Are Low HDL Levels Prognostically Important in Statin-treated Patients?
Abstract & Commentary
By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.
Synopsis: HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who have attained very low concentrations of LDL-cholesterol.
Source: Ridker PM, et al. HDL cholesterol and residual risk of first cardiovascular events after treatment with potent statin therapy: An analysis from the JUPITER trial. Lancet 2010;376:333-339.
Primary and secondary coronary artery heart disease prevention trials utilizing randomized statin therapy have consistently reported large, significant reductions in the incidence of myocardial infarctions, strokes, and other vascular diseases in the participants receiving statin drug therapy.1-4 Nevertheless, a relatively large residual cardiovascular risk remains in the treatment arm of all statin trials and many investigators have suggested that this residual risk might be explained in part because many patients have low residual concentrations of HDL-cholesterol after effective LDL-cholesterol-lowering therapy, suggesting that the low levels of HDL-cholesterol could be a target for additional preventive therapy. However, careful analyses of two very important trials of patients with known cardiovascular disease have demonstrated that the relationship between on-treatment HDL-cholesterol values and subsequent risk was significantly attenuated and actually not significant in those patients allocated to receive atorvastatin at a dosage of 80 mg per day.5,6 These findings have been considered to be particularly important for primary prevention because the economic impact of the additional agents, which would be needed to raise HDL-cholesterol over a lifetime, could prove to be quite substantial.
Paul Ridker and his associates from the JUPITER Trial Study Group7 utilized the JUPITER Trial cohort to analyze whether HDL-cholesterol concentrations were inversely associated with the occurrence of cardiovascular events, as had been demonstrated in numerous previous studies8,9 of patients in whom the LDL-cholesterol concentration had been reduced to very low ranges with high-dose statin treatment. In the 8901 patients given a placebo, the HDL-cholesterol concentrations were, as expected, inversely related to vascular risk both at baseline and on-treatment; however, among the patients given rosuvastatin 20 mg, no significant inverse relationships to vascular risk were noted to occur either at baseline or while on treatment. The authors concluded that although measurement of HDL-cholesterol is useful as part of an initial cardiovascular risk assessment, HDL-cholesterol concentrations are not predictive of residual vascular risk among patients who attain very low concentrations of LDL-cholesterol when treated with potent statin therapy.
Commentary
In the setting of primary prevention of cardiovascular disease in patients with very low concentrations of LDL-cholesterol, the residual HDL-cholesterol concentration may not accurately predict cardiovascular risk. Other studies have revealed that the predictive value of HDL-cholesterol was preserved even with extremely low LDL-cholesterol levels being present.5 These conflicting results have suggested to some investigators that in patients with very low LDL-cholesterol concentrations, other lipid measures such as apolipoprotein B to A1 ratios, total cholesterol:HDL, and non-HDL-cholesterol may provide more accurate prediction of cardiovascular risk than do simple HDL-cholesterol measurements. In any case, whether increasing HDL-cholesterol in patients with very low LDL-cholesterol will have any beneficial effect on cardiovascular risk remains to be demonstrated in large randomized trials. However, the results of the JUPITER trial suggest that getting the LDL-cholesterol low enough with statin therapy may be all that is needed from a practical clinical point of view.
The Ridker data should not reduce the enthusiasm for measuring HDL-cholesterol nor detract from the fact that raising HDL-cholesterol may yet prove to be a major treatment strategy for the reduction of cardiovascular disease in all patients, but especially in the large majority of patients who do not achieve adequate reduction of LDL-cholesterol values with statin therapy. Also, let's not forget that lifestyle changes such as aerobic exercise, weight loss, smoking cessation, limiting alcohol intake, and appropriate dietary changes should all be tried since these simple measures might result in modest increases in HDL-cholesterol and lowering of LDL-cholesterol. Drugs that specifically elevate HDL-cholesterol without the off-target effects previously observed with torcetrapid are being tested but, for the time being, simple niacin has proven to be very effective for many patients. With the advent of more potent drugs, the issue of whether raising HDL-cholesterol concentration reduces primary cardiovascular risk in all patients and not just in those with very low LDL-cholesterol needs to be tested in expanded and well-controlled clinical studies.
References
1. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. Lancet 2002;360:7-22.
2. Shepherd J, et al. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. N Engl J Med 1995;333:1301-1307.
3. Downs JR, et al; for the Air Force/Texas Coronary Atherosclerosis Prevention Study. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: Results of AFCAPS/TexCAPS. JAMA 1998;279:1615-1622.
4. Ridker PM, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
5. Barter P, et al. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-1310.
6. Ray KK, et al. Prognostic utility of apoB/AI, total cholesterol/HDL, non-HDL cholesterol, or hs-CRP as predictors of clinical risk in patients receiving statin therapy after acute coronary syndromes: Results from PROVE IT-TIMI 22. Arterioscler Thromb Vasc Biol 2009;29:424-430.
7. Ridker PM, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular events after initiation of rosuvastatin: A prospective study of the JUPITER trial. Lancet 2009;373:1175-1182.
8. Sharrett AR, et al. Coronary heart disease prediction from lipoprotein cholesterol levels, triglycerides, lipoprotein (a), apolipoproteins A-1 and B, and HDL density subfractions: The Atherosclerosis Risk in Communities (ARIC) Study. Circulation 2001;104:1108-1113.
9. Ridker PM, et al. Non HDL-cholesterol, apolipoproteins A-1 and B100, standard lipid measures, lipid ratios, and CRP as risk factors for cardiovascular disease in women. JAMA 2005;294:326-333.
HDL-cholesterol concentrations are not predictive of residual vascular risk among patients treated with potent statin therapy who have attained very low concentrations of LDL-cholesterol.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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