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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 anadverse cardiovascular (CV) event (myocardial infarction, stroke, CV death) later inlife. 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-calledprediabetes manifest all of the same CV risk factors (dysglycemia, dyslipidemia,hypertension, obesity, physical inactivity, insulin resistance, procoagulant state, en-dothelial dysfunction, inflammation) that place patients with type 2 diabetes at highrisk for macrovascular complications. The treatment of these CV risk factors shouldfollow the same guidelines established for patients with type 2 diabetes, and shouldbe aggressively followed to reduce future CV events. © 2011 Elsevier Inc. All rights
reserved. (Am J Cardiol 2011;108[suppl]:3B–24B)
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“Prediabetes” is a general term that refers to an intermediatestage between normal glucose tolerance (NGT) and overttype 2 diabetes mellitus. As such, it represents 2 groups ofindividuals, those with impaired glucose tolerance (IGT)and those with impaired fasting glucose (IFG). IGT and IFGoften are lumped together, but they have distinct pathophys-iologic etiologies. According to the American Diabetes As-sociation (ADA),1 individuals with isolated IGT have aasting plasma glucose (FPG) concentration �100 mg/dL [1g/dL � 0.05555 mmol/L] and a 2-hour plasma glucose

(PG) concentration, measured by a 75-g oral glucose toler-ance test (OGTT), ranging between �140 mg/dL and �200mg/dL. Individuals with isolated IFG have a 2-hour PG(measured by an OGTT) of �140 mg/dL and a FPG be-tween �100 mg/dL and �126 mg/dL. Subjects with iso-lated IGT have moderate-to-severe insulin resistance inmuscle and impaired first- and second-phase insulin secre-tion, while individuals with IFG have moderate insulinresistance in the liver, impaired first-phase insulin secretion,and normal/near-normal muscle insulin sensitivity.2–6 Sub-jects with IGT or IFG are at high risk for developing bothtype 2 diabetes7–17 and clinically significant atheroscleroticardiovascular 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, SanAntonio, Texas, USA.

Publication of this supplement was supported by funding from NovoNordisk. Editorial support was provided by Dr. Ruth Kleinpell and MaryLou Briglio.

Statement of author disclosure: Please see the Author Disclosuresection at the end of this article.

*Address for reprints: Ralph A. DeFronzo, MD, Diabetes Division,niversity of Texas Health Science Center, 7703 Floyd Curl Drive, Sanntonio, Texas 78229.

E-mail address: [email protected].

002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved.doi:10.1016/j.amjcard.2011.03.013

redictor of macrovascular complications. In a meta-analy-is of 20 studies including 95,783 nondiabetic subjects withmean follow-up of 12.4 years, Coutinho and colleagues37

recorded 3,707 cardiovascular (CV) events. An exponentialcorrelation between CV events and both FPG and postloadPG concentration was found, and this relationship ex-tended below diagnostic blood glucose levels (Figure1).37 In the Diabetes Epidemiology: Collaborative Anal-ysis of Diagnostic Criteria in Europe (DECODE),19,20

Hoorn,34 DECODA (Diabetes Epidemiology: CollaborativeAnalysis of Diagnostic Criteria in Asia),33 and Funagata Dia-betes32 studies, CV mortality in subjects with IGT was close tohat of individuals with overt type 2 diabetes and much greaterhan in subjects with IFG.

rediabetes and Type 2 Diabetes Mellitus:re They Different?

he natural history of type 2 diabetes has been well de-cribed in multiple populations and has been reviewed byeFronzo.38,39 Individuals destined to develop type 2 dia-etes inherit a set of genes from their parents that make theirissues resistant to insulin.38–46 In the liver, the insulin

resistance is manifest by an overproduction of glucoseduring the basal state despite the presence of fastinghyperinsulinemia47and an impaired suppression of hepaticglucose production in response to insulin, as occurs follow-ing a meal.48 In muscle43,49,50 insulin resistance is manifesty impaired glucose uptake after ingestion of a carbohy-rate-rich meal and results in postprandial hyperglycemia.48

Although the origins of the insulin resistance can be tracedto their genetic background,39,41,44 the epidemic of diabetesthat has enveloped westernized countries is related to the
epidemic of obesity and physical inactivity.51 Both obesity52
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4B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011

and decreased physical activity53 are insulin-resistant statesnd, when added to the genetic burden of the insulin resis-ance, place a major stress on the pancreatic �-cells to

augment their secretion of insulin to offset the defect in insulinaction.43 As long as the �-cells are able to augment theirsecretion of insulin sufficiently to offset the insulin resistance,glucose tolerance remains normal.54 However, with time, post-meal glucose levels and subsequently FPG concentration beginto rise, leading to the onset of overt diabetes. Collectively, the

Figure 2. Natural history of type 2 diabetes mellitus. The plasma insulinresponse (open circles) depicts the classic Starling’s curve of the pancreas.1

Closed circles � insulin-mediated glucose uptake (top panel). DIAB �iabetes; Hi INS � high insulin secretion; IGT � impaired glucoseolerance; Lo INS � low insulin secretion; NGT � normal glucose toler-nce; OB � obese; OGTT � oral glucose tolerance test. (Reprinted with

Figure 1. Relation between cardiovascular events and fasting and postloadplasma glucose concentrations in a meta-analysis of 20 studies including95,783 nondiabetic subjects with a mean follow up of 12.4 years. Thecurves and 95% confidence intervals are shown. (Reprinted with permis-sion from The American Diabetes Association.37)

rermission from The American Diabetes Association.39)

insulin resistance in muscle and liver and �-cell failure havebeen referred to as “the triumvirate.”55

As illustrated in Figure 2,39 individuals with NGT whore destined to develop type 2 diabetes already manifestoderate-to-severe insulin resistance, which is genetic in

rigin and made worse by accompanying obesity and phys-cal inactivity. Although the transition from NGT to IGT isssociated with a worsening of the insulin resistance, glu-ose tolerance is only mildly impaired because of the com-ensatory increase in insulin secretion and resultant hyper-nsulinemia. However, plasma insulin levels should not bequated with �-cell function. The �-cell responds to an

incremental change in glucose with an incremental changein insulin, and this response is modulated by the severity ofinsulin resistance.2–6,39,56 Therefore, the “gold standard”ormula for �-cell function is �I/�G � IR (where �I rep-

resents an incremental change in insulin, �G is the incre-mental change in glucose, and IR is insulin resistance). Asshown in Figure 3,39 individuals in the upper tertile of NGT(2-hour PG � 120–139 mg/dL) have a loss of �50% oftheir �-cell function, compared with a loss of 70%–80% forndividuals in the upper tertile of IGT (2-hour PG � 180–99 mg/dL). Thus, from the pathophysiologic standpoint,ubjects with IGT should be considered to have type 2iabetes. 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 ofovert type 2 diabetes.

The recently published results of the Diabetes PreventionProgram (DPP)58 have raised further concern about thelinical implications of the term “prediabetes.” In the DPP,ndividuals who entered with a diagnosis of IGT and stillad IGT 3 years later had a 7.9% incidence of backgroundiabetic retinopathy at the time of study end. Individuals,ho entered the DPP with IGT but who progressed toiabetes after 3 years, had a 12.6% incidence of diabetic

Figure 3. Insulin secretion/insulin resistance (disposition) index (defined aschange in insulin/change in glucose � insulin resistance [�INS/�GLU �IR]) in individuals with normal glucose tolerance (NGT), impaired glucosetolerance (IGT), and type 2 diabetes mellitus (T2DM) as a function of the2-hour plasma glucose (PG) concentration in lean (closed circles) andobese (open circles) subjects. (Reprinted with permission from The Amer-ican Diabetes Association.39)

etinopathy at the end of study. Moreover, these individ-

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5BDeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG

uals who remained with IGT or who progressed to dia-betes developed diabetic retinopathy with hemoglobin A1c

(HbA1c) levels of 5.9% and 6.1%, respectively, values muchlower than the current ADA treatment goal of 7.0%. Pe-ripheral neuropathy also is a common finding in IGT, oc-curring in as many as 5%–10% of patients.59,60

In summary, individuals with IGT are maximally or nearmaximally insulin resistant, have lost 80% of their �-cellunction, and have an approximate 10% incidence of dia-etic retinopathy. By both pathophysiologic and clinicaltandpoints, these individuals with prediabetes who haveGT should be considered to have type 2 diabetes. Thelinical implications of these findings for the prevention ofype 2 diabetes and associated complications are that thehysician must intervene early, at the stage of IGT or IFG,ith interventions that target pathogenic mechanismsnown to cause �-cell failure and insulin resistance. From

the standpoint of cardiovascular disease (CVD), it is equallyimportant for the physician to recognize that IGT and type2 diabetes are CV risk equivalents (see subsequent discus-sion).

Impaired Glucose Tolerance and Type 2 DiabetesMellitus Are Major Cardiovascular Risk Factors

Although microvascular complications are a major cause ofmorbidity in type 2 diabetes, macrovascular complicationsrepresent the primary cause of mortality, with heart attacksand stroke accounting for �80% of all deaths.61 In patients

ith type 2 diabetes without a prior history of myocardialnfarction (MI), the 7-year incidence of MI is equal to orreater than the 7-year incidence of heart attack in nondia-etic individuals with prior MI.62 In patients with diabetesith a previous history of heart attack, the 7-year incidencef subsequent MI is more than double that for nondiabeticndividuals.62 Similarly, the recurrence rate of major ath-rosclerotic events in patients with type 2 diabetes with arior CV event is very high, around 6% per year.63 Theseesults document that diabetes is a major CV risk equiva-ent.

The DECODE study19,20,64,65 analyzed databases fromultiple European populations and concluded that peopleith type 2 diabetes had twice the risk for CVD (including

oronary artery disease [CAD] and stroke) compared withondiabetic individuals, after adjustment for other CV riskactors. Furthermore, DECODE demonstrated that the rela-ion between glycemia and CV risk started within the nor-al blood glucose range, with a linear relationship and no

vidence of a threshold effect.19,20 Both the FPG and post-hallenge PG levels were correlated with CV risk (Figure),19 although the strongest correlation was with the post-

prandial glucose level; addition of the FPG level to thepostprandial glucose level did not further increase the risk.Similar observations have been reported in the Framing-
ham Offspring Study66 and the Hoorn Study.34 The Fu- N
agata Study also showed a higher CV mortality rate inersons with IGT compared with individuals with IFG.32

Similar results have been published by the DECODAStudy Group21 in Asian populations. Multiple cohort stud-ies27,67–69 have demonstrated an increased CV risk in sub-ects with IGT, although the later studies did not comparehese subjects with individuals with IFG. In a recentlyublished Austrian Study of 1,040 patients who underwentoronary arteriography for suspected/established CAD andho were followed for a mean of 3.8 years, CV event-free

urvival was similar in individuals with IGT and with newlyiagnosed type 2 diabetes, and both were significantlyreater compared with individuals with NGT (Figure 5).70

The progression of abnormal glucose metabolism fromNGT to IGT to type 2 diabetes in 5,000 patients withestablished with CAD in the Euro Heart Survey71 also wasssociated with worsening CV prognosis. After 1 year ofollow up, all-cause mortality was 2.2% in patients with

Figure 4. Cumulative hazard curves for cardiovascular disease based on theAmerican Diabetes Association (ADA) fasting glucose criteria and WorldHealth Association (WHO) 2-hour glucose criteria adjusted by age, sex,and study center. (Reprinted with permission from Elsevier, Inc.19)

GT, 2.7%–3.7% in subjects with IGT/IFG, 5.5% in pa-

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tients with newly diagnosed type 2 diabetes, and 7.7% inpatients with known diabetes. A notable exception to thegreater CV risk in patients with IGT compared with IFG isthe Australian Diabetes Study.36 Although, after 6 years offollow up, individuals with IGT had a higher cumulativeincidence of all-cause mortality compared with individualswith IFG, the incidence of CVD mortality was similar in the2 groups and was higher for both compared with subjectswith NGT.

Several potential explanations could account for thehigher rates of CVD in subjects with IGT compared withIFG. First, postprandial hyperglycemia contributes more tothe overall day-long glycemic exposure in individuals withIGT compared with IFG.2,3,72 Second, individuals with IGThave a higher prevalence of the metabolic syndrome,73–81 aluster of abnormalities including central obesity dyslipide-ia, hypertension, and dysglycemia, that by itself increases

he risk for ASCVD.82–84 Third, postprandial blood glucoseoncentrations are associated with the highest diurnal levelsf glycemia and the greatest fluctuations in blood glucoseoncentrations that may have a more damaging effect on theasculature,85–90 including increased oxidative stress, acti-ation of inflammatory pathways, increased procoagulanttate, and abnormal vasomotion.

ncidence of Prediabetes and Diabetes Mellitus inndividuals with Coronary Artery Disease

he prevalence of previously unrecognized postchallengeyperglycemia (IGT and type 2 diabetes) in patients under-oing coronary angiography exceeds 60%,91–96 and the se-erity of postchallenge hyperglycemia correlates closelyith the extent of angiographically determined CAD91 andith future macrovascular events and total mortality.36 The

Figure 5. Event-free survival with respect to glycemic state in 1,040patients who underwent coronary arteriography for suspected/establishedcoronary artery disease. IGT � impaired glucose tolerance; NGT � normalglucose tolerance. (Reprinted with permission from Oxford UniversityPress.70)

IGAMI (Diabetes Insulin Glucose and Myocardial Infarc-

ion) Study94 examined the prevalence of dysglycemia(OGTT performed at hospital discharge) in 164 patientsadmitted to the hospital with an acute MI, with assessmentrepeated 4–5 days later (n � 164) and 3 months later (n �44). Prediabetes and newly diagnosed type 2 diabetes,espectively, were diagnosed in 35% and 31% of patients.he similar incidence of abnormal glucose tolerance de-

ected 3 months later excluded acute illness and increasedympathetic tone as the cause of the disturbance in glucoseetabolism. Similar findings have been reported in 3 longer

tudies, the 25-country Euro Heart Survey,93 the ChinaHeart Survey,96 and a study from Austria.36

In summary, �60% of individuals with previously un-diagnosed prediabetes or diabetes who experience an MI orcome to coronary catheterization because of suspected CADhave IGT, IFG, or type 2 diabetes. Because of this very highincidence of dysglycemia, it is recommended that all pa-tients with acute MI and new-onset angina or CAD shouldhave a 75-g, 2-hour OGTT. Individuals with stable chronicCAD also should have an OGTT to exclude underlyingprediabetes/diabetes.

Assessing Cardiovascular Risk and the Need forScreening in Patients with Prediabetes

There are no prospective studies that have evaluated whichasymptomatic individuals with prediabetes should bescreened for CAD. However, because prediabetes, like overttype 2 diabetes, is a CV risk equivalent, it is reasonable touse the same criteria applied to diabetes. Recently, theADA97 revised its 1998 Consensus Conference Guidelines98

about screening for diabetes because of failure of studies todemonstrate that the load of traditional risk factors predictedinducible ischemia in nuclear or echocardiographic myocar-dial perfusion studies.99,100 Moreover, efforts using datarom the Framingham study and the United Kingdom Pro-pective Diabetes Study (UKPDS) have proved only mod-stly successful.101

In the absence of symptomatic CAD, clinical featuresthat identify patients with diabetes at increased risk for MIor cardiac death include clinical evidence of ASCVD in-volving the lower extremity, cerebral, or renal arteries,102,103

microalbuminuria,104,105 abnormal electrocardiogram (Q-aves, T-wave inversion, left bundle branch block),106,107

autonomic neuropathy,108 retinopathy,109 age, and sex. Al-though CAD screening studies in patients with type 2 dia-betes have failed to establish an association between thenumber of CV risk factors and inducible ischemic onperfusion imaging,100 multiple risk factors (hypertension,dyslipidemia, obesity [especially visceral], smoking,physical inactivity, evidence of inflammation, insulin re-sistance) in the same individual markedly increase thelikelihood of experiencing a CV event.74 –77,80,81 Becauseprediabetes and type 2 diabetes are part of a continuous
spectrum, it is not unreasonable to assume that these

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same abnormalities predict increased CV risk in individ-uals with prediabetes.

Although the presence of multiple CV risk factors doesnot identify individuals at risk for inducible ischemia onperfusion imaging, it does identify people at high risk for asubsequent coronary event. Consistent with this, autopsystudies in type 2 diabetes have demonstrated severe multi-vessel coronary atherosclerosis even in asymptomatic indi-viduals.110 Subjects with the metabolic syndrome, the ma-ority of whom have some form of dysglycemia,111 are at

increased risk for type 2 diabetes and CVD, accounting forup to half of new cases of type 2 diabetes and up to one thirdof new CVD cases over 8 years of follow up.112,113 Thus, its reasonable to consider individuals with prediabetes withultiple CV risk factors at high risk for CVD, and they

hould receive aggressive multifactorial intervention (seeubsequent discussion), which has been shown to be effec-ive in reducing CV events in patients with type 2 diabetesn the Steno-2,114,115 Clinical Outcomes Utilizing Revascu-

larization and Aggressive Drug Evaluation (COUR-AGE),116 and Multiple Risk Factor Intervention TrialMRFIT)117 studies. If screening is to be undertaken in

subjects with prediabetes, newer CAD diagnostic modalitiesincluding computed tomographic angiography,118 coronaryartery calcium score using electron-beam or multislice tech-nology,119,120 or cardiac magnetic resonance imaging is rec-ommended.121

The recently reported results of the DPP in the UnitedStates provide support for the approach advocated above.81

In the DPP 3,324 individuals with IGT were randomized tointensive lifestyle modification, metformin, or placebo. CVrisk 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 IGTto type 2 diabetes and improved with reversion to NGT,especially in the lifestyle intervention group. Based onchanges in risk factor levels, the incremental risk associatedwith conversion to diabetes was quite modest. Of note, CVrisk factors were associated with glycemia in a linear fash-ion, without any unique effect of conversion to diabetes.Moreover, most of the increased CV risk, based on thesetraditional risk factors, was well established at the stage ofIGT. Similarly, nondiabetic (NGT and IGT) participants inthe San Antonio Heart Study (SAHS) who developed type 2diabetes over an 8-year follow-up period had higher total/LDL cholesterol (LDL-C) and TG concentrations, systolicand diastolic blood pressure, and body mass index (BMI),and lower HDL-C levels than subjects who did not developdiabetes.77 Based on these observations, the SAHS investi-ators put forward the “ticking clock” hypothesis, whichtates that the clock for CAD starts to tick long before thenset of overt diabetes (Figure 6). The Nurses Healthtudy122 and the Botnia Study80 also demonstrated the pres-

ence of abnormal CV risk factors long before the develop-
ment of overt diabetes.
In summary, multiple studies demonstrate that individu-als with prediabetes, especially those with multiple riskfactors for CVD, are at increased risk for a CV event overthe subsequent follow-up period of 10 years.

Insulin Resistance, Hyperinsulinemia, andAtherosclerotic Cardiovascular Disease:the Missing Links

Insulin and atherosclerosis: Insulin resistance and hy-perinsulinemia have been implicated as the missing links inthe increased risk for CVD.123 In vivo and in vitro studieshave demonstrated that insulin can promote atherogene-sis.124–126 Insulin enhances de novo lipogenesis and aug-ments hepatic very-low-density lipoprotein (VLDL) synthe-sis127,128 via stimulation of sterol regulatory element–binding protein-1c and inhibition of acetyl-coenzyme A–1carboxylase.129 In cultured arterial smooth muscle cells,nsulin increases LDL-C transport,130 augments collagenynthesis,131,132 stimulates arterial smooth muscle cell pro-iferation,133,134 and activates multiple genes involved innflammation.132 In vivo studies in dogs,135 rabbits,136 and

chickens137 provide further evidence that insulin promotesatherogenesis. Rats chronically infused with insulin, whilemaintaining euglycemia, become markedly resistant to thestimulation of glucose uptake and suppression of plasmafree fatty acids by insulin138 and become hypertensive.139

Two other points about hyperinsulinemia are noteworthy. Inhumans with NGT, insulin infusion to raise the fastingplasma insulin (FPI) from 57 to 104 pmol/L for 3 daysproduces severe insulin resistance,140,141 a risk factor forCVD (see subsequent discussion). Hyperinsulinemia andinsulin therapy are also associated with weight gain,142 andobesity is a major risk factor for CVD.143,144 Weight gainromotes atherogenesis via multiple mechanisms includingyslipidemia and hypertension, while fat deposition in therterial wall promotes inflammation, which directly accel-rates atherogenesis.145–147

Insulin resistance (metabolic) syndrome: Much evi-

Figure 6. Schematic representation of the ticking clock hypothesis. CAD �coronary artery disease; T2DM � type 2 diabetes mellitus.

dence indicates that insulin resistance per se and associated

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components of the insulin resistance (metabolic) syn-drome38–40 play a pivotal role in the development of ASCVD.t is noteworthy that individuals with prediabetes are asnsulin resistant as lean patients with type 2 diabetes andbese subjects with NGT (Figure 7).123 In fact, insulinesistance is fully established in the NGT offspring of 2arents with type 2 diabetes.40,43,45 In all of these groups,nsulin resistance primarily affects the glycogen syntheticathway (Figure 7).38–43,45,46,148,149 Type 2 diabetes61,62 andbesity143,144 are major CV risk factors, and it is not sur-

prising, therefore, that patients with prediabetes also are atincreased risk for CVD. A common thread linking all com-ponents of the insulin resistance syndrome is the basiccellular/molecular cause of the insulin resistance,40,123

which not only promotes inflammation and atherogenesisbut also leads to and/or aggravates other components of thesyndrome, which themselves are independent and majorCVD risk factors.

Insulin resistance is a central feature of the metabolic(insulin resistance) syndrome, and it primarily involves theglycogen synthetic pathway (Figure 7).150–152 Hypertensionalso is a well-established risk factor for CVD.153

Individuals with type 2 diabetes and obesity, as well assubjects with prediabetes, develop dyslipidemia character-ized by hypertriglyceridemia, reduced HDL-C, and small,dense atherogenic LDL particles.82–84,149,154–157 Hypertri-lyceridemia, but not hypercholesterolemia, is associatedith insulin resistance (Figure 7).154,157–159 The frequency

of hypercholesterolemia is not increased in patients withtype 2 diabetes.156 However, elevated LDL-C acts synergis-tically with other risk factors to accelerate atherogenesis.160

Studies by Bressler et al161 were the first to conclusivelydemonstrate that individuals with diffuse CAD were mark-edly insulin resistant compared with participants with NGT

Figure 7. Insulin-stimulated glucose disposal (40 mU/m2 per min, eugly-cemic-hyperinsulinemic clamp) in lean healthy control (CON) participants,obese participants with normal glucose tolerance (NGT), lean drug-naiveparticipants with type 2 diabetes mellitus (T2DM), lean participants withNGT and hypertension (HTN), participants with NGT and hypertriacylg-lycerolemia (Hypertriacyl), and nondiabetic participants with coronaryartery disease (CAD). White bar sections indicate nonoxidative glucosedisposal (glycogen synthesis); black bar sections indicate glucose oxida-tion. *p �0.01 vs CON; †p �0.001 vs CON. (With kind permission from

pringer Science�Business Media: Diabetologia, Insulin resistance, lipo-oxicity, type 2 diabetes and atherosclerosis: the missing links [the Claudeernard Lecture 2009], Volume 53, 2010, DeFronzo RA, Figure 1.123)

who had clean coronary arteries. Again, the insulin resis- i

tance primarily affected the glycogen synthetic pathway inskeletal muscle (Figure 7).161 Studies by Reaven149 and

aternostro and colleagues162 also have shown that nondi-betic individuals with established CAD are resistant tonsulin. The myocardium of nondiabetic individuals withAD and patients with type 2 diabetes without CAD also is

esistant to insulin.162–164

In summary, each component of the metabolic syndromeis characterized by insulin resistance involving the glycogensynthetic pathway (Figure 7). The insulin resistance is pres-ent at the stage of IGT,2,3 ie, prediabetes, even before anybnormality in glucose tolerance is observed43,45,46,165

and is an independent risk factor for CVD (see subse-quent discussion).

Insulin Resistance and the Insulin ResistanceSyndrome Predict Future Cardiovascular Disease

Multiple prospective studies, including the SAHS166 andthe Botnia Study,80 have demonstrated that insulin resis-ance in subjects with NGT predicts future CVD, evenfter adjustment for multiple CV risk factors. Each com-onent of the insulin resistance syndrome, as well asnsulin resistance per se, is associated with a 1.5- to-fold increase in the incidence of CVD. Similar obser-ations have been made in the Bruneck,167 Verona Dia-

betes,168 and Insulin Resistance Atherosclerosis StudiesIRAS).169 A strong relation between insulin resistancend carotid intima-media thickness—a surrogate measuref ASCVD—also been demonstrated,170 as has an asso-iation between insulin resistance and a greater CV riskactor load.171 The analysis by D’Agostino and col-

leagues172 of 6 prospective studies further supports anndependent role for insulin resistance in CVD. Using theramingham cardiovascular risk calculator,173 only 69%f the observed risk for CVD could be explained, leaving1% unaccounted for (Figure 8A).172 Similarly, in the

Atherosclerosis Risk in Communities (ARIC) Study (Fig-ure 8B),174 only �70% of the increase in carotid intima-media thickness could be accounted for by dyslipidemia,hypertension, glucose intolerance, or obesity. It is likelythat this unexplained risk can be attributed in part to theunderlying molecular etiology of insulin resistance,which involves impaired insulin signaling through theinsulin receptor substrate–1 (IRS-1)/phosphatidylinositol(PI) 3-kinase pathway and increased insulin signalingthrough the MAP kinase pathway.40,123

The molecular etiology of insulin resistance in skeletaland vascular smooth muscle cells is genetic in origin andcan be demonstrated in the lean NGT offspring of 2 parentswith type 2 diabetes.45,46,124 These offspring are at very highisk to develop type 2 diabetes and their tissues are beingncubated in a sea of molecular insulin resistance andtherogenicity from a very early stage of life. This explains,
n part, why clinically evident ASCVD is present in 5%–

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20% of individuals with type 2 diabetes at initial diagno-sis175 and why insulin resistance and ASCVD are so closelylinked.123

In summary, individuals with prediabetes manifest thesame molecular defect in insulin action as patients with type2 diabetes and obesity, placing them at increased risk forCVD.

Assessment and Treatment of Prediabetes: a RationalPathophysiologic and Cardiovascular RiskFactor–based Approach

Because prediabetes (IGT and IFG) and diabetes represent acontinuum of dysglycemia and CV risk, the same principlesthat apply to the assessment and treatment of type 2 diabetes

Figure 8. (A) Predictive value (%) of cardiovascular disease (CVD) usingthe Framingham risk calculator from Framingham Heart Study (FHS), theAtherosclerosis Risk in Community Study (ARIC), the Honolulu HeartProgram (HHP), the Puerto Rico Heart Health Program (PR), the StrongHeart Study (SHS), and the Cardiovascular Health Study (CHS). On mean,the Framingham Risk calculator predicts only 69% of the risk of a futurecardiovascular event. Amer � American; F � female; M � male.Adapted with and reprinted permission from JAMA.172 Copyright

(2001) American Medical Association. All rights reserved.) (B) Excessarotid intima-media thickness (IMT) in relation to the individual compo-ents of the insulin resistance syndrome (IRS) as listed. GLU � glucose;DL � high-density lipoprotein; HTN � hypertension; TG � triglycer-

des; 1 � increase; 2 � decrease. (With kind permission from Springercience�Business Media: Diabetologia, Insulin resistance, lipotoxicity,

ype 2 diabetes and atherosclerosis: the missing links [the Claude Bernardecture 2009], Volume 53, 2010, DeFronzo RA, Figure 1.123)

should apply to the prediabetic state (Table 1).

Dysglycemia: Subjects with IFG should have a formal2-hour OGTT, because �33% of these individuals will havetype 2 diabetes. Both individuals with IFG but without type2 diabetes and subjects with IGT should have a repeat FPGtest annually and a repeat OGTT every 1–2 years based onthe FPG results and the discretion of the physician.

Within the prediabetic range, both the FPG and 2-hourPG are independent risk factors for the development ofASCVD.19,20,32,34,37,64–81 In DECODE, the risk for CADnd stroke increased progressively from IFG to IGT to typediabetes,19,20 indicating that hyperglycemia is a continu-

ous risk factor for CV mortality.176 In the UKPDS, HbA1c

was the third greatest risk factor for CVD in type 2 diabe-tes.177 In MRFIT, CV mortality increased with an increasingumber of coexisting CV risk factors, and the risk wasagnified by concomitant hyperglycemia in subjects with

ype 2 diabetes.156,164 Similarly, in UKPDS178 a potent in-eraction between hyperglycemia and blood pressure to in-rease the risk of MI and stroke was documented. Thesebservations highlight the important role of dysglycemia asmajor risk factor for ASCVD.No CV intervention study has targeted the prediabetic

opulation specifically. However “tight” glycemic controln the extension of the UKPDS179 and DCCT180 demon-trated that treatment of hyperglycemia in patients withiabetes significantly decreased CV events181,182 In the Pro-

spective Pioglitazone Clinical Trial in Macrovascular Events(PROactive) trial,183,184 pioglitazone reduced the second prin-cipal endpoint of all-cause mortality, MI, and stroke in patientswith type 2 diabetes with a prior CV event, although the CVbenefit most likely was the result of combined improvementsin the HbA1c, dyslipidemia, blood pressure, and other inflam-matory markers that were not measured.

The results of the Study to Prevent Non–Insulin-Depen-dent Diabetes Mellitus (STOP-NIDDM) trial185 providesupport for the specific treatment of postprandial glucoselevels. This study, which demonstrated a 30% reduction inthe conversion rate of IGT to type 2 diabetes, was associated

able 1ardiovascular risk assessment in prediabetes (IGT/IFG)

● HyperglycemiaX FastingX Postprandial

● Obesity● Physical activity● Dyslipidemia

X HypercholesterolemiaXSmall dense LDL particlesX HypertriglyceridemiaX Low HDL cholesterolX Non-HDL cholesterol

● Hypertension● Procoagulant state● Endothelial dysfunction
● Inflammation

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with reductions in any CV event (by 49%), acute MI (by91%), and development of hypertension (by 34%).

Both IGT and IFG are major independent risk factors forthe development of type 2 diabetes, and individuals withcombined IGT and IFG are at especially high risk.7–17 Life-tyle intervention, including weight loss and increasedhysical activity,186–189 should be the mainstay of therapy in

individuals with IGT and/or IFG. Pharmacologic interven-tion185,186,190–198 also has been shown to be effective ineducing the conversion rate of IGT to type 2 diabetes. Inhe DPP studies in the United States186 and Finland (FIN-

D2D),187 lifestyle modification in subjects with IGT reducedhe conversion rate to diabetes by 62% and 58%, respec-ively. Other CV benefits also were noted in these studies,ncluding reduction in systolic/diastolic blood pressure,lasma TG, LDL-C, insulin, and C-reactive protein (CRP)evels and an increase in HDL-C. However, as has beenbserved with most weight loss programs, the majority ofhe lost weight was regained despite moderately intensiveollow-up programs in both the US and Finnish trials.199,200

In both the US DPP190 and Indian198 (IDPP) studies,etformin was effective in reducing the conversion of IGT

o type 2 diabetes, by 31% and 26%, respectively, but theecrease was only approximately half of that observed withifestyle changes. An ADA Consensus statement201 has rec-mmended use of metformin in high-risk (aged �60 years,MI �30, HbA1c �6.0%) patients with IGT.

The most impressive results preventing the conversion ofIGT to type 2 diabetes have been observed with the thiazo-lidinedione (TZD) class of drugs, which consistently havereduced the conversion rate of IGT to type 2 diabetes by50%–70%.191–194 In ACT NOW (Actos Now for the Pre-vention of Diabetes), the conversion rate of IGT to type 2diabetes was reduced by 72% with pioglitazone, and 48% ofIGT individuals reverted to NGT. Significant reductions inblood pressure, TG levels, and rate of progression of carotidintima-media thickness, and an increase in HDL-C alsowere observed. Although the glycemic benefits of the TZDsare clearly established, physicians must be cognizant oftheir potential side effects including fluid retention andbone fractures. Although concern has been raised aboutthe CV safety of rosiglitazone,202 both PROactive183,184

and a meta-analysis203 have shown that pioglitazone doesnot increase CV events and, to the contrary, improves CVDoutcomes. Although weight gain commonly is observedwith the TZDs, the greater the weight gain is, the greateralso is the decline in HbA1c, the improvement in insulinsensitivity, and the improvement in �-cell function.204,205

Thus, the TZD-related weight gain primarily represents acosmetic concern. The results of the CANOE (CanadianNormoglycemia Outcomes Evaluation) study,195 whichevaluated the use of low-dose combination therapy withrosiglitazone (2 mg/day) plus metformin (1,000 mg/day),are especially encouraging. The conversion rate of IGT totype 2 diabetes was reduced by 66% without weight gain or
fluid retention. Because of the CV safety issues with rosigli- I
tazone, low-dose pioglitazone (15–30 mg/day) plus met-formin (500–1,000 mg/day) represents a logical choice forthe treatment of IGT when lifestyle intervention fails toachieve the desired effect. However, it should be empha-sized that, at present, the US Food and Drug Administration(FDA) has not approved any pharmacologic therapy for thetreatment of IGT or IFG.

Obesity: As part of the assessment of individuals withIGT and IFG, body weight (on every visit) and heightshould be recorded and BMI calculated. It also is recom-mended that waist circumference be measured.206

Obesity, especially visceral obesity, is a major risk factorfor ASCVD.143,144 It also is associated with moderate-to-evere insulin resistance, is the driving force behind thelobal epidemic of type 2 diabetes,51,207 and is associated

with the insulin resistance syndrome and multiple risk fac-tors for CVD.82–84 Therefore, an effort should be directed atweight loss in patients with prediabetes, the majority ofwhom are overweight. The ADA recommends screening fortype 2 diabetes in persons with a BMI �25 and in those�45 years of age.208 Such screening would be expected toidentify large numbers of individuals with prediabetes (IGTand IFG). Moreover, lifestyle intervention with caloric re-striction/increased physical activity is recommended byboth the ADA and the American Heart Association(AHA).208–211 Such interventions significantly decrease theconversion rate of IGT to type 2 diabetes, reduce HbA1c

levels, enhance insulin sensitivity, and improve CV riskfactors.212–217 No long-term study with sufficient numbersof patients has been completed to assess the effect of weightloss on CV outcomes, but the Look Action for Health inDiabetes (Look AHEAD) trial in patients with type 2 dia-betes with a BMI �25 is designed to address this issue.218

A detailed description of the principles of medical nutritiontherapy for achieving weight loss and improving the CVrisk profile has been provided by the ADA and theAHA.208–212,219

Physical inactivity: The level of physical activityshould be assessed in all subjects with prediabetes.208 Thiscan be done by use of simple questionnaires or with apedometer. A more quantitative measure can be obtained bydetermination of maximum oxygen consumption (VO2max),lthough this is not routinely recommended.

Physical inactivity, as manifested by a low VO2max,is a major risk factor for both type 2 diabetes andASCVD.210 –213,220,221 In subjects with IGT and type 2 di-abetes reduced physical fitness is associated with increasedCV mortality, whereas enhanced physical activity reducesthe risk of CVD.222–226 Moreover, incorporation of routinephysical activity of moderate intensity, 3–4 times per week,has been shown to reduce the conversion of IGT to type 2diabetes and improve the CV risk factor profile213,214 andhould be an integral part of any intervention programesigned to reduce CV risk and prevent diabetes in IGT and
FG individuals. To improve glycemic control, promote

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weight maintenance, and reduce CV risk, the ADA andAHA recommend �30 minutes of moderate-intensity phys-ical activity 3 days per week, and preferably 45–60 minutesof moderate intensity physical activity 5 days per week.208

Insulin resistance: Use of the euglycemic insulin clamps the gold standard for quantitating the severity of insulinesistance,227 but this is impractical on an individual basis orn large-scale epidemiologic trials. The homeostatic modelssessment of insulin resistance (HOMA-IR; calculated asPG in millimoles per liter � FPI in milliunits per liter �2.5) �3–4 is a surrogate measure of insulin resistance228

that correlates reasonably well with insulin resistance mea-sured with the euglycemic insulin clamp.229 An alternativemeasure is FPI concentration or stimulated insulin concen-tration �75% above the upper limit of normal.230 A TG–

DL-C ratio �3.0 also has been suggested as a surrogateeasure of insulin resistance.231 Measurement of BMI also

can be useful. The great majority (�80%–90%) of individ-uals with a BMI �30 are insulin resistant,232 as are mostpeople with visceral obesity (�102 cm in males and �88m in females).233 From the clinical standpoint, if the pa-ient has IGT, the physician can assume that he or she isnsulin resistant.2–6

Insulin resistance is a core defect responsible for thedevelopment 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 NGTffspring of parents with type 2 diabetes.43,45,46 Moreover,

insulin resistance is an independent risk factor for the de-velopment of ASCVD123 and is the major factor underlyinghe insulin resistance (metabolic) syndrome.84,123–126 Theathogenic mechanisms via which insulin resistance with itsompensatory hyperinsulinemia leads to each component ofhe insulin resistance syndrome have been reviewed in de-ail.82,84,124–126,149,150 A total of 25%–50% of individualsith prediabetes have the insulin resistance syndrome asefined by National Cholesterol Education ProgramNCEP) Adult Treatment Panel III (ATP III),111 and �50%

of these individuals have �2 components of the insulinresistance syndrome,234 placing them at high risk for

SCVD.From the therapeutic standpoint, the TZDs are potent insu-

in sensitizers in muscle, liver, and adipocytes39,123,235–237 andalso enhance �-cell function.39,238 Not surprisingly, the

ZDs have proved highly effective in preventing therogression of IGT/IFG to type 2 diabetes.190–195 Inhe PROactive study, pioglitazone significantly reduced theombined endpoint of all-cause mortality, MI, and stroke,183

and in a meta-analysis of all published studies significantlydecreased CV events in patients with type 2 diabetes.203

Therefore, the TZDs—especially at low doses and in com-bination with metformin—represent a rational choice toameliorate insulin resistance, prevent the progression ofIGT/IFG to type 2 diabetes, and possibly to reduce the high
incidence of CV events in individuals with prediabetes and o
type 2 diabetes. In subjects with these conditions, TZDs alsoreduce CRP, circulating inflammatory markers, and proco-agulant factors.239,240

Metformin also is an insulin sensitizer but its primaryeffect is on the liver, with a weak effect on muscle.241–243 Inhe US DPP study, metformin decreased the conversion ratef IGT to type 2 diabetes by 32%,190 but this decrease

represented only about 50% of the effectiveness of use oflifestyle intervention or TZDs.191–194 Metformin also de-creased CV events in the UKPDS.244 Because of its provenfficacy, cost-effectiveness, and safety, the ADA has rec-mmended metformin for the treatment of high-risk indi-iduals with IGT or IFG.201

Dyslipidemia: Any assessment of the patient with pre-diabetes should involve the measurement of plasma LDL-C,non–HDL-C (total cholesterol minus HDL-C), HDL-C, andTG concentrations. Whether LDL particle size and numbershould be measured as part of the general evaluation of thepatient with prediabetes remains at the discretion of theindividual physician.

Elevated LDL-C, non–HDL-C, small, dense LDL parti-cles (phenotype B), and reduced HDL-C are major riskfactors for ASCVD in individuals with NGT and in personswith prediabetes and type 2 diabetes.245–250 The role oflevated TGs as a major CV risk factor remains controver-ial.251 In individuals with prediabetes and type 2 diabetes,he incidence of hypercholesterolemia is not increased com-ared with the general population,252 but the incidence ofmall, dense atherogenic LDL particles (phenotype B) isarkedly increased and represents a major risk factor for

ccelerated atherogenesis.250 Small, dense LDL particles arelosely associated with insulin resistance.253

LDL-C: Multiple studies have documented the benefitof LDL-C reduction in individuals with type 2 diabetes. Inthe Heart Protection Study254,255 reduction in LDL-C withimvastatin was shown to be effective in decreasing CVvents in patients with diabetes with and without a historyf CAD, an HbA1c level �7.0 or �7.0%, and irrespective ofhe starting levels of LDL-C (�115 mg/dL or �115 mg/L), HDL-C (�35 mg/dL or �35 mg/dL) [1 mg/dL �.0259 mmol/L], and TGs (�182 mg/dL or �182 mg/dL [1g/dL � 0.0113 mmol/L]). In the Scandinavian Simvastatinurvival Study (4S),256 simvastatin was effective in reduc-

ing coronary events in individuals with normal fasting glu-cose, IFG, and diabetes. Similarly, the subgroup analysis inthe Cholesterol and Recurrent Events (CARE) trial246 dem-onstrated that, for similar initial cholesterol levels, prava-statin was more effective in reducing CV events in patientswith IFG and diabetes compared with individuals with anormal fasting glucose concentration. In the CollaborativeAtorvastatin Diabetes Study (CARDS),257,258 use of atorva-tatin in patients with diabetes reduced major CV events by7% and stroke by 48%. Of note, the patients with diabetesn CARDS had “normal” cholesterol levels and no evidence
f CVD. In the Treating to New Targets (TNT) trial,259

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intensive therapy with atorvastatin (80 mg/day) reduced therate of major CV events by 25%, compared with 10 mg/dayof atorvastatin in patients with diabetes with CAD. TheLDL-C level at study end in the 2 treatment groups was 77mg/dL and 99 mg/dL, respectively. In the recently pub-lished JUPITER (Justification for the use of Statins in Pre-vention: an International Trial Evaluating Rosuvastatin)trial patients with diabetes but without evidence of CADand a starting LDL-C level of 108 mg/dL were treated withrosuvastatin to achieve a goal of 54 mg/dL.260 The incidencef CV events was reduced by 46% with rosuvastatin com-ared with placebo.

Because prediabetes and diabetes are CV risk equiva-ents, the goals for LDL-C level should be similar in bothroups261,262: LDL-C �70 mg/dL in patients with predia-

betes/diabetes with known CVD or without CVD but with�1 additional major CV risk factor; and LDL-C �100mg/dL in patients with prediabetes/diabetes without CVDand without any major CV risk factor. However, it shouldbe noted that identification of patients with diabetes withoutCVD and without major CV risk factors (obesity, dyslipi-demia, hypertension) is distinctly uncommon. Moreover,the results of JUPITER strongly suggest that even patientswith diabetes without CVD or CV risk factors should betreated to an LDL-C goal of 70 mg/dL.260

LDL particle size and number: Many studies, bothcross-sectional263 and prospective,264–268 have demonstratedhat LDL particle number and size may be better indicatorsf CV risk than LDL-C concentration. Small, dense LDLarticles are especially atherogenic and also are an impor-ant predictor of CVD.269,270 Therefore, the physician mayish to obtain a nuclear magnetic resonance measurementf LDL particle number or size. However, if the goal ofherapy is to reduce the LDL-C concentration to 70 mg/dL,he role of more aggressive therapy with a 3-hydroxy-3ethylglutaryl coenzyme A reductase inhibitor (statin),

ven if LDL particle number/size is not normalized, is notlear. On the other hand, if the goal of therapy is an LDL-Carget of 100 mg/dL, the finding of an increased number ofmall, dense LDL particles might push the physician tourther reduce LDL-C to 70 mg/dL.

HDL-C: Many studies have demonstrated that a lowDL-C level is a risk factor for CVD in individuals with

nd without diabetes.271,272 The ADA recommends thera-peutic goals for HDL-C of �40 mg/dL in men and �50mg/dL in women,208 whereas the AHA recommends raisingHDL-C without setting a specific goal.111,273 The most ef-ective drug for raising HDL-C is nicotinic acid, but thereave been no large, long-term CV outcomes trials specifi-ally targeting either diabetic or prediabetic populations.oreover, it is difficult to define the specific role of raisingDL-C in preventing CVD because all interventions that

aise HDL-C also improve the concentrations of other lipo-roteins.274 The Veterans Affairs High-Density Lipoprotein
holesterol Intervention Trial (VA-HIT)275 examined the
effect of gemfibrozil in individuals, including 625 patientswith diabetes, with CAD and low HDL-C levels. A post hocanalysis showed a modest reduction in CV events thatcorrelated with the increase in HDL-C level.275 Althoughnot 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 theHDL-C level278 and has other benefits, including improvedinsulin sensitivity, protection against the development oftype 2 diabetes in individuals with prediabetes, and reduc-tion in CV events. Dietary intake of omega-3 fatty acids alsocan cause a modest elevation in HDL-C.279

Plasma TGs: During the fasting state, plasma TGs pri-marily are located in VLDL, and the plasma TG concentra-tion has been used as a surrogate measure of VLDL. In moststudies plasma TGs are a univariate predictor of CVD butthey drop out as a predictor in multivariate analyses, mostlikely because elevated plasma TG concentrations areclosely linked to reduced HDL-C and, to a lesser extent, toelevated LDL-C.280 In the FIELD (Fenofibrate Interventionand Event Lowering in Diabetes) study, fenofibrate causeda nonsignificant reduction in the primary outcome of totalCV events in patients with diabetes.251 The secondary out-come of nonfatal MI decreased, but fatal MI increased.Decreased nonfatal MI without benefit on fatal MI or totalmortality also has been seen with clofibrate,281 gemfibro-il,275,282 and bezafibrate.283 The largely negative results of

FIELD251 have been attributed to the low starting plasmaTG concentration (173 mg/dL) and higher statin drop-in ratein the placebo group. In the Helsinki Heart Study,282 thesubgroup of patients with diabetes who had very high TGand low HDL-C levels experienced a reduction in CVevents with gemfibrozil. Similarly, in the Action to ControlCardiovascular Risk in Diabetes (ACCORD) trial, in thesubgroup of patients with diabetes who had high plasma TG(�204 mg/dL) and low HDL-C (�34 mg/dL) levels, areduction in CV events (p � 0.06) was observed.284 Basedon the results summarized above, treatment to LDL-C andnon–HDL-C (see below) goals should remain the primaryand secondary focuses of lipid intervention therapy, respec-tively, in patients with prediabetes or type 2 diabetes. In-terventions to raise HDL-C should be the tertiary aim.

Non–HDL-C: Non–HDL-C represents the differencebetween total cholesterol and HDL-C concentrations andreflects the amount of cholesterol within those lipoproteinparticles that have been demonstrated to be atherogenic.Several studies have documented that non–HDL-C is a betterpredictor of CVD than the LDL-C concentration.285–288 TheADA, American College of Cardiology (ACC), and ATP IIIrecommend targeting LDL-C first, with non–HDL-C as asecondary target.262,273 The non–HDL-C goals should be 30mg/dL greater than the LDL goal. Thus, for the great ma-jority of patients with prediabetes or diabetes in whom theLDL-C goal is 70 mg/dL, the non–HDL-C goal will be 100
mg/dL. Interventional strategies for treating non–HDL-C

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include use of low-fat diet, niacin, fibrates, pioglitazone,and omega-3 fatty acids.

Blood pressure: All patients with prediabetes shouldave their systolic and diastolic blood pressure measuredfter 5 minutes in the reclining position and after standing.he Joint National Committee on Prevention, Detection,valuation, and Treatment of High Blood Pressure (JNC7)lassifies 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)tage 2 hypertension, �160/�100 mm Hg.289

Hypertension is a major risk factor for CVD,290 occurs in50%–60% of individuals with type 2 diabetes,291 and is 2–3times more common in individuals with prediabetes com-pared with nondiabetic subjects.292 Diabetes and hyperten-ion,293,294 as well as prediabetes and hypertension,295 aredditive risk factors for atherosclerosis and CVD. Epidemi-logic studies show that the increased risk for CV events andortality starts at a blood pressure level �115/75 mm Hg in

he general population and doubles for every 20-mm Hgystolic and 10-mm Hg diastolic increase.296 The ADA/

AHA suggest that the blood pressure goal in patients withtype 2 diabetes should be 130/80 mm Hg,261 while the JNC7ecommendation is �140/90 mm Hg. However, the optimalevel of blood pressure control remains controversial. In theypertension Optimal Treatment (HOT) trial,297 subjects

with and without diabetes were randomized to 1 of 3 dia-stolic blood pressure categories (�90, �85, or �80 mmHg). In the group with diabetes, patients randomized to adiastolic target of �80 mm Hg had 50% of the risk of majorCV events compared with the �90-mm Hg target group.297

Most recently, the ACCORD Study298 randomized 4,733atients with type 2 diabetes to a systolic blood pressurearget �120 mm Hg or �140 mm Hg for 4.7 years. At 1ear, mean blood pressure was 119 mm Hg in the inten-ively treated group and 133 mm Hg in the standard therapyroup. The respective values for diastolic blood pressureere 64 mm Hg and 70 mm Hg. The primary compositeutcome of nonfatal MI, stroke, and death from CV causesas similar in both groups (hazard ratio [HR] � 0.88, p �.20). The HR for stroke was significantly reduced in thentensive 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 ther-apy occurred in 3.3% of intensively treated patients withdiabetes compared with 1.3% in the standard therapy group(p �0.001). Overall, targeting systolic blood pressure to120 mm Hg versus 140 mm Hg did not reduce the risk forCV events and increased the risk for serious adverse events.The achievement of lower blood pressure in the intensivetherapy group required a greater number of drugs fromevery class (mean number of medications, 3.4). Of note, inthe ABCD (Appropriate Blood Pressure Control in Diabe-tes) trial, a mean systolic blood pressure of 132 mm Hg was
achieved in the intensively treated group, but no significant
decrease in CVD endpoints occurred although total mortal-ity was reduced.299 In the ADVANCE (Action in Diabetesnd Vascular Disease: Preterax and Diamicron Modifiedelease Controlled Evaluation) trial, the fixed combinationf an angiotensin-converting enzyme (ACE) inhibitor plushe diuretic indapamide in patients with diabetes reducedhe risk of both microvascular and macrovascular compli-ations by 9% and decreased the risk of CV death by 18%egardless of the initial blood pressure level.300 In summary,

the HOT trial indicates that targeting diastolic blood pres-sure to 80 mm Hg significantly reduces CV risk. However,the ideal target for systolic blood pressure (ie, �140 mm Hgvs �120 mm Hg) remains controversial. For now the ADA/AHA goal of systolic blood pressure �130 mmHg remainsreasonable.261

With regard to the choice of antihypertensive agents, arecent meta-analysis of 147 randomized, controlled bloodpressure trials in patients with and without diabetes con-cluded that all classes of blood pressure–lowering drugs hada similar effect on reduction of CV events for a givenreduction in blood pressure.289 The exception was the�-blockers which, when given shortly after an MI and whencontinued for 1–2 years thereafter, significantly reduced CVrisk compared with other categories of drugs.289 Becausemultiple trials suggest that the beneficial effects of ACEinhibitors and angiotensin receptor blockers (ARBs) are notlimited to blood pressure reduction,301–304 and because ACEnhibitors/ARBs have a specific preventive effect on dia-etic nephropathy,305,306 they are recommended as the drugs

of choice in patients with diabetes, and it seems reasonableto use them as first-line therapy in patients with prediabetesas well. However, it should be noted that most patients withprediabetes or diabetes require at least 2–4 antihypertensivemedications to achieve optimal blood pressure control.

Procoagulant state: No specific assessment of coagula-bility is recommended in patients with prediabetes. How-ever, antiplatelet therapy is advocated in patients with thiscondition who are at high risk for CVD. Diabetes is ahypercoagulable state, and multiple coagulation abnormal-ities have been described, including increased levels ofplasminogen activator inhibitor–1 and fibrinogen, as well asincreased platelet adherence.307 Meta-analyses of 195 trialsncluding �135,000 patients (4,961 with diabetes) at highisk for CVD given antiplatelet drugs (aspirin, clopidogrel,r dipyridamole alone or in combination) revealed a 25%eduction in stroke, MI, or vascular death.308–310 The opti-al effective aspirin dose was 75–150 mg/dL. In patientsith diabetes and established CVD, clopidogrel gave thereatest protection against CV events.311–313 The most re-ent AHA/ADA guidelines recommend aspirin as primaryrevention in patients with diabetes at increased CV risk,261

and it is reasonable to use the same approach in patientswith prediabetes.

Tobacco smoking: All patients with prediabetes should
be questioned about their history of smoking. Cigarette

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smoking is a strong CV risk factor in individuals with orwithout diabetes,314,315and smoking cessation leads to asignificant reduction in mortality with a trend toward reduc-tion in CV death.316 All patients with prediabetes or diabeteshould be cautioned against smoking, and those who smokehould be referred to a formal smoking-cessation programnd/or considered for treatment with nicotine substitutesnd/or bupropion hydrochloride.

Endothelial dysfunction: The assessment of endothelialysfunction (postischemic brachial arterial dilation or ace-ylcholine-induced brachial arterial vasodilation) is notractical for the primary care physician. However, it iseasonable to assume that patients with prediabetes or dia-etes who are insulin-resistant also have moderate-to-severendothelial dysfunction.317

The endothelium plays a pivotal role in arterial vascularsmooth muscle cell relaxation317–320 by releasing nitric ox-de (NO), formed intracellularly by NO synthase, from

L-arginine in response to a variety of stimuli includingnsulin. NO is a potent vasodilator and antiatherogenic mol-cule.317–320 NO stimulates muscle guanylyl cyclase to form

cyclic guanosine monophosphate, leading to vasodilation ofvascular smooth muscle cells. In states of NO deficiency, asoccurs in prediabetes321 and type 2 diabetes,322 the athero-clerotic process is accelerated, blood pressure is increased,nd paradoxical coronary arterial vasoconstriction occurs.ecause NO generation is dependent on an intact insulin

ignaling (IRS-1/PI-3 kinase/Akt) pathway, states of insulinesistance, such as prediabetes and type 2 diabetes, areharacterized by NO deficiency, endothelial dysfunction,ypertension, and accelerated atherosclerosis.123 Insulin-ensitizing drugs, in particular the TZDs, have a majormpact on improvement of endothelial dysfunction.

Inflammation: Chronic inflammation is a characteristiceature of type 2 diabetes,320,322 and elevated circulating

levels of inflammatory cytokines (eg, interleukin-6)323 haveeen reported in individuals with prediabetes. Some centersave advocated the measurement of CRP as part of thevaluation of CV risk,324and the FDA has approved the usef rosuvastatin in patients without diabetes with an LDL-Cevel �100 mg/dL and an elevated CRP level �2.0 mg/dL1 mg/dL � 9.52 nmol/L]. However, routine measurementf CRP has yet to be endorsed by the AHA or the ADA.

Absolute risk assessment: It generally is recommendedhat all patients identified as having increased CV risk (eg,atients with prediabetes) have a global risk assessment forheir 10-year risk for CVD.206 A global risk assessment cane performed using the Framingham cardiovascular riskalculator173 or the Prospective Cardiovascular Münster

(PROCAM) scoring system.294 These methods use easy-to-collect 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%), andmoderate (�10%) 10-year CV event risk categories.

Conclusion

Prediabetes (IGT and/or IFG) is a CV risk equivalent, andpatients with IGT or IFG should be aggressively treated tocorrect all CV risk factors. Lifestyle modification and, in high-risk individuals, pharmacologic intervention, should be initi-ated to prevent the progression of IGT/IFG to overt type 2diabetes.

Author Disclosures

The authors who contributed to this article have disclosedthe following industry relationships:

Ralph A. DeFronzo, MD, is a member of the Speakers’Bureau of Novo Nordisk A/S; serves on the advisory boardsof Amylin Pharmaceuticals, Inc., Boehringer Ingelheim, EliLilly and Company, Isis Pharmaceuticals, Inc., and TakedaPharmaceuticals North America, Inc.; and has received re-search/grant support from Amylin Pharmaceuticals, Inc., EliLilly and Company, and Takeda Pharmaceuticals NorthAmerica, Inc.

Muhammad Abdul-Ghani, MD, PhD, reports no rela-tionships to disclose with any manufacturer of a product ordevice discussed in this supplement.

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