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Going Beyond LDL: ApoA-1 Milano, HDL, and Triglycerides

Antonio M. Gotto, Jr., MD, DPhil

Redefining current treatment targets in lipid-lowering therapy

The benefits of aggressive, long-term lipid management to reduce coronary and cardiovascular risk are well established. Despite the evidence of benefit, however, cholesterol management remains underimplemented, even in the patients at highest risk for cardiovascular events.^1,2 Based on estimates from the Third National Health and Nutrition Examination Survey (NHANES), 75% of the 9.3 million US patients with coronary artery disease (CAD) and elevated low-density lipoprotein cholesterol (LDL-C) levels remain either untreated or undertreated (see Figure 1).³

What can be done to improve implementation of treatment? Although the event reductions seen in studies using the HMG-CoA reductase inhibitors (or statins) were statistically significant, these trials generally have reported only an approximate 30% reduction in coronary events with treatment. Therefore, even though statin therapy lowered the treated patients risk compared with those receiving placebo, 60%-70% of coronary events occur despite interventions aimed at lowering LDL-C.⁴ Devising a treatment that will completely neutralize coronary risk may be impossible, but devising a strategy to complement the risk reductions achieved with statins has occupied many investigators interested in preventive cardiology and may help encourage intervention. One approach has explored expanding the importance of high-density lipoprotein cholesterol (HDL-C) and triglycerides, both in risk assessment and as targets for intervention.

Identifying other treatment targets besides LDL-C may be extremely important in a number of patients with abnormal blood lipid levels.⁵ For example, metabolic syndrome or diabetes may be present in a number of young adults who suffer a myocardial infarction, but who only have a mild elevation of LDL-C.⁶

HDL-C and Triglycerides as Risk Factors
Guidelines in the United States base their goals and action limits on LDL-C as the primary target of intervention.⁷ There are no goals per se for HDL-C or triglycerides (TGs), although guidelines define optimal levels of these lipid fractions. HDL-C values less than 40 mg/dL are low and are a positive risk factor for coronary disease, while a value greater than 60 mg/dL is cardioprotective (see Table 1). Triglycerides less than 150 mg/dL are ideal, while a value of 500 mg/dL or greater is very high. Patients with TGs at the latter level should receive TG reduction in order to minimize the risk for pancreatitis.

Epidemiologic data have established a strong, independent, inverse relation between HDL-C and CAD.⁵,⁸ Research suggests a 2%-3% decrease in coronary risk associated with each 1 mg/dL increase in HDL-C. The case for TGs has proved more controversial. Univariate analyses have supported an independent role for TGs, although the relation generally disappears in multivariate analyses, especially when controlled for HDL-C, the metabolism of which is closely related to that of TGs. Data from animal studies suggest a proatherogenic effect of endogenously produced TG-rich lipoproteins (ie, very-low-density lipoprotein or intermediate-density lipoprotein) and their remnant particles. The role of TGs in the development of atherosclerosis is biologically plausible and persuasive, even if observational data are inconsistent.

Perhaps most importantly, low HDL-C and high TGs interact with moderate-to-high LDL-C to increase CAD risk exponentially, in what is called the "lipid triad."^9,10 In the Helsinki Heart Study of gemfibrozil, the greatest risk reduction was observed in the subgroup of patients who had this lipid phenotype. The lipid triad combines with abdominal obesity, hyperglycemia, and hypertension to make up the constellation of CAD-risk enhancing attributes known as the metabolic syndrome. In the US, the metabolic syndrome is a secondary target of therapy, after the control of LDL-C elevations. Abnormal levels of HDL-C and TGs are also commonly present in diabetic patients, whom guidelines describe as a high-risk group that warrants aggressive treatment.

HDL as a Target for Therapy
Because of the emphasis on LDL-C management and the lack of agents that target only these fractions, very few trials have examined the effects of isolated modification of HDL-C and TGs on atherosclerotic disease. The Veterans Affairs High Density Lipoprotein Cholesterol Intervention Trial (VA-HIT), a randomized, controlled, double-blind study assessing the role of fibrate therapy in the prevention of recurrent CAD, revealed a strong correlation between raising HDL-C level and decreased number of nonfatal MIs and CAD death.^11,12 This correlation was independent of changes in LDL-C and TGs. Another randomized, double-blind study, the Air Force/Texas Coronary Atherosclerosis Prevention Study, found that lovastatin reduced the risk of first major coronary events in men and women with below-average HDL-C.¹³ Importantly, the participants in this study had average LDL-C and TG levels, demonstrating the importance of risk-reduction therapy in patients with low HDL-C even without significant abnormalities in other lipid parameters.

New and exciting evidence indicating that HDL and its components may have direct impact on atherosclerotic burden has recently been published.¹⁴ Apolipoprotein A-1 (apoA-1) is considered the major antiatherosclerotic protein component of HDL particles. Like HDL, it has an inverse relation to CAD risk. Genetic studies in animal models have suggested that upregulation of this protein may protect against atherosclerosis and regress existing plaques. ApoA-1 Milano is a mutant form of apoA-1 with a cysteine substitution for arginine at position 173. Human carriers of the apoA-1 Milano gene tend to have very low HDL-C, but increased lifespan and paradoxically decreased burden of CAD.

Nissen et al investigated the effect of intravenous administration of recombinant apoA-1 Milano on coronary atherosclerosis in patients with acute coronary syndromes.¹⁵ This group infused recombinant apoA-1 Milano/phospholipid complexes in patients with known recent acute coronary event. Patients were randomized to placebo or apoA-1 Milano infusions at 2 different doses weekly for 5 weeks. Atheromas were evaluated by intravascular ultrasound after the acute event and repeated after the 5 infusions. The recombinant infusion produced a measurable and significant reduction in coronary atherosclerosis. Though promising as a future treatment, apoA-1 Milano infusion as a cardiovascular disease (CVD) preventive therapy still requires additional research, such as a study to assess its effects on clinical events.

Triglycerides as a Target for Therapy
While significant evidence is mounting regarding the importance of HDL-C, the significance of TGs as a target for therapy is more controversial. The VA-HIT, using a multivariable analysis, found no correlation between the change in levels of TGs and coronary events, despite the major lipid change in the study being the reduction in TGs.¹¹ TGs as a single baseline variable had significant correlation with coronary events. In a post hoc analysis of the Bezafibrate Infarction Prevention (BIP) study, only those patients in the subgroup with highest TG levels experienced clinical benefit.¹⁶

The benefits of decreasing TG levels in patients with only moderately elevated TG levels, such as patients with impaired glucose tolerance or type 2 diabetes, remains unclear. Nonetheless, a number of studies have highlighted TGs as an independent risk factor. The Caerphilly (Wales) Heart Disease Study, which studied a prospective cohort of 2512 middle-aged men, established an association between TG levels and the risk of ischemic heart disease independent of total cholesterol and HDL-C.¹⁷

Guidelines for the Practitioner
The Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III or ATP III) has attempted to integrate the findings surrounding HDL-C and TGs into guidelines for the practitioner.⁷ In the ATP III, LDL-C remains the primary target of risk-reduction treatment in patients with low HDL-C or moderate hypertriglyceridemia. Once the LDL-C goal is reached, the guidelines stress the amelioration of non-HDL-C in patients with TGs of 200 mg/dL or greater. The use of non-HDL-C is intended to capture the contribution of atherogenic TG-rich lipoproteins (VLDL-C) and may be calculated by subtracting the HDL-C number from the total cholesterol. The goals for non-HDL-C are 30 mg/dL greater than those for LDL-C. Once LDL-C and non-HDL-C are under control, the physician may make an effort to raise HDL-C through weight reduction and increased physical activity, especially if the metabolic syndrome is present.

Lifestyle modification will have beneficial impact on the major lipid fractions. For patients who require drug therapy, fibrates will reduce TGs effectively and increase HDL-C modestly, and gemfibrozil has reduced coronary event risks in trials. Of available drugs, nicotinic acid will have the greatest effect on raising HDL-C, while also lowering LDL-C and triglycerides. There are also some data demonstrating coronary and mortality benefits with this agent.^18-20 However, its side effects may hinder compliance.

Statins have been shown to decrease LDL-C and TG levels while modestly increasing HDL-C levels. Rosuvastatin is the newest member of this compound class. A randomized, double-blind, placebo-controlled trial in patients with type IIa or IIb hypercholesterolemia (LDL-C =160 mg/dL and <250 mg/dL and triglyceride levels = 400 mg/dL) of rosuvastatin reported LDL-C reductions of between 40% and 43%, respectively, and HDL-C increases of 13% and 12%, respectively. Overall, total cholesterol and apolipoprotein B reductions and apolipoprotein A-1 also increased significantly, whereas TG level reductions appeared similar to those of other members of the statin class.²¹

Overall, more than 50,000 people have been randomized to either placebo or statin in clinical trials with no serious morbidity or mortality secondary to treatment. Most people tolerate statins with few or no adverse events. Increased creatinine kinase, or myositis, is rare and usually occurs in those patients with multiple medical problems or with polypharmacy.²² Newer statins, such as rosuvastatin, may help achieve even greater modification of the lipid profile.²³

A wealth of new and interesting data is becoming available concerning new targets for lipid therapy. These data demonstrate that both HDL and TG levels are important for cardiovascular health, although the independent effect of TG levels often lessens when other factors are taken into account, and the effect of lowering TGs appears to be greatest in those patients with the highest levels. As further studies come to fruition, new modalities of treatment such as new statins and apoA-1 Milano may take center stage. More research is needed to further elucidate the benefits and goals of treatment as well as to develop new treatment modalities.

Read this editorial in the complete APOLLO Newsletter: Volume 1 2004