Approximately 12 million Americans have type 2 diabetes (formerly known as non– insulin-resistant diabetes), and an estimated 20 million more Americans have some degree of glucose intolerance.¹ The greatest cause of mortality in type 2 diabetes is atherosclerotic vascular disease and its sequelae. Between 75 and 80 percent of adult patients with diabetes die of macrovascular complications.² Once clinical cardiovascular disease develops, patients with type 2 diabetes have a poorer prognosis for survival than normoglycemic patients with cardiovascular disease.^3,4 This article reviews successful strategies for the reduction of cardiovascular risk factors in patients with type 2 diabetes.

Atherogenic Mechanisms in Diabetes

Links between endothelial dysfunction, atherosclerosis and diabetes have been increasingly recognized. One of the earliest discernible atherogenic changes in diabetes is endothelial dysfunction, which is characterized by inhibited vasodilation, vascular smooth-muscle proliferation, increased thrombogenesis and proatherogenic cellular processes.⁵ Abnormal endothelium-dependent vasodilation also occurs in the microcirculation of patients with diabetes, where it may contribute to ischemia and its sequelae.⁶

Hyperglycemia and atherosclerosis in type 2 diabetes are related. Hyperglycemia causes glycosylation of virtually all proteins, inducing collagen cross-linking with other extracellular matrix proteins in the arterial wall.⁷ Long-term exposure to elevated glucose levels alone can cause the endothelial cell dysfunction observed in diabetes. Accelerated atherosclerosis, thrombosis, hypertension and hyperlipidemia all participate in the pathogenesis of vascular disease in patients with diabetes, and endothelial dysfunction is probably involved in each of these vascular abnormalities.⁸

The pathogenesis of atherosclerosis also involves oxidation of low-density lipoprotein (LDL) cholesterol.⁹ Exposure to glycosylation end products can prolong the half-life of LDL cholesterol, increasing the likelihood that it will be trapped in the vascular wall where it is more susceptible to oxidation.⁷

ATHEROGENIC DYSLIPIDEMIA

An interrelated group of lipoprotein abnormalities, collectively known as “atherogenic dyslipidemia,” predispose patients to develop coronary heart disease (Table 1).¹⁰ The risk of heart disease associated with these lipoprotein abnormalities equals or exceeds the risk from an LDL cholesterol concentration of 150 to 220 mg per dL (3.90 to 5.70 mmol per L).¹⁰ Patients with type 2 diabetes often have key elements of this complex. The combination of elevated triglyceride levels and decreased high-density lipoprotein (HDL) cholesterol levels, which constitutes the most common dyslipidemic pattern in type 2 diabetes, is known as “diabetic dyslipidemia.” Such patients also tend to have a preponderance of atherogenic small, dense LDL cholesterol particles, whether or not LDL cholesterol levels are elevated.¹⁰

METABOLIC SYNDROME

Atherogenic dyslipidemia is often associated with other risk factors for coronary heart disease. This constellation of risk factors, evolved from older concepts of syndrome X and the insulin resistance syndrome, has been termed the “metabolic syndrome” (Table 2).¹⁰ It is not unusual for all elements of this syndrome to be present in a single patient. Indeed, most patients with atherogenic dyslipidemia are insulin-resistant.¹⁰

Dyslipidemia and hypertension commonly coexist, and the frequent reports of a positive association between insulin resistance and hypertension warrant the inclusion of elevated blood pressure in the metabolic syndrome. Together, hypertension and overt diabetes double the risk of cardiovascular disease.^3,11

Most patients with impaired glucose tolerance or type 2 diabetes have some degree of insulin resistance.¹² Obesity, frequently observed in patients with type 2 diabetes, is virtually always accompanied by insulin resistance.¹³ Insulin resistance is also strongly associated with many risk factors for coronary artery disease, such as hypertension, increased plasma triglyceride levels and decreased HDL cholesterol levels.¹² The best established of these associations is the one between high plasma triglyceride levels and low HDL cholesterol levels.¹⁴

Obesity is a prominent feature of the metabolic syndrome.¹⁰ The association between obesity and hypertension is well documented, and obesity can worsen other risk factors.¹⁵ Obesity in patients with type 2 diabetes is associated with atherogenic changes in lipids and lipoproteins.² For example, triglyceride levels are generally higher in obese persons than in lean persons.¹⁵

The distribution of fat, rather than overall obesity, determines risk. The reported association between increased abdominal (upper body) fat and an increased risk of coronary heart disease relates to visceral fat, for which the waist-to-hip ratio is a convenient index. A waist-to-hip ratio of greater than 1.0 in men and 0.8 in women indicates abdominal obesity.¹⁶ The waist circumference alone also correlates well with the amount of visceral fat, and the relationship is similar in men and women.¹⁷

At least two other abnormalities secondary to insulin resistance or hyperinsulinemia have been linked to the metabolic syndrome. Increased concentrations of plasminogen activator inhibitor 1 are associated with deficient fibrinolysis.¹⁸ In addition, the 16-year follow-up of the First National Health and Nutrition Examination Survey suggests that hyperuricemia is significantly and independently associated with the risk of cardiovascular mortality.¹⁹

HYPERHOMOCYSTEINEMIA

Hyperhomocysteinemia has recently been recognized as an independent risk factor for cardiovascular disease. This condition has an estimated prevalence of 5 to 30 percent in the general population.²⁰

A large-scale prospective study found that the five-year mortality risk was almost two times higher in patients with hyperhomocysteinemia and type 2 diabetes than in patients with hyperhomocysteinemia but no diabetes.²⁰ A recent meta-analysis found that folic acid in a dosage of 0.5 to 5 mg per day can lower serum total homocysteine levels by 15 to 40 percent within about six weeks.²¹ This treatment may be particularly important in patients with diabetes. However, no interventional evidence has related blood levels of homocysteine reduced by folic acid to reduced rates of cardiovascular disease in controlled trials. Therefore, attention should not be diverted from traditional risk-lowering strategies in favor of folic acid supplementation.²²

Need for Coronary Heart Disease Prevention in Type 2 Diabetes

Atherosclerosis is accelerated in patients with diabetes, and the development of coronary heart disease worsens the prognosis.⁴ Control of predisposing risk factors is an effective strategy for both cardiovascular disease and diabetes (Table 3).^3,23

With the exception of smoking, all potentially reversible risk factors for coronary heart disease are more prevalent in patients with diabetes than in the general population. Based on the outcomes of major interventional trials in large cohorts of diabetic patients, aggressive treatment of lipid abnormalities is warranted. Because one half of patients with type 2 diabetes already have evidence of coronary heart disease at the time their diabetes is diagnosed,²³ the distinction between primary prevention in high-risk patients and secondary prevention in those with clinical coronary heart disease may be arbitrary in patients with diabetes.⁴

Attenuating Risk Factors for Coronary Heart Disease in Type 2 Diabetes

Based on the results of clinical trials in patients with and without diabetes, the American Diabetes Association (ADA) has issued treatment goals and guidelines for managing dyslipidemia (Table 4).²⁴ New recommendations on nutrition²⁵ and exercise²⁶ have also been published.

DIET AND EXERCISE

Dietary modification and increased physical activity are the mainstays of nonpharmacologic treatment.²⁴ The American Heart Association's step I and step II diets emphasize the consumption of foods that are low in fat (especially saturated fat) and cholesterol. Weight loss can improve glucose control and reduce lipid levels. Weight loss seems preferentially to reduce atherogenic visceral fat, and the resultant metabolic improvement appears to be disproportionately greater than the amount of weight lost.¹⁷

Today there is no one prescribed “diabetic” or ADA diet. Current ADA guidelines for medical nutrition therapy stress the use of an individual approach, preferably in consultation with a registered dietitian and with consideration given to the patient's usual eating habits and lifestyle.²⁵ The diet should be geared toward achieving treatment goals for glucose control, lipid levels and blood pressure, as well as maintaining reasonable weight and adequate nutrition. No matter what the patient's starting weight is, moderate weight loss (4.5 to 9.1 kg [10 to 20 lb]) has been shown to reduce hyperglycemia, dyslipidemia and hypertension.²⁵

Similarly, exercise can substantially improve the metabolic abnormalities in type 2 diabetes. An exercise program is most effective when it is instituted early in the disease process. Benefits include an improved lipoprotein profile, reduced blood pressure and increased cardiovascular fitness.²⁶ Exercise may also enhance weight loss, and a disproportionate effect of exercise on abdominal fat has been reported.²⁶ The patient should be evaluated before an exercise program is prescribed (Table 5).³ The specific recommended program will depend on the evidence of cardiovascular disease.

SMOKING CESSATION

Cigarette smoking doubles the risk of cardiovascular disease in patients with diabetes and attenuates whatever benefits accrue from modifying other risk factors.³ The Multiple Risk Factor Intervention Trial quantified an independent and increasing risk of coronary heart disease mortality based on the number of cigarettes smoked per day.²⁷ Cigarette smoking appears to act synergistically with hypercholesterolemia, possibly by enhancing the oxidation of LDL cholesterol.²⁸

ANTIOXIDANT THERAPY

Given the current focus on lipid oxidation in the pathogenesis of atherosclerosis, the increase in oxidized LDL cholesterol found in patients with diabetes would seem to provide a rationale for antioxidant therapy.^7,9 Observational and epidemiologic studies have suggested that persons and populations with high plasma levels of vitamin E have lower rates of coronary heart disease, and an inverse relationship has been found between β-carotene and cardiovascular mortality.²⁹ A prospective study of high doses of vitamin E from natural sources, however, led to the conclusion that vitamin E had no demonstrable effect on cardiovascular outcomes in a high-risk population followed for four to six years.³⁰ Further research may clarify these contradictions. Current opinion is that dietary antioxidants are strongly recommended.

ANTIHYPERGLYCEMIC THERAPY

Glycemic control improves the characteristic dyslipidemia of diabetes, particularly elevated triglyceride levels. Although first-step therapy in glucose control is weight loss and exercise, pharmacologic measures may be necessary if lifestyle changes prove inadequate.³ Combined therapy using several agents, such as a sulfonylurea and metformin (Glucophage), is increasingly common.⁷ Insulin is recommended as third-step therapy and can also be combined with other agents.^3,7 Note, however, that plasma lipoprotein abnormalities persist in most patients despite antihyperglycemic therapy.²⁴

ASPIRIN THERAPY

The platelets in patients with type 2 diabetes and cardiovascular disease have been reported to release excess thromboxane, a potent accelerator of platelet aggregation. Because aspirin rapidly and irreversibly inhibits thromboxane synthesis, low-dose aspirin therapy has been suggested as both a primary and secondary prevention strategy in patients with diabetes. A low dosage of aspirin (75 to 325 mg per day) is apparently as effective as higher dosages (up to 1,500 mg per day) in blocking thromboxane synthesis.³¹

LDL CHOLESTEROL TARGET LEVELS

Current ADA guidelines accord lowering LDL cholesterol levels the highest treatment priority, followed by raising HDL cholesterol levels and lowering triglyceride levels (Table 6).²⁴ LDL cholesterol levels in patients with type 2 diabetes may be similar to those in normoglycemic patients, but the composition of the particles (smaller and denser) may make them more atherogenic.⁷

LDL cholesterol levels in all adults with diabetes should optimally be less than 100 mg per dL (2.60 mmol per L), the same level recommended for patients with coronary heart disease. If behavioral interventions do not reduce LDL cholesterol levels sufficiently, pharmacologic therapy is indicated. In patients with multiple risk factors even in the absence of clinical coronary heart disease, some authorities recommend drug therapy when LDL cholesterol levels exceed 100 mg per dL.²⁴

STATINS

“Statin” is the term applied to 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. Statins are the first-line agents for use in reaching target LDL cholesterol levels, with a bile acid sequestrant (binding resin) added if needed^23,24 (Table 6²⁴ and 7^32,33). After four to eight weeks of therapy, statins generally reduce LDL cholesterol levels by 20 to 60 percent, which can also favorably affect triglyceride levels.^23,24,34 In patients with triglyceride levels in the range of 200 to 250 mg per dL (2.26 to 2.82 mmol per L), the percent reduction in the triglyceride levels will equal the reduction in the LDL cholesterol level.³⁵ Statins lower very-low-density lipoprotein (VLDL) cholesterol levels as well as LDL cholesterol levels; benefits in patients with diabetes may relate to the combined activity.^34,35

The rationale for considering the LDL cholesterol level as the primary lipoprotein level to modify is based on the results of recent long-term clinical trials such as the Scandinavian Simvastatin Survival Study (4S)⁴ and the Cholesterol and Recurrent Events (CARE) trial.³⁶ In these five-year trials, lowering LDL cholesterol levels strikingly reduced the risk of major coronary events in patients with and without diabetes. In the 4S study,⁴ the risk of major coronary events in patients with diabetes was reduced by 35 percent, and the risk of any atherosclerotic event was reduced by 37 percent; similar risk reductions were observed in patients who did not have diabetes. Total mortality in patients with diabetes was reduced by 43 percent. In the CARE trial,³⁶ which included patients with diabetes and so-called “normal” cholesterol levels, the risk of major coronary events was reduced by 25 percent in patients with diabetes and by 23 percent in patients without diabetes.

The effects of statins on coronary end points in patients with diabetes are currently being assessed in the Atorvastatin as Prevention of CHD Endpoints in Patients with Non-Insulin–Dependent Diabetes Mellitus (ASPEN) study and the Collaborative Atorvastatin Diabetes Study (CARDS). Both studies have enrolled patients with type 2 diabetes, dyslipidemia and other cardiovascular risk factors, and with and without a history of myocardial infarction. These studies are expected to be completed in 2003 (ASPEN) and 2004 (CARDS).

BILE ACID SEQUESTRANTS

Bile acid sequestrants are effective in decreasing LDL cholesterol and total cholesterol levels, but they may worsen hypertriglyceridemia.⁷ Long-term use appears to be safe, and these agents are particularly useful for treating younger patients and women who are considering pregnancy.³⁴ Because bile acid sequestrants can elevate VLDL cholesterol and triglyceride levels, they are a questionable choice for monotherapy in patients with type 2 diabetes.³⁴

FIBRIC ACID DERIVATIVES

Fibric acid derivatives, often termed “fibrates,” reduce VLDL cholesterol and triglyceride levels, increase HDL cholesterol levels and have variable effects on LDL cholesterol levels.³⁴ In the Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial (VAHIT),³⁷ gemfibrozil increased HDL cholesterol levels and decreased triglyceride levels compared with placebo in men with and without diabetes who had coronary heart disease and low HDL cholesterol levels as the primary lipid abnormality. After five years, VAHIT investigators found that the risk of a major coronary event was 22 percent lower and the risk of the combined outcome of coronary heart disease death, nonfatal myocardial infarction or stroke was 24 percent lower in gemfibrozil-treated patients compared with placebo-treated patients (P < 0.05 for major coronary event and combined outcome).

Fibric acid derivatives as a class may increase the occurrence of cholelithiasis, which is already more prevalent in patients with diabetes. In patients with extremely high triglyceride levels, gemfibrozil (Lopid) may elevate LDL cholesterol levels as it lowers triglyceride levels.^7,34

NICOTINIC ACID

When given in dosages well above those needed for the vitamin requirement, nicotinic acid (niacin [Nicolar]) favorably affects all lipids and lipoproteins. It also raises HDL cholesterol levels. The high frequency of side effects associated with nicotinic acid is a major disadvantage, however. Flushing, which results from vasodilation, is particularly troublesome, although aspirin or other prostaglandin synthesis inhibitors can decrease this adverse effect.³⁴ Because nicotinic acid is associated with hyperglycemia and possibly increases insulin resistance, many authorities do not use this agent in patients with type 2 diabetes.⁷

ANTIHYPERTENSIVE DRUG THERAPY

Control of hypertension is a cornerstone of treatment to prevent cardiovascular complications in patients with diabetes. The risk of these complications is lowest in adult patients whose average blood pressure is less than 120/80 mm Hg. The risk of complications increases incrementally as blood pressure increases. In patients who do not have diabetes, medical therapy is warranted if lifestyle changes do not lower blood pressure below 140/90 mm Hg. In patients with diabetes, the threshold for instituting medical therapy is a blood pressure of 130/85 mm Hg.¹¹

Tight control of blood pressure has been shown to reduce cardiovascular morbidity and mortality in patients with diabetes. The UK Prospective Diabetes Study included more than 1,100 patients with hypertension and type 2 diabetes.³⁸ In this study, patients assigned to tight blood pressure control achieved a mean blood pressure of 144/82 mm Hg (goal blood pressure: less than 150/85 mm Hg) compared with 154/87 mm Hg in those assigned to less stringent control. Patients in the tight-control group had a 34 percent reduction in risk of macrovascular diseases compared with those who maintained less stringent control. In the tight-control group, cardiovascular risk was reduced as follows: diabetes-related death by 32 percent, microvascular disease by 37 percent, stroke by 44 percent and heart failure by 56 percent.

Because of efficacy and a low incidence of side effects, angiotensin-converting enzyme (ACE) inhibitors are a reasonable first choice in patients with diabetes, hypertension and albuminuria. ACE inhibitors, alpha blockers, calcium channel blockers and low-dose diuretics have relatively few adverse effects on glucose homeostasis, lipid profiles and renal function.¹¹