Whether elevated triglycerides are causal for increased risk for cardiovascular disease (CVD) has long been the subject of debate.
On the one hand, univariate analyses of epidemiologic studies in the general population showed association, although this was attenuated after correcting for other standard lipids including plasma levels of high-density lipoprotein cholesterol (HDL-C).(1) Analyses from statin trials have been conflicting, in showing either an association or lack thereof between triglycerides and clinical CVD risk.(2,3)
On the other hand, mechanistic and genetic studies implicate elevated levels of triglyceride-rich lipoproteins (TRLs), for which elevated triglycerides are a marker, and increased coronary risk. In animal models, TRL remnants have been shown to be retained in the arterial intima, and have been identified in atherosclerotic plaques, implying that TRL remnant cholesterol contributes to plaque formation and progression.(4-6) There is also increasing genetic evidence of a direct causal association between pathways implicated in TRL metabolism and coronary risk. Previous analysis of a specific APOA5 variant (1131T>C) that regulates triglycerides showed an association with coronary risk.(7) Most recently, data from the CARDIoGRAM collaborative group, discussed in this month’s Focus On article, provide further evidence of a causal association of triglycerides, or more specifically TRLs, in coronary risk, even after correction for confounding due to secondary effects on other lipids.(8) Furthermore, a Mendelian randomisation study provides direct causal evidence of an association between remnant cholesterol, contained in TRL, and ischaemic heart disease risk. Notably, each 1 mmol/L (39 mg/dL) increase in remnant cholesterol associated with genetic variants was associated with a 2.8-fold causal risk for IHD, independent of HDL-C plasma levels.(9)
Indeed, genetic evidence implicating TRLs in atherosclerosis is stronger than that for HDL-C, given that a recent genome-wide association study of HDL-related genes failed to show any association with cardiovascular risk.(10) Added to the failure of recent outcome trials involving treatments that target HDL, the pendulum has increasingly shifted to re-focus on the role of TRLs in cardiovascular risk. Similar thinking applies in the context of residual cardiovascular risk.
The key area of contention has been conflicting evidence from outcome studies specifically targeting different baseline triglyceride levels. There have been positive findings from some studies, such as the JELIS (Japan Eicosapentaenoic acid Lipid Intervention Study), with a significant 50% reduction in residual cardiovascular risk observed with treatment with eicosapentaenoic acid (EPA) against a background of residual elevated triglycerides (≥150 mg/dL or 1.7 mmol/L) and low HDL-C, despite statin therapy.(11) However, other studies such as the Alpha-Omega and ORIGIN (Outcome Reduction with an Initial Glargine Intervention) failed to show any benefit associated with lowering of triglycerides with omega-3 supplementation on outcomes.(12,13) Recent news that a Food and Drug Administration (FDA) advisory panel has voted overwhelmingly against recommending approval of an expanded indication for a purified EPA ethyl ester in combination with a statin in the treatment of high-risk patients with mixed dyslipidaemia due to lack of outcomes evidence, adds further controversy.
Given mechanistic and genetic insights, the question must be why? Could it be that against a background of best evidence-based treatments, the dose regimens of interventions selected were inappropriate to sufficiently impact triglycerides levels? Were the patient populations an issue? Do patient selection criteria, specifically relating to triglycerides levels, warrant a re-think? Or are findings limited by the fact that these studies have measured levels of triglycerides rather than the specific TRL remnants, given that such measurements are not routinely available to the clinician. These questions warrant urgent consideration.
Persistent hypertriglyceridemia, increasingly implicated as an important contributor to residual CV risk, is clearly an issue facing clinicians, as highlighted by recent data from the EUROASPIRE III survey(14) (see News from the Literature). In recognising this unmet clinical need, the Residual Risk Reduction Initiative (R3i) calls for a well-designed outcome study using an appropriate treatment regimen targeting elevated triglycerides to resolve ongoing debate
. The REDUCE-IT trial with EPA in more than 8000 high-risk patients is addressing this question (NCT01492361),(15) but results will not be available until 2016.
1. The Emerging Risk Factors Collaboration. Major lipids, apolipoproteins, and risk of vascular disease. JAMA 2009;302:1993-2000.
2. Miller M, Cannon CP, Murphy SA et al; PROVE IT-TIMI 22 Investigators. Impact of triglyceride levels beyond low-density lipoprotein cholesterol after acute coronary syndrome in the PROVE IT-TIMI 22 trial. J Am Coll Cardiol 2008;51:724-730.
3. Pedersen TR, Olsson AG, Faergeman O et al. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study (4S). Circulation 1998;97:1453-60.
4. Daugherty A, Lange LG, Sobel BE, Schonfeld G. Aortic accumulation and plasma clearance of βVLDL and HDL: effects of diet-induced hypercholesterolemia in rabbits, J Lipid Res 1985;26:955-963
5. Nordestgaard BG, Wootton R, Lewis B. Selective retention of VLDL, IDL, and LDL in the arterial intima of genetically hyperlipidemic rabbits in vivo. Molecular size as a determinant of fractional loss from the intima-inner media. Arterioscler Thromb Vasc Biol 1995;15:534-42
6. Proctor SD, Mamo JCL. Retention of fluorescent-labelled chylomicron remnants within the intima of the arterial wall – evidence that plaque cholesterol may be derived from post-prandial lipoproteins. Eur J Clin Invest 1998;28:497-504
7. 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;375:1634-1639
8. Do R, Willer CJ, Schmidt EM et al. Common variants associated with plasma triglycerides and risk for coronary artery disease. Nat Genet 2013 Oct 6. doi: 10.1038/ng.2795. [Epub ahead of print].
9. 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
10. Voight BF, Peloso GM, Orho-Melander M et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012 Aug 11;380(9841):572-80
11. Saito Y, Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K; JELIS Investigators, Japan: Effects of EPA on coronary artery disease in hypercholesterolemic patients with multiple risk factors: sub-analysis of primary prevention cases from the Japan EPA Lipid Intervention Study (JELIS). Atherosclerosis 2008,200:135-140
12. Kromhout D, Giltay EJ, Geleijnse JM; Alpha Omega Trial Group: N-3 fatty acids and cardiovascular events after myocardial infarction. N Engl J Med 2010,363:2015-2026.
13. ORIGIN Trial Investigators, Bosch J, Gerstein HC, Dagenais GR et al. N-3 fatty acids and cardiovascular outcomes in patients with dysglycemia. N Engl J Med 2012,367:309-318.
14. Reiner Z, De Bacquer D, Kotseva K et al. Treatment potential for dyslipidaemia management in patients with coronary heart disease across Europe: Findings from the EUROASPIRE III survey. Atherosclerosis (2013), doi: 10.1016/j.atherosclerosis.2013.09.020.
15. A Study of AMR101 to Evaluate Its Ability to Reduce Cardiovascular Events in High Risk Patients With Hypertriglyceridemia and on Statin. The Primary Objective is to Evaluate the Effect of 4 g/Day AMR101 for Preventing the Occurrence of a First Major Cardiovascular Event. (REDUCE-IT). ClinicalTrials.gov Identifier:
NCT01492361. Available at http://clinicaltrials.gov/show/NCT01492361.