Assessment and Treatment of Cardiovascular Risk in Prediabetes:

Transcription

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
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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
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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-
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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
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
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%–
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
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
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
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
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
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.
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Assessment and Treatment of Cardiovascular Risk in Prediabetes:

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