Reviews/Commentaries/ADA Statements CONSENSUS STATEMENT Impaired Fasting Glucose and Impaired Glucose Tolerance Implications for care 1 5 DAVID M. NATHAN, MD ROBERT R. HENRY, MD had other recognized risk factors for diabe- 2 6 MAYER B. DAVIDSON, MD RICHARD PRATLEY, MD tes including obesity, a prior history of ges- 3 7 RALPH A. DEFRONZO, MD BERNARD ZINMAN, MD 4 tational diabetes, or a positive family history ROBERT J. HEINE, MD, PHD, FRCP of diabetes. All of these trials demonstrated reductions in the development of diabetes of 25–60% over the period of follow-up. ype 2 diabetes is now epidemic. In the glucose tolerance (IGT), to diabetes may The largest reductions (ϳ60%) were ac- U.S., there has been a 61% increase in take many years; however, current esti- complished with lifestyle interventions T incidence between 1990 and 2001 mates indicate that most individuals (per- aimed at weight loss and increasing physical (1). There are currently 1.5 million new haps up to 70%) with these pre-diabetic activity and with thiazolidinediones cases per year, and the prevalence in 2005 states eventually develop diabetes (4–10). (4,5,24,25,27). Lesser degrees of reduction was almost 21 million (2). The epidemic has During the pre-diabetic state, the risk of a (25–30%) have been achieved with other affected developed and developing coun- CVD event is modestly increased (11–22). drugs (5,23,24,28). tries alike, and the worldwide prevalence of With the development of diabetes, how- The availability of interventions that diabetes is projected to increase dramati- ever, there is a large increase in risk for have been shown to decrease the develop- cally by 2025 (3). The increase in type 2 CVD, as well as for long-term complications ment of diabetes has stimulated consider- diabetes is related to lifestyle changes that affecting the eyes, kidneys, and nervous sys- ation whether such interventions should be have resulted in overweight, obesity, and tem. The complications of diabetes, which recommended and implemented, in whom, decreased physical activity levels. These en- are the cause of major morbidity and mor- and under what circumstances. To address vironmental changes, superimposed on ge- tality, are related to its duration, chronic these issues, the American Diabetes Associ- netic predisposition, increase insulin level of glycemia, and other risk factors. ation convened a consensus development resistance, which, in concert with progres- Although clinical trials have demon- conference on 16–18 October 2006 focus- sive ␤-cell failure, results in rising glycemia strated the effectiveness of intensive glyce- ing on the pre-diabetic states of IFG and in the nondiabetic range. In addition to the mic and blood pressure control to reduce IGT. Following the presentations of invited risk for diabetes, insulin resistance and im- the long-term complications of diabetes, the speakers and in-depth discussions, a seven- paired insulin secretion are accompanied by public health burden of the disease remains member panel of experts in diabetes, endo- a host of major cardiovascular disease enormous. The magnitude of the epidemic, crinology, and metabolism developed this (CVD) risk factors including hypertension coupled with complex treatment require- consensus position based on the questions and dyslipidemia. Further reduction in in- ments that are difficult and costly to imple- below. The expert members were also asked sulin secretion over time results in increas- ment, make the prevention of diabetes a to note where additional information or ing glycemia and the development of critical public health goal. Between 1997 studies would be necessary to answer these diabetes, which in turn is associated with and 2006, eight major clinical trials exam- questions. the development of microvascular and car- ined whether lifestyle or pharmacologic in- diovascular complications. terventions would prevent or delay the The transition from the early metabolic development of diabetes in populations at QUESTION 1: What are IFG abnormalities that precede diabetes, im- high risk by virtue of having IFG and/or IGT and IGT, and what is their paired fasting glucose (IFG) and impaired (4,5,23–28). The study populations often natural history? — How much does IFG, IGT, or the combination of both ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● conditions increase the risk for subse- From 1Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; the 2Clinical quent development of diabetes? Does IFG Center for Research Excellence, Charles R. Drew University of Medicine and Science, Los Angeles, California; and/or IGT increase the development of 3 4 the University of Texas Health Science Center, San Antonio, Texas; the Diabetes Center, VU University cardiovascular disease? If so, are the ef- Medical Center, Amsterdam, the Netherlands; the 5Department of Medicine, University of California, San Diego, California; the 6Department of Medicine, University of Vermont, Burlington, Vermont; and the fects of IFG and/or IGT independent of 7Departments of Endocrinology and Metabolism, Mount Sinai Hospital, University of Toronto, Toronto, associated known cardiovascular risk fac- Ontario, Canada. tors including the subsequent develop- Address correspondence to Richard Kahn, American Diabetes Association, 1701 North Beauregard St., ment of diabetes? Alexandria, VA 22311. E-mail: [email protected]. IFG and IGT represent intermediate Panel disclosures can be found on p. 757. Abbreviations: CVD, cardiovascular disease; DPP, Diabetes Prevention Program; DREAM, Diabetes states of abnormal glucose regulation that Reduction Assessment with Ramipril and Rosiglitazone Medication; FPG, fasting plasma glucose; IGT, exist between normal glucose homeosta- impaired glucose tolerance; IFG, impaired fasting glucose; NGT, normal glucose tolerance; OGTT, oral sis and diabetes. IFG is now defined by an glucose tolerance test. elevated fasting plasma glucose (FPG) A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion Ն Ͻ factors for many substances. concentration ( 100 and 126 mg/dl) DOI: 10.2337/dc07-9920 (29). IGT is defined by an elevated 2-h © 2007 by the American Diabetes Association. plasma glucose concentration (Ն140 and DIABETES CARE, VOLUME 30, NUMBER 3, MARCH 2007 753 Consensus Statement Table 1—Classification of glucose tolerance states 2-h plasma glucose in FPG level OGTT State (mg/dl) (mg/dl)* IFG 100–125 Ͻ200 Isolated IFG 100–125 Ͻ140 IGT Ͻ126 140–199 Isolated IGT Ͻ100 140–199 Combined IFG/IGT 100–125 140–199 NGT Ͻ100 Ͻ140 *Standard 75-g OGTT. Ͻ200 mg/dl) after a 75-g glucose load on the oral glucose tolerance test (OGTT) in the presence of an FPG concentration Ͻ126 mg/dl (29,30). With the definitions above, there is overlap between the two groups. To study the separate characteristics of IFG and Figure 1—Plasma glucose concentration during an OGTT performed in subjects with IFG, IGT, IGT, classifications of isolated IFG and NGT, or combined IFG/IGT (CGI). Adapted with permission from ref. 54. isolated IGT that are mutually exclusive have been created (isolated IFG ϭ FPG of groups (30–34). IFG and IGT also differ ing diabetes associated with IFG needs to be 100–125 mg/dl with the 2-h value Ͻ140 significantly in their age and sex distribu- reevaluated. mg/dl; isolated IGT ϭ 2-h value of 140– tion; the prevalences of both metabolic Numerous longitudinal studies indi- 199 mg/dl with the fasting level Ͻ100 disorders increase with advancing age. cate that both IFG and IGT are associated mg/dl). The combined characteristics of IGT is more frequent in women than in with a modest increase in the hazard ratio IFG and IGT have been studied by iden- men (34–36). Unfortunately, most of the (ϳ1.1–1.4) for CVD, with IGT being a tifying populations that fulfill both crite- published literature on IFG is based upon slightly stronger risk predictor (11–22). ria (FPG ϭ 100–125 mg/dl and 2-h the older cut point (110–125 mg/dl). The majority of this risk appears to be con- value ϭ 140–199 mg/dl). Conversely, The natural history of both IFG and ferred by progression to diabetes, when the normal glucose tolerance (NGT) is de- IGT is variable, with ϳ25% progressing risk of CVD increases two- to fourfold. fined as FPG Ͻ100 mg/dl and 2-h plasma to diabetes, 50% remaining in their ab- Many cardiovascular risk factors (e.g., low glucose Ͻ140 mg/dl (Table 1). normal glycemic state, and 25% reverting HDL cholesterol, hypertension, and ele- IFG was defined in 1997 by the to NGT over an observational period of vated triglycerides) are prevalent in IFG and American Diabetes Association as a means 3–5 years (9,37–38). Individuals who are IGT, but it is unclear whether they occur of classifying individuals who had fasting older, overweight, and have other diabe- more frequently in one state than the other glucose levels between normal and diabe- tes risk factors are more likely to progress. (44–49). However, after adjustment for tes (30). It was meant to be analogous to Moreover, low insulin secretion and se- known cardiovascular risk factors, both IFG IGT as an intermediate metabolic state be- vere insulin resistance identify individu- and IGT remain as independent, albeit tween normal and diabetes, but based on als more likely to progress to diabetes weak, risk factors for CVD in some studies the FPG. The original FPG range (110– (39). With longer observation, the major- but not in others (11–22). Even so, it is un- 125 mg/dl) was changed in 2003 to 100– ity of individuals with IFG or IGT appear clear whether the CVD risk associated with 125 mg/dl so that the population risk of to develop diabetes. IFG or IGT can be attributed to the devel- developing diabetes with IFG would be Both IFG and IGT have a heteroge- opment of diabetes during follow-up or similar to that with IGT (29).