Treating dyslipidemia in the high-risk patient
How low should LDL levels be pushed and how important are other lipoproteins in our efforts to reduce CV risk? Here’s an update.
TABLE 2
NCEP risk categories and LDL-cholesterol goals2,19
| Risk category | 10-Year CHD risk | LDL-C goal | Initiate drug therapy |
|---|---|---|---|
| High and very high risk Established CHD and/or CHD risk equivalents | >20% | <100 mg/dL; <70 mg/dL is a reasonable option | ≥100 mg/dL (<100 mg/dL: consider drug options) |
| Moderately high risk Multiple (2+) risk factors | 10%-20% | <130 mg/dL (optional: <100 mg/dL) | ≥130 mg/dL (100-129 mg/dL: consider drug options) |
| Moderate risk Multiple (2+) risk factors | <10% | <130 mg/dL | ≥160 mg/dL |
| Lower risk 0-1 risk factor | <10% | <160 mg/dL | ≥190 mg/dL (160-189 mg/dL: consider drug options) |
| CHD, coronary heart disease; LDL-C, low-density lipoprotein cholesterol; NCEP, National Cholesterol Education Program. | |||
In 2006, <70 became a “reasonable goal”
Guidelines for secondary prevention jointly issued by the American Heart Association and the American College of Cardiology in 2006 and endorsed by the National Heart, Lung, and Blood Institute (NHLBI) agree that a goal of <70 mg/dL is “reasonable” for all patients with CHD and other clinical forms of atherosclerotic disease, even those whose baseline LDL-cholesterol level is between 70 and 100 mg/dL.5
Lowering LDL may cause atherosclerosis to regress
Intensive lipid lowering has shown promise in inducing regression of atherosclerotic plaque.20,21 The Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial compared the effects on atheroma volume, as measured by intracoronary intravascular ultrasound, of intensive (atorvastatin 80 mg/d) vs moderate (pravastatin 40 mg/d) lipid lowering over 18 months in patients who had 1 or more vessels with a luminal narrowing of 20% or more.20 In the intensive treatment group, which attained a mean LDL-cholesterol level of 79 mg/dL, the 0.4% reduction in atheroma volume indicated no disease progression from baseline and a significantly lower progression rate (P=.02). By contrast, the group on moderate treatment that achieved a mean LDL-cholesterol level of 110 mg/dL had a 2.7% increase in atheroma volume, indicating net progression of atheroma volume compared with baseline.20
ASTEROID shows actual regression
A study of the effect of rosuvastatin on disease progression (A Study to Evaluate the Effect of Rosuvastatin on Intravascular Ultrasound-Derived Coronary Atheroma Burden, or ASTEROID) evaluated the effect of rosuvastatin 40 mg/d on coronary disease progression assessed by intravascular ultrasound at baseline and after 24 months, with the patients serving as their own controls.21 The results showed the mean change in percent atheroma volume (PAV), a measure of disease progression and regression, for the entire vessel being measured was –0.98%, compared with baseline (P<.001). A second efficacy measure, change in atheroma volume in the 10-mm subsegment with the greatest disease severity, also showed a reduction, with a mean change of –6.1 mm3 compared with baseline (P<.001).21 The ASTEROID investigators attributed disease regression to intensive statin treatment, leading to an LDL-cholesterol mean of 61 mg/dL together with significantly increasing HDL-cholesterol levels to 49 mg/dL, up 5% from baseline.21
Combination therapy fails to ENHANCE atherosclerosis regression
In a controversial study in patients with familial hypercholesterolemia utilizing B-mode ultrasound measurements of carotid intima-media thickness, lowered LDL-cholesterol levels did not result in regression of atherosclerosis. The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial evaluated simvastatin 80 mg plus ezetimibe 10 mg compared with simvastatin 80 mg alone.22 Despite a significant 16.5% greater lowering of LDL-cholesterol with combination therapy (P<.01), no difference was observed in progression of carotid intima-media thickness between the 2 treatment groups.
No LDL is too low for safety
Given the physiologic importance of cholesterol in the body, the very low cholesterol levels achieved with intensive statin therapy in some trials has raised questions about the safety of such an approach.23 A substudy of the PROVE IT-TIMI 22 trial focused on the 11% of 1825 atorvastatin-treated patients whose LDL-cholesterol levels had dropped to 40 mg/dL or lower after 4 months of treatment. There were fewer cardiovascular events in this group compared with the patients with LDL-cholesterol levels between 80 and 100 mg/dL, and no relationship between this low level and adverse events over 24 months.23 Similarly, the TNT study group analyzed cardiovascular events across quintiles of LDL-cholesterol and found that the lowest quintile (LDL <64 mg/dL, mean 54 mg/dL) had the lowest event rate, without a difference in adverse events over 5 years.24
LDL isn’t the whole story
It is clear from the statin clinical trials that cardiovascular events occur even after LDL-cholesterol is optimally treated. Why is this so? One possibility is that levels of other lipids—too-high triglycerides or too-low HDL-cholesterol—also contribute to CHD risk. These lipid abnormalities often cluster with other risk factors, including obesity, insulin resistance, hyperglycemia, and hypertension. Such patients are considered to have mixed, or atherogenic, dyslipidemia, and frequently include those with metabolic syndrome and type 2 diabetes. In patients whose triglyceride levels remain high (>200 mg/dL) or HDL-cholesterol levels low (<40 mg/dL) even after they have achieved their LDL-cholesterol goals, the NCEP ATP III guidelines recommend non–HDL-cholesterol as a secondary target of therapy.2 Non–HDL-cholesterol (calculated as total cholesterol minus HDL-cholesterol) is a measure of all the atherogenic, apolipoprotein B-containing lipoproteins (LDL, intermediate-density lipoprotein [IDL], and very-low-density lipoprotein [VLDL]).
