.86 87 88 89 90 Consequently, the general guidelines for noninvasive, medical management in secondary prevention can be applied when patients with diabetes have clinical atherosclerotic CVD. Table 5
summarizes
the AHA/ACC guide103 to comprehensive risk reduction in
patients with clinical coronary and other vascular disease, as
modified for CVD patients with diabetes.
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A few general comments can be made about application of these
guidelines to patients with diabetes. Because cigarette smoking remains
a powerful risk factor in patients with diabetes, a major effort must
be made to overcome the smoking habit. The AHA has recently published
practical guidelines for assisting patients in smoking
cessation.104 For lipid management, the primary goal of
therapy is to reduce LDL-cholesterol levels to 
100
mg/dL.103 This goal should be achieved by addition of drug
therapy (when necessary) to maximal dietary therapy. Statins are
first-line therapy to achieve an LDL cholesterol of 100
mg/dL. When triglycerides remain >200 mg/dL in patients
receiving statin therapy, consideration should be given to adding a
fibrate to achieve the secondary goal of lipid management, ie, a
triglyceride <200 mg/dL. Although nicotinic acid
effectively lowers triglycerides and raises HDL levels in
patients with type 2 diabetes, its tendency to worsen hyperglycemia
causes it to be relatively contraindicated. The goal of blood pressure
control is to reduce blood pressure to <135/85 mm Hg in
hypertensive patients105 ; this goal often will require
antihypertensive drug therapy.
Treatment of hyperglycemia is stepwise and typically dependent on
duration of disease. To prevent microangiopathy,
neuropathy, and perhaps macrovascular disease, a prudent
therapeutic goal is to reduce the glycohemoglobin to 1% above the
upper limit of normal.39 106 Weight loss and increased
exercise are first-line therapy for reducing hyperglycemia. If
hyperglycemia persists, a sulfonylurea or metformin can be used next.
The recent UK Prospective Diabetes Study39 revealed the
safety and efficacy of sulfonylureas in control of hyperglycemia in
diabetic patients. Metformin also proved efficacious, although an
apparent increase in death rates on the combination of metformin and
sulfonylureas calls for more study on the safety of this
combination.107
Another promising group of agents for treatment of type 2 diabetes includes the thiazolidenediones. These agents lower glucose levels by reducing insulin resistance. The first drug in this class to be approved for clinical use was troglitazone. This agent is approved for use in combination with insulin therapy to improve glycemic control. Unfortunately, troglitazone produces rare but severe liver toxicity108 109 110 ; the possibility of this adverse reaction requires close monitoring of patients. Nonetheless, despite its potential hepatotoxicity, troglitazone is currently being widely used to treat hyperglycemia. New drugs of the same class, rosiglitazone and pioglitazone, may have less potential hepatotoxicity. A different type of drug available for glucose control is acarbose; this agent partially blocks glucose absorption. In patients who fail to achieve glucose control and near-normal hemoglobin A1c levels by changes in life habits and oral hypoglycemic agents, insulin should be initiated.
Other risk-reduction strategies in patients with diabetes deserve attention equal to that given glucose control. Patients with type 2 diabetes should increase physical activity and eliminate excess body weight; both may be facilitated with the help of professional guidance. Antiplatelet agents have become almost routine in patients with atherosclerotic CVD, and their use can be extended to patients with diabetes who have established atherosclerotic disease. ß-Blockers reduce cardiovascular mortality after myocardial infarction. They may be particularly effective in patients with diabetes, who are at risk for symptomatic ischemic episodes secondary to increased sympathetic activity.111 ß-Blockers are often mentioned as being contraindicated for patients with diabetes because of their blocking of hypoglycemic symptoms in the presence of a hypoglycemic regimen. Clinicians should be aware of this potential danger, although this side effect need not preclude use of ß-blockers when CHD patients have diabetes. Angiotensin-converting enzyme (ACE) inhibitors are widely prescribed in the post–myocardial infarction period to favorably influence myocardial remodeling and fibrosis, and they should be continued indefinitely in all patients with reduced left ventricular ejection fraction or symptoms of heart failure. Unfortunately, limited data are available on use of estrogen replacement therapy in postmenopausal women with diabetes; a recent clinical trial calls into question its putative benefit in postmenopausal, nondiabetic women with established CHD.112
Management of Diabetic Nephropathy
More than one strategy has been shown to slow the progression of
nephropathy in patients with diabetes. A general approach
is outlined in Table 6. Specific
interventions include control of hyperglycemia, treatment of
hypertension (particularly by use of ACE inhibitors),
sodium restriction, and dietary protein restriction. Treatment of
hypertension with ACE inhibitors can retard the progression
of diabetic nephropathy. ACE inhibitors in fact
may have favorable effects on nephropathy even in the
absence of hypertension, although it is uncertain whether normotensive
patients should use them clinically for this purpose.
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Invasive Management of Coronary Artery Disease
Recent studies113 114 115 116 indicate that
coronary angioplasty is less efficacious for patients with
diabetes than for those without; these reports further reveal that
coronary artery bypass surgery is the preferred therapy in
patients with diabetes when invasive management is required. Most of
the benefit from coronary bypass grafting seems to result from
use of the internal mammary artery. Thus, at present, the preferred
invasive approach for coronary
revascularization in patients with diabetes is use
of internal mammary arteries with bypass grafting. Extensive data are
not yet available with use of coronary stents in patients with
diabetes, but regardless, bypass grafting seems to be preferred.
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Primary Prevention |
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Type 2 diabetes can be viewed as the end product of years of metabolic stress accompanying a state of insulin resistance. It seems that in patients with insulin resistance, the "clock starts ticking" for acceleration of atherogenesis long before the onset of hyperglycemia.11 Thus, early detection of the risk factors associated with the metabolic syndrome is needed for institution of appropriate primary prevention measures in patients at risk for diabetes. Clinical evidence of insulin resistance includes abdominal obesity (or borderline abdominal obesity), high-normal blood pressure (or mild hypertension), high-normal triglycerides (150 to 250 mg/dL), reduced HDL cholesterol (<40 mg/dL in men; <50 mg/dL in women), borderline high-risk LDL cholesterol (130 to 159 mg/dL), and in some patients, IFG (110 to 126 mg/dL). The detection of IFG seems particularly significant; it usually signifies long-standing insulin resistance and is a strong risk factor for type 2 diabetes. The AHA has recently published a guide to primary prevention of CVD.117 This guide integrates well with efforts for early detection of the metabolic syndrome, and it recommends interventions to reduce the risk for CVD for patients without established CVD. If these guidelines are followed, they probably would delay the onset of type 2 diabetes as well as reducing risk for CVD. The American Diabetes Association likewise has recently updated its recommendations for management and risk reduction in patients with diabetes.118
Primary Prevention of CVD in Diabetic Patients
The guide outlined for primary prevention of CVD is expanded to
include diabetic patients in Table 7. Goals for smoking cessation,
blood pressure control, physical activity, and weight management are
the same as for nondiabetic patients. However, more aggressive
management of cholesterol and other lipids is indicated for
diabetic patients, as discussed by the recent American Diabetes
Association reports.118 119 120 Treatment of hyperglycemia
should follow the same regimen as discussed under secondary
prevention.
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Implications for Treatment of Patients With Type I Diabetes |
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The predominant risk factor for CHD in patients with type 1 diabetes is duration of disease. Nonetheless, smoking, hypertension, renal disease (macroalbuminuria and renal insufficiency), and dyslipidemia remain important. Effective treatment of hyperglycemia reduces microvascular complications of type 1 diabetes.106 It also may reduce risk for macrovascular disease.106 Modification of other CVD risk factors almost certainly will reduce risk. This would include not only tobacco avoidance but also maintenance of blood pressures <130/85 mm Hg, screening for microalbuminuria, and reducing triglycerides to at least <200 mg/dL and perhaps lower. The optimal LDL-cholesterol level in patients with diabetes is
100 mg/dL; however, use of cholesterol-lowering drugs
to achieve this goal in younger patients with type 1 diabetes may not
be appropriate. Aspirin also can be administered in patients who have
long-standing type 1 diabetes and in whom goals for glycohemoglobin are
not achieved.
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Footnotes |
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This statement was approved by the American Heart Association Science Advisory and Coordinating Committee in April 1999. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0175. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 214-706-1466, fax 214-691-6342, or
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 H. M. Krumholz, J. L. Anderson, B. L. Bachelder, F. M. Fesmire, S. D. Fihn, J. M. Foody, P. M. Ho, M. N. Kosiborod, F. A. Masoudi, and B. K. Nallamothu ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for ST-Elevation and Non-ST-Elevation Myocardial Infarction) Developed in Collaboration With the American Academy of Family Physicians and American College of Emergency Physicians Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, Society for Cardiovascular Angiography and Interventions, and Society of Hospital Medicine J. Am. Coll. Cardiol., December 9, 2008; 52(24): 2046 - 2099. [Full Text] [PDF]
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WRITING COMMITTEE MEMBERS, H. M. Krumholz, J. L. Anderson, B. L. Bachelder, F. M. Fesmire, S. D. Fihn, J. M. Foody, P. M. Ho, M. N. Kosiborod, F. A. Masoudi, et al. ACC/AHA 2008 Performance Measures for Adults With ST-Elevation and Non-ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for ST-Elevation and Non-ST-Elevation Myocardial Infarction): Developed in Collaboration With the American Academy of Family Physicians and the American College of Emergency Physicians: Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation, Society for Cardiovascular Angiography and Interventions, and Society of Hospital Medicine Circulation, December 9, 2008; 118(24): 2596 - 2648. [Full Text] [PDF]
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N. Mzhavia, S. Yu, S. Ikeda, T. T. Chu, I. Goldberg, and H. M. Dansky Neuronatin: A New Inflammation Gene Expressed on the Aortic Endothelium of Diabetic Mice Diabetes, October 1, 2008; 57(10): 2774 - 2783. [Abstract] [Full Text] [PDF]
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R. T. Demmer, D. R. Jacobs Jr., and M. Desvarieux Periodontal Disease and Incident Type 2 Diabetes: Results from the First National Health and Nutrition Examination Survey and its Epidemiologic Follow-Up Study Diabetes Care, July 1, 2008; 31(7): 1373 - 1379. [Abstract] [Full Text] [PDF]
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A. J. Hayes, P. M. Clarke, P. G. Glasziou, R. J. Simes, P. L. Drury, and A. C. Keech Can Self-Rated Health Scores Be Used for Risk Prediction in Patients With Type 2 Diabetes? Diabetes Care, April 1, 2008; 31(4): 795 - 797. [Abstract] [Full Text] [PDF]
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D. A. Ingram, I. Z. Lien, L. E. Mead, M. Estes, D. N. Prater, E. Derr-Yellin, L. A. DiMeglio, and L. S. Haneline In Vitro Hyperglycemia or a Diabetic Intrauterine Environment Reduces Neonatal Endothelial Colony-Forming Cell Numbers and Function Diabetes, March 1, 2008; 57(3): 724 - 731. [Abstract] [Full Text] [PDF]
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 J.-P. Despres, P. Poirier, J. Bergeron, A. Tremblay, I. Lemieux, and N. Almeras From individual risk factors and the metabolic syndrome to global cardiometabolic risk Eur. Heart J. Suppl., March 1, 2008; 10(suppl_B): B24 - B33. [Abstract] [Full Text] [PDF]
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R. S. Blumenthal, C. N. Bairey Merz, V. Bittner, and T. J. Gluckman Task Force 10: Training in Preventive Cardiovascular Medicine J. Am. Coll. Cardiol., January 22, 2008; 51(3): 393 - 398. [Full Text] [PDF]
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E. L. Air and B. M. Kissela Diabetes, the Metabolic Syndrome, and Ischemic Stroke: Epidemiology and possible mechanisms Diabetes Care, December 1, 2007; 30(12): 3131 - 3140. [Full Text] [PDF]
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N. Cheung, J. J. Wang, R. Klein, D. J. Couper, A. R. Sharrett, and T. Y. Wong Diabetic Retinopathy and the Risk of Coronary Heart Disease: The Atherosclerosis Risk in Communities Study Diabetes Care, July 1, 2007; 30(7): 1742 - 1746. [Abstract] [Full Text] [PDF]
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 P. Herrero, Z. Kisrieva-Ware, C. S. Dence, B. Patterson, A. R. Coggan, D.-H. Han, Y. Ishii, P. Eisenbeis, and R. J. Gropler PET Measurements of Myocardial Glucose Metabolism with 1-11C-Glucose and Kinetic Modeling J. Nucl. Med., June 1, 2007; 48(6): 955 - 964. [Abstract] [Full Text] [PDF]
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Y. Li, S. Hazarika, D. Xie, A. M. Pippen, C. D. Kontos, and B. H. Annex In Mice With Type 2 Diabetes, a Vascular Endothelial Growth Factor (VEGF)-Activating Transcription Factor Modulates VEGF Signaling and Induces Therapeutic Angiogenesis After Hindlimb Ischemia Diabetes, March 1, 2007; 56(3): 656 - 665. [Abstract] [Full Text] [PDF]
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T. Mazzone, P. M. Meyer, G. T. Kondos, M. H. Davidson, S. B. Feinstein, R. B. D'Agostino Sr., A. Perez, and S. M. Haffner Relationship of Traditional and Nontraditional Cardiovascular Risk Factors to Coronary Artery Calcium in Type 2 Diabetes Diabetes, March 1, 2007; 56(3): 849 - 855. [Abstract] [Full Text] [PDF]
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M. J. Abrahamson A 74-Year-Old Woman With Diabetes JAMA, January 10, 2007; 297(2): 196 - 204. [Abstract] [Full Text] [PDF]
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V. J. Dzau, E. M. Antman, H. R. Black, D. L. Hayes, J. E. Manson, J. Plutzky, J. J. Popma, and W. Stevenson The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease) Circulation, December 19, 2006; 114(25): 2850 - 2870. [Full Text] [PDF]
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T. D. Miller, R. F. Redberg, and F. J.T. Wackers Screening Asymptomatic Diabetic Patients for Coronary Artery Disease: Why Not? J. Am. Coll. Cardiol., August 15, 2006; 48(4): 761 - 764. [Abstract] [Full Text] [PDF]
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T. Yoshimura, E. Suzuki, K. Egawa, Y. Nishio, H. Maegawa, S. Morikawa, T. Inubushi, A. Hisatomi, K. Fujimoto, and A. Kashiwagi Low Blood Flow Estimates in Lower-Leg Arteries Predict Cardiovascular Events in Japanese Patients With Type 2 Diabetes With Normal Ankle-Brachial Indexes Diabetes Care, August 1, 2006; 29(8): 1884 - 1890. [Abstract] [Full Text] [PDF]
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S. Jesmin, S. Zaedi, N. Yamaguchi, S. Maeda, N. Shimojo, K. Masuzawa, I. Yamaguchi, K. Goto, and T. Miyauchi Differential effects of selective endothelin type a receptor antagonist on the gene expression of vascular endothelial growth factor and its receptors in streptozotocin-induced diabetic heart. Experimental Biology and Medicine, June 1, 2006; 231(6): 902 - 906. [Abstract] [Full Text] [PDF]
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S. Itoh, B. Ding, T. Shishido, N. Lerner-Marmarosh, N. Wang, N. Maekawa, B. C. Berk, Y. Takeishi, C. Yan, B. C. Blaxall, et al. Role of p90 Ribosomal S6 Kinase-Mediated Prorenin-Converting Enzyme in Ischemic and Diabetic Myocardium Circulation, April 11, 2006; 113(14): 1787 - 1798. [Abstract] [Full Text] [PDF]
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H. Koga, S. Sugiyama, K. Kugiyama, H. Fukushima, K. Watanabe, T. Sakamoto, M. Yoshimura, H. Jinnouchi, and H. Ogawa Elevated levels of remnant lipoproteins are associated with plasma platelet microparticles in patients with type-2 diabetes mellitus without obstructive coronary artery disease Eur. Heart J., April 1, 2006; 27(7): 817 - 823. [Abstract] [Full Text] [PDF]
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R. L. Sacco, R. Adams, G. Albers, M. J. Alberts, O. Benavente, K. Furie, L. B. Goldstein, P. Gorelick, J. Halperin, R. Harbaugh, et al. Guidelines for Prevention of Stroke in Patients With Ischemic Stroke or Transient Ischemic Attack: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association Council on Stroke: Co-Sponsored by the Council on Cardiovascular Radiology and Intervention: The American Academy of Neurology affirms the value of this guideline. Circulation, March 14, 2006; 113(10): e409 - e449. [Abstract] [Full Text] [PDF]
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N. Chaowalit, A. L. Arruda, R. B. McCully, K. R. Bailey, and P. A. Pellikka Dobutamine Stress Echocardiography in Patients With Diabetes Mellitus: Enhanced Prognostic Prediction Using a Simple Risk Score J. Am. Coll. Cardiol., March 7, 2006; 47(5): 1029 - 1036. [Abstract] [Full Text] [PDF]
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R. Marfella, M. D'Amico, K. Esposito, A. Baldi, C. Di Filippo, M. Siniscalchi, F. C. Sasso, M. Portoghese, F. Cirillo, F. Cacciapuoti, et al. The Ubiquitin-Proteasome System and Inflammatory Activity in Diabetic Atherosclerotic Plaques: Effects of Rosiglitazone Treatment Diabetes, March 1, 2006; 55(3): 622 - 632. [Abstract] [Full Text] [PDF]
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F. Blaschke, Y. Takata, E. Caglayan, R. E. Law, and W. A. Hsueh Obesity, Peroxisome Proliferator-Activated Receptor, and Atherosclerosis in Type 2 Diabetes Arterioscler Thromb Vasc Biol, January 1, 2006; 26(1): 28 - 40. [Abstract] [Full Text] [PDF]
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X. Jouven, R. N. Lemaitre, T. D. Rea, N. Sotoodehnia, J.-P. Empana, and D. S. Siscovick Diabetes, glucose level, and risk of sudden cardiac death Eur. Heart J., October 2, 2005; 26(20): 2142 - 2147. [Abstract] [Full Text] [PDF]
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A. Elhendy, A. Huurman, A. F.L. Schinkel, J. J. Bax, R. T. van Domburg, R. Valkema, E. Biagini, and D. Poldermans Association of Ischemia on Stress99mTc-Tetrofosmin Myocardial Perfusion Imaging with All-Cause Mortality in Patients with Diabetes Mellitus J. Nucl. Med., October 1, 2005; 46(10): 1589 - 1595. [Abstract] [Full Text] [PDF]
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F. C. Sasso, D. Torella, O. Carbonara, G. M. Ellison, M. Torella, M. Scardone, C. Marra, R. Nasti, R. Marfella, D. Cozzolino, et al. Increased Vascular Endothelial Growth Factor Expression But Impaired Vascular Endothelial Growth Factor Receptor Signaling in the Myocardium of Type 2 Diabetic Patients With Chronic Coronary Heart Disease J. Am. Coll. Cardiol., September 6, 2005; 46(5): 827 - 834. [Abstract] [Full Text] [PDF]
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S. B. King III, G. Dangas, J. W. Moses, S. B. King III, G. Dangas, and J. W. Moses Surgery Is Preferred for the Diabetic With Multivessel Disease Circulation, September 6, 2005; 112(10): 1500 - 1515. [Full Text] [PDF]
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P. Sorajja, P. Chareonthaitawee, N. Rajagopalan, T. D. Miller, R. L. Frye, D. O. Hodge, and R. J. Gibbons Improved Survival in Asymptomatic Diabetic Patients With High-Risk Spect Imaging Treated With Coronary Artery Bypass Grafting Circulation, August 30, 2005; 112(9_suppl): I-311 - I-316. [Abstract] [Full Text] [PDF]
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A. Elhendy, J. M. Tsutsui, E. L. O'Leary, F. Xie, A. C. McGrain, and T. R. Porter Noninvasive Diagnosis of Coronary Artery Disease in Patients With Diabetes by Dobutamine Stress Real-Time Myocardial Contrast Perfusion Imaging Diabetes Care, July 1, 2005; 28(7): 1662 - 1667. [Abstract] [Full Text] [PDF]
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H. Koga, S. Sugiyama, K. Kugiyama, K. Watanabe, H. Fukushima, T. Tanaka, T. Sakamoto, M. Yoshimura, H. Jinnouchi, and H. Ogawa Elevated Levels of VE-Cadherin-Positive Endothelial Microparticles in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease J. Am. Coll. Cardiol., May 17, 2005; 45(10): 1622 - 1630. [Abstract] [Full Text] [PDF]
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C. Zhang, J. D. Knudson, S. Setty, A. Araiza, U. D. Dincer, L. Kuo, and J. D. Tune Coronary arteriolar vasoconstriction to angiotensin II is augmented in prediabetic metabolic syndrome via activation of AT1 receptors Am J Physiol Heart Circ Physiol, May 1, 2005; 288(5): H2154 - H2162. [Abstract] [Full Text] [PDF]
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J. R. Sowers, W. B. White, B. Pitt, A. Whelton, L. S. Simon, N. Winer, A. Kivitz, H. van Ingen, T. Brabant, J. G. Fort, et al. The Effects of Cyclooxygenase-2 Inhibitors and Nonsteroidal Anti-inflammatory Therapy on 24-Hour Blood Pressure in Patients With Hypertension, Osteoarthritis, and Type 2 Diabetes Mellitus Arch Intern Med, January 24, 2005; 165(2): 161 - 168. [Abstract] [Full Text] [PDF]
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W. N. Kernan, C. M. Viscoli, S. E. Inzucchi, L. M. Brass, D. M. Bravata, G. I. Shulman, and J. C. McVeety Prevalence of Abnormal Glucose Tolerance Following a Transient Ischemic Attack or Ischemic Stroke Arch Intern Med, January 24, 2005; 165(2): 227 - 233. [Abstract] [Full Text] [PDF]
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A. Tajaddini, D. L. Kilpatrick, P. Schoenhagen, E. M. Tuzcu, M. Lieber, and D. G. Vince Impact of age and hyperglycemia on the mechanical behavior of intact human coronary arteries: an ex vivo intravascular ultrasound study Am J Physiol Heart Circ Physiol, January 1, 2005; 288(1): H250 - H255. [Abstract] [Full Text] [PDF]
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M. Tsuchiya, E. Suzuki, K. Egawa, Y. Nishio, H. Maegawa, S. Inoue, K. Mitsunami, S. Morikawa, T. Inubushi, and A. Kashiwagi Stiffness and Impaired Blood Flow in Lower-Leg Arteries Are Associated With Severity of Coronary Artery Calcification Among Asymptomatic Type 2 Diabetic Patients Diabetes Care, October 1, 2004; 27(10): 2409 - 2415. [Abstract] [Full Text] [PDF]
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J. R. Sowers Treatment of Hypertension in Patients With Diabetes Arch Intern Med, September 27, 2004; 164(17): 1850 - 1857. [Abstract] [Full Text] [PDF]
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G. Vrentzos, J. A. Papadakis, N. Malliaraki, E. A. Zacharis, K. Katsogridakis, A. N. Margioris, P. E. Vardas, and E. S. Ganotakis Association of Serum Total Homocysteine with the Extent of Ischemic Heart Disease in a Mediterranean Cohort Angiology, September 1, 2004; 55(5): 517 - 524. [Abstract] [PDF]
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N. F. Sheard, N. G. Clark, J. C. Brand-Miller, M. J. Franz, F. X. Pi-Sunyer, E. Mayer-Davis, K. Kulkarni, and P. Geil Dietary Carbohydrate (Amount and Type) in the Prevention and Management of Diabetes: A statement by the American Diabetes Association Diabetes Care, September 1, 2004; 27(9): 2266 - 2271. [Full Text] [PDF]
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Task Force Members, J. Lopez-Sendo, K. Swedberg, J. McMurray, J. Tamargo, A. P. Maggioni, H. Dargie, M. Tendera, F. Waagstein, J. Kjekshus, et al. Expert consensus document on {beta}-adrenergic receptor blockers: The Task Force on Beta-Blockers of the European Society of Cardiology Eur. Heart J., August 1, 2004; 25(15): 1341 - 1362. [Full Text] [PDF]
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J. F. LaDisa Jr., J. G. Krolikowski, P. S. Pagel, D. C. Warltier, and J. R. Kersten Cardioprotection by glucose-insulin-potassium: dependence on KATP channel opening and blood glucose concentration before ischemia Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H601 - H607. [Abstract] [Full Text] [PDF]
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O. Vaccaro, L. E. Eberly, J. D. Neaton, L. Yang, G. Riccardi, J. Stamler, and for the Multiple Risk Factor Intervention Trial R Impact of Diabetes and Previous Myocardial Infarction on Long-term Survival: 25-Year Mortality Follow-up of Primary Screenees of the Multiple Risk Factor Intervention Trial Arch Intern Med, July 12, 2004; 164(13): 1438 - 1443. [Abstract] [Full Text] [PDF]
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V. Franco, S. Oparil, and O. A. Carretero Hypertensive Therapy: Part II Circulation, June 29, 2004; 109(25): 3081 - 3088. [Full Text] [PDF]
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D. Weihrauch, N. L. Lohr, B. Mraovic, L. M. Ludwig, W. M. Chilian, P. S. Pagel, D. C. Warltier, and J. R. Kersten Chronic Hyperglycemia Attenuates Coronary Collateral Development and Impairs Proliferative Properties of Myocardial Interstitial Fluid by Production of Angiostatin Circulation, May 18, 2004; 109(19): 2343 - 2348. [Abstract] [Full Text] [PDF]
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A. Tenenbaum, M. Motro, E. Z. Fisman, E. Schwammenthal, Y. Adler, I. Goldenberg, J. Leor, V. Boyko, L. Mandelzweig, and S. Behar Peroxisome Proliferator-Activated Receptor Ligand Bezafibrate for Prevention of Type 2 Diabetes Mellitus in Patients With Coronary Artery Disease Circulation, May 11, 2004; 109(18): 2197 - 2202. [Abstract] [Full Text] [PDF]
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P. Raggi, L. J. Shaw, D. S. Berman, and T. Q. Callister Prognostic value of coronary artery calcium screening in subjects with and without diabetes J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1663 - 1669. [Abstract] [Full Text] [PDF]
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 J. A. Morgan, R. John, A. D. Weinberg, N. J. Colletti, D. M. Mancini, and N. M. Edwards Heart transplantation in diabetic recipients: A decade review of 161 patients at Columbia Presbyterian J. Thorac. Cardiovasc. Surg., May 1, 2004; 127(5): 1486 - 1492. [Abstract] [Full Text] [PDF]
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S. R. Wilson, B. A. Vakili, W. Sherman, T. A. Sanborn, and D. L. Brown Effect of Diabetes on Long-Term Mortality Following Contemporary Percutaneous Coronary Intervention: Analysis of 4,284 cases Diabetes Care, May 1, 2004; 27(5): 1137 - 1142. [Abstract] [Full Text] [PDF]
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J. A. Cramer A Systematic Review of Adherence With Medications for Diabetes Diabetes Care, May 1, 2004; 27(5): 1218 - 1224. [Abstract] [Full Text] [PDF]
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A. J. Davidoff, M. M. Mason, M. B. Davidson, M. W. Carmody, K. K. Hintz, L. E. Wold, D. A. Podolin, and J. Ren Sucrose-induced cardiomyocyte dysfunction is both preventable and reversible with clinically relevant treatments Am J Physiol Endocrinol Metab, May 1, 2004; 286(5): E718 - E724. [Abstract] [Full Text] [PDF]
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N. L. Smith, L. Chen, D. H. Au, M. McDonell, and S. D. Fihn Cardiovascular Risk Factor Control Among Veterans With Diabetes: The Ambulatory Care Quality Improvement Project Diabetes Care, May 1, 2004; 27(suppl_2): B33 - B38. [Abstract] [Full Text] [PDF]
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M. J Zellweger, R. Hachamovitch, X. Kang, S. W Hayes, J. D Friedman, G. Germano, M. E Pfisterer, and D. S Berman Prognostic relevance of symptoms versus objective evidence of coronary artery disease in diabetic patients Eur. Heart J., April 1, 2004; 25(7): 543 - 550. [Abstract] [Full Text] [PDF]
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 D. Fetterolf and R. West The Business Case for Quality: Combining Medical Literature Research with Health Plan Data to Establish Value for Nonclinical Managers American Journal of Medical Quality, March 1, 2004; 19(2): 48 - 55. [Abstract] [PDF]
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C. A. Witczak and M. Sturek Exercise prevents diabetes-induced impairment in superficial buffer barrier in porcine coronary smooth muscle J Appl Physiol, March 1, 2004; 96(3): 1069 - 1079. [Abstract] [Full Text] [PDF]
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 H Laine, J Sundell, P Nuutila, O T Raitakari, M Luotolahti, T Ronnemaa, T Elomaa, P Koskinen, and J Knuuti Insulin induced increase in coronary flow reserve is abolished by dexamethasone in young men with uncomplicated type 1 diabetes Heart, March 1, 2004; 90(3): 270 - 276. [Abstract] [Full Text] [PDF]
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Y. Shimoni, M. Chuang, E. D. Abel, and David. L. Severson Gender-dependent attenuation of cardiac potassium currents in type 2 diabetic db/db mice J. Physiol., March 1, 2004; 555(2): 345 - 354. [Abstract] [Full Text] [PDF]
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C. D. Lee, A. R. Folsom, J. S. Pankow, F. L. Brancati, and For the Atherosclerosis Risk in Communities (ARIC) Cardiovascular Events in Diabetic and Nondiabetic Adults With or Without History of Myocardial Infarction Circulation, February 24, 2004; 109(7): 855 - 860. [Abstract] [Full Text] [PDF]
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A. V. Chobanian, G. L. Bakris, H. R. Black, W. C. Cushman, L. A. Green, J. L. Izzo Jr, D. W. Jones, B. J. Materson, S. Oparil, J. T. Wright Jr, et al. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure Hypertension, December 1, 2003; 42(6): 1206 - 1252. [Abstract] [Full Text] [PDF]
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M.-S. Wong, K. Gu, D. Heng, S.-K. Chew, L.-S. Chew, and E. S. Tai The Singapore Impaired Glucose Tolerance Follow-Up Study: Does the ticking clock go backward as well as forward? Diabetes Care, November 1, 2003; 26(11): 3024 - 3030. [Abstract] [Full Text] [PDF]
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