Diabetes and Cprediabetes 201D in cardiovascular disease

The prevalence of diabetes has been increasing for the past several decades. The total number of people with diabetes in the world is projected to increase from 171 million in the year 2000 to 366 million in 2030,1 with more than 90% of them having type 2 diabetes. Both type 2 diabetes and its precursor, impaired glucose tolerance, increase with age. In the United States, approximately 20% of people 60 years of age or older have type 2 diabetes, and another 15% have impaired fasting glucose,2 which is an underestimate of impaired glucose tolerance. The risk is even higher in certain ethnic populations, such as Hispanic, African American, and Asian American.3 Diabetes also has a substantial effect on morbidity and mortality.

Although the microvascular complications of diabetes are a reflection of the severity of hyperglycemia the patient has experienced over the years, the cardiovascular complications are not closely related to the duration or extent of hyperglycemia. Several large epidemiologic studies, such as the Diabetes Epidemiology Collaborative Analysis of Diagnostic Criteria in Europe study, have shown a 1.5- to twofold increased risk of cardiovascular disease and mortality in people with impaired glucose tolerance and a relatively weaker association with impaired fasting glucose.4 The increased risk of cardiovascular disease events and mortality may be seen in the presence of impaired glucose tolerance, even when it does not progress to diabetes on long-term follow-up5 (as documented in the FINMONICA stroke register, a Finnish subset of the World Health Organization [WHO] MONItoring of trends and determinants of CArdiovascular disease study). These observations support the role of underlying atherogenic risk factors in the presence of impaired glucose tolerance. Some of the clinically recognizable risk factors frequently accompanying “prediabetes” (impaired glucose tolerance or impaired fasting glucose) include hypertension, central obesity, insulin resistance, microalbuminuria, and dyslipidemia, collectively now well recognized as the metabolic syndrome by the National Cholesterol Education Program Adult Treatment Panel III, WHO, the American Association of Clinical Endocrinologists, and other organizations. Recently published cross-sectional analyses of more than 10,000 subjects in the Third National Health and Nutrition Examination Survey (NHANES III)6 and a meta-analysis of 11 prospective European studies, including more than 11,500 subjects,7 have confirmed a significant predictability of the multiple components of the metabolic syndrome for cardiovascular disease events or mortality.

Although the presence of impaired fasting glucose is an infrequent component of the metabolic syndrome,8 impaired glucose tolerance is more often seen in patients with cardiovascular disease or cardiovascular disease—associated risk factors,9 in keeping with the epidemiologic observations.4-7 Recently, several prospective studies have addressed the issue of the prevalence of diabetes in patients with established cardiovascular disease and in those at high risk for cardiovascular disease events (Table). Norhammar and colleagues evaluated a group of 181 patients (mean age, 63.5 years) following acute myocardial infarction (MI) and discovered that, 3 months after MI, 25% of those patients had previously undiagnosed diabetes and an additional 40% had impaired glucose tolerance, as shown by oral glucose tolerance tests.10 Thus, a total of 65% of those subjects had evidence of abnormal glucose homeostasis, of which more than 50% would have been missed by fasting blood glucose alone.

Two recent reports are from the largest studies of glucose tolerance tests in patients with cardiovascular disease or at high risk for cardiovascular disease. The first was a prospective, observational study in 25 European countries, the Euro Heart survey, involving 4,961 patients with acute or stable coronary artery disease.11 Of these, 31% had previously diagnosed diabetes mellitus. However, on oral glucose tolerance testing of approximately 1,900 patients without known diabetes, about 4% had impaired fasting glucose, 32% had impaired glucose tolerance, 18% had diabetes mellitus, and 45% had normal glucose tolerance. The second study was an even larger multinational survey performed during the screening of eligible patients for the ongoing Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research (NAVIGATOR) trial.12 In this survey, 43,509 nondiabetic subjects (mean age, 63 years; mean body mass index, 29.7 kg/m2; 49% men, 51% women) were screened for a diagnosis of impaired glucose tolerance. Of these, 9,125 had evidence of prior cardiovascular disease. In addition, 31,047 had no prior cardiovascular disease but had one or more risk factors for cardiovascular disease, including positive family history of premature cardiovascular disease, smoking, hypertension, low-density lipoprotein cho-lesterol level above 160 mg/dL, high-density lipoprotein cholesterol level below 38 mg/dL, triglyceride level above 200 mg/dL, left ventricular hypertrophy, or microalbuminuria. Among those with prior cardiovascular disease, the proportion of patients with normal glucose tolerance, impaired fasting glucose, impaired glucose tolerance, and diabetes mellitus were 34%, 12%, 29%, and 24%, respectively. Similarly, among those without prior cardiovascular disease but with one or more risk factors, the distribution

of these categories was 38%, 12%, 29%, and 21%, respectively, virtually identical to the group with previous evidence of cardiovascular disease. Thus, this rather large survey confirmed that approximately one of five people had previously undiagnosed diabetes, similar to the expected number in this age group, but an additional one of four had other abnormalities of glucose tolerance (prediabetes). Of note, impaired glucose tolerance was more than twice as common as impaired fasting glucose in those with prediabetes (impaired glucose tolerance and impaired fasting glucose).

This major database of the ongoing NAVIGATOR trial underscores the preponderance and significance of prediabetes and undiagnosed diabetes in patients with cardiovascular disease. In addition, there was an impressive similar frequency of these disorders, even for those who may have been considered to be in a “pre-

cardiovascular” disease state in view of the presence of several cardiovascular disease risk factors, which accounted for the 51% prevalence of metabolic syndrome in this population. Furthermore, it underscores the need for earlier diagnosis of impaired glucose tolerance in this population which, when detected, will provide an opportunity to possibly prevent progression to diabetes and to intervene with earlier detection and management of cardiovascular disease risk factors. Finally, these observations further support the likelihood of common antecedents (eg, endothelial dysfunction, subclinical inflammation, and augmented sympathetic and/or renin-angiotensin system activity) in the pathogenesis of type 2 diabetes as well as cardiovascular disease.

In addition to practical lifestyle measures that have been shown to reduce the progression to diabetes, a number of pharmacologic agents are being evaluated for their potential efficacy in diabetes prevention. These include metformin (Glucophage), thiazolidinediones, alpha-glucosidase inhibitors, and anti-obesity drugs, such as orlistat (Xenical). Of great interest is the possibility that, based on the subanalyses from a number of recent trials, drugs that antagonize the renin-angiotensin system, such as angiotensin-converting enzyme inhibitors,13 angiotensin receptor blockers,14-16 and even certain calcium channel blocking agents,17 may have significant benefits in diabetes prevention (ie, a 20%—30% reduction). This is the subject of ongoing trials, including the Diabetes Reduction Approaches with Ramipril and Rosiglitazone Medications and NAVIGATOR studies, which examine this possibility in an a priori design with such agents.