EPIDEMIOLOGY OF NON-INSULIN-DEPENDENT DIABETES MELLITUS AND ITS MACROVASCULAR COMPLICATIONS

EPIDEMIOLOGY AND CLINICAL DECISION MAKING

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EPIDEMIOLOGY OF NON-INSULIN-DEPENDENT DIABETES MELLITUS AND ITS MACROVASCULAR COMPLICATIONS A Basis for the Development of Cost-Effective Programs James H. Warram, MD, ScD, Jan Kopczynski, MD, PhD, Hans U. Tanka, MD, PhD, and Andrzej S. Krolewski, MD, PhD

Non-insulin-dependent diabetes mellitus (NIDDM) is a major health problem in developed countries. Historically, the diagnosis of NIDDM has been defined in terms of specific levels of hypergly~emia.~’ However, hyperglycemia is only one of several metabolic abnormalities present in NIDDM, many of which are now recognized to precede the onset of hyperglycemia by decades. These abnormalities are also increasingly considered to be contributors to the development of the consequences of NIDDM. In this review, NIDDM is viewed as three different but overlapping processes: (1) the development of insulin resistance, (2) the deterioration of glucose tolerance to overt NIDDM, and (3) the accelerated progression of atherosclerotic lesions in large arteries. Several decades are required to traverse all of these stages. In Caucasian populations, the most common outcome is a fatal or nonfatal vascular complication in the form of coronary artery disease (CAD) or peripheral vascular disease (PVD).

From the Section on Epidemiology and Genetics, Research Division, Joslin Diabetes Center (JHW, ASK); the Department of Epidemiology, Harvard School of Public Health (JHW, ASK); the Department of Medicine, Harvard Medical School (ASK), Boston, Massachusetts; the Department of Epidemiology, Warsaw Medical School, Warsaw, Poland (JK); and the Department of Internal Medicine, Bremen Medical School, Bremen, Germany (HUJ)

ENDOCRlNOLOGY AND METABOLISM CLINICS OF NORTH AMERICA VOLUME 26 * NUMBER 1 * MARCH 1997

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Cost-effective programs to reduce the excess morbidity and early mortality in patients with NIDDM must focus on interventions that reduce the occurrence of CAD and PVD. The optimal timing of these interventions will most likely be during the prediabetic stage and early diabetic stage. EPIDEMIOLOGY OF NIDDM AND PREDIABETIC EXPOSURES Insulin Resistance as a Prediabetic Exposure

Regarding the antecedent abnormalities in the development of NIDDM, several studies have shown that hyperinsulinemia and insulin resistance are 52, 60, 11" The earliest documentation of these abnormalities was major in a follow-up study conducted at the Joslin Diabetes A large group of normoglycemic young adults whose parents had NIDDM were recruited for a longitudinal study and followed up for 25 years. During the first 8 years of follow-up, there were few cases of NIDDM among the subjects, but during the subsequent decade, NIDDM developed in one of six offspring. The group in whom NIDDM developed was more insulin-resistant at baseline (as assessed with Bergman's minimal model) when compared with the group that remained normoglycemic.6nAll but 2 of 25 offspring in whom diabetes developed were below the median value of insulin sensitivity for the total group. Despite this, the group with NIDDM had baseline blood glucose levels, both fasting and after an oral glucose challenge [oral glucose tolerance test, (OGTT)] that were similar to the levels in the group that remained normoglycemic. They differed significantly, however, with regard to insulin levels. At baseline, fasting and postchallenge insulin levels in the offspring destined to have NIDDM were almost twice those in offspring who remained normoglycemic during follow-up. Obesity was also more prevalent in the offspring in whom diabetes developed, but the hyperinsulinemia of the prediabetic offspring persisted after the data were adjusted for the differences between the distributions of body weight in the two groups. To study this prediabetic metabolic state, we examined all of the data on individuals in whom NIDDM developed during follow-up and selected those individuals with frequent follow-up examinations whose onset of diabetes was promptly detected by this frequent screening. The characteristics evident in this period are distinct from any that can be attributed to the period of undiagnosed diabetes which typically precedes the diagnosis of NIDDM by several years. Selected data from the 15 years before the onset of NIDDM are summarized in Figure 1. The rise in glycemia, both fasting and postchallenge, was almost imperceptible until close to the time of NIDDM diagnosis. Measurements taken during the last 5 years before the diagnosis of NIDDM averaged 86 mg/dL and 124 mg/dL for fasting and 2 hours postchallenge, respectively. In contrast, postchallenge hyperinsulinemia was not only present at baseline but worsened until about 5 or 10 years before the onset of NIDDM, at which time it began a decline, heralding the onset of hyperglycemia. Unlike the rise and fall in postchallenge insulin levels, fasting insulin remained at an elevated but constant level until it rose moderately near the diagnosis of NIDDM. Fasting triglycerides, on the other hand, paralleled the changes in postchallenge insulin. All of the subjects were obese, but this characteristic did not change during the 15 years before the onset of diabetes. During the prediabetic period, one to two decades before the diagnosis of NIDDM, the offspring were obese and insulin-resistant and were exposed to

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Figure 1. Selected variables [fasting glucose and 2-hour glucose, fasting and 2-hour insulin, body weight expressed as O/i IBW, and fasting triglycerides (mg/dL)] measured during the 15 years before and 2 years aHer the onset of diabetes that was detected by frequent screening Data are summarized for five individuals who began follow-up aHer age 35 years and were followed for a minimum of 10 years They were examined 5 5 times on average in each 5-year interval (Data from Warram JH. Martin BC, Krowlewski AS, el al Slow glucose-removal rate and hyperinsulinemia precede the development of type I I diabetes in offspring with diabetic parents Ann Intern Med 113 309-315. 1990, and Martin BC, Warram JH. Krolewski AS, et al Role of glucose and insulin resistance in development of type 2 diabetes mellitus Results of a 25-year follow-up study Lancet 340 925-929. 1992 )

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hyperinsulinemia-not hypoinsulinemia-and hypertriglyceridemia. Hyperglycemia emerged late after many years of hyperinsulinemia. These unique data describing the prediabetic period are in agreement with other follow-up studies on the development of NIDDM.30,52 In all of these studies, insulin resistance has been shown to be associated with a complex of metabolic characteristics, sometimes called the insulin resistance syndrome.91In addition to hyperinsulinemia, the complex includes lipid abnormalities, hypertension, and CAD as well as a high risk of diabetes. As discussed later, although there are inconsistencies in the composition of the complex in comparisons across racial groups, there are important similarities in all groups that can legitimately be considered a “prediabetic metabolic state” which includes hyperinsulinemia/insulin resistance, dyslipidemia, and obesity.

Epidemiology of NIDDM

The fact that the onset of NIDDM is asymptomatic presents problems for a timely diagnosis and prompt initiation of treatment. Unlike the diabetes in the individuals presented in Figure 1 who were subjected to frequent rescreening, the onset of diabetes in the general population usually goes undetected for years until classical symptoms appear, an interval which has been estimated to be 4 to 7 years.34This obstacle to the timely initiation of treatment is also a problem for epidemiologic studies of diabetes. Because one must screen populations to detect undiagnosed cases, few data are available from which to assemble the descriptive epidemiology of NIDDM. The prevalence of diabetes (mainly NIDDM), physician-diagnosed as well as undiagnosed, was estimated to be 6.6% (more than 8 million persons) for the US population aged 20 to 74 years from the 1976 to 1980 National Health and Nutrition Examination Survey which used National Diabetes Data Group Previously diagnosed diabetes accounted for one half (3.4%) of the cases. The prevalence of undiagnosed diabetes increased with age in parallel with that of diagnosed diabetes so that the prevalence of the two remained approximately equal at all ages. The increase with age was similar for men and women and for blacks and whites, but the prevalence was slightly higher among women than men in the group aged 65 to 74 years. The prevalence among blacks was higher than that among whites at all ages and for both sexes. Figure 2 compares the prevalence of diabetes, both diagnosed and undiagnosed, in the US white population aged 20 to 74 years with the cumulative incidence of physician-diagnosed diabetes in Rochester, Minnesota.“, h7 The total prevalence (undiagnosed and diagnosed) of diabetes rose more steeply with age in comparison with the cumulative incidence of diagnosed diabetes in Rochester (1960 through 1969), a pattern implying a much higher incidence rate of diabetes in young adults than generally realized. Even for diagnosed diabetes, the prevalence in 1976 to 1980 was higher at young ages than the cumulative incidence a decade earlier (1960 to 1969). The difference may reflect a temporal increase in the incidence rate for symptomatic diabetes or merely an increased detection of a portion of the large reservoir of undiagnosed diabetes as a result of increased screening activity by physicians. The prevalence of diagnosed diabetes after age 50 years rose less steeply and eventually fell below the cumulative incidence rate, a change that presumably reflects the removal of prevalent cases because of excess mortality in persons with diabetes and that illustrates graphically how prevalence data underestimate the cumulative incidence in older age groups.

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Figure 2. Prevalence of diagnosed (dark shading] and undiagnosed (light shading] NIDDM in the white population of the United States aged 20 through 74 years, 1976 to 1980 and the cumulative incidence of diagnosed NIDDM in Rochester, Minn., 1960 through 1969 (dashed line). (From Warram JH, Rich SS, Krolewski AS: Epidemiology and genetics of diabetes mellitus. ln Kahn CR, Weir GC (eds): Joslin's Diabetes Mellitus. Philadelphia, Lea and Febiger, 1994, pp 201-215; with permission.)

Risk Factors for the Development of NIDDM Scant data are available on risk factors for insulin resistance. However, because NIDDM is one of the outcomes of insulin resistance, its occurrence can be considered a marker of insulin resistance; therefore, the risk factors that have been identified for NIDDM can be assumed to apply to insulin resistance as well. Variation According to Obesity and Physical Activity

Excellent data on the relationship between body weight and the risk for diabetes and impaired glucose tolerance were obtained from the participants in the 1976 to 1980 National Health and Nutrition Examination Survey.7zParticipants were grouped according to the increase in weight after age 25 years expressed as a percentage of ideal body weight (Fig. 3). Even among the groups whose maximal weight gain was no more than 10% to 2070, the prevalence of diabetes was 4%. This percentage increased little until the weight gain exceeded 40%. Among those with a weight gain greater than 40%, however, the prevalence rose steeply. Similar results have been reported in other studies.", '' One interpretation of these findings is that although obesity is strongly related with NIDDM in a subgroup of individuals who are particularly prone to gaining large amounts of weight, in most individuals, obesity is a weak discriminator between those who will experience diabetes and those who will not.

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Increase in Weight as a Percentage of Ideal Body Weight Figure 3.Total prevalence of diagnosed and undiagnosed NIDDM according to the increase in weight from age 25 years to maximum adult weight expressed as a percentage of ideal body weight. (Adapted from Warram JH, Rich SS, Krolewski AS: Epidemiology and genetics of diabetes mellitus. In Kahn CR,Weir GC [eds]: Joslin's Diabetes Mellitus. Philadelphia, Lea and Febiger, 1994, pp 201-215; with permission.)

Evidence for a role of physical activity as a risk factor for NIDDM is substantial. An inverse relationship with the risk of NIDDM has been demon55, 57, 58 Interestingly, this effect is particularly strated in follow-up evident among the obese. For example, among those in the highest quartile of the distribution of body mass index, the risk was 40% lower in those who exercised vigorously at least once a week relative to the risk for those who engaged in vigorous exercise less freq~ently?~ Thus, there is a large benefit from exercise even in the presence of obesity. Ethnic and Geographic Differences The consideration of geographic and ethnic differences in the occurrence of NIDDM is simplified by concentrating on a narrow age range (45 through 54 years) and one sex (men, because more data are available). Because few patients with NIDDM die before the age of 55 years, these prevalence data can be considered reasonable estimates of cumulative incidence until the age of 50 years. The prevalences of diagnosed and undiagnosed NIDDM in various ethnic groups in the United States and around the world are summarized in Figure 4. In the examination of a representative sample of the United States population from 1976 to 1980, the prevalence of NIDDM was 7.7% among whites and 11.1% among blacks in the age group 45 to 54 years. The prevalence among Hispanic minorities (Cubans in Florida and Mexican-Americans in the border states) was

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even higher but did not approach that among the Pima Indians of Arizona. The prevalence of NIDDM in European populations is low in comparison with the prevalence in these American populations. Several populations in Europe have been subjected to screening for undiagnosed diabetes. In each of these populations, the combined prevalence of diagnosed and undiagnosed diabetes is less than half that in American whites, even though less stringent diagnostic criteria [World Health Organization (WHO)] were used. The prevalence of NIDDM in Saudi Arabia was similar to that in the United States, whereas, in Kazakstan, the prevalence among men aged 50 to 59 years was similar to that in European men surveyed at a slightly younger age (45 to 54 years). The substantial differ-

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ence in the occurrence of diabetes among white populations, particularly between ethnically similar populations in Europe and the United States, points to an environmental factor. Data on obesity and physical activity in these populations are not available. Therefore, it is unknown how much of the differences are attributable to obesity and physical activity and how much are caused by other as yet unknown factors. Differences among ethnic groups can be attributable to differences in genetic predisposition. For example, insulin resistance, which seems to be the most significant predisposing factor for NIDDM in various ethnic groups,””,52,60, 110 has been shown to cluster in families6,59, 61, 9b In Caucasians, as much as 50% of its variability in the population may be genetically determined.59 How large the contribution of genes is in other races is not yet known. These predispositions have profound influences on the exposures that prevail during the prediabetic period. However, from studies of the insulin resistance syndrome in various races and ethnic groups, one can anticipate that the components of the syndrome differ among prediabetic individuals in different races. For example, in normoglycemic whites but not in Pima Indians or blacks, blood pressure is correlated with fasting hyperinsulinemia and insulin re~istance.9~ EPIDEMIOLOGY OF MACROVASCULAR COMPLICATIONS IN NIDDM

Macrovascular complications, such as CAD and PVD are the major health problems in patients with NIDDM. In Caucasian patients with NIDDM, their contribution to morbidity and mortality overrides the impact of microvascular ~omplications.4~ Descriptive Epidemiology Regarding CAD-NIDDM Relationship

An excess of CAD in NIDDM has been found in a large number of crosssectional and prospective investigations that have been summed up in several highly informative reviews.*5,” The most recent addition to this evidence is a report on the Multiple Risk Factor Intervention Trial (MRFIT), a large prospective study of the mortality rate in more than 5000 diabetic and 300,000 nondiabetic persons during a 12-year follow-up p e r i ~ d . ~ ’ Prediabetic Exposures and CAD

Diabetes-associated exposures begin long before the onset of NIDDM. Hyperinsulinemia and insulin resistance antedate the onset of NIDDM by two or more decades.60,110 Companions to these include obesity, elevated diastolic blood pressure, and serum hypertriglyceridemia.’”,*,’ 31, 91 Additions to this list, based on other studies, are other ”classic” risk factors for cardiovascular disease, notably central fat distribution, a small increase in serum levels of low-density cholesterol (LDL), lower high-density (HDL) cholesterol serum concentrations, and less physical exertion during leisure time.’, 9. 64, 77, 76, 86, Other disturbances related to insulin resistance include abnormalities of the fibrinolytic systema7 both well-established precursors of CAD. and uric acid Hyperinsulinemia clusters with these cardiovascular risk factors not only in euglycemic individualsz9,’ I 3 but in persons with impaired glucose tolerances,23, 79

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and patients with established NIDDM.lYThis multitude of risk factors manifest a self-perpetuated quality. Subjects with more cardiovascular risk factors at baseline examination tend to acquire still more abnormalities in subsequent follow-up examinations, a likely mediating factor being increased insulin resistance.31 Regardless of whether normoglycemia or impaired glucose tolerance prevails, the prediabetic period seems a particularly fertile ground for promoting CAD as well as NIDDM by virtue of an atherogenic profile of risk variables with hyperinsulinemia or insulin resistance. Demonstration of the atherogenic role of hyperinsulinemia/insulin resistance in population studies has been elusive despite abundant in vitro and experimental evidence."'* Several early crosssectional surveys and prospective studies seeking confirmation of this hypothesis in the general population were incon~lusive.'~ The results of recent studies, however, provide strong support. Data from both the Quebec Cardiovascular StudyI5 and the Insulin Resistance Atherosclerosis Study (IRAS)'" have shown convincingly that hyperinsulinemia/insulin resistance may, in fact, be responsible for the risk of CAD and accelerated atherosclerosis in the general population. In the Quebec study, male subjects with a first occurrence of myocardial infarction or coronary death ascertained during a 5-year follow-up period had higher fasting baseline insulin levels irrespective of cardiovascular risk factors when compared with carefully matched controls.Is The effect of hyperinsulinemia on the occurrence of CAD events was particularly profound among those with elevated levels of apolipoprotein B. In the IRAS investigation, a large and meticulously performed cross-sectional study, white and Hispanic participants showed a negative relationship between insulin sensitivity and intimal and medial thickening in the internal carotid artery even after adjustment for most risk factors for CAD and NIDDM, including intrinsic insulin itself.3xThis relationship was not evident, however, in black participants.3x Magnitude of Excess Risk of CAD in NIDDM

Patients in whom NIDDM develops continue to have prediabetic exposures combined with new exposures specific to overt diabetes and characterized primarily by hyperglycemia and associated abnormalities. The effect of these two exposures (prediabetic and diabetic) on the risk for CAD can be illustrated by comparing the mortality data from a 24-year follow-up study of a large group of patients with NIDDM seen at the Joslin Clinic with the data from the Framingham nondiabetic population followed for the same period of time (Fig. 5).snIn the Framingham sample, the steadily increasing risk of CAD with the duration of follow-up reflects the effect of aging, whereas the rise in the Joslin diabetic cohort reflects the effect of aging combined with the cumulative effect of prediabetic and diabetic exposures. The risk in the diabetic cohort, therefore, is already elevated from the moment of diagnosis of diabetes and rises more steeply with the duration of follow-up in women as well as men. Similar results were obtained in the large cohort observed in the Nurses Health Study. An initially slow and a subsequently sharp rise of the relative risk of both nonfatal myocardial infarction and fatal CAD occurred in women with NIDDM in comparison with nondiabetic women in the same cohort.s6 A remarkably similar pattern has been found in the 22-year follow-up study of diabetic men and women in Warsaw, Poland48 (J. Kopcynzski, MD, and colleagues, unpublished data). All of these results are compatible with the biologic interpretation that the cumulative effect of diabetes exposure is an acceleration of the progression of

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Duration of Follow-Up (y) Figure 5. Mortality caused by coronary artery disease (CAD) during 24 years of follow-up of a cohort of diabetic men (A) and women (B) who were diagnosed between ages 35 and 64 years and who came to the Joslin Clinic (Boston, Mass.) soon after the diagnosis (solid line), and in a group of similarly aged nondiabetic participants of the Frarningharn study (broken line). The increased CAD mortality in the J o s h cohort, already evident during the first 3 years of follow-up, increased significantly during the subsequent intervals of observation. (Reprinted by permission of the publisher from Krolewski AS, Warrarn JH, Valsania P, et al: Evolving natural history of coronary artery disease in diabetes rnellitus. Am J Med 90 [suppl 2A]:565-615, copyright 1991 by Excerpta Medica Inc.)

CAD in persons with existing atherosclerotic lesions.s" In terms of pathogenetic processes, the increasing risk for CAD with the duration of NIDDM most likely reflects the promoting action of diabetic exposure on the late stages of atherogenesis, notably, the formation of atheromas and fibroatheromas.sn Risk Factors for CAD in NlDDM The clustering of classic cardiovascular risk factors in the prediabetic period in patients in whom NIDDM develops has been emphasized by many investiga-

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M, “’ Some investigators presenting data from population-based studies have suggested on the basis of apparently small effects of hyperglycemia and diabetes duration on CAD mortality that classical cardiovascular risk factors account for all of the excess mortality ascribed to the effect of diabetes.20However, these studies have been small and lack the statistical power to examine this issue. Data from the MRFIT, the largest study comparing the mortality experience of diabetic and nondiabetic persons, permitted examination of the role of diabetes exposure on CAD after taking into account the effect of classical risk factors (smoking, serum cholesterol, and blood pressure).’” Among men with diabetes, a large excess mortality is evident regardless of the number of risk factors present (Fig. 6). The specific elements of diabetes exposure that are responsible for the excess of CAD in NIDDM are unclear. Although many unknown diabetesspecific factors may operate, we consider the two known factors-hyperglycemia and diabetic nephropathy. Only fragmentary knowledge is available to evaluate the relationship between the level of hyperglycemia and the risk of CAD. The results of the Diabetes Control and Complications Trial (DCCT), a 9-year clinical trial, indicated that the risk of CAD was reduced among patients with IDDM who were treated intensively to achieve good glycemic control in comparison with the risk among patients treated conventionally and who had worse glycemic contr01.I~ The differences, however, did not attain statistical significance. The results of a 10-year randomized clinical trial in patients with NIDDM conducted by the University Group Diabetes Program (UGDP) and published more then a decade

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Figure 6. Age-adjusted cardiovascular mortality rates according to the number of risk factors present in men screened for Multiple Risk Factor Intervention Trial with (white bars) and without (black bars) diabetes at baseline. (From Stamler J, Vaccaro 0, Neaton JD: Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434-444, 1993; with permission.)

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ago showed that mortality and nonfatal cardiovascular events occurred with equal frequency among patients who received intensive insulin treatment and among patients who were treated with only diet and whose glycemic control deteriorated over time.47The recently conducted Veterans Affairs Cooperative Study on Glycemic Control and Complications in NIDDM (VACSDM)" showed an increased risk of total cardiovascular events in the intensively treated group in comparison with the conventionally treated group. The differences, however, did not attain statistical significance. The results of a United Kingdom study currently in progress have not been reported despite long follow-up and a large sample size.'05 Apparently, no statistically significant difference has emerged to precipitate termination of the trial. Similar to the ambiguity of the results from clinical trials, the results of observational studies are unconvincing. Two cohort studies showed a weak positive relation between the level of hyperglycemia and mortality caused by CAD.51,70 These findings, however, were confounded by other factors associated with severe hyperglycemia. The persistence of high levels of glycemia in NIDDM generally leads to the initiation of insulin treatment, and it has been the treatment with insulin (rather than the severe hyperglycemia) which has been postulated to be associated with a high risk of CAD in several 42, 46, 53, 89, y4, Io7 The interpretation of the high risk for CAD among patients with NIDDM who are treated with insulin is unclear. Hyperinsulinemia has been implicated in the acceleration of coronary atherosclerosis.'ozThus, one can hypothesize that the exogenous insulin may contribute to the excess CAD mortality. One cannot, however, exclude the possibility that metabolic or cellular abnormalities underlying insulin resistance and causing the severe hyperglycemia which requires insulin treatment are the true risk factors for the acceleration of atherosclerosis.24, 43, Y2, 101 Diabetic nephropathy is the most potent risk factor/indicator for CAD in Caucasian patients with NIDDM. Many investigators have shown that the risk for CAD is elevated in patients with microalbuminuria and even more so among 44,62, lo" These effects are clearly seen in Figure those with clinical protein~ria?~, 7, which shows the results of a 5-year follow-up of a cohort of patients with NIDDM in Denmark according to nephropathy status at baseline examinationJ7 The reason for this excess risk is obscure. Some investigators postulate that, in response to poor glycemic control, a generalized angiopathy occurs which is responsible for multiple vascular pathologies, including the lesions in large arteries.14A substantial body of literature demonstrates that diabetic nephropathy is determined by genetic factors in IDDM and NIDDM.75,90 Phenotypically, patients in whom diabetic nephropathy develops are more insulin-resistant than those without it and have more hypertension and lipid abnormalities?8,74, 76 Their relatives are also more insulin-resistant and have elevated blood pre~sure?~, Io3 Thus, it is unclear whether the exposures that are associated with diabetic nephropathy and that lead to a high risk for CAD are the result of kidney damage or whether the presence of diabetic nephropathy is just an indicator of the exposures which existed long before this complication developed. Different Natural History of CAD in NIDDM in Different Races

In some populations of patients with diabetes, CAD is an infrequent complication. The WHO multinational study of vascular disease in diabetes documented a marked variation in the occurrence of CAD among 14 samples of middle-aged patients with NIDDM throughout the world. In the cross-sectional

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Survival (y) Figure 7 . Cumulative survival curves for three levels of albuminuria in 328 patients with NIDDM. Norrnoalbuminuria(dofted line; n = 191); rnicroalburninuria (dashed line; n = 86); macroalburninuria (solid line; n = 51). (From Gall MA, Borch-Johnsen K, Hougaard P, et al: Alburninuria and poor glycernic control predict mortality in NIDDM. Diabetes 44:13031309, 1995; with permission.)

portion of this study conducted in the 1970s, high prevalences of indicators of cardiovascular disease, such as electrocardiographic abnormalities and chest pain symptoms, were found in diabetic patients from Switzerland, Berlin, and London.18Low prevalences of these indices were found in patients from Tokyo and Hong Kong and among the Native-Americans (Pima Indians) in Arizona.lR Similar findings were obtained during the 7-year follow-up study. The mortality rate associated with CAD was highest in the samples of diabetic patients from Berlin, Switzerland, and London and lowest in the samples from Tokyo and Hong Kong and in the Pima 111dians.3~ A similar conclusion can be drawn from a comparison of CAD mortality experience in a cohort of patients with NIDDM in Tokyo and a similar cohort from the Joslin Clinic in Boston.6’Whereas mortality rates increased steeply with the duration of diabetes in Boston, there was minimal CAD mortality in the Tokyo cohort regardless of duration (Fig. 8). In Pima Indians, CAD mortality is also low and does not increase with the duration of diabetes.” More than half of this population have NIDDM, and most of these patients are insulin-resistant and hyperinsulinemic for most of their lives. Furthermore, renal complications are common in Pima Indians.” The wide variation in the occurrence of CAD among different diabetic populations is consistent with the hypothesis that certain components of prediabetic exposure ( e g , insulin resistance) as well as exposures during diabetes have an impact only on the progression of atherosclerotic lesions. However, these exposures have no impact on the frequency of atherosclerosis in diabetic

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Duration of Follow-Up (y) Figure 8. Mortality rate of patients with coronary artery disease (CAD) by duration of followup in the Tokyo University (black bars; n = 377) and Joslin Clinic (white bars; n = 877) cohorts. (From Matsumoto T, Ohashi Y, Yamada N, et al: Coronary heart disease mortality is actually low in diabetic Japanese by direct comparison with the J o s h cohort. Diabetes Care 17:1062-1063, 1994; with permission.)

patients from populations in which the initiation of atherosclerosis is infrequent, such as the Pima Indians, Japanese in Tokyo, and Chinese in Hong K ~ n g . ~ ~ Descriptive Epidemiology Regarding PVD-NIDDM Relationship

Arterial PVD is a major cause of morbidity in patients with NIDDM.7 It occurs more frequently and progresses more rapidly in diabetic persons than in nondiabetic subjects. PVD leads to clinical complications such as intermittent claudication, gangrene of the foot, and leg amputation.” 82 Currently, diabetes (mainly NIDDM) accounts for more than 50% of all nontraumatic amputations in the general p ~ p u l a t i o n . ~ ~

Occurrence of PVD and Its Outcomes Noninvasive testing with Doppler ultrasonography represents a major improvement in our ability to detect PVD. An international workshop has recommended that all physician offices providing routine care to adult diabetic patients use Doppler techniques to measure ankle and brachial blood pressure to determine the ankle brachial index (ABI) to screen for early PVD.so An ABI index of less than 0.9 is considered suggestive of PVD and one less than 0.8 diagnostic of PVD regardless of symptoms.80 Using these criteria, the prevalence of PVD has been found to be higher in

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diabetic persons than in nondiabetic patients in population-based as well as clinic-based studies?, 82, lop In the Hoorn Study in Holland, the overall prevalence of PVD was 20.9% in diabetic patients and 7.0% in normoglycemic controls.4 The Schwabing study in Germany, however, showed that PVD was infrequent before age 50 years, but that its prevalence increased steeply thereafter (Fig. ,).,I In that study, a correlation of PVD with the duration of diabetes has been regularly observed.41A similar correlation was found in the diabetic residents of Rochester, M i n n e ~ o t a PVD . ~ ~ as diagnosed by pulse deficits was present in 8% of subjects at the time of the initial diagnosis of diabetes, in 15% after 10 years, and in 45% after 20 years of diabetes duration. In both the German and US studies, the effect of diabetes duration was confounded by age. The occurrence of PVD as reported in prospective studies in Caucasian patients with NIDDM is remarkably consistent. Based on Doppler ultrasound techniques, the cumulative incidence of PVD increased proportionally with the 81 From these data, a mean incidence rate duration of the observation of 25 cases of PVD per 1000 patients per year can be calculated. Similar incidence rates have been reported in studies using intermittent claudication as the evidence of PVD.7,s3This implies that PVD progresses from an asymptomatic stage to claudication at the same rate as an ABI reading progresses from normal to pathologic. In both the Rochester and Framingham studies, the incidence rate of PVD was slightly higher in men than in women. In comparison with nondiabetic subjects, the rates in patients with diabetes mellitus were higher by a factor of 2.7 in men and 3.4 in women.7 Lower-extremity amputations can be regarded as a major end point of PVD.

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Age (Y) Figure 9. Prevalence of peripheral vascular disease (PVD) according to age in the Schwabing study of PVD in patients with NIDDM (From Janka HU, Standl E, Mehnert H: Peripheral vascular disease in diabetes mellitus and its relation to cardiovascular risk factors: Screening with the Doppler ultrasonic technique. Diabetes Care 3:207-211, 1980; with permission.)

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In the Rochester study, the incidence rate of amputation among residents with These patients had almost a 12-fold NIDDM was 3.9 per 1000 person-year~.~~ risk of below-knee amputation in comparison with nondiabetic individuals. Similar rates were observed in the German city of Le~erkusen.'"~ For diabetic patients, the rate was 2.09 per 1000 person-years as compared with 0.09 for the nondiabetic population, a relative risk of 22.2. The major outcome in patients with NIDDM and PVD is premature mortality. The presence of PVD is an indicator of impending or coexisting atherosclerosis in the coronary or cerebral circulation and carries a high risk of early cardiovascular death.16 The Framingham study has demonstrated that the risk for myocardial infarction and death due to CAD is increased when diabetes coexists with intermittent cla~dication.~ Nonpalpable pedal pulses were associated with more than a twofold excess of coronary heart disease and cardiac fai1~re.I~ In the Schwabing study, preexisting PVD was the strongest risk indicator for all-cause and cardiovascular death, with a much stronger association than the well-known cardiovascular risk factors such as hypertension, dyslipidemia, or hypergly~emia.~" Risk Factors for PVD

Diabetic patients with PVD frequently exhibit the well-known cardiovascular risk factors of hypertension, dyslipidemia, cigarette smoking, and android adip~sity.~, 45, 84 A typical feature of diabetic patients, particularly those with NIDDM, is the frequent coexistence of several risk factors associated with hyperinsulinemia and insulin resistance?] The effect of these risk factors may be synergistic in the development of the atherosclerotic lesions of limb arteries, although this has not been systematically studied. Population-based studies have uniformly demonstrated that diabetes mellitus is a strong risk factor for PVD, gangrene, and foot amputations.', 26, R4 Several prevalence studies imply that the close relationship of diabetes mellitus and PVD can be explained by the duration of exposure to hyperglycemia and the quality of blood glucose IoY In the Hoorn study, for instance, PVD was significantly associated with HbAI,, fasting, and 2-hour post-load plasma glucose even after correction for cardiovascular risk factor^.^ Few prospective studies have been performed to identify specific risk factors for PVD in diabetes and address the question of the contribution of blood glucose control to definite end points. In the second Schwabing study, patients with NIDDM were carefully screened for PVD with Doppler ultrasound and electronic oscillometry with an exercise test at baseline and again at 9-year follow-up.4oOf the diabetic patients free of PVD at baseline, PVD developed in 24 subjects, and 101 remained without PVD. Table 1 compares baseline characteristics of the two groups. The patients with PVD were older, more often treated with insulin, and had higher systolic blood pressure, more hyperlipidemia, and poorer glycemic control. Multivariate analysis, however, showed only elevated systolic blood pressure and low HDL cholesterol as significant predictors of PVD. The other factors did not reach statistical significance. Markers of dyslipidemia were also found to be risk factors for the development of PVD in NIDDM in a 5-year prospective study in Finland.'06 Although not risk factors for PVD, hyperglycemia and elevated HbAI, levels have been reported to be risk determinants for gangrene of the foot and amputation~.'~PVD is only one factor in the pathogenesis of foot lesions in diabetes. Other contributing factors such as neuropathy might be even more aggravated by poor metabolic control in this complex setting.

181

EPIDEMIOLOGY OF NON-INSULIN-DEPENDENT DIABETES MELLITUS

Table 1. RISK VARIABLES FOR PATIENTS WITH NIDDM FREE OF VASCULAR DISEASE AT BASELINE WITH AND WITHOUT PVD AT 9-YEAR FOLLOW-UP (MEAN + SD) Variable at Baseline

PVD (n=24)

No PVD (n=101)

Male gender Age (years) Duration of diabetes (years) Insulin therapy Systolic blood pressure Diastolic blood pressure Weight (“ideal /. weight) Fasting blood glucose (mg/dL) Hemoglobin A, (%) Serum cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglycerides (ng/dL) Proteinuria (Albustix) Cigarette smoker Previous smoker

41.7% 64.5 f 7.3 11.7 5.2 54.2% 159 + 18 87 + 12 127 21 171 57 12.1 + 3.3 255.2 48.9 45.2 15.2 255.3 166.4 12.5% 20.8% 58.4%

43.6% 58.7 10.0 4.7 9.5 31.6% 142 + 23 84 10 20 123 147 67 10.8 + 3.2 230.1 56.4 14.1 51.0 133.5 189.8 5.9% 14.9% 53.4%

+

+ +

+ + +

+ +

+ + +

+ + +

Significance NS 0.01 NS 0.05 0.001 NS NS 0.03 0.08 0.03 0.01 0.03

NS NS NS

NS = a nonsignificant Wilcoxon test. From Janka HU,Becker A, Muller R: Arterielle Verschlusskrankheit der Extremitaten bei Diabetikern: lnzidenz und ihre Ursachen. Die Schwabinger Studie II. Diab Stoffw 2:68-72,1993; with permission.

CHANGING THE MAGNITUDE OF MACROVASCULAR COMPLICATIONS IN NIDDM

The macrovascular complications in NIDDM are summarized in Figure 10 as a schematic model for a cost-effectiveness analysis. Although the probabilities of progression from one stage to another have not been determined exactly, it is clear that atherosclerosis in large arteries (CAD and PVD) develops in a large proportion of Caucasian patients with NIDDM. New strategies are required to reduce the burden of morbidity and premature mortality associated with this complication. From the foregoing discussion of the impact of insulin resistance and traditional risk factors in the prediabetic period as well as after the onset of NIDDM, a move toward earlier intervention is in order. Several possible strategies are outlined in the following sections. Different Strategies to Prevent CAD and PVD in NIDDM

The earliest point for intervention is the prediabetic stage characterized by insulin resistance and hyperinsulinemia. There, efforts would be directed toward improving insulin sensitivity. In effect this would convey on “insulin resistance” the status of “disease.” It also shifts the goal of the prevention. Halting or retarding the advance of atherosclerosis becomes the primary goal (outcome), while the possible deterioration of glucose tolerance to diabetes becomes a troublesome complication and a secondary endpoint. Several tasks need to be completed before an intervention at the prediabetic stage can be designed. The first is to develop a measure of insulin resistance that is suitable for screening purposes. Once that is chosen, diagnostic criteria for intervention must be established, as has been done for hypertension and

182

WARRAMetal

Normal I

0

/ I \

Insulin resistance

\

n

+-I

I

\ \

Overt

diabetes

I Microvascular k complications

Figure 10. Model of the stages of NIDDM beginning with the normal population. The rectangles represent states of health; arrows represent the possible transitions between health states. Individuals in each state may develop CAD or PVD and ultimately die. Instead, individuals in each state may die without developing CAD or PVD (not shown). Arrows from a rectangle that circle back on the same rectangle indicate that a patient can remain in that state for more than one follow-up interval. A dashed arrow from a rectangle to a rectangle above it indicates that a transition may be reversibte. (See refs. 54, 68, and 98 for more information regarding the development of cost-effectiveness models).

other cardiovascular risk factors. The last task is to choose which preventive measures to use. Interventions focused on reducing caloric intake, decreasing body mass, and increasing exercise levels may be effective, as may some oral agents that improve insulin sensitivity. A demanding standard that must be met by any intervention considered for this early stage is that it be sustainable for decades. The next level for an intervention strategy is with the stages of impaired glucose tolerance or early NIDDM as diagnosed by screening. As in the previous strategy, intervention would be focused on reducing insulin resistance, and the goal would be shifted toward halting atherosclerosis regardless of whether NIDDM can be prevented when the intervention is delayed to such a late stage. Several problems must be dealt with before an intervention at this stage can be designed. Although the screening test, an oral glucose tolerance test, and the diagnostic criteria have already been established, this procedure is not wellsuited for screening purposes and has not been well-accepted by patients or physicians. Moreover, given the brevity of the stage of impaired glucose tolerance in many patients (see Fig. l), effort must be invested in determining the optimal interval between repeat screenings. The candidate interventions are the same as in the earlier stage. A placebo-controlled, randomized clinical trial testing these interventions in patients with impaired glucose tolerance began in early 1996. Unfortunately, the end point for the trial is the deterioration of impaired glucose tolerance to NIDDM, and the 6-year duration of the trial may

EPIDEMIOLOGY OF NON-INSULIN-DEPENDENT DIABETES MELLlTUS

183

not be long enough to evaluate whether the interventions retard or halt the progression of cardiovascular disease in these individuals. The third alternative strategy is current standard practice in which NIDDM is diagnosed after symptoms have appeared. In this intervention, some attention is paid to reducing cardiovascular risk factors, and most of the available effort is spent on the task of controlling hyperglycemia. Except for the new oral agents which are thought to increase insulin sensitivity, effort is not directed toward reducing insulin resistance. A recent study which modeled the known effects of improving hyperglycemia showed that the health gains of such a strategy are minimal, with CAD morbidity and mortality overriding its effect.loR Cost Comparison

To choose among the strategies for reducing the cardiovascular complications of NIDDM, a cost comparison is required. Cost-effective analysis provides an analytic structure for weighing the costs of alternative programs against the 68 Every program involves three types differences in results that they prod~ce.5~. of costs: (1) costs for detecting or diagnosing cases; (2) costs for intervening to ameliorate their condition; and (3) costs of the morbidity that occurs despite the intervention (and sometimes because of it). To obtain the cost of an intervention, data on the natural history of the stages represented in Figure 10 are assembled, Transition probabilities corresponding to each of the arrows in the figure must be derived from available data or estimated. The second step is to superimpose the components of an intervention strategy on the natural history of NIDDM, that is, all possible outcomes of the screening procedure together with their respective probabilities and all possible outcomes (CAD and PVD events) of the intervention and their probabilities. The cost of the program is then determined by summing the cost of each possible outcome weighted by its probability. Clearly, much of the data needed to complete one of these models are missing or of uncertain quality. Nevertheless, the exercise of assembling even imperfect information into comprehensive models is a valuable 98 Missing information that is critical for ranking alternative strategies according to their cost-effectiveness can be identified. Guided by these priorities, appropriate studies can be designed to lead to an effective means of reducing the burden of the cardiovascular complications in NIDDM. References 1. Abbott RD, Brand FN, Kannel WB: Epidemiology of some peripheral arterial findings in diabetic men and women: Experiences from the Framingham Study. Am J Med 88:376-383, 1990 2. Autin MA, Mykkanen L, Kuusisto J, et a 1 Prospective study of small LDLs as a risk factor for non-insulin-dependent diabetes mellitus in elderly men and women. Circulation 92:1770-1778, 1995 3. Beach KW, Bedford GR, Bergelin RO, et al: Progression of lower-extremity arterial occlusive disease in type I1 diabetes mellitus. Diabetes Care 11:464472, 1988 4. Beks PJ, Mackaay AJC, de Neeling JND, et al: Peripheral arterial disease in relation to glycemic level in an elderly Caucasian population: The Hoorn Study. Diabetologia 38:8&96, 1995 5. Bendick PJ, Glover JL, Keubler TW, et al: Progression of atherosclerosis in diabetics. Surgery 935334-838, 1983

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Address reprint requests to James H. Warram, MD, ScD Research Division Joslin Diabetes Center Boston, MA 02215