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Original Studies |
Department of Medicine, Stanford University School of Medicine, Stanford, California; and Shaman Pharmaceuticals, Incorporated, South San Francisco, California 94080-4812
Address all correspondence and requests for reprints to: Gerald M. Reaven, Shaman Pharmaceuticals, Incorporated, 312 East Grand Avenue, South San Francisco, California 94080-4812. E-mail: greaven{at}shaman.com
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Abstract |
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Clinical end points developed in 13 subjects during the follow-up period; hypertension in 5, coronary artery disease in 4, cerebrovascular accident in 3, and peripheral vascular disease in 1. There was a significant univariate relationship between SSPG and CVD (P < 0.002), with the majority of the events taking place in the tertile of subjects with the highest SSPG concentration, i.e. the greatest degree of insulin resistance. In contrast, no CVD events were observed in the tertile with the lowest SSPG concentrations; the most insulin sensitive. SSPG was also related significantly to diastolic blood pressure, triglyceride, and low-density lipoprotein and high-density lipoprotein cholesterol concentrations, and the glucose and insulin responses to oral glucose. All of these relationships were independent of age, gender, body mass index, estimates of physical activity, and smoking history. When SSPG was paired with each of the other variables in a series of multiple regression models, only SSPG, or insulin response, were independent predictors of CVD events.
In conclusion, approximately one of every five healthy, nonobese subjects in the most insulin-resistant tertile, followed for approximately 5 yr, had a serious clinical event. These data highlight the importance of insulin resistance as a predictor of CVD.
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Methods |
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30 kg/m2 were contacted by mail in 1995/1996
for follow-up. Baseline evaluation included a physical examination, an electrocardiogram, and a complete blood count, and blood chemistry panel to ensure good general health. All subjects with a past history of CVD or hypertension were excluded, as were individuals with an abnormal electrocardiogram. In addition, a blood pressure (BP) >145/90 mmHg, or a history of taking any medication known to affect glucose or lipid metabolism or hypertension were the basis for exclusion. Baseline measurements included weight, height, sitting BP, and fasting lipid and lipoproteins (16). A 75-g oral glucose tolerance test was done with blood samples for glucose (17) and insulin (18) drawn at 0, 30, 60, 120, and 180 min. The area under the curve was calculated by the trapezoidal formula to estimate the postload glucose and insulin areas. Any subject who was found to be diabetic by oral glucose tolerance according to the WHO criteria was eliminated from the study. Insulin resistance was measured by insulin suppression test as previously described (19). Information on smoking history was obtained. Smokers were those who were currently smoking cigarettes or had done so within the last 5 yr; all others were classified as nonsmokers. Physical activity was measured by the number of physical activities per week that were associated with sweating (20).
At follow-up, each subject was asked about current medication use and history of neurological deficits and asked to complete a screening questionnaire on chest pain and intermittent claudication (21). Whenever there was a positive report for antihypertensive/cardiac medication, chest pain, or calf pain, the subject was interviewed over the telephone by JY/FF and permission sought to contact the primary care physician to clarify the nature of the symptom. For those who could not be reached and failed to return the questionnaire, it was assumed that either they had moved away without leaving a forwarding address or had died. The names of these individuals were submitted to the Office of State Registrar in California for search against the death registry and the examination of the death certificate.
The study end points were the development of hypertension or CVD; the latter category included fatal or nonfatal coronary artery disease, fatal or nonfatal cerebral vascular accident, or peripheral vascular disease. Hypertension was defined by the use of antihypertensive medication. Coronary artery disease included chest pain with positive stress test, percutaneous transluminal angioplasty, coronary bypass surgery, or documented myocardial infarction. Cerebral vascular accident included documented clinical neurological deficit, lasting over 24 h, with or without radiographic evidence. The diagnosis of peripheral vascular disease was made clinically by history and examination, which demonstrated diminished pedal pulses with poor capillary return or arterial ulceration.
All results are expressed as arithmetic or geometric mean ± SE. Results were analyzed by ANOVA and contingency table as appropriate. Nonparametric variables: triglycerides, postload insulin area, and steady state plasma glucose concentration were log-transformed before analysis. Univariate and multivariate logistic regression analyses were used to assess the relationship and interaction of baseline variables and the presence of cardiovascular disease as a categorical outcome.
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Results |
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A diagnosable disease developed in 13 subjects (6 males, 7 females) during the follow-up period: hypertension in 5, coronary artery disease in 4, cerebral vascular accident in 3, and 1 with peripheral vascular disease. There was one noncardiovascular death reported. The search through the State of California Death Registry between 1989 and the end of 1995 was negative for those individuals who were lost to follow-up.
The relationship between the development of disease, hypertension plus
CVD, as a function of tertiles of baseline SSPG, is shown in the
top half of Fig. 1
. It is
clear from these data that neither hypertension nor CVD developed in
the one third of the population that was most insulin sensitive
(tertile I). In contrast, almost one of every five individuals in the
most insulin-resistant tertile (tertile III) developed hypertension or
CVD during the period of observation.
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illustrates the incidence at which
specific manifestations of CVD developed as a function of degree of
insulin resistance. As in the case of the combined events shown above,
CVD did not develop in the most insulin-sensitive tertile. In marked
contrast, seven of the eight subjects in whom CVD was documented came
from the most insulin-resistant tertile.
The baseline characteristics of the three tertiles are seen in Table 1. When subjects in the highest tertile
(highest SSPG values) were compared with those in the lowest tertile,
it can be seen that they differed in multiple variables. To evaluate
the link between SSPG and CVD events, it seemed necessary at first to
define the relationship between SSPG and its related variables,
adjusting for difference in age, gender, BMI, smoking, and estimates of
physical activity. The results of this analysis are given in Table 2, and it is apparent that SSPG was
significantly related to diastolic blood pressure, plasma triglyceride
concentration, low-density lipoprotein (LDL) and high-density
lipoprotein (HDL) cholesterol concentrations, and the glucose and
insulin responses to oral glucose.
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, it was not possible to
determine whether insulin resistance (SSPG), or some variable related
to SSPG, was linked to CVD. Consequently, we ascertained the
relationship between SSPG, the variables related to it as seen in Table 2, and CVD. The results of this analyses are seen in Table 3, and demonstrate the presence of a
significant univariate relationship between CVD and diastolic blood
pressure, triglyceride and HDL cholesterol concentrations, SSPG,
and the plasma glucose and insulin responses to the glucose
challenge.
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was attributable to insulin resistance, as
differentiated from the metabolic abnormalities shown in Table 2 to be
linked to this defect. This was done by comparing the degree to which
SSPG and each of the relevant individual variables defined in Table 3
predicted CVD. These results are shown in Table 4, and it is apparent that SSPG remained
significantly related to CVD when compared with any of the other
individual CVD risk factors. Furthermore, it can be seen that SSPG was
the only variable that remained significantly related to CVD when all
of the significant factors from Table 3 were entered into the model.
Because SSPG and the insulin response are highly correlated (r =
0.83, P < 0.001), insulin response was not employed in
the regression analyses shown in Table 4. However, essentially similar
results were seen when SSPG was replaced by insulin response.
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Discussion |
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The results shown in Fig. 1 indicate that the development of
hypertension and CVD segregated as a function of degree of insulin
resistance (SSPG). Either CVD or hypertension developed in nine
subjects (18%) in the tertile with the highest SSPG values, compared
to four from the middle (8%), and none from the bottom tertile during
the period of follow-up. Focusing on CVD alone, it is apparent that
seven of the eight subjects who developed CVD during the period of
observation were in the most insulin-resistant tertile. These data
provide substantial support for the view that the presence of insulin
resistance identifies a subset of the population who will develop CVD
over a relatively short time period.
On the other hand, the data in Table 1 clearly demonstrate that
the tertile of the most insulin-resistant subjects share a variety of
known risk factors for CVD. Consequently, any effort to identify
insulin resistance as the predictor of the observed CVD events must
take these other factors into account. This analysis was performed, and
results from Table 2 identify six CVD risk factors that were
independently related to SSPG (adjusting for differences in age,
gender, BMI and history of smoking and activity level): diastolic blood
pressure, triglyceride and LDL and HDL cholesterol
concentrations, and the plasma glucose and insulin responses to oral
glucose. Furthermore, the results in Table 3 show that SSPG, as well as
all of the above variables (with the exception of LDL cholesterol) were
significantly correlated with a CVD event.
The information in Tables 2 and 3 were then used in multiple logistic
regression analysis with CVD as the outcome, in which SSPG was paired
with each of the other variables significantly related to CVD. The
results of this analysis are given in Table 4, and show that SSPG was
the only independent predictor of CVD. When the plasma insulin response
to oral glucose was substituted for SSPG in this analysis, the results
were quite similar. Thus, when either SSPG or the insulin response were
taken into account, none of the other variables associated with SSPG
were independently related to CVD events.
Measures of insulin resistance and insulin response were highly correlated in this study (r = 0.83). Consequently, using conventional statistical techniques to decide which of these two variables is the best predictor of CVD is not without problems. At the least, it is necessary that two highly related variables are similar in terms of the inter- and intraindividual variability to make such approaches valid. This is certainly not the case as regards determination of insulin resistance and plasma insulin response to oral glucose. The method used to quantify insulin resistance in this study is somewhat complicated to perform, but provides a precise measure of a specific physiological function that varied from person to person by <10% in 75% of subjects studied on two occasions (22). Although determination of the plasma insulin response to oral glucose is much simpler, it represents a complex function of differences in degree of insulin resistance, pancreatic B-cell function, and peripheral insulin catabolism. As such, it should not be surprising that the plasma insulin concentration, measured 120 min after oral glucose on two occasions within 48 h, varied by >30% in half of those studied (23). Given the difficulties in attempting to differentiate between insulin resistance and compensatory hyperinsulinemia on a statistical basis as the independent risk factor for CVD, we think the only prudent conclusion to draw from this prospective study is that insulin resistance and/or compensatory hyperinsulinemia are predictors of CVD.
Finally, although the results of the present prospective study demonstrate that resistance to insulin-mediated glucose disposal and/or compensatory hyperinsulinemia predict the development of CVD independently of other known risk factors, certain caveats must be emphasized. The experimental population only consisted of 147 volunteers, and hard clinical end points were only seen in 13 subjects and CVD only in 8. On the other hand, neither high blood pressure nor CVD developed in patients in the low SSPG tertile, whereas approximately 1 out of 5 middle-aged volunteers in the highest SSPG tertile developed high blood pressure or had a CVD event within 5 yr. The total number of events may have been modest, but their distribution strongly supports the view that being insulin resistant is a powerful predictor of subsequent CVD.
In conclusion, in this study we have determined the development of hypertension or CVD in a group of healthy volunteers divided into tertiles on the basis of their degree of insulin resistance. At baseline, the most insulin-resistant tertile was shown to have a cluster of risk factors for the two clinical end points, and the correlation between degree of insulin resistance and these CVD risk factors was highly significant. During follow-up period of approximately 5 yr, 18% of the most insulin-resistant group had developed either high blood pressure or had a CVD event. Finally, insulin resistance and/or compensatory hyperinsulinemia were found to predict CVD independently of the other risk factors shared by individuals with these defects.
Received March 11, 1998.
Revised April 20, 1998.
Accepted April 24, 1998.
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