R3i Editorial

Despite best standards of care, cardiovascular disease (CVD) remains the major cause of disease burden in developed countries. In the US, the total cost of CVD (both direct and indirect costs) now exceeds $300 billions annually.(1) Against the epidemics of obesity and type 2 diabetes this is expected to more than double over the next 10 years. And this is not just an issue for developed countries, as data from the Asia-Pacific region also highlight a rising pandemic of obesity and cardiometabolic disease.(2)

The Residual Risk Reduction Initiative (R3i), in agreement with other expert bodies,(3) argues that renewed emphasis on lifestyle, both diet and increased physical activity, is long overdue. In support, in this month’s Focus article, the PREDIMED study showed that a Mediterranean diet, supplemented by either extra-virgin olive oil or nuts, can reduce the risk of a first CV event by up to 30% over 5 years in high-risk individuals with cardiometabolic disease.(4)

However, it is important to realise that best treatment plus lifestyle intervention still leaves a high residual risk of CV events, with atherogenic dyslipidemia – the combination of elevated triglyceride-rich lipoproteins (for which triglycerides are a marker) and low plasma concentration of high-density lipoprotein cholesterol (HDL-C) – an important and modifiable driver of this risk.(5) Therefore, it is a key priority for clinicians and scientists to investigate new approaches to reduce this residual risk – the mission of the R3i.

What have we learned so far? To date the only beneficial effect on outcomes has been achieved in type 2 diabetes patients with the combination of fenofibrate plus statin therapy, as shown by subgroup analysis from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid study.(6) There have been many disappointments along the way, including niacin in AIM-HIGH(7) and HPS2-THRIVE (due to be reported next month)8, and the first two cholesteryl ester transfer protein (CETP) inhibitors, torcetrapib and most recently dalcetrapib.(9.10)

PCSK9: New hope on the horizon

However, there may be new hope for targeting lipid-related residual risk with novel therapies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9). Inhibition of PCSK9 leads to an increase in hepatic low-density lipoprotein (LDL) receptors, increased uptake of LDL from the circulation, and thus lower circulating LDL cholesterol (LDL-C) concentration.(11) On the basis of risk/benefit analysis of the available data, humanized monoclonal antibody therapy targeting PCSK9 is a promising approach, with data from clinical trials showing sustained reduction of >60% in LDL-C levels for at least 2 weeks after a single injection.(12,13) In another study, treatment with REGN727 150 mg every 2 weeks produced superior LDL-C lowering compared with a strategy based on up-titration of atorvastatin (by 66.2% versus 17.3%) in patients on a stable dose of atorvastatin 10 mg/day and with LDL-C levels >100 mg/dL (2.6 mmol/L) at baseline. All patients who received REGN727 attained LDL-C targets, compared with 52% on atorvastatin 80 mg.(14)

Monoclonal antibody therapy targeting PCSK9 not only lowers LDL-C but also has beneficial effects on atherogenic dyslipidemia, as well as lipoprotein(a), another modifiable CV risk factor. Indeed, phase II data with two of these agents most advanced in development, AMG-145 and SAR236553(REGN727), show reduction in triglycerides (by up to 30%) and modest elevation in HDL-C on top of statin therapy.(12,13) SAR236553(REGN727) is now in phase III development, including an outcomes study (ODYSSEY OUTCOMES), which is highlighted in this month’s Landmark Trials. It is anticipated that an outcomes study for AMG 145 is not far behind.

Taken together, these data suggest that targeting PCSK9 may be a novel approach to reduce residual cardiovascular risk in high risk patients with concomitant atherogenic dyslipidemia characteristic of cardiometabolic disease.

It has been a long, rocky road for therapies targeting residual cardiovascular risk. However, the R3i believes that PCSK9-targeted therapy may be a beacon of hope for pharmacotherapeutic intervention aimed at reducing the burden of residual vascular risk.

References

1. Go AS, Mozaffarian D, Roger VL et al. AHA Statistical Update. Heart Disease and Stroke Statistics—2013 Update. Circulation 2013; 127: e6-e245.
2. Creeping epidemic of obesity hits Asia Pacific region. Available at http://www.escardio.org/about/press/press-releases/pr-13/Pages/epidemic-obesity-hits-asia.aspx. Accessed 21 February, 2013.
3. Reiner Z, Catapano AL, De Backer G et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011;32:1769-818.
4. Estruch R, Ros E, Salas-Salvado J; PREDIMED Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med 2013;Epub ahead of print 25 February, 2013.
5. 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.
6. Ginsberg HN, Elam MB, Lovato LC et al. Effects of combination lipid therapy in type 2 diabetes mellitus. N Engl J Med 2010;362:1563-74.
7. AIM-HIGH Investigators, Boden WE, Probstfield JL, Anderson T et al. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
8. Merck Announces HPS2-THRIVE Study of TREDAPTIVE™ (Extended-Release Niacin/Laropiprant) Did Not Achieve Primary Endpoint. Available from: http://www.mercknewsroom.com/press-release/prescription-medicine-news/merck-announces-hps2-thrive-study-tredaptive-extended-relea, December 20, 2012.
9. Barter PJ, Caulfield M, Eriksson M et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007; 357:2109-122.
10. 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.
11. Horton JD, Cohen JC, Hobbs HH. Molecular biology of PCSK9: its role in LDL metabolism, Trends in Biochem Sci 2007;32:71-7.
12. 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.
13. 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.
14. Roth EM, McKenney JM, Hanotin C, Asset G, Stein EA. Atorvastatin with or without an antibody to PCSK9 in primary hypercholesterolemia. N Engl J Med. 2012;367:1891–900/