Diabetes and Atherosclerosis

REVIEW
CLINICIANS CORNER
Diabetes and Atherosclerosis

Epidemiology, Pathophysiology, and Management
Joshua A. Beckman, MD, MS
Mark A. Creager, MD
Peter Libby, MD
IABETES MELLITUS MAGNIFIES
the risk of cardiovascular

morbidity and mortality.1 Besides the well-recognized microvascular complications of diabetes,
such as nephropathy and retinopathy,
there is a growing epidemic of macrovascular complications, including diseases of coronary arteries, peripheral arteries, and carotid vessels, particularly
in the burgeoning type 2 diabetic population. Despite this challenge, many primary care physicians have not yet
adopted evidence-based management
strategies. The traditional therapeutic approaches emphasize glycemic control,
which limits microvascular disease but
lacks an established benefit in macrovascular disease. Understanding atherosclerosis in diabetes and instituting
therapy guided by emerging evidence
should improve outcomes in patients.
The evidence supports aggressive antiatherosclerotic management strategies
upon diagnosis of type 2 diabetes to
minimize the risk of cardiovascular morbidity and mortality.
This review of diabetes and atherosclerosis considers 3 main topics: epidemiology of atherosclerosis in diabetes, the pathophysiology of the diabetic
blood vessel, and medical and invasive treatment for atherosclerotic complications of diabetes. We focus on type
2 diabetes, characterized by insulin resistance and inadequate beta cell insulin secretion, because these patients represent more than 90% of those with
diabetes and atherosclerosis.
Context Complications of atherosclerosis cause most morbidity and mortality in patients with diabetes mellitus. Despite the frequency and severity of disease, proven
medical therapy remains incompletely understood and underused.
Objective To review the epidemiology, pathophysiology, and medical and invasive
treatment of atherosclerosis in patients with diabetes mellitus.
Data Sources Using the index terms diabetes mellitus, myocardial infarction, peripheral vascular diseases, cerebrovascular accident, endothelium, vascular smooth
muscle, platelets, thrombosis, cholesterol, hypertension, hyperglycemia, insulin, angioplasty, and coronary artery bypass, we searched the MEDLINE and EMBASE databases from 1976 to 2001. Additional data sources included bibliographies of
identified articles and preliminary data presented at recent cardiology conferences.
Study Selection We selected original investigations and reviews of the epidemiology, pathophysiology, and therapy of atherosclerosis in diabetes. We selected randomized, double-blind, controlled studies, when available, to support therapeutic recommendations. Criteria for data inclusion (168 of 396) included publication in a peerreviewed journal or presentation at a national cardiovascular societysponsored meeting.
Data Extraction Data quality was determined by publication in peer-reviewed literature. Data extraction was performed by one of the authors.
Data Synthesis Diabetes mellitus markedly increases the risk of myocardial infarction,
stroke, amputation, and death. The metabolic abnormalities caused by diabetes induce
vascular dysfunction that predisposes this patient population to atherosclerosis. Blood pressure control, lipid-lowering therapy, angiotensin-converting enzyme inhibition, and antiplatelet drugs significantly reduce the risk of cardiovascular events. Although diabetic
patients undergo revascularization procedures because of acute coronary syndromes or
critical limb ischemia, the outcomes are less favorable than in nondiabetic cohorts.
Conclusions Since most patients with diabetes die from complications of atherosclerosis, they should receive intensive preventive interventions proven to reduce their
cardiovascular risk.
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JAMA. 2002;287:2570-2581
EPIDEMIOLOGY
Clinical manifestations of atherosclerosis occur primarily in 3 vascular beds:
coronary arteries, lower extremities, and

extracranial carotid arteries. Diabetes increases the incidence and accelerates the
Author Affiliations: Leducq Center for Cardiovascular Research, Cardiovascular Division, Department of
Medicine, Brigham and Womens Hospital; and Harvard Medical School, Boston, Mass.
Financial Disclosures: Dr Creager has been a consultant for Bristol-Myers Squibb/Sanofi-Synthelabo Partnership, Pfizer, Otsuka America Pharmaceuticals, ENOS
Pharmaceuticals, and Eli Lilly; has been on the speakers bureau of Bristol-Myers Squibb/SanofiSynthelabo Partnership, Pfizer, and Otsuka America
Pharmaceuticals; and has received research support from
Bristol-Myers Squibb/Sanofi-Synthelabo Partnership,
Pfizer, Otsuka America Pharmaceuticals, and Eli Lilly.
Dr Libby has been a consultant for AstraZeneca, Avant

Immunotherapeutics, Bayer, Bristol-Myers Squibb, CorKey, Fournier, Interleukin Genetics, Merck, Millennium Pharmaceuticals, Novartis, Pfizer, Pierre Fabre, Sankyo, Sanofi, Schering Plough, and GlaxoSmithKline; has
been on the speakers bureau for Bayer, Bristol-Myers
Squibb, Merck, Novartis, and Pfizer; and has received
research support from Bayer, Bristol-Myers Squibb,
Fournier, Merck, Millennium Pharmaceuticals, Novartis, Pfizer, Sankyo, and GlaxoSmithKline.
Corresponding Author and Reprints: Peter Libby, MD,
228 Longwood Ave, Suite 307, Boston, MA 02115
(e-mail: plibby@rics.bwh.harvard.edu).
2570 JAMA, May 15, 2002Vol 287, No. 19 (Reprinted)
2002 American Medical Association. All rights reserved.
Downloaded from www.jama.com on April 6, 2008
DIABETES AND ATHEROSCLEROSIS
clinical course of each. Fortunately, we

now have therapies that, when implemented, can lessen their impact.
Coronary Artery Disease
Coronary artery disease (CAD) causes

much of the serious morbidity and mortality in patients with diabetes, who have
a 2- to 4-fold increase in the risk of
CAD.2 In one population-based study,3
the 7-year incidence of first myocardial
infarction (MI) or death for patients with
diabetes was 20% but was only 3.5% for
nondiabetic patients. History of MI increased the rate of recurrent MI or cardiovascular death events for both groups
(18.8% in nondiabetic persons and 45%
in those with diabetes). Thus, patients
with diabetes but without previous MI
carry the same level of risk for subsequent acute coronary events as nondiabetic patients with previous MI. Such results led the Adult Treatment Panel III
of the National Cholesterol Education
Program to establish diabetes as a CAD
risk equivalent mandating aggressive antiatherosclerotic therapy.4
Diabetes also worsens early and late
outcomes in acute coronary syndromes. In unstable angina pectoris or
nonQ-wave MI compared with control, the presence of diabetes increases
the risk of in-hospital MI, complications of MI, and mortality.5 In the OASIS registry, a 6-nation study of unstable angina and nonQ-wave MI,
diabetes independently increased the
risk of death by 57%. 6 The ageadjusted relative risk (RR) of mortality for patients with diabetes in the
GISSI-2 trial of fibrinolytic therapy in
MI was 1.4 for men and 1.9 for women,
regardless of intervention assignment.7 In the SHOCK trial of revascularization for MI complicated by cardiogenic shock, the RR of death for
patients with diabetes was 1.36 compared with that of nondiabetic patients.8 Regardless of the severity of
clinical presentation, patients who have
diabetes and coronary events experience increased rates of MI and death.
Patients with diabetes also have an
adverse long-term prognosis after MI,
including increased rates of reinfarc-
tion, congestive heart failure, and

death.6 A Finnish study9 on the trends
of MI showed that diabetes increased
28-day mortality by 58% in men (hazard ratio [HR], 1.58; 95% confidence
interval [CI], 1.15-2.18) and 160% for
women (HR, 2.60; 95% CI, 1.71-3.95).
In fact, the 5-year mortality rate following MI may be as high as 50% for
diabetic patientsmore than double
that of nondiabetic patients.10
Peripheral Arterial Disease
Epidemiological evidence confirms an

association between diabetes and increased prevalence of peripheral arterial disease (PAD). Individuals with diabetes have a 2- to 4-fold increase in the
rates of PAD,11 more often have femoral bruits and absent pedal pulses,12
and have rates of abnormal anklebrachial indices ranging from 11.9% to
16%.13,14 The duration and severity of
diabetes correlate with incidence and
extent of PAD.15
Diabetes changes the nature of PAD.
Diabetic patients more commonly have
infrapopliteal arterial occlusive disease and vascular calcification than nondiabetic cohorts.15 The Hoorn study16
examined the rates of PAD among
groups ranging from patients with normal glucose tolerance to those with diabetes requiring multiple medications.
The 7% prevalence of abnormal anklebrachial indices in individuals with normal glucose tolerance increased to
20.9% in those requiring multiple hypoglycemic medications.
Patients with diabetes more commonly develop the symptomatic forms
of PAD, intermittent claudication and
amputation.17 In the Framingham cohort,18 the presence of diabetes increased the risk of claudication by 3.5fold in men and 8.6-fold in women.
Worse, diabetes causes most nontraumatic lower extremity amputations in
the United States.19 The RR for lower
extremity amputation in patients with
diabetes was 12.7 (95% CI, 10.9-14.9)
compared with that of nondiabetic patients in the Medicare population and
as high as 23.5 (95% CI, 19.3-29.1) for
diabetic persons aged 65 to 74 years.19
Cerebrovascular Disease
Diabetes adversely affects cerebrovascular arterial circulation, akin to its effects in the coronary and lower extremity vasculature. Patients with diabetes
have more extracranial atherosclerosis.20 In patients undergoing dental panoramic radiographs, diabetic patients
had 5-fold excess prevalence of calcified carotid atheroma.21
The frequency of diabetes among patients presenting with stroke is 3 times
more than that of matched controls.22
The risk of stroke is increased 150% to
400% for patients with diabetes,23-25 and
worsening glycemic control relates directly to stroke risk. In the Multiple Risk
Factor Intervention Trial (MRFIT)26 of
347978 men, subjects taking medications for diabetes were 3 times as likely
to develop a stroke (P.01).
Diabetes particularly affects the risk
of stroke among younger patients.27 In
the stroke population younger than 55
years, diabetes increases the risk of
stroke more than 10-fold (odds ratio,
11.6; 95% CI, 1.2-115.2).28 The Baltimore-Washington Cooperative Young
Stroke Study29 examined 296 cases of
incident ischemic stroke among black
and white subjects aged 18 to 44 years.
The presence of diabetes markedly increased the odds ratio for stroke, ranging from 3.3 for black women to as high
as 23.1 for white men.
Diabetes affects stroke outcome as
well. It increases the risk of strokerelated dementia more than 3-fold,30
doubles the risk of recurrence,31 and increases total and stroke-related mortality.32
Female Sex and Atherosclerosis
Although women experience relative

protection from cardiovascular disease compared with men in the general population, diabetes blunts the benefit of female sex. Diabetes increases the
incidence of MI, claudication, and
stroke in women more than in men,
equalizing the age-adjusted rates.18,25,33,34
Indeed, outcomes in women with diabetes have lagged compared with that
of their nondiabetic cohorts. In the First
National Health and Nutrition Exami-
(Reprinted) JAMA, May 15, 2002Vol 287, No. 19
2571
nation Survey (NHANES) and the

NHANES Epidemiologic Follow-up
Survey conducted 10 years later, ageadjusted heart disease mortality decreased in nondiabetic men and
women, less so in diabetic men, but increased by 23% in diabetic women.35
The systemic nature of atherosclerosis and its complications implies a commonality of effects on blood vessels. Indeed, diabetes alters functions of arteries
that predispose these patients to the development and progression of atherosclerosis.
PATHOPHYSIOLOGY OF
DIABETIC VASCULAR DISEASE
The abnormal metabolic state that
accompanies diabetes causes arterial dysfunction. Relevant abnormalities include chronic hyperglycemia, dyslipidemia, and insulin resistance. These
factors render arteries susceptible to atherosclerosis. Diabetes alters function of

multiple cell types, including endothelium, smooth muscle cells, and platelets, indicating the extent of vascular disarray in this disease.
Endothelial Cell Dysfunction
A single layer of endothelial cells lines

the inner surface of all blood vessels, providing a metabolically active interface
between blood and tissue that modulates blood flow, nutrient delivery, coagulation and thrombosis, and leukocyte
diapedesis.36 It synthesizes important
bioactive substances, including nitric
oxide and other reactive oxygen species, prostaglandins, endothelin, and
angiotensin II, that regulate blood vessel function and structure. Nitric oxide
potently dilates vessels and mediates
much of the endotheliums control of
Figure 1. Endothelial Dysfunction in Diabetes
Diabetes Mellitus
Hyperglycemia
Excess Free Fatty Acids
Insulin Resistance
Oxidative Stress
Protein Kinase C Activation
Receptor for Advanced Glycation
End Product (RAGE) Activation
ENDOTHELIUM
Nitric Oxide
Endothelin-1
Angiotensin II
Nitric Oxide
Activation of NF-B
Nitric Oxide
Tissue Factor
Angiotensin II
Plasminogen Activator
Inhibitor-1
Prostacyclin
Activation of
Activator Protein-1
Vasoconstriction
Inflammation
Thrombosis
Hypertension
Release of Chemokines
Hypercoagulation
Vascular Smooth
Muscle Cell Growth
Release of Cytokines
Platelet Activation
Expression of Cellular
Adhesion Molecules
Decreased Fibrinolysis
Atherogenesis
In diabetes, hyperglycemia, excess free fatty acid release, and insulin resistance engender adverse metabolic
events within the endothelial cell. Activation of these systems impairs endothelial function, augments vasoconstriction, increases inflammation, and promotes thrombosis. Decreasing nitric oxide and increasing endothelin-1 and angiotensin II concentrations increase vascular tone and vascular smooth muscle cell growth and
migration. Activation of the transcription factors nuclear factor B (NF-B) and activator protein 1 induces
inflammatory gene expression, with liberation of leukocyte-attracting chemokines, increased production of
inflammatory cytokines, and augmented expression of cellular adhesion molecules. Increased production of
tissue factor and plasmin activator inhibitor 1 creates a prothrombotic milieu, while decreased endotheliumderived nitric oxide and prostacyclin favors platelet activation.
vascular relaxation.37 Further, it inhibits platelet activation, limits inflammation by reducing leukocyte adhesion to
endothelium and migration into the vessel wall, and diminishes vascular smooth
muscle cell proliferation and migration.37-39 Taken together, these properties inhibit atherogenesis and protect the
blood vessel.
Diabetes impairs endotheliumdependent (nitric oxidemediated) vasodilation before the formation of atheroma (FIGURE 1).40,41 A number of
fundamental mechanisms contribute to
the decreased bioavailability of endothelium-derived nitric oxide in diabetes. Hyperglycemia inhibits production of nitric oxide by blocking eNOS
synthase activation and increasing the
production of reactive oxygen species, especially superoxide anion (O2),
in endothelial and vascular smooth
muscle cells.42 Superoxide anion directly quenches nitric oxide by forming the toxic peroxynitrite ion,43 which
uncouples eNOS by oxidizing its cofactor, tetrahydrobiopterin, and causes
eNOS to produce O2.43
Other common abnormalities in type
2 diabetes also decrease endotheliumderived nitric oxide. Insulin resistance
leads to excess liberation of free fatty acids from adipose tissue,44 which activate the signaling enzyme protein kinase C, inhibit phosphatidylinositol-3
(PI-3) kinase (an eNOS agonist pathway), and increase the production of reactive oxygen speciesmechanisms that
directly impair nitric oxide production
or decrease its bioavailability once produced.45 Production of peroxynitrite decreases synthesis of the vasodilatory and
antiplatelet prostanoid prostacyclin.46
Thus, as nitric oxide bioavailability progressively decreases, concomitant increases in peroxynitrite further impair
production of subsidiary vasodilators.
In addition to reducing ambient concentrations of nitric oxide, diabetes increases the production of vasoconstrictors, most important, endothelin-1,
which activates endothelin-A receptors on vascular smooth muscle cell to
induce vasoconstriction (Figure 1). In
addition to its modulation of vascular
tone, endothelin-1 increases renal salt

and water retention, stimulates the renin-angiotensin system, and induces vascular smooth muscle hypertrophy.47 Endothelin-1 activity may rise in response
to insulin-mediated increases in gene expression and receptor formation, stimulation of the receptor for advanced glycation end products, and increased gene
transcription induced by oxidized lowdensity lipoprotein (LDL) cholesterol.48-50 Diabetes increases other endothelium-derived vasoactive substances
such as vasoconstrictor prostanoids and
angiotensin II, and investigation into
their pathophysiological relevance in
diabetes continues.51,52
Migration of T-cell lymphocytes and
monocytes into the intima participates
integrally in atherogenesis. T cells secrete
cytokines that modulate lesion formation.53 Monocytes, upon reaching the
subendothelial space, ingest oxidized
LDL via scavenger receptors and become
foam cells. Localized accumulation of
foam cells leads to formation of fatty
streaks, the hallmark of early atherosclerotic lesions.54 Diabetes augments
these pathologic processes. Hyperglycemia via decreased nitric oxide,
increased oxidative stress, and receptor
for advanced glycation end products activation increases the activation of the transcription factors nuclear factor B and
activator protein 1 (Figure 1). These factors regulate the expression of the genes
encoding a number of mediators of atherogenesis; for example, leukocyte-cell
adhesion molecules on the endothelial
surface, leukocyte-attracting chemokines, such as monocyte chemoattractant proteins that recruit lymphocytes and monocytes into the vascular
wall, and proinflammatory mediators
found in atheroma, including interleukin 1 and tumor necrosis factor.55-57 Lipid
abnormalities commonly found in diabetes, such as increased very lowdensity lipoprotein (VLDL) and excess
free fatty acid liberation, also increase
endothelial nuclear factor B and subsequent cell adhesion molecule and cytokine expression.58
In addition to enhancing the initiation of atherogenesis, diabetes pro-
motes plaque instability and clinical sequelae. Diabetic endothelial cells

elaborate cytokines that decrease the de
novo synthesis of collagen by vascular
smooth muscle cells.59 Diabetes also enhances the production of matrix metalloproteinases that lead to breakdown of
collagen.60 Collagen confers mechanical stability to the plaques fibrous cap.
When collagen breakdown increases and
synthesis decreases, plaques may rupture more readily, a trigger to thrombus formation. Finally, an important
modulator of the severity of plaque rupture is the extent of vascular occlusion
by thrombus formation. In diabetes, endothelial cells increase production of tissue factor, the major procoagulant found
in atherosclerotic plaques along with
alterations in soluble coagulation and
fibrinolytic factors (Figure 1).61
Vascular Smooth Muscle
Dysfunction in Diabetes
Arteries affected by diabetes and atherosclerosis have altered vasomotor

function. In particular, patients with
type 2 diabetes have impaired nitric oxidemediated vasodilation, reflecting an
abnormality of vascular smooth muscle
cell function or signal transduction.40
These patients also have decreased vasoconstriction to infusion of endothelin-1 and angiotensin compared with
that of controls.51,62,63 Most patients with
diabetes have peripheral autonomic impairment on diagnosis,64 a condition
that decreases arterial resistance.65 Despite evidence of increased endothelin-1, angiotensin II, and abnormal sympathetic nervous system activity, the
mechanism of vascular smooth muscle
cell dysfunction and hypertension in
diabetes remains unknown.
Diabetes stimulates atherogenic activity of vascular smooth muscle cells.
Hyperglycemia activates protein kinase C, receptor for advanced glycation end products, and nuclear factor B
in vascular smooth muscle cells, as it
does in endothelial cells. Activation of
these systems augments production of
O2, contributing to the oxidant-rich milieu.45 Vascular smooth muscle cells are
integral in the development of athero-
sclerosis. Once the macrophage-rich

fatty streak forms, vascular smooth
muscle cells in the medial layer of the
arteries migrate into the nascent intimal lesion, replicate, and lay down a
complex extracellular matrix, important steps in the progression to advanced atherosclerotic plaque. Arterial
vascular smooth muscle cells cultured
from patients with type 2 diabetes demonstrate enhanced migration.66 As the
source of collagen, vascular smooth
muscle cells strengthen the atheroma,
making it less likely to rupture and cause
thrombosis. Indeed, lesions that have
disrupted and caused fatal thrombosis
tend to have few vascular smooth muscle
cells.54 Advanced atherosclerotic lesions in diabetic patients have fewer vascular smooth muscle cells compared
with those of controls.67 Hyperglycemic lipid modifications of LDL may in
part regulate the increased migration and
then apoptosis of vascular smooth
muscle cells in atherosclerotic lesions.
Low-density lipoprotein that has undergone nonenzymatic glycation induces
vascular smooth muscle cell migration
in vitro, while oxidized glycated LDL can
induce apoptosis of vascular smooth
muscle cells.68 Thus, diabetes alters vascular smooth muscle function in ways
that promote atherosclerotic lesion formation, plaque instability, and clinical
events.
Impaired Platelet Functions
Platelets can modulate vascular function and participate significantly in

thrombus formation. Abnormalities in
platelet function may exacerbate the
progression of atherosclerosis and the
consequences of plaque rupture. Intraplatelet glucose concentration mirrors the extracellular concentration,
since glucose entry into the platelet does
not depend on insulin.69 In the platelet, as in endothelial cells, elevated glucose levels lead to activation of protein kinase C, decreased production of
platelet-derived nitric oxide, and increased formation of O2.70 In diabetes, platelets also show disordered calcium homeostasis.71 Disordered calcium
regulation may contribute signifi-
2573
cantly to abnormal activity, since intraplatelet calcium regulates platelet

shape change, secretion, and aggregation and thromboxane formation.
Moreover, patients with diabetes have
increased platelet-surface expression of
glycoprotein Ib (GpIb), which mediates binding to von Willebrand factor,
and GpIIb/IIIa, which mediates plateletfibrin interaction.69 These abnormalities may result from decreased endothelial production of the antiaggregants
nitric oxide and prostacyclin, increased production of fibrinogen, and
increased production of platelet activators, such as thrombin and von Willebrand factor.69 Taken together, diabetic abnormalities increase intrinsic
platelet activation and decrease endogenous inhibitors of platelet activity.
These mechanisms may explain the enhanced thrombotic potential characteristic of diabetes.
Abnormal Coagulation in Diabetes
In addition to potentiating platelet function, diabetes augments blood coagulability, making it more likely that atherosclerotic plaque rupture or erosion
will result in thrombotic occlusion of
the artery. Patients with type 2 diabetes have impaired fibrinolytic capacity
because of elevated levels of plasminogen activator inhibitor type 1 in atherosclerotic lesions and in nonatheromatous arteries.72 Diabetes increases the
expression of tissue factor, a potent procoagulant, and plasma coagulation factors such as factor VII and decreases levels of endogenous anticoagulants such
Figure 2. Antiatherosclerosis Therapy in Diabetes
Hypertension
Dyslipidemia
ACE Inhibitors
Angiotensin Receptor Blockers
Statins
Fibric Acid Derivatives
Thiazolidinediones?
-Blockers
ATHEROSCLEROSIS
Diuretics
Hyperglycemia
Insulin Resistance
Calcium Channel Blockers
Platelet Activation
and Aggregation
Insulin
Metformin
Aspirin
Thiazolidinediones
Clopidogrel
Sulfonylureas
Ticlopidine
Nonsulfonylurea
Secretagogues
Diabetic patients require therapy of each metabolic abnormality to attenuate atherogenesis. Excess liberation
of free fatty acids results in the typical diabetic dyslipidemic phenotype consisting of increased triglycerides,
decreased high-density lipoprotein, and increased oxidized, low-density lipoprotein. Statins and fibric acid derivatives improve the lipid profile and decrease its atherogenic tendency. Treatment of hypertension significantly decreases the rate of myocardial infarction and stroke in diabetes. Initial therapy should include agents
that modify the renin-angiotensin system because of their proven additional microvascular and atherosclerosis
benefits. -Blocker therapy in diabetic patients with cardiovascular disease decreases morbidity and mortality.
The heightened thrombotic potential of the diabetic state supports consideration of antiplatelet therapy to
decrease the incidence of myocardial infarction and death in persons with diabetes. Although strict treatment
of hyperglycemia does not significantly reduce the incidence of myocardial infarction or death, the preponderance of epidemiologic and pathophysiologic evidence suggests that hyperglycemia increases cardiovascular event rates and worsens outcome. The improvement in microvascular outcomes itself warrants vigorous
pursuit of rigorous glycemic control in diabetes. ACE indicates angiotensin-converting enzyme.
as antithrombin III and protein C.73-75

Many of these abnormalities correlate
with the presence of hyperglycemia and
proinsulin split products.76 Thus, in diabetes an increased tendency toward
coagulation, coupled with impaired
fibrinolysis, favors formation and persistence of thrombi.
MEDICAL TREATMENT
Throughout the last decade, the perception of type 2 diabetes has evolved
from a focus on dysregulated glucose
and insulin to encompass a global metabolic disorder characterized by dyslipidemia, hypertension, and hypercoagulability in addition to hyperglycemia
and hyperinsulinemia (FIGURE 2). Each
of these abnormalities plays an important role in cardiovascular disease development and progression and provides targets for therapy.
Hyperglycemia and Insulin
Resistance as Targets
for Treatment
Hyperglycemia, a cardinal manifestation of diabetes, adversely affects vascular function, lipids, and coagulation.
Intensive treatment of hyperglycemia
reduces the risk of microvascular complications such as nephropathy and
retinopathy, as shown by the United
Kingdom Prospective Diabetes Study
(UKPDS),77 but does not confer the same
benefit in the conduit, muscular arteries. In the UKPDS, treatment with either
oral hypoglycemic agents or insulin did
not significantly reduce macrovascular
end points.77 Although these data support a distinct pathogenesis of microvascular and macrovascular sequelae in
diabetes, they do not exclude glycemic
control as an important part of the treatment of the dysmetabolic syndrome. Epidemiological studies support the concept that increasing levels of glycemia
commensurately increase cardiovascular events. In the UKPDS, this increase
in risk began above a hemoglobin A1c
(HbA 1c ) level of 6.2%. 78 In a metaanalysis of more than 95000 diabetic
patients, increases in cardiovascular risk
depended directly on plasma glucose
concentrations and began with concen-
trations below the diabetic threshold.79

Continued improvements in therapy will
permit even more effective glycemic control and enable retesting of the hypothesis that intense control of glycemia
reduces atherosclerotic macrovascular
complications.
Insulin resistance, another cardinal
feature of type 2 diabetes, may promote atherosclerosis. The degree of insulin resistance relates directly to increasing rates of MI,80 stroke,24,81 and
PAD.82 In the UKPDS, improving insulin resistance with metformin decreased macrovascular events. This result has engendered some controversy
because the addition of metformin to
sulfonylurea therapy seemed to increase cardiovascular risk.77,83 Ongoing clinical trials should determine
whether improvements in insulin resistance will decrease cardiovascular
events.
The recent availability of the thiazolidinediones (TZDs) provides a novel
approach to glycemic control. Thiazolidinediones improve glycemia by decreasing insulin resistance.84 The TZDs
bind and activate peroxisome proliferator-activated receptor , a nuclear receptor that participates in adipose and
vascular cell differentiation.85 The first
agent in this class, troglitazone, was removed from the market because of
idiosyncratic hepatotoxicity. Two other
TZDs, rosiglitazone and pioglitazone,
now available in the United States, appear not to share this liability. Because
peroxisome proliferator-activated
receptor activity may have antiinflammatory activity, TZDs may directly benefit the atherosclerotic lesion.86 Studies in progress will evaluate
this possibility.
Dyslipidemia
Characteristic abnormalities in the lipid

profile in type 2 diabetes include elevated triglyceride levels, decreased
atheroprotective high-density lipoprotein (HDL) levels, and increased levels of small dense LDL. Increased
efflux of free fatty acids from adipose
tissue and impaired insulin-mediated
skeletal muscle uptake of free fatty
acids increase hepatic free fatty acid

concentrations.87 In response, the liver
increases VLDL production and cholesteryl ester synthesis.88 Free fatty acids combine with a cholesterol molecule to form a cholesteryl ester.
Cholesteryl ester concentrations may
regulate VLDL production, with increased concentrations resulting in elevated VLDL synthesis.89 Overproduction of triglyceride-rich lipoproteins and
impaired clearance by lipoprotein lipase lead to the hypertriglyceridemia
common in diabetes.89
Low levels of HDL represent the second common abnormality in type 2 diabetes. Elevated levels of triglyceriderich lipoproteins lower HDL levels by
promoting exchanges of cholesterol
from HDL to VLDL via cholesteryl ester transfer protein. 89 Diabetic patients with CAD more commonly have
the combination of elevated triglycerides and low HDL than elevated total
and LDL cholesterol levels.90 Functional defects in HDL may also contribute. High-density lipoprotein in diabetic patients does not prevent LDL
oxidation as well as HDL in nondiabetic patients does.91
Diabetic patients commonly have
elevated concentrations of small dense
LDL even in the face of average plasma
LDL levels.92,93 This change in LDL particles results from increased VLDL secretion and abnormal cholesterol and triglyceride transfer between VLDL and
LDL. The modification depends on
increased concentrations of VLDL and
usually occurs when triglyceride concentrations exceed 130 mg/dL (1.47
mmol/L).94 Small dense LDL particles are
proatherogenic, bind more readily to intimal proteoglycans, enhancing their
metabolism, and readily undergo oxidative modification, which drives their
uptake by monocytes and vascular
smooth muscle cells in the vessel wall.95,96
The lipid abnormalities that develop
in diabetes and their role in atherogenesis have important therapeutic implications. Poor glycemic control exacerbates diabetic dyslipidemia. Thus, strict
glycemic regulation may lessen free fatty
acid flux and hepatic VLDL produc-
tion.97 Metabolic and lipid abnormalities improve with weight loss, exercise, smoking cessation, and dietary
modification98; hence, lifestyle modification is the first mode of therapy.
Pharmacological interventions also
decrease cardiovascular events in diabetes, as borne out by large-scale clinical trials (TABLE 1). Indeed, diabetic
patients at increased risk of recurrent
cardiovascular events may experience
greater risk reduction by lipid lowering than nondiabetic patients.99,100 The
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins)
increase LDL clearance and decrease
VLDL secretion.101 In the Scandinavian Simvastatin Survival Study,100 simvastatin reduced the risk of total mortality by 43% in diabetic patients vs 29%
in nondiabetic patients and reduced the
risk of MI by 55% in diabetic patients
vs 32% in nondiabetic patients. In the
Heart Protection Study (HPS),102 which
included more than 4000 subjects with
diabetes, simvastatin decreased the risk
of acute coronary syndrome, stroke, or
revascularization by 25% in the diabetic subgroup.
Fibric acid derivatives represent other
medications potentially of benefit in diabetic dyslipidemia because they raise
HDL levels and lower triglyceride levels. In the Veterans Affairs HighDensity Lipoprotein Cholesterol Intervention Trial (VA-HIT),103 patients with
diabetes represented 25% of the 2531
male participants. Treatment with gemfibrozil reduced risk of MI by 24%, comparable to that observed in nondiabetic
patients. As with TZDs, fibrates may
have antiatherogenic effects independent of lipid lowering. Fibrates bind to
peroxisome proliferator-activated receptor (as opposed to TZDs, which
bind to peroxisome proliferatoractivated receptor ). Peroxisome proliferator-activated receptor ligation by
fibrates can exert anti-inflammatory effects. For example, fibrates decrease endothelial cell activation by proinflammatory cytokines and reduce tissue
factor production by human macrophages.104,105 Fibric acid derivatives can
prove useful in diabetic patients with
2575
occurs more often in patients with type

2 diabetes than in matched controls.110
Vigorous control of blood pressure
decreases the rate of cardiovascular
events more in patients with diabetes
than in those without diabetes.111,112
Indeed, control of high blood pressure
represents the most important intervention, limiting cardiovascular events far
more effectively than tight glycemic control (TABLE 2). In the UKPDS, aggressive blood pressure reduction significantly reduced stroke and deaths.113
Captopril and atenolol as initial therapy
had similar efficacy.114 Achieving American Diabetes Association target blood
pressure (130/80 mm Hg) usually
requires more than one agent.110,112,113
Diuretics, -blockers, angiotensinconverting enzyme (ACE) inhibitors,
angiotensin receptor blockers, and calcium channel antagonists all effectively
persistently elevated triglyceride levels

and low HDL levels, despite tight glycemic control. Combination therapy of
statins and fibrates warrants careful
monitoring for muscle injury. Nicotinic acid may also increase HDL levels
in diabetic patients, but glycemic control requires supervision in this population.106
In addition to improving lipid abnormalities via improvements in glycemic
control, TZDs may decrease the concentration of small dense LDL107 and increase the resistance of LDL to oxidation,108 although total, LDL, and HDL
cholesterol concentrations increase.109
The clinical effects of TZDs on vascular outcomes await clinical trials.
Treatment of Hypertension
Hypertension, a common comorbid condition in the dysmetabolic syndrome,
decrease blood pressure in diabetic

patients. Modulation of the reninangiotensin system seems particularly
important in diabetes. In the recent Heart
Outcomes and Prevention Evaluation
(HOPE) study,115 ramipril significantly
decreased the rates of MI, stroke, and
death in patients with diabetes and one
additional cardiovascular risk factor. Further, in the Losartan Intervention for
Endpoint Reduction in Hypertension
(LIFE) study,116 losartan reduced total
and cardiovascular mortality more than
atenolol did in diabetic patients with
hypertension and left ventricular hypertrophy. ACE inhibitors seem to reduce
cardiovascular end points more than
dihydropyridine calcium channel blockers as well. 117 We recommend the
use of drugs that inhibit the reninangiotensin system as an integral component in the treatment of diabetes.
Table 1. Medical Therapy of Dyslipidemia

Indication
Drug Dose, mg/d
Acute coronary syndrome and

total cholesterol 270 mg/dL
(6.98 mmol/L)165
Stable coronary artery disease
and elevated total
cholesterol100
Stable coronary artery disease
and average total
cholesterol99
Atorvastatin, 80
Stable coronary artery disease,

average total cholesterol
level, and low high-density
lipoprotein level103
Diabetes mellitus102
Gemfibrozil, 1200
Patients With
Diabetes Mellitus, %
Follow-up
Event
23.2 (Mixed)
16 wk
Death, myocardial infarction, stroke,

recurrent acute coronary
syndrome
Cardiovascular death, myocardial
infarction
38

infarction, coronary artery
bypass grafting, percutaneous
transluminal coronary angioplasty
Stroke, myocardial infarction
13
Simvastatin, 20-40
100
5.3 y
Pravastatin, 40
100
5y
Simvastatin, 40
25 (Mixed)
100
5.1 y
5y
Coronary heart disease, stroke,

coronary artery revascularization
NNT*
4.4
23
14
*NNT indicates number needed to treat to avoid 1 event throughout the follow-up period.
Table 2. Medical Therapy of Hypertension*

Indication
Diabetes mellitus and hypertension113
Diabetes mellitus, hypertension, and
left ventricular hypertrophy117
Diabetes mellitus and 1
cardiovascular risk factor116
Diabetes mellitus, 1 cardiovascular
risk factor, and creatinine
1.4 mg/dL (124 mol/L)166
Drug Dose, mg/d

Captopril, 50-100
Atenolol, 50-100
Captopril, 50-100
Atenolol, 50-100
Losartan, 50-100
Type of Diabetes
Type 2
Type 2
Type 2
Type 2
Diabetes mellitus (aged 55-80 y)
Follow-up, y
9
9
9
9
4.7
Ramipril, 10
Diabetes mellitus (100%)
4.5
Ramipril, 10
Diabetes mellitus (100%)
4.5
Event
Stroke
Stroke
Diabetes-related death
Diabetes-related death
Total mortality
infarction, stroke
infarction, stroke
NNT
27
27
20
20
17
22
17
*The comparison group was placebo, except for diabetes mellitus, hypertension, and left ventricular hypertrophy, which was atenolol. NNT indicates number needed to treat to
avoid 1 event throughout the follow-up period.

Medical Therapy of CAD
In diabetic patients with CAD, platelet inhibition and anticoagulation assume particular importance (TABLE 3).
Platelet antagonists, as reviewed by the
Antiplatelet Trialists Collaboration
Group,118 lowered the combined risk of
vascular death, MI, and stroke by 19%
in diabetic patients (P.01). In unstable angina, low-molecular-weight
heparin confers event reduction in patients with diabetes similar to that in
those without diabetes. 119 Platelet
GpIIb/IIIa inhibitors also have benefits in unstable coronary syndromes.
In the PRISM-PLUS study,120 the addition of tirofiban to heparin decreased
the rates of death and MI in patients
with diabetes more than in nondiabetic patients. A meta-analysis of 10
clinical trials of GpIIb/IIIa inhibitors
showed that diabetic patients experienced twice the absolute event rate reduction of patients without diabetes.121 Several studies have established
that diabetic patients benefit from the
use of thrombolytic therapy in acute
MI.122,123 In a meta-analysis of more than
43 000 patients, including 4529 patients with diabetes, the Fibrinolytic
Therapy Trialists Collaborative
Group124 demonstrated that the reduction in absolute mortality in those with
diabetes exceeded that of patients without diabetes, 3.7% vs 2.1% (P.01).124
Practitioners have had reservations
regarding the use of -blockers in diabetic patients because of the perceived
risk of masking hypoglycemia and reduced insulin production. However,

-blockers decrease the risk of reinfarction and cardiac mortality of patients with diabetes more than of
matched controls.125,126 In a retrospective study of more than 45 000 patients,126 -blockers reduced the risk of
MI by 23% (95% CI, 0.67-0.88) in patients with type 2 diabetes without increasing diabetes-related complications. We advocate the use of -blockers
in diabetes after MI and urge patient
education to decrease the frequency of
diabetes-related events.
Coronary Revascularization
Diabetic and nondiabetic patients have

similar immediate success rates with percutaneous coronary revascularization.127 However, soon after diabetic patients leave the catheterization laboratory,
they experience clinical events at higher
rates than nondiabetic patients do. Patients with diabetes have a clear trend toward increased rates of in-stent thrombosis.128 In the National Heart, Lung, and
Blood Institute PTCA Registry,129 diabetic patients more commonly reached
a composite end point that included mortality, nonfatal MI, and emergency surgery (11.0% vs 6.7%; P.01) and had
higher rates of death (3.2% vs 0.5%;
P.01) than nondiabetic patients. Several studies have demonstrated a greater
long-term risk of restenosis after balloon angioplasty.130,131 Moreover, the severity of diabetes affects outcome after
stent implantation. In a study of 954 patients who underwent coronary artery

stent implantation,132 insulin-requiring
patients with diabetes faced a 28% risk
of late revascularization and a 40% risk
of adverse cardiac events compared with
16.3% and 24% in nondiabetic control
patients, respectively. In multivariate
analysis, insulin requirement entailed a
2-fold increased risk of adverse cardiac
events and target vessel revascularization at 1 year (P.01).132 Increased rates
of restenosis may in part result from an
increased intimal proliferative response, but the mechanisms remain unclear.130,133
Diabetic patients also have a worse
prognosis following surgical revascularization than nondiabetic patients. In
the Bypass Angioplasty Revascularization Investigation (BARI),134 diabetic
patients had significantly lower 5-year
survival rates (73.3% vs 91.3%) than
nondiabetic patients. Yet insulinrequiring diabetic patients do significantly better with surgery than with percutaneous intervention.135,136 In the BARI
trial, diabetic patients who underwent
multivessel bypass surgery had significantly higher rates of survival than those
who underwent percutaneous interventions, 80.6% vs 65.5%.135 The benefit
may result from use of the internal mammary artery in the surgical arm.
Treatment of PAD
Despite the marked increase in risk of

lower extremity atherosclerosis, we have
Table 3. Medical Therapy of Coronary Artery Disease

Indication
Diabetes118,167
Drug Dose
Aspirin, 650 mg/d
Recent myocardial infarction126
-Blockers, meta
Recent myocardial infarction126
-Blockers, meta
NonST-segment elevation
myocardial infarction168
NonST-segment elevation
myocardial infarction and
percutaneous coronary
intervention168
Acute myocardial infarction124
Platelet glycoprotein IIb/IIIa

antagonists, meta
Platelet glycoprotein IIb/IIIa
antagonists, meta
Thrombolytic therapy, meta
Group
Type 1, 33%; type 2,
33%; type unknown,
33%
Insulin-treated diabetes
mellitus
Noninsulin-treated
diabetes mellitus
Diabetes mellitus
Follow-up
Event
NNT*
5y
Death, myocardial
infarction, stroke
29
1y
Death
19
1y
Death
16
30 d
Death
63
Diabetes mellitus
30 d
Death
36
Diabetes mellitus
35 d
Death
77
*NNT indicates number needed to treat to avoid 1 event throughout the follow-up period.
Meta refers to the accumulated data for several medications of varying dosage within the same class.
2577
inadequate information regarding the

role of medical therapies in diabetic
patients with PAD. No evidence shows
that tight glycemic control, aggressive
blood pressure management, or the use
of antiplatelet agents decreases the incidence of intermittent claudication or
critical limb ischemia.113 Although simvastatin decreased the rates of reported
claudication in patients with CAD in the
Scandinavian Simvastatin Survival
Study, the trial did not report data specific to patients with diabetes.137 Even
in the absence of definitive data, we recommend that patients with diabetes
receive therapies of proven benefit in
broader patient populations because
cardiovascular events remain the
principal cause of death in patients
with PAD.17
cise specifically in diabetes, we advocate a prescription for supervised exercise for its benefits in walking
distance, risk factor modification, and
insulin sensitivity.
Cilostazol, a type III phosphodiesterase inhibitor, antagonizes platelet activity and exerts favorable lipid effects, yet the mechanism by which it
improves walking distance remains unclear.147-149 Cilostazol increases walking distance by 35% to 50% above placebo in patients with claudication;
however, we lack specific information
for diabetic patients.150 Pentoxifylline,
a xanthine derivative, may affect blood
rheology and decrease blood viscosity.151 Pentoxifylline improves claudication in some studies but not in others, and outcomes specific to patients
with diabetes remain unknown.152
Medical Therapy of Symptomatic

PAD in Diabetes
Lower Extremity Revascularization
Diabetic persons have a particular propensity to develop foot ulcers. Risk factors for diabetic ulcers include male sex,
hyperglycemia, and diabetes duration.138 Foot ulcers often result from severe macrovascular disease,139,140 and diabetic neuropathy exacerbates the
risk.140,141 Patients with diabetes need intensive self-examination and physician
examination of the foot, specifically
checking the nails and skin for cracking and small ulceration. Use of therapeutic footwear can decrease the risk of
ulceration.142 Once ulceration occurs, patients with diabetes have a much higher
risk of amputation, highlighting the
paramount importance of prevention.
Two noninvasive therapies have demonstrated benefit in improving walking distance in patients with PAD: exercise therapy and cilostazol. Supervised
exercise therapy produces impressive
increases in walking distance. In a metaanalysis of exercise programs, supervised exercise programs increased walking distance 122%.143,144 The mechanism
underlying the benefit is unclear but
may derive from improved cardiovascular fitness, increased production of
nitric oxide, or modification of cardiovascular risk factors.145,146 Even though
we lack data on the benefits of exer-
As in coronary circulation, outcomes

of percutaneous revascularization depend on many variables, including lesion location, lesion length, stenosis or
occlusion, and the nature of the distal
runoff.144 Diabetes alters the distribution of lower extremity atherosclerosis so that these patients tend to have
severe arterial occlusive disease below
the knee in the runoff vessels. As distal runoff declines, the results of percutaneous interventions worsen.
The success of iliac artery stenting in
diabetic patients varies among studies, but several groups have shown better than 90% patency at 1 year.144 With
femoral artery interventions, 1-year patency rates range from 29% to 80%, and
diabetes adversely affects these rates of
success.153,154 This finding may result in
part from poor runoff in patients with
diabetes because in patients with good
runoff, patency rates were comparable
to that of nondiabetic patients.155 For
infrainguinal ischemia, the outcomes of
surgical revascularization in diabetes
resemble those in patients without diabetes in terms of limb salvage,156 albeit
more distal than that of nondiabetic
patients.157 In general, in patients with
severe claudication or critical limb
ischemia, surgery is probably superior
to percutaneous transluminal angioplasty for revascularization in the femoral, popliteal, and infrapopliteal
vessels, but this comes at a price of
increased periprocedural cardiovascular morbidity and mortality.144
Cerebrovascular Disease
Diabetic patients with cerebrovascular

atherosclerosis should also receive platelet antagonists, statins, and ACE inhibitors. A strategy of surgical revascularization with medical therapy for
asymptomatic and symptomatic patients with hemodynamically significant internal carotid artery atherosclerosis resulted in fewer strokes then
medical therapy alone.158,159 Diabetic subjects represented 23% of the total population in the Asymptomatic Carotid Atherosclerosis Study (ACAS) and 19% in
the North American Symptomatic Carotid Endarterectomy Trial (NASCET)
and therefore should receive treatment
similar to that of nondiabetic patients
with carotid artery disease. Several studies have demonstrated increased cardiovascular mortality following carotid endarterectomy in patients with diabetes,
both at 30 days and 1 year.160 The mortality derives from an increased rate of
coronary heart disease events.161 The
rates of perioperative major and minor
stroke do not differ significantly between diabetic and nondiabetic patients162; however, hospital length of stay
tends to increase.163 Despite the increased use of stenting for the treatment of carotid artery atherosclerosis, we
lack direct outcome data in diabetic patients, but evidence suggests that outcomes may be similar to those of patients without diabetes.164
CONCLUSION
Atherosclerosis causes most of the death
and much of the disability in patients
with diabetes. Dysresgulation of
metabolism in diabetes adversely affects
every cellular element within the vascular wall. Intensive treatment of the
gamut of metabolic abnormalities associated with diabetes beyond hyperglycemia reduces the rates of MI and death.
As this high-risk population increases,
strategies to encourage the aggressive

use of targeted medical and revascularization therapies will reduce the magnified rates of death and disability.
Author Contributions: Study concept and design:
Beckman, Creager, Libby.
Acquisition of data: Beckman.
Analysis and interpretation of data: Beckman.
Drafting of the manuscript: Beckman, Creager, Libby.
Critical revision of the manuscript for important intellectual content: Creager, Libby.
Statistical expertise: Beckman.
Obtained funding: Creager.
Administrative, technical, or material support: Creager,
Libby.
Study supervision: Creager.
Funding/Support: This research was supported by
National Institutes of Health grant PO1 HL-48743
(Drs Creager and Libby) and K23 HL-04169 (Dr
Beckman).
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Diabetes and Atherosclerosis

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REVIEW

Diabetes and Atherosclerosis

IABETES MELLITUS MAGNIFIES

the risk of cardiovascular

coronary arteries, lower extremities, and

Dr Libby has been a consultant for AstraZeneca, Avant

2570 JAMA, May 15, 2002Vol 287, No. 19 (Reprinted)

2002 American Medical Association. All rights reserved.

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DIABETES AND ATHEROSCLEROSIS

clinical course of each. Fortunately, we

Coronary artery disease (CAD) causes

tion, congestive heart failure, and

Epidemiological evidence confirms an

2002 American Medical Association. All rights reserved.

Although women experience relative

(Reprinted) JAMA, May 15, 2002Vol 287, No. 19

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DIABETES AND ATHEROSCLEROSIS

nation Survey (NHANES) and the

factors render arteries susceptible to atherosclerosis. Diabetes alters function of

A single layer of endothelial cells lines

Figure 1. Endothelial Dysfunction in Diabetes

Excess Free Fatty Acids

2002 American Medical Association. All rights reserved.

Downloaded from www.jama.com on April 6, 2008

DIABETES AND ATHEROSCLEROSIS

tone, endothelin-1 increases renal salt

motes plaque instability and clinical sequelae. Diabetic endothelial cells

Arteries affected by diabetes and atherosclerosis have altered vasomotor

2002 American Medical Association. All rights reserved.

sclerosis. Once the macrophage-rich

Platelets can modulate vascular function and participate significantly in

(Reprinted) JAMA, May 15, 2002Vol 287, No. 19

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DIABETES AND ATHEROSCLEROSIS

cantly to abnormal activity, since intraplatelet calcium regulates platelet

Figure 2. Antiatherosclerosis Therapy in Diabetes

Calcium Channel Blockers

as antithrombin III and protein C.73-75

2002 American Medical Association. All rights reserved.

Downloaded from www.jama.com on April 6, 2008

DIABETES AND ATHEROSCLEROSIS

trations below the diabetic threshold.79

Characteristic abnormalities in the lipid

acids increase hepatic free fatty acid

2002 American Medical Association. All rights reserved.

(Reprinted) JAMA, May 15, 2002Vol 287, No. 19

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DIABETES AND ATHEROSCLEROSIS

occurs more often in patients with type

persistently elevated triglyceride levels

Hypertension, a common comorbid condition in the dysmetabolic syndrome,

decrease blood pressure in diabetic

Table 1. Medical Therapy of Dyslipidemia

Drug Dose, mg/d

Acute coronary syndrome and

Stable coronary artery disease,

Death, myocardial infarction, stroke,

Cardiovascular death, myocardial

Coronary heart disease, stroke,

Table 2. Medical Therapy of Hypertension*

Drug Dose, mg/d

Diabetes mellitus (100%)