Mar 7, 2014 - Research Funding: S.S. Martin, the Pollin Cardiovascular Preven- tion Fellowship and the Marie-Josée and Henry R. Kravis endowed.
Papers in Press. Published March 7, 2014 as doi:10.1373/clinchem.2013.220970 The latest version is at http://hwmaint.clinchem.org/cgi/doi/10.1373/clinchem.2013.220970
Editorials
Clinical Chemistry 60:5 000 – 000 (2014)
Genetically Low Triglycerides and Mortality: Further Support for “the Earlier the Better”? Seth S. Martin and Michael J. Blaha*
In this issue of Clinical Chemistry, Mette Thomsen and colleagues contribute another gem from the treasure trove that is the Copenhagen City Heart Study (1 ). This Mendelian randomization study builds upon the investigators’ prior work linking genetically increased circulating triglyceride concentrations (a marker of remnant lipoproteins) with higher risk of ischemic heart disease (2 ). The present study gives the other bookend, linking genetically lower nonfasting circulating triglyceride concentrations with lower all-cause mortality. This work at the intersection of lipidology and preventive cardiology will be of interest to those working at many different scientific and clinical levels to improve the prevention of cardiovascular disease. Strengths of the study include the long duration of follow-up spanning 2 decades and the completeness of outcome ascertainment, with 100% of patients accounted for thanks to the Danish Central Person Register. In addition, the study takes advantage of a modern epidemiologic technique—the so-called “randomized trial of biomarkers”—Mendelian randomization. In linking genetic information with biomarker concentrations and clinical outcomes, this technique is thought to limit much of the bias in traditional epidemiologic approaches and allow causal inference. An additional strength of this study is the nonfasting measurement of circulating triglyceride concentrations. Indeed, we as humans spend most of our lives in a nonfasting state and nonfasting triglyceride concentrations have a stronger association with incident cardiovascular events than fasting values (3 ). Triglycerides measured 2– 4 h postprandially have an especially strong association with cardiovascular disease risk, illuminating the importance of postprandial lipid metabolism in cardiovascular disease. The authors took a 2-pronged approach, beginning with observational analyses of 13 957 persons who were followed for 24 years with 9991 deaths. A concentration-dependent association of nonfasting
Johns Hopkins Ciccarone Center for the Prevention of Heart Disease, Baltimore, MD. * Address correspondence to this author at: Johns Hopkins Hospital, 1800 Orleans St., Baltimore, MD 21287. Fax 410-614-9190, e-mail mblaha1@ jhmi.edu. Received February 14, 2014; accepted February 19, 2014. Previously published online at DOI: 10.1373/clinchem.2013.220970
triglycerides with all-cause mortality was observed. Compared to the reference group with triglycerides of 266 – 442 mg/dL (3–5 mmol/L), there was a graded decrease in risk with lower triglycerides: 11% lower estimated mortality risk in those with triglycerides of 177– 265 mg/dL (2–3 mmol/L), 26% lower risk in those with triglycerides of 89 –176 mg/dL (1–2 mmol/L), and 41% lower risk in those with triglycerides ⬍89 mg/dL (⬍1 mmol/L). In the second stage of the analysis, genetic variation in lipoprotein lipase leading to lower nonfasting plasma triglyceride concentrations was associated with reduced all-cause mortality. For a 1-mmol/L (89-mg/ dL) lower nonfasting triglyceride value, the investigators found the odds of mortality to be cut in half [odds ratio, 0.50 (95% CI, 0.30 – 0.82] over 17 years of follow-up with 4005 deaths. The findings were not significantly altered by adjustment for HDL cholesterol (HDL-C), suggesting that the results are not explained by the inverse association of triglycerides with HDL-C. In sensitivity analyses distinguishing between cardiovascular mortality and mortality from other causes, the results in both stages of the analysis reached similar conclusions. Overall, the results provide evidence for the benefit of early and long-term exposure to low circulating concentrations of triglycerides. We agree with the interpretation of the authors that the results likely reflect triglycerides as a marker for remnant lipoproteins. In the circulation, triglycerides are preferentially incorporated into remnant lipoproteins, which represent a hydrolyzed form of atherogenic lipoproteins. Remnants have become more important in modern medicine in the setting of epidemics of obesity and metabolic syndrome (4 ). From a biologic standpoint, many of us view triglyceride-remnant lipoproteins as encompassing intermediate-density lipoproteins and the dense subfraction of VLDLs (5 ). However, as a matter of practicality based on the availability of the standard lipid profile only, the Copenhagen group has modeled remnant lipoprotein cholesterol as estimated VLDL-C (triglycerides/5) (2 ). This modeling is rooted in the classical definition of LDL by the Friedewald equation(6 ) and  quantification, which is inclusive of intermediatedensity lipoprotein and lipoprotein(a). By this construct, what remains as remnants comprises VLDL. 1
Copyright (C) 2014 by The American Association for Clinical Chemistry
Editorials Dividing triglycerides by the fixed number 5 to get an estimate of VLDL-C has provided an easy and widely available clinical construct to capture some information about remnant lipoprotein cholesterol. However, from a biochemical standpoint, it is not the same thing as remnant lipoprotein cholesterol. Moreover, from a pathophysiologic perspective, many believe that the larger, more buoyant forms of VLDL are too large to penetrate the endothelial border and hence are not atherogenic. We have long known that it is difficult to obtain an accurate estimate of VLDL-C (2 ). We recently demonstrated in the Very Large Database of Lipids that the amount of VLDL-C by Friedewald estimation tends to be overestimated in persons with lower cholesterol concentrations and higher triglycerides (7 ). Since the Friedewald formula(6 ) subtracts VLDL-C from non– HDL-C to derive LDL-C, this will tend to produce an underestimation of LDL-C. As a solution, we recently published a novel method to estimate VLDL-C on the basis of an adjustable factor according to the cholesterol and triglyceride concentrations (8 ). This in turn provides a more accurate estimation of VLDL-C and in turn LDL-C. The approach uses 180 different factors, and an automated Excel-based calculator is available at ldlcalculator.com to facilitate ongoing research. Like the Copenhagen City Heart Study, the Very Large Database of Lipids will provide a fruitful platform for investigation of lipoproteins and mortality, with the latter database having the distinctive advantage of directly measured remnant lipoprotein cholesterol (9 ). Until now several barriers have prevented applying what we know about remnant lipoproteins to clinical practice. First, studies often have not accurately quantified remnants and have instead used measures like triglycerides and non–HDL-C concentrations as gross markers of their presence. Second, as noted, there have been competing definitions of remnant lipoprotein cholesterol in the literature. Third, some believe that it remains unclear whether there is an independent and causal contribution from remnant lipoproteins to cardiovascular disease. This study makes important strides in addressing the third barrier. However, since we think the causal substance is remnants, not actually triglycerides, we need a Mendelian randomization study mapped to directly measured remnants. As we move forward as a research community, it will be increasingly important that we use standardized definitions of remnant lipoproteins to promote the comparability of study results and facilitate synthesis of data. In some parts of the world, it is routine to directly measure remnant lipoprotein cholesterol quickly and at low cost. 2
Clinical Chemistry 60:5 (2014)
For clinical purposes at this time, though not a precise measure of remnants, non-HDL-C provides a global summary measure of the cholesterol content of all apolipoprotein B– containing atherogenic lipid fractions, including LDL and remnant lipoproteins. When remnants are low, non–HDL-C will approach LDL-C. However, when remnants are high—such as in obesity and insulin-resistant states—there can be a substantial difference between non–HDL-C and LDL-C, often much more than the 30-mg/dL (0.78mmol/L) difference frequently cited in guidelines (10 ). Non–HDL-C is a good starting point in assessing global atherogenic lipid burden, but there remains a need for more consistent laboratory reporting (11 ). 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. Intriguingly, PCSK9 inhibitors are moving rapidly along in drug development. It will be critical to evaluate the ability of this new drug class and other emerging therapeutic options to reduce LDL, remnant lipoproteins, and cardiovascular risk. Interestingly, the observed decreased risk of individuals with PCSK9 deficiency is lower than what has been achieved with pharmaceutical lipid-lowering applied later in life. 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 ). In conclusion, we congratulate these distinguished authors on this fine contribution to the literature. The data provide further evidence for the pathologic role of triglyceride-rich remnant lipoproteins and highlight the benefits of early and long-term exposure to lower concentrations. Future studies that physically separate and quantify remnant lipoproteins, along with outcomes studies of pharmacologic remnant lowering, will help move this field move further forward.
Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.
Editorials Authors’ Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: Employment or Leadership: S.S. Martin, American College of Cardiology Dyslipidemia Community. Consultant or Advisory Role: None declared. Stock Ownership: None declared. Honoraria: None declared. Research Funding: S.S. Martin, the Pollin Cardiovascular Prevention Fellowship and the Marie-Jose´e and Henry R. Kravis endowed fellowship. Expert Testimony: None declared. Patents: S.S. Martin, co-inventor on a pending patent filed by Johns Hopkins University for a method of LDL cholesterol estimation.
References 1. Thomsen M, Varbo A, Tybjaerg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a Mendelian randomization study. Clin Chem 2014;60:XX–XX. 2. Varbo A, Benn M, Tybjaerg-Hansen A, Jorgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36. 3. Bansal S, Buring JE, Rifai N, Mora S, Sacks FM, Ridker PM. Fasting compared with nonfasting triglycerides and risk of cardiovascular events in women. JAMA 2007;298:309 –16. 4. Blaha MJ, Bansal S, Rouf R, Golden SH, Blumenthal RS, Defilippis AP. A practical “ABCDE” approach to the metabolic syndrome. Mayo Clic Proc 2008;83:932– 41. 5. Twickler TB, Dallinga-Thie GM, Cohn JS, Chapman MJ. Elevated remnant-like particle cholesterol concentration: a characteristic feature of the atherogenic lipoprotein phenotype. Circulation 2004;109:1918 –25.
6. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18:499 –502. 7. Martin SS, Blaha MJ, Elshazly MB, Brinton EA, Toth PP, McEvoy JW, et al. Friedewald-estimated versus directly measured low-density lipoprotein cholesterol and treatment implications. J Am Coll Cardiol 2013;62:732–9. 8. Martin SS, Blaha MJ, Elshazly MB, Toth PP, Kwiterovich PO, Blumenthal RS, Jones SR. Comparison of a novel method vs the Friedewald equation for estimating low-density lipoprotein cholesterol levels from the standard lipid profile. JAMA 2013;310:2061– 8. 9. Martin SS, Blaha MJ, Toth PP, Joshi PH, McEvoy JW, Ahmed HM, et al. Very Large Database of Lipids: rationale and design. Clin Cardiol [Epub ahead of print 2013 Oct 1]. 10. Elshazly MB, Martin SS, Blaha MJ, Joshi PH, Toth PP, McEvoy JW, et al. Non-high-density lipoprotein cholesterol, guideline targets, and population percentiles for secondary prevention in 1.3 million adults: the VLDL-2 study (very large database of lipids). J Am Coll Cardiol 2013;62:1960 –5. 11. Blaha MJ, Blumenthal RS, Brinton EA, Jacobson TA; National Lipid Association Taskforce on Non-HDL-Cholesterol. The importance of non-HDL cholesterol reporting in lipid management. J Clin Lipidol 2008;2:267–73. 12. Steinberg D, Grundy SM. The case for treating hypercholesterolemia at an earlier age: moving toward consensus. J Am Coll Cardiol 2012;60:2640 –2. 13. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a metaanalysis of data from 170,000 participants in 26 randomised trials. Lancet 2010;376:1670 – 81. 14. Mihaylova B, Emberson J, Blackwell L, Keech A, Simes J, Barnes EH, et al. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012;380:581–90. 15. Martin SS, Blaha MJ, Blankstein R, Agatston A, Rivera JJ, Virani SS, et al. Dyslipidemia, coronary artery calcium, and incident atherosclerotic cardiovascular disease: implications for statin therapy from the Multi-Ethnic Study of Atherosclerosis. Circulation 2014;129:77– 86.
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