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Increased 1-hour postload plasma glucose was associated with increased risk of fatal CHD
There was a weak association between insulin levels and risk of CVD
Ruige JB, Assendelft WJJ, Dekker JM et al. Insulin and risk of cardiovascular disease. A meta-analysis. Circulation 1997; 97:996-1001
Objective To examine the relationship between hyperinsulinemiaand CVD, and to identify study characteristics which may modify this relationship in non-diabetic populations. Data sources 17 articles were identified from MEDLINE and Embase, as well as citation tracking. Key words were: insulin, prospective, cohort, follow-up, cardiovascular, MI and electrocardiography. 12 articles provided sufficient information. Study selection Studies were selected if they were prospective, population-based cohort or
nested case-control studies on insulin levels and MI, death from CHD or ECG abnormalities. Data extraction Data pertaining to fasting and non-fasting insulin levels, type of outcome (MI, death from CHD or ECG abnormality) and other potential confounders (mean age of study population, sex, follow-up period, type of insulin assay involved and ethnic background). Associations between insulin and risk of CVD were re-expressed in a uniform manner.
Main results Overall, an increase of 50 pmol/L fasting insulin (equivalent to the difference between the 75th and the 25th percentiles
Increased 1-hour postload plasma glucose was associated with increased risk of fatal CHD Orencia AJ, Daviglus ML, Dyer AR et al. One-hourpostloadplasma glucose and risks of fatal coronary heart disease and stroke among nondiabetic men and women: The Chicago Heart Association Detection Project in Industry (CHA) Study. J Clin Epidemiol 1997; 50:1369-1376
Objective To examine the relationship between plasma glucose level and risk of fatal CHD and stroke among non-diabetic men and women. Design Longitudinal cohort study with mean duration of follow-up of 22 years.
SEPTEMBER 1998
Setting Employees of 84 companies and organizations in the greater Chicago area, IL, USA between 1967 and 1973. Participants 39 573 participants were screened and 9647 were excluded. Women of young age (< 39 years) were excluded as a result
of the general population in the Netherlands) was associated with a RR of CVD of 1.18 (95% CI 1.08-1.29). An increase of 250 pmol/L non-fasting insulin was associated with a RR of 1.25 (95% CI 1.03-1.51). There was, however. significant heterogeneity across studies of non-fasting insulin (P = 0.007). Studies of non-fasting insulin among people of nonwhite and white ethnic origin yielded RRs of 1.04 (95% CI 0.93-1.16) and 1.43 (95% CI 1.23-1.66) respectively. Since ethnic background was highly correlated with mean age and type of outcome studied, conclusions regarding the study characteristic responsible for this heterogeneity could not be drawn. Studies of white populations were conducted among older subjects with MI and CHD as outcomes. There was some evidence of heterogeneity among studies of both fasting and non-fasting insulin in white populations (P = 0.09 and 0.11, respectively).
Conclusions There was a weak but significant association between fasting and nonfasting insulin levels and risk of CVD. The relationship may have been modified by both ethnic background and by the type of insulin assay involved. of insufficient cases of fatal CHD and stroke (n = 7836). Other exclusions included clinical diabetes (n = 814), pre-existing CHD (n = 109) and missing follow-up data (n = 100). A further 1674 participants were excluded because blood for the 1-hour postload glucose determination was drawn > 65 min following the 50 g glucose load or the time delay was missing or implausible. A further 1486 participants were excluded due to the potential effect of antihypertensive therapy (mainly diuretics) on glucose. A total of 26 753 participants (72.9% men) were included in the analysis. Men were aged 18-74 while women were aged 40-74 years.
Assessment of risk factors Demographic data, smoking history, previous medical diagnoses and treatments, body-mass index (BMI), a single casual supine BP, non-fasting serum total cholesterol and plasma glucose determination 1 h following a 50 g oral glucose load.
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
67
Main outcome measures Fatal CHD, stroke, and CVD and all-cause mortality. Main results Following adjustment for age within strata, race, education, systolic BP, cigarette smoking, serum cholesterol, BMI and ECG abnormalities, a 40 mg/dL increase in 1-hour postload glucose was associated with increasing risk of death
:OMMENTAR'~ The relationship between plasma glucose levels and the risk of CVD is a matter of considerable debate. The study by Orencia and colleagues indicates that 1-hour postload plasma glucose is related to longterm risk of fatal CVD in non-diabetic middle-aged men and women as well as in elderly women, even after multivariate adjustment for a series of traditional risk factors. A number of study limitations have been discussed by the authors in their original manuscript. The advantage of investigatmg the study outcomes over a long-term follow-up period is counterbalanced by the lack of information on incident diabetes during that period. Since diabetes mellitus is an important risk factor for CVD, and because a significant proportton of participants with high postload plasma glucose at baseline may have converted to diabetes during follow-up, it is not possible based on the available data to determine whether the risk of CVD attrtbuted to increased 1-hour glucose levels reflects in fact the risk attributable to diabetes. Similarly, it could be hypothesized that most of the CVD risk is seen in individuals with glucose intolerance at entry and that 1-hour plasma glucose may not be associated with a significant increase in the risk of CVD across a 'normal' spectrum of glucose tolerance. Additional studies are therefore clearly needed to determine whether plasma glucose per se, glucose intolerance and/or diabetes mellitus are responsible for the equivocal association between plasma glucose levels and the risk of CVD. To say that the association between plasma insulin levels and the risk of CVD is controversial is an understatement. For many clinicians and researchers, the fact that the 'cure' for diabetes mellitus may be linked to
68
from CHD in men and women aged 40-59 years and women aged 60-74 years (RR 1.07, 1.14, 1.18; all P < 0.05, respectively). The association of increasing glucose with death due to stroke was significant in men aged 40-59 years (RR 1.19, P < 0.01) and 60-74 years; (RR 1.23, P < 0.05). The association with increasing glucose and CVD was significant among men aged 40-59 years (RR 1.09, P < 0.001) and women aged
60-74 years (RR 1.18; P < 0.01). A 40 mg/dL increase in 1-hour postload glucose was associated with increasing risk of all-cause mortality in all but the youngest men (18-39 years) (RR 1.09-1.15).
an increased risk seems inconceivable. While studies have suggested that endogenous hyperinsulinemia may be associated with an increased risk of CVD, such findings certainly do not provide information as to whether exogenous insulin has similar proatherogenic properties. The meta-analysis performed by Ruige and colleagues suggests that fasting and/or non-fasting hyperinsulinemia is associated with a weak, but significant increase in the risk of CVD. It must be stressed that the analysis was based on data obtained from studies in nondiabetic populations only and, therefore, one cannot infer that endogenous (and even more so exogenous) hyperinsulinemia shows similar associations with CVD in populations of diabetic patients. There is also a clear lack of emphasis on the fact that the reported association between plasma insulin levels and the risk of CVD is based on the multivariate association between these two variables in each of the indivtdual studies considered in this meta-analysis. Hence, from a 'pure' epidemiologic and statistical standpoint, the association between plasma msulin and the risk of CVD may appear as weak, but from a clinical perspective, the results suggest that measuring plasma insulin levels may provide more information on the risk than any combination of traditional risk factors. The authors noted a significant heterogeneity between non-white and white populations. The type of insulin assay (specific vs non-specific) also appeared as a potential source of heterogeneity between studies. In other words, the lack of a consensus on the potentially pro-atherogenic properties of insulin in previous 'narrative' reviews may have arisen from the fact that the data from different populations (male vs female, white vs non-white, young vs old, diabetic vs non-diabetic) and based on different insulin assays have yielded inconsistent results.
The primary objective of epidemiologic studies, that is, to identify markers of an outcome, is quite frequently entangled with our need to justify the presence of a significant relationship on the basis of a causal association between the marker and the outcome. Clearly, the meta-analysis by Ruige and colleagues does not resolve the issue of whether hyperinsulinemia per se causes CVD. It may be that hyperinsulinemia reflects a state of insulin resistance, which in turn ts associated with a metabolic condition highly predictive of an increased risk of CVD? In that context, hyperinsulinemia would only act as a marker of a cluster of htgh atherogenic risk factors. On the other hand, hyperinsulinemia has been assooated with pro-thrombogenic changes which, per se, may increase the susceptibility to CVDf Should plasma insulin levels (fasting or non-fasting) be measured systematically in all individuals in primary prevention of CVD? This meta-analysis alone does not provide an answer to this very important question. However, t h e r e is accumulating evidence, including results of this meta-analysis, that plasma insulin levels - possibly as a marker of additional pro-atherogenic and thrombogenic metabolic complications - could improve our ability to predict the onset of CVD, at least in selected populations, Beno~t Lamarche, PhD Department of Nutrition and CHUL Research Center Caval University Ste-Foy, Quebec, Canada
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
Conclusion Increased 1-hour postload plasma glucose was associated with increased risk of fatal CHD and stroke among middle-aged and older non-diabetic men and women.
O t h e r sources 1. Laakso M. Curt Opin Lipido11996; 7: 217-226 2. Juhan-Vague I, Alessi MC, Vague P, Diabetologia 1991; 34:457-462
SEPTEMBER 1998
Ruige JB, Assendelft WJJ, Dekker JM et al. Insulin and risk of cardiovascular disease. A meta-analysis. Circulation 1997; 97:996-1001
Objective To examine the relationship between hyperinsulinemiaand CVD, and to identify study characteristics which may modify this relationship in non-diabetic populations. Data sources 17 articles were identified from MEDLINE and Embase, as well as citation tracking. Key words were: insulin, prospective, cohort, follow-up, cardiovascular, MI and electrocardiography. 12 articles provided sufficient information. Study selection Studies were selected if they were prospective, population-based cohort or
nested case-control studies on insulin levels and MI, death from CHD or ECG abnormalities. Data extraction Data pertaining to fasting and non-fasting insulin levels, type of outcome (MI, death from CHD or ECG abnormality) and other potential confounders (mean age of study population, sex, follow-up period, type of insulin assay involved and ethnic background). Associations between insulin and risk of CVD were re-expressed in a uniform manner.
Main results Overall, an increase of 50 pmol/L fasting insulin (equivalent to the difference between the 75th and the 25th percentiles
Increased 1-hour postload plasma glucose was associated with increased risk of fatal CHD Orencia AJ, Daviglus ML, Dyer AR et al. One-hourpostloadplasma glucose and risks of fatal coronary heart disease and stroke among nondiabetic men and women: The Chicago Heart Association Detection Project in Industry (CHA) Study. J Clin Epidemiol 1997; 50:1369-1376
Objective To examine the relationship between plasma glucose level and risk of fatal CHD and stroke among non-diabetic men and women. Design Longitudinal cohort study with mean duration of follow-up of 22 years.
SEPTEMBER 1998
Setting Employees of 84 companies and organizations in the greater Chicago area, IL, USA between 1967 and 1973. Participants 39 573 participants were screened and 9647 were excluded. Women of young age (< 39 years) were excluded as a result
of the general population in the Netherlands) was associated with a RR of CVD of 1.18 (95% CI 1.08-1.29). An increase of 250 pmol/L non-fasting insulin was associated with a RR of 1.25 (95% CI 1.03-1.51). There was, however. significant heterogeneity across studies of non-fasting insulin (P = 0.007). Studies of non-fasting insulin among people of nonwhite and white ethnic origin yielded RRs of 1.04 (95% CI 0.93-1.16) and 1.43 (95% CI 1.23-1.66) respectively. Since ethnic background was highly correlated with mean age and type of outcome studied, conclusions regarding the study characteristic responsible for this heterogeneity could not be drawn. Studies of white populations were conducted among older subjects with MI and CHD as outcomes. There was some evidence of heterogeneity among studies of both fasting and non-fasting insulin in white populations (P = 0.09 and 0.11, respectively).
Conclusions There was a weak but significant association between fasting and nonfasting insulin levels and risk of CVD. The relationship may have been modified by both ethnic background and by the type of insulin assay involved. of insufficient cases of fatal CHD and stroke (n = 7836). Other exclusions included clinical diabetes (n = 814), pre-existing CHD (n = 109) and missing follow-up data (n = 100). A further 1674 participants were excluded because blood for the 1-hour postload glucose determination was drawn > 65 min following the 50 g glucose load or the time delay was missing or implausible. A further 1486 participants were excluded due to the potential effect of antihypertensive therapy (mainly diuretics) on glucose. A total of 26 753 participants (72.9% men) were included in the analysis. Men were aged 18-74 while women were aged 40-74 years.
Assessment of risk factors Demographic data, smoking history, previous medical diagnoses and treatments, body-mass index (BMI), a single casual supine BP, non-fasting serum total cholesterol and plasma glucose determination 1 h following a 50 g oral glucose load.
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
67
Main outcome measures Fatal CHD, stroke, and CVD and all-cause mortality. Main results Following adjustment for age within strata, race, education, systolic BP, cigarette smoking, serum cholesterol, BMI and ECG abnormalities, a 40 mg/dL increase in 1-hour postload glucose was associated with increasing risk of death
:OMMENTAR'~ The relationship between plasma glucose levels and the risk of CVD is a matter of considerable debate. The study by Orencia and colleagues indicates that 1-hour postload plasma glucose is related to longterm risk of fatal CVD in non-diabetic middle-aged men and women as well as in elderly women, even after multivariate adjustment for a series of traditional risk factors. A number of study limitations have been discussed by the authors in their original manuscript. The advantage of investigatmg the study outcomes over a long-term follow-up period is counterbalanced by the lack of information on incident diabetes during that period. Since diabetes mellitus is an important risk factor for CVD, and because a significant proportton of participants with high postload plasma glucose at baseline may have converted to diabetes during follow-up, it is not possible based on the available data to determine whether the risk of CVD attrtbuted to increased 1-hour glucose levels reflects in fact the risk attributable to diabetes. Similarly, it could be hypothesized that most of the CVD risk is seen in individuals with glucose intolerance at entry and that 1-hour plasma glucose may not be associated with a significant increase in the risk of CVD across a 'normal' spectrum of glucose tolerance. Additional studies are therefore clearly needed to determine whether plasma glucose per se, glucose intolerance and/or diabetes mellitus are responsible for the equivocal association between plasma glucose levels and the risk of CVD. To say that the association between plasma insulin levels and the risk of CVD is controversial is an understatement. For many clinicians and researchers, the fact that the 'cure' for diabetes mellitus may be linked to
68
from CHD in men and women aged 40-59 years and women aged 60-74 years (RR 1.07, 1.14, 1.18; all P < 0.05, respectively). The association of increasing glucose with death due to stroke was significant in men aged 40-59 years (RR 1.19, P < 0.01) and 60-74 years; (RR 1.23, P < 0.05). The association with increasing glucose and CVD was significant among men aged 40-59 years (RR 1.09, P < 0.001) and women aged
60-74 years (RR 1.18; P < 0.01). A 40 mg/dL increase in 1-hour postload glucose was associated with increasing risk of all-cause mortality in all but the youngest men (18-39 years) (RR 1.09-1.15).
an increased risk seems inconceivable. While studies have suggested that endogenous hyperinsulinemia may be associated with an increased risk of CVD, such findings certainly do not provide information as to whether exogenous insulin has similar proatherogenic properties. The meta-analysis performed by Ruige and colleagues suggests that fasting and/or non-fasting hyperinsulinemia is associated with a weak, but significant increase in the risk of CVD. It must be stressed that the analysis was based on data obtained from studies in nondiabetic populations only and, therefore, one cannot infer that endogenous (and even more so exogenous) hyperinsulinemia shows similar associations with CVD in populations of diabetic patients. There is also a clear lack of emphasis on the fact that the reported association between plasma insulin levels and the risk of CVD is based on the multivariate association between these two variables in each of the indivtdual studies considered in this meta-analysis. Hence, from a 'pure' epidemiologic and statistical standpoint, the association between plasma msulin and the risk of CVD may appear as weak, but from a clinical perspective, the results suggest that measuring plasma insulin levels may provide more information on the risk than any combination of traditional risk factors. The authors noted a significant heterogeneity between non-white and white populations. The type of insulin assay (specific vs non-specific) also appeared as a potential source of heterogeneity between studies. In other words, the lack of a consensus on the potentially pro-atherogenic properties of insulin in previous 'narrative' reviews may have arisen from the fact that the data from different populations (male vs female, white vs non-white, young vs old, diabetic vs non-diabetic) and based on different insulin assays have yielded inconsistent results.
The primary objective of epidemiologic studies, that is, to identify markers of an outcome, is quite frequently entangled with our need to justify the presence of a significant relationship on the basis of a causal association between the marker and the outcome. Clearly, the meta-analysis by Ruige and colleagues does not resolve the issue of whether hyperinsulinemia per se causes CVD. It may be that hyperinsulinemia reflects a state of insulin resistance, which in turn ts associated with a metabolic condition highly predictive of an increased risk of CVD? In that context, hyperinsulinemia would only act as a marker of a cluster of htgh atherogenic risk factors. On the other hand, hyperinsulinemia has been assooated with pro-thrombogenic changes which, per se, may increase the susceptibility to CVDf Should plasma insulin levels (fasting or non-fasting) be measured systematically in all individuals in primary prevention of CVD? This meta-analysis alone does not provide an answer to this very important question. However, t h e r e is accumulating evidence, including results of this meta-analysis, that plasma insulin levels - possibly as a marker of additional pro-atherogenic and thrombogenic metabolic complications - could improve our ability to predict the onset of CVD, at least in selected populations, Beno~t Lamarche, PhD Department of Nutrition and CHUL Research Center Caval University Ste-Foy, Quebec, Canada
EVIDENCE-BASED CARDIOVASCULAR MEDICINE
Conclusion Increased 1-hour postload plasma glucose was associated with increased risk of fatal CHD and stroke among middle-aged and older non-diabetic men and women.
O t h e r sources 1. Laakso M. Curt Opin Lipido11996; 7: 217-226 2. Juhan-Vague I, Alessi MC, Vague P, Diabetologia 1991; 34:457-462
SEPTEMBER 1998