Significance and treatment of individual risk factors

Dyslipidemia

Hypertriglyceridemia was one of the first metabolic abnormalities recognized as associated with insulin resistance. The mechanism of the hypertriglyceridemia is understood to result from varying sensitivities to insulin in the tissues in the individual's body. Defects in the ability of insulin to mediate muscle use of glucose and to inhibit lipolysis in adipose tissues seem to be the primary abnormalities causing the insulin-resistant state [10]. The resistance at the level of the muscle and adipose tissue leads to persistently higher ambient levels of insulin and free fatty acids. In response to the higher levels of free fatty acid, the hepatic tissue increases the rate of conversion of free fatty acids to triglycerides. This increased conversion is accentuated by the normal insulin sensitivity of the hepatic tissues in the face of compensatory hyperinsulinemia. The appreciation of the differences in the insulin sensitivity of the various tissues has led to better understanding of the abnormalities caused by insulin resistance. Although the classical diabetic dyslipidemia is characterized by high serum triglyceride levels, low levels of HDL-C, and an increased number of small, dense LDL particles, there are additional lipid abnormalities as well [11,12]. LDL-C is the major cholesterol-rich lipoprotein that mediates the link between serum cholesterol and atherosclerosis. The interaction of LDL-C with mono-cytes transforms them into the foam cells that are seen in atherosclerotic plaques. This interaction of the monocytes with LDL occurs only when the LDL is modified by acetylation, oxidation, or glycosylation, as realized in diabetes mellitus. Moreover the small, dense LDL particles that are abundant in diabetes mellitus are particularly atherogenic [13]. Thus quantitative and qualitative lipid abnormalities mediate the increased risk of atherosclerosis in diabetes mellitus as shown by the Multiple Risk Factor Intervention Trial Study [14] and the United Kingdom Prospective Diabetes Study (UKPDS) [15]. This topic is discussed more fully elsewhere in this issue.

Dyslipidemia associated with the metabolic syndrome is characterized by increased conversion of HDL-C from large, buoyant HDL2-C particles to more dense HDL3-C particles and conversion of large, buoyant LDL-C particles to small, dense LDL particles. A decrease in plasma levels of cardioprotective HDL2-C accompanied by increase in atherogenic small, dense LDL is associated with a higher risk of coronary artery disease. Stratification of risk factors for coronary artery disease in type 2 diabetes shows that LDL-C and HDL-C levels are the best predictors of coronary heart disease (Table 2). In the diabetic population,

Table 2

Stepwise selection of risk factors* in 2693 diabetics with dependent variable as time to first event

Table 2

Stepwise selection of risk factors* in 2693 diabetics with dependent variable as time to first event

Position in model

Variable

P value

Coronary Artery Disease (n = 280)

First

LDL cholesterol

<0.0001

Second

HDL cholesterol

0.0001

Third

Hemoglobin A1c

0.0022

Fourth

Systolic blood

0.0065

pressure

Fifth

Smoking

0.056

* Adjusted for age and sex.

Data from Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316:823-8.

* Adjusted for age and sex.

Data from Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ 1998;316:823-8.

hypertriglyceridemia and low HCL-C levels are approximately twice as prevalent as in the non-diabetic population, but the prevalence of a high LDL-C level is similar in the two groups [16]. Although there are no major clinical outcome trials involving only diabetics, many of the major clinical intervention trials on dyslipidemia, including the Scandinavian Simvastatin Survival Study (4S) and Cholesterol and Recurrent Events (CARE) trials, have enrolled a substantial number of subjects with diabetes mellitus [17,18]. In the 4S study, simvastatin led to a 35% decrease in LDL-C resulting in a 42% decrease in incidence of nonfatal myocardial infarctions and CV mortality. A meta-analysis of the CARE and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies showed a 25% decrease in the incidence of major coronary events and revascularizations in the subgroup of diabetic patients. Although these studies included only diabetic patients with established coronary heart disease, the recently reported findings from the Heart Protection Study support the use of lipid-lowering therapy in diabetics without clinically evident atherosclerotic disease [19]. This study which included almost 4000 diabetics without prior coronary heart disease, demonstrated a 26% risk reduction of nonfatal myocardial infarction, death from CV disease, stroke, or re-vascularizations in the group of subjects treated with simvastatin. The Heart Protection Study also challenges the cut point set forth by the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program for target LDL-C. Trials are being conducted to determine the desired threshold for LDL-C in secondary prevention.

More recently, in June 2003, the Collaborative Atorvastatin Diabetes Study (CARDS), involving 2800 patients with type 2 diabetes, was halted 2 years early because patients allocated to atorvas-tatin had significant reduction in myocardial infarction, stroke, and surgical procedures compared with those receiving placebo (Fig. 2) [20].

In this study, 2838 persons with type 2 diabetes between the ages of 40 and 75 years with no previous history of coronary heart disease, stroke, or other major CV events and a documented history of at least one risk factor (retinopathy, micro- or macroalbuminuria, hypertension, current smoking, LDL levels of 4.14 mmol/L [160 mg/dL] or lower, and triglyceride levels of 6.78 mmol/L [600 mg/dL] or lower) were randomly assigned to either placebo or atrovastatin (10 mg/d). Patients who received 10 mg of atorvastatin per day had a 37% reduction in major CV events such as acute myocardial infarction, stroke, angina, and revascularization compared with control patients. In all, 48% fewer patients in the ator-vastatin group than in the placebo group suffered strokes, and all-cause mortality was 27% lower among patients in the active treatment group compared with the control group. This landmark trial was designed specifically to determine the value of primary prevention of micro- and macro-vascular disease in the diabetic population. Treatment with atorvastatin resulted in benefit even in individuals with LDL levels lower than 100 mg/dL before treatment.

Hence a wealth of evidence supports the use of statins for reducing CV risk in diabetics. There is less evidence for interventions directed at the diabetic dyslipidemia (high triglyceride and low HDL levels). In the Veterans Affairs HDL-cholesterol Intervention Trial (VA-HIT), subjects received gemfibrozil to increase HDL-C in patients with coronary heart disease and low LDL-C [21]. In the diabetic subgroup, a 32% decrease in the incidence of the primary endpoint (combination of nonfatal myocardial infarction, stroke, and CV death) was noted.

Details of treatment of hyperlipidemia have been elaborated in another article in this issue. To summarize, the choice of a particular agent depends on the baseline lipid profile. A statin would be the drug of choice if LDL-C is greater than 100 mg/dL. If the predominant lipid abnormality is hypertriglyceridemia, fibric acid derivative would be the appropriate medicine to use. If LDL-C is concurrently high, however, treatment with a statin is necessary. The insulin sensitizers

Number of patients with an event (%)

Primary endpoint Acute coronary events

Coronary revascularization

Stroke

Secondary endpoint Death from any cause

Placebo

Any acute cardiovascular 189 (13.4%) disease event

Atorvastatin 10 mg

Hazard ratio (95% CI)

0.63 (0.48-0.83) 0.001 0.64 (0.45-0.90) 0.69 (0.41-1.16) 0.52 (0.31-0.89)

Fig. 2. Effect of treatment on primary and secondary endpoints. (Adapted from Colhoun HM, Betteridge DJ, Durrington PN, et al, CARDS investigators. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicenter randomized placebo-controlled trial. Lancet 2004;364(9435):685-96; with permission.)

(thiazolidinediones, TZDs), have also been shown to have favorable effects on serum triglyceride and HDL-C levels independent of glucose control, and these agents may also reduce the levels of small, dense LDL cholesterol. More long term studies are needed to document the benefits of these agents.

The goals of therapy as recommended by the ATP III of the National Cholesterol Education Program include a LDL-C target of less than 100 mg/dL, a serum triglyceride level less than 150 mg/dL, and an HDL-C level greater than 40 mg/dL [22]. The panel also recommends a secondary target of therapy in non-HDL-C (total cholesterol minus HDL-C). In diabetic individuals with a triglyceride level greater than or equal to 200 mg/dL, the non-HDL-C goal is 130 mg/dL. Although there is no official modification by the National Cholesterol Education Program (NCEP), a recent advisory from the NCEP suggests that because of the associated high risk of coronary events the appropriate LDL target for the diabetic population may be 70 mg/dL [23].

Hypertension

Hypertension is seen in about 60% to 80% of individuals with type 2 diabetes. As with the metabolic syndrome, hypertension often predates the manifestation of overt diabetes. There is a significant association between the blood pressure and insulin sensitivity [24,25]. The mechanisms thought to mediate hypertension include insulin resistance and diabetic nephropathy. Insulin resistance and concurrent hyperinsulinemia possibly cause sodium retention by the kidneys, stimulate growth of vascular smooth muscle cell, and affect endothelial function, vascular reactivity, and blood flow.

Several trials have been published regarding the treatment of hypertension in diabetes mellitus. They have shown beyond reasonable doubt that adequate control of blood pressure can protect against macrovascular and microvascular complications. In the Hypertension in Diabetes Study (substudy of the UKPDS), diabetic subjects were randomly assigned into groups with different blood pressure control targets (Fig. 3). After a mean follow-up of more than 8 years, diabetes-related mortality decreased by 32%, incidence of stroke decreased by 44%, and the incidence of congestive heart failure decreased by 56% in the aggressively treated group (mean blood pressure of 144/82 mm Hg during treatment) as compared with the less aggressively treated group (mean blood pressure of 154/87 mm Hg) [26].

In the Hypertension Optimal Treatment (HOT) trial, targeting of diastolic blood pressure to less than 80 mm Hg in diabetic patients was associated with 51% reduction of CV mortality

Any diabetes- Diabetes-related related Micro-

Any diabetes- Diabetes-related related Micro-

Fig. 3. UKPDS: Comparison between tight control of blood pressure and glycemia on risk of diabetes complications. (Adapted from United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications of type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13 and United Kingdom Prospective Diabetes Study 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 1998;352:837-53; with permission.)

Fig. 3. UKPDS: Comparison between tight control of blood pressure and glycemia on risk of diabetes complications. (Adapted from United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications of type 2 diabetes: UKPDS 38. BMJ 1998;317:703-13 and United Kingdom Prospective Diabetes Study 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 1998;352:837-53; with permission.)

over a 4-year period compared with the group with a target diastolic blood pressure of less than 90 mm Hg [27]. If the diabetic subgroup was removed from the analysis, the benefit in the rest of the population did not achieve statistical significance. Similar data substantiating the benefit of aggressive blood pressure reduction in diabetic patients have been shown in a number of other randomized, controlled trials and are discussed in detail in another article in this issue.

Because of the current evidence from randomized clinical trials, the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (in its seventh report, JNC 7) and all other major organizations have recommended a target blood pressure of less than 130/80 mm Hg in patients with diabetes. In patients with diabetic nephropathy and overt proteinuria, the target is 125/75 mm Hg or less [28]. These trials have also shown that adequate control of blood pressure generally requires the use of two or more antihypertensive agents (Fig. 4) [29].

Information regarding the choice of specific antihypertensive agents is more elusive, because most of the trials addressed composite endpoints and not specifically cardioprotection. In general, the degree of blood pressure reduction obtained is more important than the particular agents used, but some conclusions can be drawn from the available data to help in the choice of antihypertensives. Angiotensin-converting enzyme (ACE) inhibitors have been generally recommended as preferred initial drugs. Persuasive data from the Heart Outcomes Prevention Evaluation (HOPE) study supports of the use of ACE inhibitors [30]. Participants in this study were randomly assigned to either placebo or ramipril. Approximately 3500 diabetic patients with at least one additional classic CV risk factor were enrolled into this trial. Patients with proteinuria, congestive heart failure, recent myocardial infarction, or stroke were excluded, because these conditions are established indications for ACE inhibitors. The combined outcome of myocardial infarction, stroke, and CV deaths was significantly lower in the ramipril-treated group. There was no difference in the blood pressure control between the two groups, and the benefit from ramipril was independent of a patient history of hypertension, CV events, or microalbuminuria.

Some recent studies, however, have shown that angiotensin receptor blockers (ARBs) may be the appropriate initial medication in patients with type 2 diabetes mellitus. For patients with type 1 diabetes and nephropathy, ACE inhibitors remain the cornerstone of therapy. The Reduction of End Points in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) study showed that losartan

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