The Case for Treating Hypercholesterolemia at an Earlier Age

Abstract

From time to time we need to remind ourselves that atherosclerosis begins in childhood as fatty streaks. These lesions are of course benign in that they are asymptomatic, do not obstruct blood flow, and do not predispose to thrombosis. However, they are actually anything but benign. They are the precursors of the advanced lesions that ultimately-decades later-will precipitate coronary thrombosis and myocardial infarction (1,2). Fatty streak lesions and even some fibrous plaques are already well established in young adulthood. Their anatomic locations in the arterial tree are very much the same as those of the later See page 2631 lesions (1,3). Moreover, the risk factors that correlate with the extent of such early lesions are the same risk factors that correlate with myocardial infarction later in life (2,4,5). In other words, the disease does not somehow morph into another form as we get older; the disease progresses, and the lesions get larger and become life-threatening. Based on these insights into the natural history of atherogenesis, pathologists began urging many years ago that preventive measures should be instituted earlier in life (6). However, the drugs available at the time were less than ideal, and there was no way to directly assess the value of early intervention and make a meaningful risk/benefit assessment, so the issue was moot. Today, thanks to advances in our understanding of the mechanisms regulating blood cholesterol levels and the genes involved in that regulation, it has become clear that earlier intervention could improve in a major way the impact of lowering blood cholesterol levels on coronary heart disease (CHD) risk. The newer genetic evidence. The work by Cohen et al. (7) on the PCSK9 gene represented a breakthrough in this area. The PCSK9 gene plays a key role in the regulation of the low-density lipoprotein (LDL) receptor, suppressing the expression of the receptor and thus increasing LDL levels. Mutations causing overexpression of PCSK9 can increase LDL to levels as high as those found in familial hypercholesterolemia (8). Conversely, nonsense mutations in the PCSK9 gene allow increased expression of the receptor, thus lowering plasma LDL levels. What Cohen et al. discovered is that individuals with a particular nonsense mutation in PCSK9 had an LDL level 28% lower than that in the rest of the population under study. The astonishing finding was that the CHD risk in these individuals was reduced by Ͼ80%! By comparison, the same 28% decrease in LDL in the statin trials has only reduced CHD risk by 25% to 35%. Cohen et al. proposed that the much greater effect was due to the fact that LDL levels in people with PCSK9 loss of function mutations were lower right from birth, not just for the 5 or 6 years of a statin trial, a trial that usually started in middle age. Their findings have been amply confirmed (9,10).In this issue of the Journal, Ference et al. (11) have provided a meta-analysis of published data that points up the magnitude of protection potentially offered by a lifetime lo...

Individualized Statin Benefit for Determining Statin Eligibility in the Primary Prevention of Cardiovascular Disease

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Genetically Low Triglycerides and Mortality: Further Support for “the Earlier the Better”?

“…It is important to note that the findings in this study are consistent with those for genetically low LDL-C and cardiovascular risk (12 ). In particular, individuals who have genetically low LDL-C due to PCSK9 deficiency have much lower cardiovascular risk.…”

“…Along these lines, there is also a signal in the Cholesterol Treatment Trialists metaregression analyses (13,14 ) suggesting a greater proportional benefit of lipid lowering with statin therapy in lower risk categories. Such signals have sparked the concept "the earlier, the better" (12 ), but the practical clinical challenge is identifying the right patients in whom to intervene early. We strongly believe that direct detection of early atherosclerosis, perhaps through imaging, will play an important role in clinical decision-making (15 ).…”

An International Atherosclerosis Society Position Paper: Global recommendations for the management of dyslipidemia

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