R3i Editorial

In 2013, the Residual Risk Reduction Initiative published a second ‘call to action’ on residual cardiovascular risk, following the initial paper in 2008.^1,2 Five years later, are we any closer to defining management approaches that effectively reduce this risk?

Over this time, we have, however, gained a number of important insights. With respect to lipid-related residual cardiovascular risk, it is now clear that even lowering low-density lipoprotein cholesterol (LDL-C) to levels below those recommended by current guidelines does not eliminate this risk.³ A number of candidates are under investigation as additional and potentially modifiable contributors to lipid-related residual cardiovascular risk; the strongest evidence to date is for fasting and nonfasting triglyceride-rich lipoproteins and their remnants (for which triglycerides are a marker).⁴ There are also accumulating data for lipoprotein(a). Indeed, this month’s Landmark report shows that genetic variation at the LPA locus, the major determinant of circulating lipoprotein(a) levels, is associated with risk for coronary heart disease events among individuals on statin therapy independent of the extent of LDL-C lowering.⁵

Yet, the proof of efficacy for targeting these different candidates remains incomplete, due to the lack of definitive evidence from cardiovascular outcomes trials. Admittedly, the fibrate trials did indicate a benefit in patients with atherogenic dyslipidaemia (defined as the combination of elevated triglycerides and low high-density lipoprotein cholesterol (HDL-C) concentration), although this was predominantly based on post hoc findings.⁶ Additionally, we await news from the first of two large cardiovascular outcomes studies with omega-3 fatty acids due to report later this year; the REDUCE-IT (Reduction of Cardiovascular Events Outcomes) trial, evaluated the effectiveness of an EPA- (eicosapentaenoic acid) only omega-3 as an add-on to statin therapy in reducing major cardiovascular events in statin-treated high-risk patients⁷. With respect to lipoprotein(a), specific agents that are capable of lowering lipoprotein(a) levels by up to 80-90% are now entering phase III trials, although there is still debate regarding the extent of reduction that is required against a background of well-managed LDL-C levels.⁸

Undoubtedly, genetic studies have driven the development of novel agents for the management of atherogenic hypertriglyceridaemia. These include antisense and monoclonal antibody therapies aimed at key targets in the regulation of triglyceride metabolism, such as apolipoprotein CIII, and angiopoietin-like proteins 3 and 4.⁹ There is also evidence to support apoA5 as potentially atheroprotective (see this month’s Focus), although clinical trials lag behind.

Other new therapies have taken a different course for development. The shining example here is the development of pemafibrate, a first in class selective peroxisome proliferator-activated receptor alpha (PPAR?) modulator (SPPARM), in which modulating the unique receptor–cofactor binding profile of PPAR provided an opportunity to identify the most potent molecules that induce PPAR?-mediated beneficial effects while at the same time avoiding unwanted side effects. Comprehensive structural and protein-ligand binding elucidation along with comprehensive in vitro testing identified pemafibrate as a novel SPPARM? from about 1,400 compounds screened for SPPARM activity.¹⁰ Phase II/III trials have been encouraging, showing a lipid-modifying profile that includes substantial lowering of triglyceride-rich lipoproteins and their remnants and raising of HDL-C. The PROMINENT study, a major cardiovascular outcomes study, is now in progress and we wait for answers….

It is, however, important to remember that residual cardiovascular risk is multifaceted, as illustrated by CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study). In patients with well-managed LDL-C levels but high residual inflammatory risk, treatment with canakinumab, an anti interleukin 1? monoclonal antibody, reduced major adverse cardiovascular events.¹¹As with LDL-C lowering, there was evidence of a dose-response relationship for clinical benefit, with patients with higher baseline levels of C-reactive protein (a marker of inflammatory risk) gaining greater absolute clinical benefit.¹²

Our knowledge of residual cardiovascular risk, and potential approaches to its management, is expanding. We have now a number of novel agents in development, which may provide the key to ameliorating this risk; the next 5 years promise an exciting time in lipid and non-lipid residual risk research.

References

1. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008;102(10 Suppl):1K-34K.
2. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol 2014;13:26.
3. Sabatine MS, Giugliano RP, Keech AC et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med 2017;376):1713-22.
4. Ganda OP, Bhatt DL, Mason RP et al. Unmet need for adjunctive dyslipidemia therapy in hypertriglyceridemia management. J Am Coll Cardiol 2018 Jun 16. pii: S0735-1097(18)34817-4
5. Wei WQ, Li X, Feng Q et al. LPA Variants are associated with residual cardiovascular risk in patients receiving statins. Circulation 2018 doi: 10.1161/CIRCULATIONAHA.117.031356. [Epub ahead of print]
6. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
7. 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. https://clinicaltrials.gov/ct2/show/NCT01492361
8. Burgess S, Ference BA, Staley JR et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol 2018 Jun 20. doi: 10.1001/jamacardio.2018.1470. [Epub ahead of print]
9. Olkkonen VM, Sinisalo J, Jauhiainen M. New medications targeting triglyceride-rich lipoproteins: Can inhibition of ANGPTL3 or apoC-III reduce the residual cardiovascular risk? Atherosclerosis 2018;272:27-32.
10. Fruchart JC. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor alpha modulator for management of atherogenic dyslipidaemia. Cardiovasc Diabetol 2017;16(1):124
11. Ridker PM, Everett BM, Thuren T et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med 2017;377:1119-31.
12. Ridker PM, MacFadyen JG, Everett BM et al. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet 2018;391:319-28.