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For the prevention of first and recurrent cardiovascular disease (CVD) events, identification and treatment of dyslipidemia in at-risk individuals is one of the most important approaches. Over the past 2 decades, a wealth of randomized clinical trial (RCT) data has consistently confirmed that reducing the number of atherogenic lipid particles results in lower rates of coronary heart disease (CHD) and stroke events. Although low-density-lipoprotein cholesterol (LDL-C) has generally been designated as the surrogate measure of atherogenic particles, other measures are probably even better predictors, such as non-high-density-lipoprotein cholesterol (HDL-C), apolipoprotein B, and NMR-derived particle member.1 Regardless of which of these measures is used, treatment with statins lowers the level of each measure, and, as a drug class, statins have been the preferred therapeutic choice. Other drugs, such as bile-acid resins and cholesterol-absorption inhibitors, can reduce LDL-C (less effectively than statins) and can be treatment options, either as monotherapy or in combination with statins. National lipid guidelines recommend that high-risk individuals, such as those who have stable CHD or a recent history of acute coronary syndrome, should have an LDL-C goal of <70 mg/dL, while high-risk primary prevention individuals should have an LDL-C goal of <100 mg/dL.
Although the RCTs have been the basis for these guidelines, there are many at-risk individuals who have other lipid risks, such as low HDL-C, high triglycerides, or both. Some observational data indicate that increasing HDL-C contributes to CVD risk reduction; but because RCT data are very limited, there are no HDL-C goals for treatment. Similarly, observational data suggest that high triglyceride levels (in most cases, >150 mg/dL) confer significant CVD risk—yet there are no RCTs to demonstrate a benefit for treating triglycerides specifically. The drugs that increase HDL-C and lower triglycerides, such as niacin and fibrates, are not considered first-line treatments because of their slight, and in some cases neutral, effects as monotherapy. National guidelines recommend adding niacin or fibrates to statins in order to further reduce particle numbers (non-HDL-C, for example) and to increase HDL-C in appropriate at-risk people, which includes individuals who have mixed dyslipidemia (or cardiometabolic risk) and those who meet metabolic syndrome criteria or have type 2 diabetes mellitus.
Several RCTs have been performed with lipid therapies in special populations, but they unfortunately have not demonstrated any CVD benefit. These include statins for preventing aortic stenosis progression (SEAS, ASTRONOMER), statins to reduce the progression of mild Alzheimer's disease (LEADe), statins to reduce CVD events in class III–IV heart failure (GISSI-HF, CORONA), and statins to reduce CVD events in end-stage renal disease (AURORA). Some special clinical conditions, such as isolated low HDL-C and isolated high triglycerides, have not been tested in RCTs.
As mentioned above, a LDL-C goal of <70 mg/dL is reasonable for all people who have stable CHD or a recent history of acute coronary syndrome. A frequent safety question is whether LDL-C can be too low: in other words, is there an LDL-C level at which there is little CVD benefit in comparison with non-CVD risk? The available RCT data are drawn from post hoc analyses of intensive versus standard statin therapy (the TNT and PROVE IT trials), and the results suggest not only that there is some incremental benefit for LDL-C levels of less than 50 mg/dL compared with levels of greater than 80 mg/dL, but, more importantly, that there is no evidence of noncardiovascular detriment.
Recently, one of the most important RCTs to be reported was the JUPITER trial.2 In this primary prevention study, 17,802 men and women (>50 and >60 years old, respectively) who had baseline LDL-C levels of <130 mg/dL and high-sensitivity C-reactive protein (hs-CRP) levels of >2 mg/L were randomized to placebo or rosuvastatin 20 mg/day. It revealed a highly significant (44%) reduction in the composite CVD endpoint, as well as a 20% reduction in all-cause death, after a mean of only 2 years of treatment. This result highlighted the potential of novel biomarkers, such as hs-CRP, in identifying individuals who are at higher risk than can be predicted on the basis of traditional risk factors. Some investigators have suggested that CRP is not only a marker of risk but might be a participant in promoting atherosclerosis. Several recent publications,3-5 however, do not provide support for a causative role for CRP. To see what role hs-CRP and other candidate biomarkers might play in the assessment of risk in the primary prevention setting, we shall have to await an update to the National Cholesterol Education Program Adult Treatment Panel guidelines (ATP IV).
Although statins have established themselves as the monotherapy standard of care, the role of combination lipid therapy must await the conclusion of ongoing RCTs. In order to achieve an optimal LDL-C goal, the AIM HIGH trial randomizes CHD patients who have low HDL-C levels either to statin alone or to statin plus extended-release niacin; and in order to shed light on the incremental benefit and safety of treating lipid abnormalities beyond LDL-C, the lipid arm of ACCORD6 randomized type 2 diabetes mellitus patients either to optimal statin monotherapy or to statin plus fenofibrate. This trial recently showed that the combination treatment produced a nonsignificant 8% reduction in the composite primary endpoint, without any significant safety issues. In a pre-specified subgroup analysis, the subjects with baseline triglyceride levels >204 mg/dL and HDL-C levels <34 mg/dL had a significant reduction in the primary endpoint.6
Finally, some recent trial data6,7 have been useful in exploring the concept that inhibiting cholesterol synthesis with statins does more than lower LDL-C: reducing the prenylation of certain small G-proteins via statin use might improve disease outcomes by reducing inflammation and favorably altering all other cellular functions. The results of the NAPLES II7 and ARMYDA-RECAPTURE8 trials suggest that giving high-dose statins within 24 hours before percutaneous coronary intervention can improve 30-day outcomes, compared with placebo.
In conclusion, statin treatment is an important mainstay in the prevention of 1st and recurrent CVD events. Intensive goal attainment for LDL-C levels, as well as for other measures such as non-HDL-C and apolipoprotein B, are now the standard of care. Novel biomarkers, such as hs-CRP, might prove very useful in guiding the initiation or intensification of lipid treatment (or both), and we await updates to the national guidelines to determine how this approach should be used in daily clinical practice.
Address for reprints: Peter H. Jones, MD, FACP, 6565 Fannin St., #A601, Houston, TX 77030
Presented at the 9th Texas Update in Cardiovascular Advancements; Houston, Texas; 4–5 December 2009
Program Director: James T. Willerson, MD