R3i Editorial

This first post for 2013 highlights exciting research that re-emphasises the importance of atherogenic dyslipidemia to residual cardiovascular risk.


This month’s Focus article highlights novel evidence from Varbo and colleagues (2013)(1) that remnant cholesterol contained within triglyceride-rich lipoproteins is a causal factor for coronary artery disease. In the fasting state, remnant cholesterol is carried in very low-density lipoproteins and intermediate-density lipoproteins, and in the non-fasting state, these two lipoproteins plus chylomicron remnants. There is extensive mechanistic evidence supporting a role for triglyceride-rich lipoproteins in atherogenesis. Indeed, a recent expert consensus statement has drawn attention to the importance of triglyceride-rich lipoproteins in atherosclerosis, particularly in the context of cardiometabolic disease.(2)


What Varbo and colleagues add to the evidence-base is key. First, using a Mendelian randomization approach, a ‘natural randomized trial’, they showed a causal association between remnant cholesterol and risk for coronary artery disease. Each 1 mmol/L (39 mg/dL) genetic increase in remnant cholesterol was associated with a 2.8-fold causal risk for coronary artery disease. This increase in risk was higher than that based on observational data alone (Hazards ratio 1.4, 95% CI: 1.3 to 1.5), which would suggest that lifelong exposure through genetically elevated levels may have a larger effect on risk.


Second, this risk was independent of high-density lipoprotein cholesterol (HDL-C). Variants causing only lifelong low HDL-C were not associated with increased coronary risk. Thus, while HDL-C is typically associated with elevated triglyceride-rich lipoproteins, due to linked metabolic pathways, it does not appear to influence coronary risk. This second finding may help in at least partly explaining the failure of recent outcomes studies testing whether raising HDL-C concentration translates to reduced cardiovascular outcomes. In dal-OUTCOMES,(3) raising HDL-C with dalcetrapib, a cholesteryl ester transfer protein inhibitor which has negligible effect on low-density lipoprotein cholesterol (LDL-C), failed to improve cardiovascular outcomes in acute coronary syndrome patients receiving best evidence-based therapy, including statin. While it has been argued that this patient population may not have been ideal for study, this finding is not unexpected in the light of the work by Varbo and colleagues.


Evidence that remnant cholesterol in triglyceride-rich lipoproteins is causal for coronary risk reaffirms the importance of targeting therapeutic intervention beyond LDL-C. Indeed, this is the clear mission of the R3i. Implicit in this is the need to re-align lipid targets. Indeed, a recent review(4) questions whether LDL-C should be the primary lipid target, against the pandemic of obesity, diabetes and metabolic syndrome in the 21st century. Non-HDL-C – or even remnant cholesterol - may be a preferable target as this better reflects the burden of atherogenic lipoproteins. No doubt this debate will continue.


However, we also need to consider general preventative and therapeutic interventions especially in view of questions about niacin. In the spotlight is the potential of targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). Inhibition of PCSK9 leads to more liver LDL receptors, increased uptake of LDL from the circulation, and thus lower LDL-C concentration.(5) On risk/benefit analysis, humanized monoclonal antibody therapy targeting PCSK9 may be a preferable approach, with data from clinical trials showing reduction of >60% in LDL-C levels for at least 2 weeks after a single injection.


There is now information from key trials showing that targeting PCSK9 has benefits beyond LDL-C reduction. In the two phase II trials reviewed in Landmark Trials, treatment with either AMG-145 or SAR236553/REGN727 on top of statin therapy, not only improved LDL-C goal achievement but also lowered triglycerides, a marker of triglyceride-rich lipoproteins.(6,7) Thus, these data suggest a paradigm shift in the clinical management of dyslipidemic patients to reduce residual cardiovascular risk, which is likely to have clinical, economic and societal implications.


Undoubtedly the Residual Risk Reduction Initiative will continue to be at the forefront of activity targeting atherogenic dyslipidemia to reduce residual vascular risk.



References


1. Varbo A, Benn M, Tybjærg-Hansen A et al. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427–36.
2. 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.
3. Schwartz GC, Olsson AG, Abt M et al. Effects of dalcetrapib in patients with a recent acute coronary syndrome. New Engl J Med 2012; 367:2089-99.
4. Rizzo M, Barylski M, Rizvi AA, Montalto G, Mikhailidis DP, Banach M. Combined dyslipidemia: should the focus be LDL cholesterol or atherogenic dyslipidemia? Curr Pharm Des. 2012 Dec 26. [Epub ahead of print]
5. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism, Trends in Biochem Sci 2007;32:71-7.
6. Giugliano RP, Desai NR, Kohli P, et al on behalf of the LAPLACE-TIMI 57 Investigators. Efficacy, safety, and tolerability of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 in combination with a statin in patients with hypercholesterolaemia (LAPLACE-TIMI 57): a randomised, placebo-controlled, dose-ranging, phase 2 study. Lancet 2012;380:2007-17.
7. McKenney JM, Koren MJ, Kereiakes DJ, Hanotin C, Ferrand AC, Stein EA. Safety and efficacy of a monoclonal antibody to proprotein convertase subtilisin/kexin type 9 serine protease, SAR236553/REGN727, in patients with primary hypercholesterolemia receiving ongoing stable atorvastatin therapy. J Am Coll Cardiol 2012;59:2344-53.