Correspondence
Diabetes and Coronary Heart Disease
N Engl J Med 1998; 339:1714-1716December 3, 1998
- Article
To the Editor:
Haffner et al. (July 23 issue)1 have shown that diabetic subjects without prior myocardial infarction (mean age, approximately 58 years) have as high a risk of myocardial infarction as nondiabetic subjects with prior myocardial infarction. These findings were “population-based,” according to the investigators, but they actually used a population register of diabetic subjects. We would like to report our observations in a cohort drawn from a true cross section of the population.
The Dubbo Study is an ongoing prospective study of cardiovascular disease in a cohort of elderly Australian subjects (mean age, approximately 70 years) who were first evaluated in 1988–1989.2,3 Subjects were classified as having diabetes if they had previously received a diagnosis of diabetes from a physician, if they were using medication for diabetes, or if they had a single fasting plasma glucose level of at least 7.8 mmol per liter. The remaining subjects were considered to be nondiabetic if the fasting plasma glucose level was less than 6.1 mmol per liter. Because of the age of the population, cases of diabetes were predominantly type 2. Documentation of prior coronary heart disease was based on positive responses to a myocardial-infarction questionnaire or the Rose angina questionnaire or on diagnostic electrocardiographic changes.2 Incident coronary-heart-disease events were hospital admissions with any manifestation of coronary heart disease (International Classification of Diseases, 9th Revision, Clinical Modification codes 410 through 414).
In a five-year follow-up analysis of the cohort, overall mortality was twice as high in diabetic subjects as in nondiabetic subjects, among both men and women, and the incidence of coronary heart disease was two times as high in diabetic men and three times as high in diabetic women.3 We have now completed 98 months of follow-up for coronary heart disease; the key findings are presented in Table 1Table 1
Incidence of Coronary Heart Disease (CHD) in Diabetic and Nondiabetic Subjects..Cox proportional-hazards models were used to compare the risk of coronary heart disease in subjects who had diabetes but no prior coronary heart disease with the risk in nondiabetic subjects with or without prior coronary heart disease. The models were adjusted for age, sex, and other cardiovascular risk factors.2,3 The hazard ratio was 0.67 (95 percent confidence interval, 0.46 to 0.97; P<0.04) for the comparison with nondiabetic subjects who had prior coronary heart disease and 1.43 (95 percent confidence interval, 1.00 to 2.03; P<0.05) for the comparison with nondiabetic subjects who did not have prior coronary heart disease.
Our findings confirm the overall increased risk of coronary heart disease in patients with type 2 diabetes. However, the relative risk for diabetic subjects without prior coronary heart disease is still significantly lower than that for nondiabetic subjects with prior coronary heart disease. Differences between the findings reported by Haffner et al. and our findings may be related to differences in the selection criteria for the study populations, the definition of diabetes, the age and size of the groups, and the different end points (myocardial infarction in the study by Haffner et al. and coronary heart disease in our study).
3 ReferencesLeon A. Simons, M.D.
Judith Simons, M.A.C.S.
St. Vincent's Hospital, Darlinghurst, NSW 2010, Australia1
Haffner SM ,Lehto S ,Ronnemaa T ,Pyorala K ,Laakso M . Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med 1998;339:229-234
Full Text | Web of Science | Medline2
Simons LA ,Friedlander Y ,McCallum J ,Simons J . Risk factors for coronary heart disease in the prospective Dubbo Study of Australian elderly. Atherosclerosis 1995;117:107-118
CrossRef | Web of Science | Medline3
Simons LA ,McCallum J ,Friedlander Y ,Simons J . Diabetes, mortality and coronary heart disease in the prospective Dubbo study of Australian elderly. Aust N Z J Med 1996;26:66-74
CrossRef | Medline
To the Editor:
Haffner et al. found that patients with type 2 diabetes but without previous myocardial infarction had as high a risk of myocardial infarction as nondiabetic patients with previous myocardial infarction. Furthermore, the authors state that the hazard ratio for death from coronary artery disease was not significantly different from 1.0 for diabetic subjects without prior myocardial infarction as compared with nondiabetic subjects with prior myocardial infarction. A potentially important element missing from this analysis is the risk associated with oral sulfonylurea therapy, which is frequently given to patients with type 2 diabetes.
The University Group Diabetes Program found that oral sulfonylurea therapy was associated with an increased rate of death from cardiovascular causes as compared with only dietary treatment of type 2 diabetes.1 Possible mechanisms by which sulfonylurea drugs increase morbidity and mortality in patients with coronary artery disease have recently been identified and reviewed.2 This class of drugs appears to prevent the phenomenon of cardiac preconditioning and may worsen the effect of acute myocardial ischemia in patients with chronic ischemic heart disease. I wonder whether the investigators have considered the potential effect of this therapy as a risk factor for death from coronary artery disease in their study.
2 ReferencesRobert L. Engler, M.D.
Veterans Affairs San Diego Healthcare System, San Diego, CA 92161-60021
A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetesDiabetes 1970;19:747-830
Web of Science2
Engler RL ,Yellon DM . Sulfonylurea KATP blockade in type II diabetes and preconditioning in cardiovascular disease: time for reconsideration. Circulation 1996;94:2297-2301
Web of Science | Medline
To the Editor:
Haffner and colleagues provide further evidence of the high rate of cardiovascular-related mortality associated with type 2 diabetes mellitus. Their data complement similar findings in other prospective studies and support the argument that the high risk warrants an aggressive management strategy.
We agree with this interpretation but were surprised that the authors concentrated exclusively on the role of statins, neglecting the role of aspirin in the primary prevention of vascular disease. It is now well recognized that the increased mortality rate associated with type 2 diabetes cannot be explained solely by the presence of the classic risk factors such as smoking, hypertension, and hypercholesterolemia.1 The clinical manifestations of vascular disease in diabetic subjects represent a final common response to a diverse range of insults, of which dyslipidemia is but one. Since the majority of cardiovascular events occur in patients without marked abnormalities in their lipid profiles, statin therapy alone is unlikely to result in a substantial reduction of the overall burden of vascular disease in this population.
By inhibiting platelet aggregation at the site of a ruptured or unstable atherosclerotic plaque, aspirin disrupts the processes leading to the clinical presentation of vascular disease, irrespective of the initial cause of the underlying proatherosclerotic process. Aspirin has been clearly demonstrated to reduce mortality from vascular causes when used either for primary or for secondary prevention, and there are already data suggesting that these effects also apply to the diabetic population.2-4 Unlike the statins, aspirin is cheap, requires no monitoring of its effects, and has minimal side effects when used at platelet-inhibiting doses.
4 ReferencesColm McGurk, M.D.
Roy Harper, M.D.
David R. McCance, M.D.
Royal Victoria Hospital, Belfast BT12 6BA, Northern Ireland1
Stamler J ,Vaccaro O ,Neaton JD ,Wentworth D . Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-444
CrossRef | Web of Science | Medline2
The Steering Committee of the Physicians' Health Study Research Group
Full Text | Web of Science | Medline3
The Antiplatelet Trialists' Collaboration
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The ETDRS Investigators
CrossRef | Web of Science
To the Editor:
Haffner et al. conclude that the risk of myocardial infarction in patients with diabetes mellitus but without prior infarction is similar to the risk of recurrent myocardial infarction in patients without diabetes but with prior infarction. These data are of great importance for the primary prevention of coronary heart disease in patients with diabetes. The authors state that, in combination with the results of the Scandinavian Simvastatin Survival Study1 and the Cholesterol and Recurrent Events study,2 which show the efficacy of lipid-lowering therapy in diabetic patients with coronary heart disease, their findings suggest that all patients with diabetes should be treated as aggressively as patients with documented coronary artery disease. They propose that a clinical trial compare only the effect of different levels of lipid-lowering therapy in the primary prevention of coronary heart disease in diabetic patients.
However, other studies have shown the beneficial effects of intensive management of diabetes with the aim of glycemic control3 and of regular physical exercise4 on the development and progression of coronary heart disease. For optimal primary prevention of coronary heart disease in patients with diabetes, we believe it may be insufficient to treat only elevated lipid levels. Furthermore, these studies do not address the question of how to treat diabetic patients with normal lipid levels.
4 ReferencesHans Krankenberg, M.D.
Bernward Lauer, M.D.
Gerhard Schuler, M.D.
Universität Leipzig, 04289 Leipzig, Germany1
The Scandinavian Simvastatin Survival Study Group
Web of Science | Medline2
Sacks FM ,Pfeffer MA ,Moye LA , et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 1996;335:1001-1009
Full Text | Web of Science | Medline3
The Diabetes Control and Complications Trial (DCCT) Research Group
CrossRef | Web of Science | Medline4
Lee I-M ,Hsieh C-C ,Paffenbarger RS Jr . Exercise intensity and longevity in men: the Harvard Alumni Health Study. JAMA 1995;273:1179-1184
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Author/Editor Response
The authors reply:
To the Editor: We thank the authors of the letters for their interest in our report. Krankenberg et al. state that other interventions besides lipid-lowering therapy may be useful in the prevention of coronary heart disease in patients with type 2 diabetes. We agree. We should point out, however, that the role of glycemic control in the prevention of vascular events is controversial. Indeed, the recent report on the United Kingdom Prospective Diabetes Study noted a modest but not significant reduction (16 percent) in the incidence of coronary heart disease and no decrease in the incidence of stroke.1 The Diabetes Complications and Control Trial, a study of type 1 diabetes, showed a suggestive but not significant decline in coronary-heart-disease events.
Dr. Engler has raised the important issue of whether our results might be due to the increased cardiotoxic effects of sulfonylurea drugs. We have repeated the analysis presented in Table 3 of our article, using a model that includes dummy variables for sulfonylurea therapy, and have found no change in the hazard ratio, suggesting that this issue is not critical in our study. Indeed, sulfonylurea use is not associated with a worse prognosis in this cohort. Furthermore, recent data from the United Kingdom Prospective Diabetes Study1 suggest that there is no increased cardiotoxicity in subjects randomly assigned to sulfonylurea agents as compared with those assigned to conventional therapy. McGurk et al. point out that other interventions such as aspirin therapy may be beneficial even in diabetic subjects without prior coronary heart disease. We agree, and the American Diabetes Association's recent position paper endorses this view.2 Indeed, other interventions such as beta-blockade or angiotension-converting–enzyme inhibition may also be useful, especially after myocardial infarction.
Simons and Simons suggest that our report was not a population-based study. However, our study approach, with the use of a registry, was population-based with a response rate of more than 80 percent, as was also the case for the population-based control group. This approach resulted in the enrollment of more than 1000 subjects with type 2 diabetes, which is roughly five times as many as in the study described by Simons and Simons. Aside from the minor issue noted above, there are three possible reasons for the different findings of the two studies. The first is that the difference is due to chance. The second is that type 2 diabetes is a weaker risk factor for coronary heart disease in elderly persons than in middle-aged persons,3 and thus the subjects with more severe diabetes may have died before inclusion in the study described by Simons and Simons (which involved an elderly population). This is usually referred to as a survival bias. The last reason is misclassification. In our study, we excluded patients with type 1 diabetes diagnosed on the basis of C-peptide levels (about 10 percent of the potential cohort); subjects with type 1 diabetes were included in the Dubbo cohort.
We believe the second possibility is the most likely explanation for the differences in the findings of the studies. We have also presented preliminary data showing that among middle-aged subjects, those with type 2 diabetes but without clinical coronary heart disease have an intimal–medial wall thickness in both the common and internal carotid arteries that is similar to the wall thickness in nondiabetic subjects with clinical coronary heart disease.4 Clearly, however, additional replication of the findings in both middle-aged and elderly populations is needed to resolve these issues.
4 ReferencesSteven M. Haffner, M.D.
University of Texas Health Science Center, San Antonio, TX 78284-7873Seppo Lehto, M.D.
Markku Laakso, M.D.
University of Kuopio, 70211 Kuopio, Finland1
The UK Prospective Diabetes Study (UKPDS) Group
CrossRef | Web of Science | Medline2
The American Diabetes Association 3
Kannel WB ,McGee DL . Diabetes and cardiovascular disease: the Framingham study. JAMA 1979;241:2035-2038
CrossRef | Web of Science | Medline4
Haffner SM ,D'Agostino R Jr ,Saad MF , et al. Atherosclerosis in type 2 diabetic and non-diabetic subjects with and without clinical coronary artery diseases: the Insulin Resistance Atherosclerosis Study. Diabetologia 1998;41:Suppl 1:A335-A335 abstract.
Web of Science
- Citing Articles (12)
Citing Articles
1
Ignacio Conget, Marga Giménez. (2011) Hypoglycemia, diabetes and atherosclerosis: is there a link?. Diabetes Management 1:3, 291-297
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Ignacio Conget. (2011) Hypoglycaemia and cardiovascular disease. The fatal linkage. Avances en Diabetología 27:2, 39-41
CrossRef3
Hussein H. Karnib, Fuad N. Ziyadeh. (2010) The cardiorenal syndrome in diabetes mellitus. Diabetes Research and Clinical Practice 89:3, 201-208
CrossRef4
Peter M. Nilsson, Adie Viljoen, Anthony S. Wierzbicki. 2010. Cardiovascular Risk Factors. , 657-683.
CrossRef5
Christoph H. Saely, Stefan Aczel, Lorena Koch, Fabian Schmid, Thomas Marte, Kurt Huber, Heinz Drexel. (2010) Diabetes as a coronary artery disease risk equivalent: before a change of paradigm?. European Journal of Cardiovascular Prevention & Rehabilitation 17:1, 94-99
CrossRef6
José Miguel González-Clemente, Silvia Palma, Jaume Arroyo, Carme Vilardell, Assumpta Caixàs, Olga Giménez-Palop, Miguel Delgado-Rodríguez. (2007) ¿La diabetes mellitus es un equivalente de riesgo coronario? Resultados de un metaanálisis de estudios prospectivos. Revista Española de Cardiología 60:11, 1167-1176
CrossRef7
A. E. Buyken, A. von Eckardstein, H. Schulte, P. Cullen, G. Assmann. (2007) Type 2 diabetes mellitus and risk of coronary heart disease: results of the 10-year follow-up of the PROCAM study. European Journal of Cardiovascular Prevention & Rehabilitation 14:2, 230-236
CrossRef8
Ronald Goldberg. 2006. Type 2 Diabetes. , 187-254.
CrossRef9
(2006) Coronary risk prediction for those with and without diabetes. European Journal of Cardiovascular Prevention & Rehabilitation 13:1, 30-36
CrossRef10
P Ducimetière. (2005) Cardiovascular risks in type 2 diabetes and secondary cardiovascular prevention. Diabetes & Metabolism 31:5, 503-506
CrossRef11
Gerd Assmann, Paul Cullen, Jean-Charles Fruchart, Heiner Greten, Marek Naruszewicz, Anders Olsson, Rodolfo Paoletti, Walter Riesen, Monika Stoll, Matti Tikkanen, Arnold von Eckardstein. (2005) Implications of emerging risk factors for therapeutic intervention. Nutrition, Metabolism and Cardiovascular Diseases 15:5, 373-381
CrossRef12
C. Carroll, E. Naylor, P. Marsden, T. Dornan. (2003) How do people with Type 2 diabetes perceive and respond to cardiovascular risk?. Diabetic Medicine 20:5, 355-360
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