Background Type 2 (non-insulin-dependent) diabetes is associatedwith a marked increase in the risk of coronary heart disease.It has been debated whether patients with diabetes who havenot had myocardial infarctions should be treated as aggressivelyfor cardiovascular risk factors as patients who have had myocardialinfarctions.
Methods To address this issue, we compared the seven-year incidenceof myocardial infarction (fatal and nonfatal) among 1373 nondiabeticsubjects with the incidence among 1059 diabetic subjects, allfrom a Finnish population-based study.
Results The seven-year incidence rates of myocardial infarctionin nondiabetic subjects with and without prior myocardial infarctionat base line were 18.8 percent and 3.5 percent, respectively(P<0.001). The seven-year incidence rates of myocardial infarctionin diabetic subjects with and without prior myocardial infarctionat base line were 45.0 percent and 20.2 percent, respectively(P<0.001). The hazard ratio for death from coronary heartdisease for diabetic subjects without prior myocardial infarctionas compared with nondiabetic subjects with prior myocardialinfarction was not significantly different from 1.0 (hazardratio, 1.4; 95 percent confidence interval, 0.7 to 2.6) afteradjustment for age and sex, suggesting similar risks of infarctionin the two groups. After further adjustment for total cholesterol,hypertension, and smoking, this hazard ratio remained closeto 1.0 (hazard ratio, 1.2; 95 percent confidence interval, 0.6to 2.4).
Conclusions Our data suggest that diabetic patients withoutprevious myocardial infarction have as high a risk of myocardialinfarction as nondiabetic patients with previous myocardialinfarction. These data provide a rationale for treating cardiovascularrisk factors in diabetic patients as aggressively as in nondiabeticpatients with prior myocardial infarction.
Diabetes is associated with a marked increase (by a factor oftwo to four) in the risk of coronary heart disease.1,2,3,4 Clinicallyestablished coronary heart disease itself is associated withan increase in mortality from coronary heart disease by a factorof three to seven, depending on the mode of presentation.5,6The plasma cholesterol level is a strong predictor of the riskof cardiovascular events both in patients with diabetes4,7 andin patients with coronary heart disease.5,6 The high-risk statusof these groups of patients and their need for more aggressivelipid-lowering therapy have been recognized by both the NationalCholesterol Education Program8 and the American Diabetes Association.9
The reduction in plasma lipids recommended by the National CholesterolEducation Program is greater for patients with coronary heartdisease than for patients with diabetes. However, there werediffering opinions among members of the National CholesterolEducation Program panel, with some suggesting that diabeticpatients should have the same intensity of cholesterol-loweringtherapy as patients with coronary heart disease. Thus, thereis controversy about how aggressively to treat cardiovascularrisk factors in patients with diabetes. It has been suggestedthat such patients should be treated as if they had establishedcoronary heart disease.10
Additional interest has focused on the role of lipid-loweringtherapy in reducing coronary heart disease in patients withdiabetes since data on the efficacy of lipid-lowering therapywith simvastatin and pravastatin in patients with both diabetesand preexisting coronary heart disease were published by theScandinavian Simvastatin Survival Study11,12 and the Cholesteroland Recurrent Events study.13 In the Scandinavian SimvastatinSurvival Study,12 lipid-lowering therapy produced a greaterreduction in the rate of coronary events in diabetic subjectsthan in nondiabetic subjects (55 percent vs. 32 percent). However,in the Cholesterol and Recurrent Events study,13 there weresimilar reductions in diabetic and nondiabetic subjects (27percent and 25 percent, respectively).
One way to assess whether patients with diabetes and patientswho already have clinical coronary heart disease have a similarrisk of cardiovascular events is to compare the risk of suchevents in diabetic subjects with and without prior coronaryheart disease with that in nondiabetic subjects with and withoutprior coronary heart disease. In previous reports, the excessrisk of coronary events in patients with prior myocardial infarction(a six-to-sevenfold difference)5,6 was higher than the excessrisk in diabetic patients (a two-to-fourfold difference).1,2,3,4However, comparisons across populations are difficult. Furthermore,diabetic patients are overrepresented among patients with myocardialinfarction,1,2,3,4 and diabetic patients with myocardial infarctionhave a worse prognosis than nondiabetic patients with myocardialinfarction.14,15,16 Little information is available on mortalityfrom coronary heart disease in diabetic patients without priormyocardial infarction as compared with nondiabetic patientswith prior myocardial infarction. We examined this issue ina well-characterized Finnish population-based cohort using standardizedcriteria for both type 2 diabetes and myocardial infarction.17
Methods
The study was approved by the ethics committees of Kuopio UniversityHospital and the Turku University Central Hospital. All subjectsgave informed consent.
Cross-Sectional Study
Subjects with Type 2 Diabetes
The Finnish Social Insurance Institution maintains a centralregister of all patients with diabetes who receive reimbursementfor drugs. On the basis of information from this register, weidentified all diabetic patients 45 to 64 years of age bornand living in the Kuopio University Hospital district in easternFinland or the Turku University Central Hospital district inwestern Finland. The formation of the final patient population,consisting of 510 diabetic subjects from eastern Finland and549 from western Finland who participated in the study from1982 to 1984 (participation rates, 83 and 79 percent, respectively)has been previously described.18 One hundred twenty-eight subjectswith insulin-dependent diabetes had previously been excludedon the basis of C-peptide measurements. None of the subjectswho were classified as having type 2 diabetes according to WorldHealth Organization (WHO) criteria19 and who were included inthe final study population had a history of ketoacidosis. Onlynine subjects (seven men and two women) with type 2 diabeteswere receiving hypolipidemic drugs at base line.
Nondiabetic Subjects
A random control sample of subjects born and living in the KuopioUniversity Hospital district or the Turku University CentralHospital district was taken from the population register thatlisted all persons 45 to 64 years of age living in these districts.18The participation rates were 79 percent in the Kuopio districtand 85 percent in the Turku district.
The study protocol was carried out during one outpatient visitat the Clinical Research Unit of the University of Kuopio orthe Rehabilitation Research Center of the Social Insurance Institutionin Turku. These methods have been previously described in detail.18The visit included an interview concerning smoking, alcoholintake, physical activity, the use of drugs, and any historyof chest pain suggestive of coronary heart disease. All medicalrecords of subjects who reported that they had been admittedto the hospital for chest pain were reviewed. Review of themedical records was performed by two investigators after a carefulstandardization of the methods. The WHO criteria for verifieddefinite or possible myocardial infarction, based on chest-painsymptoms, electrocardiographic changes, and enzyme determinations,were used to define previous myocardial infarction.20
The WHO criteria for verified definite or possible stroke wereused in the ascertainment of the diagnosis of previous stroke,which was defined as a clinical syndrome consisting of neurologicsymptoms persisting for more than 24 hours.21 Thromboembolicand hemorrhagic strokes, but not subarachnoid hemorrhage, wereincluded in the diagnosis of stroke.
Smoking status was based on an interview. In all statisticalanalyses, subjects were classified as nonsmokers, former smokers,or current smokers.
Blood pressure was measured to the nearest 2 mm Hg with a mercurysphygmomanometer with the subject in the sitting position aftera five-minute rest. Subjects were classified as having hypertensionif they were receiving drug treatment for hypertension or ifthey had a systolic pressure of at least 160 mm Hg or a diastolicpressure of at least 95 mm Hg. Hypertension was treated as adichotomous variable in our statistical analyses.
Blood specimens were drawn at 8 a.m. after a 12-hour fast. Fastingplasma glucose was determined by the glucose oxidase method(Boehringer Mannheim, Mannheim, Germany). Serum lipids and lipoproteinswere measured in fresh serum samples.18 Lipids and lipoproteinswere treated as continuous variables in the statistical analyses.
Follow-Up Study
In 1990, a questionnaire about hospitalization for acute chestpain and symptoms suggestive of stroke was sent to every survivingmember of the original study cohort. All medical records ofthe subjects who died between the base-line examination andDecember 31, 1989, or who reported on the questionnaire thatthey had been admitted to the hospital because of chest painor symptoms suggestive of stroke between the base-line examinationand December 31, 1989, were reviewed by one of the investigators.The modified WHO criteria for definite or possible myocardialinfarction, which are based on chest pain, electrocardiographicchanges, and enzyme determinations, were used in the ascertainmentof the diagnosis of myocardial infarction, as was done in thebase-line study.20 In the final classification of the causesof death, hospital records and autopsy records were used, ifavailable. To ensure that the data collection was complete,a computerized hospital-discharge register was used to checkfor hospital admissions of all participants in the base-linestudy; in cases of symptoms of myocardial infarction or stroke,medical records were also checked. Copies of death certificatesof the subjects who had died were obtained from the CentralStatistical Office of Finland.
The WHO definition of definite and possible stroke used in theascertainment of a new stroke event was similar to that usedin the base-line study that is, a clinical syndromeconsisting of a neurologic deficit persisting for more than24 hours (nonfatal stroke), without the presence of other diseasesthat explained the symptoms.21 The causes of death from strokeincluded codes 431 through 434 of the International Classificationof Diseases, Ninth Revision.
Statistical Analysis
Data analyses were performed with the SPSSX and SPSS/PC programs(SPSS, Chicago). The results for continuous variables are givenas means (±SE) or percentages. The differences amongthe groups were assessed by logistic regression (for dichotomousdata) or Student's two-tailed t-test (for continuous data) forindependent samples, when appropriate. Univariate and multivariateCox regression models22 were used to investigate the associationof cardiovascular risk factors with the incidence of cardiovascularevents. KaplanMeier survival curves were used to constructfigures for mortality from coronary heart disease. The numbersof subjects at risk for cardiovascular events during the follow-upperiod were as follows. Of nondiabetic subjects without priormyocardial infarction at base line, 1278 were at risk at twoyears, 1266 at four years, 1246 at six years, and 681 at sevenyears. Of nondiabetic subjects with prior myocardial infarctionat base line, 64 were at risk at two years, 58 at four years,56 at six years, and 27 at seven years. Of subjects with type2 diabetes without prior myocardial infarction at base line,819 were at risk at two years, 762 at four years, 691 at sixyears, and 455 at seven years. Of subjects with type 2 diabeteswith myocardial infarction at base line, 155 were at risk attwo years, 138 at four years, 105 at six years, and 731 at sevenyears. Since the maximal follow-up period was 7.93 years, nosubjects were at risk at 8 years. All P values are two-sided.
Results
Table 1 shows the clinical characteristics of the subjects accordingto diabetic status and history of myocardial infarction at baseline. In the overall population, type 2 diabetes was associatedwith older age, higher body-mass index, a greater prevalenceof hypertension, higher triglyceride levels, and lower levelsof low-density lipoprotein (LDL) and high-density lipoprotein(HDL) cholesterol. In the overall population, prior myocardialinfarction was associated with male sex, smoking, older age,hypertension, obesity, higher total and LDL cholesterol andtriglyceride levels, and lower HDL cholesterol levels.
Table 1. Risk Factors for Coronary Heart Disease at Base Line in Relation to the History of Myocardial Infarction in Subjects with Type 2 Diabetes and in Nondiabetic Subjects.
Table 2 shows the seven-year incidence of cardiovascular eventsin relation to diabetic status and history of myocardial infarctionat base line. In both diabetic and nondiabetic subjects, a historyof myocardial infarction at base line was significantly associatedwith an increased incidence of myocardial infarction (fataland nonfatal), stroke (fatal and nonfatal), and death from cardiovascularcauses. The incidence of myocardial infarction among nondiabeticsubjects was 18.8 percent in those with prior myocardial infarctionand 3.5 percent in those without prior myocardial infarction.Among diabetic subjects, the incidence of myocardial infarctionwas 45.0 percent in those with prior myocardial infarction and20.2 percent in those without prior myocardial infarction. Inthe overall population, both diabetes and the prevalence ofmyocardial infarction were associated with an increased incidenceof cardiovascular events.
Table 2. Incidence of Cardiovascular Events during a Seven-Year Follow-up in Relation to History of Myocardial Infarction in Subjects with Type 2 Diabetes and in Nondiabetic Subjects.
Figure 1 shows the KaplanMeier estimates of the probabilityof death from coronary heart disease. Diabetic subjects withprior myocardial infarction had the worst prognosis, whereasnondiabetic subjects without prior myocardial infarction hadthe best prognosis. Diabetic subjects without prior myocardialinfarction and nondiabetic subjects with prior myocardial infarctionhad an intermediate survival rate, and these two groups hadsimilar outcomes.
Figure 1. KaplanMeier Estimates of the Probability of Death from Coronary Heart Disease in 1059 Subjects with Type 2 Diabetes and 1378 Nondiabetic Subjects with and without Prior Myocardial Infarction.
MI denotes myocardial infarction. I bars indicate 95 percent confidence intervals.
Table 3 shows the results of a Cox proportional-hazards modelcomparing diabetic subjects without prior myocardial infarctionwith nondiabetic subjects with prior myocardial infarction.The age- and sex-adjusted hazard ratio was not significantlydifferent from 1.0 (hazard ratio, 1.4; 95 percent confidenceinterval, 0.7 to 2.6), suggesting that these groups have similarmortality rates. Further adjustment for LDL cholesterol, HDLcholesterol, triglyceride, smoking, and hypertension did notsignificantly change the results.
Table 3. Results of Cox Proportional-Hazards Model Comparing Mortality from Coronary Heart Disease in 890 Subjects with Type 2 Diabetes without Prior Myocardial Infarction with That in 69 Nondiabetic Subjects with Prior Myocardial Infarction during a Seven-Year Follow-up.
Discussion
We confirmed earlier reports14,15,16 that both diabetic andnondiabetic subjects with prior myocardial infarction have anincreased incidence of cardiovascular events. The seven-yearrate of major cardiovascular events for diabetic subjects withprevious myocardial infarction in this study was similar tothat reported for diabetic subjects in the Scandinavian SimvastatinSurvival Study (45 percent)12 over a period of 5.4 years, asomewhat shorter period of follow-up. As expected, diabeticsubjects had much higher mortality from coronary heart diseasethan nondiabetic subjects, confirming previous results.1,2,3,4
The more critical issue is whether diabetic subjects withoutprior myocardial infarction have a risk of infarction similarto that of nondiabetic subjects with prior myocardial infarction.If this is true, it suggests a similar base-line risk of cardiovasculardisease, and perhaps that similar management of cardiovascularrisk factors in these groups is indicated. Our data indicatea similar incidence of cardiovascular disease in these groups,both after adjustment for demographic variables (age and sex)and after further adjustment for other cardiovascular risk factors(smoking, hypertension, and LDL cholesterol, HDL cholesterol,total cholesterol, and triglyceride levels). The number of diabeticsubjects in this report was large, and the samples of subjectswith diabetes and without diabetes were population-based, suggestingthat these results may be generalizable. However, the confidenceintervals around the risk ratios were wide, indicating thatthe power of the study to detect differences between the twogroups was limited.
It was recently shown that the one-year case fatality rate fora first myocardial infarction (from the onset of symptoms, thusincluding prehospitalization mortality) in the population studiedin the Finnish Monitoring International Cardiovascular Disease(FINMONICA) trial16 was 45 percent in diabetic men and 39 percentin diabetic women. These case fatality rates were significantlyhigher than the rates in nondiabetic subjects (38 percent formen and 25 percent for women). Of the diabetic subjects whodied, 50 percent of men and 25 percent of women died beforehospitalization. These patients, by definition, could not benefitfrom secondary prevention strategies, indicating (especiallyin diabetic men) that aggressive management of cardiovascularrisk factors in diabetic subjects should precede the onset ofclinical coronary heart disease.
Several clinical trials have shown that 3-hydroxy-3-methylglutarylcoenzymeA (HMG-CoA) reductase inhibitor therapy reduces the incidenceof cardiovascular events in diabetic patients with prior coronaryheart disease. In the Scandinavian Simvastatin Survival Study,simvastatin reduced the incidence of coronary heart diseaseevents in diabetic subjects by 55 percent.12 In the Cholesteroland Recurrent Events study, pravastatin reduced the incidenceof cardiovascular events in diabetic subjects by 27 percent.13Unfortunately, there are no results from clinical trials oflipid-lowering therapy with HMG-CoA reductase inhibitors indiabetic patients without prior coronary heart disease. Suchtrials are currently under way.
One potential limitation of the current study is that the ratesof mortality from coronary heart disease in Finland are amongthe highest in the world.23 However, for a number of reasons,we believe our data are likely to be generalizable to countrieswith lower rates of coronary heart disease. Within Finland,rates of coronary heart disease vary widely,23 ranging fromvery high in eastern Finland (Kuopio) to lower in western Finland(Turku). In Turku, the rate of coronary heart disease in menis somewhat higher than that in men in the United States, whereasthe rate of coronary heart disease in women in Turku is actuallylower than that in women in the United States.23 Furthermore,in this population, the relation between type 2 diabetes andboth the prevalence18 and incidence24 of coronary heart diseaseis similar in both high-risk areas (eastern Finland) and moderate-riskareas (western Finland).
Finally, we completed a preliminary analysis of atherosclerosis(indicated by intimal-wall thickness as assessed by B-mode ultrasonographyof the common and internal carotid arteries) in the InsulinResistance Atherosclerosis Study, a multiethnic study involvingHispanics, non-Hispanic whites, and African Americans in theUnited States.25 Carotid-artery intimal-wall thickness was verysimilar in diabetic subjects without clinical coronary arterydisease and nondiabetic subjects with clinical coronary arterydisease. Diabetic subjects with coronary artery disease hadthe greatest intimal-wall thickness, and nondiabetic subjectswithout coronary artery disease had the lowest. These resultssupport the current findings and, furthermore, suggest thatthe high rate of coronary heart disease in diabetic patientswithout vascular disease at base line may be due to acceleratedatherosclerosis.
In conclusion, we have shown that patients with type 2 diabeteswho have not had a myocardial infarction have a risk of infarctionsimilar to that among nondiabetic patients who have had a priormyocardial infarction. This observation, combined with the resultsof previous studies showing the efficacy of lipid-lowering therapyin diabetic patients with coronary heart disease12,13 and thehigh mortality (including prehospital mortality) after myocardialinfarction,14,15,16 suggests that all persons with diabetescould be treated as if they had prior coronary heart disease.The best way to answer this question more definitively wouldbe to conduct a clinical trial comparing the effect of differentlevels of lipid-lowering therapy on coronary heart disease indiabetic subjects. Clinical trials, however, are very expensiveand take many years to complete. In the short term, furtherconfirmation of our findings may come from other observationalstudies.
Supported by grants from the Academy of Finland, the FinnishHeart Research Foundation, and the Aarne and Ali Turunen Foundation.
Source Information
From the Department of Medicine, University of Texas Health Science Center at San Antonio, San Antonio (S.M.H.); the Department of Medicine, University of Kuopio, Kuopio, Finland (S.L., K.P., M.L.); and the Department of Medicine, Turku University, Turku, Finland (T.R.).
Address reprint requests to Dr. Haffner at the Department of Medicine, University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, TX 78284-7873.
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Diabetes and Coronary Heart Disease
Simons L. A., Simons J., Engler R. L., McGurk C., Harper R., McCance D. R., Krankenberg H., Lauer B., Schuler G., Haffner S. M., Lehto S., Laakso M.
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N Engl J Med 1998;
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Correspondence
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Gowdak, L. H. W., de Paula, F. J., Cesar, L. A. M., Filho, E. E. M., Ianhez, L. E., Krieger, E. M., Ramires, J. A. F., De Lima, J. J. G.
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Westerbacka, J.
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Erdmann, E., Dormandy, J. A., Charbonnel, B., Massi-Benedetti, M., Moules, I. K., Skene, A. M., on behalf of the PROactive Investigators,
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Pundziute, G., Schuijf, J. D., Jukema, J. W., Boersma, E., Scholte, A. J.H.A., Kroft, L. J.M., van der Wall, E. E., Bax, J. J.
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