Background Prospective studies suggest that hyperinsulinemiamay be an important risk factor for ischemic heart disease.However, it has not been determined whether plasma insulin levelsare independently related to ischemic heart disease after adjustmentfor other risk factors, including plasma lipoprotein levels.
Methods In 1985 we collected blood samples from 2103 men fromsuburbs of Quebec City, Canada, who were 45 to 76 years of ageand who did not have ischemic heart disease. A first ischemicevent (angina pectoris, acute myocardial infarction, or deathfrom coronary heart disease) occurred in 114 men (case patients)between 1985 and 1990. Each case patient was matched for age,body-mass index, smoking habits, and alcohol consumption witha control selected from among the 1989 men who remained freeof ischemic heart disease during follow-up. After excludingmen with diabetes, we compared fasting plasma insulin and lipoproteinconcentrations at base line in 91 case patients and 105 controls.
Results Fasting insulin concentrations at base line were 18percent higher in the case patients than in the controls (P<0.001).Logistic-regression analysis showed that the insulin concentrationremained associated with ischemic heart disease (odds ratiofor ischemic heart disease with each increase of 1 SD in theinsulin concentration, 1.7; 95 percent confidence interval,1.3 to 2.4) after adjustment for systolic blood pressure, useof medications, and family history of ischemic heart disease.Further adjustment by multivariate analysis for plasma triglyceride,apolipoprotein B, low-density lipoprotein cholesterol, and high-densitylipoprotein cholesterol concentrations did not significantlydiminish the association between the insulin concentration andthe risk of ischemic heart disease (odds ratio, 1.6; 95 percentconfidence interval, 1.1 to 2.3).
Conclusions High fasting insulin concentrations appear to bean independent predictor of ischemic heart disease in men.
Insulin resistance and hyperinsulinemia are conditions knownto be associated with hypertriglyceridemia and low high-densitylipoprotein (HDL) cholesterol concentrations.1,2 Four prospectivestudies, in which fasting plasma insulin concentrations wereused as an index of insulin sensitivity, found that elevatedinsulin levels are associated with an increased risk of ischemicheart disease in men,3,4,5,6 but this finding has not been confirmedin all studies.7
Whether the relation between hyperinsulinemia and ischemic heartdisease is independent of related risk factors, such as hypertriglyceridemia,low HDL cholesterol concentrations, and hypertension, is notclear, however. Fontbonne and colleagues8,9,10 reported thathyperinsulinemia was not associated with an increased risk ofischemic heart disease unless accompanied by elevated plasmatriglyceride concentrations. Results from the Caerphilly prospectivestudy also suggested that the risk associated with hyperinsulinemiawas not independent of concomitant variations in triglycerideconcentrations.6 We examined this issue by measuring fastingplasma insulin levels in men with no evidence of ischemic heartdisease at study entry, in some of whom ischemic heart diseasedeveloped during the subsequent five years. The men with ischemicheart disease were compared with a group of matched controlswho remained free of such disease during the same period.
Methods
Study Cohort and Follow-Up
The Quebec Cardiovascular Study cohort has been described indetail previously.11,12 Briefly, 4637 men from 35 to 64 yearsof age, almost all of French Canadian descent, were recruitedin 1973 from seven counties in the Quebec City, Canada, metropolitanarea for a study of risk factors for cardiovascular disease,including nonfasting cholesterol concentrations. Men with clinicalevidence of ischemic heart disease at entry (n = 266) were excludedfrom further follow-up in the study. Subsequent evaluationswere carried out in 1974 and 1975, 1980, and 1985. From 1973through 1985, 371 men died. In 1985, further evaluation of riskfactors, including the fasting lipoprotein–lipid profile,was performed in 2443 (61 percent) of the remaining 4000 menscreened in 1973. Among the other 1557 men, 10 percent couldnot be located in 1985, 19 percent came to the clinic in a nonfastingstate, and 71 percent either declined to participate or wereevaluated in a nonfasting state at their homes by nurses participatingin the project.
In 1990 and 1991, all participants were contacted by mail andinvited to answer a short, standardized questionnaire coveringsmoking habits, use of medication, history of cardiovasculardisease, and diabetes mellitus. For those who reported suchdiseases and those who had died, all hospital charts were reviewed.For those who reported exertional angina and who were not hospitalized,a study cardiologist obtained the history to ascertain the characteristicsof the angina. Telephone calls were made to participants whodid not answer a second letter or, if this was unsuccessful,to a close family member.
Data on mortality were obtained for 99 percent of the entirecohort and data on morbidity for 96 percent. Analyses performedwith the 1973 data revealed that the age distribution of the2443 participants tested in 1985 was representative of the 1973cohort and that there was no significant difference in mortalitydue to ischemic heart disease between the 2443 participantsand the 1557 nonparticipants. Men who had ischemic heart diseasein 1985 (n = 253) were excluded; a complete risk-factor profilewas obtained for 2103 of the men who were free of ischemic heartdisease in 1985.12
Definition of Events
Criteria for the diagnosis of a first ischemic event includedexertional angina, coronary insufficiency,13 nonfatal myocardialinfarction, and death from coronary disease,14 as previouslydescribed.11,12 Confirmation of myocardial infarction requireddiagnostic electrocardiographic changes or two of the threefollowing criteria: the presence of symptoms, elevations incardiac-enzyme levels, or ischemic electrocardiographic changes.The diagnosis of exertional angina was based on typical symptomsof retrosternal squeezing or pressure-type discomfort occurringon exertion and relieved by rest, nitroglycerin, or both. Coronaryinsufficiency was defined as typical retrosternal chest painlasting at least 15 minutes and associated with transient ischemicchanges on the electrocardiogram (Minnesota code 5-1 or 5-2),but without elevation in the level of creatine kinase. All electrocardiogramswere interpreted by the same cardiologist, who was unaware ofthe participants' risk profile. Criteria for classifying a deathas due to coronary disease included confirmation of the diagnosison the death certificate or an autopsy report confirming thepresence of coronary disease and the absence of noncardiac diseasethat could explain death. Myocardial infarction was consideredfatal if death occurred within four weeks after the event orif myocardial infarction was diagnosed at autopsy. Myocardialinfarction and death related to ischemic heart disease wereconfirmed by data from the Provincial Death Registry. Informedconsent was obtained from the subjects to review the relevanthospital files. Autopsies were performed in about a third ofthe patients who died.
Evaluation of Risk Factors
In 1985, data on demographic and lifestyle variables, medicalhistory, and medication use were obtained by means of a standardizedquestionnaire administered by trained nurses and further reviewedby a physician. Each subject's weight and height were recorded.Resting blood pressure was measured after a five-minute restwith the patient sitting up; phase I and phase V of the Korotkoffsounds were used to measure systolic and diastolic blood pressure,respectively. The mean of two blood-pressure measurements obtainedfive minutes apart was used in the analyses. Information compiledfrom the questionnaire included family and personal historyof diabetes, smoking habits, alcohol consumption, and use ofmedications. The use of hypolipidemic drugs was not very commonin 1985; about 1 percent of the cohort received such therapy.The men in whom ischemic heart disease developed during follow-upwere more likely than those who remained free of ischemic heartdisease to use beta-blockers (11 percent vs. 6.5 percent) anddiuretics (7.5 percent vs. 2.8 percent). Alcohol intake wascomputed from the number of ounces of each type of beverage(beer, wine, or spirits) consumed per week and then standardizedas an absolute quantity of alcohol (1 oz = 22.5 g).15 Men wereclassified as having a family history of ischemic heart diseaseif they had at least one parent or sibling with a history ofischemic heart disease.
Matching Procedures
Of the initial sample of 2103 men who were free of clinicalsigns of ischemic heart disease in 1985, ischemic heart diseasedeveloped in 114 during five years of follow-up, which endedin September 1990.12 Each subject with confirmed ischemic heartdisease (case patient) was matched with a control subject selectedfrom among the 1989 men who had no clinical evidence of ischemicheart disease during follow-up. Subjects were matched on thebasis of age, cigarette smoking, body-mass index (the weightin kilograms divided by the square of the height in meters),and weekly alcohol intake. The mean differences in matched case–controlpairs were 0.6 year for age, 0.2 for body-mass index, and 0.2oz (4.5 g) per week for alcohol intake. The mean differencewithin pairs of cigarette smokers was 0.3 cigarette per day;all nonsmokers were matched with nonsmokers. Eight men wereexcluded from the analysis either because they had such highvalues for the number of cigarettes smoked per day that no matchedcontrol was available or because they had missing values forthe insulin concentration. Men who reported having diabetesmellitus or who were receiving hypoglycemic therapy at the base-lineevaluation (15 case patients and 1 control) were also excluded.
Laboratory Analyses
After the subjects had fasted for 12 hours, blood samples wereobtained from an antecubital vein while the subjects were sitting.A tourniquet was used but released before the withdrawal ofblood into Vacutainer tubes (Becton Dickinson, Mountain View,Calif.) containing EDTA. Plasma was separated from blood cellsby centrifugation and immediately used for measurement of lipidsand apolipoprotein B. Aliquots of fasting plasma were frozenat the time of collection for the subsequent assessment of insulinlevels. Plasma cholesterol and triglyceride concentrations weredetermined with an AutoAnalyzer II (Technicon Instruments, Tarrytown,N.Y.), as previously described.16 HDL cholesterol was measuredin the supernatant after precipitation of apolipoprotein B–containinglipoproteins with heparin–manganese chloride.17 Low-densitylipoprotein (LDL) cholesterol concentrations were estimatedwith the equation of Friedewald et al.18 for men with triglycerideconcentrations below 400 mg per deciliter (4.5 mmol per liter).Plasma apolipoprotein B concentrations were measured by therocket-immunoelectrophoresis method of Laurell,19 as describedpreviously.16 Serum standards for the apolipoprotein assay wereprepared in our laboratory and calibrated against serum samplesfrom the Centers for Disease Control and Prevention. The standardswere lyophilized and stored at -85°C until use. Peak heightsbetween 15 and 35 mm yielded linear and reliable results. Thecoefficients of variation for cholesterol, HDL cholesterol,triglyceride, and apolipoprotein measurements were all lessthan 3 percent.
Fasting insulin concentrations were measured with a commercialdouble-antibody radioimmunoassay (human-insulin–specificradioimmunoassay method, LINCO Research, St. Louis). In thisassay insulin shows little cross-reactivity (<0.2 percent)with human proinsulin.20 The coefficients of variation were3.5 percent for lower insulin concentrations (8 to 25 µUper milliliter [50 to 150 pmol per liter]), and 5.2 percentfor higher concentrations (33 to 83 µU per milliliter[200 to 500 pmol per liter]).
Statistical Analysis
Student's t-tests were used to compare mean values at base linein men in whom ischemic heart disease developed with those inthe men who remained free of such disease during the five-yearfollow-up. Differences in frequency were tested by chi-squareanalysis. Associations among variables were assessed with thePearson and Spearman correlation coefficients for parametricand nonparametric variables, respectively. Preliminary analysesshowed that the relation between metabolic risk factors andischemic heart disease was linear across their distribution.Logistic-regression analyses were therefore performed with plasmalipid, lipoprotein, and apolipoprotein concentrations includedas continuous variables.
Odds ratios for ischemic heart disease were computed as thechange in the risk of disease associated with an increase of1 SD in the concentration of the substance in question, accordingto unconditional logistic-regression analysis. Odds were adjustedfor the confounding effects of systolic blood pressure, useof medications, and family history of ischemic heart disease.
The study design eliminated the association between age, smoking,obesity, and alcohol intake, on the one hand, and the risk ofischemic heart disease, on the other. Inclusion of these variablesin the logistic models had no effect on the estimates of theassociation between other risk factors and ischemic heart disease.In addition, the use of conditional logistic regression, whichtakes into consideration the potentially confounding effectsof the variables used to match case patients and controls, yieldedresults that were essentially the same as those of the unconditionalregression analyses (data not shown).
For these reasons, variables used in the matching procedurewere not included in the analyses. Multiplicative terms of interactionwere also used to assess the potential interactions betweenfasting insulin concentrations and lipid, lipoprotein, and apolipoproteinconcentrations in relation to the risk of ischemic heart disease.All statistical tests were performed with the SAS software package(SAS Institute, Cary, N.C.).
Results
In the overall sample of 2103 men who were free of ischemicheart disease at study entry, the prevalence of diabetes mellituswas higher among the men in whom ischemic heart disease subsequentlydeveloped than among those who remained free of ischemic heartdisease (16 percent vs. 4 percent, P<0.001). After the exclusionof patients with diabetes from the matched analysis, the 91nondiabetic men in whom ischemic heart disease developed alsohad higher base-line plasma total cholesterol, LDL cholesterol,triglyceride, and apolipoprotein B concentrations than the 105matched controls who remained free of disease (Table 1). A significantdifference in the insulin concentration in fasting subjectswas observed between case patients and controls. Men in whomischemic heart disease developed had base-line insulin levelswhile fasting that were 18 percent higher than those of menwho had no ischemic heart disease (P<0.001). The ratio oftotal cholesterol to HDL cholesterol was also markedly higher(18 percent higher) among the men who subsequently had ischemicheart disease.
Table 1. Base-Line Characteristics of 91 Men with Clinical Manifestations of Ischemic Heart Disease (Case Patients) and 105 Matched Controls from the Quebec Cardiovascular Study.
We investigated the association between the insulin concentrationand the risk of ischemic heart disease, both before and afteradjustment for plasma lipid and apolipoprotein concentrations,using multiple logistic-regression analysis (Table 2). Higherplasma concentrations of insulin were associated with a significantincrease in the risk of ischemic heart disease (odds ratio forischemic heart disease with each increase of 1 SD in the insulinconcentration, 1.7; 95 percent confidence interval, 1.3 to 2.4);this association was independent of systolic blood pressure,medication use, and family history of ischemic heart disease.The odds ratio for ischemic heart disease in patients with higherinsulin concentrations after fasting was essentially unchangedwhen the variables used in matching (age, body-mass index, smokingstatus, and alcohol consumption) were included in the logisticmodel (odds ratio, 2.1; 95 percent confidence interval, 1.4to 3.0). Further adjustment for the potentially confoundingeffects of the triglyceride, LDL cholesterol, HDL cholesterol,and apolipoprotein B concentrations (models 2 through 6 in Table 2)did not substantially weaken the relation between insulinand the risk of ischemic heart disease. Accordingly, the associationbetween the concentrations of LDL cholesterol, triglycerides,and apolipoprotein B and the total:HDL cholesterol ratio, onthe one hand, and the risk of ischemic heart disease, on theother, remained significant after adjustment for insulin levels.Finally, the relation between plasma insulin concentrationsand the risk of ischemic heart disease was not altered significantlywhen the additive contribution of the triglyceride, HDL cholesterol,and apolipoprotein B concentrations to risk was accounted for(model 7); this finding suggests that the increased risk ofischemic heart disease associated with hyperinsulinemia wasat least partly independent of variations in plasma lipoproteinconcentrations.
Table 2. Relation between Insulin Concentrations at Base Line in Fasting Subjects and the Subsequent Development of Ischemic Heart Disease, before and after Adjustment for Plasma Lipid and Apolipoprotein B Levels, from Seven Models in the Multivariate Logistic Analysis.
The potential interaction between hyperinsulinemia and plasmalipoproteins was tested by subdividing the sample into thirdsaccording to insulin concentration and either low or high triglyceridelevels, apolipoprotein B levels, and total:HDL cholesterol ratios.The results, presented in Figure 1, indicate that the risk ofischemic heart disease associated with hyperinsulinemia didnot appear to be further increased in the presence of elevatedtriglyceride levels (odds ratios for insulin concentrations>15 µU per milliliter [>92 pmol per liter], 5.3in men with triglyceride concentrations below the 50th percentileand 6.7 in men with concentrations at or above the 50th percentile,as compared with the reference group; P<0.001]). Among menwith an elevated total:HDL cholesterol ratio (i.e., one at orabove the 50th percentile), those with high or intermediateinsulin concentrations (>12 µU per milliliter) hadthe greatest increase in risk. Furthermore, men with high plasmainsulin concentrations but with a total:HDL cholesterol ratiobelow 6 (the 50th percentile) were also at greater risk forischemic heart disease than men in the lowest third of the samplewith respect to insulin (odds ratio, 7.1; P= 0.001). Elevatedplasma insulin concentrations were also associated with an increasedrisk of ischemic heart disease among men with low apolipoproteinB concentrations (odds ratio, 3.2; P = 0.04). However, the mostsubstantial increase in the risk of ischemic heart disease wasobserved among men with elevated concentrations of both insulinand apolipoprotein B (odds ratio, 11.0; P<0.001). Althougha test for multiplicative interaction between apolipoproteinB and insulin did not indicate significance (P = 0.2), the absoluteeffect of hyperinsulinemia on ischemic heart disease appearedto depend largely on the apolipoprotein B concentration.
Figure 1. Odds Ratios for Ischemic Heart Disease According to Plasma Insulin and Triglyceride Concentrations, Total:HDL Cholesterol Ratios, and Apolipoprotein B Concentrations.
Insulin was measured after subjects had fasted for 12 hours. The median triglyceride concentration (150 mg per deciliter [1.7 mmol per liter]), total:HDL cholesterol ratio (6.0), and apolipoprotein B concentration (119 mg per deciliter) were used to define men with either low levels (below the 50th percentile) or high levels (at or above the 50th percentile) for these variables. The results of tests for multiplicative interactions did not reach significance at the 0.05 level for any of the combinations. P values are for comparisons with the reference group, which was assigned an odds ratio of 1.0. To convert values for insulin to picomoles per liter, multiply by 6.
Although statistically significant, the associations betweenplasma insulin concentrations in fasting subjects and body-massindex (r = 0.41, P<0.001), triglyceride concentrations (r= 0.23, P = 0.001), apolipoprotein B concentrations (r = 0.16,P = 0.02), HDL cholesterol concentrations (r = -0.28, P<0.001)and the total:HDL cholesterol ratio (r = 0.25, P<0.001) wereof only moderate magnitude; these findings therefore providefurther support for the concept that the risk of ischemic heartdisease associated with hyperinsulinemia appears to be largelyindependent of variations in plasma lipoprotein concentrations.No association was found between plasma insulin concentrationsand systolic or diastolic blood pressure.
Discussion
Our results agree with those of previous prospective investigations,which have found that a high plasma insulin concentration infasting subjects is associated with an increased incidence ofischemic heart disease in nondiabetic men.2,3,4,5,6 The mechanismsresponsible for this association, however, remain speculative.It had been suggested that the risk associated with hyperinsulinemiawas largely explained by the lipid abnormalities that are commonamong men with elevated insulin concentrations.6,8,9,10,21,22Although we found significant associations between insulin levelsin fasting subjects and lipoprotein concentrations, furtheranalyses revealed that the risk of ischemic heart disease relatedto hyperinsulinemia was largely independent of the concomitantdyslipidemic state. A synergistic effect was noted, however,since the combination of hyperinsulinemia and elevated apolipoproteinB concentrations or an increased total:HDL cholesterol ratiosubstantially increased the risk of ischemic heart disease inmen who had both these metabolic alterations.
These results support the notion that hyperinsulinemia may increasethe risk of ischemic heart disease through alterations in metabolicprocesses other than the related dyslipidemia. In this regard,it has been reported that plasma concentrations of plasminogen-activatorinhibitor type 1 are increased in patients with hyperinsulinemicinsulin resistance,23 an alteration that may impair fibrinolysisand increase susceptibility to thrombosis in men with hyperinsulinemia.Furthermore, the concomitant elevation of blood pressure mayalso be a contributing factor,24 although the association betweenhyperinsulinemia and ischemic heart disease in our study wasunchanged by adjustment for blood pressure.
On the other hand, it has been suggested that hyperinsulinemiain persons without diabetes may be a marker for a cluster ofmetabolic abnormalities, including hypertension, dyslipidemia,impaired fibrinolysis, and impaired insulin-mediated glucoseuptake.1 The concept of the insulin-resistance syndrome hasevolved considerably since its introduction by Reaven in 1988,1and it has been suggested that visceral obesity may also bea common component of the cluster of metabolic abnormalitiesfound in insulin-resistant subjects.25,26 We have shown thatpersons in whom overweight is characterized by the accumulationof only small amounts of visceral adipose tissue, as measuredby computed tomography, did not differ substantially from normal-weightcontrols in terms of risk factors for cardiovascular disease.27,28,29Overweight patients in whom there was a large amount of visceraladipose tissue were, on the other hand, characterized by a clusterof metabolic disturbances that included glucose intolerance,hyperinsulinemia, hypertriglyceridemia, elevated apolipoproteinB concentrations, abnormally low HDL cholesterol concentrations,and an elevated total:HDL cholesterol ratio.27,29 Analyses ofthe Paris Prospective Study cohort suggested that the abdomen-to-thighratio, a crude anthropometric estimate of upper-body fat, wasan independent predictor of the risk of death from ischemicheart disease, whereas the insulin concentration in fastingsubjects was no longer independently associated with ischemicheart disease after this variable was controlled for.30 Althoughadditional work is clearly warranted to clarify this issue,the results of our study suggest that the relation of hyperinsulinemiato ischemic heart disease may be largely independent of alterationsin body weight, blood pressure, and plasma lipoprotein concentrations.
The presence of hyperinsulinemia in fasting subjects may thereforeserve as a crude but clinically relevant marker for other metabolicand hemostatic disturbances — namely, visceral obesity,a procoagulant state, and alterations in growth factor levels— all of which are associated with an increased risk ofischemic heart disease.31 However, laboratory standardizationof insulin measurements remains a problem, and there is currentlyno universally accepted criterion for hyperinsulinemia in thefasting state. We believe that it is relevant to raise thisissue, since we used a radioimmunoassay that did not cross-reactwith pro-insulin32; this was not the case in previous prospectivestudies, in which insulin could not be identified as an independentpredictor of ischemic heart disease after adjustment for otherrisk factors. Since an insulin-resistant, hyperinsulinemic stateincreases the risk of type II diabetes mellitus,33 our resultsalso support the notion that maintaining an adequate level ofinsulin sensitivity and low plasma insulin concentrations throughproper diet and exercise habits not only may be of value inpreventing type II diabetes, but also may reduce the risk ofheart disease.
Supported by the National Health Research Development Program,Health and Welfare Canada, by the Heart and Stroke Foundationof Canada, and by Fournier Pharma, Inc. Mr. Lamarche is therecipient of a fellowship from the Medical Research Councilof Canada.
We are indebted to Mr. Paul-Marie Bernard, M.Sc., for his experthelp with the statistical analyses; to Dr. N. Michelle Robitaillefor her important support in the collection of the data; toMiss Louise Fleury and Mr. André Tchernof; and to the4637 participants in the Quebec Cardiovascular Study, whosecooperation made this study possible.
Source Information
From the Lipid Research Center, Laval University Hospital Research Center, Quebec (J.-P.D., B.L., P.M., B.C., S.M., P.-J.L.); and the Department of Medicine, University of Montreal, Montreal (G.R.D.) — both in Canada.
Address reprint requests to Dr. Després at the Lipid Research Center, CHUL Research Center, 2705 Laurier Blvd., Ste.-Foy, QC G1V 4G2, Canada.
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