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 вђ¤-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. В© 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108[suppl]:3BвЂ“24B) вЂњPrediabetesвЂќ 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 ПЅ100 mg/dL [1 mg/dL П 0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between Х†140 mg/dL and ПЅ200 mg/dL. Individuals with isolated IFG have a 2-hour PG (measured by an OGTT) of ПЅ140 mg/dL and a FPG between Х†100 mg/dL and ПЅ126 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.2вЂ“ 6 Subjects with IGT or IFG are at high risk for developing both type 2 diabetes7вЂ“17 and clinically significant atherosclerotic cardiovascular disease (ASCVD).18 вЂ“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/$ вЂ“ see front matter В© 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 вЂ“ 46 In the liver, the insulin resistance is manifest by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia47and an impaired suppression of hepatic glucose production in response to insulin, as occurs following a meal.48 In muscle43,49,50 insulin resistance is manifest by impaired glucose uptake after ingestion of a carbohydrate-rich meal and results in postprandial hyperglycemia.48 Although the origins of the insulin resistance can be traced to their genetic background,39,41,44 the epidemic of diabetes that has enveloped westernized countries is related to the epidemic of obesity and physical inactivity.51 Both obesity52 www.AJConline.org 4B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011 Figure 3. Insulin secretion/insulin resistance (disposition) index (defined as change in insulin/change in glucose П¬ insulin resistance [вЊ¬INS/вЊ¬GLU П¬ 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 вђ¤-cells to augment their secretion of insulin to offset the defect in insulin action.43 As long as the вђ¤-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 StarlingвЂ™s curve of the pancreas.1 Closed circles П insulin-mediated glucose uptake (top panel). DIAB П diabetes; Hi INS П high insulin secretion; IGT П impaired glucose tolerance; Lo INS П low insulin secretion; NGT П normal glucose tolerance; OB П obese; OGTT П oral glucose tolerance test. (Reprinted with permission from The American Diabetes Association.39) insulin resistance in muscle and liver and вђ¤-cell failure have been referred to as вЂњthe triumvirate.вЂќ55 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 вђ¤-cell function. The вђ¤-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.2вЂ“ 6,39,56 Therefore, the вЂњgold standardвЂќ formula for вђ¤-cell function is вЊ¬I/вЊ¬G П¬ IR (where вЊ¬I represents an incremental change in insulin, вЊ¬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 П 120 вЂ“139 mg/dL) have a loss of Пі50% of their вђ¤-cell function, compared with a loss of 70%вЂ“ 80% for individuals in the upper tertile of IGT (2-hour PG П 180 вЂ“ 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 вђ¤-cell volume, suggesting that there is a significant loss of вђ¤-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 вЂњprediabetes.вЂќ In the DPP, individuals who entered with a diagnosis of IGT and still had IGT 3 years later had a 7.9% incidence of background diabetic retinopathy at the time of study end. Individuals, who entered the DPP with IGT but who progressed to diabetes after 3 years, had a 12.6% incidence of diabetic retinopathy at the end of study. Moreover, these individ- DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG 5B uals who remained with IGT or who progressed to diabetes developed diabetic retinopathy with hemoglobin A1c (HbA1c) levels of 5.9% and 6.1%, respectively, values much lower than the current ADA treatment goal of 7.0%. Peripheral neuropathy also is a common finding in IGT, occurring in as many as 5%вЂ“10% of patients.59,60 In summary, individuals with IGT are maximally or near maximally insulin resistant, have lost 80% of their вђ¤-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 вђ¤-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 Пі80% 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 studies27,67вЂ“ 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%вЂ“3.7% in subjects with IGT/IFG, 5.5% in pa- 6B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011 Figure 5. Event-free survival with respect to glycemic state in 1,040 patients who underwent coronary arteriography for suspected/established coronary artery disease. IGT П impaired glucose tolerance; NGT П 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,73вЂ“ 81 a cluster of abnormalities including central obesity dyslipidemia, hypertension, and dysglycemia, that by itself increases the risk for ASCVD.82вЂ“ 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,85вЂ“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%,91вЂ“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 вЂ“5 days later (n П 164) and 3 months later (n П 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, Пѕ60% 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 вЂ“77,80,81 Because prediabetes and type 2 diabetes are part of a continuous spectrum, it is not unreasonable to assume that these DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG same abnormalities predict increased CV risk in individuals with prediabetes. Although the presence of multiple CV risk factors does not identify individuals at risk for inducible ischemia on perfusion imaging, it does identify people at high risk for a subsequent coronary event. Consistent with this, autopsy studies in type 2 diabetes have demonstrated severe multivessel coronary atherosclerosis even in asymptomatic individuals.110 Subjects with the metabolic syndrome, the majority of whom have some form of dysglycemia,111 are at increased risk for type 2 diabetes and CVD, accounting for up to half of new cases of type 2 diabetes and up to one third of new CVD cases over 8 years of follow up.112,113 Thus, it is reasonable to consider individuals with prediabetes with multiple CV risk factors at high risk for CVD, and they should receive aggressive multifactorial intervention (see subsequent discussion), which has been shown to be effective in reducing CV events in patients with type 2 diabetes in the Steno-2,114,115 Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE),116 and Multiple Risk Factor Intervention Trial (MRFIT)117 studies. If screening is to be undertaken in subjects with prediabetes, newer CAD diagnostic modalities including computed tomographic angiography,118 coronary artery calcium score using electron-beam or multislice technology,119,120 or cardiac magnetic resonance imaging is recommended.121 The recently reported results of the DPP in the United States provide support for the approach advocated above.81 In the DPP 3,324 individuals with IGT were randomized to intensive lifestyle modification, metformin, or placebo. CV risk factors (high-density lipoprotein [HDL] cholesterol [HDL-C], systolic/diastolic blood pressure, triglycerides [TG], and low-density lipoprotein [LDL] particle size) worsened as glucose tolerance status deteriorated from IGT to type 2 diabetes and improved with reversion to NGT, especially in the lifestyle intervention group. Based on changes in risk factor levels, the incremental risk associated with conversion to diabetes was quite modest. Of note, CV risk factors were associated with glycemia in a linear fashion, without any unique effect of conversion to diabetes. Moreover, most of the increased CV risk, based on these traditional risk factors, was well established at the stage of IGT. Similarly, nondiabetic (NGT and IGT) participants in the San Antonio Heart Study (SAHS) who developed type 2 diabetes over an 8-year follow-up period had higher total/ LDL cholesterol (LDL-C) and TG concentrations, systolic and diastolic blood pressure, and body mass index (BMI), and lower HDL-C levels than subjects who did not develop diabetes.77 Based on these observations, the SAHS investigators put forward the вЂњticking clockвЂќ 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 П coronary artery disease; T2DM П 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 вЂ“126 Insulin enhances de novo lipogenesis and augments hepatic very-low-density lipoprotein (VLDL) synthesis127,128 via stimulation of sterol regulatory elementвЂ“ binding protein-1c and inhibition of acetyl-coenzyme AвЂ“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.145вЂ“147 Insulin resistance (metabolic) syndrome: Much evidence indicates that insulin resistance per se and associated 8B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011 Figure 7. Insulin-stimulated glucose disposal (40 mU/m2 per min, euglycemic-hyperinsulinemic clamp) in lean healthy control (CON) participants, obese participants with normal glucose tolerance (NGT), lean drug-naive participants with type 2 diabetes mellitus (T2DM), lean participants with NGT and hypertension (HTN), participants with NGT and hypertriacylglycerolemia (Hypertriacyl), and nondiabetic participants with coronary artery disease (CAD). White bar sections indicate nonoxidative glucose disposal (glycogen synthesis); black bar sections indicate glucose oxidation. *p ПЅ0.01 vs CON; вЂ p ПЅ0.001 vs CON. (With kind permission from Springer ScienceП©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 вЂ“ 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 вЂ“ 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 вЂ“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.82вЂ“ 84,149,154 вЂ“157 Hypertriglyceridemia, but not hypercholesterolemia, is associated with insulin resistance (Figure 7).154,157вЂ“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.162вЂ“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 thicknessвЂ”a surrogate measure of ASCVDвЂ”also been demonstrated,170 as has an association between insulin resistance and a greater CV risk factor load.171 The analysis by DвЂ™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 Пі70% 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 substrateвЂ“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%вЂ“ DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG Figure 8. (A) Predictive value (%) of cardiovascular disease (CVD) using the Framingham risk calculator from Framingham Heart Study (FHS), the Atherosclerosis Risk in Community Study (ARIC), the Honolulu Heart Program (HHP), the Puerto Rico Heart Health Program (PR), the Strong Heart Study (SHS), and the Cardiovascular Health Study (CHS). On mean, the Framingham Risk calculator predicts only 69% of the risk of a future cardiovascular event. Amer П American; F П female; M П male. (Adapted with and reprinted permission from JAMA.172 Copyright В© (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 П glucose; HDL П high-density lipoprotein; HTN П hypertension; TG П triglycerides; 1 П increase; 2 П decrease. (With kind permission from Springer ScienceП©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 FactorвЂ“ 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 Пі33% 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 1вЂ“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 вЂ“ 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 вЂњtightвЂќ 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 NonвЂ“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) в—Џ Hyperglycemia X Fasting X Postprandial в—Џ Obesity в—Џ Physical activity в—Џ Dyslipidemia X Hypercholesterolemia XSmall dense LDL particles X Hypertriglyceridemia X Low HDL cholesterol X Non-HDL cholesterol в—Џ Hypertension в—Џ Procoagulant state в—Џ Endothelial dysfunction в—Џ Inflammation 10B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011 with reductions in any CV event (by 49%), acute MI (by 91%), and development of hypertension (by 34%). Both IGT and IFG are major independent risk factors for the development of type 2 diabetes, and individuals with combined IGT and IFG are at especially high risk.7вЂ“17 Lifestyle intervention, including weight loss and increased physical activity,186 вЂ“189 should be the mainstay of therapy in individuals with IGT and/or IFG. Pharmacologic intervention185,186,190 вЂ“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 ПЅ60 years, BMI Пѕ30, HbA1c Пѕ6.0%) 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%вЂ“70%.191вЂ“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 вђ¤-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 (15вЂ“30 mg/day) plus metformin (500 вЂ“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.82вЂ“ 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 Пѕ25 and in those Пѕ45 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 вЂ“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.212вЂ“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 Х†25 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 вЂ“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 вЂ“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.222вЂ“226 Moreover, incorporation of routine physical activity of moderate intensity, 3вЂ“ 4 times per week, has been shown to reduce the conversion of IGT to type 2 diabetes and improve the CV risk factor profile213,214 and should be an integral part of any intervention program designed to reduce CV risk and prevent diabetes in IGT and IFG individuals. To improve glycemic control, promote DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG weight maintenance, and reduce CV risk, the ADA and AHA recommend Х†30 minutes of moderate-intensity physical activity 3 days per week, and preferably 45вЂ“ 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 П« FPI in milliunits per liter П¬ 22.5) Пѕ3вЂ“ 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 Пѕ75% above the upper limit of normal.230 A TGвЂ“ HDL-C ratio Пѕ3.0 also has been suggested as a surrogate measure of insulin resistance.231 Measurement of BMI also can be useful. The great majority (Пѕ80%вЂ“90%) of individuals with a BMI Пѕ30 are insulin resistant,232 as are most people with visceral obesity (Пѕ102 cm in males and Пѕ88 cm in females).233 From the clinical standpoint, if the patient has IGT, the physician can assume that he or she is insulin resistant.2вЂ“ 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)2вЂ“ 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.84,123вЂ“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 вЂ“126,149,150 A total of 25%вЂ“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 Пѕ50% of these individuals have Х†2 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 adipocytes39,123,235вЂ“237 and also enhance вђ¤-cell function.39,238 Not surprisingly, the TZDs have proved highly effective in preventing the progression of IGT/IFG to type 2 diabetes.190 вЂ“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 TZDsвЂ” especially at low doses and in combination with metforminвЂ”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.241вЂ“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.191вЂ“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, nonвЂ“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, nonвЂ“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.245вЂ“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 Пѕ7.0 or ПЅ7.0%, and irrespective of the starting levels of LDL-C (Пѕ115 mg/dL or ПЅ115 mg/ dL), HDL-C (Пѕ35 mg/dL or ПЅ35 mg/dL) [1 mg/dL П 0.0259 mmol/L], and TGs (Пѕ182 mg/dL or ПЅ182 mg/dL [1 mg/dL П 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 вЂњnormalвЂќ cholesterol levels and no evidence of CVD. In the Treating to New Targets (TNT) trial,259 12B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011 intensive therapy with atorvastatin (80 mg/day) reduced the rate of major CV events by 25%, compared with 10 mg/day of atorvastatin in patients with diabetes with CAD. The LDL-C level at study end in the 2 treatment groups was 77 mg/dL and 99 mg/dL, respectively. In the recently published JUPITER (Justification for the use of Statins in Prevention: an International Trial Evaluating Rosuvastatin) trial patients with diabetes but without evidence of CAD and a starting LDL-C level of 108 mg/dL were treated with rosuvastatin to achieve a goal of 54 mg/dL.260 The incidence of CV events was reduced by 46% with rosuvastatin compared with placebo. Because prediabetes and diabetes are CV risk equivalents, the goals for LDL-C level should be similar in both groups261,262: LDL-C ПЅ70 mg/dL in patients with prediabetes/diabetes with known CVD or without CVD but with Х†1 additional major CV risk factor; and LDL-C ПЅ100 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 вЂ“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 Пѕ40 mg/dL in men and Пѕ50 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 вЂ“ 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 (Х†204 mg/dL) and low HDL-C (Х…34 mg/dL) levels, a reduction in CV events (p П 0.06) was observed.284 Based on the results summarized above, treatment to LDL-C and nonвЂ“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. NonвЂ“HDL-C: NonвЂ“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 nonвЂ“HDL-C is a better predictor of CVD than the LDL-C concentration.285вЂ“288 The ADA, American College of Cardiology (ACC), and ATP III recommend targeting LDL-C first, with nonвЂ“HDL-C as a secondary target.262,273 The nonвЂ“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 nonвЂ“HDL-C goal will be 100 mg/dL. Interventional strategies for treating nonвЂ“HDL-C DeFronzo and Abdul-Ghani/Cardiovascular Risk in Prediabetes: IGT and IFG include use of low-fat diet, niacin, fibrates, pioglitazone, and omega-3 fatty acids. Blood pressure: All patients with prediabetes should have their systolic and diastolic blood pressure measured after 5 minutes in the reclining position and after standing. The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7) classifies blood pressure in 4 categories: (1) normal, ПЅ120/ ПЅ80 mm Hg; (2) prehypertension, 120 вЂ“129/80 вЂ“ 89 mm Hg; (3) stage 1 hypertension, 140 вЂ“150/90 вЂ“99 mm Hg; and (4) stage 2 hypertension, Пѕ160/Х†100 mm Hg.289 Hypertension is a major risk factor for CVD,290 occurs in 50%вЂ“ 60% of individuals with type 2 diabetes,291 and is 2вЂ“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 Пѕ115/75 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 ПЅ140/90 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 (Х…90, Х…85, or Х…80 mm Hg). In the group with diabetes, patients randomized to a diastolic target of Х…80 mm Hg had 50% of the risk of major CV events compared with the Х…90-mm Hg target group.297 Most recently, the ACCORD Study298 randomized 4,733 patients with type 2 diabetes to a systolic blood pressure target ПЅ120 mm Hg or ПЅ140 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] П 0.88, p П 0.20). The HR for stroke was significantly reduced in the intensive group (HR П 0.59, p П 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 ПЅ0.001). 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, ПЅ140 mm Hg vs ПЅ120 mm Hg) remains controversial. For now the ADA/ AHA goal of systolic blood pressure Х…130 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 pressureвЂ“lowering drugs had a similar effect on reduction of CV events for a given reduction in blood pressure.289 The exception was the вђ¤-blockers which, when given shortly after an MI and when continued for 1вЂ“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,301вЂ“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 2вЂ“ 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 inhibitorвЂ“1 and fibrinogen, as well as increased platelet adherence.307 Meta-analyses of 195 trials including Пѕ135,000 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 вЂ“310 The optimal effective aspirin dose was 75вЂ“150 mg/dL. In patients with diabetes and established CVD, clopidogrel gave the greatest protection against CV events.311вЂ“313 The most recent AHA/ADA guidelines recommend aspirin as primary prevention in patients with diabetes at increased CV risk,261 and it is reasonable to use the same approach in patients with prediabetes. Tobacco smoking: All patients with prediabetes should be questioned about their history of smoking. Cigarette 14B The American Journal of Cardiology (www.AJConline.org) Vol 108 (3S) August 2, 2011 smoking is a strong CV risk factor in individuals with or without diabetes,314,315and smoking cessation leads to a significant reduction in mortality with a trend toward reduction in CV death.316 All patients with prediabetes or diabetes should be cautioned against smoking, and those who smoke should be referred to a formal smoking-cessation program and/or considered for treatment with nicotine substitutes and/or bupropion hydrochloride. Endothelial dysfunction: The assessment of endothelial dysfunction (postischemic brachial arterial dilation or acetylcholine-induced brachial arterial vasodilation) is not practical for the primary care physician. However, it is reasonable to assume that patients with prediabetes or diabetes who are insulin-resistant also have moderate-to-severe endothelial dysfunction.317 The endothelium plays a pivotal role in arterial vascular smooth muscle cell relaxation317вЂ“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.317вЂ“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 ПЅ100 mg/dL and an elevated CRP level Пѕ2.0 mg/dL [1 mg/dL П 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 MГјnster (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 (Пѕ20%), moderately high (10%вЂ“20%), and moderate (ПЅ10%) 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 SpeakersвЂ™ Bureau of Novo Nordisk A/S; serves on the advisory boards of Amylin Pharmaceuticals, Inc., Boehringer Ingelheim, Eli Lilly and Company, Isis Pharmaceuticals, Inc., and Takeda Pharmaceuticals North America, Inc.; and has received research/grant support from Amylin Pharmaceuticals, Inc., Eli Lilly and Company, and Takeda Pharmaceuticals North America, Inc. Muhammad Abdul-Ghani, MD, PhD, reports no relationships to disclose with any manufacturer of a product or device discussed in this supplement. 1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2008;31:S55вЂ“S60. 2. Abdul-Ghani MA, Jenkinson CP, Richardson DK, Tripathy D, DeFronzo RA. Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study. Diabetes 2006;55:1430 вЂ“1435. 3. Abdul-Ghani MA, Tripathy D, DeFronzo RA. 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