Advertisement

Assessment and Treatment of Cardiovascular Risk in Prediabetes: Impaired Glucose Tolerance and Impaired Fasting Glucose

      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 β-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.
      “Prediabetes” is a general term that refers to an intermediate stage between normal glucose tolerance (NGT) and overt type 2 diabetes mellitus. As such, it represents 2 groups of individuals, those with impaired glucose tolerance (IGT) and those with impaired fasting glucose (IFG). IGT and IFG often are lumped together, but they have distinct pathophysiologic etiologies. According to the American Diabetes Association (ADA),
      American Diabetes Association
      Diagnosis and classification of diabetes mellitus.
      individuals with isolated IGT have a fasting plasma glucose (FPG) concentration <100 mg/dL [1 mg/dL = 0.05555 mmol/L] and a 2-hour plasma glucose (PG) concentration, measured by a 75-g oral glucose tolerance test (OGTT), ranging between ≥140 mg/dL and <200 mg/dL. Individuals with isolated IFG have a 2-hour PG (measured by an OGTT) of <140 mg/dL and a FPG between ≥100 mg/dL and <126 mg/dL. Subjects with isolated IGT have moderate-to-severe insulin resistance in muscle and impaired first- and second-phase insulin secretion, while individuals with IFG have moderate insulin resistance in the liver, impaired first-phase insulin secretion, and normal/near-normal muscle insulin sensitivity.
      • Abdul-Ghani M.A.
      • Jenkinson C.P.
      • Richardson D.K.
      • Tripathy D.
      • DeFronzo R.A.
      Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study.
      • Abdul-Ghani M.A.
      • Tripathy D.
      • DeFronzo R.A.
      Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose.
      • Abdul-Ghani M.
      • Matsuda M.
      • Sabbah M.
      • Jenkinson C.
      • Richardson D.K.
      • DeFronzo R.A.
      The relative contribution of insulin resistance and β-cell failure to the transitiion from normal to impaired glucose tolerance varies in different ethnic groups.
      • Gastaldelli A.
      • Ferrannini E.
      • Miyazaki Y.
      • Matsuda M.
      • DeFronzo R.A.
      β-Cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.
      • Ferrannini E.
      • Gastaldelli A.
      • Miyazaki Y.
      • Matsuda M.
      • Mari A.
      • DeFronzo R.A.
      β-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis.
      Subjects with IGT or IFG are at high risk for developing both type 2 diabetes
      • Charles M.A.
      • Fontbonne A.
      • Thibult N.
      • Warnet J.M.
      • Rosselin G.E.
      • Eschwege E.
      Risk factors for NIDDM in white population: Paris Prospective Study.
      • Motala A.A.
      • Omar M.A.
      • Gouws E.
      High risk of progression to NIDDM in South-African Indians with impaired glucose tolerance.
      • Kahn S.E.
      • Leonetti D.L.
      • Prigeon R.L.
      • Boyko E.J.
      • Bergstom R.W.
      • Fujimoto W.Y.
      Proinsulin levels predict the development of non-insulin-dependent diabetes mellitus (NIDDM) in Japanese-American men.
      • Saad M.F.
      • Knowler W.C.
      • Pettitt D.J.
      • Nelson R.G.
      • Mott D.M.
      • Bennett P.H.
      The natural history of impaired glucose tolerance in the Pima Indians.
      • King H.
      • Zimmet P.
      • Raper L.R.
      • Balkau B.
      The natural history of impaired glucose tolerance in the Micronesian population of Nauru: a six-year follow-up study.
      • de Vegt F.
      • Dekker J.M.
      • Jager A.
      • Hienkens E.
      • Kostense P.J.
      • Stehouwer C.D.
      • Nijpels G.
      • Bouter L.M.
      • Heine R.J.
      Relation of impaired fasting and postload glucose with incident type 2 diabetes in a Dutch population: the Hoorn Study.
      • Ferrannini E.
      • Nannipieri M.
      • Williams K.
      • Gonzales C.
      • Haffner S.M.
      • Stern M.P.
      2004 Mode of onset of type 2 diabetes from normal or impaired glucose tolerance.
      • Haffner S.M.
      • Miettinen H.
      • Gaskill S.P.
      • Stern M.P.
      Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans.
      • Wong M.S.
      • Gu K.
      • Heng D.
      • Chew S.K.
      • Chew L.S.
      • Tai E.S.
      The Singapore impaired glucose tolerance follow-up study: does the ticking clock go backward as well as forward?.
      • Ko G.T.
      • Chan J.C.
      • Cockram C.S.
      Change of glycaemic status in Chinese subjects with impaired fasting glycaemia.
      • Gerstein H.C.
      • Santaguida P.
      • Raina P.
      • Morrison K.M.
      • Balion C.
      • Hunt D.
      • Yazdi H.
      • Booker L.
      Annual incidence and relative risk of diabetes in people with various categories of dysglycemia: a systematic overview and meta-analysis of prospective studies.
      and clinically significant atherosclerotic cardiovascular disease (ASCVD).
      • Barr E.L.
      • Boyko E.J.
      • Zimmet P.Z.
      • Wolfe R.
      • Tonkin A.M.
      • Shaw J.E.
      Continuous relationships between non-diabetic hyperglycaemia and both cardiovascular disease and all-cause mortality: the Australian Diabetes, Obesity, and Lifestyle (AusDiab) study.
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      • Qiao Q.
      • Pyorala K.
      • Pyorala M.
      • Nissinen A.
      • Lindstrom J.
      • Tilvis R.
      • Tuomilehto J.
      Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose.
      • Nakagami T.
      Hyperglycaemia and mortality from all causes and from cardiovascular disease in five populations of Asian origin.
      • Hyvarinen M.
      • Qiao Q.
      • Tuomilehto J.
      • Laatikainen T.
      • Heine R.J.
      • Stehouwer C.D.
      • Alberti K.G.
      • Pyorala K.
      • Zethelius B.
      • Stegmayr B.
      Hyperglycemia and stroke mortality: comparison between fasting and 2-h glucose criteria.
      • Ning F.
      • Tuomilehto J.
      • Pyorala K.
      • Onat A.
      • Soderberg S.
      • Qiao Q.
      Cardiovascular disease mortality in europeans in relation to fasting and 2h plasma glucose levels within a normoglycemic range.
      • Fuller J.H.
      • Shipley M.J.
      • Rose G.
      • Jarrett R.J.
      • Keen H.
      Coronary-heart-disease risk and impaired glucose tolerance: the Whitehall Study.
      • Rodriguez B.L.
      • Lau N.
      • Burchfiel C.M.
      • Abbott R.D.
      • Sharp D.S.
      • Yano K.
      • Curb J.D.
      Glucose intolerance and 23-year risk of coronary heart disease and total mortality: the Honolulu Heart Program.
      • Balkau B.
      • Shipley M.
      • Jarrett R.J.
      • Pyorala K.
      • Pyorala M.
      • Forhan A.
      • Eschwege E.
      High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men: 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.
      • Barr E.L.
      • Zimmet P.Z.
      • Welborn T.A.
      • Jolley D.
      • Magliano D.J.
      • Dunstan D.W.
      • Cameron A.J.
      • Dwyer T.
      • Taylor H.R.
      • Tonkin A.M.
      • et al.
      Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).
      • Jarrett R.J.
      • McCartney P.
      • Keen H.
      The Bedford survey: ten year mortality rates in newly diagnosed diabetics, borderline diabetics and normoglycaemic controls and risk indices for coronary heart disease in borderline diabetics.
      • Butler W.J.
      • Ostrander Jr, L.D.
      • Carman W.J.
      • Lamphiear D.E.
      Mortality from coronary heart disease in the Tecumseh study Long-term effect of diabetes mellitus, glucose tolerance and other risk factors.
      • Barzilay J.I.
      • Spiekerman C.F.
      • Wahl P.W.
      • Kuller L.H.
      • Cushman M.
      • Furberg C.D.
      • Dobs A.
      • Polak J.F.
      • Savage P.J.
      Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria.
      • Tominaga M.
      • Eguchi H.
      • Manaka H.
      • Igarashi K.
      • Kato T.
      • Sekikawa A.
      Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study.
      • Lawes C.M.
      • Parag V.
      • Bennett D.A.
      • Suh I.
      • Lam T.H.
      • Whitlock G.
      • Barzi F.
      • Woodward M.
      Blood glucose and risk of cardiovascular disease in the Asia Pacific region.
      • de Vegt F.
      • Dekker J.M.
      • Ruhe H.G.
      • Stehouwer C.D.
      • Nijpels G.
      • Bouter L.M.
      • Heine R.J.
      Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study.
      • Rijkelijkhuizen J.M.
      • Nijpels G.
      • Heine R.J.
      • Bouter L.M.
      • Stehouwer C.D.
      • Dekker J.M.
      High risk of cardiovascular mortality in individuals with impaired fasting glucose is explained by conversion to diabetes: the Hoorn study.
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      Most,
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      • Qiao Q.
      • Pyorala K.
      • Pyorala M.
      • Nissinen A.
      • Lindstrom J.
      • Tilvis R.
      • Tuomilehto J.
      Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose.
      • Ning F.
      • Tuomilehto J.
      • Pyorala K.
      • Onat A.
      • Soderberg S.
      • Qiao Q.
      Cardiovascular disease mortality in europeans in relation to fasting and 2h plasma glucose levels within a normoglycemic range.
      but not all
      • Barr E.L.
      • Zimmet P.Z.
      • Welborn T.A.
      • Jolley D.
      • Magliano D.J.
      • Dunstan D.W.
      • Cameron A.J.
      • Dwyer T.
      • Taylor H.R.
      • Tonkin A.M.
      • et al.
      Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab).
      studies have shown that IGT is stronger than IFG as a 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 colleagues
      • Coutinho M.
      • Gerstein H.C.
      • Wang Y.
      • Yusuf S.
      The relationship between glucose and incident cardiovascular events A meta regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.
      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).
      • Coutinho M.
      • Gerstein H.C.
      • Wang Y.
      • Yusuf S.
      The relationship between glucose and incident cardiovascular events A meta regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.
      In the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE),
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      Hoorn,
      • de Vegt F.
      • Dekker J.M.
      • Ruhe H.G.
      • Stehouwer C.D.
      • Nijpels G.
      • Bouter L.M.
      • Heine R.J.
      Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study.
      DECODA (Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Asia),
      • Lawes C.M.
      • Parag V.
      • Bennett D.A.
      • Suh I.
      • Lam T.H.
      • Whitlock G.
      • Barzi F.
      • Woodward M.
      Blood glucose and risk of cardiovascular disease in the Asia Pacific region.
      and Funagata Diabetes
      • Tominaga M.
      • Eguchi H.
      • Manaka H.
      • Igarashi K.
      • Kato T.
      • Sekikawa A.
      Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study.
      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.
      Figure thumbnail gr1
      Figure 1Relation 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.
      • Coutinho M.
      • Gerstein H.C.
      • Wang Y.
      • Yusuf S.
      The relationship between glucose and incident cardiovascular events A meta regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.
      )

      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.
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes mellitus.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      Individuals destined to develop type 2 diabetes inherit a set of genes from their parents that make their tissues resistant to insulin.
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes mellitus.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      • Bajaj M.
      • DeFronzo R.A.
      Metabolic and molecular basis of insulin resistance.
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.
      • Eriksson J.
      • Franssila-Kallunki A.
      • Ekstrand A.
      • Saloranta C.
      • Widen E.
      • Schalin C.
      • Groop L.
      Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus.
      • Pendergrass M.
      • Bertoldo A.
      • Bonadonna R.
      • Nucci G.
      • Mandarino L.
      • Cobelli C.
      • DeFronzo R.A.
      Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.
      • Groop L.
      • Lyssenko V.
      Genes and type 2 diabetes mellitus.
      • Pratipanawatr W.
      • Pratipanawatr T.
      • Cusi K.
      • Berria R.
      • Adams J.M.
      • Jenkinson C.P.
      • Maezono K.
      • DeFronzo R.A.
      • Mandarino L.J.
      Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation.
      • Morino K.
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • Frattini J.
      • Shatzkes N.
      • Neschen S.
      • White M.F.
      • Bilz S.
      • Sono S.
      • Pypaert M.
      • Shulman G.I.
      Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
      In the liver, the insulin resistance is manifest by an overproduction of glucose during the basal state despite the presence of fasting hyperinsulinemia
      • DeFronzo R.A.
      • Ferrannini E.
      • Simonson D.C.
      Fasting hyperglycemia in non-insulin-dependent diabetes mellitus: contributions of excessive hepatic glucose production and impaired tissue glucose uptake.
      and an impaired suppression of hepatic glucose production in response to insulin, as occurs following a meal.
      • Ferrannini E.
      • Simonson D.C.
      • Katz L.D.
      • Reichard Jr, G.
      • Bevilacqua S.
      • Barrett E.J.
      • Olsson M.
      • DeFronzo R.A.
      The disposal of an oral glucose load in patients with non-insulin-dependent diabetes.
      In muscle
      • Pendergrass M.
      • Bertoldo A.
      • Bonadonna R.
      • Nucci G.
      • Mandarino L.
      • Cobelli C.
      • DeFronzo R.A.
      Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.
      • DeFronzo R.A.
      • Gunnarsson R.
      • Bjorkman O.
      • Olsson M.
      • Wahren J.
      Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus.
      • Groop L.C.
      • Bonadonna R.C.
      • DelPrato S.
      • Ratheiser K.
      • Zyck K.
      • Ferrannini E.
      • DeFronzo R.A.
      Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus Evidence for multiple sites of insulin resistance.
      insulin resistance is manifest by impaired glucose uptake after ingestion of a carbohydrate-rich meal and results in postprandial hyperglycemia.
      • Ferrannini E.
      • Simonson D.C.
      • Katz L.D.
      • Reichard Jr, G.
      • Bevilacqua S.
      • Barrett E.J.
      • Olsson M.
      • DeFronzo R.A.
      The disposal of an oral glucose load in patients with non-insulin-dependent diabetes.
      Although the origins of the insulin resistance can be traced to their genetic background,
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.
      • Groop L.
      • Lyssenko V.
      Genes and type 2 diabetes mellitus.
      the epidemic of diabetes that has enveloped westernized countries is related to the epidemic of obesity and physical inactivity.
      • James W.P.
      The fundamental drivers of the obesity epidemic.
      Both obesity
      • DeFronzo R.A.
      • Soman V.
      • Sherwin R.S.
      • Hendler R.
      • Felig P.
      Insulin binding to monocytes and insulin action in human obesity, starvation, and refeeding.
      and decreased physical activity
      • Koivisto V.A.
      • Yki-Jarvinen H.
      • DeFronzo R.A.
      Physical training and insulin sensitivity.
      are insulin-resistant states and, when added to the genetic burden of the insulin resistance, place a major stress on the pancreatic β-cells to augment their secretion of insulin to offset the defect in insulin action.
      • Pendergrass M.
      • Bertoldo A.
      • Bonadonna R.
      • Nucci G.
      • Mandarino L.
      • Cobelli C.
      • DeFronzo R.A.
      Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.
      As long as the β-cells are able to augment their secretion of insulin sufficiently to offset the insulin resistance, glucose tolerance remains normal.
      • Diamond M.P.
      • Thornton K.
      • Connolly-Diamond M.
      • Sherwin R.S.
      • DeFronzo R.A.
      Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance.
      However, with time, postmeal glucose levels and subsequently FPG concentration begin to rise, leading to the onset of overt diabetes. Collectively, the insulin resistance in muscle and liver and β-cell failure have been referred to as “the triumvirate.”
      • DeFronzo R.A.
      The triumvirate: β-cell, muscle, liver A collusion responsible for NIDDM [Lilly Lecture 1987].
      As illustrated in Figure 2,
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      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 β-cell function. The β-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.
      • Abdul-Ghani M.A.
      • Jenkinson C.P.
      • Richardson D.K.
      • Tripathy D.
      • DeFronzo R.A.
      Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study.
      • Abdul-Ghani M.A.
      • Tripathy D.
      • DeFronzo R.A.
      Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose.
      • Abdul-Ghani M.
      • Matsuda M.
      • Sabbah M.
      • Jenkinson C.
      • Richardson D.K.
      • DeFronzo R.A.
      The relative contribution of insulin resistance and β-cell failure to the transitiion from normal to impaired glucose tolerance varies in different ethnic groups.
      • Gastaldelli A.
      • Ferrannini E.
      • Miyazaki Y.
      • Matsuda M.
      • DeFronzo R.A.
      β-Cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.
      • Ferrannini E.
      • Gastaldelli A.
      • Miyazaki Y.
      • Matsuda M.
      • Mari A.
      • DeFronzo R.A.
      β-Cell function in subjects spanning the range from normal glucose tolerance to overt diabetes: a new analysis.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      • Bergman R.N.
      • Finegood D.T.
      • Kahn S.E.
      The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes.
      Therefore, the “gold standard” formula for β-cell function is ΔI/ΔG ÷ IR (where ΔI represents an incremental change in insulin, ΔG is the incremental change in glucose, and IR is insulin resistance). As shown in Figure 3,
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      individuals in the upper tertile of NGT (2-hour PG = 120–139 mg/dL) have a loss of ∼50% of their β-cell function, compared with a loss of 70%–80% for individuals in the upper tertile of IGT (2-hour PG = 180–199 mg/dL). Thus, from the pathophysiologic standpoint, subjects with IGT should be considered to have type 2 diabetes. In a postmortem analysis, Butler et al
      • Butler A.E.
      • Janson J.
      • Bonner-Weir S.
      • Ritzel R.
      • Rizza R.A.
      • Butler P.C.
      β-Cell deficit and increased β-cell apoptosis in humans with type 2 diabetes.
      have shown that individuals with IFG have a 50% decrease in β-cell volume, suggesting that there is a significant loss of β-cell mass in the prediabetic state, long before the onset of overt type 2 diabetes.
      Figure thumbnail gr2
      Figure 2Natural history of type 2 diabetes mellitus. The plasma insulin response (open circles) depicts the classic Starling's curve of the pancreas.
      American Diabetes Association
      Diagnosis and classification of diabetes mellitus.
      Closed circles = insulin-mediated glucose uptake (top panel). DIAB = diabetes; Hi INS = high insulin secretion; IGT = impaired glucose tolerance; Lo INS = low insulin secretion; NGT = normal glucose tolerance; OB = obese; OGTT = oral glucose tolerance test.
      (Reprinted with permission from The American Diabetes Association.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      )
      Figure thumbnail gr3
      Figure 3Insulin secretion/insulin resistance (disposition) index (defined as change in insulin/change in glucose ÷ insulin resistance [ΔINS/ΔGLU ÷ 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.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      )
      The recently published results of the Diabetes Prevention Program (DPP)
      Diabetes Prevention Research Group
      The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program.
      have raised further concern about the clinical implications of the term “prediabetes.” In the DPP, individuals who entered with a diagnosis of IGT and still had IGT 3 years later had a 7.9% incidence of background diabetic retinopathy at the time of study end. Individuals, who entered the DPP with IGT but who progressed to diabetes after 3 years, had a 12.6% incidence of diabetic retinopathy at the end of study. Moreover, these individuals who remained with IGT or who progressed to diabetes developed diabetic retinopathy with hemoglobin A1c (HbA1c) levels of 5.9% and 6.1%, respectively, values much lower than the current ADA treatment goal of 7.0%. Peripheral neuropathy also is a common finding in IGT, occurring in as many as 5%–10% of patients.
      • Ziegler D.
      • Rathmann W.
      • Dickhaus T.
      • Meisinger C.
      • Mielck A.
      Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdominal obesity and macroangiopathy: the MONICA/KORA Augsburg Surveys S2 and S3.
      • Smith A.G.
      • Russell J.
      • Feldman E.L.
      • Goldstein J.
      • Peltier A.
      • Smith S.
      • Hamwi J.
      • Pollari D.
      • Bixby B.
      • Howard J.
      • Singleton J.R.
      Lifestyle intervention for pre-diabetic neuropathy.
      In summary, individuals with IGT are maximally or near maximally insulin resistant, have lost 80% of their β-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 β-cell failure and insulin resistance. From the standpoint of cardiovascular disease (CVD), it is equally important for the physician to recognize that IGT and type 2 diabetes are CV risk equivalents (see subsequent discussion).

      Impaired Glucose Tolerance and Type 2 Diabetes Mellitus Are Major Cardiovascular Risk Factors

      Although microvascular complications are a major cause of morbidity in type 2 diabetes, macrovascular complications represent the primary cause of mortality, with heart attacks and stroke accounting for ∼80% of all deaths.
      • Morrish N.J.
      • Wang S.L.
      • Stevens L.K.
      • Fuller J.H.
      • Keen H.
      Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.
      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.
      • Haffner S.M.
      • Lehto S.
      • Ronnemaa T.
      • Pyorala K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      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.
      • Haffner S.M.
      • Lehto S.
      • Ronnemaa T.
      • Pyorala K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      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.
      • Giorda C.B.
      • Avogaro A.
      • Maggini M.
      • Lombardo F.
      • Mannucci E.
      • Turco S.
      • Alegiani S.S.
      • Raschetti R.
      • Velussi M.
      • Ferrannini E.
      Recurrence of cardiovascular events in patients with type 2 diabetes: epidemiology and risk factors.
      These results document that diabetes is a major CV risk equivalent.
      The DECODE study
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group
      Consequences of the new diagnostic criteria for diabetes in older men and women DECODE Study.
      DECODE Study Group
      Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases?.
      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.
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      Both the FPG and postchallenge PG levels were correlated with CV risk (Figure 4),
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      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 Study
      • Meigs J.B.
      • Nathan D.M.
      • D'Agostino Sr, R.B.
      • Wilson P.W.
      Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study.
      and the Hoorn Study.
      • de Vegt F.
      • Dekker J.M.
      • Ruhe H.G.
      • Stehouwer C.D.
      • Nijpels G.
      • Bouter L.M.
      • Heine R.J.
      Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study.
      The Funagata Study also showed a higher CV mortality rate in persons with IGT compared with individuals with IFG.
      • Tominaga M.
      • Eguchi H.
      • Manaka H.
      • Igarashi K.
      • Kato T.
      • Sekikawa A.
      Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study.
      Similar results have been published by the DECODA Study Group
      • Qiao Q.
      • Pyorala K.
      • Pyorala M.
      • Nissinen A.
      • Lindstrom J.
      • Tilvis R.
      • Tuomilehto J.
      Two-hour glucose is a better risk predictor for incident coronary heart disease and cardiovascular mortality than fasting glucose.
      in Asian populations. Multiple cohort studies
      • Balkau B.
      • Shipley M.
      • Jarrett R.J.
      • Pyorala K.
      • Pyorala M.
      • Forhan A.
      • Eschwege E.
      High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men: 20-year follow-up in the Whitehall Study, the Paris Prospective Study, and the Helsinki Policemen Study.
      • Pyorala K.
      • Savolainen E.
      • Lehtovirta E.
      • Punsar S.
      • Siltanen P.
      Glucose tolerance and cornary heart disease: Helsinki Policemen Study.
      • Fuller J.H.
      • Shipley M.J.
      • Rose G.
      • Jarrett R.J.
      • Keen H.
      Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study.
      • Fujishima M.
      • Kiyohara Y.
      • Kato I.
      • Ohmura T.
      • Iwamoto H.
      • Nakayama K.
      • Ohmori S.
      • Yoshitake T.
      Diabetes and cardiovascular disease in a prospective population survey in Japan: the Hisayama Study.
      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).
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      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 Survey
      • Lenzen M.
      • Ryden L.
      • Ohrvik J.
      • Bartnik M.
      • Malmberg K.
      • Scholte Op Reimer W.
      • Simoons M.L.
      Diabetes known or newly detected, but not impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro Heart Survey on diabetes and the heart.
      also was associated with worsening CV prognosis. After 1 year of follow up, all-cause mortality was 2.2% in patients with NGT, 2.7%–3.7% in subjects with IGT/IFG, 5.5% in patients 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.
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      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.
      Figure thumbnail gr4
      Figure 4Cumulative 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.
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      )
      Figure thumbnail gr5
      Figure 5Event-free survival with respect to glycemic state in 1,040 patients who underwent coronary arteriography for suspected/established coronary artery disease. IGT = impaired glucose tolerance; NGT = normal glucose tolerance.
      (Reprinted with permission from Oxford University Press.
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      )
      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.
      • Abdul-Ghani M.A.
      • Jenkinson C.P.
      • Richardson D.K.
      • Tripathy D.
      • DeFronzo R.A.
      Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study.
      • Abdul-Ghani M.A.
      • Tripathy D.
      • DeFronzo R.A.
      Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose.
      • Woerle H.J.
      • Pimenta W.P.
      • Meyer C.
      • Gosmanov N.R.
      • Szoke E.
      • Szombathy T.
      • Mitrakou A.
      • Gerich J.E.
      Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma glucose and hemoglobin A1c values.
      Second, individuals with IGT have a higher prevalence of the metabolic syndrome,
      • Blake D.R.
      • Meigs J.B.
      • Muller D.C.
      • Najjar S.S.
      • Andres R.
      • Nathan D.M.
      Impaired glucose tolerance, but not impaired fasting glucose, is associated with increased levels of coronary heart disease risk factors: results from the Baltimore Longitudinal Study on Aging.
      • Medalie J.H.
      • Papier C.M.
      • Goldbourt U.
      • Herman J.B.
      Major factors in the development of diabetes mellitus in 10,000 men.
      • McPhillips J.B.
      • Barrett-Connor E.
      • Wingard D.L.
      Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults.
      • Mykkanen L.
      • Kuusisto J.
      • Pyorala K.
      • Laakso M.
      Cardiovascular disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects.
      • Haffner S.M.
      • Stern M.P.
      • Hazuda H.P.
      • Mitchell B.D.
      • Patterson J.K.
      Cardiovascular risk factors in confirmed prediabetic individuals Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?.
      • Haffner S.M.
      Insulin resistance, inflammation, and the prediabetic state.
      • Haffner S.M.
      • Mykkanen L.
      • Festa A.
      • Burke J.P.
      • Stern M.P.
      Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state.
      • Isomaa B.
      • Almgren P.
      • Tuomi T.
      • Forsen B.
      • Lahti K.
      • Nissen M.
      • Taskinen M.R.
      • Groop L.
      Cardiovascular morbidity and mortality associated with the metabolic syndrome.
      • Goldberg R.B.
      • Temprosa M.
      • Haffner S.
      • Orchard T.J.
      • Ratner R.E.
      • Fowler S.E.
      • Mather K.
      • Marcovina S.
      • Saudek C.
      • Matulik M.J.
      • Price D.
      Diabetes Prevention Program Research Group
      Effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: the Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group.
      a cluster of abnormalities including central obesity dyslipidemia, hypertension, and dysglycemia, that by itself increases the risk for ASCVD.
      • Grundy S.M.
      Metabolic syndrome pandemic.
      • Noto D.
      • Barbagallo C.M.
      • Cefalu A.B.
      • Falletta A.
      • Sapienza M.
      • Cavera G.
      • Amato S.
      • Pagano M.
      • Maggiore M.
      • Carroccio A.
      • Notarbartolo A.
      • Averna M.R.
      The metabolic syndrome predicts cardiovascular events in subjects with normal fasting glucose: results of a 15 years follow-up in a Mediterranean population.
      • Miranda P.J.
      • DeFronzo R.A.
      • Califf R.M.
      • Guyton J.R.
      Metabolic syndrome: evaluation of pathological and therapeutic outcomes.
      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,
      • Monnier L.
      • Lapinski H.
      • Colette C.
      Contributions of fasting and postprandial plasma glucose increments to the overall diurnal hyperglycemia of type 2 diabetes patients.
      • Ceriello A.
      Impaired glucose tolerance and cardiovascular disease: the possible role of post-prandial hyperglycemia.
      • Ceriello A.
      • Taboga C.
      • Tonutti L.
      • Quagliaro L.
      • Piconi L.
      • Bais B.
      • Da Ros R.
      • Motz E.
      Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment.
      • Scognamiglio R.
      • Negut C.
      • De Kreutzenberg S.V.
      • Tiengo A.
      • Avogaro A.
      Postprandial myocardial perfusion in healthy subjects and in type 2 diabetic patients.
      • Hanefeld M.
      • Fischer S.
      • Julius U.
      • Schulze J.
      • Schwanebeck U.
      • Schmechel H.
      • Ziegelasch H.J.
      • Lindner J.
      Risk factors for myocardial infarction and death in newly detected NIDDM: the Diabetes Intervention Study, 11-year follow-up.
      • Cavalot F.
      • Petrelli A.
      • Traversa M.
      • Bonomo K.
      • Fiora E.
      • Conti M.
      • Anfossi G.
      • Costa G.
      • Trovati M.
      Postprandial blood glucose is a stronger predictor of cardiovascular events than fasting blood glucose in type 2 diabetes mellitus, particularly in women: lessons from the San Luigi Gonzaga Diabetes Study.
      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%,
      • Saely C.H.
      • Drexel H.
      • Sourij H.
      • Aczel S.
      • Jahnel H.
      • Zweiker R.
      • Langer P.
      • Marte T.
      • Hoefle G.
      • Benzer W.
      • Wascher T.C.
      Key role of postchallenge hyperglycemia for the presence and extent of coronary atherosclerosis: an angiographic study.
      • Wascher T.C.
      • Sourij H.
      • Roth M.
      • Dittrich P.
      Prevalence of pathological glucose metabolism in patients undergoing elective coronary angiography.
      • Bartnik M.
      • Ryden L.
      • Ferrari R.
      • Malmberg K.
      • Pyorala K.
      • Simoons M.
      • Standl E.
      • Soler-Soler J.
      • Ohrvik J.
      The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe: the Euro Heart Survey on diabetes and the heart.
      • Norhammar A.
      • Tenerz A.
      • Nilsson G.
      • Hamsten A.
      • Efendic S.
      • Ryden L.
      • Malmberg K.
      Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study.
      • Harris M.I.
      • Klein R.
      • Welborn T.A.
      • Knuiman M.W.
      Onset of NIDDM occurs at least 4-7 yr before clinical diagnosis.
      • Hu D.Y.
      • Pan C.Y.
      • Yu J.M.
      The relationship between coronary artery disease and abnormal glucose regulation in China: the China Heart Survey.
      and the severity of postchallenge hyperglycemia correlates closely with the extent of angiographically determined CAD
      • Saely C.H.
      • Drexel H.
      • Sourij H.
      • Aczel S.
      • Jahnel H.
      • Zweiker R.
      • Langer P.
      • Marte T.
      • Hoefle G.
      • Benzer W.
      • Wascher T.C.
      Key role of postchallenge hyperglycemia for the presence and extent of coronary atherosclerosis: an angiographic study.
      and with future macrovascular events and total mortality.
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      The DIGAMI (Diabetes Insulin Glucose and Myocardial Infarction) Study
      • Norhammar A.
      • Tenerz A.
      • Nilsson G.
      • Hamsten A.
      • Efendic S.
      • Ryden L.
      • Malmberg K.
      Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: a prospective study.
      examined the prevalence of dysglycemia (OGTT performed at hospital discharge) in 164 patients admitted to the hospital with an acute MI, with assessment repeated 4–5 days later (n = 164) and 3 months later (n = 144). Prediabetes and newly diagnosed type 2 diabetes, respectively, were diagnosed in 35% and 31% of patients. The similar incidence of abnormal glucose tolerance detected 3 months later excluded acute illness and increased sympathetic tone as the cause of the disturbance in glucose metabolism. Similar findings have been reported in 3 longer studies, the 25-country Euro Heart Survey,
      • Bartnik M.
      • Ryden L.
      • Ferrari R.
      • Malmberg K.
      • Pyorala K.
      • Simoons M.
      • Standl E.
      • Soler-Soler J.
      • Ohrvik J.
      The prevalence of abnormal glucose regulation in patients with coronary artery disease across Europe: the Euro Heart Survey on diabetes and the heart.
      the China Heart Survey,
      • Hu D.Y.
      • Pan C.Y.
      • Yu J.M.
      The relationship between coronary artery disease and abnormal glucose regulation in China: the China Heart Survey.
      and a study from Austria.
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      In summary, >60% of individuals with previously undiagnosed prediabetes or diabetes who experience an MI or come to coronary catheterization because of suspected CAD have IGT, IFG, or type 2 diabetes. Because of this very high incidence of dysglycemia, it is recommended that all patients with acute MI and new-onset angina or CAD should have a 75-g, 2-hour OGTT. Individuals with stable chronic CAD also should have an OGTT to exclude underlying prediabetes/diabetes.

      Assessing Cardiovascular Risk and the Need for Screening in Patients with Prediabetes

      There are no prospective studies that have evaluated which asymptomatic individuals with prediabetes should be screened for CAD. However, because prediabetes, like overt type 2 diabetes, is a CV risk equivalent, it is reasonable to use the same criteria applied to diabetes. Recently, the ADA
      • Bax J.J.
      • Young L.H.
      • Frye R.L.
      • Bonow R.O.
      • Steinberg H.O.
      • Barrett E.J.
      Screening for coronary artery disease in patients with diabetes.
      revised its 1998 Consensus Conference Guidelines
      American Diabetes Association
      Consensus development conference on the diagnosis of coronary heart disease in people with diabetes.
      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.
      • Scognamiglio R.
      • Negut C.
      • Ramondo A.
      • Tiengo A.
      • Avogaro A.
      Detection of coronary artery disease in asymptomatic patients with type 2 diabetes mellitus.
      • Wackers F.J.
      • Young L.H.
      • Inzucchi S.E.
      • Chyun D.A.
      • Davey J.A.
      • Barrett E.J.
      • Taillefer R.
      • Wittlin S.D.
      • Heller G.V.
      • Filipchuk N.
      • et al.
      Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study.
      Moreover, efforts using data from the Framingham study and the United Kingdom Prospective Diabetes Study (UKPDS) have proved only modestly successful.
      • Guzder R.N.
      • Gatling W.
      • Mullee M.A.
      • Mehta R.L.
      • Byrne C.D.
      Prognostic value of the Framingham cardiovascular risk equation and the UKPDS risk engine for coronary heart disease in newly diagnosed Type 2 diabetes: results from a United Kingdom study.
      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,
      • Golomb B.A.
      • Dang T.T.
      • Criqui M.H.
      Peripheral arterial disease: morbidity and mortality implications.
      • Mann J.F.
      • Gerstein H.C.
      • Pogue J.
      • Bosch J.
      • Yusuf S.
      Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial.
      microalbuminuria,
      • Gerstein H.C.
      • Mann J.F.
      • Yi Q.
      • Zinman B.
      • Dinneen S.F.
      • Hoogwerf B.
      • Halle J.P.
      • Young J.
      • Rashkow A.
      • Joyce C.
      • Nawaz S.
      • Yusuf S.
      Albuminuria and risk of cardiovascular events, death, and heart failure in diabetic and nondiabetic individuals.
      • Grimm Jr, R.H.
      • Svendsen K.H.
      • Kasiske B.
      • Keane W.F.
      • Wahi M.M.
      MRFIT Research Group
      Proteinuria is a risk factor for mortality over 10 years of follow-up: Multiple Risk Factor Intervention Trial.
      abnormal electrocardiogram (Q-waves, T-wave inversion, left bundle branch block),
      • Rajagopalan N.
      • Miller T.D.
      • Hodge D.O.
      • Frye R.L.
      • Gibbons R.J.
      Identifying high-risk asymptomatic diabetic patients who are candidates for screening stress single-photon emission computed tomography imaging.
      • Rutter M.K.
      • McComb J.M.
      • Brady S.
      • Marshall S.M.
      Silent myocardial ischemia and microalbuminuria in asymptomatic subjects with non-insulin-dependent diabetes mellitus.
      autonomic neuropathy,
      • Vinik A.I.
      • Maser R.E.
      • Mitchell B.D.
      • Freeman R.
      Diabetic autonomic neuropathy.
      retinopathy,
      • Hiller R.
      • Sperduto R.D.
      • Podgor M.J.
      • Ferris III, F.L.
      • Wilson P.W.
      Diabetic retinopathy and cardiovascular disease in type II diabetics: the Framingham Heart Study and the Framingham Eye Study.
      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,
      • Wackers F.J.
      • Young L.H.
      • Inzucchi S.E.
      • Chyun D.A.
      • Davey J.A.
      • Barrett E.J.
      • Taillefer R.
      • Wittlin S.D.
      • Heller G.V.
      • Filipchuk N.
      • et al.
      Detection of silent myocardial ischemia in asymptomatic diabetic subjects: the DIAD study.
      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.
      • Medalie J.H.
      • Papier C.M.
      • Goldbourt U.
      • Herman J.B.
      Major factors in the development of diabetes mellitus in 10,000 men.
      • McPhillips J.B.
      • Barrett-Connor E.
      • Wingard D.L.
      Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults.
      • Mykkanen L.
      • Kuusisto J.
      • Pyorala K.
      • Laakso M.
      Cardiovascular disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects.
      • Haffner S.M.
      • Stern M.P.
      • Hazuda H.P.
      • Mitchell B.D.
      • Patterson J.K.
      Cardiovascular risk factors in confirmed prediabetic individuals Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?.
      • Isomaa B.
      • Almgren P.
      • Tuomi T.
      • Forsen B.
      • Lahti K.
      • Nissen M.
      • Taskinen M.R.
      • Groop L.
      Cardiovascular morbidity and mortality associated with the metabolic syndrome.
      • Goldberg R.B.
      • Temprosa M.
      • Haffner S.
      • Orchard T.J.
      • Ratner R.E.
      • Fowler S.E.
      • Mather K.
      • Marcovina S.
      • Saudek C.
      • Matulik M.J.
      • Price D.
      Diabetes Prevention Program Research Group
      Effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: the Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group.
      Because prediabetes and type 2 diabetes are part of a continuous spectrum, it is not unreasonable to assume that these same abnormalities predict increased CV risk in individuals with prediabetes.
      Although the presence of multiple CV risk factors does not identify individuals at risk for inducible ischemia on perfusion imaging, it does identify people at high risk for a subsequent coronary event. Consistent with this, autopsy studies in type 2 diabetes have demonstrated severe multivessel coronary atherosclerosis even in asymptomatic individuals.
      • Goraya T.Y.
      • Leibson C.L.
      • Palumbo P.J.
      • Weston S.A.
      • Killian J.M.
      • Pfeifer E.A.
      • Jacobsen S.J.
      • Frye R.L.
      • Roger V.L.
      Coronary atherosclerosis in diabetes mellitus: a population-based autopsy study.
      Subjects with the metabolic syndrome, the majority of whom have some form of dysglycemia,
      Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults
      Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).
      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.
      • Wilson P.W.
      • D'Agostino R.B.
      • Parise H.
      • Sullivan L.
      • Meigs J.B.
      Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus.
      • Rutter M.K.
      • Meigs J.B.
      • Sullivan L.M.
      • D'Agostino Sr, R.B.
      • Wilson P.W.
      Insulin resistance, the metabolic syndrome, and incident cardiovascular events in the Framingham Offspring Study.
      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,
      • Gaede P.
      • Vedel P.
      • Larsen N.
      • Jensen G.V.
      • Parving H.H.
      • Pedersen O.
      Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes.
      • Gaede P.
      • Lund-Andersen H.
      • Parving H.H.
      • Pedersen O.
      Effect of a mulifactorial interventiion on mortality in type 2 diabetes.
      Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE),
      • Boden W.E.
      • O'Rourke R.A.
      • Teo K.K.
      • Hartigan P.M.
      • Maron D.J.
      • Kostuk W.
      • Knudtson M.
      • Dada M.
      • Casperson P.
      • Harris C.L.
      • et al.
      Design and rationale of the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial Veterans Affairs Cooperative Studies Program no. 424.
      and Multiple Risk Factor Intervention Trial (MRFIT)
      The Multiple Risk Factor Intervention Trial Research Group
      Mortality after 16 years for participants randomized to the Multiple Risk Factor Intervention Trial.
      studies. If screening is to be undertaken in subjects with prediabetes, newer CAD diagnostic modalities including computed tomographic angiography,
      • Schuijf J.D.
      • Pundziute G.
      • Jukema J.W.
      • Lamb H.J.
      • van der Hoeven B.L.
      • de Roos A.
      • van der Wall E.E.
      • Bax J.J.
      Diagnostic accuracy of 64-slice multislice computed tomography in the noninvasive evaluation of significant coronary artery disease.
      coronary artery calcium score using electron-beam or multislice technology,
      • Mazzone T.
      The role of electron beam computed tomography for measuring coronary artery atherosclerosis.
      • Anand D.V.
      • Lim E.
      • Hopkins D.
      • Corder R.
      • Shaw L.J.
      • Sharp P.
      • Lipkin D.
      • Lahiri A.
      Risk stratification in uncomplicated type 2 diabetes: prospective evaluation of the combined use of coronary artery calcium imaging and selective myocardial perfusion scintigraphy.
      or cardiac magnetic resonance imaging is recommended.
      • Schuijf J.D.
      • Bax J.J.
      • Shaw L.J.
      • de Roos A.
      • Lamb H.J.
      • van der Wall E.E.
      • Wijns W.
      Meta-analysis of comparative diagnostic performance of magnetic resonance imaging and multislice computed tomography for noninvasive coronary angiography.
      The recently reported results of the DPP in the United States provide support for the approach advocated above.
      • Goldberg R.B.
      • Temprosa M.
      • Haffner S.
      • Orchard T.J.
      • Ratner R.E.
      • Fowler S.E.
      • Mather K.
      • Marcovina S.
      • Saudek C.
      • Matulik M.J.
      • Price D.
      Diabetes Prevention Program Research Group
      Effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: the Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group.
      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.
      • Haffner S.M.
      • Stern M.P.
      • Hazuda H.P.
      • Mitchell B.D.
      • Patterson J.K.
      Cardiovascular risk factors in confirmed prediabetic individuals Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?.
      Based on these observations, the SAHS investigators put forward the “ticking clock” hypothesis, which states that the clock for CAD starts to tick long before the onset of overt diabetes (Figure 6). The Nurses Health Study
      • Hu F.B.
      • Stampfer M.J.
      • Haffner S.M.
      • Solomon C.G.
      • Willett W.C.
      • Manson J.E.
      Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes.
      and the Botnia Study
      • Isomaa B.
      • Almgren P.
      • Tuomi T.
      • Forsen B.
      • Lahti K.
      • Nissen M.
      • Taskinen M.R.
      • Groop L.
      Cardiovascular morbidity and mortality associated with the metabolic syndrome.
      also demonstrated the presence of abnormal CV risk factors long before the development of overt diabetes.
      Figure thumbnail gr6
      Figure 6Schematic representation of the ticking clock hypothesis. CAD = coronary artery disease; T2DM = type 2 diabetes mellitus.
      In summary, multiple studies demonstrate that individuals with prediabetes, especially those with multiple risk factors for CVD, are at increased risk for a CV event over the subsequent follow-up period of 10 years.

      Insulin Resistance, Hyperinsulinemia, and Atherosclerotic Cardiovascular Disease: the Missing Links

      Insulin and atherosclerosis

      Insulin resistance and hyperinsulinemia have been implicated as the missing links in the increased risk for CVD.
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      In vivo and in vitro studies have demonstrated that insulin can promote atherogenesis.
      • Kashyap S.R.
      • DeFronzo R.A.
      The insulin resistance syndrome: physiological considerations.
      • DeFronzo R.A.
      • Ferrannini E.
      Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease.
      • DeFronzo R.A.
      Is insulin resistance atherogenic? Possible mechanisms.
      Insulin enhances de novo lipogenesis and augments hepatic very-low-density lipoprotein (VLDL) synthesis
      • Koopmans S.J.
      • Kushwaha R.S.
      • DeFronzo R.A.
      Chronic physiologic hyperinsulinemia impairs suppression of plasma free fatty acids and increases de novo lipogenesis but does not cause dyslipidemia in conscious normal rats.
      • Tobey T.A.
      • Greenfield M.
      • Kraemer F.
      • Reaven G.M.
      Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics, and plasma triglyceride levels in normotriglyceridemic man.
      via stimulation of sterol regulatory element–binding protein-1c and inhibition of acetyl-coenzyme A–1 carboxylase.
      • Azzout-Marniche D.
      • Becard D.
      • Guichard C.
      • Foretz M.
      • Ferre P.
      • Foufelle F.
      Insulin effects on sterol regulatory-element-binding protein-1c (SREBP-1c) transcriptional activity in rat hepatocytes.
      In cultured arterial smooth muscle cells, insulin increases LDL-C transport,
      • Stout R.W.
      The effect of insulin on the incorporation of sodium (1-14C)-acetate into the lipids of the rat aorta.
      augments collagen synthesis,
      • King G.L.
      • Goodman A.D.
      • Buzney S.
      • Moses A.
      • Kahn C.R.
      Receptors and growth-promoting effects of insulin and insulinlike growth factors on cells from bovine retinal capillaries and aorta.
      • Coletta D.K.
      • Balas B.
      • Chavez A.O.
      • Baig M.
      • Abdul-Ghani M.
      • Kashyap S.R.
      • Folli F.
      • Tripathy D.
      • Mandarino L.J.
      • Cornell J.E.
      • Defronzo R.A.
      • Jenkinson C.P.
      Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo.
      stimulates arterial smooth muscle cell proliferation,
      • Nakao J.
      • Ito H.
      • Kanayasu T.
      • Murota S.
      Stimulatory effect of insulin on aortic smooth muscle cell migration induced by 12-l-hydroxy-5,8,10,14-eicosatetraenoic acid and its modulation by elevated extracellular glucose levels.
      • Pfeifle B.
      • Ditschuneit H.
      Effect of insulin on growth of cultured human arterial smooth muscle cells.
      and activates multiple genes involved in inflammation.
      • Coletta D.K.
      • Balas B.
      • Chavez A.O.
      • Baig M.
      • Abdul-Ghani M.
      • Kashyap S.R.
      • Folli F.
      • Tripathy D.
      • Mandarino L.J.
      • Cornell J.E.
      • Defronzo R.A.
      • Jenkinson C.P.
      Effect of acute physiological hyperinsulinemia on gene expression in human skeletal muscle in vivo.
      In vivo studies in dogs,
      • Cruz Jr, A.B.
      • Amatuzio D.S.
      • Grande F.
      • Hay L.J.
      Effect of intra-arterial insulin on tissue cholesterol and fatty acids in alloxan-diabetic dogs.
      rabbits,
      • Duff G.L.
      • McMillan G.C.
      The effect of alloxan diabetes on experimental cholesterol atherosclerosis in the rabbit.
      and chickens
      • Stamler J.
      • Pick R.
      • Katz L.N.
      Effect of insulin in the induction and regression of atherosclerosis in the chick.
      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 insulin
      • Koopmans S.J.
      • Ohman L.
      • Haywood J.R.
      • Mandarino L.J.
      • DeFronzo R.A.
      Seven days of euglycemic hyperinsulinemia induces insulin resistance for glucose metabolism but not hypertension, elevated catecholamine levels, or increased sodium retention in conscious normal rats.
      and become hypertensive.
      • Meehan W.P.
      • Buchanan T.A.
      • Hsueh W.
      Chronic insulin administration elevates blood pressure in rats.
      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,
      • Del Prato S.
      • Leonetti F.
      • Simonson D.C.
      • Sheehan P.
      • Matsuda M.
      • DeFronzo R.A.
      Effect of sustained physiologic hyperinsulinaemia and hyperglycaemia on insulin secretion and insulin sensitivity in man.
      • Iozzo P.
      • Pratipanawatr T.
      • Pijl H.
      • Vogt C.
      • Kumar V.
      • Pipek R.
      • Matsuda M.
      • Mandarino L.J.
      • Cusi K.J.
      • DeFronzo R.A.
      Physiological hyperinsulinemia impairs insulin-stimulated glycogen synthase activity and glycogen synthesis.
      a risk factor for CVD (see subsequent discussion). Hyperinsulinemia and insulin therapy are also associated with weight gain,
      • Holman R.R.
      • Thorne K.I.
      • Farmer A.J.
      • Davies M.J.
      • Keenan J.F.
      • Paul S.
      • Levy J.C.
      Addition of biphasic, prandial, or basal insulin to oral therapy in type 2 diabetes.
      and obesity is a major risk factor for CVD.
      • Calle E.E.
      • Thun M.J.
      • Petrelli J.M.
      • Rodriguez C.
      • Heath Jr, C.W.
      Body-mass index and mortality in a prospective cohort of U.S. adults.
      • Allison D.B.
      • Fontaine K.R.
      • Manson J.E.
      • Stevens J.
      • VanItallie T.B.
      Annual deaths attributable to obesity in the United States.
      Weight gain promotes atherogenesis via multiple mechanisms including dyslipidemia and hypertension, while fat deposition in the arterial wall promotes inflammation, which directly accelerates atherogenesis.
      • Wang L.
      • Sapuri-Butin A.R.
      • Aung H.H.
      • Parikh A.N.
      • Rutledge J.C.
      Triglyceride-rich lipoprotein lipolysis increases aggregation of endothelial membrane microdomains an dproduces reactive oxygen species.
      • Felton C.V.
      • Crook D.
      • Davies M.J.
      • Oliver M.F.
      Relation of plaque lipid composition and morphology to the stability of human aortic plaques.
      • Felton C.V.
      • Crook D.
      • Davies M.J.
      • Oliver M.F.
      Dietary polyunsaturated fatty acids and composition of human aortic plaques.

      Insulin resistance (metabolic) syndrome

      Much evidence indicates that insulin resistance per se and associated components of the insulin resistance (metabolic) syndrome
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes mellitus.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      • Bajaj M.
      • DeFronzo R.A.
      Metabolic and molecular basis of insulin resistance.
      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).
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      In fact, insulin resistance is fully established in the NGT offspring of 2 parents with type 2 diabetes.
      • Bajaj M.
      • DeFronzo R.A.
      Metabolic and molecular basis of insulin resistance.
      • Pendergrass M.
      • Bertoldo A.
      • Bonadonna R.
      • Nucci G.
      • Mandarino L.
      • Cobelli C.
      • DeFronzo R.A.
      Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.
      • Pratipanawatr W.
      • Pratipanawatr T.
      • Cusi K.
      • Berria R.
      • Adams J.M.
      • Jenkinson C.P.
      • Maezono K.
      • DeFronzo R.A.
      • Mandarino L.J.
      Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation.
      In all of these groups, insulin resistance primarily affects the glycogen synthetic pathway (Figure 7).
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes mellitus.
      • DeFronzo R.A.
      From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].
      • Bajaj M.
      • DeFronzo R.A.
      Metabolic and molecular basis of insulin resistance.
      • DeFronzo R.A.
      Pathogenesis of type 2 diabetes: metabolic and molecular implications for identifying diabetes genes.
      • Eriksson J.
      • Franssila-Kallunki A.
      • Ekstrand A.
      • Saloranta C.
      • Widen E.
      • Schalin C.
      • Groop L.
      Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus.
      • Pendergrass M.
      • Bertoldo A.
      • Bonadonna R.
      • Nucci G.
      • Mandarino L.
      • Cobelli C.
      • DeFronzo R.A.
      Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.
      • Pratipanawatr W.
      • Pratipanawatr T.
      • Cusi K.
      • Berria R.
      • Adams J.M.
      • Jenkinson C.P.
      • Maezono K.
      • DeFronzo R.A.
      • Mandarino L.J.
      Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation.
      • Morino K.
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • Frattini J.
      • Shatzkes N.
      • Neschen S.
      • White M.F.
      • Bilz S.
      • Sono S.
      • Pypaert M.
      • Shulman G.I.
      Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
      • Bonadonna R.C.
      • Groop L.
      • Kraemer N.
      • Ferrannini E.
      • Del Prato S.
      • DeFronzo R.A.
      Obesity and insulin resistance in humans: a dose-response study.
      • Reaven G.M.
      Role of insulin resistance in human disease [Banting lecture 1988].
      Type 2 diabetes
      • Morrish N.J.
      • Wang S.L.
      • Stevens L.K.
      • Fuller J.H.
      • Keen H.
      Mortality and causes of death in the WHO Multinational Study of Vascular Disease in Diabetes.
      • Haffner S.M.
      • Lehto S.
      • Ronnemaa T.
      • Pyorala K.
      • Laakso M.
      Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction.
      and obesity
      • Calle E.E.
      • Thun M.J.
      • Petrelli J.M.
      • Rodriguez C.
      • Heath Jr, C.W.
      Body-mass index and mortality in a prospective cohort of U.S. adults.
      • Allison D.B.
      • Fontaine K.R.
      • Manson J.E.
      • Stevens J.
      • VanItallie T.B.
      Annual deaths attributable to obesity in the United States.
      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,
      • Bajaj M.
      • DeFronzo R.A.
      Metabolic and molecular basis of insulin resistance.
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      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.
      Figure thumbnail gr7
      Figure 7Insulin-stimulated glucose disposal (40 mU/m2 per min, euglycemic-hyperinsulinemic clamp) in lean healthy control (CON) participants, obese participants with normal glucose tolerance (NGT), lean drug-naive participants with type 2 diabetes mellitus (T2DM), lean participants with NGT and hypertension (HTN), participants with NGT and hypertriacylglycerolemia (Hypertriacyl), and nondiabetic participants with coronary artery disease (CAD). White bar sections indicate nonoxidative glucose disposal (glycogen synthesis); black bar sections indicate glucose oxidation. *p <0.01 vs CON; p <0.001 vs CON.
      (With kind permission from Springer Science+Business Media: Diabetologia, Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009], Volume 53, 2010, DeFronzo RA, Figure 1.
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      )
      Insulin resistance is a central feature of the metabolic (insulin resistance) syndrome, and it primarily involves the glycogen synthetic pathway (Figure 7).
      • Reaven G.
      Insulin resistance, hypertension, and coronary heart disease.
      • Ferrannini E.
      • Buzzigoli G.
      • Bonadonna R.
      • Giorico M.A.
      • Oleggini M.
      • Graziadei L.
      • Pedrinelli R.
      • Brandi L.
      • Bevilacqua S.
      Insulin resistance in essential hypertension.
      • Solini A.
      • DeFronzo R.A.
      Insulin resistance, hypertension, and cellular ion transport systems.
      Hypertension also is a well-established risk factor for CVD.
      • Law M.R.
      • Morris J.K.
      • Wald N.J.
      Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies.
      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.
      • Grundy S.M.
      Metabolic syndrome pandemic.
      • Noto D.
      • Barbagallo C.M.
      • Cefalu A.B.
      • Falletta A.
      • Sapienza M.
      • Cavera G.
      • Amato S.
      • Pagano M.
      • Maggiore M.
      • Carroccio A.
      • Notarbartolo A.
      • Averna M.R.
      The metabolic syndrome predicts cardiovascular events in subjects with normal fasting glucose: results of a 15 years follow-up in a Mediterranean population.
      • Miranda P.J.
      • DeFronzo R.A.
      • Califf R.M.
      • Guyton J.R.
      Metabolic syndrome: evaluation of pathological and therapeutic outcomes.
      • Reaven G.M.
      Role of insulin resistance in human disease [Banting lecture 1988].
      • DeFronzo R.A.
      Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis.
      • Rana J.S.
      • Visser M.E.
      • Arsenault B.J.
      • Despres J.P.
      • Stroes E.S.
      • Kastelein J.J.
      • Wareham N.J.
      • Boekholdt S.M.
      • Khaw K.T.
      Metabolic dyslipidemia and risk of future coronary heart disease in apparently healthy men and women: the EPIC-Norfolk prospective population study.
      • Stamler J.
      • Vaccaro O.
      • Neaton J.D.
      • Wentworth D.
      Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
      • Sheu W.H.
      • Shieh S.M.
      • Fuh M.M.
      • Shen D.D.
      • Jeng C.Y.
      • Chen Y.D.
      • Reaven G.M.
      Insulin resistance, glucose intolerance, and hyperinsulinemia Hypertriglyceridemia versus hypercholesterolemia.
      Hypertriglyceridemia, but not hypercholesterolemia, is associated with insulin resistance (Figure 7).
      • DeFronzo R.A.
      Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidaemia and atherosclerosis.
      • Sheu W.H.
      • Shieh S.M.
      • Fuh M.M.
      • Shen D.D.
      • Jeng C.Y.
      • Chen Y.D.
      • Reaven G.M.
      Insulin resistance, glucose intolerance, and hyperinsulinemia Hypertriglyceridemia versus hypercholesterolemia.
      • Jeppesen J.
      • Hollenbeck C.B.
      • Zhou M.Y.
      • Coulston A.M.
      • Jones C.
      • Chen Y.D.
      • Reaven G.M.
      Relation between insulin resistance, hyperinsulinemia, postheparin plasma lipoprotein lipase activity, and postprandial lipemia.
      • Galvan A.Q.
      • Santoro D.
      • Natali A.
      • Sampietro T.
      • Boni C.
      • Masoni A.
      • Buzzigoli G.
      • Ferrannini E.
      Insulin sensitivity in familial hypercholesterolemia.
      The frequency of hypercholesterolemia is not increased in patients with type 2 diabetes.
      • Stamler J.
      • Vaccaro O.
      • Neaton J.D.
      • Wentworth D.
      Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
      However, elevated LDL-C acts synergistically with other risk factors to accelerate atherogenesis.
      • Howard B.V.
      • Robbins D.C.
      • Sievers M.L.
      • Lee E.T.
      • Rhoades D.
      • Devereux R.B.
      • Cowan L.D.
      • Gray R.S.
      • Welty T.K.
      • Go O.T.
      • Howard W.J.
      LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: the Strong Heart Study.
      Studies by Bressler et al
      • Bressler P.
      • Bailey S.R.
      • Matsuda M.
      • DeFronzo R.A.
      Insulin resistance and coronary artery disease.
      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 resistance primarily affected the glycogen synthetic pathway in skeletal muscle (Figure 7).
      • Bressler P.
      • Bailey S.R.
      • Matsuda M.
      • DeFronzo R.A.
      Insulin resistance and coronary artery disease.
      Studies by Reaven
      • Reaven G.M.
      Role of insulin resistance in human disease [Banting lecture 1988].
      and Paternostro and colleagues
      • Paternostro G.
      • Camici P.G.
      • Lammerstma A.A.
      • Marinho N.
      • Baliga R.R.
      • Kooner J.S.
      • Radda G.K.
      • Ferrannini E.
      Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease: a study with positron emission tomography.
      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.
      • Paternostro G.
      • Camici P.G.
      • Lammerstma A.A.
      • Marinho N.
      • Baliga R.R.
      • Kooner J.S.
      • Radda G.K.
      • Ferrannini E.
      Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease: a study with positron emission tomography.
      • Iozzo P.
      • Chareonthaitawee P.
      • Dutka D.
      • Betteridge D.J.
      • Ferrannini E.
      • Camici P.G.
      Independent association of type 2 diabetes and coronary artery disease with myocardial insulin resistance.
      • Lautamaki R.
      • Airaksinen K.E.
      • Seppanen M.
      • Toikka J.
      • Luotolahti M.
      • Ball E.
      • Borra R.
      • Harkonen R.
      • Iozzo P.
      • Stewart M.
      • Knuuti J.
      • Nuutila P.
      Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study.
      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,
      • Abdul-Ghani M.A.
      • Jenkinson C.P.
      • Richardson D.K.
      • Tripathy D.
      • DeFronzo R.A.
      Insulin secretion and action in subjects with impaired fasting glucose and impaired glucose tolerance: results from the Veterans Administration Genetic Epidemiology Study.
      • Abdul-Ghani M.A.
      • Tripathy D.
      • DeFronzo R.A.
      Contributions of β-cell dysfunction and insulin resistance to the pathogenesis of impaired glucose tolerance and impaired fasting glucose.
      ie, prediabetes, even before any abnormality in glucose tolerance is observed
      • Pendergrass M.
      • Bertoldo A.
      • Bonadonna R.
      • Nucci G.
      • Mandarino L.
      • Cobelli C.
      • DeFronzo R.A.
      Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals.
      • Pratipanawatr W.
      • Pratipanawatr T.
      • Cusi K.
      • Berria R.
      • Adams J.M.
      • Jenkinson C.P.
      • Maezono K.
      • DeFronzo R.A.
      • Mandarino L.J.
      Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation.
      • Morino K.
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • Frattini J.
      • Shatzkes N.
      • Neschen S.
      • White M.F.
      • Bilz S.
      • Sono S.
      • Pypaert M.
      • Shulman G.I.
      Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
      • Gulli G.
      • Ferrannini E.
      • Stern M.
      • Haffner S.
      • DeFronzo R.A.
      The metabolic profile of NIDDM is fully established in glucose-tolerant offspring of two Mexican-American NIDDM parents.
      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 SAHS
      • Hanley A.J.
      • Williams K.
      • Stern M.P.
      • Haffner S.M.
      Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study.
      and the Botnia Study,
      • Isomaa B.
      • Almgren P.
      • Tuomi T.
      • Forsen B.
      • Lahti K.
      • Nissen M.
      • Taskinen M.R.
      • Groop L.
      Cardiovascular morbidity and mortality associated with the metabolic syndrome.
      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,
      • Bonora E.
      • Kiechl S.
      • Willeit J.
      • Oberhollenzer F.
      • Egger G.
      • Meigs J.B.
      • Bonadonna R.C.
      • Muggeo M.
      Insulin resistance as estimated by homeostasis model assessment predicts incident symptomatic cardiovascular disease in caucasian subjects from the general population: the Bruneck study.
      Verona Diabetes,
      • Bonora E.
      • Formentini G.
      • Calcaterra F.
      • Lombardi S.
      • Marini F.
      • Zenari L.
      • Saggiani F.
      • Poli M.
      • Perbellini S.
      • Raffaelli A.
      • et al.
      HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study.
      and Insulin Resistance Atherosclerosis Studies (IRAS).
      • Howard G.
      • O'Leary D.H.
      • Zaccaro D.
      • Haffner S.
      • Rewers M.
      • Hamman R.
      • Selby J.V.
      • Saad M.F.
      • Savage P.
      • Bergman R.
      Insulin Resistance Atherosclerosis Study (IRAS) Investigators
      Insulin sensitivity and atherosclerosis.
      A strong relation between insulin resistance and carotid intima-media thickness—a surrogate measure of ASCVD—also been demonstrated,
      • Hedblad B.
      • Nilsson P.
      • Janzon L.
      • Berglund G.
      Relation between insulin resistance and carotid intima-media thickness and stenosis in non-diabetic subjects: results from a cross-sectional study in Malmo, Sweden.
      as has an association between insulin resistance and a greater CV risk factor load.
      • Ferrannini E.
      • Balkau B.
      • Coppack S.W.
      • Dekker J.M.
      • Mari A.
      • Nolan J.
      • Walker M.
      • Natali A.
      • Beck-Nielsen H.
      Insulin resistance, insulin response, and obesity as indicators of metabolic risk.
      The analysis by D'Agostino and colleagues
      • D'Agostino Sr, R.B.
      • Grundy S.
      • Sullivan L.M.
      • Wilson P.
      Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation.
      of 6 prospective studies further supports an independent role for insulin resistance in CVD. Using the Framingham cardiovascular risk calculator,
      • Wilson P.W.
      • D'Agostino R.B.
      • Levy D.
      • Belanger A.M.
      • Silbershatz H.
      • Kannel W.B.
      Prediction of coronary heart disease using risk factor categories.
      only 69% of the observed risk for CVD could be explained, leaving 31% unaccounted for (Figure 8A ).
      • D'Agostino Sr, R.B.
      • Grundy S.
      • Sullivan L.M.
      • Wilson P.
      Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation.
      Similarly, in the Atherosclerosis Risk in Communities (ARIC) Study (Figure 8B),
      • Golden S.H.
      • Folsom A.R.
      • Coresh J.
      • Sharrett A.R.
      • Szklo M.
      • Brancati F.
      Risk factor groupings related to insulin resistance and their synergistic effects on subclinical atherosclerosis: the Atherosclerosis Risk in Communities Study.
      only ∼70% of the increase in carotid intima-media thickness could be accounted for by dyslipidemia, hypertension, glucose intolerance, or obesity. It is likely that this unexplained risk can be attributed in part to the underlying molecular etiology of insulin resistance, which involves impaired insulin signaling through the insulin receptor substrate–1 (IRS-1)/phosphatidylinositol (PI) 3-kinase pathway and increased insulin signaling through the MAP kinase pathway.
      • Bajaj M.
      • DeFronzo R.A.
      Metabolic and molecular basis of insulin resistance.
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      Figure thumbnail gr8
      Figure 8(A) Predictive value (%) of cardiovascular disease (CVD) using the Framingham risk calculator from Framingham Heart Study (FHS), the Atherosclerosis Risk in Community Study (ARIC), the Honolulu Heart Program (HHP), the Puerto Rico Heart Health Program (PR), the Strong Heart Study (SHS), and the Cardiovascular Health Study (CHS). On mean, the Framingham Risk calculator predicts only 69% of the risk of a future cardiovascular event. Amer = American; F = female; M = male. (Adapted with and reprinted permission from JAMA.
      • D'Agostino Sr, R.B.
      • Grundy S.
      • Sullivan L.M.
      • Wilson P.
      Validation of the Framingham coronary heart disease prediction scores: results of a multiple ethnic groups investigation.
      Copyright © (2001) American Medical Association. All rights reserved.) (B) Excess carotid intima-media thickness (IMT) in relation to the individual components of the insulin resistance syndrome (IRS) as listed. GLU = glucose; HDL = high-density lipoprotein; HTN = hypertension; TG = triglycerides; ↑ = increase; ↓ = decrease.
      (With kind permission from Springer Science+Business Media: Diabetologia, Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009], Volume 53, 2010, DeFronzo RA, Figure 1.
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      )
      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.
      • Pratipanawatr W.
      • Pratipanawatr T.
      • Cusi K.
      • Berria R.
      • Adams J.M.
      • Jenkinson C.P.
      • Maezono K.
      • DeFronzo R.A.
      • Mandarino L.J.
      Skeletal muscle insulin resistance in normoglycemic subjects with a strong family history of type 2 diabetes is associated with decreased insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation.
      • Morino K.
      • Petersen K.F.
      • Dufour S.
      • Befroy D.
      • Frattini J.
      • Shatzkes N.
      • Neschen S.
      • White M.F.
      • Bilz S.
      • Sono S.
      • Pypaert M.
      • Shulman G.I.
      Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents.
      • Kashyap S.R.
      • DeFronzo R.A.
      The insulin resistance syndrome: physiological considerations.
      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%–20% of individuals with type 2 diabetes at initial diagnosis
      • Uusitupa M.I.
      • Niskanen L.K.
      • Siitonen O.
      • Voutilainen E.
      • Pyorala K.
      Ten-year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects.
      and why insulin resistance and ASCVD are so closely linked.
      • DeFronzo R.A.
      Insulin resistance, lipotoxicity, type 2 diabetes and atherosclerosis: the missing links [the Claude Bernard Lecture 2009].
      In summary, individuals with prediabetes manifest the same molecular defect in insulin action as patients with type 2 diabetes and obesity, placing them at increased risk for CVD.

      Assessment and Treatment of Prediabetes: a Rational Pathophysiologic and Cardiovascular Risk Factor–based Approach

      Because prediabetes (IGT and IFG) and diabetes represent a continuum of dysglycemia and CV risk, the same principles that apply to the assessment and treatment of type 2 diabetes should apply to the prediabetic state (Table 1).
      Table 1Cardiovascular risk assessment in prediabetes (IGT/IFG)
      • Hyperglycemia
       ∘ Fasting
       ∘ Postprandial
      • Obesity
      • Physical activity
      • Dyslipidemia
       ∘ Hypercholesterolemia
       ∘Small dense LDL particles
       ∘ Hypertriglyceridemia
       ∘ Low HDL cholesterol
       ∘ Non-HDL cholesterol
      • Hypertension
      • Procoagulant state
      • Endothelial dysfunction
      • Inflammation

      Dysglycemia

      Subjects with IFG should have a formal 2-hour OGTT, because ∼33% of these individuals will have type 2 diabetes. Both individuals with IFG but without type 2 diabetes and subjects with IGT should have a repeat FPG test annually and a repeat OGTT every 1–2 years based on the FPG results and the discretion of the physician.
      Within the prediabetic range, both the FPG and 2-hour PG are independent risk factors for the development of ASCVD.
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      • Tominaga M.
      • Eguchi H.
      • Manaka H.
      • Igarashi K.
      • Kato T.
      • Sekikawa A.
      Impaired glucose tolerance is a risk factor for cardiovascular disease, but not impaired fasting glucose: the Funagata Diabetes Study.
      • de Vegt F.
      • Dekker J.M.
      • Ruhe H.G.
      • Stehouwer C.D.
      • Nijpels G.
      • Bouter L.M.
      • Heine R.J.
      Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study.
      • Coutinho M.
      • Gerstein H.C.
      • Wang Y.
      • Yusuf S.
      The relationship between glucose and incident cardiovascular events A meta regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years.
      The DECODE Study Group, on behalf of the European Diabetes Epidemiology Group
      Consequences of the new diagnostic criteria for diabetes in older men and women DECODE Study.
      DECODE Study Group
      Is the current definition for diabetes relevant to mortality risk from all causes and cardiovascular and noncardiovascular diseases?.
      • Meigs J.B.
      • Nathan D.M.
      • D'Agostino Sr, R.B.
      • Wilson P.W.
      Fasting and postchallenge glycemia and cardiovascular disease risk: the Framingham Offspring Study.
      • Pyorala K.
      • Savolainen E.
      • Lehtovirta E.
      • Punsar S.
      • Siltanen P.
      Glucose tolerance and cornary heart disease: Helsinki Policemen Study.
      • Fuller J.H.
      • Shipley M.J.
      • Rose G.
      • Jarrett R.J.
      • Keen H.
      Mortality from coronary heart disease and stroke in relation to degree of glycaemia: the Whitehall study.
      • Fujishima M.
      • Kiyohara Y.
      • Kato I.
      • Ohmura T.
      • Iwamoto H.
      • Nakayama K.
      • Ohmori S.
      • Yoshitake T.
      Diabetes and cardiovascular disease in a prospective population survey in Japan: the Hisayama Study.
      • Sourij H.
      • Saely C.H.
      • Schmid F.
      • Zweiker R.
      • Marte T.
      • Wascher T.C.
      • Drexel H.
      Post-challenge hyperglycaemia is strongly associated with future macrovascular events and total mortality in angiographied coronary patients.
      • Lenzen M.
      • Ryden L.
      • Ohrvik J.
      • Bartnik M.
      • Malmberg K.
      • Scholte Op Reimer W.
      • Simoons M.L.
      Diabetes known or newly detected, but not impaired glucose regulation, has a negative influence on 1-year outcome in patients with coronary artery disease: a report from the Euro Heart Survey on diabetes and the heart.
      • Woerle H.J.
      • Pimenta W.P.
      • Meyer C.
      • Gosmanov N.R.
      • Szoke E.
      • Szombathy T.
      • Mitrakou A.
      • Gerich J.E.
      Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma glucose and hemoglobin A1c values.
      • Blake D.R.
      • Meigs J.B.
      • Muller D.C.
      • Najjar S.S.
      • Andres R.
      • Nathan D.M.
      Impaired glucose tolerance, but not impaired fasting glucose, is associated with increased levels of coronary heart disease risk factors: results from the Baltimore Longitudinal Study on Aging.
      • Medalie J.H.
      • Papier C.M.
      • Goldbourt U.
      • Herman J.B.
      Major factors in the development of diabetes mellitus in 10,000 men.
      • McPhillips J.B.
      • Barrett-Connor E.
      • Wingard D.L.
      Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults.
      • Mykkanen L.
      • Kuusisto J.
      • Pyorala K.
      • Laakso M.
      Cardiovascular disease risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects.
      • Haffner S.M.
      • Stern M.P.
      • Hazuda H.P.
      • Mitchell B.D.
      • Patterson J.K.
      Cardiovascular risk factors in confirmed prediabetic individuals Does the clock for coronary heart disease start ticking before the onset of clinical diabetes?.
      • Haffner S.M.
      Insulin resistance, inflammation, and the prediabetic state.
      • Haffner S.M.
      • Mykkanen L.
      • Festa A.
      • Burke J.P.
      • Stern M.P.
      Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state.
      • Isomaa B.
      • Almgren P.
      • Tuomi T.
      • Forsen B.
      • Lahti K.
      • Nissen M.
      • Taskinen M.R.
      • Groop L.
      Cardiovascular morbidity and mortality associated with the metabolic syndrome.
      • Goldberg R.B.
      • Temprosa M.
      • Haffner S.
      • Orchard T.J.
      • Ratner R.E.
      • Fowler S.E.
      • Mather K.
      • Marcovina S.
      • Saudek C.
      • Matulik M.J.
      • Price D.
      Diabetes Prevention Program Research Group
      Effect of progression from impaired glucose tolerance to diabetes on cardiovascular risk factors and its amelioration by lifestyle and metformin intervention: the Diabetes Prevention Program randomized trial by the Diabetes Prevention Program Research Group.
      In DECODE, the risk for CAD and stroke increased progressively from IFG to IGT to type 2 diabetes,
      The DECODE Study Group
      Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria.
      DECODE Study Group
      Glucose tolerance and cardiovascular mortality: comparison of fasting and 2-hour diagnostic criteria.
      indicating that hyperglycemia is a continuous risk factor for CV mortality.
      • Gerstein H.C.
      Is glucose a continuous risk factor for cardiovascular mortality?.
      In the UKPDS, HbA1c was the third greatest risk factor for CVD in type 2 diabetes.
      UK Prospective Diabetes Study (UKPDS) Group
      Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).
      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.
      • Stamler J.
      • Vaccaro O.
      • Neaton J.D.
      • Wentworth D.
      Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial.
      • Lautamaki R.
      • Airaksinen K.E.
      • Seppanen M.
      • Toikka J.
      • Luotolahti M.
      • Ball E.
      • Borra R.
      • Harkonen R.
      • Iozzo P.
      • Stewart M.
      • Knuuti J.
      • Nuutila P.
      Rosiglitazone improves myocardial glucose uptake in patients with type 2 diabetes and coronary artery disease: a 16-week randomized, double-blind, placebo-controlled study.
      Similarly, in UKPDS
      • Stratton I.M.
      • Cull C.A.
      • Adler A.I.
      • Matthews D.R.
      • Neil H.A.
      • Holman R.R.
      Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75).
      a potent interaction between hyperglycemia and blood pressure to increase the risk of MI and stroke was documented. These observations highlight the important role of dysglycemia as a major risk factor for ASCVD.
      No CV intervention study has targeted the prediabetic population specifically. However “tight” glycemic control in the extension of the UKPDS
      • Holman R.R.
      • Paul S.K.
      • Bethel M.A.
      • Neil H.A.
      • Matthews D.R.
      Long-term follow-up after tight control of blood pressure in type 2 diabetes.
      and DCCT
      • Nathan D.M.
      • Cleary P.A.
      • Backlund J.Y.
      • Genuth S.M.
      • Lachin J.M.
      • Orchard T.J.
      • Raskin P.
      • Zinman B.
      Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes.
      demonstrated that treatment of hyperglycemia in patients with diabetes significantly decreased CV events
      • Gerstein H.C.
      • Miller M.E.
      • Byington R.P.
      • Goff Jr, D.C.
      • Bigger J.T.
      • Buse J.B.
      • Cushman W.C.
      • Genuth S.
      • Ismail-Beigi F.
      • Grimm Jr, R.H.
      • et al.
      Effects of intensive glucose lowering in type 2 diabetes.
      • Patel A.
      • MacMahon S.
      • Chalmers J.
      • Neal B.
      • Billot L.
      • Woodward M.
      • Marre M.
      • Cooper M.
      • Glasziou P.
      • Grobbee D.
      • et al.
      Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes.
      In the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) trial,
      • Dormandy J.A.
      • Charbonnel B.
      • Eckland D.J.
      • Erdmann E.
      • Massi-Benedetti M.
      • Moules I.K.
      • Skene A.M.
      • Tan M.H.
      • Lefebvre P.J.
      • Murray G.D.
      • et al.
      Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial.