The Residual Risk Reduction Initiative (R3i) has long been an advocate of targeting atherogenic dyslipidaemia, elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C), a driver of lipid-related residual cardiovascular risk in patients managed according to current standards of care, including statins.1
In the past, research had been focused on HDL-C, later shown to be a flawed presumption,2,3
implying that HDL-C is most likely a marker rather than a factor of cardiovascular risk.
In 2009, the Emerging Risk Factors Collaboration (2009)4
indicated that the association between triglycerides and cardiovascular risk was abolished when adjustment was made for HDL-C and other lipids. Subsequently, attention has returned to triglycerides. A growing body of evidence shows that triglycerides – or more specifically, triglyceride-rich lipoproteins (TRLs) and their remnants - are indeed associated with cardiovascular risk. Findings from epidemiological, genetic and Mendelian randomisation studies support the assertion that elevated triglycerides (TRLs and their remnants) are associated with cardiovascular risk.5-11
Most recently, the Circulatory Risk in Communities Study (CIRCS),12
discussed in this month’s Focus, showed that non-fasting triglycerides are predictive of risk of ischaemic cardiovascular disease in Japanese men and women, thus extending the evidence-base to both Western and Asian populations. It is likely that the apparent discrepancy between the Emerging Risk Factors Collaboration and other studies and meta-analyses may relate to heterogeneity in TRL particles, in terms of size, composition and atherogenicity.
Indeed, re-consideration of the role of triglycerides is very much the ‘flavour of the month’ in the literature, as highlighted in this month’s News from the Literature. In recent reviews,13-15
there has been a call to reconsider the role of TRLs in cardiovascular disease. Indeed, Khetarpal and Rader (2015)14
argue that insights from genetic studies make a convincing case for a causal association between key triglyceride-regulating pathways, specifically those involving lipoprotein lipase, and coronary artery disease risk. Libby (2014)15
also argues that mechanistically, TRLs may promote atherogenesis via a number of mechanisms beyond those influencing lipoproteins, including inflammatory and thrombotic pathways.
While there is now a plethora of evidence supporting the association between triglycerides and cardiovascular risk, the confirmatory test will be whether targeting elevated triglycerides will improve cardiovascular outcomes. This in turn has stimulated the development of novel agents which act at key targets influencing the metabolism of TRLs. Attention has refocused on apolipoprotein C-III (apoC-III),16
given that it represents both an independent risk factor and a key regulator of triglycerides metabolism. Additionally, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. Antisense oligonucleotides that target apoC-III have already entered clinical development, and results of ongoing trials are awaited with interest.17
There is also the tantalising possibility for the future of gene therapy targeting triglycerides metabolism.18
The R3i believes that such ongoing developments have important therapeutic implications. The tide is clearing turning for triglycerides. Specific targeting of triglycerides may offer potential to effectively reduce residual cardiovascular risk that persists in patients who attain low-density lipoprotein cholesterol goal. If supported by clinical studies, such novel therapies offer smart biological antiatherosclerotic therapies for the future.
1. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
2. AIM-HIGH Investigators, Boden WE, Probstfield JL et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
3. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013;34:1279-91.
4. Emerging Risk Factors Collaboration, Di Angelantonio E, Sarwar N, Perry P et al. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
5. Nordestgaard BG, Benn M, Schnohr P, Tybjaerg-Hansen A. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women. JAMA. 2007; 298: 299–308.
6. Varbo A, Nordestgaard BG, Tybjaerg-Hansen A, Schnohr P, Jensen GB, Benn M. Nonfasting triglycerides, cholesterol, and ischemic stroke in the general population. Ann Neurol 2011;69:628-34.
7. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen 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.
8. Thomsen M, Varbo A, Tybjærg-Hansen A, Nordestgaard BG. Low nonfasting triglycerides and reduced all-cause mortality: a mendelian randomization study. Clin Chem 2014;60:737-46.
9. Triglyceride Coronary Disease Genetics Consortium and Emerging Risk Factors Collaboration, Sarwar N, Sandhu MS, Ricketts SL et al. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies. Lancet 2010;375:1634-9.
10. Jørgensen AB1, Frikke-Schmidt R, West AS, Grande P, Nordestgaard BG, Tybjærg-Hansen A. Genetically elevated non-fasting triglycerides and calculated remnant cholesterol as causal risk factors for myocardial infarction. Eur Heart J 2013;34:1826-33.
11. Miller M, Stone NJ, Ballantyne C et al. Triglycerides and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2011;123:2292-333.
12. Iso H, Imano H, Yamagishi K et al; CIRCS Investigators. Fasting and non-fasting triglycerides and risk of ischemic cardiovascular disease in Japanese men and women: the Circulatory Risk in Communities Study (CIRCS). Atherosclerosis 2014;237:361-8.
13. Tenenbaum A, Klempfner R, Fisman EZ. Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor Cardiovascular Diabetology 2014, 13:159.
14. Khetarpal SA, Rader DJ. Triglyceride-rich lipoproteins and coronary artery disease risk. New insights from human genetics. Arterioscler Thromb Vasc Biol 2015 [Epub ahead of print].
15. Libby P. Triglycerides on the rise: should we swap seats on the seesaw? Eur Heart J 2014 [Epub ahead of print]
16. Huff MW, Hegele RA. Apolipoprotein C-III: going back to the future for a lipid drug target. Circ Res 2013;112:1405-8.
17. Graham MJ, Lee RG, Bell TA 3rd et al. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans. Circ Res 2013;112:1479-90.
18. Huynh K. Gene therapy: Targeting apoc-III to lower triglycerides. Nat Rev Cardiol 2014 [Epub ahead of print]