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. 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),1American Diabetes AssociationDiagnosis and classification of diabetes mellitus.Diabetes Care. 2008; 31: S55-S60Crossref PubMed Scopus (569) Google Scholar 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.2Abdul-Ghani M.A. Jenkinson C.P. Richardson D.K. Tripathy D. DeFronzo R.A. 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Reciprocal variations in insulin-stimulated glucose uptake and pancreatic insulin secretion in women with normal glucose tolerance.J Soc Gyn Invest. 1995; 2: 708-715Crossref PubMed Google Scholar 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.”55DeFronzo R.A. The triumvirate: β-cell, muscle, liver A collusion responsible for NIDDM [Lilly Lecture 1987].Diabetes. 1988; 37: 667-687Crossref PubMed Google Scholar As illustrated in Figure 2,39DeFronzo R.A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].Diabetes. 2009; 58: 773-795Crossref PubMed Scopus (515) Google Scholar 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.2Abdul-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.Diabetes. 2006; 55: 1430-1435Crossref PubMed Scopus (193) Google Scholar, 3Abdul-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.Diabetes Care. 2006; 29: 1130-1139Crossref PubMed Google Scholar, 4Abdul-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.Diabetes Metab Syndr. 2007; 1: 105-112Crossref Scopus (14) Google Scholar, 5Gastaldelli A. Ferrannini E. Miyazaki Y. Matsuda M. DeFronzo R.A. β-Cell dysfunction and glucose intolerance: results from the San Antonio metabolism (SAM) study.Diabetologia. 2004; 47: 31-39Crossref PubMed Scopus (143) Google Scholar, 6Ferrannini 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.J Clin Endocrinol Metab. 2005; 90: 493-500Crossref PubMed Scopus (218) Google Scholar, 39DeFronzo R.A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].Diabetes. 2009; 58: 773-795Crossref PubMed Scopus (515) Google Scholar, 56Bergman R.N. Finegood D.T. Kahn S.E. The evolution of β-cell dysfunction and insulin resistance in type 2 diabetes.Eur J Clin Invest. 2002; 32: 35-45Crossref PubMed Google Scholar 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 3,39DeFronzo R.A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].Diabetes. 2009; 58: 773-795Crossref PubMed Scopus (515) Google Scholar 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 al57Butler 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.Diabetes. 2003; 52: 102-110Crossref PubMed Scopus (1699) Google Scholar 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 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.39DeFronzo R.A. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus [Banting lecture].Diabetes. 2009; 58: 773-795Crossref PubMed Scopus (515) Google Scholar)View Large Image Figure ViewerDownload Hi-res image Download (PPT) The recently published results of the Diabetes Prevention Program (DPP)58Diabetes Prevention Research GroupThe prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program.Diabet Med. 2007; 24: 137-144Crossref PubMed Scopus (117) Google Scholar 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.59Ziegler D. Rathmann W. Dickhaus T. Meisinger C. Mielck A. Prevalence of polyneuropathy in pre-diabetes and diabetes is associated with abdom