ment of diabetes may result in less coronary heart disease, tion because evidence is good that diabetes can be pre shared between diabetes and coro …
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Review
Early Recognition and Treatment of Glucose Abnormalities to Prevent Type 2 Diabetes Mellitus and Coronary Heart Disease
WARREN G THOMPSON, MD
Striking parallels exist in both risk and protective factors between coronary heart disease and type 2 diabetes mellitus Patients with insulin resistance are more likely to develop diabetes and coronary heart disease Better treatment of diabetes may result in less coronary heart disease, although this has not yet been established Reliance on fasting glucose determinations alone will overlook a substantial number of patients at risk for diabetes and subsequent coronary heart disease Measurement of glycosylated hemoglobin should be a routine part of screening for patients at risk for diabetes Patients with glycosylated hemoglobin levels in the high-normal range should be treated more aggressively with diet, exercise, and medication because evidence is good that diabetes can be prevented or its onset delayed Patients with borderline elevations of low-density lipoprotein cholesterol concentrations and with high-normal glycosylated hemoglobin levels
should be considered for statin therapy, and patients with hypertension with high-normal glycosylated hemoglobin levels should be treated with angiotensin-converting enzyme inhibitors as first-line agents Studies to determine whether metformin is useful in this population are ongoing Mayo Clin Proc 2001;76:1137-1143
ADA American Diabetes Association; HDL high-density lipoprotein; LDL low-density lipoprotein; WHO World Health Organization
oronary heart disease is the leading cause of death both in the United States and in the world Diabetes triples the risk of coronary heart disease in men1 and increases the risk in women 6-fold controlling for other risk factors associated with diabetes and coronary heart disease modestly attenuates this figure2 Whether patients with elevated fasting glucose levels 110-125 mg/dL are at increased risk for coronary heart disease is less clear as the data are conflicting3 It seems likely, however, that patients at risk for the development of diabetes are also at risk for the development of coronary heart disease In 1995 Stern4 called attention to the common soil between diabetes and cardiovascular disease In that review he summarized the evidence
for the parallel antecedents of the 2 diseases: low birth weight, obesity, central obesity, hypertension, and low high-density lipoprotein HDL cholesterol He noted that elevated triglyceride, insulin, and glucose levels were risk factors for diabetes and possibly risk factors for cardiovascular disease Three studies have been published since then confirming that hypertension and a low HDL cholesterol level frequently precede the development of diabetes5-7 Fasting triglyceride level was a predictor in 2 of these studies5,6 The Atherosclerosis Risk in Communities study,
From the Division of Preventive and Occupational Medicine and Internal Medicine, Mayo Clinic, Rochester, Minn Address reprint requests and correspondence to Warren G Thompson, MD, Division of Preventive and Occupational Medicine, Mayo Clinic, 200 First St SW, Rochester, MN 55905 Mayo Clin Proc 2001;76:1137-1143 1137
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which included a large number of African American subjects, found that the relative risk of diabetes was nearly 25 times greater in hypertensive patients8 Since Sterns review, weight gain in adulthood has also been related to the risk of diabetes and coronary heart disease9-11 In this review, I discuss
several other antecedents that diabetes and coronary heart disease have in common, including alcohol and tobacco use, diet, and exercise Table 1 The common soil shared between diabetes and coronary heart disease suggests that physicians should make an aggressive effort to diagnose and treat patients at risk The relationship between fasting glucose, insulin, postprandial glucose, and glycosylated hemoglobin levels and coronary heart disease is then discussed to show that relying on the fasting glucose level alone will result in substantial failure to diagnose patients at risk Finally, I discuss the treatment implications of the risk factor studies as well as the results of some seminal randomized trials that could result in improved treatment RISK FACTORS FOR DIABETES AND CORONARY HEART DISEASE Alcohol Alcohol use is inversely related to coronary heart disease in more than 60 prospective studies12 Most studies do not show an added benefit from red wine12 Alcohol in moderation 1 drink daily has been associated with an approximately 40 lower risk of developing diabetes after controlling for weight, family history, and exercise in 4
2001 Mayo Foundation for Medical Education and
Research
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Table 1 Common Risk and Protective Factors for Diabetes and Coronary Heart Disease Risk factors Low birth weight High body mass index Central obesity waist-to-hip ratio Weight gain Hypertension Low high-density lipoprotein cholesterol level High fasting triglyceride level controversial for heart disease Cigarette smoking High glycemic load and glycemic index controversial High trans fatty acid intake controversial for diabetes Elevated high-sensitivity C-reactive protein more data needed for diabetes Protective factors Alcohol consumption in moderation Exercise benefit in both physical activity and physical fitness Whole grain and fiber intake Fish and fish oil intake controversial for diabetes
and a 20 reduction in diabetes in the highest quintile group Refined grains were not protective in either of these studies Multiple prospective studies have shown a reduced incidence of coronary heart disease with increased fiber intake34-40 Three prospective studies have shown a decreased risk of diabetes in subjects consuming more fiber33,41,42 One randomized trial of cereal fiber43 failed to
show a reduced incidence of coronary death and myocardial infarction, but 2 other randomized trials showed significant reductions in coronary heart disease with altered diet including increased fiber44,45 One randomized trial of glucose-intolerant Chinese subjects showed that diet which included increased fiber lowered the incidence of diabetes46 Patients at risk for coronary heart disease and diabetes should be advised to increase their intake of whole grains and fiber Glycemic Index and Glycemic Load Foods with a high glycemic index cause a greater increase in blood glucose and insulin levels than foods with a low glycemic index47 White bread has a higher glycemic index than whole grain bread, potatoes have a higher glycemic index than broccoli, and orange juice has a higher glycemic index than an orange Experimental studies suggest that low glycemic index diets may result in improved diabetic control48,49 The Nurses Health Study followed 65,173 women and the Health Professionals Study followed 42,759 men for 6 years41,42 Both studies found that diets with a high glycemic index were associated with the subsequent development of diabetes relative risk, 137 Glycemic load the
product of glycemic index and carbohydrate intake was also related to risk of diabetes relative risk, 147 Glycemic index was not related to subsequent development of diabetes in the Iowa Womens Health Study33 All of these studies controlled for age, body mass index, family history of diabetes, physical activity, and other risk factors Glycemic load was significantly related to coronary heart disease risk in the Nurses Health Study50 The relative risk was doubled in the highest quintile Glycemic index was also related to coronary heart disease, but the relative risk was 13 A much smaller Dutch study found no relation between glycemic index and subsequent coronary heart disease51 More studies are needed before glycemic index or glycemic load can be accepted as risk factors for diabetes and coronary heart disease Exercise The evidence that exercise reduces the risk of coronary heart disease is strong52 Better physical fitness and more physical activity reduce the risk of coronary heart disease53 There is considerable evidence that increased physical activity is associated with a lower incidence of type 2 diabe-
prospective studies13-16 Furthermore, alcohol has been associated with a
reduced incidence of coronary heart disease in diabetic patients17-19 Moderate alcohol intake has been associated with improved sensitivity to insulin20 Tobacco Seven prospective studies have documented a relationship between smoking and type 2 diabetes14,21-26 The risk is especially prominent in men with normal body mass index Heavy cigarette smoking approximately doubles the risk of developing diabetes One large study failed to find a relationship in multivariate analysis; however, unlike the positive studies, family history was not evaluated as a possible confounder5 Only one of the positive studies was performed in women Smoking is associated with lower body mass index and might be thought to reduce the risk of diabetes However, smoking is positively related to central obesity,27 and it may increase insulin resistance28 Thus, patients at risk for the development of diabetes should be especially counseled not to smoke Whole Grain and Fiber Intake The Nurses Health Study followed 75,521 nurses for 10 years29-31 Coronary heart disease developed in 761, ischemic stroke in 352, and diabetes in 1879 subjects The highest quintile of whole grain consumption was associated with a 25
reduction in coronary heart disease, a 30 reduction in ischemic stroke, and a 40 reduction in diabetes The Iowa Womens Health Study followed approximately 35,000 women older than 55 years for 6 to 9 years and documented 438 coronary deaths and 1141 cases of diabetes32,33 There was a 30 reduction in coronary death
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tes5,54-58 The risk reduction varies between 25 and 40 in these studies There is also evidence that improved physical fitness is associated with a lower incidence of diabetes59,60 Physically unfit men are 3 to 4 times as likely to develop diabetes A randomized trial in Chinese men with impaired glucose tolerance demonstrated a 46 reduction in the 5-year incidence of diabetes with exercise46 Similarly, the risk of cardiovascular events is reduced in diabetic patients who exercise regularly61,62 Patients at risk for coronary heart disease or diabetes should be advised to exercise regularly Other Risk Factors Evidence that other coronary risk factors are predictors for diabetes is insufficient However, any known risk factor for coronary heart disease should be evaluated as a risk factor
for diabetes because of the overlap demonstrated above Inflammatory markers and hemostatic markers should be further evaluated to see if they are predictive of diabetes63,64 High-sensitivity C-reactive protein relative risk, 42 and, to a lesser extent, interleukin 6 were significant predictors of the subsequent development of diabetes in the Womens Health Study65 There is strong evidence that C-reactive protein predicts the development of coronary heart disease66 and some evidence that interleukin 6 does as well67 Increased consumption of fish might also be associated with a lower incidence of diabetes, but further data are needed68 The Nurses Health Study recently reported that omega-6 and omega-3 fatty acids are associated with a reduced incidence of diabetes, while trans fatty acids are associated with an increased incidence total fat, monounsaturated fat, and saturated fat were not related69 Because of the possibility of error in assessing trans fats in the diet, these data require confirmation70 Trans fatty acids have been associated with a reduced risk of coronary heart disease in several prospective studies71 Fish43 and fish oil72 have significant benefit in secondary
prevention trials of coronary heart disease FAILURE TO DIAGNOSE PATIENTS AT RISK In 1997 the American Diabetes Association ADA changed the criteria for the definition of diabetes73 The diagnostic glucose level was reduced from 140 mg/dL to 126 mg/dL, and use of the oral glucose tolerance test was abandoned It was felt that the simpler screening procedure would result in diagnosis of more cases of diabetes Abandonment of the oral glucose tolerance test has come under attack The World Health Organization WHO continues to incorporate use of the oral glucose tolerance test in its criteria for diagnosis of diabetes74,75 The ADA created a new category, impaired fasting glucose 110-125 mg/dL, analogous to the WHO category of impaired glucose toler-
Table 2 Hazard Ratios 95 Confidence Intervals for Mortality Based on ADA and WHO Criteria Men Diabetes ADA Diabetes WHO Impaired fasting glucose Impaired glucose tolerance 181 149-220 202 166-246 121 105-141 151 132-172 Women 179 118-269 277 196-392 108 070-166 160 122-210
Data derived from DECODE Study Group77 ADA American Diabetes Association; WHO World Health Organization 110-125 mg/dL 140-199 mg/dL
ance 2-hour postload glucose level,
140-199 mg/dL Impaired glucose tolerance has been the traditional way to identify patients at risk for the development of diabetes Studies have clearly demonstrated that the ADA and WHO criteria for prediabetes identify 2 overlapping but different populations at risk for the development of diabetes76-79 Impaired fasting glucose does not seem to be as sensitive for predicting coronary heart disease as impaired glucose tolerance A meta-analysis of 13 prospective European studies evaluated 18,048 men and 7316 women followed for an average of 7 years80 The main results are shown in Table 2 Results of the 2-hour oral glucose tolerance test added prognostic information to the fasting glucose determination, but the converse was not true The number of men with impaired fasting glucose was approximately equal to the number of men with impaired glucose tolerance However, 114 excess deaths were attributed to impaired glucose tolerance and only 37 to impaired fasting glucose More than twice as many women had impaired glucose tolerance as had impaired fasting glucose There were 45 excess deaths attributed to impaired glucose tolerance vs only 8 attributed to impaired fasting glucose There were
121 excess deaths attributed to impaired glucose tolerance in individuals who had normal fasting glucose; 22 excess deaths were attributed to impaired fasting glucose in individuals who had normal glucose tolerance; 80 excess deaths were attributed to diabetes by ADA criteria and 95 by WHO criteria Thus, more deaths were attributed to impaired glucose tolerance than to impaired fasting glucose because of the greater hazard, while more deaths were attributed to impaired glucose tolerance than to diabetes because of the substantially greater prevalence The Cardiovascular Health Study followed 4515 men and women older than 65 years living in 4 US communities for 6 years81 The hazard ratios for impaired glucose tolerance and impaired fasting glucose were equal, but the prevalence of impaired glucose tolerance was more than twice the prevalence of impaired fasting glucose Hence, the
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number of deaths attributable to impaired glucose tolerance was substantially higher The National Health and Nutrition Examination Survey also found that the prevalence of impaired glucose tolerance gets substantially
higher than the prevalence of impaired fasting glucose as the population ages82 A Japanese cohort study of 2651 subjects found that the cardiovascular mortality over 7 years was markedly elevated for those with impaired glucose tolerance but not for those with impaired fasting glucose83 Impaired glucose tolerance was a better predictor of the subsequent development of diabetes than impaired fasting glucose in 3 studies84-86 and equally as efficacious in 2 studies87,88 Thus, evidence is good that the 2-hour oral glucose tolerance test is a better test to predict outcomes in populations than the fasting glucose determination The oral glucose tolerance test has 2 major problems when it is used in individuals The test is considerably less convenient and more expensive than the fasting glucose determination The variability of the 2-hour glucose level is substantially higher, which makes it less useful as a predictor in an individual The biologic coefficient of variation is approximately 5 for fasting glucose and glycosylated hemoglobin and 11 for 2-hour glucose89,90 The glycosylated hemoglobin concentration has less variability than the 2-hour glucose level, and its determination is
more convenient As a measure of average glucose over the previous 3 months, the glycosylated hemoglobin level may be a good predictor of cardiovascular morbidity and mortality Three prospective studies of glycosylated hemoglobin and cardiovascular disease have been done In the Rancho Bernardo Study of 1239 nondiabetic older adults followed for 8 years, the glycosylated hemoglobin sum of Hgb A1a, Hgb A1b, and Hgb A1c was an important predictor of cardiovascular disease in women but not in men91 This was true in only the highest quintile of glycosylated hemoglobin Neither impaired fasting glucose nor impaired glucose tolerance was a significant predictor in this population The Hoorn Study followed 2363 subjects between the ages of 50 and 75 years for 8 years and found that glycosylated hemoglobin Hgb A1c and 2-hour glucose levels were significant predictors of cardiovascular mortality while the fasting glucose level was not92 Khaw et al93 followed 4662 men aged 45 to 79 years for 4 years and found that glycosylated hemoglobin Hgb A1c was continuously related to all-cause, cardiovascular, and ischemic heart disease mortality A 28 increase in mortality occurred for every 1 increase in
glycosylated hemoglobin even when subjects with a glycosylated hemoglobin level higher than 7 were excluded The majority of the excess deaths attributable to elevated glycosylated hemoglobin in this population occurred in the group with levels between 5 and 69 The glycosylated hemoglobin determination
measures a third overlapping but distinct population when compared with fasting glucose and glucose tolerance tests94 Far more data exist for impaired fasting glucose and impaired glucose tolerance Nevertheless, measurement of glycosylated hemoglobin is promising because the glycosylated hemoglobin level seems to be a better predictor of cardiovascular events than impaired fasting glucose and is more convenient and less variable than impaired glucose tolerance The glycosylated hemoglobin Hgb A1c level is a strong predictor for the subsequent development of diabetes even for values less than 6565 IMPLICATIONS Measurement of glycosylated hemoglobin has great potential as a screening test However, more data are needed before it can be recommended in the general population Large prospective studies should evaluate whether the level of glycosylated hemoglobin is superior to fasting blood
glucose values in predicting all-cause and cardiovascular mortality In the meantime, consideration should be given to checking glycosylated hemoglobin levels in patients who are obese, who have a family history of diabetes, or who have a fasting blood glucose level higher than 100 mg/dL Once a patient is identified with impaired fasting glucose, an abnormal glucose tolerance test, or high-normal glycosylated hemoglobin calculated Hgb A1c 50, physicians should act aggressively to prevent diabetes and coronary heart disease The Finnish Diabetes Prevention Study95 provides the best evidence that diabetes can be prevented The trial randomized 522 overweight subjects to a control group receiving an educational pamphlet and to an intervention group that met with a dietitian at least 4 times a year and had access to supervised exercise sessions The goals of the intervention were 5 weight loss; intake of 15 g of fiber per 1000 kcal, no more than 30 fat and 10 saturated fat; and 30 minutes of daily exercise Fortynine intervention patients and 15 control patients achieved 4 or 5 of the intervention goals None developed diabetes Thirteen intervention patients and 48 control patients achieved
none of the goals, and one third of these subjects developed diabetes The prospective data outlined above suggest that patients should also be advised to stop smoking, to drink alcohol in moderation recommendations to patients to start drinking alcohol should be made with hesitation, to exercise at least the equivalent of walking 30 minutes every day, and to consume more fiber, more whole grain products, and fewer refined grain products Patients should be counseled about the factors associated with weight gain: television viewing, lack of exercise, and poor diet eg, whole milk rather than skim milk, meat instead of fish, refined grains instead of whole grains, and insufficient fruits and vegetables in the diet96,97 Patients with hyper-
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tension at risk for diabetes should be treated with angiotensin-converting enzyme inhibitors because 2 randomized trials have shown a reduced incidence of diabetes in subjects treated with these agents98,99 The Heart Outcomes Prevention Evaluation investigators98 demonstrated a 35 reduction in the incidence of new diabetes with the use of ramipril P001, although
this trial was not designed to test the hypothesis that ramipril reduces the incidence of diabetes Thus, this study should be confirmed prior to using angiotensin-converting enzyme inhibitors just for the purpose of preventing diabetes Pravastatin resulted in a 30 lower incidence of diabetes in the West of Scotland trial100 Thus, consideration should be given to pravastatin therapy in patients with borderline elevations 130-159 mg/ dL of low-density lipoprotein LDL cholesterol who also have impaired fasting glucose or high-normal glycosylated hemoglobin levels Metformin is currently being tested for prevention of diabetes and is promising101 Metformins potential benefit on waist-to-hip ratio102 and LDL cholesterol levels103 suggests that it may also be useful in preventing coronary heart disease in a population at risk for diabetes The cost-effectiveness of these pharmacologic interventions remains to be demonstrated; however, the nonpharmacologic interventions described in the Finnish Diabetes Prevention Study should be instituted in all patients at risk for diabetes Abnormal glucose tolerance is common and should be identified The burden of diabetes and coronary heart disease
could be substantially reduced if physicians performed glycosylated hemoglobin determinations in highrisk populations and treated patients with either impaired fasting glucose or high-normal glycosylated hemoglobin levels with intensive lifestyle changes and medication where appropriate
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