Managing Patients With Diabetes and Dyslipidemia Frederick F. Samaha, MD

Cardiac Risk in Patients With Diabetes

Patients with diabetes have a higher degree of atherosclerotic burden than people without diabetes. This added risk was recognized in the recent Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III [ATP III]). The report raised the risk factor of patients with diabetes without known coronary heart disease (CHD) to CHD equivalent, and defined further risk guidelines based on Framingham risk score. It defined low-density lipoprotein cholesterol (LDL-C) goals for three risk levels. Target LDL-C for patients with diabetes and others with CHD risk equivalent is <100 mg/dL.¹

During the initiation of atherosclerosis (Figure 1), LDL-C accumulates in the subendothelial extracellular space within the arterial wall. Local vascular cells mildly oxidize LDL to a form known as minimally modified LDL, which is able to stimulate recruitment of monocytes and eventual deposition of macrophages.² These further oxidize LDL to a form that can be scavenged and internalized, resulting in so-called foam cells,² which form the earliest visible lesion of atherosclerosis, the fatty streak.³

Figure 1. Development of atherosclerotic plaques.

The aggregation of LDL-rich foam cells, derived from macrophages and T lymphocytes within the intima, progresses to development of an atherosclerotic plaque.³ This results from the death and rupture of the lipid-laden foam cells in the fatty streak. A crucial component of the maturing plaque is the formation of a fibrous cap that separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors.⁴ Stable atherosclerotic plaques are characterized by the necrotic lipid core covered by a thicker, almost protective vascular smooth muscle cell-rich fibrous cap.⁴ Such a cap can be strengthened and maintained by reducing LDL-C.⁴

The ATP III recommendations are substantiated by data from numerous studies on fatal and nonfatal cardiac events in patients with diabetes. Over a 10-year period, 47% of deaths recorded among patients with diabetes who received intensive treatment in the United Kingdom Prospective Diabetes Study (UKPDS) were caused by myocardial infarction (MI) or sudden death⁵ (Figure 2).

Figure 2. Cause of death: UKPDS 10-year follow-up.5

The East-West Study in Finland⁶ and the Scandinavian Simvastatin Survival Study⁷ both noted that patients with diabetes have a markedly increased risk of CHD. As illustrated in Figure 3, the East-West Study compared fatal and nonfatal MI in patients with and without diabetes and found significantly higher incidence in patients with diabetes.⁶ Similarly, the OASIS (Organization to Assess Strategies for Ischemic Syndromes) Registry concluded that, following hospitalization for unstable coronary artery disease, diabetic patients with no history of cardiovascular disease have the same long-term morbidity and mortality as nondiabetic patients with established cardiovascular disease.⁸

Figure 3. The East-West Study: Type 2 diabetes and CHD.6

Although mortality from heart disease in the US population has declined significantly in recent years,⁶ the subgroup of patients with diabetes has not experienced these same declines. Analyses of two representative national cohorts noted a 13.1% decline for diabetic men in age-adjusted heart disease mortality as compared to a 36.4% decline in nondiabetic men. In women, mortality declined 27% in nondiabetic women but actually increased 23% in diabetic women.¹⁰ This illustrates the need for aggressive intervention to reduce risk factors in diabetic patients.

Lowering LDL-C in Patients With Diabetes Reduces Coronary Risk

Despite the evidence supporting the NCEP's ATP III guidelines, a significant number of people have not achieved the recommended cholesterol goals. An evaluation of patients in the Lipid Treatment Assessment Project (L-TAP) reported that large proportions of dyslipidemic patients did not reach NCEP target levels for LDL-C despite lipid-lowering therapy. The L-TAP survey found that, while 68% of low-risk patients achieved LDL-C target levels, only 37% of high-risk patients reached goal levels¹¹ (Figure 4). This suggests that even more aggressive lipid-lowering therapy for high-risk patients is warranted.

Figure 4. Are we reaching LDL-C targets?11

There are a number of lipid-lowering agents, including statins and bile acid sequestrants, among others.

Statins
Five major trials published since 1994 have researched treatment with statins.^7,12-17 Results show that treatment with simvastatin, pravastatin, or lovastatin, compared with dietary therapy alone, resulted in a significant decline in cardiovascular endpoints over 5 years.¹⁸ In addition, results indicate that the absolute benefit of cholesterol lowering in terms of events prevented is higher in diabetic and other high-risk patients because of their higher event rate,^12,13 and that underlying clinical risk, not baseline lipid levels, determines the benefit from statin therapy.¹⁵

For patients who cannot tolerate statins or who fail to reach target LDL-C on them, there are other lipid-lowering drugs that can be used alone or in combination therapy.

Bile Acid Sequestrants
Bile acid sequestrants, also known as bile acid resins, block bile acid uptake from the gut, decreasing the cholesterol pool in the liver and causing it to use more cholesterol. Because bile acid sequestrants tend to cause a secondary increase in HMGCoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase activity, they are best used in combination with a statin. The Lipid Research Clinics Coronary Primary Prevention Trial (LRC-CPPT) found a strong and consistent link between therapy with cholestyramine resin, lowering of cholesterol levels, and reduction of CHD risk.^16,20 Bile acid sequestrants are not absorbed from the gastrointestinal tract and thus lack systemic toxicity. However, cholestyramine and colestipol can cause gastrointestinal (GI) side effects (constipation, bloating, abdominal pain, nausea, and flatulence) severe enough to necessitate dose reduction or cessation. They also interefere with the absorption of other drugs from the gastrointestinal tract.¹⁹ A newer agent, colesevelam, causes fewer GI side effects.²¹

Ezetimibe
Like the bile acid sequestrants, ezetimibe works to lower LDL-C by blocking cholesterol uptake from the gut. Ezetimibe inhibits the absorption of dietary and biliary cholesterol. In a recent study, ezetimibe, used in combination therapy with statins, was shown to significantly lower LDL-C and triglycerides while increasing HDL-C (high-density lipoprotein cholesterol). The drug was well tolerated, and side effects in the treatment group were similar to those in the placebo group.²²

Niacin
Niacin (nicotinic acid) lowers LDL-C by decreasing production and release of very-low-density lipoprotein (VLDL) and reducing the release of free fatty acids from fat cells. In combination with simvastatin, niacin markedly reduces risk of coronary events in patients with coronary disease and low HDL levels.²³ Nicotinic acid can increase insulin resistance and cause transient increases in fasting blood glucose, causing cautionary warnings against use in patients with diabetes.²⁴ The Arterial Disease Multiple Intervention Trial (ADMIT) concluded that niacin can be safely used in patients with diabetes,²⁵ but careful monitoring and aggressive management are warranted.

Fibrates
Fibric acid derivatives such as gemfibrozil lower cholesterol and triglycerides by affecting lipoprotein lipase activity and fatty acid uptake. They also increase the buoyancy of LDL particles.²⁶ In the VA-HIT (Veterans Affairs Cooperative Studies Program High-Density Lipoprotein Cholesterol Intervention Trial), gemfibrozil safely reduced the risk of death from coronary heart disease or nonfatal MI by 22%. Trial participants were men with CHD and low HDL-C without high-risk LDL cholesterol levels.²⁷

Stanol Esters
Dietary plant sterols, typically used in margarines and spreads, block the uptake of cholesterol from the digestive system, thereby reducing serum cholesterol.²⁸ A dose response of 1 to 3 tablespoons yields a 5% to 15% reduction in LDL-C. No further gains are noted with dose elevation.

Atherogenic Dyslipidemia in Diabetes
Patients with diabetes are characteristically insulin resistant and often demonstrate atherogenic dyslipidemia characterized by an elevated level of total triglyceride, reduced level of HDL-C, and an increased proportion of small, dense LDL-C particles.²⁴ Insulin appears to play a central role in controlling triglyceride (TG) metabolism, and elevated insulin levels are associated with elevated triglyceride levels²⁹ (Figure 5). Small, dense LDL particles have been associated with an increased risk of ischemic heart disease.³⁰ Researchers in the Quebec Cardiovascular Study observed that hyperinsulinemia increases the risk of ischemic heart disease but were unable to determine conclusively whether the increased risk is independent of other risk factors, such as hypertriglyceridemia.³¹

Figure 5. Insulin resistance and hypertriglyceridemia.29

In patients without atherogenic dyslipidemia, measuring and controlling LDL-C, which comprises about 70% of circulating cholesterol, is effective. Like LDL-C, however, the triglyceride-rich VLDLs have atherogenic potential. Patients with atherogenic dyslipidemia have high levels of these triglyceride-rich lipoproteins: VLDL, VLDL remnants (VLDL_R), and IDL (intermediate-density lipoprotein). Total apoliprotein B (apo B) level represents the total number of lipoprotein particles in LDL+VLDL+IDL. The Quebec Cardiovascular Study identified high insulin level combined with elevated apo B as being strongly predictive of ischemic heart disease (Figure 6).³¹

Figure 6. Plasma insulin predicts ischemic heart disease.31

Controlling Atherogenic Dyslipidemia

Because many labs do not measure apo B, the ATP III guidelines recommend measuring non-HDL cholesterol (total cholesterol minus HDL cholesterol) in patients with triglycerides greater than 200 mg/dL. Target goals for non-HDL cholesterol are 30 mg/dL higher than those for LDL cholesterol.

To reduce CHD risk in patients with diabetes, two interventions might be used simultaneously, for example, a lipid-lowering agent (eg, a statin) to lower apo B and an antidiabetic agent (eg, metformin) to increase insulin sensitivity.²⁴ The VA-HIT showed gemfibrozil to be effective in raising HDL-C and lowering triglycerides, leading to a decrease in incidence of death from CHD and nonfatal MI.²⁷ Similarly, niacin plus simvastatin dramatically reduced VLDL, LDL, IDL, and triglycerides while raising HDL.²³ Niacin is the only drug that reduces Lp (a) lipoprotein, an atherogenic LDL particle that is otherwise unresponsive to treatment. Although this trial did not study niacin therapy alone, a decrease in Lp (a) levels were also shown.²³

Discussion

New national cholesterol guidelines raise the risk factor of patients with diabetes without known CHD to CHD equivalent, a guideline substantiated by the results of numerous studies. In addition, patients with diabetes often have atherogenic dyslipidemia, characterized by elevated total triglyceride levels, reduced HDL-C levels, and an increased proportion of small, dense LDL-C particles. To reduce the risk of coronary events in patients with diabetes, whether or not atherogenic dyslipidemia is present, aggressive lipid-lowering therapy is warranted. There are a number of proven agents that can be used alone or in combination therapy to lower LDL-C levels, raise HDL-C levels, and reduce triglyceride-rich lipoprotein levels. In addition, because hyperinsulinemia has been associated with an increased CHD risk independent of lipid levels, patients with diabetes can further reduce their coronary risk by controlling hyperinsulinemia and insulin resistance.

References

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