RS is a 75-year-old Caucasian man with essential hypertension and type 2 diabetes mellitus of 7 years duration. He denies diabetic complications and takes only glipizide and atenolol. Physical exam shows weight 218 pounds, height 70”, body mass index 31, blood pressure 152/82 mm Hg, and absent reflexes at the ankles. Patients such as RS, who represent a common office scenario, raise several important questions regarding appropriate treatment:

• What are the risk factors for atherosclerotic vascular disease (ASVD) in this patient?
• Could he already have subclinical disease?
• How does diabetes contribute to the progression of atherosclerosis?
• As a patient in his 8th decade, can he still benefit from aggressive treatment of multiple risk factors, including improved glycemic control, or is it too late?

This article summarizes the current evidence regarding these questions, and provides the clinician with recommendations for preventing and treating macrovascular disease in older persons with diabetes.

Currently, there are 8.6 million Americans, 18.3% of adults, 60 years or older with diabetes.1 An additional 42% of adults over age 60 have the metabolic syndrome and/or prediabetes, both of which often precede the development of overt diabetes and indicate an atherosclerotic milieu associated with increased macrovascular risk.2 Given the aging of our population, the increased prevalence of being overweight or obese, and the age-related body composition changes leading to increased insulin resistance and type 2 diabetes, it is not surprising that cardiovascular disease (CVD) is the leading cause of diabetes-related deaths, with rates 2-4 times higher than in adults without diabetes.1 Together, heart disease and stroke account for 65% of deaths in older persons with diabetes.1 When diagnosed with diabetes at 60 years of age, life expectancy in men is reduced by 7.3 years and in women by 9.5 years.3,4

Although diabetes is strictly defined by plasma glucose levels, it is also a vascular disease, with the vasculature representing the “target organ” for accelerated atherosclerosis.5-8 Given that this process diffusely affects the arterial system, a patient with diabetes and CVD may be expected to have coexistent peripheral vascular disease (PVD), cerebrovascular disease, and/or an abdominal aortic aneurysm. The powerful influence of diabetes on accentuated atherosclerosis was demonstrated in the landmark study by Haffner and colleagues,9 which showed that the incidence of first myocardial infarction (MI) after 7 years of follow-up in patients with type 2 diabetes was the same (20%) as the incidence of MI in patients without diabetes who had had a previous MI (19%). Because of these observations, the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III) reclassified diabetes as a coronary heart disease (CHD) equivalent in the highest risk category.10

Older patients with diabetes are particularly clinically challenging, as they represent a heterogeneous population with differences in functional status as well as in duration, severity, and complications of diabetes.11 Added to the challenge of how to prioritize care for individuals such as RS is the recognition that ASVD in older adults is often clinically silent. Using a composite index of noninvasive methods from different arterial vascular beds, the overall prevalence of subclinical ASVD in adults 65 years and older was 37%.12 As shown by Chaves and colleagues,12 subclinical vascular disease increases with age and is at least as prevalent as clinically recognized disease. Using electron beam computed tomography to quantitate coronary artery calcium as a marker of subclinical CVD, one finds that asymptomatic patients with diabetes have significantly higher scores than age-matched persons without diabetes who are at least 70 years of age.13,14

Given that atherosclerosis begins years before the diagnosis of diabetes and is associated with more extensive, diffuse disease and poorer outcomes in patients with diabetes,1,4,8,15 it is imperative that the management of vascular disease and its risk factors be a high priority. Time is of the essence, as improved control of blood pressure and lipids can result in significant reductions in diabetes-related macrovascular events within 2-3 years—a key consideration in older patients.11

MECHANISMS AND PATHOPHYSIOLOGY OF ATHEROSCLEROSIS IN DIABETES
Although a detailed discussion of the pathophysiology of diabetic vascular disease is beyond the scope of this article, this section summarizes the current understanding of atherosclerosis in diabetes and provides a framework for recognizing how multiple risk factors promote the development and progression of this disease.

The concept of diabetes-related atherosclerosis as an inflammatory vasculopathy is now well established.6-8,16,17 The abnormal cluster of hyperglycemia, elevated free fatty acids, and insulin resistance, which characterizes both the metabolic syndrome and diabetes, acts in concert to target the endothelial cell, resulting in oxidative stress and endothelial dysfunction. Because the endothelium is an organ consisting of a single cell layer lining the intimal surface of the vasculature, it serves as an interface between circulation and the body tissues. As part of the endothelial cell’s normal paracrine and autocrine functions, it synthesizes a variety of substances that mediate vascular relaxation, control local inflammation, inhibit leukocyte migration, and influence platelet activation. When exposed to the metabolic derangements of diabetes, these functions are markedly disturbed. As shown in the Figure,7 endothelial dysfunction encompasses multiple abnormalities, including altered vasomotor reactivity, vascular smooth muscle cell (VSMC) dysfunction, overproduction of inflammatory cytokines and chemokines, impaired platelet function, and abnormal coagulation. Taken together, these perturbations lead to increased vasoconstriction, inflammation, and thrombosis.

In diabetes, impaired vasodilation results from reduced nitric oxide (NO) production and increased NO inactivation.16 Because NO preserves endothelial health by inhibiting smooth muscle cell growth, platelet aggregation, monocyte adhesion, local inflammation, and oxidation, reduced availability of NO is critically important in the process of atherogenesis. Although insulin is normally a vasodilator and stimulates NO production, these actions are defective in insulin resistance.16 As summarized in recent reviews,8,16 studies have demonstrated that endothelial dysfunction with impaired NO release is present not only in patients with type 2 diabetes but also in insulin-resistant persons even before carbohydrate intolerance develops.8,16 Elevated levels of free fatty acids also contribute to reduced NO production, further impairing vascular relaxation.8,16 Enhanced production of opposing vasoconstrictive factors, such as endothelin-1 and angiotensin II, accentuate endothelial cell injury and induce VSMC proliferation.7

The inflammatory component of atherosclerosis begins with the migration of lymphocytes and monocytes into the arterial wall and the secretion of proinflammatory cytokines and chemokines. Substances such as leukocyte cell adhesion molecules and interleukin-1 attract more leukocytes into the intima, resulting in the ingestion of oxidized low-density lipoprotein cholesterol (LDL-C) by scavenger macrophages and formation of the fatty streak, the earliest detectable atherosclerotic lesion. Inflammatory markers, such as C-reactive protein, promote this process by stimulating leukocyte adhesion and migration and by suppressing NO production.8 Glycosylation of proteins and oxidized LDL-C, increased by hyperglycemia, leads to the deposition of advanced glycosylated end products in the vessel wall, further disrupting endothelial cell health. What ensues is a vicious cycle of relentless leukocyte migration, production of proinflammatory substances, and the ongoing formation of atherosclerotic plaque.

Vascular smooth muscle cell dysfunction also plays an integral role in the progression of diabetes-related atherosclerosis. Hyperglycemia stimulates protein kinase C and other factors within the VSMC, ultimately leading to the deposition of a complex atherosclerotic matrix in the arterial wall. By producing a fibrous cap of collagen, VSMCs normally strengthen the atheromatous plaque, making it less likely to rupture. In diabetes, VSMCs undergo accelerated apoptosis, resulting in fewer numbers of cells, reduced collagen production, increased plaque instability, and greater propensity for rupture.7

The final event in ASVD following plaque rupture is thrombosis leading to vascular occlusion. Thrombogenic risk is heightened in diabetes by the presence of a prothrombotic state characterized by impaired fibrinolysis and platelet hyperaggregability. Levels of plasminogen activator inhibitor 1 (PAI-1), a factor that decreases fibrinolysis, are increased in both plasma and atheromatous material from patients with diabetes. Other prothrombotic substances, such as fibrinogen and factor VII, are also increased in diabetes. In the platelet, hyperglycemia disrupts the normal regulatory system for controlling aggregation and thromboxane formation. Platelet hyperaggregability results from the reduced production of inhibitors of platelet aggregation, including NO and prostacyclin, and from the increased production of thrombin and other factors that increase platelet activity.

In summary, the pathogenesis of atherosclerosis involves multiple abnormalities in the endothelium, the VSMC, platelet function, and the clotting system. At every step, insulin resistance and hyperglycemia worsen these processes and accelerate atherogenesis and thrombosis.

RISK FACTORS FOR ATHEROSCLEROSIS
As stated previously, atherosclerosis is a multifactorial process that develops through the complex interactions of a number of recognizable factors. Persons with diabetes are known to carry a greater burden of atherogenic risk factors, such as hypertension, dyslipidemia, and central obesity identified by an increased waist-to-hip ratio. Because these traditional risk factors do not fully explain the excess risk in diabetes, other nontraditional or “novel” risk factors have also been identified, including microalbuminuria, coagulation abnormalities, endothelial dysfunction, hyperglycemia, and inflammatory markers (Table).18,19 In essence, treatment of diabetic vascular disease is synonymous with risk factor reduction.

Whether the established and powerful relationship between the various risk factors and atherosclerosis persists in the elderly population is a critical question because it directly impacts our decisions for treatment. An analysis of nearly 19,000 participants age 45 to over 75 years from the Atherosclerosis Risk In Communities (ARIC) study and the Cardiovascular Health Study (CHS) demonstrated that most risk factors continue to be strongly associated with increased atherosclerosis at a consistent magnitude across the age spectrum.20,21 Only in white men over age 75 years was the risk for vascular disease no different between men with or without diabetes.20 Thus, as in middle-aged adults with diabetes, treatment of accelerated atherosclerosis in older persons with diabetes uses a strategy of intensive risk factor reduction. In this section, we review the benefits of current treatments for several of the recognized risk factors.

Hypertension
Hypertension, which is present in over 60-70% of older adults with diabetes, is the single most important risk factor for vascular complications.1,22 As summarized in several reviews, multiple studies have documented that treatment of hypertension in older persons with diabetes is dramatically beneficial, reducing CVD risk by 33-50%.23-25

The most compelling data come from the United Kingdom Prospective Diabetes Study (UKPDS),26 the Hypertension Optimal Treatment (HOT) trial,27 and the Systolic Hypertension in the Elderly Program (SHEP).28 In the UKPDS, patients assigned to intensive blood pressure control (144/82 mm Hg) versus conventional control (154/87 mm Hg) experienced risk reductions of 24-56% in various macrovascular endpoints, including death. For each 10 mm Hg reduction in systolic pressure, MI was reduced by 11%, with the lowest risk for all endpoints observed at a systolic pressure lower than 120 mm Hg.26 In the SHEP trial of more than 550 participants with diabetes who were age 60 years and older, treatment of isolated systolic hypertension significantly reduced incidence of cerebrovascular and coronary events—even in patients age 80 years and older.28

Although systolic blood pressure is a more robust cardiovascular risk factor than diastolic pressure in adults age 60 years and older, the HOT trial demonstrated a 50% risk reduction in patients with diabetes who achieved diastolic levels of 80 mm Hg or lower, as compared with levels of 90 mm Hg or lower.27,29 Thus, achieving tight blood pressure control to levels of 130/80 mm Hg or lower, if tolerated, usually with multiple medications, can provide dramatic benefit to older adults with diabetes.

Dyslipidemia
Lipid abnormalities, present in 30-55% of adults with diabetes, are characterized by average-to-high levels of LDL-C, low levels of high-density lipoprotein cholesterol (HDL-C), and high levels of triglycerides with qualitative differences in lipoprotein fractions, such as small, dense LDL-C.18 Although LDL-C is not consistently elevated in diabetes, its importance as a strong risk factor for CVD comes from the statin trials, which have included participants with diabetes.30-38 Both the Scandinavian Simvastatin Survival Study (4S) and a subsequent analysis that included data from the Prospective Pravastatin Pooling (PPP) project published in the 1990s showed benefits of statin therapy, with reduced vascular event rates of up to 44% in persons with diabetes, even with an initial LDL-C level of less than 125 mg/dL.31,32 As in middle-aged patients with diabetes, benefits from lipid-lowering therapy are seen within 6 months to 2 years in the elderly, indicating that the atherosclerotic process does not differ and is not irreversible in older patients.33,34

In 2004, based on the findings of five major clinical trials of statin therapy, the ATP III issued updated guidelines for the treatment of hyperlipidemia with the recommendation that older persons not be denied lipid-lowering treatment based on age alone.35 Results from the Heart Protection Study (HPS)36 and the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study37 documented the benefit of LDL-C lowering in older adults with diabetes. In the HPS, which included nearly 6000 persons with diabetes (ages 40-80 years) with an average baseline LDL-C of 131 mg/dL, simvastatin 40 mg per day significantly reduced first-event rates for CVD and stroke, irrespective of age, by 22% over 5 years. In participants with pretreatment LDL-C levels of lower than 116 mg/dL, macrovascular complications were also lowered by an impressive 27%.36 In the recent Collaborative AtoRvastatin Diabetes Study (CARDS),38 first CVD events were reduced by 37% and strokes by 48% in more than 2800 participants with type 2 diabetes, age 40-75 years, treated with atorvastatin 10 mg per day for a median duration of 3.9 years.38 These findings confirm the HPS observations and support the use of statins in older persons with diabetes, despite the initial level of LDL-C. Based on the updated ATP III guidelines, LDL-C should be lowered 30-40% regardless of baseline and in “very-high-risk” patients with diabetes with established macrovascular disease; the target LDL-C is now lower than 70 mg/dL.35

Glycemic control
The effect of glycemic control on the risk for ASVD is relatively weak compared to other risk factors such as blood pressure and LDL-C. A possible explanation for this observation is the existence of a prediabetic atherogenic state for several years prior to the development of overt diabetes. Nevertheless, there is a definite impact of poor control of hyperglycemia on vascular risk. Updated data from the UKPDS of nearly 5000 patients with diabetes followed for a median of 10 years demonstrated a significant effect of A1c levels—from 5.5% to 11%—on CVD event rates.39 For each 1% reduction in A1c level, there was a 12-14% reduction in fatal and nonfatal MI and stroke, and a 43% reduction in amputation or death from PVD.39

In addition to overall glycemic control, attention has recently focused on postprandial hyperglycemia as an additional and independent risk factor for CVD in both subjects with and without diabetes.40-42 In the CHS of adults age 65 years and older, Smith et al41 observed that a fasting glucose of higher than 114 mg/dL was associated with a 66% increased CVD risk, and that after adjusting for fasting glucose levels, a 2-hour post-challenge glucose of higher than 153 mg/dL was associated with a 28% and 42% increased risk of CVD and stroke, respectively.41 How these findings will translate into clinical practice is uncertain. Several large clinical trials are currently underway to address the question of whether tight glycemic control is associated with reduction in CVD outcomes.43 The Action to Control CardiOvascular Risk in Diabetes (ACCORD) trial, a multicenter study of 10,000 subjects up to age 70, is designed to answer whether normoglycemia with an A1c of lower than 6.0% can reduce the rate of CVD complications compared to an A1c of 7-7.9%.43

Inflammatory markers
C-reactive protein, a marker of vascular inflammation, is an acute-phase protein produced by the liver. Multiple studies have documented that elevated C-reactive protein levels are associated with increased rates of CVD and mortality in the elderly.18,21,44 The importance of it as an independent predictor of CVD was recently shown in a group of older subjects, more than 50% of whom had diabetes or the metabolic syndrome.45 After adjusting for diabetes and hypertension, C-reactive protein levels of at least 3.0 mg/L conferred a relative risk of 1.68.45

Nontraditional risk factors
Although nontraditional risk factors are of considerable interest, their role in clinical practice remains to be determined with two exceptions.18,21,44 Microalbuminuria, a marker of early arterial disease, has unequivocally been shown to be a potent risk factor for CVD and stroke in adults with diabetes.18,46 Activation of the renin-angiotensin system also contributes to macrovascular risk in diabetes as indicated by observations from the Heart Outcomes Prevention Evaluation (HOPE) study and the MIcroalbuminuria, Cardiovascular, and Renal Outcomes in HOPE (MICRO-HOPE) substudy.46 In more than 3500 persons with diabetes, treatment with an angiotensin-converting enzyme inhibitor (ramipril) significantly lowered the rates of MI, stroke, and CV death by 25-30% beyond the effects of blood pressure reduction alone.

Multi-interventional risk factor reduction
In diabetes, multifactorial risk reduction is the name of the game. The value of this strategy was demonstrated in the Steno-2 trial of 160 patients with diabetes who had microalbuminuria followed for 7.8 years. Intensive treatment targeted an A1c lower than 6.5%, blood pressure lower than 130/80 mm Hg, and total cholesterol lower than 190 mg/dL in the early years, and lower than 175 mg/dL for the last 2 years. After adjusting for age, sex, and duration of diabetes, an intensified approach reduced cardiac and other vascular endpoints by an impressive 55%.47

SUMMARY
The first part of this two-part article summarized the epidemiologic impact of ASVD in the older adult with diabetes, the pathogenic mechanisms of atherosclerosis, and the numerous traditional and nontraditional risk factors that accelerate atherogen-esis. In the case patient, RS, risk factors for ASVD include age, obesity, hypertension, diabetes, and laboratory data that showed an LDL-C of 145 mg/dL and an elevated microalbumin/Cr ratio. Although the likelihood of subclinical or preexistent CVD in this patient is high (> 40%), studies have documented that patients such as RS in the 8th decade of life with longstanding diabetes can still benefit from the intensive and simultaneous treatment of multiple risk factors.

As current estimates indicate that 88% of older persons with diabetes have either established or subclinical CHD, the importance of diabetes-related ASVD and its impact on the older population cannot be overstated.

Part II of this article will discuss the rationale and strategies for treatment of ASVD in the older person with diabetes, and provide an easy-to-remember checklist to help busy clinicians implement this approach.