In mixed, or atherogenic, dyslipidemia, the LDL particles are usually smaller and the calculated LDL-cholesterol content does not reflect the increased particle number. Several observational studies suggest that non–HDL-cholesterol is a better predictor of risk at any given LDL-cholesterol level.
The IDEAL predictor
To highlight the predictive value of non–HDL-cholesterol, Kastelein and colleagues analyzed pooled data from TNT and IDEAL (Incremental Decrease in End Points through Aggressive Lipid Lowering). IDEAL was a large (N=8888), randomized clinical trial in which patients with established CHD were assigned to usual-dose or high-dose statin treatment.25 In the investigators’ statistical models, while LDL-cholesterol levels were positively associated with cardiovascular outcome, that relationship turned out to be less significant than the relationship with non–HDL-cholesterol and apolipoprotein B. The ratio of total cholesterol to HDL (Total/HDL) and the ratio of apolipoprotein B to apolipoprotein A-I were each more closely associated with outcome than any of the individual proatherogenic lipoprotein parameters.25
Another post hoc analysis of TNT data has shown that HDL-cholesterol levels in patients receiving statins predicted major cardiovascular events. Among subjects with LDL-cholesterol levels <70 mg/dL, those in the highest quintile of HDL-cholesterol were at less risk for major cardiovascular events than those in the lowest quintile (P=.03).26 Both of these analyses support the concept that there is residual CHD risk after optimal statin treatment, and that the easily obtained non–HDL-cholesterol and HDL-cholesterol levels are predictive of that risk.
Setting goals for non–HDL-cholesterol
The ATP III–recommended goal for non–HDL-cholesterol is 30 mg/dL above the LDL goal, since maximum acceptable cholesterol carried in the triglyceride-rich lipoproteins (VLDL/IDL) is one-fifth of the acceptable triglyceride level (150/5=30 mg/dL). Thus, a high-risk person whose LDL-cholesterol goal is <100 mg/dL would have a non–HDL-cholesterol goal of <130 mg/dL. ATP III recommends lowering non–HDL-cholesterol by intensifying statin therapy to further reduce LDL as well as considering the addition of niacin or a fibrate to further decrease VLDL and triglycerides.2 Although not specifically recommended by ATP III, omega-3 fatty acids at a sufficient dose (3-4 g/d of ecosapentanoic acid + decosahexanoic acid) can reduce triglycerides as monotherapy, or when added to statins.27
Total atherogenic particles
A 2008 consensus conference report from the American Diabetes Association and the American College of Cardiology states that in patients with high cardiometabolic risk, LDL-cholesterol levels alone do not adequately capture risk and that measurements of total atherogenic particles are better.28 These measurements include non–HDL-cholesterol, apolipoprotein B, and the number of LDL particles identified by nuclear magnetic resonance. In individuals in the highest-risk category (known clinical cardiovascular disease or diabetes plus 1 or more CHD risk factors in addition to dyslipidemia), the report recommends a non–HDL-cholesterol goal of <100 mg/dL and an apolipoprotein B goal of <80 mg/dL.28
Combining therapies: AIM-HIGH and ACCORD
Two ongoing trials are comparing combination therapy (statin with either niacin or a fibrate) with statin therapy alone in patients with atherogenic dyslipidemia to assess the incremental benefit of combination therapy. AIM-HIGH (Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides and Impact on Global Health outcomes) is a 5-year study in 3300 patients with vascular disease and low HDL-cholesterol. This study is designed to find out whether lowering LDL to <80 mg/dL with simvastatin plus niacin can delay the time to a first major cardiovascular event for longer than simvastatin therapy alone.29
The 6-year ACCORD trial (Action to Control Cardiovascular Risk in Diabetes) randomizes patients with type 2 diabetes into 2 groups, 1 receiving statin-fibrate combination therapy and the other statin monotherapy. ACCORD is designed to find out whether raising HDL-cholesterol and lowering triglycerides along with targeted reductions in LDL-cholesterol will improve CHD outcomes more than LDL lowering alone.29
Raising HDL-cholesterol is promising, but complex
Improving residual CHD risk after statin treatment has emphasized raising HDL-cholesterol as a therapeutic target. The validity of raising HDL-cholesterol is supported by epidemiologic evidence showing an inverse relationship between HDL-cholesterol levels and cardiovascular risk: an increase of 1 mg/dL in HDL-cholesterol is associated with a 2% to 3% decrease in risk of cardiovascular disease.30 Therapeutic lifestyle changes, such as weight loss, exercise, and smoking cessation are effective at increasing HDL-cholesterol and these interventions are always encouraged. Most statins modestly (5%-10%) increase HDL-cholesterol, with rosuvastatin generally producing the largest increases, as shown in the ASTEROID study.
Niacin raises HDL
Currently, the most efficacious HDL-raising drug is niacin. As monotherapy, niacin can increase HDL-cholesterol by 15% to 35%.2 The problem is that niacin often causes flushing, a side effect patients find unpleasant enough that they don’t continue therapy.31 Extended-release preparations cause less flushing than immediate-release forms of niacin, and specific flush-reducing agents (laropiprant) are under investigation to improve tolerance.32