R3i Editorial

The last 12 months has been an exciting time for lipid research, led by the advance of proprotein convertase subtilisin/kexin type 9 (PCSK9) targeted therapy. Indeed, the American Heart Association (AHA) has cited the PCSK9 inhibitors alirocumab and evolocumab as two of the top 10 research advances of 2015 ¹. Preliminary data in March suggested that PCSK9 monoclonal antibody therapy, on top of statin, reduced major cardiovascular events by about 50% in high cardiovascular risk patients ^2,3. Despite the lack of definitive outcomes data, the first two agents in this class were licensed in Europe and the USA earlier this year. With the first of the outcomes studies with these agents (evolocumab) due to report in late 2016, we will finally be able to evaluate whether these novel agents can reduce lipid-related residual cardiovascular risk that persists despite statin therapy.

While these agents predominantly target low-density lipoprotein (LDL) cholesterol, effects on other lipoproteins are not negligible. Indeed, a focus of interest has been reduction in lipoprotein(a) [Lp(a)], an established cardiovascular risk factor and potential contributor to lipid-related residual cardiovascular risk ^4,5. Available data indicate that PCSK9 monoclonal antibody therapy lowers Lp(a) by 25-30% across the spectrum of high cardiovascular risk patients ^6,7. As Lp(a) is essentially refractory to current treatment options (beyond niacin, currently only available in the Americas), PCSK9 targeted therapy may therefore offer the possibility to target this atherothrombogenic lipoprotein. However, other novel agents are also in development, most notably ISIS-APO(a)Rx, a second-generation antisense drug targeting apolipoprotein(a), a component of Lp(a). A phase I trial in subjects with elevated Lp(a) >25 nmol/L has shown reduction in Lp(a) of more than 80% after multiple dosing. With a favourable safety profile to date, these findings therefore provide a strong rationale for continued development ⁸. Thus, the future may offer the possibility of testing whether targeting elevated Lp(a) reduces lipid-related cardiovascular risk.

Other developments offer new hope for addressing atherogenic dyslipidaemia, so far undertreated, as highlighted in this month’s Landmark report. Apolipoprotein (apo) CIII, a key player in the metabolism of triglyceride-rich lipoproteins, is one potential target for intervention, supported by genetic insights that carriage of loss-of-function variants of the gene encoding apoCIII (APOC3) was associated with reduced risk of subclinical atherosclerosis and coronary heart disease ^9,10. Additionally, in individuals with type 2 diabetes, increased plasma apoCIII concentration was associated with higher triglyceride levels, less favourable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis ¹¹. These emerging lines of evidence have been drivers for the development of a second-generation antisense inhibitor of apoCIII synthesis (ISIS 304801). In a phase II study in individuals with baseline triglycerides 4-22.6 mmol/L (350-2000 mg/dl), treatment with ISIS 304801 (either alone or with a fibrate) resulted in reduction in plasma apoCIII levels by up to 80%, with a similar decrease in plasma triglycerides ¹². Given a favourable safety profile to date, further development is merited.

Another option of critical interest is the development of selective peroxisome proliferator-activated receptor alpha (PPAR?) modulators (SPPARMs), which overcome issues related to potency and selectivity with current PPAR? agonists (fibrates). The SPPARM? K-877 (Kowa Limited), filed in Japan and in Phase II/III development in Europe and beyond, has been shown to be effective in managing atherogenic dyslipidaemia and residual hypertriglyceridaemia, especially in individuals with type 2 diabetes, with no evidence of elevation in serum creatinine, or clinically meaningful adverse effects on renal or hepatic function during treatment for up to 24 weeks ^13-15. Clearly, an agent to watch for the future.

However, 2015 has also had its share of disappointments. Perhaps the most newsworthy has been the termination of yet another cholesteryl ester transfer protein (CETP) inhibitor, evacetrapib. The phase III cardiovascular outcomes study ACCELERATE was closed on the recommendation of the Independent Data Monitoring Committee following periodic data reviews which suggested there was a low probability the study would achieve its primary endpoint. Evacetrapib was not terminated due to safety issues ¹⁶. Anacetrapib remains the last CETP inhibitor in Phase III development. Merck recently issued a release confirming that following a planned review of unblinded study the Data Monitoring Committee of the REVEAL study recommended the study continue with no changes ¹⁷.

All of these developments augur for an exciting time for lipid research in the next 1-2 years, with outcomes data available from studies with the PCSK9 inhibitors and anacetrapib. However, it is also important to reaffirm the importance of lifestyle intervention, given that the pandemic of obesity and type 2 diabetes has been largely driven by poor diet and sedentary lifestyle. Not only does lifestyle intervention significantly reduce the development of type 2 diabetes, but also there is also evidence that improvement in the control of just one of seven major modifiable cardiovascular risk factors resulted in 6% reduction in the risk of a cardiovascular event over the following 4 years ^18,19. Clearly a renewed focus on lifestyle is the critical foundation to pharmacotherapeutic intervention targeting residual cardiovascular risk.

On this final note, the Editors wish all readers the very best for 2016 – and look forward to exciting news from forthcoming developments in lipid research.

References

1. AHA names two injectable PCSK9 inhibitors among 2015's top research advances. http://patientdaily.com/stories/510654421-aha-names-two-injectable-pcsk9-inhibitors-among-2015-s-top-research-advances
2. Sabatine MS, Giugliano RP, Wiviott SD, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1500-9.
3. Robinson JG, Farnier M, Krempf M, et al. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med 2015; 372:1489-99.
4. Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 2010;31:2844-53.
5. Khera AV, Everett BM, Caulfield MP et al. Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER Trial (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin). Circulation 2014;129:635-42.
6. Raal FJ, Giugliano RP, Sabatine MS et al. Reduction in lipoprotein(a) with PCSK9 monoclonal antibody evolocumab (AMG 145): a pooled analysis of more than 1,300 patients in 4 phase II trials. J Am Coll Cardiol 2014;63:1278–88.
7. Gaudet D, Kereiakes DJ, McKenney JM et al. Effect of alirocumab, a monoclonal proprotein convertase subtilisin/kexin 9 antibody, on lipoprotein(a) concentrations (a pooled analysis of 150mg every two weeks dosing from phase 2 trials). Am J Cardiol 2014; 114:711–5.
8. Tsimikas S, Viney NJ, Hughes SG et al. Antisense therapy targeting apolipoprotein(a): a randomised, double-blind, placebo-controlled phase 1 study. Lancet 2015;386:1472-83.
9. 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.
10. Blood I, Crosby J, Peloso GM, et al; Tg, Hdl Working Group of the Exome Sequencing Project NHL. Loss-of-function mutations in apoc3, triglycerides, and coronary disease. New Engl J Med 2014;371:22–31
11. Qamar A, Khetarpal SA, Khera AV et al. Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics. Arterioscler Thromb Vasc Biol 2015;35:1880-8.
12. Gaudet D, Alexander VJ, Baker BF et al. Antisense Inhibition of Apolipoprotein C-III in Patients with Hypertriglyceridemia. N Engl J Med 2015;373:438-47.
13. Fruchart JC. Selective peroxisome proliferator-activated receptor ? modulators (SPPARM?): the next generation of peroxisome proliferator-activated receptor ?-agonists. Cardiovasc Diabetol 2013;12:82.
14. Kastelein JP, Senko Y, Hounslow N, Hovingh GK, Ginsberg HN. K-877, a selective PPAR alpha modulator (SPPARM alpha), ameliorates dyslipidaemia in patients with well-controlled LDL Cholesterol levels on statin therapy, without increases in serum creatinine. Eur Heart J 2015;36(Abstract Supplement):1048 [abstract].
15. Kastelein JJP, Senko Y, Hounslow N, Nojima T, Suganami H, Hovingh GK, Ginsberg HN. K-877, a selective PPAR alpha modulator (SPPARM alpha), improves dyslipidaemia in statin-treated patients with type 2 diabetes mellitus. Eur Heart J 2015;36( Abstract Supplement):1048[abstract].
16. Lilly to Discontinue Development of Evacetrapib for High-Risk Atherosclerotic Cardiovascular Disease. https://investor.lilly.com/releasedetail.cfm?ReleaseID=936130
17. Merck Provides Update on REVEAL Outcomes Study. http://www.mercknewsroom.com/news-release/research-and-development-news/merck-provides-update-reveal-outcomes-study
18. Diabetes Prevention Program Research Group. Long term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. Lancet Diabetes Endocrinol 2015; Published Online September 14, 2015.
19. Avanzini F, Marzona I, Baviera M et al; Risk and Prevention Study Collaborative Group. Improving cardiovascular prevention in general practice: Results of a comprehensive personalized strategy in subjects at high risk. Eur J Prev Cardiol 2015 [Epub ahead of print].