Diabetes Spectrum
Volume 12 Number 2, 1999, Pages 80–83

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From Research to Practice / Diabetes and Coronary Heart Disease

Diabetes and Coronary Heart Disease


Preface

Coronary heart disease (CHD) is common in people with diabetes mellitus (DM).1 In the 197680 National Health and Nutrition Examination Survey II, the prevalence of angina was higher in people with than in those without diabetes.2 The 1989 U.S. National Health Interview Study showed a higher prevalence of CHD in people with diabetes.2 In the Multiple Risk Factor Intervention Trial, the age-adjusted incidence of CHD was four times greater in people with than in those without diabetes.3

In people with diabetes, CHD causes almost 60% of their deaths. They have a two- to threefold increased risk for CHD and two- to fourfold higher CHD morbidity and mortality rates. In people with diabetes, CHD occurs at a younger age, and women are affected as often as men.

Glycemic Control and CHD
In such a close relationship, does the degree of hyperglycemia increase the risk of developing CHD events or mortality? In people with type 1 diabetes, it does not, while in people with type 2 diabetes, a relationship appears to exist.

In people with type 1 diabetes, the Pittsburgh Epidemiology of Diabetes Complications Study reported no association between glycosylated hemoglobin (HbA1c) and the 4-year incidence of CHD.4 In contrast, the incidence of CHD mortality and events increased with each tertile of HbA1c in elderly men with type 2 diabetes in Kuopio, Finland. The most important single risk factor associated with CHD death or event was HbA1c. This was present after adjusting for gender, history of previous myocardial infarction (MI), current smoking, waist-hip ratio, systolic blood pressure, high-density lipoprotein (HDL) cholesterol, and duration of diabetes. In this study, patients in the highest HbA1c tertile had a threefold higher risk of CHD compared with those in the lowest tertile.5

In newly diagnosed, middle-aged (4564 years old) patients with type 2 diabetes, the same group found that the incidence of cardiovascular mortality increased with rising fasting plasma glucose (FPG) at baseline during a 10-year study. In all patients, irrespective of treatment mode, this association was found. A high FPG level significantly predicted cardiovascular mortality independent of other risk factors in multiple regression analysis.6

In the Framingham Heart Study, HbA1c was related to the prevalence of cardiovascular disease (CVD) among older women but not men.7 At quartiles (Q) 1 and 2 (in which HbA1c was <6%), the prevalence rates of CVD were 17 and 18%. At Q 3, the prevalence was 24%, and at Q 4 (in which HbA1c spanned the upper limit of normal and diabetic range), it was 31%. The relative odds of CVD increased 1.4-fold for increases in HbA1c of 1% (from Q 1 to Q 4).

In the San Antonio Heart Study, cardiovascular mortality increased in people with type 2 diabetes as FPG increased. In Q 1 and 2 (FPG <8 mmol/L), the mortality was 2.8 per 1,000 person-years. This increased to 6.3 in people with FPG 811.5 mmol/L (Q 3) and 11.6 in people with FPG >11.5 mmol/L (Q 4). After adjustment for other risk factors, subjects in Q 4 had a 4.9-fold greater risk for CVD mortality than did subjects in Q 1 and 2.8

If there is a positive correlation between hyperglycemia and CHD events and mortality, does the correction of hyperglycemia in people with diabetes affect them? In the Diabetes Control and Complications Trial involving younger people with type 1 diabetes, intensive therapy did not significantly reduce the incidence of major cardiovascular events (P = 0.08). The number of combined major cardiovascular events was 40 in the conventional therapy group versus 23 in the intensive-treatment group.9

In the UKPDS, the development of fatal or nonfatal MI had a nonsignificant 16% relative risk reduction (P = 0.052).10 The effect was the same irrespective of the initial therapy—insulin or sulfonylurea—used to correct hyperglycemia. However, UKPDS overweight patients treated with metformin had a significant relative risk reduction of fatal or nonfatal MI of 39% (P = 0.023).11 This would indicate that metformin is the preferred anti-hyperglycemic medication to prevent MI in obese patients with type 2 diabetes. However, one must be cautious, as patients put on metformin after sulfonylurea failure had a significant increased risk of diabetes-related death (P = 0.039). The reasons for this are unclear.

That correction of hyperglycemia does not reduce CHD events and mortality is new information uncovered in the past 5 years. In this From Research to Practice section, three other advances in the DM-CHD connection are reviewed—reducing CHD mortality, taking a global approach to preventing CHD, and understanding the use of sulfonylureas in people with diabetes.

Reducing CHD Mortality in Diabetes
Diabetic patients with MI have a two- to threefold higher mortality than do their nondiabetic counterparts. The most important factor for this is increased left ventricular failure,12 which may be due to a "diabetic cardiomyopathy" that is not related to the atherosclerosis.13 Another possible factor is the higher prevalence of silent ischemia that can lead to delayed diagnosis of CHD in people with diabetes.14 Diabetic patients with MI also have worse long-term prognosis than do their nondiabetic counterparts.

The DIGAMI study, reviewed by Cummings and associates (p. 84), demonstrated that people with diabetes had lower mortality following MI if they were treated intensively with an insulin infusion immediately after the event, followed by a multiple-dose insulin regimen, when compared with those treated by conventional methods.15

Taking a Global Approach to Prevent CHD
As hyperglycemia alone does not explain all the increased risk for CHD in people with type 2 diabetes, other factors must be considered. It has been postulated that rather than being a complication of DM, CHD and DM share common genetic and environmental antecedents.16 They have in common many CHD risk factors, and a possible link between them is insulin resistance syndrome. Compared with the nondiabetic population, the prevalence of dyslipidemia, hypertension, obesity, and sedentary lifestyle is higher in people with type 2 diabetes. In addition, people with diabetes have multiple risk factors more often than do their nondiabetic counterparts.17 Many of these risk factors can be modified. Arch and Korytkowski discuss strategies for a global approach to changing them (p. 88).

Evidence for correcting dyslipidemia in people with diabetes has now been reported. People with diabetes tend to have higher low-density lipoprotein (LDL) cholesterol and triglycerides and lower HDL. In them, LDL particles tend to be smaller and denser, and this probably increases the risk for atherosclerosis. Lowering LDL in patients with diabetes and CHD with simvastatin has been shown to decrease cardiac mortality and events in a sub-study of the Scandinavian Simvastatin Survival Study.18 In a sub-study of the CARE trial, lowering LDL with pravastatin showed similar benefits.19 The Diabetes Atherosclerosis Intervention Study will hopefully uncover information on whether correcting the dyslipidemia in people with type 2 diabetes will decrease CHD events and/or mortality.20

Sulfonylureas and CHD
The mode of treatment of hyperglycemia in people with type 2 diabetes may increase the risk for CHD. The University Group Diabetes Program raised this issue originally with the observation that people with type 2 diabetes treated with tolbutamide or phenformin had increased cardiovascular mortality.21 This led to much controversy and debate. With the publication of the UKPDS, it is now established that people with type 2 diabetes treated with sulfonylurea do not have increased cardiovascular mortality.10 In this issue, Rodger discusses the sulfonylurea and heart disease relationship (p. 95).

The Veterans Affairs Cooperative Study of Diabetes Mellitus reported men with type 2 diabetes on intensive therapy had a nonsignificant increase in cardiovascular events (32 vs. 20%) than those on conventional therapy.22 Similarly, the UKPDS showed that people with type 2 diabetes treated with insulin did not have higher cardiovascular mortality, putting to rest the concern that exogenous hyperinsulinemia can increase the risk for athersclerosis.

Blood Glucose: A Continuous CHD Risk Factor?
People with impaired glucose tolerance have a higher risk for CHD. Even in the presence of normoglycemia, an increase in cardiovascular risk is observed as the glucose increases. It has been proposed that glucose is a continuous cardiovascular risk factor, similar to hypercholesterolemia and hypertension.

In the Whitehall Study, there was an increase of 1.5- to 2-fold in CHD mortality for people with a 2-hour post-50-g glucose load of 5.4 mmol/L (~95th percentile), independent of age, smoking, blood pressure, cholesterol, and occupation.23

The Rancho Bernado Study of 3,458 men and women followed for an average of 14 years showed a linear increase in ischemic heart disease mortality rates with increasing fasting blood glucose (FBG) in men.24 The threshold effect of increased mortality with FBG in women was an FBG of >110 mg/dl.

Based on the above, dysglycemia has been proposed as a cardiovascular risk factor.25 Gerstein postulated that plasma glucose concentrations are associated with different risk at different concentrations:

  • in the diabetic range, glucose is associated with an increasing risk of macroangiopathies and microangiopathies.
  • in the impaired glucose tolerance range, glucose is associated with an increased risk for diabetes and CVD.
  • in the yet-to-be-defined "dysglycemia" glucose levels in the nor mal range, glucose is associated with increased risk for CVD alone.26

Recently, FBG was called an underestimated risk factor for cardiovascular death. An FBG >85 mg/dl had a relative risk of cardiovascular death for men of 1.4 even after adjusting for age, smoking habits, serum lipids, blood pressure, and physical fitness.27 A meta-regression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years showed the progressive relationship between glucose levels and cardiovascular risk extends below the diabetic threshold.28

Conclusion
The DM-CHD connection is complex. Hyperglycemia in the diabetic range does not explain all of it. The prevalence and incidence of CHD are increased in people with diabetes. Many, but not all, studies show an increased risk for CHD with rising fasting and post-challenge plasma glucose, even in the nondiabetic range. Dysglycemia appears to be a continuous cardiovascular risk factor.

It appears that diabetes, with hyperglycemia as its hallmark, is a major risk factor for development of CHD and the adverse outcomes after MI. Intensive insulin therapy following MI in diabetic patients reduces mortality.

Although adults with diabetes have a higher prevalence of cardiovascular risk factors, these account for <50% of the excess mortality associated with diabetes. Clustering of cardiovascular risk factors is more common in people with diabetes.

Although much new knowledge has been uncovered on the DM-CHD connection in the past decade, more research to elucidate it is urgently needed. This is important, for it can affect significantly the morbidity and mortality of diabetes.


References

1Laakso M, Lehto S: Epidemiology of macrovascular disease in diabetes. Diabetes Rev 5:294-315, 1997.

2Wingard DL, Barrett-Connor E: Heart disease and diabetes. In Diabetes in America. 2nd edition. Harris MI, ed. Bethesda, Md., National Institutes of Health (NIH publication no. 95-1468), 1995, p 429-48.

3Stamler J, Vaccaro O, Neaton J, Wentworth D, for the Multiple Risk Factor Intervention Trial Research Group: Diabetes, other risk factors, and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16:434-44, 1993.

4Orchard TJ: From diagnosis and classification to complications and therapy. DCCT Part II? The 1993 Kelly West Lecture. Diabetes Care 17:326-28, 1994.

5Kuusisto J, Mykkanen L, Pyorala K, Laakso M: NIDDM and its metabolic control predict coronary heart disease in elderly subjects. Diabetes 43:960-67, 1994.

6Uusitupa MI, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K: Ten year cardiovascular mortality in relation to risk factors and abnormalities in lipoprotein composition in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Diabetologia 36:1175-84, 1993.

7Singer DE, Nathan DM, Anderson KM, Wilson PWF, Evans JC: Association of HbA1c with prevalent cardiovascular disease in the original cohort of the Framingham Heart Study. Diabetes 41: 202-208, 1992.

8Wei M, Gaskill SP, Haffner SM, Stern MP: Effects of diabetes and level of glycemia on all-cause and cardiovascular mortality. Diabetes Care 21:1167-72, 1998.

9The DCCT Research Group: Effect of intensive diabetes management on macrovascular events and risk factors in the Diabetes Control and Complications Trial. Am J Cardiol 75:894-903, 1995.

10UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837-53, 1998.

11UK Prospective Diabetes Study (UKPDS) Group: Intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352: 854-65, 1998.

12Savage MP, Krolewski AS, Kenein GG, Lebeis MP, Christlieb AR, Lewis SM: Acute myocardial infarction in diabetes mellitus and significance of congestive heart failure as a prognostic factor. Am J Cardiol 62:665-69, 1988.

13Fein FS: Diabetic cardiomyopathy. Diabetes Care 13:1169-79, 1990.

14Scheidt-Nave C, Barrett-Connor E, Wingard DL: Resting electrocardiographic abnormalities suggestive of asymptomatic ischemic heart disease associated with non-insulin-dependent diabetes mellitus in a defined population. Circulation 81:899-906, 1990.

15Malmberg K for the DIGAMI Study Group: Prospective randomized study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. Br Med J 314:1512-15, 1997.

16Stern MP: Do non-insulin dependent diabetes mellitus and cardiovascular disease share common antecedents? Ann Intern Med 124 (1 pt 2):110-16, 1996.

17Tan MH, MacLean DR: Epidemiology of diabetes mellitus in Canada. Clin Invest Med 18:240-46, 1995.

18Pyorala K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G, The Scandanavian Simvastatin Survival Study (4S) Group: Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease: a subgroup analysis of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 20:614-20, 1997.

19Sacks FM, Pfeiffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E, for the Cholesterol and Recurrent Events Trial Investigators: The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. N Engl J Med 335:1001-1009, 1996.

20Steiner G for the DAIS Project Group: The Diabetes Atherosclerosis Intervention Study (DAIS): a study conducted in cooperation with the World Health Organization. Diabetologia 39:1655-61, 1996.

21University Group Diabetes Program: A study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. V. Evaluation of phenformin therapy. Diabetes 24 (Suppl 1):65-184, 1975.

22Abraira C, Colwell J, Nuttall F, Sawin CT, Henderson W, Comstock JP, Emanuele NV, Levin SR, Pacold I, Lee HS: Veterans Affairs Cooperative Study on glycemic control and complications in type II diabetes (VACSDM): cardiovascular events and correlates in the VA feasibility trial (VACSDM). Arch Int Med 157:181-87, 1997.

23Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H: Mortality from coronary heart disease and stroke in relation to degrees of glycaemia: the Whitehall study. Br Med J 287:867-70, 1983.

24Scheidt-Nave C, Barrett-Connor E, Wingard DL, Cohn BA, Edelstein SL: Sex differences in fasting glycemia as a risk factor for ischemic heart disease death. Am J Epidemiol 133:565-76, 1991.

25Gerstein HC, Yusuf S: Dysglycaemia and risk of cardiovascular disease. Lancet 347:949-50, 1996.

26Gerstein HC: Glucose: a continuous risk factor for cardiovascular disease. Diabetic Med 14:S25-31, 1997.

27Bjornholt JV, Erikssen G, Aaser E, Sandvik L, Nitter-Hauge S, Jervell J, Erikssen J, Thaulow E: Fasting blood glucose: an underestimated risk factor for cardiovascular death. Diabetes Care 22:45-49, 1999.

28Coutinho M, Gerstein HC, Wang Y, Yusuf S: The relationship between glucose and incident cardiovascular events. Diabetes Care 22:233-40, 1999.


Meng Hee Tan MD, FRCP(C), FACP


MengTan.JPG (26035 bytes)
Meng Hee Tan, MD, FRCP(C), FACP

Guest Editor

Meng Hee Tan, MD, FRCP(C), FACP, received his medical degree (cum laude) from Dalhousie University, in Halifax, Canada. He trained in internal medicine at Dalhousie University, in diabetes at the Joslin Diabetes Center at Harvard University in Boston, and in lipid metabolism at the Cardiovascular Research Institute at the University of California, San Francisco.

He was a professor of medicine and biochemistry and an associate professor of community medicine and epidemiology at his alma mater, Dalhousie University. There, he was also head of the Division of Endocrinology & Metabolism and deputy head of the Department of Medicine. He is currently director of the Bermuda Hospitals Board Diabetes Center.

His research interests are in diabetes and cardiovascular disease. He has published more than 110 papers on diabetes and/or lipid metabolism.

Over the years, he has served as a volunteer for many diabetes organizations, including the Canadian Diabetes Association (president), the Canadian Diabetes Advisory Board (chair), the Expert Panel on Clinical Practice Guidelines for Treatment of Diabetes in Canada (chair), the International Diabetes Federation (vice-president), and IDF's North American Regional Council (chair).



Call for Applications for the Editorship of

Diabetes Spectrum

The American Diabetes Association seeks letters of interest in the editorship of the journal Diabetes Spectrum.

The appointment is for three years, with a possible two-year extension. The editorship begins in January 2001, following a one-year transition period beginning in January 2000. An annual honorarium of $5,000, salary support of $5,200, and support for office costs are provided.

Diabetes Spectrum assists health care professionals in the development of strategies to individualize treatment and diabetes self-management education for purposes of improved quality of life and diabetes control. These goals are achieved by presenting articles on topics in clinical diabetes management, professional and patient education, nutrition, behavioral science and counseling, educational program development, and advocacy. In each issue, the From Research to Practice section explores, in depth, a diabetes care topic and provides practical application of current research findings.

Interested parties must submit a letter of interest by July 1, 1999. A curriculum vitae should be included. Please address correspondence to Peter Banks, Publisher, American Diabetes Association, 1701 North Beauregard Street, Alexandria, VA 22314.


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