Lipid disorders in patients with type 2 diabetes

Meeting the challenges of early, aggressive treatment

Alan O. Marcus, MD

VOL 110 / NO 1 / JULY 2001 / POSTGRADUATE MEDICINE

CME learning objectives

• To identify the risk factors for coronary artery disease in patients with type 2 diabetes
• To review study results that justify aggressive lipid lowering in these patients
• To underscore the treatment goals for lipid lowering in diabetic patients

Dr Marcus is medical director of Minimed Inc, serves on the advisory boards of Takeda Pharmaceuticals America Inc and Sankyo Parke Davis and on the speakers' bureau of Pfizer Inc, and has received an unrestricted educational grant from Bristol-Myers Squibb.

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Preview: Because patients with type 2 diabetes are at high risk for cardiovascular events, lipid abnormalities in these patients should be aggressively and efficiently treated. What is the rationale behind such an approach, and what are the goals of therapy? Dr Marcus addresses these questions and provides up-to-date recommendations for lipid-lowering treatment.
Marcus AO. Lipid disorders in patients with type 2 diabetes: meeting the challenges of early, aggressive treatment. Postgrad Med 2001;110(1):111-23

Patients with type 2 diabetes mellitus have a twofold to fourfold excess risk of coronary artery disease (CAD) compared with nondiabetic patients (1). Indeed, 75% to 80% of adult diabetic patients die of CAD, cerebrovascular disease, peripheral vascular disease, or a combination of these conditions (2). Data from a 12-year follow-up of the Multiple Risk Factor Intervention Trial (3) showed that in men aged 35 to 57 without a history of myocardial infarction, the risk of CAD was increased by the presence of multiple risk factors and the risk of cardiovascular mortality was progressively greater in those with diabetes than in those without diabetes (figure 1: not shown).

Patients with type 2 diabetes can have many lipid abnormalities, including hyperchylomicronemia; elevated levels of very low-density lipoprotein cholesterol (VLDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides; and low levels of high-density lipoprotein cholesterol (HDL-C) (4). These patients have a preponderance of abnormalities in the composition of LDL-C (smaller, denser particles), which increase atherogenicity even if the absolute concentration of LDL-C is not significantly increased. The combination of elevated levels of small, dense LDL-C particles and high triglyceride levels represents a lethal cholesterol abnormality known as pattern B.

About 20% of patients with type 2 diabetes have hypertriglyceridemia or low HDL-C levels (5). These abnormalities, as well as high VLDL-C levels and high total and VLDL-related triglyceride levels, are powerful risk indicators for CAD in patients with type 2 diabetes. In addition, the combination of elevated total cholesterol level, hypertension, and uncontrolled hyperglycemia is implicated in the development of nephropathy.

Epidemiologic evidence suggests that high total triglyceride and low HDL-C levels may be even stronger risk factors for CAD in diabetic patients than in nondiabetic persons (5). New evidence supports the independent benefits of lowering triglyceride levels and raising HDL-C levels. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (6) was the first major double-blind study designed to determine if raising HDL-C levels and lowering triglyceride levels would prove beneficial for patients whose primary lipid abnormality was a low HDL-C level (mean, 32 mg/dL) in the presence of a low to normal LDL-C level (mean, 111 mg/dL) and a moderate triglyceride level (mean, 160 mg/dL). In this multicenter trial, 2,531 men with CAD were randomly assigned to receive either 1,200 mg of gemfibrozil or placebo daily. After 1 year, HDL-C levels were on average 6% higher and triglyceride levels on average 31% lower in patients receiving gemfibrozil than in patients receiving placebo. Among the gemfibrozil-treated patients, the study revealed a 24% reduction in the combined outcome of death from CAD, nonfatal myocardial infarction, and stroke (P<.0001).

Although elevated triglyceride levels may be a common lipid abnormality in patients with type 2 diabetes, an elevated LDL-C level is the most significant indicator of risk and is the primary target for intervention in both US (7) and European (8) treatment guidelines for dyslipidemia.

Lipid abnormalities may be the result of the unbalanced metabolic state of diabetes (ie, hyperglycemia and insulin resistance). Improved control of hyperglycemia does moderate diabetes-associated dyslipidemia, but even if ideal glycemic control is achieved, elevated cholesterol levels persist and need to be specifically treated. Therefore, lipid-modifying treatment is warranted in many diabetic patients.

This article reviews the treatment of dyslipidemia in patients with type 2 diabetes. In particular, the lipid-modifying effects and safety record of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors ("statins") are compared. These agents have become the most common first-line therapy for dyslipidemia in all types of patients.

Patient care guidelines

To counteract the various dyslipidemic patterns seen in patients with diabetes, a three-step approach is recommended: (1) diet, exercise, and lifestyle modifications (eg, smoking cessation), (2) glucose control, and (3) lipid-modifying pharmacologic therapy, if necessary (9). Weight loss and exercise can reduce triglyceride levels, increase HDL-C levels, and modestly lower LDL-C levels. Many questions remain regarding the optimal dietary modification needed to minimize the risk of atherosclerotic complications in diabetic patients. The American Diabetes Association (ADA) suggests a reduction in the proportion of dietary saturated fat, with concomitant increases in carbohydrates or monounsaturated fat, or both, to compensate.

Treatment with glucose-lowering agents reduces triglyceride levels in patients with type 2 diabetes and does not change, or only modestly raises, HDL-C levels (4). Small reductions (10% to 15%) in LDL-C levels may be achieved through optimal glycemic control.

Improved glycemic control, however, may only modestly reduce the likelihood of CAD in patients with type 2 diabetes. In the Veterans Affairs Cooperative Study in Type II Diabetes (10), for example, diabetic patients had significant reductions in triglyceride levels from baseline with 2 years of intensive stepped insulin therapy but not with standard insulin therapy. However, significant reductions in LDL-C levels and increases in HDL-C levels were seen in the standard insulin therapy group but not in the intensive insulin therapy group.

Table 1 outlines recommendations for treatment of elevated LDL-C levels in diabetic patients. These recommendations basically follow guidelines of both the National Cholesterol Education Program (NCEP) (7) and the ADA (9). Drug therapy should be initiated after behavioral interventions have been tried, except for patients with clinical CAD or very high LDL-C levels (>200 mg/dL), who should receive drug therapy when behavior therapy is initiated. In adults with diabetes, the optimal LDL-C level is less than 100 mg/dL and the optimal HDL-C level is more than 45 mg/dL; triglyceride levels of less than 200 mg/dL are desirable (4).

Table 1. Approach to treatment of adults with diabetes according to LDL-C levels
	Patient status	Medical nutrition therapy		Drug therapy
	Initiate when LDL-C level is	LDL-C goal	Initiate when LDL-C level is	LDL-C goal
CAD, PVD, or CVD present	>100 mg/dL	<100 mg/dL	>100 mg/dL	<100 mg/dL
CAD, PVD, or CVD not present	>100 mg/dL	<100 mg/dL	>130 mg/dL*	<100 mg/dL
CAD, coronary artery disease; CVD, cerebrovascular disease; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PVD, peripheral vascular disease. *For diabetic patients with multiple CAD risk factors (HDL-C level, <35 mg/dL; hypertension; smoking; family history of CVD, microalbuminuria, or proteinuria), some authorities recommend initiation of drug therapy when LDL-C levels are between 100 and 130 mg/dL. Information from Haffner (4).

Rationale for aggressive lipid lowering

Results of a number of important clinical trials on primary and secondary prevention (11-15) suggest that the degree of cardiovascular event reduction is directly related to the degree of lipid lowering. Data from these landmark studies have shown that reducing total cholesterol levels by 20% to 25% with statin therapy decreases cardiovascular events by about 25% to 35% (figure 2: not shown).

In a recent meta-analysis, Gould and associates (16) suggested that the effect of statin treatment on CAD and total mortality risk is directly proportional to the degree of lipid lowering. This analysis estimated that for every 10% reduction in total cholesterol levels, risk of CAD mortality would be reduced by 15% (P<.001) and risk of total mortality by 11% (P<.001).

Results of the Air Force/Texas Coronary Atherosclerosis Prevention Study (14), the Long-term Intervention With Pravastatin in Ischaemic Disease (LIPID) Study (15), and a post hoc analysis of the Scandinavian Simvastatin Survival Study (4S) (17) support the theory that there is no apparent threshold level below which further lipid lowering would not provide additional benefit. Added support for this conjecture comes from the Post Coronary Artery Bypass Graft Trial (18), in which aggressive treatment to reduce LDL-C levels to 93 to 97 mg/dL slowed atherosclerotic progression in bypass grafts to a greater extent than did less aggressive treatment to reduce lipid levels to 132 to 136 mg/dL. However, there were no reductions in the "hard" end points of cardiovascular events in this study, despite obtaining end points in LDL-C levels of 85 to 90 mg/dL in 1,300 patients.

Results of the recent Atorvastatin versus Revascularization Treatment study (19) showed that patients with stable CAD achieved significant benefit (ie, a reduced need for subsequent percutaneous transluminal coronary angioplasty [PTCA]) from aggressive lowering of LDL-C levels to below 100 mg/dL. During the 18-month trial, 87% of atorvastatin-treated patients who were originally candidates for angioplasty continued to receive drug therapy without experiencing any cardiovascular events. The incidence of cardiovascular events (eg, nonfatal myocardial infarction, coronary artery bypass graft [CABG] surgery, revascularization, worsening angina) was reduced 36% in the atorvastatin group compared with the group receiving angioplasty followed by usual care. Mean LDL-C levels were 77 mg/dL in the atorvastatin group and 119 mg/dL in the angioplasty group. This study suggests that angioplasty-eligible patients can benefit from a reduction in LDL-C to below 100 mg/dL but also raises an interesting possibility that PTCA done without stenting and abciximab (ReoPro) therapy results in the need for recurrent PTCA or CABG surgery, or both, in this treatment group.

Results of the Bypass Angioplasty Revascularization Investigation (BARI) (20), which included 353 diabetic patients out of 1,829 total patients, showed that 5-year mortality rates were significantly higher (P<.001) for diabetic patients with multivessel disease who underwent PTCA than for those who underwent CABG surgery. Among the nondiabetic patients, there were no significant (P=.91) differences in cardiac mortality.

These results are important, especially when viewed in the context of the following data from a recent study of 1,373 nondiabetic patients and 1,059 patients with type 2 diabetes (2). In this study, the 7-year incidence of myocardial infarction among diabetic patients who did not have CAD was similar to that among nondiabetic patients who had already had a myocardial infarction; this was true for both male and female diabetic patients (figure 3: not shown). These findings, along with those of the BARI study (20), provide further rationale for aggressive lipid-lowering intervention among diabetic patients. Intervention for lipid disorders among diabetic patients should be as rigorous as that for secondary prevention among CAD patients. The scientific evidence for lipid-lowering treatment among diabetic patients is strong and is based on large-scale clinical studies such as the Helsinki Heart Study, the Cholesterol and Recurrent Events (CARE) Trial, 4S, and the LIPID trial.

Lipid-lowering drug treatment options

According to the American Heart Association (AHA), the primary goal of therapy for adult diabetic patients without CAD is an LDL-C level of less than 130 mg/dL. According to the ADA, the primary goals of therapy for diabetic patients with or without CAD are an LDL-C level of less than 100 mg/dL and a triglyceride level of less than 200 mg/dL. For HDL-C levels, the AHA recommends a goal of 35 mg/dL or higher and the ADA a goal of more than 45 mg/dL.

Because data suggest that the risk of future coronary events is similar in patients with diabetes and nondiabetic patients who have had coronary events, treatment to achieve an LDL-C level of 100 mg/dL or less according to NCEP guidelines seems justified (7). To achieve this goal in diabetic patients, it is often necessary to exceed the average 22% reduction usually obtained with most statins. Typically, the degree of decline needed to achieve optimal risk reduction in this population is 40% or more, a percentage that often can be achieved only with atorvastatin calcium (Lipitor) or high doses of simvastatin (Zocor), which result in LDL-C reductions of 40% to 60%.

Unfortunately, there are few available data from studies that examined only diabetic patients to confirm the positive effects of lipid-lowering therapy on morbidity and mortality in these patients. In a post hoc study of the 4S (21), analysis of a subgroup of 202 diabetic patients of the 4,444 patients with a history of CAD revealed that mean changes in serum lipid levels produced by simvastatin therapy were nearly identical in diabetic and nondiabetic patients. The risk of major CAD events was reduced by 55% (P=.002) in diabetic patients and by 32% (P<.0001) in nondiabetic patients. Total mortality was also reduced in both the diabetic group (43%; P=.087) and the nondiabetic group (29%; P=.001) but did not reach statistical significance in the diabetic group because of the small sample size.

In the CARE trial of more than 4,000 patients with myocardial infarction (13), pravastatin treatment significantly reduced a broadly defined CAD event end point (ie, fatal CAD, confirmed nonfatal myocardial infarction, CABG, or coronary angioplasty) by 23% (P<.001) in nondiabetic patients and by 25% (P=.05) in the 586 diabetic patients. Thus, subgroup analyses from 4S and CARE strongly suggest that lipid-lowering treatment with statins improves prognosis in diabetic patients even more so than in nondiabetic patients when both groups have CAD.

Statins
Statins are appropriately considered first-line therapy for lowering LDL-C in diabetic patients with hyperlipidemia (table 2). These agents typically reduce total cholesterol levels by 10% to 15%, LDL-C by 20% to 40%, and triglycerides by 10% to 20%. Statins also modestly increase HDL-C levels by 5% to 10% (22).Statins safely and effectively lower LDL-C levels in both nondiabetic and diabetic patients and have also been shown to reduce the morbidity and mortality of CAD in long-term prevention trials.

Table 2. Priorities for treatment of hyperlipidemia in adults with type 2 diabetes

1. Decrease LDL-C level     First choice: "statins"     Second choice: resins or fenofibrate (Tricor) 2. Increase HDL-C level     Behavioral interventions (weight loss, exercise, smoking cessation)     Glycemic control     Therapy with fibrates (gemfibrozil [Lopid], fenofibrate) or nicotinic acid (difficult because drug is relatively contraindicated) 3. Decrease triglyceride level     Glycemic control (first priority)     Fibrate therapy     Statins (moderately effective) 4. Treat combined hyperlipidemia     First choice: improved glycemic control plus high-dose statin     Second choice: improved glycemic control plus statin plus fibrate     Third choice: improved glycemic control plus resin plus fibrate or improved glycemic control plus statin plus niacin (carefully monitor glycemic control) HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol. Information from Haffner (4).

Atorvastatin and simvastatin appear to be the most effective statins for lowering LDL-C levels; with atorvastatin, reductions of up to 61% have been reported in patients with primary hypercholesterolemia (23). Atorvastatin also has been shown to produce greater reductions in LDL-C than milligram-equivalent doses of other statins (24), and it appears to be more efficient than other statins in achieving NCEP target LDL-C levels (24,25). Significantly more atorvastatin-treated patients achieved target LDL-C levels at the initial starting dosage of 10 mg/day than did patients treated with other statins at "entry level" dosages (23-25). In addition, 20 mg of simvastatin and 10 mg of atorvastatin were found to be similar in potency (24), a finding that reinforces the need for clinicians to consider dose responses as part of prescribing practices. Although statins are usually only moderately effective in reducing triglyceride levels, an added benefit of atorvastatin and high-dose simvastatin is the ability to lower triglyceride levels to a greater degree than that typically observed with other statins; however, fibrates and nicotinic acid are clearly more efficacious in lowering elevated VLDL-C levels (26).

The US Food and Drug Administration (FDA) recently approved simvastatin for the elevation of HDL-C levels because of the agent's demonstrated ability to increase this important marker for coronary well-being. Pravastatin sodium (Pravachol) is the only statin with FDA approval for stroke and cardiac event reduction. Among the statins, pravastatin has demonstrated the earliest onset of benefit (6 months in the CARE study) as well as significant reduction in CAD events after less than 1 year of therapy (12,27,28).

Statins are generally well tolerated, do not adversely affect glycemic control, and are useful in young and elderly patients with multiple risk factors (7). Also, the rate of patient compliance is higher with statins than with other classes of hypolipidemic agents. The most important adverse effects are transient asymptomatic increases in hepatic transaminase levels (in about 1% of patients) and, rarely, myopathy (29).

An added benefit of statins may be their ability to serve as anti-inflammatory agents, which harks back 100 years to Virchow's description of atherosclerosis as the result of injury and inflammation.

Fibrates
Fibrates, such as gemfibrozil (Lopid), bezafibrate,* and fenofibrate (Tricor), generally produce larger decreases in triglyceride levels and larger increases in HDL-C levels than do statins (22). Fenofibrate is slightly better than gemfibrozil in lowering triglyceride and LDL-C levels and in raising HDL-C levels. Fibrates also decrease hepatic production of VLDL-related triglycerides and are therefore the agents of choice for diabetic patients when hypertriglyceridemia is the primary lipid abnormality (table 2) (4). The most cost-effective fibrate is generic gemfibrozil, which also has clinical outcome data demonstrating its benefit in reducing both coronary and cerebral events (6). Data from the Diabetes Atherosclerosis Intervention Study presented at the XIIth International Symposium on Atherosclerosis (30) showed that 200 mg of fenofibrate administered over 3 years resulted in a 40% reduction in focal atherosclerotic lesions. A risk of fibrate use, particularly in combination with statins, is a myositic flulike syndrome, which occurs in up to 5% of patients (7).

Nicotinic acid
Nicotinic acid (niacin) reduces LDL-C and triglyceride levels and raises HDL-C levels (22). However, it is poorly tolerated (causing gastrointestinal effects, flushing, and pruritus) and potentiates the effects of antihypertensive agents (7). In addition, the agent can cause hyperglycemia. Diabetic patients receiving nicotinic acid should be carefully monitored (table 2), and according to ADA clinical care recommendations, the agent may not be appropriate for patients whose whole blood glucose levels are not well controlled (hemoglobin A_1c target, <7) (4,7).

Bile acid sequestrants
Bile acid sequestrants (resins) decrease LDL-C levels and slightly increase HDL-C levels (22). Because resins can induce hypertriglyceridemia, triglyceride levels should be monitored in patients receiving therapy (7,22). The agents can be inconvenient to take and unpalatable--factors that reduce compliance. They often cause gastrointestinal symptoms (eg, constipation, reflux esophagitis, dyspepsia), and their use requires considerable patient education (7). A newer, possibly more tolerable, agent of this class--colesevelam hydrochloride (Welchol)--has recently received FDA approval, and its success will be monitored as its clinical use becomes widespread.

Summary and conclusion

Elevated LDL-C levels are a common lipid abnormality in patients with type 2 diabetes. The risk of CAD events in diabetic patients with this abnormality is similar to that in nondiabetic patients who have already had a CAD event. Although elevated triglyceride levels are also common in patients with type 2 diabetes, this lipid abnormality can often be improved with glycemic control and lifestyle changes. Moreover, data from recent clinical and angiographic trials support the concept of aggressive lowering of LDL-C levels in patients at highest risk for CAD events, and LDL-C is the primary target for lipid-lowering drug therapy according to consensus guidelines.

Statins are the agents of first choice for lowering lipid levels in patients with type 2 diabetes without significant hypertriglyceridemia. Their effectiveness is associated with their ability to lower LDL-C levels and may also be linked to the anti-inflammatory benefits unique to this class of lipid-lowering agents.

Whether a statin is used as monotherapy or in combination with fibrate, bile acid sequestrant, or nicotinic acid, lipid-lowering treatment in patients with type 2 diabetes and dyslipidemia must be early, aggressive, and persistent to neutralize the very high risk of CAD. Use of statins in patients with previous cardiovascular events (whose risk of subsequent coronary disease is equivalent to that of patients with diabetes) is not only clinically beneficial but also cost-effective, even for patients aged 75 years or older (31).

*Available in Canada and Europe.

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Dr Marcus is associate clinical professor, division of diabetes, endocrinology, and hypertension, department of medicine, University of Southern California School of Medicine, Los Angeles, and is in private practice in endocrinology, Laguna Hills, California. Correspondence: Alan O. Marcus, MD, South Orange County Endocrinology, 23961 Calle De Le Magdalena, Suite 531, Laguna Hills, CA 92653. E-mail: aomarcus@aol.com.

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