Type 2 diabetes and coronary heart disease

Type 2 diabetes increases the risk of coronary heart disease (CHD) events at least by two- to threefold in type 2 diabetic subjects compared with nondiabetic subjects. In type 2 diabetic women the relative risk is even greater.

Diabetes mellitus

Persons with type II diabetes mellitus are up to four times more likely to develop coronary heart disease (CVD). In fact, two thirds of the patients with type II diabetes die from cardiovascular causes. Such association exists for several reasons:

  1. Hypertension – about eight in ten type II diabetics have hypertension and six in ten show atherogenic diabetic dyslipidemia (Table 1), characterized by:
    1. elevated plasma triglycerides,
    2. low levels of HDL cholesterol,
    3. an increased number of small, dense LDL particles and
    4. elevated plasma apolipoprotein B.

This atherogenic dyslipidemic state is a component of a cluster of atherogenic, prothrombotic and inflammatory abnormalities that is often found in individuals with insulin resistance and is sometimes referred to as the metabolic syndrome. Contrary to popular belief, LDL cholesterol levels in patients with type 2 diabetes mellitus (or type 1 diabetes mellitus) are not different from those in the general population.

  1. Chronic Hyperglycemia (CH) –  CH produces glycation of lipoproteins, which exhibit a prolonged residence and cannot be metabolised normally and stay in the circulation for a long period of time. Chronic hyperglycemia also generates free radicals, potentiating oxidative stress and leading to production of protein adducts called advanced glycation end products. These can harm the vascular wall and initiate a chronic inflammatory response.
  2. Cardiovascular risk is particularly high in patients with diabetes mellitus who exhibit microalbuminuria, frank proteinuria or renal impairment. Persons with type 2 diabetes mellitus who suffer Myocardial Infarction (Heart Attack) or MI show increased mortality both immediately and in the long term. Late diagnosis and thus poor prognosis is also contributed to by the fact that MI in persons with diabetes may be painless due to the presence of autonomic neuropathy.

Table 1. Characteristics of the diabetic dyslipidemic profile.

Parameter Consequence
Raised triglyceride levels Enhanced thrombogenicity
Increased remnant triglyceride-rich lipoproteins
Reduced HDL plasma levels
Increased small dense LDL particles
Small dense LDL Increased penetration of arterial intima
Enhanced proteoglycan binding
Increased oxidation potential
Reduced plasma HDL levels Reduced antioxidant and anti-inflammatory activity
Increased apolipoprotein B levels Increased remnant particles
Increased small dense LDL particles

Important points to remember

Patients with type 2 diabetes and the metabolic syndrome exhibit the highest cardiovascular risk. Since moderate weight loss produces a selective loss of visceral fat and improves all features of the metabolic syndrome, weight loss is at a premium in this population.

Diabetes abolishes the sex advantage with regard to coronary risk. Women with type 2 diabetes mellitus exhibit, on average, the same coronary risk as diabetic men of the same age.
Patients with type 2 diabetes mellitus often display several conventional coronary risk factors. It is therefore important to calculate coronary risk using a scheme such as the PROCAM score that includes both diabetes and these factors. An alternative to the use of a general score such as PROCAM is to use a risk score specifically designed for diabetics. One such is the UKPDS Risk Engine, a type 2 diabetes–specific risk calculator based on 53,000 patient years of data from the United Kingdom Prospective Diabetes Study, which also provides an approximate margin of error for each estimate


Metabolic syndrome

Aggregation of risk factors: the metabolic syndrome

The metabolic syndrome refers to an aggregation of atherogenic risk factors including dyslipidemia, hypertension, hyperglycemia and the presence of prothrombotic and inflammatory risk markers. The syndrome may represent the metabolic complications of abdominal obesity, with insulin resistance playing a major role. Individuals with the metabolic syndrome are at increased risk for type 2 diabetes mellitus. It has been suggested that the CHD risk of persons with the metabolic syndrome should be regarded as being greater than that calculated purely on the basis of, for example, the PROCAM score. Unfortunately, three sets of criteria for diagnosing the metabolic syndrome are in common use (WHO 1999 [insulin resistance], ATP III 2003 [environment], IDF 2005 [obesity]). These were proposed by the Third Adult Treatment Panel of the U.S. National Cholesterol Education Program (NCEP ATP), the World Health Organization (WHO) and the International Diabetes Federation (IDF). While showing a large degree of overlap, these criteria differ in the following important respects:

The NCEP ATP criteria emphasize environmental causes and suggest that abdominal obesity is a consequence of an energy-rich diet and a sedentary lifestyle. Recently, these criteria suggested lowering the threshold for normal fasting plasma glucose to 100 mg/dL (5.5 mmol/L). These criteria are widely used in the U.S. and Europe.

The WHO criteria emphasize the presence of insulin resistance and, in some subjects, require the measurement of fasting plasma insulin and formal assessment of insulin resistance using the homeostasis model assessment (HOMA) index. For these reasons these criteria are less frequently used in clinical practice.

The IDF emphasizes the presence of an elevated waist circumference as a mandatory clinical criterion of the metabolic syndrome. Population-specific waist circumference cutoffs to define abdominal obesity were proposed, although these have not been validated against clinical endpoints.

Recently, there has been much discussion on the usefulness of the metabolic syndrome as a nosologic entity, with some claiming that “diagnosis of the metabolic syndrome is redundant in those who already have diabetes and adds nothing to the management of those who do not1. However, the term is still in common usage and is therefore discussed here at some length.

Gale, A.M., Albertik, K.G.M.M., Zimmet, P.Z. Should we dump the metabolic syndrome? Br Med J 2008; 336: 640-641.


Aggregation of risk factors: the metabolic syndrome

The metabolic syndrome refers to an aggregation of atherogenic risk factors including dyslipidemia, hypertension, hyperglycemia and the presence of prothrombotic and inflammatory risk markers.


Integrating metabolic syndrome into global risk assessment

Although the metabolic syndrome increases the relative risk of CHD, its diagnosis alone is not sufficient to properly assess this risk,1 which should be assessed on the basis of traditional risk factors using available algorithms.2 The global CVD risk resulting from the presence of traditional risk factors and from the metabolic abnormalities of abdominal obesity and the metabolic syndrome has been defined as the global cardiometabolic risk.3

Cardiometabolic risk is the overall risk of CVD resulting from both the presence of metabolic syndrome and of traditional risk factors such as dyslipidemia (raised LDL cholesterol and low HDL cholesterol), hypertension, diabetes, age, male sex, smoking and other unknown risk factors (including genetic factors that cannot be properly assessed in clinical practice at the present time). The additional degree of risk contributed by the metabolic syndrome is unclear at the present time.

Kahn, R., Buse, J., Ferrannini, E. et al. The metabolic syndrome: Time for a critical appraisal: Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28: 2289-2304.
Després, J.P., Lemieux, I. Abdominal obesity and metabolic syndrome. Nature 2006; 14: 881-887.
Tuomilehto, J. Cardiovascular risk: Prevention and treatment of the metabolic syndrome.
Diabetes Res Clin Pract 2005; 68 (Suppl. 2): S28-S35.


Diabetes mellitus and metabolic syndrome: special categories of high risk

Pathophysiology of the metabolic syndrome

Insulin resistance plays a central role in the metabolic syndrome and is associated with atherogenic dyslipidemia and with hyperglycemia leading to diabetes and hypertension1. With introduction of the NCEP ATP III clinical criteria of the metabolic syndrome, a cluster of abnormalities that were initially defined on the basis of pathophysiology (insulin resistance) was developed into an operational definition to facilitate clinical diagnosis. Thus, while the NCEP ATP III or the IDF criteria are helpful in identifying a group of individuals likely to be insulin resistant, not every patient with a clinical diagnosis of the metabolic syndrome is insulin resistant.2

There is substantial evidence that the pathophysiology of insulin resistance is linked to an impairment in the metabolism of free fatty acids.3-5 Obesity, especially abdominal obesity associated with an excess of visceral adipose tissue and with ectopic fat deposition in the liver, heart, skeletal muscle and pancreas, is not only associated with insulin resistance and impaired free fatty acid metabolism, but also with inflammation and an altered production of adiponectin.6 On that basis, it has been proposed that the most prevalent form of the metabolic syndrome is associated with a dysfunctional and insulinresistant adipose tissue and with an altered production of inflammatory cytokines and adipokines. Visceral obesity and ectopic fat deposition are therefore frequent partners of insulin resistance and of the metabolic syndrome, although the respective roles of these two factors are not yet clear.

Prevalence of metabolic syndrome according to age

Irrespective of the clinical criteria used, the prevalence of the metabolic syndrome increases with age. This phenomenon might be explained by the sedentary lifestyle habits of older individuals and their consumption of an energy-dense diet that contributes to a positive energy balance, weight gain and abdominal obesity.

Influence of metabolic syndrome on risk of MI

Meta-analyses and several reviews have concluded that a clinical diagnosis of metabolic syndrome approximately doubles the risk of CHD. Essentially, the risk of developing all manifestations of CVD is increased by the metabolic syndrome.7,8 Metabolic syndrome is highly prevalent among individuals who suffer an MI, in whom it is associated with lower survival rates9. To reduce cardiovascular mortality, it is therefore of primary importance to prevent the development of the metabolic syndrome. If present in a patient who has experienced an acute coronary event, vigorous treatment of existing cardiovascular risk factors and weight loss are recommended on the basis of indirect evidence, although no trial has yet shown that reducing weight and intra-abdominal fat improve short- and long-term survival of patients who have had an acute coronary event.

Reducing coronary risk in patients with diabetes mellitus and impaired glucose tolerance or impaired fasting glucose

Because of the increased CVD risk of patients with diabetes and the metabolic syndrome, all risk factors in such patients should be treated vigorously.10-12 Studies have shown the benefits of statin therapy13-16 and of lowering blood pressure.17,18 In addition, because the most prevalent form of the metabolic syndrome is abdominal obesity, weight loss (which leads to a selective loss of visceral fat19) should be promoted by a lifestyle modification program that incorporates healthy eating and more physical activity. Such a program has been shown to reduce substantially the risk of developing type 2 diabetes among high-risk prediabetic subjects who were abdominally obese.20,21

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Ferrannini, E. Is insulin resistance the cause of the metabolic syndrome? Ann Med 2006;
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Bajaj, M., Defronzo, R.A. Metabolic and molecular basis of insulin resistance. J Nucl Cardiol 2003; 10: 311-323.
Després, J.P., Lemieux, I. Abdominal obesity and metabolic syndrome. Nature 2006; 14: 881-887.
Galassi, A., Reynolds, K., He, J. Metabolic syndrome and risk of cardiovascular disease: A meta-analysis. Am J Med 2006; 119: 812-819.
Gami, A.S., Witt, B.J., Howard, D.E. et al. Metabolic syndrome and risk of incident cardiovascular events and death: A systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49: 403-414.
Zeller, M., Steg, P.G., Ravisy, J. et al. Prevalence and impact of metabolic syndrome on hospital outcomes in acute myocardial infarction. Arch Intern Med 2005; 165: 1192-1198.
Kahn, R., Buse, J., Ferrannini, E. et al. The metabolic syndrome: Time for a critical ppraisal: Joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2005; 28: 2289-2304.
Tuomilehto, J. Cardiovascular risk: Prevention and treatment of the metabolic syndrome. Diabetes Res Clin Pract 2005; 68 (Suppl. 2): S28-S35.
Poirier, P., Després, J.P. Lipid disorders in diabetes. In: Pickup, J.C., Williams, G. (Eds.). Textbook of diabetes 2002; 54.1-54.21.
Fujioka, K. Metabolic syndrome treatment strategies. Pharmacotherapy 2006; 26: 222S- 226S.
Collins, R., Armitage, J., Parish, S. et al. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet 2003; 361: 2005-2016.
Deedwania, P., Barter, P., Carmena, R. et al. Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease and metabolic syndrome: Analysis of the Treating to New Targets study. Lancet 2006; 368: 919-928.
Pyörälä, K., Ballantyne, C.M., Gumbiner, B. et al. Reduction of cardiovascular events by simvastatin in nondiabetic coronary heart disease patients with and without the metabolic syndrome: Subgroup analyses of the Scandinavian Simvastatin Survival Study (4S). Diabetes Care 2004; 27: 1735-1740.
Ballantyne, C.M., Stein, E.A., Paoletti, R. et al. Efficacy of rosuvastatin 10 mg in patients with the metabolic syndrome. Am J Cardiol 2003; 91: 25C-28C.
Kintscher, U., Bramlage, P., Paar, W.D. et al. Irbesartan for the treatment of hypertension in patients with the metabolic syndrome: A sub analysis of the Treat to Target post authorization survey. Prospective observational, two armed study in 14,200 patients. Cardiovasc Diabetol 2007; 6: 12.
Azadbakht, L., Mirmiran, P., Esmaillzadeh, A. et al. Beneficial effects of a Dietary Approaches to Stop Hypertension eating plan on features of the metabolic syndrome. Diabetes Care 2005; 28: 2823-2831.
Després, J.P., Lemieux, I., Prud’homme, D. Treatment of obesity: Need to focus on high risk abdominally obese patients. Br Med J 2001; 322: 716-720.
Knowler, W.C., Barrett-Connor, E., Fowler, S.E. et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 2002; 346: 393-403.
Tuomilehto, J., Lindström, J., Eriksson, J.G. et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1343-1350.


Diabetes mellitus and metabolic syndrome: special categories of high risk

Insulin resistance plays a central role in the metabolic syndrome and is associated with atherogenic dyslipidemia and with hyperglycemia leading to diabetes and hypertension. With introduction of the NCEP ATP III clinical criteria of the metabolic syndrome, a cluster of abnormalities that were initially defined on the basis of pathophysiology (insulin resistance) was developed into an operational definition to facilitate clinical diagnosis. Thus, while the NCEP ATP III or the IDF criteria are helpful in identifying a group of individuals likely to be insulin resistant, not every patient with a clinical diagnosis of the metabolic syndrome is insulin resistant.


Integrating metabolic syndrome into global risk

Although the metabolic syndrome increases the relative risk of CHD, its diagnosis alone is not sufficient to properly assess this risk, which should be assessed on the basis of traditional risk factors using available algorithms. The global CVD risk resulting from the presence of traditional risk factors and from the metabolic abnormalities of abdominal obesity and the metabolic syndrome has been defined as the global cardiometabolic risk.


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