Assessment and Treatment of Cardiovascular Risk in Prediabetes:

Document technical information

Format pdf
Size 702.4 kB
First found Jun 9, 2017

Document content analysis

Language
English
Type
not defined
Concepts
no text concepts found

Persons

Mike Tyson
Mike Tyson

wikipedia, lookup

John F. Kennedy
John F. Kennedy

wikipedia, lookup

Organizations

Places

Transcript

Assessment and Treatment of Cardiovascular Risk in Prediabetes:
Impaired Glucose Tolerance and Impaired Fasting Glucose
Ralph A. DeFronzo, MD,* and Muhammad Abdul-Ghani, MD, PhD
Individuals with impaired glucose tolerance (IGT) and/or impaired fasting glucose
(IFG) are at high risk, not only to develop diabetes mellitus, but also to experience an
adverse cardiovascular (CV) event (myocardial infarction, stroke, CV death) later in
life. The underlying pathophysiologic disturbances (insulin resistance and impaired
␤-cell function) responsible for the development of type 2 diabetes are maximally/
near maximally expressed in subjects with IGT/IFG. These individuals with so-called
prediabetes manifest all of the same CV risk factors (dysglycemia, dyslipidemia,
hypertension, obesity, physical inactivity, insulin resistance, procoagulant state, endothelial dysfunction, inflammation) that place patients with type 2 diabetes at high
risk for macrovascular complications. The treatment of these CV risk factors should
follow the same guidelines established for patients with type 2 diabetes, and should
be aggressively followed to reduce future CV events. © 2011 Elsevier Inc. All rights
reserved. (Am J Cardiol 2011;108[suppl]:3B–24B)
“Prediabetes” is a general term that refers to an intermediate
stage between normal glucose tolerance (NGT) and overt
type 2 diabetes mellitus. As such, it represents 2 groups of
individuals, those with impaired glucose tolerance (IGT)
and those with impaired fasting glucose (IFG). IGT and IFG
often are lumped together, but they have distinct pathophysiologic etiologies. According to the American Diabetes Association (ADA),1 individuals with isolated IGT have a
fasting plasma glucose (FPG) concentration ⬍100 mg/dL [1
mg/dL ⫽ 0.05555 mmol/L] and a 2-hour plasma glucose
(PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between ⱖ140 mg/dL and ⬍200
mg/dL. Individuals with isolated IFG have a 2-hour PG
(measured by an OGTT) of ⬍140 mg/dL and a FPG between ⱖ100 mg/dL and ⬍126 mg/dL. Subjects with isolated IGT have moderate-to-severe insulin resistance in
muscle and impaired first- and second-phase insulin secretion, while individuals with IFG have moderate insulin
resistance in the liver, impaired first-phase insulin secretion,
and normal/near-normal muscle insulin sensitivity.2– 6 Subjects with IGT or IFG are at high risk for developing both
type 2 diabetes7–17 and clinically significant atherosclerotic
cardiovascular disease (ASCVD).18 –36 Most,20,21,24 but not
all28 studies have shown that IGT is stronger than IFG as a
Diabetes Division, University of Texas Health Science Center, San
Antonio, Texas, USA.
Publication of this supplement was supported by funding from Novo
Nordisk. Editorial support was provided by Dr. Ruth Kleinpell and Mary
Lou Briglio.
Statement of author disclosure: Please see the Author Disclosures
section at the end of this article.
*Address for reprints: Ralph A. DeFronzo, MD, Diabetes Division,
University of Texas Health Science Center, 7703 Floyd Curl Drive, San
Antonio, Texas 78229.
E-mail address: [email protected]
0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjcard.2011.03.013
predictor of macrovascular complications. In a meta-analysis of 20 studies including 95,783 nondiabetic subjects with
a mean follow-up of 12.4 years, Coutinho and colleagues37
recorded 3,707 cardiovascular (CV) events. An exponential
correlation between CV events and both FPG and postload
PG concentration was found, and this relationship extended below diagnostic blood glucose levels (Figure
1).37 In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE),19,20
Hoorn,34 DECODA (Diabetes Epidemiology: Collaborative
Analysis of Diagnostic Criteria in Asia),33 and Funagata Diabetes32 studies, CV mortality in subjects with IGT was close to
that of individuals with overt type 2 diabetes and much greater
than in subjects with IFG.
Prediabetes and Type 2 Diabetes Mellitus:
Are They Different?
The natural history of type 2 diabetes has been well described in multiple populations and has been reviewed by
DeFronzo.38,39 Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their
tissues resistant to insulin.38 – 46 In the liver, the insulin
resistance is manifest by an overproduction of glucose
during the basal state despite the presence of fasting
hyperinsulinemia47and an impaired suppression of hepatic
glucose production in response to insulin, as occurs following a meal.48 In muscle43,49,50 insulin resistance is manifest
by impaired glucose uptake after ingestion of a carbohydrate-rich meal and results in postprandial hyperglycemia.48
Although the origins of the insulin resistance can be traced
to their genetic background,39,41,44 the epidemic of diabetes
that has enveloped westernized countries is related to the
epidemic of obesity and physical inactivity.51 Both obesity52
www.AJConline.org
4B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
Figure 3. Insulin secretion/insulin resistance (disposition) index (defined as
change in insulin/change in glucose ⫼ insulin resistance [⌬INS/⌬GLU ⫼
IR]) in individuals with normal glucose tolerance (NGT), impaired glucose
tolerance (IGT), and type 2 diabetes mellitus (T2DM) as a function of the
2-hour plasma glucose (PG) concentration in lean (closed circles) and
obese (open circles) subjects. (Reprinted with permission from The American Diabetes Association.39)
Figure 1. Relation between cardiovascular events and fasting and postload
plasma glucose concentrations in a meta-analysis of 20 studies including
95,783 nondiabetic subjects with a mean follow up of 12.4 years. The
curves and 95% confidence intervals are shown. (Reprinted with permission from The American Diabetes Association.37)
and decreased physical activity53 are insulin-resistant states
and, when added to the genetic burden of the insulin resistance, place a major stress on the pancreatic ␤-cells to
augment their secretion of insulin to offset the defect in insulin
action.43 As long as the ␤-cells are able to augment their
secretion of insulin sufficiently to offset the insulin resistance,
glucose tolerance remains normal.54 However, with time, postmeal glucose levels and subsequently FPG concentration begin
to rise, leading to the onset of overt diabetes. Collectively, the
Figure 2. Natural history of type 2 diabetes mellitus. The plasma insulin
response (open circles) depicts the classic Starling’s curve of the pancreas.1
Closed circles ⫽ insulin-mediated glucose uptake (top panel). DIAB ⫽
diabetes; Hi INS ⫽ high insulin secretion; IGT ⫽ impaired glucose
tolerance; Lo INS ⫽ low insulin secretion; NGT ⫽ normal glucose tolerance; OB ⫽ obese; OGTT ⫽ oral glucose tolerance test. (Reprinted with
permission from The American Diabetes Association.39)
insulin resistance in muscle and liver and ␤-cell failure have
been referred to as “the triumvirate.”55
As illustrated in Figure 2,39 individuals with NGT who
are destined to develop type 2 diabetes already manifest
moderate-to-severe insulin resistance, which is genetic in
origin and made worse by accompanying obesity and physical inactivity. Although the transition from NGT to IGT is
associated with a worsening of the insulin resistance, glucose tolerance is only mildly impaired because of the compensatory increase in insulin secretion and resultant hyperinsulinemia. However, plasma insulin levels should not be
equated with ␤-cell function. The ␤-cell responds to an
incremental change in glucose with an incremental change
in insulin, and this response is modulated by the severity of
insulin resistance.2– 6,39,56 Therefore, the “gold standard”
formula for ␤-cell function is ⌬I/⌬G ⫼ IR (where ⌬I represents an incremental change in insulin, ⌬G is the incremental change in glucose, and IR is insulin resistance). As
shown in Figure 3,39 individuals in the upper tertile of NGT
(2-hour PG ⫽ 120 –139 mg/dL) have a loss of ⬃50% of
their ␤-cell function, compared with a loss of 70%– 80% for
individuals in the upper tertile of IGT (2-hour PG ⫽ 180 –
199 mg/dL). Thus, from the pathophysiologic standpoint,
subjects with IGT should be considered to have type 2
diabetes. In a postmortem analysis, Butler et al57 have
shown that individuals with IFG have a 50% decrease in
␤-cell volume, suggesting that there is a significant loss of
␤-cell mass in the prediabetic state, long before the onset of
overt type 2 diabetes.
The recently published results of the Diabetes Prevention
Program (DPP)58 have raised further concern about the
clinical implications of the term “prediabetes.” In the DPP,
individuals who entered with a diagnosis of IGT and still
had IGT 3 years later had a 7.9% incidence of background
diabetic retinopathy at the time of study end. Individuals,
who entered the DPP with IGT but who progressed to
diabetes after 3 years, had a 12.6% incidence of diabetic
retinopathy at the end of study. Moreover, these individ-
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
5B
uals who remained with IGT or who progressed to diabetes developed diabetic retinopathy with hemoglobin A1c
(HbA1c) levels of 5.9% and 6.1%, respectively, values much
lower than the current ADA treatment goal of 7.0%. Peripheral neuropathy also is a common finding in IGT, occurring in as many as 5%–10% of patients.59,60
In summary, individuals with IGT are maximally or near
maximally insulin resistant, have lost 80% of their ␤-cell
function, and have an approximate 10% incidence of diabetic retinopathy. By both pathophysiologic and clinical
standpoints, these individuals with prediabetes who have
IGT should be considered to have type 2 diabetes. The
clinical implications of these findings for the prevention of
type 2 diabetes and associated complications are that the
physician must intervene early, at the stage of IGT or IFG,
with interventions that target pathogenic mechanisms
known to cause ␤-cell failure and insulin resistance. From
the standpoint of cardiovascular disease (CVD), it is equally
important for the physician to recognize that IGT and type
2 diabetes are CV risk equivalents (see subsequent discussion).
Impaired Glucose Tolerance and Type 2 Diabetes
Mellitus Are Major Cardiovascular Risk Factors
Although microvascular complications are a major cause of
morbidity in type 2 diabetes, macrovascular complications
represent the primary cause of mortality, with heart attacks
and stroke accounting for ⬃80% of all deaths.61 In patients
with type 2 diabetes without a prior history of myocardial
infarction (MI), the 7-year incidence of MI is equal to or
greater than the 7-year incidence of heart attack in nondiabetic individuals with prior MI.62 In patients with diabetes
with a previous history of heart attack, the 7-year incidence
of subsequent MI is more than double that for nondiabetic
individuals.62 Similarly, the recurrence rate of major atherosclerotic events in patients with type 2 diabetes with a
prior CV event is very high, around 6% per year.63 These
results document that diabetes is a major CV risk equivalent.
The DECODE study19,20,64,65 analyzed databases from
multiple European populations and concluded that people
with type 2 diabetes had twice the risk for CVD (including
coronary artery disease [CAD] and stroke) compared with
nondiabetic individuals, after adjustment for other CV risk
factors. Furthermore, DECODE demonstrated that the relation between glycemia and CV risk started within the normal blood glucose range, with a linear relationship and no
evidence of a threshold effect.19,20 Both the FPG and postchallenge PG levels were correlated with CV risk (Figure
4),19 although the strongest correlation was with the postprandial glucose level; addition of the FPG level to the
postprandial glucose level did not further increase the risk.
Similar observations have been reported in the Framingham Offspring Study66 and the Hoorn Study.34 The Fu-
Figure 4. Cumulative hazard curves for cardiovascular disease based on the
American Diabetes Association (ADA) fasting glucose criteria and World
Health Association (WHO) 2-hour glucose criteria adjusted by age, sex,
and study center. (Reprinted with permission from Elsevier, Inc.19)
nagata Study also showed a higher CV mortality rate in
persons with IGT compared with individuals with IFG.32
Similar results have been published by the DECODA
Study Group21 in Asian populations. Multiple cohort studies27,67– 69 have demonstrated an increased CV risk in subjects with IGT, although the later studies did not compare
these subjects with individuals with IFG. In a recently
published Austrian Study of 1,040 patients who underwent
coronary arteriography for suspected/established CAD and
who were followed for a mean of 3.8 years, CV event-free
survival was similar in individuals with IGT and with newly
diagnosed type 2 diabetes, and both were significantly
greater compared with individuals with NGT (Figure 5).70
The progression of abnormal glucose metabolism from
NGT to IGT to type 2 diabetes in 5,000 patients with
established with CAD in the Euro Heart Survey71 also was
associated with worsening CV prognosis. After 1 year of
follow up, all-cause mortality was 2.2% in patients with
NGT, 2.7%–3.7% in subjects with IGT/IFG, 5.5% in pa-
6B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
Figure 5. Event-free survival with respect to glycemic state in 1,040
patients who underwent coronary arteriography for suspected/established
coronary artery disease. IGT ⫽ impaired glucose tolerance; NGT ⫽ normal
glucose tolerance. (Reprinted with permission from Oxford University
Press.70)
tients with newly diagnosed type 2 diabetes, and 7.7% in
patients with known diabetes. A notable exception to the
greater CV risk in patients with IGT compared with IFG is
the Australian Diabetes Study.36 Although, after 6 years of
follow up, individuals with IGT had a higher cumulative
incidence of all-cause mortality compared with individuals
with IFG, the incidence of CVD mortality was similar in the
2 groups and was higher for both compared with subjects
with NGT.
Several potential explanations could account for the
higher rates of CVD in subjects with IGT compared with
IFG. First, postprandial hyperglycemia contributes more to
the overall day-long glycemic exposure in individuals with
IGT compared with IFG.2,3,72 Second, individuals with IGT
have a higher prevalence of the metabolic syndrome,73– 81 a
cluster of abnormalities including central obesity dyslipidemia, hypertension, and dysglycemia, that by itself increases
the risk for ASCVD.82– 84 Third, postprandial blood glucose
concentrations are associated with the highest diurnal levels
of glycemia and the greatest fluctuations in blood glucose
concentrations that may have a more damaging effect on the
vasculature,85–90 including increased oxidative stress, activation of inflammatory pathways, increased procoagulant
state, and abnormal vasomotion.
Incidence of Prediabetes and Diabetes Mellitus in
Individuals with Coronary Artery Disease
The prevalence of previously unrecognized postchallenge
hyperglycemia (IGT and type 2 diabetes) in patients undergoing coronary angiography exceeds 60%,91–96 and the severity of postchallenge hyperglycemia correlates closely
with the extent of angiographically determined CAD91 and
with future macrovascular events and total mortality.36 The
DIGAMI (Diabetes Insulin Glucose and Myocardial Infarc-
tion) Study94 examined the prevalence of dysglycemia
(OGTT performed at hospital discharge) in 164 patients
admitted to the hospital with an acute MI, with assessment
repeated 4 –5 days later (n ⫽ 164) and 3 months later (n ⫽
144). Prediabetes and newly diagnosed type 2 diabetes,
respectively, were diagnosed in 35% and 31% of patients.
The similar incidence of abnormal glucose tolerance detected 3 months later excluded acute illness and increased
sympathetic tone as the cause of the disturbance in glucose
metabolism. Similar findings have been reported in 3 longer
studies, the 25-country Euro Heart Survey,93 the China
Heart Survey,96 and a study from Austria.36
In summary, ⬎60% of individuals with previously undiagnosed prediabetes or diabetes who experience an MI or
come to coronary catheterization because of suspected CAD
have IGT, IFG, or type 2 diabetes. Because of this very high
incidence of dysglycemia, it is recommended that all patients with acute MI and new-onset angina or CAD should
have a 75-g, 2-hour OGTT. Individuals with stable chronic
CAD also should have an OGTT to exclude underlying
prediabetes/diabetes.
Assessing Cardiovascular Risk and the Need for
Screening in Patients with Prediabetes
There are no prospective studies that have evaluated which
asymptomatic individuals with prediabetes should be
screened for CAD. However, because prediabetes, like overt
type 2 diabetes, is a CV risk equivalent, it is reasonable to
use the same criteria applied to diabetes. Recently, the
ADA97 revised its 1998 Consensus Conference Guidelines98
about screening for diabetes because of failure of studies to
demonstrate that the load of traditional risk factors predicted
inducible ischemia in nuclear or echocardiographic myocardial perfusion studies.99,100 Moreover, efforts using data
from the Framingham study and the United Kingdom Prospective Diabetes Study (UKPDS) have proved only modestly successful.101
In the absence of symptomatic CAD, clinical features
that identify patients with diabetes at increased risk for MI
or cardiac death include clinical evidence of ASCVD involving the lower extremity, cerebral, or renal arteries,102,103
microalbuminuria,104,105 abnormal electrocardiogram (Qwaves, T-wave inversion, left bundle branch block),106,107
autonomic neuropathy,108 retinopathy,109 age, and sex. Although CAD screening studies in patients with type 2 diabetes have failed to establish an association between the
number of CV risk factors and inducible ischemic on
perfusion imaging,100 multiple risk factors (hypertension,
dyslipidemia, obesity [especially visceral], smoking,
physical inactivity, evidence of inflammation, insulin resistance) in the same individual markedly increase the
likelihood of experiencing a CV event.74 –77,80,81 Because
prediabetes and type 2 diabetes are part of a continuous
spectrum, it is not unreasonable to assume that these
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
same abnormalities predict increased CV risk in individuals with prediabetes.
Although the presence of multiple CV risk factors does
not identify individuals at risk for inducible ischemia on
perfusion imaging, it does identify people at high risk for a
subsequent coronary event. Consistent with this, autopsy
studies in type 2 diabetes have demonstrated severe multivessel coronary atherosclerosis even in asymptomatic individuals.110 Subjects with the metabolic syndrome, the majority of whom have some form of dysglycemia,111 are at
increased risk for type 2 diabetes and CVD, accounting for
up to half of new cases of type 2 diabetes and up to one third
of new CVD cases over 8 years of follow up.112,113 Thus, it
is reasonable to consider individuals with prediabetes with
multiple CV risk factors at high risk for CVD, and they
should receive aggressive multifactorial intervention (see
subsequent discussion), which has been shown to be effective in reducing CV events in patients with type 2 diabetes
in the Steno-2,114,115 Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE),116 and Multiple Risk Factor Intervention Trial
(MRFIT)117 studies. If screening is to be undertaken in
subjects with prediabetes, newer CAD diagnostic modalities
including computed tomographic angiography,118 coronary
artery calcium score using electron-beam or multislice technology,119,120 or cardiac magnetic resonance imaging is recommended.121
The recently reported results of the DPP in the United
States provide support for the approach advocated above.81
In the DPP 3,324 individuals with IGT were randomized to
intensive lifestyle modification, metformin, or placebo. CV
risk factors (high-density lipoprotein [HDL] cholesterol
[HDL-C], systolic/diastolic blood pressure, triglycerides
[TG], and low-density lipoprotein [LDL] particle size)
worsened as glucose tolerance status deteriorated from IGT
to type 2 diabetes and improved with reversion to NGT,
especially in the lifestyle intervention group. Based on
changes in risk factor levels, the incremental risk associated
with conversion to diabetes was quite modest. Of note, CV
risk factors were associated with glycemia in a linear fashion, without any unique effect of conversion to diabetes.
Moreover, most of the increased CV risk, based on these
traditional risk factors, was well established at the stage of
IGT. Similarly, nondiabetic (NGT and IGT) participants in
the San Antonio Heart Study (SAHS) who developed type 2
diabetes over an 8-year follow-up period had higher total/
LDL cholesterol (LDL-C) and TG concentrations, systolic
and diastolic blood pressure, and body mass index (BMI),
and lower HDL-C levels than subjects who did not develop
diabetes.77 Based on these observations, the SAHS investigators put forward the “ticking clock” hypothesis, which
states that the clock for CAD starts to tick long before the
onset of overt diabetes (Figure 6). The Nurses Health
Study122 and the Botnia Study80 also demonstrated the presence of abnormal CV risk factors long before the development of overt diabetes.
7B
Figure 6. Schematic representation of the ticking clock hypothesis. CAD ⫽
coronary artery disease; T2DM ⫽ type 2 diabetes mellitus.
In summary, multiple studies demonstrate that individuals with prediabetes, especially those with multiple risk
factors for CVD, are at increased risk for a CV event over
the subsequent follow-up period of 10 years.
Insulin Resistance, Hyperinsulinemia, and
Atherosclerotic Cardiovascular Disease:
the Missing Links
Insulin and atherosclerosis: Insulin resistance and hyperinsulinemia have been implicated as the missing links in
the increased risk for CVD.123 In vivo and in vitro studies
have demonstrated that insulin can promote atherogenesis.124 –126 Insulin enhances de novo lipogenesis and augments hepatic very-low-density lipoprotein (VLDL) synthesis127,128 via stimulation of sterol regulatory element–
binding protein-1c and inhibition of acetyl-coenzyme A–1
carboxylase.129 In cultured arterial smooth muscle cells,
insulin increases LDL-C transport,130 augments collagen
synthesis,131,132 stimulates arterial smooth muscle cell proliferation,133,134 and activates multiple genes involved in
inflammation.132 In vivo studies in dogs,135 rabbits,136 and
chickens137 provide further evidence that insulin promotes
atherogenesis. Rats chronically infused with insulin, while
maintaining euglycemia, become markedly resistant to the
stimulation of glucose uptake and suppression of plasma
free fatty acids by insulin138 and become hypertensive.139
Two other points about hyperinsulinemia are noteworthy. In
humans with NGT, insulin infusion to raise the fasting
plasma insulin (FPI) from 57 to 104 pmol/L for 3 days
produces severe insulin resistance,140,141 a risk factor for
CVD (see subsequent discussion). Hyperinsulinemia and
insulin therapy are also associated with weight gain,142 and
obesity is a major risk factor for CVD.143,144 Weight gain
promotes atherogenesis via multiple mechanisms including
dyslipidemia and hypertension, while fat deposition in the
arterial wall promotes inflammation, which directly accelerates atherogenesis.145–147
Insulin resistance (metabolic) syndrome: Much evidence indicates that insulin resistance per se and associated
8B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
Figure 7. Insulin-stimulated glucose disposal (40 mU/m2 per min, euglycemic-hyperinsulinemic clamp) in lean healthy control (CON) participants,
obese participants with normal glucose tolerance (NGT), lean drug-naive
participants with type 2 diabetes mellitus (T2DM), lean participants with
NGT and hypertension (HTN), participants with NGT and hypertriacylglycerolemia (Hypertriacyl), and nondiabetic participants with coronary
artery disease (CAD). White bar sections indicate nonoxidative glucose
disposal (glycogen synthesis); black bar sections indicate glucose oxidation. *p ⬍0.01 vs CON; †p ⬍0.001 vs CON. (With kind permission from
Springer Science⫹Business Media: Diabetologia, Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude
Bernard Lecture 2009], Volume 53, 2010, DeFronzo RA, Figure 1.123)
components of the insulin resistance (metabolic) syndrome38 – 40 play a pivotal role in the development of ASCVD.
It is noteworthy that individuals with prediabetes are as
insulin resistant as lean patients with type 2 diabetes and
obese subjects with NGT (Figure 7).123 In fact, insulin
resistance is fully established in the NGT offspring of 2
parents with type 2 diabetes.40,43,45 In all of these groups,
insulin resistance primarily affects the glycogen synthetic
pathway (Figure 7).38 – 43,45,46,148,149 Type 2 diabetes61,62 and
obesity143,144 are major CV risk factors, and it is not surprising, therefore, that patients with prediabetes also are at
increased risk for CVD. A common thread linking all components of the insulin resistance syndrome is the basic
cellular/molecular cause of the insulin resistance,40,123
which not only promotes inflammation and atherogenesis
but also leads to and/or aggravates other components of the
syndrome, which themselves are independent and major
CVD risk factors.
Insulin resistance is a central feature of the metabolic
(insulin resistance) syndrome, and it primarily involves the
glycogen synthetic pathway (Figure 7).150 –152 Hypertension
also is a well-established risk factor for CVD.153
Individuals with type 2 diabetes and obesity, as well as
subjects with prediabetes, develop dyslipidemia characterized by hypertriglyceridemia, reduced HDL-C, and small,
dense atherogenic LDL particles.82– 84,149,154 –157 Hypertriglyceridemia, but not hypercholesterolemia, is associated
with insulin resistance (Figure 7).154,157–159 The frequency
of hypercholesterolemia is not increased in patients with
type 2 diabetes.156 However, elevated LDL-C acts synergistically with other risk factors to accelerate atherogenesis.160
Studies by Bressler et al161 were the first to conclusively
demonstrate that individuals with diffuse CAD were markedly insulin resistant compared with participants with NGT
who had clean coronary arteries. Again, the insulin resis-
tance primarily affected the glycogen synthetic pathway in
skeletal muscle (Figure 7).161 Studies by Reaven149 and
Paternostro and colleagues162 also have shown that nondiabetic individuals with established CAD are resistant to
insulin. The myocardium of nondiabetic individuals with
CAD and patients with type 2 diabetes without CAD also is
resistant to insulin.162–164
In summary, each component of the metabolic syndrome
is characterized by insulin resistance involving the glycogen
synthetic pathway (Figure 7). The insulin resistance is present at the stage of IGT,2,3 ie, prediabetes, even before any
abnormality in glucose tolerance is observed43,45,46,165
and is an independent risk factor for CVD (see subsequent discussion).
Insulin Resistance and the Insulin Resistance
Syndrome Predict Future Cardiovascular Disease
Multiple prospective studies, including the SAHS166 and
the Botnia Study,80 have demonstrated that insulin resistance in subjects with NGT predicts future CVD, even
after adjustment for multiple CV risk factors. Each component of the insulin resistance syndrome, as well as
insulin resistance per se, is associated with a 1.5- to
2-fold increase in the incidence of CVD. Similar observations have been made in the Bruneck,167 Verona Diabetes,168 and Insulin Resistance Atherosclerosis Studies
(IRAS).169 A strong relation between insulin resistance
and carotid intima-media thickness—a surrogate measure
of ASCVD—also been demonstrated,170 as has an association between insulin resistance and a greater CV risk
factor load.171 The analysis by D’Agostino and colleagues172 of 6 prospective studies further supports an
independent role for insulin resistance in CVD. Using the
Framingham cardiovascular risk calculator,173 only 69%
of the observed risk for CVD could be explained, leaving
31% unaccounted for (Figure 8A).172 Similarly, in the
Atherosclerosis Risk in Communities (ARIC) Study (Figure 8B),174 only ⬃70% of the increase in carotid intimamedia thickness could be accounted for by dyslipidemia,
hypertension, glucose intolerance, or obesity. It is likely
that this unexplained risk can be attributed in part to the
underlying molecular etiology of insulin resistance,
which involves impaired insulin signaling through the
insulin receptor substrate–1 (IRS-1)/phosphatidylinositol
(PI) 3-kinase pathway and increased insulin signaling
through the MAP kinase pathway.40,123
The molecular etiology of insulin resistance in skeletal
and vascular smooth muscle cells is genetic in origin and
can be demonstrated in the lean NGT offspring of 2 parents
with type 2 diabetes.45,46,124 These offspring are at very high
risk to develop type 2 diabetes and their tissues are being
incubated in a sea of molecular insulin resistance and
atherogenicity from a very early stage of life. This explains,
in part, why clinically evident ASCVD is present in 5%–
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
Figure 8. (A) Predictive value (%) of cardiovascular disease (CVD) using
the Framingham risk calculator from Framingham Heart Study (FHS), the
Atherosclerosis Risk in Community Study (ARIC), the Honolulu Heart
Program (HHP), the Puerto Rico Heart Health Program (PR), the Strong
Heart Study (SHS), and the Cardiovascular Health Study (CHS). On mean,
the Framingham Risk calculator predicts only 69% of the risk of a future
cardiovascular event. Amer ⫽ American; F ⫽ female; M ⫽ male.
(Adapted with and reprinted permission from JAMA.172 Copyright
© (2001) American Medical Association. All rights reserved.) (B) Excess
carotid intima-media thickness (IMT) in relation to the individual components of the insulin resistance syndrome (IRS) as listed. GLU ⫽ glucose;
HDL ⫽ high-density lipoprotein; HTN ⫽ hypertension; TG ⫽ triglycerides; 1 ⫽ increase; 2 ⫽ decrease. (With kind permission from Springer
Science⫹Business Media: Diabetologia, Insulin resistance, lipotoxicity,
type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard
Lecture 2009], Volume 53, 2010, DeFronzo RA, Figure 1.123)
20% of individuals with type 2 diabetes at initial diagnosis175 and why insulin resistance and ASCVD are so closely
linked.123
In summary, individuals with prediabetes manifest the
same molecular defect in insulin action as patients with type
2 diabetes and obesity, placing them at increased risk for
CVD.
Assessment and Treatment of Prediabetes: a Rational
Pathophysiologic and Cardiovascular Risk
Factor– based Approach
Because prediabetes (IGT and IFG) and diabetes represent a
continuum of dysglycemia and CV risk, the same principles
that apply to the assessment and treatment of type 2 diabetes
should apply to the prediabetic state (Table 1).
9B
Dysglycemia: Subjects with IFG should have a formal
2-hour OGTT, because ⬃33% of these individuals will have
type 2 diabetes. Both individuals with IFG but without type
2 diabetes and subjects with IGT should have a repeat FPG
test annually and a repeat OGTT every 1–2 years based on
the FPG results and the discretion of the physician.
Within the prediabetic range, both the FPG and 2-hour
PG are independent risk factors for the development of
ASCVD.19,20,32,34,37,64 – 81 In DECODE, the risk for CAD
and stroke increased progressively from IFG to IGT to type
2 diabetes,19,20 indicating that hyperglycemia is a continuous risk factor for CV mortality.176 In the UKPDS, HbA1c
was the third greatest risk factor for CVD in type 2 diabetes.177 In MRFIT, CV mortality increased with an increasing
number of coexisting CV risk factors, and the risk was
magnified by concomitant hyperglycemia in subjects with
type 2 diabetes.156,164 Similarly, in UKPDS178 a potent interaction between hyperglycemia and blood pressure to increase the risk of MI and stroke was documented. These
observations highlight the important role of dysglycemia as
a major risk factor for ASCVD.
No CV intervention study has targeted the prediabetic
population specifically. However “tight” glycemic control
in the extension of the UKPDS179 and DCCT180 demonstrated that treatment of hyperglycemia in patients with
diabetes significantly decreased CV events181,182 In the Prospective Pioglitazone Clinical Trial in Macrovascular Events
(PROactive) trial,183,184 pioglitazone reduced the second principal endpoint of all-cause mortality, MI, and stroke in patients
with type 2 diabetes with a prior CV event, although the CV
benefit most likely was the result of combined improvements
in the HbA1c, dyslipidemia, blood pressure, and other inflammatory markers that were not measured.
The results of the Study to Prevent Non–Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) trial185 provide
support for the specific treatment of postprandial glucose
levels. This study, which demonstrated a 30% reduction in
the conversion rate of IGT to type 2 diabetes, was associated
Table 1
Cardiovascular risk assessment in prediabetes (IGT/IFG)
● Hyperglycemia
X Fasting
X Postprandial
● Obesity
● Physical activity
● Dyslipidemia
X Hypercholesterolemia
XSmall dense LDL particles
X Hypertriglyceridemia
X Low HDL cholesterol
X Non-HDL cholesterol
● Hypertension
● Procoagulant state
● Endothelial dysfunction
● Inflammation
10B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
with reductions in any CV event (by 49%), acute MI (by
91%), and development of hypertension (by 34%).
Both IGT and IFG are major independent risk factors for
the development of type 2 diabetes, and individuals with
combined IGT and IFG are at especially high risk.7–17 Lifestyle intervention, including weight loss and increased
physical activity,186 –189 should be the mainstay of therapy in
individuals with IGT and/or IFG. Pharmacologic intervention185,186,190 –198 also has been shown to be effective in
reducing the conversion rate of IGT to type 2 diabetes. In
the DPP studies in the United States186 and Finland (FIND2D),187 lifestyle modification in subjects with IGT reduced
the conversion rate to diabetes by 62% and 58%, respectively. Other CV benefits also were noted in these studies,
including reduction in systolic/diastolic blood pressure,
plasma TG, LDL-C, insulin, and C-reactive protein (CRP)
levels and an increase in HDL-C. However, as has been
observed with most weight loss programs, the majority of
the lost weight was regained despite moderately intensive
follow-up programs in both the US and Finnish trials.199,200
In both the US DPP190 and Indian198 (IDPP) studies,
metformin was effective in reducing the conversion of IGT
to type 2 diabetes, by 31% and 26%, respectively, but the
decrease was only approximately half of that observed with
lifestyle changes. An ADA Consensus statement201 has recommended use of metformin in high-risk (aged ⬍60 years,
BMI ⬎30, HbA1c ⬎6.0%) patients with IGT.
The most impressive results preventing the conversion of
IGT to type 2 diabetes have been observed with the thiazolidinedione (TZD) class of drugs, which consistently have
reduced the conversion rate of IGT to type 2 diabetes by
50%–70%.191–194 In ACT NOW (Actos Now for the Prevention of Diabetes), the conversion rate of IGT to type 2
diabetes was reduced by 72% with pioglitazone, and 48% of
IGT individuals reverted to NGT. Significant reductions in
blood pressure, TG levels, and rate of progression of carotid
intima-media thickness, and an increase in HDL-C also
were observed. Although the glycemic benefits of the TZDs
are clearly established, physicians must be cognizant of
their potential side effects including fluid retention and
bone fractures. Although concern has been raised about
the CV safety of rosiglitazone,202 both PROactive183,184
and a meta-analysis203 have shown that pioglitazone does
not increase CV events and, to the contrary, improves CVD
outcomes. Although weight gain commonly is observed
with the TZDs, the greater the weight gain is, the greater
also is the decline in HbA1c, the improvement in insulin
sensitivity, and the improvement in ␤-cell function.204,205
Thus, the TZD-related weight gain primarily represents a
cosmetic concern. The results of the CANOE (Canadian
Normoglycemia Outcomes Evaluation) study,195 which
evaluated the use of low-dose combination therapy with
rosiglitazone (2 mg/day) plus metformin (1,000 mg/day),
are especially encouraging. The conversion rate of IGT to
type 2 diabetes was reduced by 66% without weight gain or
fluid retention. Because of the CV safety issues with rosigli-
tazone, low-dose pioglitazone (15–30 mg/day) plus metformin (500 –1,000 mg/day) represents a logical choice for
the treatment of IGT when lifestyle intervention fails to
achieve the desired effect. However, it should be emphasized that, at present, the US Food and Drug Administration
(FDA) has not approved any pharmacologic therapy for the
treatment of IGT or IFG.
Obesity: As part of the assessment of individuals with
IGT and IFG, body weight (on every visit) and height
should be recorded and BMI calculated. It also is recommended that waist circumference be measured.206
Obesity, especially visceral obesity, is a major risk factor
for ASCVD.143,144 It also is associated with moderate-tosevere insulin resistance, is the driving force behind the
global epidemic of type 2 diabetes,51,207 and is associated
with the insulin resistance syndrome and multiple risk factors for CVD.82– 84 Therefore, an effort should be directed at
weight loss in patients with prediabetes, the majority of
whom are overweight. The ADA recommends screening for
type 2 diabetes in persons with a BMI ⬎25 and in those
⬎45 years of age.208 Such screening would be expected to
identify large numbers of individuals with prediabetes (IGT
and IFG). Moreover, lifestyle intervention with caloric restriction/increased physical activity is recommended by
both the ADA and the American Heart Association
(AHA).208 –211 Such interventions significantly decrease the
conversion rate of IGT to type 2 diabetes, reduce HbA1c
levels, enhance insulin sensitivity, and improve CV risk
factors.212–217 No long-term study with sufficient numbers
of patients has been completed to assess the effect of weight
loss on CV outcomes, but the Look Action for Health in
Diabetes (Look AHEAD) trial in patients with type 2 diabetes with a BMI ⱖ25 is designed to address this issue.218
A detailed description of the principles of medical nutrition
therapy for achieving weight loss and improving the CV
risk profile has been provided by the ADA and the
AHA.208 –212,219
Physical inactivity: The level of physical activity
should be assessed in all subjects with prediabetes.208 This
can be done by use of simple questionnaires or with a
pedometer. A more quantitative measure can be obtained by
determination of maximum oxygen consumption (VO2max),
although this is not routinely recommended.
Physical inactivity, as manifested by a low VO2max,
is a major risk factor for both type 2 diabetes and
ASCVD.210 –213,220,221 In subjects with IGT and type 2 diabetes reduced physical fitness is associated with increased
CV mortality, whereas enhanced physical activity reduces
the risk of CVD.222–226 Moreover, incorporation of routine
physical activity of moderate intensity, 3– 4 times per week,
has been shown to reduce the conversion of IGT to type 2
diabetes and improve the CV risk factor profile213,214 and
should be an integral part of any intervention program
designed to reduce CV risk and prevent diabetes in IGT and
IFG individuals. To improve glycemic control, promote
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
weight maintenance, and reduce CV risk, the ADA and
AHA recommend ⱖ30 minutes of moderate-intensity physical activity 3 days per week, and preferably 45– 60 minutes
of moderate intensity physical activity 5 days per week.208
Insulin resistance: Use of the euglycemic insulin clamp
is the gold standard for quantitating the severity of insulin
resistance,227 but this is impractical on an individual basis or
in large-scale epidemiologic trials. The homeostatic model
assessment of insulin resistance (HOMA-IR; calculated as
FPG in millimoles per liter ⫻ FPI in milliunits per liter ⫼
22.5) ⬎3– 4 is a surrogate measure of insulin resistance228
that correlates reasonably well with insulin resistance measured with the euglycemic insulin clamp.229 An alternative
measure is FPI concentration or stimulated insulin concentration ⬎75% above the upper limit of normal.230 A TG–
HDL-C ratio ⬎3.0 also has been suggested as a surrogate
measure of insulin resistance.231 Measurement of BMI also
can be useful. The great majority (⬎80%–90%) of individuals with a BMI ⬎30 are insulin resistant,232 as are most
people with visceral obesity (⬎102 cm in males and ⬎88
cm in females).233 From the clinical standpoint, if the patient has IGT, the physician can assume that he or she is
insulin resistant.2– 6
Insulin resistance is a core defect responsible for the
development of type 2 diabetes39,40,123 and is maximally/
near maximally established in individuals with prediabetes
(IGT/IFG)2– 6,39 and in the genetically predisposed NGT
offspring of parents with type 2 diabetes.43,45,46 Moreover,
insulin resistance is an independent risk factor for the development of ASCVD123 and is the major factor underlying
the insulin resistance (metabolic) syndrome.84,123–126 The
pathogenic mechanisms via which insulin resistance with its
compensatory hyperinsulinemia leads to each component of
the insulin resistance syndrome have been reviewed in detail.82,84,124 –126,149,150 A total of 25%–50% of individuals
with prediabetes have the insulin resistance syndrome as
defined by National Cholesterol Education Program
(NCEP) Adult Treatment Panel III (ATP III),111 and ⬎50%
of these individuals have ⱖ2 components of the insulin
resistance syndrome,234 placing them at high risk for
ASCVD.
From the therapeutic standpoint, the TZDs are potent insulin sensitizers in muscle, liver, and adipocytes39,123,235–237 and
also enhance ␤-cell function.39,238 Not surprisingly, the
TZDs have proved highly effective in preventing the
progression of IGT/IFG to type 2 diabetes.190 –195 In
the PROactive study, pioglitazone significantly reduced the
combined endpoint of all-cause mortality, MI, and stroke,183
and in a meta-analysis of all published studies significantly
decreased CV events in patients with type 2 diabetes.203
Therefore, the TZDs— especially at low doses and in combination with metformin—represent a rational choice to
ameliorate insulin resistance, prevent the progression of
IGT/IFG to type 2 diabetes, and possibly to reduce the high
incidence of CV events in individuals with prediabetes and
11B
type 2 diabetes. In subjects with these conditions, TZDs also
reduce CRP, circulating inflammatory markers, and procoagulant factors.239,240
Metformin also is an insulin sensitizer but its primary
effect is on the liver, with a weak effect on muscle.241–243 In
the US DPP study, metformin decreased the conversion rate
of IGT to type 2 diabetes by 32%,190 but this decrease
represented only about 50% of the effectiveness of use of
lifestyle intervention or TZDs.191–194 Metformin also decreased CV events in the UKPDS.244 Because of its proven
efficacy, cost-effectiveness, and safety, the ADA has recommended metformin for the treatment of high-risk individuals with IGT or IFG.201
Dyslipidemia: Any assessment of the patient with prediabetes should involve the measurement of plasma LDL-C,
non–HDL-C (total cholesterol minus HDL-C), HDL-C, and
TG concentrations. Whether LDL particle size and number
should be measured as part of the general evaluation of the
patient with prediabetes remains at the discretion of the
individual physician.
Elevated LDL-C, non–HDL-C, small, dense LDL particles (phenotype B), and reduced HDL-C are major risk
factors for ASCVD in individuals with NGT and in persons
with prediabetes and type 2 diabetes.245–250 The role of
elevated TGs as a major CV risk factor remains controversial.251 In individuals with prediabetes and type 2 diabetes,
the incidence of hypercholesterolemia is not increased compared with the general population,252 but the incidence of
small, dense atherogenic LDL particles (phenotype B) is
markedly increased and represents a major risk factor for
accelerated atherogenesis.250 Small, dense LDL particles are
closely associated with insulin resistance.253
LDL-C: Multiple studies have documented the benefit
of LDL-C reduction in individuals with type 2 diabetes. In
the Heart Protection Study254,255 reduction in LDL-C with
simvastatin was shown to be effective in decreasing CV
events in patients with diabetes with and without a history
of CAD, an HbA1c level ⬎7.0 or ⬍7.0%, and irrespective of
the starting levels of LDL-C (⬎115 mg/dL or ⬍115 mg/
dL), HDL-C (⬎35 mg/dL or ⬍35 mg/dL) [1 mg/dL ⫽
0.0259 mmol/L], and TGs (⬎182 mg/dL or ⬍182 mg/dL [1
mg/dL ⫽ 0.0113 mmol/L]). In the Scandinavian Simvastatin
Survival Study (4S),256 simvastatin was effective in reducing coronary events in individuals with normal fasting glucose, IFG, and diabetes. Similarly, the subgroup analysis in
the Cholesterol and Recurrent Events (CARE) trial246 demonstrated that, for similar initial cholesterol levels, pravastatin was more effective in reducing CV events in patients
with IFG and diabetes compared with individuals with a
normal fasting glucose concentration. In the Collaborative
Atorvastatin Diabetes Study (CARDS),257,258 use of atorvastatin in patients with diabetes reduced major CV events by
37% and stroke by 48%. Of note, the patients with diabetes
in CARDS had “normal” cholesterol levels and no evidence
of CVD. In the Treating to New Targets (TNT) trial,259
12B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
intensive therapy with atorvastatin (80 mg/day) reduced the
rate of major CV events by 25%, compared with 10 mg/day
of atorvastatin in patients with diabetes with CAD. The
LDL-C level at study end in the 2 treatment groups was 77
mg/dL and 99 mg/dL, respectively. In the recently published JUPITER (Justification for the use of Statins in Prevention: an International Trial Evaluating Rosuvastatin)
trial patients with diabetes but without evidence of CAD
and a starting LDL-C level of 108 mg/dL were treated with
rosuvastatin to achieve a goal of 54 mg/dL.260 The incidence
of CV events was reduced by 46% with rosuvastatin compared with placebo.
Because prediabetes and diabetes are CV risk equivalents, the goals for LDL-C level should be similar in both
groups261,262: LDL-C ⬍70 mg/dL in patients with prediabetes/diabetes with known CVD or without CVD but with
ⱖ1 additional major CV risk factor; and LDL-C ⬍100
mg/dL in patients with prediabetes/diabetes without CVD
and without any major CV risk factor. However, it should
be noted that identification of patients with diabetes without
CVD and without major CV risk factors (obesity, dyslipidemia, hypertension) is distinctly uncommon. Moreover,
the results of JUPITER strongly suggest that even patients
with diabetes without CVD or CV risk factors should be
treated to an LDL-C goal of 70 mg/dL.260
LDL particle size and number: Many studies, both
cross-sectional263 and prospective,264 –268 have demonstrated
that LDL particle number and size may be better indicators
of CV risk than LDL-C concentration. Small, dense LDL
particles are especially atherogenic and also are an important predictor of CVD.269,270 Therefore, the physician may
wish to obtain a nuclear magnetic resonance measurement
of LDL particle number or size. However, if the goal of
therapy is to reduce the LDL-C concentration to 70 mg/dL,
the role of more aggressive therapy with a 3-hydroxy-3
methylglutaryl coenzyme A reductase inhibitor (statin),
even if LDL particle number/size is not normalized, is not
clear. On the other hand, if the goal of therapy is an LDL-C
target of 100 mg/dL, the finding of an increased number of
small, dense LDL particles might push the physician to
further reduce LDL-C to 70 mg/dL.
HDL-C: Many studies have demonstrated that a low
HDL-C level is a risk factor for CVD in individuals with
and without diabetes.271,272 The ADA recommends therapeutic goals for HDL-C of ⬎40 mg/dL in men and ⬎50
mg/dL in women,208 whereas the AHA recommends raising
HDL-C without setting a specific goal.111,273 The most effective drug for raising HDL-C is nicotinic acid, but there
have been no large, long-term CV outcomes trials specifically targeting either diabetic or prediabetic populations.
Moreover, it is difficult to define the specific role of raising
HDL-C in preventing CVD because all interventions that
raise HDL-C also improve the concentrations of other lipoproteins.274 The Veterans Affairs High-Density Lipoprotein
Cholesterol Intervention Trial (VA-HIT)275 examined the
effect of gemfibrozil in individuals, including 625 patients
with diabetes, with CAD and low HDL-C levels. A post hoc
analysis showed a modest reduction in CV events that
correlated with the increase in HDL-C level.275 Although
not well appreciated, the TZDs, especially pioglitazone,
raise levels of HDL-C by an average of 4 – 6 mg/dL.276,277
Chronic physical training also is effective in raising the
HDL-C level278 and has other benefits, including improved
insulin sensitivity, protection against the development of
type 2 diabetes in individuals with prediabetes, and reduction in CV events. Dietary intake of omega-3 fatty acids also
can cause a modest elevation in HDL-C.279
Plasma TGs: During the fasting state, plasma TGs primarily are located in VLDL, and the plasma TG concentration has been used as a surrogate measure of VLDL. In most
studies plasma TGs are a univariate predictor of CVD but
they drop out as a predictor in multivariate analyses, most
likely because elevated plasma TG concentrations are
closely linked to reduced HDL-C and, to a lesser extent, to
elevated LDL-C.280 In the FIELD (Fenofibrate Intervention
and Event Lowering in Diabetes) study, fenofibrate caused
a nonsignificant reduction in the primary outcome of total
CV events in patients with diabetes.251 The secondary outcome of nonfatal MI decreased, but fatal MI increased.
Decreased nonfatal MI without benefit on fatal MI or total
mortality also has been seen with clofibrate,281 gemfibrozil,275,282 and bezafibrate.283 The largely negative results of
FIELD251 have been attributed to the low starting plasma
TG concentration (173 mg/dL) and higher statin drop-in rate
in the placebo group. In the Helsinki Heart Study,282 the
subgroup of patients with diabetes who had very high TG
and low HDL-C levels experienced a reduction in CV
events with gemfibrozil. Similarly, in the Action to Control
Cardiovascular Risk in Diabetes (ACCORD) trial, in the
subgroup of patients with diabetes who had high plasma TG
(ⱖ204 mg/dL) and low HDL-C (ⱕ34 mg/dL) levels, a
reduction in CV events (p ⫽ 0.06) was observed.284 Based
on the results summarized above, treatment to LDL-C and
non–HDL-C (see below) goals should remain the primary
and secondary focuses of lipid intervention therapy, respectively, in patients with prediabetes or type 2 diabetes. Interventions to raise HDL-C should be the tertiary aim.
Non–HDL-C: Non–HDL-C represents the difference
between total cholesterol and HDL-C concentrations and
reflects the amount of cholesterol within those lipoprotein
particles that have been demonstrated to be atherogenic.
Several studies have documented that non–HDL-C is a better
predictor of CVD than the LDL-C concentration.285–288 The
ADA, American College of Cardiology (ACC), and ATP III
recommend targeting LDL-C first, with non–HDL-C as a
secondary target.262,273 The non–HDL-C goals should be 30
mg/dL greater than the LDL goal. Thus, for the great majority of patients with prediabetes or diabetes in whom the
LDL-C goal is 70 mg/dL, the non–HDL-C goal will be 100
mg/dL. Interventional strategies for treating non–HDL-C
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
include use of low-fat diet, niacin, fibrates, pioglitazone,
and omega-3 fatty acids.
Blood pressure: All patients with prediabetes should
have their systolic and diastolic blood pressure measured
after 5 minutes in the reclining position and after standing.
The Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC7)
classifies blood pressure in 4 categories: (1) normal, ⬍120/
⬍80 mm Hg; (2) prehypertension, 120 –129/80 – 89 mm Hg;
(3) stage 1 hypertension, 140 –150/90 –99 mm Hg; and (4)
stage 2 hypertension, ⬎160/ⱖ100 mm Hg.289
Hypertension is a major risk factor for CVD,290 occurs in
50%– 60% of individuals with type 2 diabetes,291 and is 2–3
times more common in individuals with prediabetes compared with nondiabetic subjects.292 Diabetes and hypertension,293,294 as well as prediabetes and hypertension,295 are
additive risk factors for atherosclerosis and CVD. Epidemiologic studies show that the increased risk for CV events and
mortality starts at a blood pressure level ⬎115/75 mm Hg in
the general population and doubles for every 20-mm Hg
systolic and 10-mm Hg diastolic increase.296 The ADA/
AHA suggest that the blood pressure goal in patients with
type 2 diabetes should be 130/80 mm Hg,261 while the JNC7
recommendation is ⬍140/90 mm Hg. However, the optimal
level of blood pressure control remains controversial. In the
Hypertension Optimal Treatment (HOT) trial,297 subjects
with and without diabetes were randomized to 1 of 3 diastolic blood pressure categories (ⱕ90, ⱕ85, or ⱕ80 mm
Hg). In the group with diabetes, patients randomized to a
diastolic target of ⱕ80 mm Hg had 50% of the risk of major
CV events compared with the ⱕ90-mm Hg target group.297
Most recently, the ACCORD Study298 randomized 4,733
patients with type 2 diabetes to a systolic blood pressure
target ⬍120 mm Hg or ⬍140 mm Hg for 4.7 years. At 1
year, mean blood pressure was 119 mm Hg in the intensively treated group and 133 mm Hg in the standard therapy
group. The respective values for diastolic blood pressure
were 64 mm Hg and 70 mm Hg. The primary composite
outcome of nonfatal MI, stroke, and death from CV causes
was similar in both groups (hazard ratio [HR] ⫽ 0.88, p ⫽
0.20). The HR for stroke was significantly reduced in the
intensive group (HR ⫽ 0.59, p ⫽ 0.01), but the total number
of strokes (36 vs 62) was relatively small in both groups.
Serious adverse events attributed to antihypertensive therapy occurred in 3.3% of intensively treated patients with
diabetes compared with 1.3% in the standard therapy group
(p ⬍0.001). Overall, targeting systolic blood pressure to
120 mm Hg versus 140 mm Hg did not reduce the risk for
CV events and increased the risk for serious adverse events.
The achievement of lower blood pressure in the intensive
therapy group required a greater number of drugs from
every class (mean number of medications, 3.4). Of note, in
the ABCD (Appropriate Blood Pressure Control in Diabetes) trial, a mean systolic blood pressure of 132 mm Hg was
achieved in the intensively treated group, but no significant
13B
decrease in CVD endpoints occurred although total mortality was reduced.299 In the ADVANCE (Action in Diabetes
and Vascular Disease: Preterax and Diamicron Modified
Release Controlled Evaluation) trial, the fixed combination
of an angiotensin-converting enzyme (ACE) inhibitor plus
the diuretic indapamide in patients with diabetes reduced
the risk of both microvascular and macrovascular complications by 9% and decreased the risk of CV death by 18%
regardless of the initial blood pressure level.300 In summary,
the HOT trial indicates that targeting diastolic blood pressure to 80 mm Hg significantly reduces CV risk. However,
the ideal target for systolic blood pressure (ie, ⬍140 mm Hg
vs ⬍120 mm Hg) remains controversial. For now the ADA/
AHA goal of systolic blood pressure ⱕ130 mmHg remains
reasonable.261
With regard to the choice of antihypertensive agents, a
recent meta-analysis of 147 randomized, controlled blood
pressure trials in patients with and without diabetes concluded that all classes of blood pressure–lowering drugs had
a similar effect on reduction of CV events for a given
reduction in blood pressure.289 The exception was the
␤-blockers which, when given shortly after an MI and when
continued for 1–2 years thereafter, significantly reduced CV
risk compared with other categories of drugs.289 Because
multiple trials suggest that the beneficial effects of ACE
inhibitors and angiotensin receptor blockers (ARBs) are not
limited to blood pressure reduction,301–304 and because ACE
inhibitors/ARBs have a specific preventive effect on diabetic nephropathy,305,306 they are recommended as the drugs
of choice in patients with diabetes, and it seems reasonable
to use them as first-line therapy in patients with prediabetes
as well. However, it should be noted that most patients with
prediabetes or diabetes require at least 2– 4 antihypertensive
medications to achieve optimal blood pressure control.
Procoagulant state: No specific assessment of coagulability is recommended in patients with prediabetes. However, antiplatelet therapy is advocated in patients with this
condition who are at high risk for CVD. Diabetes is a
hypercoagulable state, and multiple coagulation abnormalities have been described, including increased levels of
plasminogen activator inhibitor–1 and fibrinogen, as well as
increased platelet adherence.307 Meta-analyses of 195 trials
including ⬎135,000 patients (4,961 with diabetes) at high
risk for CVD given antiplatelet drugs (aspirin, clopidogrel,
or dipyridamole alone or in combination) revealed a 25%
reduction in stroke, MI, or vascular death.308 –310 The optimal effective aspirin dose was 75–150 mg/dL. In patients
with diabetes and established CVD, clopidogrel gave the
greatest protection against CV events.311–313 The most recent AHA/ADA guidelines recommend aspirin as primary
prevention in patients with diabetes at increased CV risk,261
and it is reasonable to use the same approach in patients
with prediabetes.
Tobacco smoking: All patients with prediabetes should
be questioned about their history of smoking. Cigarette
14B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
smoking is a strong CV risk factor in individuals with or
without diabetes,314,315and smoking cessation leads to a
significant reduction in mortality with a trend toward reduction in CV death.316 All patients with prediabetes or diabetes
should be cautioned against smoking, and those who smoke
should be referred to a formal smoking-cessation program
and/or considered for treatment with nicotine substitutes
and/or bupropion hydrochloride.
Endothelial dysfunction: The assessment of endothelial
dysfunction (postischemic brachial arterial dilation or acetylcholine-induced brachial arterial vasodilation) is not
practical for the primary care physician. However, it is
reasonable to assume that patients with prediabetes or diabetes who are insulin-resistant also have moderate-to-severe
endothelial dysfunction.317
The endothelium plays a pivotal role in arterial vascular
smooth muscle cell relaxation317–320 by releasing nitric oxide (NO), formed intracellularly by NO synthase, from
L-arginine in response to a variety of stimuli including
insulin. NO is a potent vasodilator and antiatherogenic molecule.317–320 NO stimulates muscle guanylyl cyclase to form
cyclic guanosine monophosphate, leading to vasodilation of
vascular smooth muscle cells. In states of NO deficiency, as
occurs in prediabetes321 and type 2 diabetes,322 the atherosclerotic process is accelerated, blood pressure is increased,
and paradoxical coronary arterial vasoconstriction occurs.
Because NO generation is dependent on an intact insulin
signaling (IRS-1/PI-3 kinase/Akt) pathway, states of insulin
resistance, such as prediabetes and type 2 diabetes, are
characterized by NO deficiency, endothelial dysfunction,
hypertension, and accelerated atherosclerosis.123 Insulinsensitizing drugs, in particular the TZDs, have a major
impact on improvement of endothelial dysfunction.
Inflammation: Chronic inflammation is a characteristic
feature of type 2 diabetes,320,322 and elevated circulating
levels of inflammatory cytokines (eg, interleukin-6)323 have
been reported in individuals with prediabetes. Some centers
have advocated the measurement of CRP as part of the
evaluation of CV risk,324and the FDA has approved the use
of rosuvastatin in patients without diabetes with an LDL-C
level ⬍100 mg/dL and an elevated CRP level ⬎2.0 mg/dL
[1 mg/dL ⫽ 9.52 nmol/L]. However, routine measurement
of CRP has yet to be endorsed by the AHA or the ADA.
Absolute risk assessment: It generally is recommended
that all patients identified as having increased CV risk (eg,
patients with prediabetes) have a global risk assessment for
their 10-year risk for CVD.206 A global risk assessment can
be performed using the Framingham cardiovascular risk
calculator173 or the Prospective Cardiovascular Münster
(PROCAM) scoring system.294 These methods use easy-tocollect clinical parameters including age, sex, use of cigarettes,
plasma lipids, and blood pressure. Based on the Framingham
score, individuals with the metabolic syndrome have been
divided into high (⬎20%), moderately high (10%–20%), and
moderate (⬍10%) 10-year CV event risk categories.
Conclusion
Prediabetes (IGT and/or IFG) is a CV risk equivalent, and
patients with IGT or IFG should be aggressively treated to
correct all CV risk factors. Lifestyle modification and, in highrisk individuals, pharmacologic intervention, should be initiated to prevent the progression of IGT/IFG to overt type 2
diabetes.
Author Disclosures
The authors who contributed to this article have disclosed
the following industry relationships:
Ralph A. DeFronzo, MD, is a member of the Speakers’
Bureau of Novo Nordisk A/S; serves on the advisory boards
of Amylin Pharmaceuticals, Inc., Boehringer Ingelheim, Eli
Lilly and Company, Isis Pharmaceuticals, Inc., and Takeda
Pharmaceuticals North America, Inc.; and has received research/grant support from Amylin Pharmaceuticals, Inc., Eli
Lilly and Company, and Takeda Pharmaceuticals North
America, Inc.
Muhammad Abdul-Ghani, MD, PhD, reports no relationships to disclose with any manufacturer of a product or
device discussed in this supplement.
1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008;31:S55–S60.
2. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired
fasting glucose and impaired glucose tolerance: results from the
Veterans Administration Genetic Epidemiology Study. Diabetes
2006;55:1430 –1435.
3. Abdul-Ghani MA, Tripathy D, DeFronzo RA. Contributions of ␤-cell
dysfunction and insulin resistance to the pathogenesis of impaired
glucose tolerance and impaired fasting glucose. Diabetes Care 2006;
29:1130 –1139.
4. Abdul-Ghani M, Matsuda M, Sabbah M, Jenkinson C, Richardson
DK, DeFronzo RA. The relative contribution of insulin resistance and
␤-cell failure to the transitiion from normal to impaired glucose
tolerance varies in different ethnic groups. Diabetes Metab Syndr
2007;1:105–112.
5. Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, DeFronzo RA.
␤-Cell dysfunction and glucose intolerance: results from the San
Antonio metabolism (SAM) study. Diabetologia 2004;47:31–39.
6. Ferrannini E, Gastaldelli A, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. ␤-Cell function in subjects spanning the range from
normal glucose tolerance to overt diabetes: a new analysis. J Clin
Endocrinol Metab 2005;90:493–500.
7. Charles MA, Fontbonne A, Thibult N, Warnet JM, Rosselin GE,
Eschwege E. Risk factors for NIDDM in white population: Paris
Prospective Study. Diabetes 1991;40:796 –799.
8. Motala AA, Omar MA, Gouws E. High risk of progression to
NIDDM in South-African Indians with impaired glucose tolerance.
Diabetes 1993;42:556 –563.
9. Kahn SE, Leonetti DL, Prigeon RL, Boyko EJ, Bergstom RW,
Fujimoto WY. Proinsulin levels predict the development of non-
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
insulin-dependent diabetes mellitus (NIDDM) in Japanese-American
men. Diabet Med 1996;13:S63–S66.
Saad MF, Knowler WC, Pettitt DJ, Nelson RG, Mott DM, Bennett
PH. The natural history of impaired glucose tolerance in the Pima
Indians. N Engl J Med 1988;319:1500 –1506.
King H, Zimmet P, Raper LR, Balkau B. The natural history of
impaired glucose tolerance in the Micronesian population of Nauru:
a six-year follow-up study. Diabetologia 1984;26:39 – 43.
de Vegt F, Dekker JM, Jager A, Hienkens E, Kostense PJ, Stehouwer
CD, Nijpels G, Bouter LM, Heine RJ. Relation of impaired fasting
and postload glucose with incident type 2 diabetes in a Dutch population: the Hoorn Study. JAMA 2001;285:2109 –2113.
Ferrannini E, Nannipieri M, Williams K, Gonzales C, Haffner SM,
Stern MP. 2004 Mode of onset of type 2 diabetes from normal or
impaired glucose tolerance. Diabetes 2004;53:160 –165.
Haffner SM, Miettinen H, Gaskill SP, Stern MP. Decreased insulin
secretion and increased insulin resistance are independently related to
the 7-year risk of NIDDM in Mexican-Americans. Diabetes 1995;
44:1386 –1391.
Wong MS, Gu K, Heng D, Chew SK, Chew LS, Tai ES. The
Singapore impaired glucose tolerance follow-up study: does the ticking clock go backward as well as forward? Diabetes Care 2003;
26:3024 –3030.
Ko GT, Chan JC, Cockram CS. Change of glycaemic status in
Chinese subjects with impaired fasting glycaemia. Diabet Med 2001;
18:745–748.
Gerstein HC, Santaguida P, Raina P, Morrison KM, Balion C, Hunt
D, Yazdi H, Booker L. Annual incidence and relative risk of diabetes
in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies. Diabetes Res Clin
Pract 2007;78:305–312.
Barr EL, Boyko EJ, Zimmet PZ, Wolfe R, Tonkin AM, Shaw JE.
Continuous relationships between non-diabetic hyperglycaemia and
both cardiovascular disease and all-cause mortality: the Australian
Diabetes, Obesity, and Lifestyle (AusDiab) study. Diabetologia
2009;52:415– 424.
The DECODE Study Group. Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. Lancet 1999;354:617– 621.
DECODE Study Group. Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria. Arch
Intern Med 2001;161:397– 405.
Qiao Q, Pyorala K, Pyorala M, Nissinen A, Lindstrom J, Tilvis R,
Tuomilehto J. Two-hour glucose is a better risk predictor for incident
coronary heart disease and cardiovascular mortality than fasting glucose. Eur Heart J 2002;23:1267–1275.
Nakagami T. Hyperglycaemia and mortality from all causes and from
cardiovascular disease in five populations of Asian origin. Diabetologia 2004;47:385–394.
Hyvarinen M, Qiao Q, Tuomilehto J, Laatikainen T, Heine RJ,
Stehouwer CD, Alberti KG, Pyorala K, Zethelius B, Stegmayr B.
Hyperglycemia and stroke mortality: comparison between fasting and
2-h glucose criteria. Diabetes Care 2009;32:348 –354.
Ning F, Tuomilehto J, Pyorala K, Onat A, Soderberg S, Qiao Q.
Cardiovascular disease mortality in europeans in relation to fasting
and 2h plasma glucose levels within a normoglycemic range. Diabetes Care 2010;33:2211–2216.
Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coronary-heartdisease risk and impaired glucose tolerance: the Whitehall Study.
Lancet 1980;1:1373–1376.
Rodriguez BL, Lau N, Burchfiel CM, Abbott RD, Sharp DS, Yano K,
Curb JD. Glucose intolerance and 23-year risk of coronary heart
disease and total mortality: the Honolulu Heart Program. Diabetes
Care 1999;22:1262–1265.
Balkau B, Shipley M, Jarrett RJ, Pyorala K, Pyorala M, Forhan A,
Eschwege E. High blood glucose concentration is a risk factor for
mortality in middle-aged nondiabetic men: 20-year follow-up in the
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
15B
Whitehall Study, the Paris Prospective Study, and the Helsinki
Policemen Study. Diabetes Care 1998;21:360 –367.
Barr EL, Zimmet PZ, Welborn TA, Jolley D, Magliano DJ, Dunstan
DW, Cameron AJ, Dwyer T, Taylor HR, Tonkin AM, et al. Risk of
cardiovascular and all-cause mortality in individuals with diabetes
mellitus, impaired fasting glucose, and impaired glucose tolerance:
the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).
Circulation 2007;116:151–157.
Jarrett RJ, McCartney P, Keen H. The Bedford survey: ten year
mortality rates in newly diagnosed diabetics, borderline diabetics and
normoglycaemic controls and risk indices for coronary heart disease
in borderline diabetics. Diabetologia 1982;22:79 – 84.
Butler WJ, Ostrander LD Jr, Carman WJ, Lamphiear DE. Mortality
from coronary heart disease in the Tecumseh study. Long-term effect
of diabetes mellitus, glucose tolerance and other risk factors. Am J
Epidemiol 1985;121:541–547.
Barzilay JI, Spiekerman CF, Wahl PW, Kuller LH, Cushman M,
Furberg CD, Dobs A, Polak JF, Savage PJ. Cardiovascular disease in
older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria.
Lancet 1999;354:622– 625.
Tominaga M, Eguchi H, Manaka H, Igarashi K, Kato T, Sekikawa A.
Impaired glucose tolerance is a risk factor for cardiovascular disease,
but not impaired fasting glucose: the Funagata Diabetes Study. Diabetes Care 1999;22:920 –924.
Lawes CM, Parag V, Bennett DA, Suh I, Lam TH, Whitlock G, Barzi
F, Woodward M. Blood glucose and risk of cardiovascular disease in
the Asia Pacific region. Diabetes Care 2004;27:2836 –2842.
de Vegt F, Dekker JM, Ruhe HG, Stehouwer CD, Nijpels G, Bouter
LM, Heine RJ. Hyperglycaemia is associated with all-cause and
cardiovascular mortality in the Hoorn population: the Hoorn Study.
Diabetologia 1999;42:926 –931.
Rijkelijkhuizen JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD,
Dekker JM. High risk of cardiovascular mortality in individuals with
impaired fasting glucose is explained by conversion to diabetes: the
Hoorn study. Diabetes Care 2007;30:332–336.
Sourij H, Saely CH, Schmid F, Zweiker R, Marte T, Wascher TC,
Drexel H. Post-challenge hyperglycaemia is strongly associated with
future macrovascular events and total mortality in angiographied
coronary patients. Eur Heart J 2010;31:1583–1590.
Coutinho M, Gerstein HC, Wang Y, Yusuf S. The relationship between glucose and incident cardiovascular events. A meta regression
analysis of published data from 20 studies of 95,783 individuals
followed for 12.4 years. Diabetes Care 1999;22:233–240.
DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin
North Am 2004;88:787– 835.
DeFronzo RA. From the triumvirate to the ominous octet: a new
paradigm for the treatment of type 2 diabetes mellitus [Banting
lecture]. Diabetes 2009;58:773–795.
Bajaj M, DeFronzo RA. Metabolic and molecular basis of insulin
resistance. J Nucl Cardiol 2003;10:311–323.
DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes. Diabetes Rev
1997;5:177–269.
Eriksson J, Franssila-Kallunki A, Ekstrand A, Saloranta C, Widen E,
Schalin C, Groop L. Early metabolic defects in persons at increased
risk for non-insulin-dependent diabetes mellitus. N Engl J Med 1989;
321:337–343.
Pendergrass M, Bertoldo A, Bonadonna R, Nucci G, Mandarino L,
Cobelli C, DeFronzo RA. Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals. Am J Physiol Endocrinol Metab 2007;292:E92–
E100.
Groop L, Lyssenko V. Genes and type 2 diabetes mellitus. Curr Diab
Rep 2008;8:192–197.
Pratipanawatr W, Pratipanawatr T, Cusi K, Berria R, Adams JM,
Jenkinson CP, Maezono K, DeFronzo RA, Mandarino LJ. Skeletal
16B
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
muscle insulin resistance in normoglycemic subjects with a strong
family history of type 2 diabetes is associated with decreased
insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation. Diabetes 2001;50:2572–2578.
Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N,
Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI.
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic
parents. J Clin Invest 2005;115:3587–3593.
DeFronzo RA, Ferrannini E, Simonson DC. Fasting hyperglycemia in
non-insulin-dependent diabetes mellitus: contributions of excessive
hepatic glucose production and impaired tissue glucose uptake. Metabolism 1989;38:387–395.
Ferrannini E, Simonson DC, Katz LD, Reichard G Jr, Bevilacqua S,
Barrett EJ, Olsson M, DeFronzo RA. The disposal of an oral glucose
load in patients with non-insulin-dependent diabetes. Metabolism
1988;37:79 – 85.
DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J.
Effects of insulin on peripheral and splanchnic glucose metabolism in
noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985;
76:149 –155.
Groop LC, Bonadonna RC, DelPrato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA. Glucose and free fatty acid metabolism in
non-insulin-dependent diabetes mellitus. Evidence for multiple sites
of insulin resistance. J Clin Invest 1989;84:205–213.
James WP. The fundamental drivers of the obesity epidemic. Obes
Rev 2008;9(suppl 1):6 –13.
DeFronzo RA, Soman V, Sherwin RS, Hendler R, Felig P. Insulin
binding to monocytes and insulin action in human obesity, starvation,
and refeeding. J Clin Invest 1978;62:204 –213.
Koivisto VA, Yki-Jarvinen H, DeFronzo RA. Physical training and
insulin sensitivity. Diabetes Metab Rev 1986;1:445– 481.
Diamond MP, Thornton K, Connolly-Diamond M, Sherwin RS, DeFronzo RA. Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose
tolerance. J Soc Gyn Invest 1995;2:708 –715.
DeFronzo RA. The triumvirate: ␤-cell, muscle, liver. A collusion
responsible for NIDDM [Lilly Lecture 1987]. Diabetes 1988;37:667–
687.
Bergman RN, Finegood DT, Kahn SE. The evolution of ␤-cell
dysfunction and insulin resistance in type 2 diabetes. Eur J Clin
Invest 2002;32(suppl 3):35– 45.
Butler AE, Janson J, Bonner-Weir S, Ritzel R, Rizza RA, Butler PC.
␤-Cell deficit and increased ␤-cell apoptosis in humans with type 2
diabetes. Diabetes 2003;52:102–110.
Diabetes Prevention Research Group. The prevalence of retinopathy
in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Diabet Med 2007;24:137–144.
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A.
Prevalence of polyneuropathy in pre-diabetes and diabetes is
associated with abdominal obesity and macroangiopathy: the
MONICA/KORA Augsburg Surveys S2 and S3. Diabetes Care
2008;31:464 – 469.
Smith AG, Russell J, Feldman EL, Goldstein J, Peltier A, Smith S,
Hamwi J, Pollari D, Bixby B, Howard J, Singleton JR. Lifestyle
intervention for pre-diabetic neuropathy. Diabetes Care 2006;29:
1294 –1299.
Morrish NJ, Wang SL, Stevens LK, Fuller JH, Keen H. Mortality and
causes of death in the WHO Multinational Study of Vascular Disease
in Diabetes. Diabetologia 2001;44(suppl 2):S14 –S21.
Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality
from coronary heart disease in subjects with type 2 diabetes and in
nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med 1998;339:229 –234.
Giorda CB, Avogaro A, Maggini M, Lombardo F, Mannucci E,
Turco S, Alegiani SS, Raschetti R, Velussi M, Ferrannini E.
Recurrence of cardiovascular events in patients with type 2 dia-
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
80.
betes: epidemiology and risk factors. Diabetes Care
2008;31:2154 –2159.
The DECODE Study Group, on behalf of the European Diabetes
Epidemiology Group. Consequences of the new diagnostic criteria
for diabetes in older men and women. DECODE Study. Diabetes
Care 1999;22:1667–1671.
DECODE Study Group. Is the current definition for diabetes relevant
to mortality risk from all causes and cardiovascular and noncardiovascular diseases? Diabetes Care 2003;26:688 – 696.
Meigs JB, Nathan DM, D’Agostino RB Sr, Wilson PW. Fasting and
postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study. Diabetes Care 2002;25:1845–1850.
Pyorala K, Savolainen E, Lehtovirta E, Punsar S, Siltanen P. Glucose
tolerance and cornary heart disease: Helsinki Policemen Study.
J Chron Dis 1979;32:373–376.
Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Mortality from
coronary heart disease and stroke in relation to degree of glycaemia:
the Whitehall study. BMJ 1983;287:867– 870.
Fujishima M, Kiyohara Y, Kato I, Ohmura T, Iwamoto H, Nakayama
K, Ohmori S, Yoshitake T. Diabetes and cardiovascular disease in a
prospective population survey in Japan: the Hisayama Study. Diabetes 1996;45(suppl 3):S14 –S16.
Sourij H, Saely CH, Schmid F, Zweiker R, Marte T, Wascher TC,
Drexel H. Post-challenge hyperglycaemia is strongly associated with
future macrovascular events and total mortality in angiographied
coronary patients. Eur Heart J 2010 ;31:1583–1590.
Lenzen M, Ryden L, Ohrvik J, Bartnik M, Malmberg K, Scholte Op
Reimer W, Simoons ML. Diabetes known or newly detected, but not
impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro
Heart Survey on diabetes and the heart. Eur Heart J 2006;27:2969 –
2974.
Woerle HJ, Pimenta WP, Meyer C, Gosmanov NR, Szoke E, Szombathy T, Mitrakou A, Gerich JE. Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma
glucose and hemoglobin A1c values. Arch Intern Med 2004;164:
1627–1632.
Blake DR, Meigs JB, Muller DC, Najjar SS, Andres R, Nathan DM.
Impaired glucose tolerance, but not impaired fasting glucose, is
associated with increased levels of coronary heart disease risk factors:
results from the Baltimore Longitudinal Study on Aging. Diabetes
2004;53:2095–2100.
Medalie JH, Papier CM, Goldbourt U, Herman JB. Major factors in
the development of diabetes mellitus in 10,000 men. Arch Intern Med
1975;135:811– 817.
McPhillips JB, Barrett-Connor E, Wingard DL. Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance
and non-insulin-dependent diabetes mellitus in a community of older
adults. Am J Epidemiol 1990;131:443– 453.
Mykkanen L, Kuusisto J, Pyorala K, Laakso M. Cardiovascular
disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects. Diabetologia 1993;36:
553–559.
Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK.
Cardiovascular risk factors in confirmed prediabetic individuals.
Does the clock for coronary heart disease start ticking before the
onset of clinical diabetes? JAMA 1990;263:2893–2898.
Haffner SM. Insulin resistance, inflammation, and the prediabetic
state. Am J Cardiol 2003;92:18J–26J.
Haffner SM, Mykkanen L, Festa A, Burke JP, Stern MP. Insulinresistant prediabetic subjects have more atherogenic risk factors than
insulin-sensitive prediabetic subjects: implications for preventing
coronary heart disease during the prediabetic state. Circulation 2000;
101:975–980.
Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M,
Taskinen MR, Groop L. Cardiovascular morbidity and mortality
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
associated with the metabolic syndrome. Diabetes Care
2001;24:683– 689.
Goldberg RB, Temprosa M, Haffner S, Orchard TJ, Ratner RE,
Fowler SE, Mather K, Marcovina S, Saudek C, Matulik MJ, Price D,
for the Diabetes Prevention Program Research Group. Effect of
progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin
intervention: the Diabetes Prevention Program randomized trial by
the Diabetes Prevention Program Research Group. Diabetes Care
2009;32:726 –732.
Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb
Vasc Biol 2008;28:629 – 636.
Noto D, Barbagallo CM, Cefalu AB, Falletta A, Sapienza M, Cavera
G, Amato S, Pagano M, Maggiore M, Carroccio A, Notarbartolo A,
Averna MR. The metabolic syndrome predicts cardiovascular events
in subjects with normal fasting glucose: results of a 15 years follow-up in a Mediterranean population. Atherosclerosis 2008;197:
147–153.
Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: evaluation of pathological and therapeutic outcomes. Am
Heart J 2005;149:20 –32.
Monnier L, Lapinski H, Colette C. Contributions of fasting and
postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetes patients. Diabetes Care 2003;26:881–
885.
Ceriello A. Impaired glucose tolerance and cardiovascular disease:
the possible role of post-prandial hyperglycemia. Am Heart J 2004;
147:803– 807.
Ceriello A, Taboga C, Tonutti L, Quagliaro L, Piconi L, Bais B,
Da Ros R, Motz E. Evidence for an independent and cumulative
effect of postprandial hypertriglyceridemia and hyperglycemia on
endothelial dysfunction and oxidative stress generation: effects of
short- and long-term simvastatin treatment. Circulation 2002;106:
1211–1218.
Scognamiglio R, Negut C, De Kreutzenberg SV, Tiengo A, Avogaro
A. Postprandial myocardial perfusion in healthy subjects and in type
2 diabetic patients. Circulation 2005;112:179 –184.
Hanefeld M, Fischer S, Julius U, Schulze J, Schwanebeck U, Schmechel H, Ziegelasch HJ, Lindner J. Risk factors for myocardial
infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up. Diabetologia 1996;39:1577–1583.
Cavalot F, Petrelli A, Traversa M, Bonomo K, Fiora E, Conti M,
Anfossi G, Costa G, Trovati M. Postprandial blood glucose is a
stronger predictor of cardiovascular events than fasting blood glucose
in type 2 diabetes mellitus, particularly in women: lessons from the
San Luigi Gonzaga Diabetes Study. J Clin Endocrinol Metab 2006;
91:813– 819.
Saely CH, Drexel H, Sourij H, Aczel S, Jahnel H, Zweiker R,
Langer P, Marte T, Hoefle G, Benzer W, Wascher TC. Key role of
postchallenge hyperglycemia for the presence and extent of coronary atherosclerosis: an angiographic study. Atherosclerosis
2008;199:317–322.
Wascher TC, Sourij H, Roth M, Dittrich P. Prevalence of pathological glucose metabolism in patients undergoing elective coronary
angiography. Atherosclerosis 2004;176:419 – 421.
Bartnik M, Ryden L, Ferrari R, Malmberg K, Pyorala K, Simoons M,
Standl E, Soler-Soler J, Ohrvik J. The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe: the Euro Heart Survey on diabetes and the heart. Eur Heart J
2004;25:1880 –1890.
Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden
L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a
prospective study. Lancet 2002;359:2140 –2144.
Harris MI, Klein R, Welborn TA, Knuiman MW. Onset of NIDDM
occurs at least 4-7 yr before clinical diagnosis. Diabetes Care 1992;
15:815– 819.
17B
96. Hu DY, Pan CY, Yu JM. The relationship between coronary artery
disease and abnormal glucose regulation in China: the China Heart
Survey. Eur Heart J 2006;27:2573–2579.
97. Bax JJ, Young LH, Frye RL, Bonow RO, Steinberg HO, Barrett EJ.
Screening for coronary artery disease in patients with diabetes. Diabetes Care 2007;30:2729 –2736.
98. American Diabetes Association. Consensus development conference
on the diagnosis of coronary heart disease in people with diabetes.
Diabetes Care 1998;21:1551–1559.
99. Scognamiglio R, Negut C, Ramondo A, Tiengo A, Avogaro A.
Detection of coronary artery disease in asymptomatic patients with
type 2 diabetes mellitus. J Am Coll Cardiol 2006;47:65–71.
100. Wackers FJ, Young LH, Inzucchi SE, Chyun DA, Davey JA, Barrett
EJ, Taillefer R, Wittlin SD, Heller GV, Filipchuk N, et al. Detection
of silent myocardial ischemia in asymptomatic diabetic subjects: the
DIAD study. Diabetes Care 2004;27:1954 –1961.
101. Guzder RN, Gatling W, Mullee MA, Mehta RL, Byrne CD. Prognostic value of the Framingham cardiovascular risk equation and the
UKPDS risk engine for coronary heart disease in newly diagnosed
Type 2 diabetes: results from a United Kingdom study. Diabet Med
2005;22:554 –562.
102. Golomb BA, Dang TT, Criqui MH. Peripheral arterial disease:
morbidity and mortality implications. Circulation 2006;114:688 –
699.
103. Mann JF, Gerstein HC, Pogue J, Bosch J, Yusuf S. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of
ramipril: the HOPE randomized trial. Ann Intern Med 2001;134:629 –
636.
104. Gerstein HC, Mann JF, Yi Q, Zinman B, Dinneen SF, Hoogwerf
B, Halle JP, Young J, Rashkow A, Joyce C, Nawaz S, Yusuf S.
Albuminuria and risk of cardiovascular events, death, and heart
failure in diabetic and nondiabetic individuals. JAMA 2001;286:
421– 426.
105. Grimm RH Jr, Svendsen KH, Kasiske B, Keane WF, Wahi MM, for
the MRFIT Research Group. Proteinuria is a risk factor for mortality
over 10 years of follow-up: Multiple Risk Factor Intervention Trial.
Kidney Int 1997;63(suppl):S10 –S14.
106. Rajagopalan N, Miller TD, Hodge DO, Frye RL, Gibbons RJ. Identifying high-risk asymptomatic diabetic patients who are candidates
for screening stress single-photon emission computed tomography
imaging. J Am Coll Cardiol 2005;45:43– 49.
107. Rutter MK, McComb JM, Brady S, Marshall SM. Silent myocardial ischemia and microalbuminuria in asymptomatic subjects
with non-insulin-dependent diabetes mellitus. Am J Cardiol 1999;
83:27–31.
108. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic
neuropathy. Diabetes Care 2003;26:1553–1579.
109. Hiller R, Sperduto RD, Podgor MJ, Ferris FL III, Wilson PW.
Diabetic retinopathy and cardiovascular disease in type II diabetics:
the Framingham Heart Study and the Framingham Eye Study. Am J
Epidemiol 1988;128:402– 409.
110. Goraya TY, Leibson CL, Palumbo PJ, Weston SA, Killian JM,
Pfeifer EA, Jacobsen SJ, Frye RL, Roger VL. Coronary atherosclerosis
in diabetes mellitus: a population-based autopsy study. J Am Coll Cardiol 2002;40:946 –953.
111. Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults. Executive Summary of the Third
Report of the National Cholesterol Education Program (NCEP)
Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA
2001;285:2486 –2497.
112. Wilson PW, D’Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2
diabetes mellitus. Circulation 2005;112:3066 –3072.
113. Rutter MK, Meigs JB, Sullivan LM, D’Agostino RB Sr, Wilson PW.
Insulin resistance, the metabolic syndrome, and incident cardiovas-
18B
114.
115.
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
128.
129.
130.
131.
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
cular events in the Framingham Offspring Study. Diabetes
2005;54:3252–3257.
Gaede P, Vedel P, Larsen N, Jensen GV, Parving HH, Pedersen O.
Multifactorial intervention and cardiovascular disease in patients
with type 2 diabetes. N Engl J Med 2003;348:383–393.
Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a
mulifactorial interventiion on mortality in type 2 diabetes. N Engl
J Med 2008;358:580 –591.
Boden WE, O’Rourke RA, Teo KK, Hartigan PM, Maron DJ, Kostuk
W, Knudtson M, Dada M, Casperson P, Harris CL, et al. Design and
rationale of the Clinical Outcomes Utilizing Revascularization and
Aggressive DruG Evaluation (COURAGE) trial Veterans Affairs
Cooperative Studies Program no. 424. Am Heart J 2006;151:
1173–1179.
The Multiple Risk Factor Intervention Trial Research Group. Mortality after 16 years for participants randomized to the Multiple Risk
Factor Intervention Trial. Circulation 1996;94:946 –951.
Schuijf JD, Pundziute G, Jukema JW, Lamb HJ, van der Hoeven
BL, de Roos A, van der Wall EE, Bax JJ. Diagnostic accuracy of
64-slice multislice computed tomography in the noninvasive evaluation of significant coronary artery disease. Am J Cardiol 2006;
98:145–148.
Mazzone T. The role of electron beam computed tomography for
measuring coronary artery atherosclerosis. Curr Diab Rep 2004;4:
20 –25.
Anand DV, Lim E, Hopkins D, Corder R, Shaw LJ, Sharp P, Lipkin
D, Lahiri A. Risk stratification in uncomplicated type 2 diabetes:
prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy. Eur
Heart J 2006;27:713–721.
Schuijf JD, Bax JJ, Shaw LJ, de Roos A, Lamb HJ, van der Wall EE,
Wijns W. Meta-analysis of comparative diagnostic performance of
magnetic resonance imaging and multislice computed tomography
for noninvasive coronary angiography. Am Heart J 2006;151:404 –
411.
Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC,
Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002;25:1129 –
1134.
DeFronzo RA. Insulin resistance, lipotoxicity, type 2 diabetes and
atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
Diabetologia 2010;53:1270 –1287.
Kashyap SR, DeFronzo RA. The insulin resistance syndrome: physiological considerations. Diab Vasc Dis Res 2007;4:13–19.
DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia,
and atherosclerotic cardiovascular disease. Diabetes Care 1991;14:
173–194.
DeFronzo RA. Is insulin resistance atherogenic? Possible mechanisms. Atheroscler Suppl 2006;7:11–15.
Koopmans SJ, Kushwaha RS, DeFronzo RA. Chronic physiologic
hyperinsulinemia impairs suppression of plasma free fatty acids and
increases de novo lipogenesis but does not cause dyslipidemia in
conscious normal rats. Metabolism 1999;48:330 –337.
Tobey TA, Greenfield M, Kraemer F, Reaven GM. Relationship
between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man. Metabolism 1981;30:165–171.
Azzout-Marniche D, Becard D, Guichard C, Foretz M, Ferre P,
Foufelle F. Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes.
Biochem J 2000;350(pt 2):389 –393.
Stout RW. The effect of insulin on the incorporation of sodium
(1-14C)-acetate into the lipids of the rat aorta. Diabetologia 1971;7:
367–372.
King GL, Goodman AD, Buzney S, Moses A, Kahn CR. Receptors
and growth-promoting effects of insulin and insulinlike growth fac-
132.
133.
134.
135.
136.
137.
138.
139.
140.
141.
142.
143.
144.
145.
146.
147.
148.
149.
150.
tors on cells from bovine retinal capillaries and aorta. J Clin Invest
1985;75:1028 –1036.
Coletta DK, Balas B, Chavez AO, Baig M, Abdul-Ghani M, Kashyap
SR, Folli F, Tripathy D, Mandarino LJ, Cornell JE, Defronzo RA,
Jenkinson CP. Effect of acute physiological hyperinsulinemia on
gene expression in human skeletal muscle in vivo. Am J Physiol
Endocrinol Metab 2008;294:E910 –E917.
Nakao J, Ito H, Kanayasu T, Murota S. Stimulatory effect of insulin
on aortic smooth muscle cell migration induced by 12-L-hydroxy5,8,10,14-eicosatetraenoic acid and its modulation by elevated extracellular glucose levels. Diabetes 1985;34:185–191.
Pfeifle B, Ditschuneit H. Effect of insulin on growth of cultured
human arterial smooth muscle cells. Diabetologia 1981;20:155–
158.
Cruz AB Jr, Amatuzio DS, Grande F, Hay LJ. Effect of intra-arterial
insulin on tissue cholesterol and fatty acids in alloxan-diabetic dogs.
Circ Res 1961;9:39 – 43.
Duff GL, McMillan GC. The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit. J Exp Med 1949;89:
611– 630.
Stamler J, Pick R, Katz LN. Effect of insulin in the induction and
regression of atherosclerosis in the chick. Circ Res 1960;8:572–576.
Koopmans SJ, Ohman L, Haywood JR, Mandarino LJ, DeFronzo
RA. Seven days of euglycemic hyperinsulinemia induces insulin
resistance for glucose metabolism but not hypertension, elevated
catecholamine levels, or increased sodium retention in conscious
normal rats. Diabetes 1997;46:1572–1578.
Meehan WP, Buchanan TA, Hsueh W. Chronic insulin administration elevates blood pressure in rats. Hypertension 1994;23:
1012–1017.
Del Prato S, Leonetti F, Simonson DC, Sheehan P, Matsuda M,
DeFronzo RA. Effect of sustained physiologic hyperinsulinaemia and
hyperglycaemia on insulin secretion and insulin sensitivity in man.
Diabetologia 1994;37:1025–1035.
Iozzo P, Pratipanawatr T, Pijl H, Vogt C, Kumar V, Pipek R, Matsuda
M, Mandarino LJ, Cusi KJ, DeFronzo RA. Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and
glycogen synthesis. Am J Physiol Endocrinol Metab 2001;280:E712–
E719.
Holman RR, Thorne KI, Farmer AJ, Davies MJ, Keenan JF, Paul
S, Levy JC. Addition of biphasic, prandial, or basal insulin to oral
therapy in type 2 diabetes. N Engl J Med 2007;357:1716 –1730.
Calle EE, Thun MJ, Petrelli JM, Rodriguez C, Heath CW Jr. Bodymass index and mortality in a prospective cohort of U.S. adults.
N Engl J Med 1999;341:1097–1105.
Allison DB, Fontaine KR, Manson JE, Stevens J, VanItallie TB.
Annual deaths attributable to obesity in the United States. JAMA
1999;282:1530 –1538.
Wang L, Sapuri-Butin AR, Aung HH, Parikh AN, Rutledge JC.
Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial membrane microdomains an dproduces reactive oxygen species. Am J Physiol Heart Circ Physiol 2008;295:H237–H244.
Felton CV, Crook D, Davies MJ, Oliver MF. Relation of plaque lipid
composition and morphology to the stability of human aortic plaques.
Arterioscler Thromb Vasc Biol 1997;17:1337–1345.
Felton CV, Crook D, Davies MJ, Oliver MF. Dietary polyunsaturated
fatty acids and composition of human aortic plaques. Lancet 1994;
344:1195–1196.
Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S,
DeFronzo RA. Obesity and insulin resistance in humans: a doseresponse study. Metabolism 1990;39:452– 459.
Reaven GM. Role of insulin resistance in human disease [Banting
lecture 1988]. Diabetes 1988;37:1595–1607.
Reaven G. Insulin resistance, hypertension, and coronary heart disease. J Clin Hypertens 2003;5:269 –274.
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
151. Ferrannini E, Buzzigoli G, Bonadonna R, Giorico MA, Oleggini M,
Graziadei L, Pedrinelli R, Brandi L, Bevilacqua S. Insulin resistance
in essential hypertension. N Engl J Med 1987;317:350 –357.
152. Solini A, DeFronzo RA. Insulin resistance, hypertension, and cellular
ion transport systems. Acta Diabetologia 1992;29:196 –200.
153. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs
in the prevention of cardiovascular disease: meta-analysis of 147
randomised trials in the context of expectations from prospective
epidemiological studies. BMJ 2009;338:b1665.
154. DeFronzo RA. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis. Neth J Med 1997;50:191–197.
155. Rana JS, Visser ME, Arsenault BJ, Despres JP, Stroes ES, Kastelein
JJ, Wareham NJ, Boekholdt SM, Khaw KT. Metabolic dyslipidemia
and risk of future coronary heart disease in apparently healthy men
and women: the EPIC-Norfolk prospective population study. Int
J Cardiol 2010;143:299 – 404.
156. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk
factors, and 12-yr cardiovascular mortality for men screened in the
Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434 –
444.
157. Sheu WH, Shieh SM, Fuh MM, Shen DD, Jeng CY, Chen YD, Reaven
GM.Insulinresistance,glucoseintolerance,andhyperinsulinemia.Hypertriglyceridemia versus hypercholesterolemia. Arterioscler Thromb 1993;
13:367–370.
158. Jeppesen J, Hollenbeck CB, Zhou MY, Coulston AM, Jones C, Chen
YD, Reaven GM. Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial
lipemia. Arterioscler Thromb Vasc Biol 1995;15:320 –324.
159. Galvan AQ, Santoro D, Natali A, Sampietro T, Boni C, Masoni A,
Buzzigoli G, Ferrannini E. Insulin sensitivity in familial hypercholesterolemia. Metabolism 1993;42:1359 –1364.
160. Howard BV, Robbins DC, Sievers ML, Lee ET, Rhoades D,
Devereux RB, Cowan LD, Gray RS, Welty TK, Go OT, Howard
WJ. LDL cholesterol as a strong predictor of coronary heart
disease in diabetic individuals with insulin resistance and low
LDL: the Strong Heart Study. Arterioscler Thromb Vasc Biol
2000;20:830 – 835.
161. Bressler P, Bailey SR, Matsuda M, DeFronzo RA. Insulin resistance
and coronary artery disease. Diabetologia 1996;39:1345–1350.
162. Paternostro G, Camici PG, Lammerstma AA, Marinho N, Baliga
RR, Kooner JS, Radda GK, Ferrannini E. Cardiac and skeletal
muscle insulin resistance in patients with coronary heart disease:
a study with positron emission tomography. J Clin Invest 1996;
98:2094 –2099.
163. Iozzo P, Chareonthaitawee P, Dutka D, Betteridge DJ, Ferrannini E,
Camici PG. Independent association of type 2 diabetes and coronary
artery disease with myocardial insulin resistance. Diabetes 2002;51:
3020 –3024.
164. Lautamaki R, Airaksinen KE, Seppanen M, Toikka J, Luotolahti M,
Ball E, Borra R, Harkonen R, Iozzo P, Stewart M, Knuuti J, Nuutila
P. Rosiglitazone improves myocardial glucose uptake in patients with
type 2 diabetes and coronary artery disease: a 16-week randomized,
double-blind, placebo-controlled study. Diabetes 2005;54:2787–
2794.
165. Gulli G, Ferrannini E, Stern M, Haffner S, DeFronzo RA. The
metabolic profile of NIDDM is fully established in glucose-tolerant
offspring of two Mexican-American NIDDM parents. Diabetes 1992;
41:1575–1586.
166. Hanley AJ, Williams K, Stern MP, Haffner SM. Homeostasis model
assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Diabetes Care
2002;25:1177–1184.
167. Bonora E, Kiechl S, Willeit J, Oberhollenzer F, Egger G, Meigs JB,
Bonadonna RC, Muggeo M. Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardio-
168.
169.
170.
171.
172.
173.
174.
175.
176.
177.
178.
179.
180.
181.
182.
183.
19B
vascular disease in caucasian subjects from the general population:
the Bruneck study. Diabetes Care 2007;30:318 –324.
Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari
L, Saggiani F, Poli M, Perbellini S, Raffaelli A, et al. HOMAestimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the
Verona Diabetes Complications Study. Diabetes Care 2002;25:
1135–1141.
Howard G, O’Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman
R, Selby JV, Saad MF, Savage P, Bergman R, for the Insulin Resistance Atherosclerosis Study (IRAS) Investigators. Insulin sensitivity
and atherosclerosis. Circulation 1996;93:1809 –1817.
Hedblad B, Nilsson P, Janzon L, Berglund G. Relation between
insulin resistance and carotid intima-media thickness and stenosis in
non-diabetic subjects: results from a cross-sectional study in Malmo,
Sweden. Diabet Med 2000;17:299 –307.
Ferrannini E, Balkau B, Coppack SW, Dekker JM, Mari A, Nolan J,
Walker M, Natali A, Beck-Nielsen H. Insulin resistance, insulin
response, and obesity as indicators of metabolic risk. J Clin Endocrinol Metab 2007;92:2885–2892.
D’Agostino RB Sr, Grundy S, Sullivan LM, Wilson P. Validation
of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation. JAMA 2001;286:
180 –187.
Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H,
Kannel WB. Prediction of coronary heart disease using risk factor
categories. Circulation 1998;97:1837–1847.
Golden SH, Folsom AR, Coresh J, Sharrett AR, Szklo M, Brancati F.
Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the Atherosclerosis Risk in
Communities Study. Diabetes 2002;51:3069 –3076.
Uusitupa MI, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K.
Ten-year cardiovascular mortality in relation to risk factors and
abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia 1993;
36:1175–1184.
Gerstein HC. Is glucose a continuous risk factor for cardiovascular
mortality? Diabetes Care 1999;22:659 – 660.
UK Prospective Diabetes Study (UKPDS) Group. Intensive bloodglucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2
diabetes (UKPDS 33). Lancet 1998;352:837– 853.
Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman
RR. Additive effects of glycaemia and blood pressure exposure on
risk of complications in type 2 diabetes: a prospective observational
study (UKPDS 75). Diabetologia 2006;49:1761–1769.
Holman RR, Paul SK, Bethel MA, Neil HA, Matthews DR. Longterm follow-up after tight control of blood pressure in type 2 diabetes.
N Engl J Med 2008;359:1565–1576.
Nathan DM, Cleary PA, Backlund JY, Genuth SM, Lachin JM,
Orchard TJ, Raskin P, Zinman B. Intensive diabetes treatment and
cardiovascular disease in patients with type 1 diabetes. N Engl J Med
2005;353:2643–2653.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse
JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, et al.
Effects of intensive glucose lowering in type 2 diabetes. N Engl
J Med 2008;358:2545–2559.
Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M,
Marre M, Cooper M, Glasziou P, Grobbee D, et al. Intensive blood
glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med 2008;358:2560 –2572.
Dormandy JA, Charbonnel B, Eckland DJ, Erdmann E, Massi-Benedetti M, Moules IK, Skene AM, Tan MH, Lefebvre PJ, Murray GD,
et al. Secondary prevention of macrovascular events in patients with
type 2 diabetes in the PROactive Study (PROspective pioglitAzone
Clinical Trial In macroVascular Events): a randomised controlled
trial. Lancet 2005;366:1279 –1289.
20B
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
184. Betteridge DJ, DeFronzo RA, Chilton RJ. PROactive: time for a
critical appraisal. Eur Heart J 2008;29:969 –983.
185. Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M.
Acarbose for prevention of type 2 diabetes mellitus: the STOPNIDDM randomised trial. Lancet 2002;359:2072–2077.
186. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin
JM, Walker EA, Nathan DM, for the Diabetes Prevention Program
Research Group. Reduction in the incidence of type 2 diabetes with
lifestyle intervention or metformin. N Engl J Med 2002;346:393–
403.
187. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H,
Ilanne-Parikka P, Keinänen-Kiukaanniemi S, Laakso M, Louheranta
A, Rastas M, et al, for the Finnish Diabetes Prevention Study Group.
Prevention of type 2 diabetes mellitus by changes in lifestyle among
subjects with impaired glucose tolerance. N Engl J Med 2001;344:
1343–1350.
188. Abdul-Ghani MA, Lyssenko V, Tuomi T, DeFronzo RA, Groop L.
Fasting versus postload plasma glucose concentration and the risk for
future type 2 diabetes: results from the Botnia Study. Diabetes Care
2009;32:281–286.
189. Eriksson KF, Lindgärde F. Prevention of type 2 (non-insulin-dependent) diabetes mellitus by diet and physical exercise: the 6-year
Malmö feasibility study. Diabetologia 1991;34:891– 898.
190. Knowler WC, Hamman RF, Edelstein SL, Barrett-Connor E,
Ehrmann DA, Walker EA, Fowler SE, Nathan DM, Kahn SE, for the
Diabetes Prevention Program Research Group. Prevention of type 2
diabetes with troglitazone in the Diabetes Prevention Program. Diabetes 2005;54:1150 –1156.
191. Berkowitz K, Peters R, Kjos SL, Goico J, Marroquin A, Dunn ME,
Xiang A, Azen S, Buchanan TA. Effect of troglitazone on insulin
sensitivity and pancreatic ␤-cell function in women at high risk for
NIDDM. Diabetes 1996;45:1572–1579.
192. Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, Ochoa C,
Kawakubo M, Buchanan TA. Effect of pioglitazone on pancreatic
beta-cell function and diabetes risk in Hispanic women with prior
gestational diabetes. Diabetes 2006;55:517–522.
193. Gerstein HC, Yusuf S, Bosch J, Pogue J, Sheridan P, Dinccag N,
Hanefeld M, Hoogwerf B, Laakso M, Mohan V, et al, for the
DREAM (Diabetes REduction Assessment with ramipril and rosiglitazone Medication) Trial Investigators. Effect of rosiglitazone on the
frequency of diabetes in patients with impaired glucose tolerance or
impaired fasting glucose: a randomised controlled trial. Lancet 2006;
368:1096 –1105.
194. DeFronzo RA, Tripathy D, Schwenke DC, Banerji M, Bray GA,
Buchanan TA, Clement SC, Henry RR, Hodis HN, Kitabchi AE, et al,
for the ACT NOW Study group. Pioglitazone for diabetes prevention
in impaired glucose tolerance. N Engl J Med 2011;364:1104 –1115.
195. Zinman B, Harris SB, Neuman J, Gerstein HC, Retnakaran RR,
Raboud J, Qi Y, Hanley AJ. Low-dose combination therapy with
rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 2010;
376:103–111.
196. Kawamori R, Tajima N, Iwamoto Y, Kashiwagi A, Shimamoto K,
Kaku K, for the Voglibose Ph-3 Study Group. Voglibose for prevention of type 2 diabetes mellitus: a randomised, double-blind trial in
Japanese individuals with impaired glucose tolerance. Lancet 2009;
373:1607–1614.
197. Torgerson JS, Hauptman J, Boldrin MN, Sjöström L. XENical in the
prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the
prevention of type 2 diabetes in obese patients. Diabetes Care 2004;
27:155–161.
198. Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD,
Vijay V, for the Indian Diabetes Prevention Programme (IDPP). The
Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects
199.
200.
201.
202.
203.
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
with impaired glucose tolerance (IDPP-1). Diabetologia
2006;49:289 –297.
Venditti EM, Bray GA, Carrion-Petersen ML, Delahanty LM, Edelstein SL, Hamman RF, Hoskin MA, Knowler WC, Ma Y, for the
Diabetes Prevention Program Research Group. First versus repeat
treatment with a lifestyle intervention program: attendance and
weight loss outcomes. Int J Obes (Lond) 2008;32:1537–1554.
Saaristo T, Moilanen L, Korpi-Hyövälti E, Vanhala M, Saltevo J,
Niskanen L, Jokelainen J, Peltonen M, Oksa H, Tuomilehto J, Uusitupa M, Keinänen-Kiukaanniemi S. Lifestyle intervention for prevention of type 2 diabetes in primary health care: one-year follow-up
of the Finnish National Diabetes Prevention Program (FIN-D2D).
Diabetes Care 2010;33:2146 –2151.
Nathan DM, Davidson MB, DeFronzo RA, Heine RJ, Henry RR,
Pratley R, Zinman B, for the American Diabetes Association. Impaired fasting glucose and impaired glucose tolerance: implications
for care. Diabetes Care 2007;30:753–759.
Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N Engl J Med
2007;356:2457–2471.
Lincoff AM, Wolski K, Nicholls SJ, Nissen SE. Pioglitazone and
risk of cardiovascular events in patients with type 2 diabetes
mellitus: a meta-analysis of randomized trials. JAMA 2007;
298:1180 –1188.
Miyazaki M, De Filippis E, Bajaj M, Wajcberg E, Glass L, Triplitt C,
Cersosimo E, Mandarino LJ, DeFronzo RA. Predictors of improved
glycaemic control with rosiglitazone therapy in type 2 diabetic patients: a practical approach for the primary care physician. Br J
Diabetes Vasc Dis 2005;5:28 –35.
Miyazaki Y, Glass L, Triplitt C, Wajcberg E, Mandarino L, DeFronzo RA. Abdominal fat distribution and peripheral and hepatic
insulin resistance in type 2 diabetes mellitus. Am J Physiol Endocrinol Metab 2002;46:E1135–E1143.
Rosenzweig JL, Ferrannini E, Grundy SM, Haffner SM, Heine RJ,
Horton ES, Kawamori R, for the Endocrine Society. Primary prevention of cardiovascular disease and type 2 diabetes in patients at
metabolic risk: an endocrine society clinical practice guideline. J Clin
Endocrinol Metab 2008 ;93:3671–3689.
Mokdad AH, Ford ES, Bowman BA, Dietz WH, Vinicor F, Bales VS,
Marks JS. Prevalence of obesity, diabetes, and obesity-related health
risk factors, 2001. JAMA 2003;289:76 –79.
American Diabetes Assocation. 2006 Standards of medical care in
diabetes—2006. Diabetes Care 2006;29(suppl 1):S4 –S42.
Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C, White
RD. Physical activity/exercise and type 2 diabetes: a consensus statement from the American Diabetes Association. Diabetes Care 2006;
29:1433–1438.
Jones LR, Wilson CI, Wadden TA. Lifestyle modification in the
treatment of obesity: an educational challenge and opportunity. Clin
Pharmacol Ther 2007;81:776 –779.
Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients
with diabetes. Part I: recent advances in prevention and noninvasive
management. J Am Coll Cardiol 2007;49:631– 642.
Lichtenstein AH, Appel LJ, Brands M, Carnethon M, Daniels S,
Franch HA, Franklin B, Kris-Etherton P, Harris WS, Howard B et al.
Diet and lifestyle recommendations revision 2006: a scientific statement from the American Heart Association Nutrition Committee.
Circulation 2006;114:82–96.
Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE,
Haffner SM, Andres R, Saudek C, Edelstein SL, Arakaki R, Murphy
MB, Shamoon H, for the Diabetes Prevention Program Research
Group. Role of insulin secretion and sensitivity in the evolution of
type 2 diabetes in the diabetes prevention program: effects of lifestyle
intervention and metformin. Diabetes 2005;54:2404 –2414.
Saaristo T, Moilanen L, Korpi-Hyövälti E, Vanhala M, Saltevo J,
Niskanen L, Jokelainen J, Peltonen M, Oksa H, Tuomilehto J, Uusitupa M, Keinänen-Kiukaanniemi S. Lifestyle intervention for pre-
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
215.
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
226.
227.
228.
229.
230.
231.
232.
vention of type 2 diabetes in primary health care: one-year follow-up
of the Finnish National Diabetes Prevention Program (FIN-D2D).
Diabetes Care 2010;33:2146 –2151.
DeFronzo RA, Soman V, Sherwin RS, Hendler R, Felig P. Insulin
binding to monocytes and insulin action in human obesity, starvation,
and refeeding. J Clin Invest 1978;62:204 –213.
Henry RR, Wallace P, Olefsky JM. Effects of weight loss on mechanisms of hyperglycemia in obese non-insulin-dependent diabetes
mellitus. Diabetes 1986;35:990 –998.
Goldhaber-Fiebert JD, Goldhaber-Fiebert SN, Tristán ML, Nathan
DM. Randomized controlled community-based nutrition and exercise
intervention improves glycemia and cardiovascular risk factors in
type 2 diabetic patients in rural Costa Rica. Diabetes Care 2003;26:
24 –29.
Ryan DH, Espeland MA, Foster GD, Haffner SM, Hubbard VS,
Johnson KC, Kahn SE, Knowler WC, Yanovski SZ. Look AHEAD
(Action for Health in Diabetes): design and methods for a clinical
trial of weight loss for the prevention of cardiovascular disease in
type 2 diabetes. Control Clin Trials 2003;24:610 – 628.
Franz MJ, Bantle JP, Beebe CA, Brunzell JD, Chiasson JL, Garg A,
Holzmeister LA, Hoogwerf B, Mayer-Davis E, Mooradian AD, Purnell JQ, Wheeler M. Nutrition principles and recommendations in
diabetes. Diabetes Care 2004;27(suppl 1):S36 –S46.
Church TS, Cheng YJ, Earnest CP, Barlow CE, Gibbons LW, Priest
EL, Blair SN. Exercise capacity and body composition as predictors
of mortality among men with diabetes. Diabetes Care 2004;27:
83– 88.
Sigal RJ, Kenny GP, Wasserman DH, Castaneda-Sceppa C. Physical
activity/exercise and type 2 diabetes. Diabetes Care 2004;27:2518 –
2539.
Wei M, Gibbons LW, Kampert JB, Nichaman MZ, Blair SN. Low
cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med 2000;132:
605– 611.
Hu FB, Stampfer MJ, Solomon C, Liu S, Colditz GA, Speizer FE,
Willett WC, Manson JE. Physical activity and risk for cardiovascular
events in diabetic women. Ann Intern Med 2001;134:96 –105.
Batty GD, Shipley MJ, Marmot M, Smith GD. Physical activity and
cause-specific mortality in men with Type 2 diabetes/impaired glucose tolerance: evidence from the Whitehall study. Diabet Med 2002;
19:580 –588.
Gregg EW, Gerzoff RB, Caspersen CJ, Williamson DF, Narayan
KM. Relationship of walking to mortality among US adults with
diabetes. Arch Intern Med 2003;163:1440 –1447.
Tanasescu M, Leitzmann MF, Rimm EB, Hu FB. Physical activity in
relation to cardiovascular disease and total mortality among men with
type 2 diabetes. Circulation 2003;107:2435–2439.
DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a
method for quantifying insulin secretion and resistance. Am J Physiol
1979;237:E214 –E223.
Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF,
Turner RC. Homeostasis model assessment: insulin resistance and
␤-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985;28:412– 419.
Matsuda M, DeFronzo RA. Insulin sensitivity indices obtained from
oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 1999;22:1462–1470.
Stern SE, Williams K, Ferrannini E, DeFronzo RA, Bogardus C,
Stern MP. Identification of individuals with insulin resistance using
routine clinical measurements. Diabetes 2005;54:333–339.
McLaughlin T, Reaven G, Abbasi F, Lamendola C, Saad M, Waters
D, Simon J, Krauss RM. Is there a simple way to identify insulinresistant individuals at increased risk of cardiovascular disease? Am J
Cardiol 2005;96:399 – 404.
Ferrannini E, Balkau B, Coppack SW, Dekker JM, Mari A, Nolan
J, Walker M, Natali A, Beck-Nielsen H, for the RISC Investiga-
233.
234.
235.
236.
237.
238.
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
21B
tors. Insulin resistance, insulin response, and obesity as indicators
of metabolic risk. J Clin Endocrinol Metab 2007;92:2885–2892.
Savva SC, Tornartis M, Savva ME, Kourides Y, Panagi A, Silikiotou
N, Georgiou C, Kafatos A. Waist circumfernce and waist-to-height
ratio are better predictors of cardiovascular disease risk factors in
children than body mass index. Nature 2000;24:1453–1458.
Alexander CM, Landsman PB, Teutsch SM, Haffner SM, for the
Third National Health and Nutrition Examination Survey (NHANES
III) and the National Cholesterol Education Program (NCEP). NCEPdefined metabolic syndrome, diabetes, and prevalence of coronary
heart disease among NHANES III participants age 50 years and
older. Diabetes 2003;52:1210 –1214.
Miyazaki Y, He H, Mandarino LJ, DeFronzo RA. Rosiglitazone
improves downstream insulin receptor signaling in type 2 diabetic
patients. Diabetes 2003;52:1943–1950.
Bajaj M, Baig R, Suraamornkul S, Hardies LJ, Coletta DK, Cline
GW, Monroy A, Koul S, Sriwijitkamol A, Musi N, Shulman GI,
DeFronzo RA. Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. J Clin Endocrinol
Metab 2010;95:1916 –1923.
Yki-Järvinen H. Thiazolidinediones. N Engl J Med 2004;351:1106 –
1118.
Gastaldelli A, Ferrannini E, Miyazaki Y, Matsuda M, Mari A, DeFronzo RA. Thiazolidinediones improve ␤-cell function in type 2
diabetic patients. Am J Physiol 2007;292:E871-E833.
Bays H, Mandarino L, DeFronzo RA. Role of the adipocyte, free fatty
acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus:
peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. J Clin Endocrinol Metab 2004;89:463–
478.
Mazzone T. Strategies in ongoing clinical trials to reduce cardiovascular disease in patients with diabetes mellitus and insulin resistance.
Am J Cardiol 2004;93(suppl):27C–31C.
Natali A, Ferrannini E. Effects of metformin and thiazolidinediones
on suppression of hepatic glucose production and stimulation of
glucose uptake in type 2 diabetes: a systematic review. Diabetologia
2006;49:434 – 441.
Cusi K, Consoli A, DeFronzo RA. Metabolic effects of metformin on
glucose and lactate metabolism in noninsulin-dependent diabetes
mellitus. J Clin Endocrinol Metab 1996;81:4059 – 4067.
Cusi K, DeFronzo RA. Metformin: a review of its metabolic effects.
Diabetes Rev 1998;6:89 –131.
UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive
blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 1998;
352:854 – 865.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V,
Fuller JH, for the CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004;364:685– 696.
Stokes J, 3rd, Kannel WB, Wolf PA, Cupples LA, D’Agostino RB.
The relative importance of selected risk factors for various manifestations of cardiovascular disease among men and women from 35 to
64 years old: 30 years of follow-up in the Framingham Study.
Circulation 1987;75:V65–V73.
Schneider CA. Improving macrovascular outcomes in type 2 diabetes: outcome studies in cardiovascular risk and metabolic control.
Curr Med Res Opin 2006;22(suppl 2):S15–S26.
Rydén L, Standl E, Bartnik M, Van den Berghe G, Betteridge J, de
Boer MJ, Cosentino F, Jönsson B, Laakso M, Malmberg K, et al, for
the Task Force on Diabetes and Cardiovascular Diseases of the
European Society of Cardiology (ESC) and the European Association
for the Study of Diabetes (EASD). Guidelines on diabetes, prediabetes, and cardiovascular diseases: executive summary. The Task
Force on Diabetes and Cardiovascular Diseases of the European
22B
249.
250.
251.
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
Society of Cardiology (ESC) and of the European Association for the
Study of Diabetes (EASD). Eur Heart J 2007;28:88 –136.
Turner RC, Millns H, Neil HA, Stratton IM, Manley SE, Matthews
DR, Holman RR. Risk factors for coronary artery disease in noninsulin dependent diabetes mellitus: United Kingdom Prospective
Diabetes Study (UKPDS: 23). BMJ 1998;316:823– 828.
Lamarche B, St-Pierre AC, Ruel IL, Cantin B, Dagenais GR, Després
JP. A prospective, population-based study of low-density lipoprotein
particle size as a risk factor for ischemic heart disease in men. Can
J Cardiol 2001;17:859 – 865.
Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR, Forder
P, Pillai A, Davis T, Glasziou P, et al. Effects of long-term fenofibrate
therapy on cardiovascular events in 9795 people with type 2 diabetes
mellitus (the FIELD study): randomised controlled trial. Lancet 2005;
366:1849 –1861.
Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk
factors, and 12-yr cardiovascular mortality for men screened in the
Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434 –
444.
Reaven GM. Role of insulin resistance in human disease [Banting
lecture 1988]. Diabetes 1988;37:1595–1607.
Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536
high-risk individuals: a randomised placebo-controlled trial. Lancet
2002;360:7–22.
Collins R, Armitage J, Parish S, Sleigh P, Peto R. MRC/BHF Heart
Protection Study of cholesterol-lowering with simvastatin in 5963
people with diabetes: a randomised placebo-controlled trial. Lancet
2003;361:2005–2016.
Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG,
Thorgeirsson G. Cholesterol lowering with simvastatin improves
prognosis of diabetic patients with coronary heart disease: a subgroup
analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 1997;20:614 – 620.
Goldberg RB, Mellies MJ, Sacks FM, Moye LA, Howard BV, Howard WJ, Davis BR, Cole TG, Pfeffer MA, Braunwald E, for the
CARE Investigators. Cardiovascular events and their reduction with
pravastatin in diabetic and glucose-intolerant myocardial infarction
survivors with average cholesterol levels: subgroup analyses in the
Cholesterol and Recurrent Events (CARE) trial. Circulation 1998;
98:2513–2519.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V,
Fuller JH. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes
Study (CARDS): multicentre randomised placebo-controlled trial.
Lancet 2004;364:685– 696.
Shepherd J, Barter P, Carmena R, Deedwania P, Fruchart JC, Haffner
S, Hsia J, Breazna A, LaRosa J, Grundy S, Waters D. Effect of
lowering LDL cholesterol substantially below currently recommended levels in patients with coronary heart disease and diabetes:
the Treating to New Targets (TNT) study. Diabetes Care 2006;29:
1220 –1226.
Ridker PM, Danielsen E, Fonseca FAH, Genest J, Gotto AM,
Kastelein JJP, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG,
et al. Rosuvastatin to prevent vascualr events in men and women
with elevated C-reactive protein. N Engl J Med 2008;359:2195–
2207.
Buse JB, Ginsberg HN, Bakris GL, Clark NG, Costa F, Eckel R,
Fonseca V, Gerstein HC, Grundy S, Nesto RW, et al. Primary
prevention of cardiovascular diseases in people with diabetes
mellitus: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2007;
115:114 –126.
Brunzell JD, Davidson M, Furberg CD, Goldberg RB, Howard BV,
Stein JH, Witztum JL. Lipoprotein management in patients with
cardiometabolic risk: consensus statement from the American Dia-
263.
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
275.
276.
betes Association and the American College of Cardiology
Foundation. Diabetes Care 2008;31:811– 822.
Mora S, Szklo M, Otvos JD, Greenland P, Psaty BM, Goff DC Jr,
O’Leary DH, Saad MF, Tsai MY, Sharrett AR. LDL particle subclasses, LDL particle size, and carotid atherosclerosis in the MultiEthnic Study of Atherosclerosis (MESA). Atherosclerosis 2007;192:
211–217.
Kuller L, Arnold A, Tracy R, Otvos J, Burke G, Psaty B, Siscovick
D, Freedman DS, Kronmal R. 2002 Nuclear magnetic resonance
spectroscopy of lipoproteins and risk of coronary heart disease in the
Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 2002;
22:1175–1180.
Rosenson RS, Otvos JD, Freedman DS. Relations of lipoprotein
subclass levels and low-density lipoprotein size to progression of
coronary artery disease in the Pravastatin Limitation of Atherosclerosis in the Coronary Arteries (PLAC-I) trial. Am J Cardiol 2002;
90:89 –94.
Blake GJ, Otvos JD, Rifai N, Ridker PM. Low-density lipoprotein
particle concentration and size as determined by nuclear magnetic
resonance spectroscopy as predictors of cardiovascular disease in
women. Circulation 2002;106:1930 –1937.
Otvos JD, Collins D, Freedman DS, Shalaurova I, Schaefer EJ,
McNamara JR, Bloomfield HE, Robins SJ. Low-density lipoprotein
and high-density lipoprotein particle subclasses predict coronary
events and are favorably changed by gemfibrozil therapy in the
Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation 2006;113:1556 –1563.
El Harchaoui K, van der Steeg WA, Stroes ES, Kuivenhoven JA,
Otvos JD, Wareham NJ, Hutten BA, Kastelein JJ, Khaw KT, Boekholdt SM. Value of low-density lipoprotein particle number and size
as predictors of coronary artery disease in apparently healthy men and
women: the EPIC-Norfolk Prospective Population Study. J Am Coll
Cardiol 2007;49:547–553.
Sacks FM, Campos H. Cardiovascular endocrinology: Low-density
lipoprotein size and cardiovascular disease: a reappraisal [clinical
review 163]. J Clin Endocrinol Metab 2003;88:4525– 4532.
Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR,
Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles
as a predictor of the risk of ischemic heart disease in men: prospective
results from the Quebec Cardiovascular Study. Circulation 1997;95:
69 –75.
Castelli WP, Garrison RJ, Wilson PW, Abbott RD, Kalousdian S,
Kannel WB. Incidence of coronary heart disease and lipoprotein
cholesterol levels: the Framingham Study. JAMA 1986;256:2835–
2838.
Sharrett AR, Ballantyne CM, Coady SA, Heiss G, Sorlie PD, Catellier D, Patsch W. Coronary heart disease prediction from lipoprotein
cholesterol levels, triglycerides, lipoprotein(a), apolipoproteins A-I
and B, and HDL density subfractions: the Atherosclerosis Risk in
Communities (ARIC) Study. Circulation 2001;104:1108 –1113.
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT,
Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation
2004;110:227–239.
Singh IM, Shishehbor MH, Ansell BJ. High-density lipoprotein as
a therapeutic target: a systematic review. JAMA 2007;298:786 –
798.
Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC,
Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler
LF, et al. Relation of gemfibrozil treatment and lipid levels with
major coronary events. VA-HIT: a randomized controlled trial. JAMA
2001;285:1585–1591.
Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire
JA, Tan MH, Khan MA, Perez AT, Jacober SJ. A comparison of lipid
and glycemic effects of pioglitazone and rosiglitazone in patients
DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG
277.
278.
279.
280.
281.
282.
283.
284.
285.
286.
287.
288.
289.
290.
291.
with type 2 diabetes and dyslipidemia. Diabetes Care
2005;28:1547–1554.
Chiquette E, Ramirez G, DeFronzo R. A meta-analysis comparing the
effect of thiazolidinediones on cardiovascular risk factors. Arch Intern Med 2004;164:2097–2104.
Kraus WE, Houmard JA, Duscha BD, Knetzger KJ, Wharton MB,
McCartney JS, Bales CW, Henes S, Samsa GP, Otvos JD, Kulkarni
KR, Slentz CA. Effects of the amount and intensity of exercise on
plasma lipoproteins. N Engl J Med 2002;347:1483–1492.
Tholstrup T, Hellgren LI, Petersen M, Basu S, Straarup EM, Schnohr
P, Sandström B. A solid dietary fat containing fish oil redistributes
lipoprotein subclasses without increasing oxidative stress in men. J
Nutr 2004;134:1051–1057.
Sarwar N, Danesh J, Eiriksdottir G, Sigurdsson G, Wareham N,
Bingham S, Boekholdt SM, Khaw KT, Gudnason V. Triglycerides
and the risk of coronary heart disease: 10,158 incident cases among
262,525 participants in 29 Western prospective studies. Circulation
2007;115:450 – 458.
Clofibrate and niacin in coronary heart disease. JAMA 1975;231:
360 –381.
Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo P,
Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V, et al. Helsinki
Heart Study: primary prevention trial with gemfibrozil in middleaged men with dyslipidemia. Safety of treatment, changes in risk
factors, and incidence of coronary heart disease. N Engl J Med
1987;317:1237–1245.
The BIP Study Group. Secondary prevention by raising HDL cholesterol and reducing triglycerides in patients with coronary artery
disease: the Bezafibrate Infarction Prevention (BIP) study. Circulation 2000;102:21–27.
Gerstein HC, Miller ME, Byington RP, Goff DC Jr, Bigger JT, Buse
JB, Cushman WC, Genuth S, Ismail-Beigi F, Grimm RH Jr, et al, for
the Action to Control Cardiovascular Risk in Diabetes Study Group.
Effects of intensive glucose lowering in type 2 diabetes. N Engl
J Med 2008;358:2545–2559.
Lu W, Resnick HE, Jablonski KA, Jones KL, Jain AK, Howard WJ,
Robbins DC, Howard BV. Non-HDL cholesterol as a predictor of
cardiovascular disease in type 2 diabetes: the Strong Heart Study.
Diabetes Care 2003;26:16 –23.
Liu J, Sempos C, Donahue RP, Dorn J, Trevisan M, Grundy SM.
Joint distribution of non-HDL and LDL cholesterol and coronary
heart disease risk prediction among individuals with and without
diabetes. Diabetes Care 2005;28:1916 –1921.
Pischon T, Girman CJ, Sacks FM, Rifai N, Stampfer MJ, Rimm EB.
Non-high-density lipoprotein cholesterol and apolipoprotein B in the
prediction of coronary heart disease in men. Circulation 2005;
112:3375–3383.
Ginsberg HN, Elam MB, Lovato LC, Crouse JR III, Leiter LA, Linz
P, Friedewald WT, Buse JB, Gerstein HC, Probstfield J, et al. Effects
of combination lipid therapy in type 2 diabetes mellitus. N Engl
J Med 2010;362:1563–1574.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA,
Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella
EJ, for the National Heart, Lung, and Blood Institute Joint National
Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure and the National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the
Joint National Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;
289:2560 –2572.
Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs
in the prevention of cardiovascular disease: meta-analysis of 147
randomised trials in the context of expectations from prospective
epidemiological studies. BMJ 2009;338:b1665.
Salomaa VV, Strandberg TE, Vanhanen H, Naukkarinen V, Sarna S,
Miettinen TA. Glucose tolerance and blood pressure: long term
follow up in middle aged men. BMJ 1991;302:493– 496.
23B
292. Segura J, Ruilope LM. Treatment of prehypertension in diabetes and
metabolic syndrome: what are the pros? Diabetes Care 2009;
32(suppl 2):S284 –S289.
293. Golden SH, Folsom AR, Coresh J, Sharrett AR, Szklo M, Brancati F.
Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the Atherosclerosis Risk in
Communities Study. Diabetes 2002;51:3069 –3076.
294. Assmann G, Cullen P, Schulte H. Simple scoring scheme for calculating the risk of acute coronary events based on the 10-year follow-up of the Prospective Cardiovascular Munster (PROCAM)
study. Circulation 2002;105:310 –315.
295. Zhang Y, Lee ET, Devereux RB, Yeh J, Best LG, Fabsitz RR,
Howard BV. Prehypertension, diabetes, and cardiovascular disease
risk in a population-based sample: the Strong Heart Study. Hypertension 2006;47:410 – 414.
296. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Age-specific
relevance of usual blood pressure to vascular mortality: a metaanalysis of individual data for one million adults in 61 prospective
studies. Lancet 2002;360:1903–1913.
297. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius
S, Menard J, Rahn KH, Wedel H, Westerling S, for the HOT Study
Group. Effects of intensive blood-pressure lowering and low-dose
aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998;
351:1755–1762.
298. Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr,
Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield
JL, et al. Effects of intensive blood-pressure control in type 2 diabetes
mellitus. N Engl J Med 2010;362:1575–1585.
299. Estacio RO, Jeffers BW, Gifford N, Schrier RW. Effect of blood
pressure control on diabetic microvascular complications in patients
with hypertension and type 2 diabetes. Diabetes Care 2000;23(suppl
2):B54 –B64.
300. Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L,
Harrap S, Poulter N, Marre M, Cooper M, et al. Effects of a fixed
combination of perindopril and indapamide on macrovascular and
microvascular outcomes in patients with type 2 diabetes mellitus (the
ADVANCE trial): a randomised controlled trial. Lancet 2007;
370:829 – 840.
301. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J,
Woodward M, MacMahon S. Effects of different blood pressurelowering regimens on major cardiovascular events in individuals
with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Arch Intern Med 2005;
165:1410 –1419.
302. Varughese GI, Lip GY. Antihypertensive therapy in diabetes mellitus: insights from ALLHAT and the Blood Pressure-Lowering Treatment Trialists’ Collaboration meta-analysis. J Hum Hypertens 2005;
19:851– 853.
303. Heart Outcomes Prevention Evaluation Study Investigators. Effects
of ramipril on cardiovascular and microvascular outcomes in people
with diabetes mellitus: results of the HOPE study and MICRO-HOPE
substudy. Lancet 2000;355:253–259.
304. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G, for the
Heart Outcomes Prevention Evaluation Study Investigators. Effects
of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med 2000;342:
145–153.
305. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB,
Ritz E, Atkins RC, Rohde R, Raz I, for the Collaborative Study
Group. Renoprotective effect of the angiotensin-receptor antagonist
irbesartan in patients with nephropathy due to type 2 diabetes. N Engl
J Med 2001;345:851– 860.
306. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE,
Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S, for the
RENAAL Study Investigators. Effects of losartan on renal and car-
24B
307.
308.
309.
310.
311.
312.
313.
314.
315.
316.
The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011
diovascular outcomes in patients with type 2 diabetes and
nephropathy. N Engl J Med 2001;345:861– 869.
Festa A, D’Agostino R Jr, Tracy RP, Haffner SM, for the Insulin
Resistance Atherosclerosis Study. Elevated levels of acute-phase
proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: the Insulin Resistance Atherosclerosis Study.
Diabetes 2002;51:1131–1137.
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002;324:71–86.
World Health Organisation European Collaborative Group. European
collaborative trial of multifactorial prevention of coronary heart disease: final report on the 6-year results. Lancet 1986;1:869 – 872.
Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the primary
prevention of cardiovascular events: a summary of the evidence for the U.S.
Preventive Services Task Force. Ann Intern Med 2002;136:161–172.
Patrono C, Bachmann F, Baigent C, Bode C, De Caterina R, Charbonnier B, Fitzgerald D, Hirsh J, Husted S, Kvasnicka J, et al, for the
Task Force on the Use of Antiplatelet Agents in Patients with Atherosclerotic Cardiovascular Disease of the European Society of Cardiology. Expert consensus document on the use of antiplatelet agents.
Eur Heart J 2004;25:166 –181.
Hirsh J, Bhatt DL. Comparative benefits of clopidogrel and aspirin in
high-risk patient populations: lessons from the CAPRIE and CURE
studies. Arch Intern Med 2004;164:2106 –2110.
Bhatt DL, Marso SP, Hirsch AT, Ringleb PA, Hacke W, Topol EJ.
Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am J Cardiol 2002;90:625– 628.
Haire-Joshu D, Glasgow RE, Tibbs TL. Smoking and diabetes. Diabetes Care 1999;22:1887–1898.
Haire-Joshu D, Glasgow RE, Tibbs TL. Smoking and diabetes. Diabetes Care 2004;27 (suppl 1):S74 –S75.
Anthonisen NR, Skeans MA, Wise RA, Manfreda J, Kanner RE,
Connett JE. The effects of a smoking cessation intervention on
317.
318.
319.
320.
321.
322.
323.
324.
14.5-year mortality: a randomized clinical trial. Ann Intern Med
2005;142:233–239.
Brunner H, Cockcroft JR, Deanfield J, Donald A, Ferrannini E,
Halcox J, Kiowski W, Luscher TF, Mancia G, Natali A, et al.
Endothelial function and dysfunction. Part II: Association with cardiovascular risk factors and diseases. A statement by the Working
Group on Endothelins and Endothelial Factors of the European Society of Hypertension. J Hypertens 2005;23:233–246.
Cersosimo E, DeFronzo RA. Insulin resistance and endothelial dysfunction: the road map to cardiovascular diseases. Diabetes Metab
Res Rev 2006;22:423– 436.
Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Nedeljkovic ZS,
Menzoian JO, Vita JA. Predictive value of noninvasively determined
endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003;
41:1769 –1775.
Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med
1999;340:115–126.
Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S,
Matthaei S, Rett K, Häring HU. Endothelial dysfunction is detectable
in young normotensive first-degree relatives of subjects with type 2
diabetes in association with insulin resistance. Circulation 2000;
101:1780 –1784.
Caballero AE. Metabolic and vascular abnormalities in subjects at
risk for type 2 diabetes: the early start of a dangerous situation. Arch
Med Res 2005;36:241–249.
Tsimikas S, Willerson JT, Ridker PM. C-reactive protein and other
emerging blood biomarkers to optimize risk stratification of vulnerable patients. J Am Coll Cardiol 2006;47:C19 –C31.
Ridker PM, Fifai N, Clearfield M, Downs JR, Weiss SE, Miles JS,
Gotto AM Jr. Measurement of C-reactive protein for the targeting of
statin therapy in the primary prevention of acute coronary events.
N Engl J Med 2001;344:1959 –1965.

Similar documents

×

Report this document