Treatment of Dyslipidemia and Hypertriglyceridemia

Risk Assessment and LDL Cholesterol Goals

Numerous large randomized clinical trials support aggressive LDL-C lowering to reduce CV events. Patients with either coronary artery disease (CAD) or CAD risk equivalents (which include all patients with PAD with or without claudication or symptoms) are considered high risk. Therefore, PAD patients have a recommended LDL-C goal of less than 100 mg/dL. For high-risk patients, both therapeutic lifestyle modification and lipid-lowering therapy should be initiated. Among patients considered very high risk—those with both CAD and risk factors such as PAD—the ATPIII update suggests a reasonable goal would be an LDL-C level lower than 70 mg/dL.

The most recent meta-analysis regarding LDL-C lowering demonstrates a few key points. There is no LDL-C level where patients do not benefit from further LDL-C-lowering. Lowering LDL-C from 100 mg/dL before treatment to 50 mg/dL yields a clinical benefit. The absolute risk reduction is driven principally by the pretreatment absolute CV risk. Hence, high-risk patients with PAD stand to benefit from LDL-C-lowering regardless of LDL-C level. In addition, the more that LDL-C is lowered by treatment, the greater the CV event reduction. There appears to be no threshold (down to <50 mg/dL) below which LDL-C-lowering does not provide CV event reductions. This benefit occurs with few excess side effects and little harm on average. Thus, we believe all patients with PAD regardless of whether they have hyperlipidemia or not (whatever the LDL-C) should be treated with a moderate- to high-potency statin to achieve the lowest-tolerated LDL-C (<70 mg/dL preferably or >50% reduction from pretreatment values). Caveats to this recommendation may be patients with pretreatment LDL lower than 70 mg/dL or those with intolerances or contraindications to statins.

In regard to PAD patients, it is noteworthy to mention the pivotal Heart Protection Study (HPS). This clinical trial included 20,536 adults aged 40 to 80 years, with a history of coronary heart disease (CHD) and/or CHD risk equivalents, including PAD. Subjects were randomized to 40 mg of simvastatin or placebo and followed for a primary outcome of total mortality and secondary outcomes of fatal and nonfatal vascular events. Among patients with PAD, those randomized to simvastatin had a significantly lower rate of first major vascular event compared to the placebo group (26.4% vs. 32.7%, p < .0001). This difference was observed for all baseline LDL levels, even levels lower than 100 mg/dL. This is the strongest evidence that patients with PAD (even without established other CV disease or CAD) benefit from statin treatment.

The IDEAL (Incremental Decrease in Clinical Endpoints through Aggressive Lipid Lowering) study compared high-dose statins with more moderate doses. Patients who were younger than 80 years and who had a history of myocardial infarction (MI) and an indication for statin therapy per current guidelines were eligible; of this total population ( N = 8888) approximately 4% also had a history of PAD. The IDEAL study found no difference in the primary composite endpoint of major coronary events or secondary endpoints of CHD death, or cardiac arrest between those randomized to atorvastatin 80 mg/day or simvastatin 20 mg/day. Lower rates of nonfatal MI were observed for subjects on atorvastatin compared to subjects on simvastatin, and a protective benefit of atorvastatin was observed for the secondary outcome of newly diagnosed PAD (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.61–0.96).

Goals for Non-HDL Cholesterol

LDL-C remains the primary target of therapy for a majority of patients. Once the LDL-C goal has been met, consideration for non–HDL-C targets is the second therapeutic concern among patients with triglycerides (TGs) 200 mg/dL or higher. Non–HDL-C includes both very-low-density lipoprotein cholesterol (VLDL-C) and LDL-C; thus, higher values in the presence of elevated TGs denote additional atherosclerotic risk caused by the presence of remnant lipoproteins. In this setting, non–HDL-C has been shown to be a superior CV risk predictor than LDL-C both with and without drug treatment. Non-HDL goals are 30 mg/dL above the LDL-C goal. A very-high-risk patient, such as one with diabetes mellitus and peripheral vascular disease (PVD) or CHD and PVD would have a goal LDL-C of less than 70 mg/dL and a non-HDL goal of less than 100 mg/dL. Based the meta-analysis, we believe that this non–HDL-C goal of less than 100 mg/dL is defensible for all patients with PAD given their high-risk status and the safety and efficacy of aggressive treatment.

This remains a complicated issue with no strong outcome evidence to guide medical treatment decisions. Current management options for increasing HDL-C beyond lifestyle changes (e.g., weight loss, exercise, smoking cessation, including mono- and polyunsaturated fats, one or two alcoholic drinks per day) include adding fibrates and nicotinic acid. In 2011, the AIM-HIGH study (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes) was stopped early for a lack of benefit of adding extended-release Niaspan to CAD patients treated with a statin. Hence, the optimal medical treatment of isolated low HDL-C remains to be fully elucidated.

The primary exception to an initial LDL-C target is among patients with elevated triglycerides. Among patients with TG levels 500 mg/dL or higher, TGs become the primary target and LDL-C is considered the secondary target. The mainstay of therapy is dietary intervention, which can result in substantial improvement in TG levels. Factors associated with elevated triglycerides include obesity, uncontrolled diabetes, physical inactivity, cigarette smoking, and excessive alcohol intake. Lifestyle modification can lead to a significant reduction in TG levels. Additionally, drugs such as corticosteroids, estrogens, retinoids, and β-blockers can contribute to elevations in TGs. These factors also are associated with reductions in HDL-C. Therefore, a careful history of comorbidities, medications, and lifestyle factors is recommended among patients with elevated TGs. Once TGs are treated to below 500 mg/dL (a safety level to prevent TG-related pancreatitis), then non–HDL-C becomes the next goal of treatment as outlined previously.