Comprehensive Risk Reduction of Cardiovascular Risk Factors in the Diabetic Patient An Integrated Approach

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Sundararajan Srikanth, MD, Prakash Deedwania, MD, FACC, FACP, FCCP, FAHA*

Department of Medicine, VA Central California Health Care System/University Medical Center, University of California, San Francisco Program at Fresno, 2615 East Clinton Avenue, Fresno, CA 93703, USA

The Egyptians recognized diabetes as a pathologic entity nearly 3500 years ago. It was noted to be a rare condition but was known to reduce longevity. The condition now defined as type 2 diabetes is seen worldwide and has reached epidemic proportions. By the year 2025, the number of individuals with diabetes mellitus in the world is expected to exceed 300 million with a prevalence of 5.4% [1]. Diabetes continues to affect a substantial proportion of adults in the United States. Data from the National Health and Nutrition Enhancement Survey 1999-2000 indicate that 8.3% of persons over the age of 20 years have either diagnosed or undiagnosed diabetes, and this percentage increases to 19.2% for persons aged more than 60 years in the United States. Men and women are affected similarly by diabetes [2]. In 1999-2000, an additional 6.1% of adults had impaired fasting glucose tolerance, increasing to 14.4% for persons aged more than 60 years and with a greater incidence in men than in women [3]. Overall, an estimated 14.4% of the United States population aged more than 20 years and 33.6% of those aged more than 60 years have either diabetes or impaired fasting glucose tolerance. Moreover, type 2 diabetes is now being diagnosed more frequently in children and adolescents concomitant with the increasing prevalence of obesity and

* Corresponding author.

E-mail address: [email protected] (P. Deedwania).

decreased physical activity being seen in this population.

Cardiovascular (CV) diseases are the leading cause of morbidity and mortality in the general population. This baseline risk of CV disease is multiplied two- to fourfold in persons with diabetes mellitus, and the case fatality rate is higher than in nondiabetic patients [4]. CV disease accounts for 65% of deaths in persons with type 2 diabetes mellitus. Much of the morbidity and mortality is from atherosclerotic coronary artery disease, congestive heart failure, and sudden cardiac death. Efforts to reduce the mortality and morbidity related to CV diseases have borne fruit with substantial reduction in CV mortality over the past few decades. Advances in medical therapy and interventional techniques have resulted in only modest improvements in mortality from CV disease in men with diabetes, however, and during the last decade mortality rates of diabetes and CV disease have risen for women (Fig. 1) [5].

The excess CV mortality and morbidity in the diabetic population seems to reflect the strong association of diabetes with insulin resistance and with well-established coronary risk factors. During the past 2 decades, significant advances have been made in elucidating the pathophysiologic determinants and consequences of the metabolic perturbations in the diabetic state. The disease is characterized by insulin resistance and is commonly associated with the metabolic syndrome.

Fig. 1. Change in age-adjusted 8- to 9-year CV mortality in National Health and Nutrition Enhancement Survey over 30 years. (From Gu K, Cowie CC, Harris MI. Diabetes and decline in heart disease mortality in US adults. JAMA 1999;281:1291-7; with permission.)

Sensitivity to insulin is variable in the population at large. Cellular insulin resistance develops as the result of a complex interplay of genetic and environmental factors. Hyperinsulinemia occurs as an adaptive response to the increasing insulin resistance. Type 2 diabetes develops when insulin-resistant individuals cannot maintain the degree of excess insulin secretion needed to overcome insulin resistance. There are two aspects to the type 2 diabetic state: hyperglycemia and hyper-insulinemia. Insulin resistance and hyperglycemia seem to set the stage for the development of the metabolic syndrome, characterized by dyslipide-mia, hypercoagulability, hypertension, and trun-cal obesity (Table 1). Several of the metabolic derangements seen with the metabolic syndrome are well-established risk factors for CV disease:

1. Increased fatty acids

2. Increased triglyceride levels

3. Decreased high-density lipoprotein cholesterol (HDL-C)

4. Increased very low density lipoprotein

5. Increased remnant particles

6. Postprandial hyperlipemia

7. Increased small, dense low-density lipopro-tein (sdLDL) particles

8. Increased oxidized LDL cholesterol (LDL-C)

Several population-based longitudinal studies have shown that hyperinsulinemia predicts the development of CV disease in individuals without diabetes. Ruige and colleagues [6] performed a meta-analysis of 17 prospective studies, measuring insulin levels in relation to CV outcomes.

They found a statistically significant correlation between insulin levels and the incidence of CV events (relative risk [RR], 1.18; confidence interval, 1.08-1.29). The use of hyperinsulinemia as a surrogate marker for an insulin-resistant state has been confirmed by recent prospective cohort studies showing that insulin resistance, measured by steady-state glucose levels during an insulin suppression test, predicts the risk of CV disease [7,8]. It is unclear whether the insulin resistance per se is directly causative of the increased CV risk. It is, however, well known that metabolic

Table 1

Clinical identification of the metabolic syndrome

Risk factor

Defining level

Abdominal obesity

Waist circumference


>40 in (>102 cm)


>35 in (>88 cm)


>150 mg/dL (>1.7 mmol/L)





<40 mg/dL (<1.04 mmol/L)


<50 mg/dL (<1.30 mmol/L)

Blood pressure


>130 mm Hg


>85 mm Hg

Fasting glucose

>100 mg/dL (>5.56 mmol/L)

Diagnosis is made when >3 risk factors are present. Modified from The third report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda (MD): National Institutes of Health; 2002. NIH Publication 02-5215.

Diagnosis is made when >3 risk factors are present. Modified from The third report of the Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Bethesda (MD): National Institutes of Health; 2002. NIH Publication 02-5215.

abnormalities associated with insulin resistance are established risk factors for CV disease.

The metabolic abnormalities seen with the insulin resistant state seem to antedate the development of overt type 2 diabetes by years. Type 2 diabetes can perhaps be seen as one of the manifestations of the insulin-resistant state. This topic is elegantly covered in another article in this issue, but a brief review is appropriate here. The metabolic syndrome, also known as the insulin resistance syndrome or CV dysmetabolic syndrome, is a constellation of metabolic abnormalities that are associated with a higher risk of CV disease and mortality [9]. The syndrome is a concurrence of three or more of the following abnormalities in an individual:

Waist circumference greater than 102 cm (40 in)

in men and 88 cm (35 in) in women Serum triglyceride level of 150 mg/dL or higher HDL-C level less than 40 mg/dL in men and

50 mg/dL in women Blood pressure of 130/85 mm Hg or higher Fasting glucose level of 110 mg/dL or higher

The metabolic risk factors for CV disease that make up the metabolic syndrome do not directly cause type 2 diabetes but are frequently associated with it. The components of the metabolic syndrome identify individuals at increased risk for CV disease and define various parameters that can be modified to reduce the risk of CV disease. The comprehensive approach to treatment of the diabetic patient should prioritize the goal of reducing CV morbidity and mortality while addressing microvascular complications (nephrop-athy and retinopathy). Interventions should be targeted at the basic pathophysiologic processes that have been identified as risk factors leading to atherosclerosis and CV disease and are manifest more aggressively in the diabetic patient. The following sections briefly review current literature pertaining to interventions aimed at individual risk factors in the diabetic patient. Subsequently the authors develop the rationale for a comprehensive risk-reduction strategy based on currently available data and explore future directions.

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