Dyslipidemia Over a Lifetime: The Case for Early Intervention on LDL Cholesterol
It is always better to prevent disease proactively rather than waiting to treat it reactively. For several decades, the field of cardiology has been working to prevent atherosclerotic cardiovascular disease (ASCVD) or slow its progression by treating patients at high risk for ASCVD with lipid lowering therapy while recommending better lifestyle habits. However, recently there has been increasing interest in intervening further upstream to prevent dyslipidemia from occurring in the first place (termed "primordial prevention"). Our current paradigm is to find people with subclinical atherosclerosis using risk prediction models that integrate information from traditional risk factors and through selective use of non-traditional risk factors (notably coronary artery calcium) and then intervene to prevent ASCVD events. In the future, we may treat average to high lipid levels much earlier to prevent atherosclerotic plaques from developing at all.
The idea of intervening on suboptimal lipid levels before patients develop atherosclerosis is supported by significant emerging data that atherosclerotic risk reflects the accumulated burden of low-density lipoprotein cholesterol (LDL-C) exposure over a lifetime.1 Early plaques (known as "fatty streaks") begin to develop in the arteries of teenagers and young adults and grow over the decades until they reach a tipping point in mid-life where the risk of clinically evident ASCVD starts to rise exponentially.1-3 This occurs even in people who have what are generally regarded as "normal" lipid levels with LDL-C in the 120-130 mg/dL range.1
This gives rise to the concept of mg-years of LDL-C exposure (as described by Ference et al.), analogous to pack-years for smoking as a way of reflecting aggregate risk exposure. A person with an average LDL-C level of 125 mg/dL will be exposed to a cumulative 5,000 mg-years of LDL-C by age 40 (which seems to be the tipping point at which ASCVD risk starts to increase), compared to only 2,800 mg-years if the average LDL-C were 70mg/dL.1 Even at LDL-C levels that are considered normal by current definitions, atherosclerotic burden and risk are accumulating during early life and middle age.
Generally, we wait until age 50 or later to start statin therapy, because our treatment decisions and guidelines are based on 10-year risk models that are driven to a large extent by chronologic age, which is not sometimes much different than biologic arterial age. However, these patients still have the plaque burden and the residual risk from decades of exposure to suboptimal lipid levels. What most clinicians and patients consider "normal" LDL-C levels are not really normal (humans living a subsistence lifestyle similar to our distant ancestors have markedly lower LDL-C),4 and certainly not optimal for preventing the development of progressive atherosclerotic disease. Moreover, adults who follow a diet rich in fruits, vegetables, legumes and who have a normal BMI with regular brisk exercise tend to have significantly lower LDL-C levels than the average American.5,6
If we could reduce LDL-C closer to optimal levels earlier in life, we might be able to achieve much more dramatic reductions in rates of ASCVD. It seems that aggressive lowering of LDL-C <70mg/dL can stop progression of atherosclerotic plaques and may cause some plaque regression based on intravascular ultrasound data,7 so an LDL-C below, or well below, this level might be considered "optimal" to minimize the risk of ASCVD. There is now compelling evidence that it is possible to achieve LDL-C levels in this range without significant adverse effects,7,8 so it is worth asking if LDL-C can practically be reduced closer to this level on a population-wide basis in a more proactive manner that we do now.
In an elegant article, Ference et al.1 suggest individualized lifestyle interventions (including n-of-1 diet trials) on a population-wide basis and starting earlier in life to reduce LDL-C to 70-80 mg/dL or less with a diet low in saturated fats and refined carbohydrates and high in fiber and plant proteins. Intervening with diet and improving exercise habits would be ideal, and reduction of mean population LDL-C to this range starting in childhood would likely result in a dramatic decrease in ASCVD. However, adherence to such a diet is likely not achievable except in a select group of highly motivated patients. Even a partial move toward improved diet would be helpful, but lifestyle changes alone are unlikely to reduce the mean population LDL-C to optimal levels.
This raises the question of whether pharmacologic intervention to lower LDL-C to the optimal range in younger patients may be beneficial. As we have noted, patients in their 30s and 40s generally have low 10-year ASCVD risk scores and are not usually prescribed lipid-lowering therapy, but they are in the process of accumulating the plaques that will eventually be the necessary substrate for heart attacks and strokes several decades down the line.
Given what we know about the pathophysiology of atherosclerosis, it seems likely that reducing LDL-C to optimal (or more physiologic) levels in this population would reduce the rate of plaque accumulation and prevent clinically evident ASCVD years later; however, it remains to be seen whether those benefits would justify the expense, disutility and potential adverse effects of starting young-to-middle aged people on statin therapy.
Answering this question will be a massive undertaking given that the benefit would only be seen over many years; however, there is an active trial to investigate this problem. The ECAD trial (Eliminate Coronary Artery Disease) is currently enrolling men starting at age 35 and women starting at age 45 who have an LDL-C ≥70 mg/dL and at least one other vascular risk factor for randomization to atorvastatin 20 mg/d versus placebo.9 Participants will be followed for 10 years for the primary outcome of ASCVD events, with anticipated completion in 2023. If this approach shows benefit, the field of cardiology may be moving towards a primordial prevention approach of trying to lower LDL-C to optimal levels decades before there is clinical evidence of atherosclerosis.
- Ference BA, Graham I, Tokgozoglu L, Catapano AL. Impact of lipids on cardiovascular health: JACC health promotion series. J Am Coll Cardiol 2018;72:1141-56.
- Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
- Ference BA, Yoo W, Alesh I, et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. J Am Coll Cardiol 2012;60:2631-9.
- Kaplan H, Thompson RC, Trumble BC, et al. Coronary atherosclerosis in indigenous South American Tsimane: a cross-sectional cohort study. Lancet 2017;389:1730-9.
- Appel LJ, Sacks FM, Carey VJ, et al. Effets of protein, monounsaturated fat, and carbohydrate intake on blood pressure and serum lipids: results of the OmniHeart randomized trial. JAMA 2005;294:2455-64.
- Halverstadt A, Phares DA, Wilund KR, Goldberg AP, Hagberg JM. Endurance exercise training raises high-density lipoprotein cholesterol and lowers small low-density lipoprotein and very low-density lipoprotein independent of body fat phenotypes in older men and women. Metabolism 2007;56:444-50.
- Nissen SE, Nicholls SJ, Sipahi I, et al. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65.
- sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376:1713-22.
- Domanski MJ, Fuster V, Diaz-Mitoma F, et al. Next steps in primary prevention of coronary heart disease: rationale for and design of the ECAD trial. J Am Coll Cardiol 2015;66:1828-36.
Keywords: Dyslipidemias, Coronary Artery Disease, Cholesterol, LDL, Risk Factors, Plaque, Atherosclerotic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Body Mass Index, Atherosclerosis, Myocardial Infarction, Stroke, Primary Prevention, Diet, Life Style, Carbohydrates, Smoking, Biological Products
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