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Response to Letter Regarding Article, “Hyperlipidemia in Early Adulthood Increases Long-Term Risk of Coronary Heart Disease”

Originally published 2015;132:e203

    We thank Dr Hayward for his interest in our article.1 First, we note that our study was not intended to negate a risk-based approach to statin therapy. In fact, some of us have pioneered and led multiple efforts in the development of risk prediction algorithms.2 Our finding that cumulative exposure to elevated non–high-density lipoprotein cholesterol increases coronary heart disease risk highlights that both cardiovascular disease risk and cardiovascular disease risk factor exposures should be considered over >10-year windows. In other words, duration of exposure to a risk factor, in this case hyperlipidemia, is important and should be used in part to identify those who may benefit from statin therapy and those who may be identified by current risk-based algorithms. Dr Hayward notes that our findings may not be relevant for a younger person with an otherwise low 10-year risk, whose risk, even if doubled, would increase only to 2%. This is true if one is concerned only with shorter-term outcomes. Figure 2 in our article demonstrates that even among adults with a predicted 10-year atherosclerotic cardiovascular disease risk of <7.5%, those with prolonged (>11 years) exposure to elevated non–high-density lipoprotein cholesterol had impressively high—nearing 15%—rates of coronary heart disease over 15 years of follow up.1

    We disagree with Dr Hayward’s assertion that “all currently available clinical trial evidence suggests that the RRR [relative risk reduction] of a statin does not vary by a person’s baseline low-density lipoprotein level.” Although statins are an important part of primary and secondary prevention for adults at otherwise high predicted risk of cardiovascular disease, we note that the evidence demonstrates that they are particularly efficacious in adults with elevated low-density lipoprotein. The Cholesterol Treatment Trialists (CTT) showed that the relative benefit of statins per 1-mmol lowering of low-density lipoprotein cholesterol is constant.3 Accordingly, the higher the baseline low-density lipoprotein cholesterol is, the greater the potential benefit is. Also important is the fact that adults with the highest starting low-density lipoprotein cholesterol values have the greatest reductions in low-density lipoprotein cholesterol with standard statin doses, with a meta-analysis suggesting a low-density lipoprotein reduction on average 0.28 mmol/L greater for every 1-mmol/L increase in pretreatment cholesterol levels.4 Thus, although statins work in adults with lower baseline low-density lipoprotein levels, those with the highest low-density lipoprotein at baseline have potentially the most to gain from statin therapy.5

    Perhaps most important, our study highlights the importance of improved rates of cholesterol screening and treatment in young adults. The current American College of Cardiology/American Heart Association guidelines, by focusing on 10-year risk, may not identify many adults with high non–high-density lipoprotein cholesterol for statin therapy. Yet, our data clearly show that many of these individuals are at increased medium-term risks for coronary heart disease. Although the degree to which earlier intervention in adults with hyperlipidemia with statins may mitigate risk is currently unknown, it seems reasonable to consider earlier treatment before irreparable damage has been done. Thus, rather than calling into question current risk-based algorithms, our results should be seen as complementary.

    Ann Marie Navar-Boggan, MD, PhDEric D. Peterson, MD, MPHDuke Clinical Research InstituteDuke University Medical CenterDurham, NCRalph B. D’Agostino, Sr, PhDBoston UniversityBoston, MABenjamin Neely, MSDuke Clinical Research InstituteDuke University Medical CenterDurham, NCAllan D. Sniderman, MDMike Rosenbloom Laboratory for Cardiovascular ResearchMcGill University Health CentreMontreal, QC, CanadaMichael J. Pencina, PhDDuke Clinical Research InstituteDuke University Medical CenterDurham, NC


    • 1. Navar-Boggan AM, Peterson ED, D’Agostino RB, Neely B, Sniderman AD, Pencina MJ. Hyperlipidemia in early adulthood increases long-term risk of coronary heart disease.Circulation. 2015; 131:451–458. doi: 10.1161/CIRCULATIONAHA.114.012477.LinkGoogle Scholar
    • 2. Pencina MJ, D’Agostino RB, Larson MG, Massaro JM, Vasan RS. Predicting the 30-year risk of cardiovascular disease: the Framingham Heart Study.Circulation. 2009; 119:3078–3084. doi: 10.1161/CIRCULATIONAHA.108.816694.LinkGoogle Scholar
    • 3. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists’ (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins.Lancet. 2005; 366:1267–1278. doi: 10.1016/S0140-6736(05)67394-1.CrossrefMedlineGoogle Scholar
    • 4. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis.BMJ. 2003; 326:1423. doi: 10.1136/bmj.326.7404.1423.CrossrefMedlineGoogle Scholar
    • 5. Toth PP, Thanassoulis G, Williams K, Furberg CD, Sniderman A. The Risk-benefit paradigm vs the causal exposure paradigm: LDL as a primary cause of vascular disease.J Clin Lipidol. 2014; 8:594–605. doi: 10.1016/j.jacl.2014.08.004.CrossrefMedlineGoogle Scholar


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