R3i Editorial

This month we focus on triglyceride-rich lipoproteins (TRLs) as a contributor to lipid-related residual vascular risk. These TRLs are comprised of intestinally-derived chylomicrons remnants, and very-low-density lipoprotein (VLDL) and VLDL remnants. It is important to emphasise that triglycerides contained within TRLs are not atherogenic; instead it is the cholesterol component of TRLs that is atherogenic.^1-3

Human genetic studies have played a key role in establishing this connection. In particular, gain-of-function and loss-of-function variants for the TRL-regulating enzyme lipoprotein lipase (LPL) have been instrumental. Gain-of-function variants in LPL were associated with lower triglyceride levels and lower coronary artery disease (CAD) risk;^4-6 in contrast, loss-of-function variants in LPL were associated with increased triglycerides levels and CAD risk.^4,6,7

Beyond LPL, strong associations have been shown for the genes APOC3 and APOA5, which encode apolipoproteins apoCIII and apoAV, respectively, as discussed recently by Khetarpal and Rader (2015).⁸ . Both of these apolipoproteins are located on TRLs, and play important roles in mediating heteroexchange between high-density lipoproteins (HDL) and TRLs, as well as regulating LPL activity (and thus triglycerides levels). Two recent studies have shown that loss-of-function variants in APOC3 conferred exposure to lower triglycerides levels and lower CAD risk by 40-41% (as discussed in previous postings on the R3i website).^9,10 However, given pleiotropic effects of apoCIII on lipoprotein metabolism and additional contributions to vascular risk, further mechanistic studies are needed to clarify the exact contribution(s) of APOC3 variants to vascular risk. In respect of APOA5, a major study identified rare APOA5 variants with increased risk for myocardial infarction (MI).¹¹ Individuals with these variants had higher triglycerides levels (by 63 mg/dL or 0.7 mmol/L) than noncarriers (as well as lower HDL cholesterol levels by 14 mg/dL or 0.36 mmol/L), although plasma LDL cholesterol levels were similar in carriers and noncarriers. Thus, these data implicate lifelong exposure to elevated TRLs in CAD/MI risk, independent of LDL cholesterol.

Taken together, these findings not only drive renewed emphasis on the importance of TRLs to residual cardiovascular risk, but also identify potential targets for novel therapeutic approaches to reduce this risk. Will these novel agents follow through in offering clinicians an effective strategy to target lipid-related residual cardiovascular risk? Only time will tell.

With renewed focus on TRLs, the next question is how best to measure this parameter. Measurement of triglycerides has been a convenient approach to estimating the mass of TRLs. However, measurement of the cholesterol contained in TRLs represents a preferable index of TRL atherogenic cholesterol load. In routine practice, specific lipoprotein measurement is not an option and consequently some have proposed remnant cholesterol, calculated as total cholesterol - (HDL cholesterol + LDL cholesterol) as a practical option.¹² More correctly, this equation calculates TRL cholesterol, i.e. the total cholesterol contained in chylomicrons, VLDL and their remnants). However, the equation cannot be used in the nonfasting state due to the limitations of the Friedewald equation for estimation of LDL cholesterol.

How then can the atherogenic load of TRLs be estimated in routine practice? This month’s Focus article addresses this issue, and proposes equations which allow for calculation of TRL cholesterol in routine nonfasting samples with high precision and discrimination.¹³ TRL-cholesterol and log[triglycerides] were shown to be similarly effective in the assessment of the atherogenic load of nonfasting TRLs. Given that nearly 50% of the variability in the triglyceride/HDL cholesterol ratio is attributable to remnant lipoprotein cholesterol,¹⁴ this provides a rationale for its applicability in grading cardiovascular risk associated with atherogenic dyslipidaemia.

The ratio of triglycerides/HDL cholesterol is also relevant for assessment of microvascular residual risk. In this month’s Landmark study,¹⁵ the triglyceride/HDL cholesterol was independently predictive of the incidence and progression of chronic kidney disease, and was a more relevant factor in subjects with diabetes compared with those without. A higher ratio of triglycerides to HDL cholesterol was a risk factor for loss of estimated glomerular filtration rate and incident chronic kidney disease in diabetic subjects, implying the existence of a vicious interaction between atherogenic dyslipidaemia, diabetes, and chronic kidney disease, in which accumulation and modification of TRLs and their remnants likely play a role.¹⁶

Thus, not only is the atherogenic load of cholesterol contained in TRLs relevant to lipid-related residual cardiovascular risk, but it is also implicated in the progression and development of chronic kidney disease, especially in individuals with diabetes. New data from the USA show that the costs of managing diabetes patients have more than doubled over the last decade compared with patients without diabetes, with renal and cardiovascular complications important contributors to these trends.¹⁷ With the tsunami of diabetes and obesity, these trends will undoubtedly be evident across developed and developing countries. There is now a clear impetus for clinicians to better identify and manage these individuals so as to reduce the clinical and economic consequences of residual vascular risk. Improved estimation of the atherogenic load of TRLs offers a practical approach to improved management in routine practice. And human genetic studies may help to establish novel therapeutic strategies with the hope of finally providing an effective counter to lipid-related residual vascular risk.

References

1. Chapman MJ, Ginsberg HN, Amarenco P et al. Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management. Eur Heart J 2011;32:1345-61.
2. Fruchart JC, Davignon J, Hermans MP, et al; Residual risk reduction initiative (R3i). Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014, 13:26.
3. Nordestgaard BG, Varbo A. Triglycerides and cardiovascular disease. Lancet 2014;384:626-35.
4. Wittrup HH, Tybjaerg-Hansen A, Nordestgaard BG. Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis. Circulation. 1999;99:2901–7.
5. Humphries SE, Nicaud V, Margalef J, Tiret L, Talmud PJ. Lipoprotein lipase gene variation is associated with a paternal history of premature coronary artery disease and fasting and postprandial plasma triglycerides: the European Atherosclerosis Research Study (EARS). Arterioscler Thromb Vasc Biol. 1998;18:526–34.
6. Teslovich TM, Musunuru K, Smith AV, et al. Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010;466:707–13.
7. Reymer PW, Gagné E, Groenemeyer BE et al. A lipoprotein lipase mutation (Asn291Ser) is associated with reduced HDL cholesterol levels in premature atherosclerosis. Nat Genet 1995;10:28–34.
8. Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk. New insights from human genetics. Arterioscler Thromb Vasc Biol 2015;35:e3-e9.
9. The TG and HDL Working Group of the Exome Sequencing Project, NHLBI. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371:22–31.
10. Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG, Tybjærg-Hansen A. Loss-of-function mutations in APOC3 and risk of ischemic vascular disease. N Engl J Med. 2014;371:32–41.
11. Do R, Stitziel NO, Won HH et al. Exome sequencing identifies rare ldlr and apoa5 alleles conferring risk for myocardial infarction. Nature Epub ahead of print. doi: 10.1038/nature13917.
12. McPherson R: Remnant cholesterol: “Non-(HDL-C + LDL-C)” as a coronary artery disease risk factor. J Am Coll Cardiol 2013, 61:437–9.
13. Hermans MP, Ahn SA, Rousseau MF. Novel unbiased equations to calculate triglyceride-rich lipoprotein cholesterol from routine non-fasting lipids. Cardiovascular Diabetology 2014, 13:56.
14. Quispe R, Manalac RJ, Faridi KF et al. Relationship of the Triglyceride to High-Density Lipoprotein Cholesterol (TG/HDLC) Ratio to the remainder of the lipid profile: The Very Large Database of Lipids – 4 (VLDL-4) Study. Atherosclerosis 2015;Epub ahead of print.
15. Tsuruya K, Yoshida H, Nagata M et al. Impact of the Triglycerides to High-Density Lipoprotein Cholesterol Ratio on the incidence and progression of CKD: A longitudinal study in a large Japanese population. Am J Kidney Dis 2015 Epub ahead of print.
16. Krane V, Wanner C. The metabolic burden of diabetes and dyslipidaemia in chronic kidney disease. Nephrol Dial Transplant 2002;17(suppl 11):23-7.
17. Ozieh MN, Bishu KG, Dismuke CE, Egede LE. Trends in healthcare expenditure in United States adults with diabetes: 2002–2011. Diabetes Care 2015; Published online before print July 22, 2015.