R3i Editorial

Atherogenic dyslipidaemia has long been recognised as a contributor to modifiable residual cardiovascular risk.¹ To date, however, definitive evidence on how best to target this to reduce residual cardiovascular risk is lacking.
The REDUCE-IT trial, discussed as this month’s Landmark Study,² supports the rationale of targeting elevated triglycerides, a key feature of atherogenic dyslipidaemia. The results of this trial, however, are confounded on the one hand by the lipid-modifying effects of the placebo, and on the other hand, by the pleiotropic effects of omega-3 fatty acids beyond triglyceride lowering.³ Additionally, previous fibrate trials had mixed results, failing to show definitive clinical benefit against a background of statin therapy.⁴ It is clear that the residual cardiovascular risk enigma continues….

The advent of novel SPPARMα agonists, however, brings new promise. Harnessing an approach used in oncology therapies,⁵ researchers developed a novel agent with high potency and selectivity for peroxisome proliferator-activated receptor α (PPARα), the nuclear receptor ‘hub’ that regulates lipid metabolism and inflammatory pathways.⁶

Evidence for the SPPARMα concept has been the focus of a recent consensus statement, authored by over 50 experts in lipid metabolism, atherosclerosis and cardiovascular disease prevention.⁷ Results to date are promising. The novel SPPARMα agonist, pemafibrate, showed robust lowering of triglycerides, remnant cholesterol and apolipoproteins B48 and C-III, together with elevation in the quantity and quality of high-density lipoprotein in short-term clinical trials.⁷ In addition, pemafibrate exhibited a favourable renal and hepatic safety profile, a moot point for current fibrates.^7,8 Thus, consensus suggests that pemafibrate offers an improved benefit-risk profile over current fibrates.

What will truly define the SPPARMα paradigm, however, is 1) definitive reduction in residual cardiovascular risk in high-risk patients with atherogenic dyslipidaemia, and 2) long-term safety. These questions are being addressed by the PROMINENT trial in 10,000 patients with type 2 diabetes and atherogenic dyslipidaemia.⁹ While the answers to these two key questions are still a few years away, evidence to date suggests that the SPPARMα paradigm offers new hope for clinicians in tackling modifiable residual cardiovascular risk.

There are also other unanswered questions. Will this novel SPPARMα agonist confer benefit against the residual risk of microvascular complications such as diabetic retinopathy, diabetic nephropathy or lower-extremity amputation, seen with fenofibrate? Are there other potential indications within the spectrum of cardiometabolic disease, in which pemafibrate may offer clinical benefit? And finally, a key consideration for patients and clinicians alike, is this novel SPPARMα agonist safe?

We are living in exciting times. The availability of new treatments that target PCSK9 (proprotein convertase subtilisin/kexin type 9) means that attainment of very low levels of low-density lipoprotein cholesterol (LDL-C) is now feasible, safe and effective. Yet even with these highly efficacious treatments, high-risk individuals remain at persistent risk of (re)current cardiovascular events.^10,11 After the disappointment of clinical trials with HDL-targeted therapies, our focus is shifting back to atherogenic dyslipidaemia, notably elevated remnant lipoproteins, as a key contributor to residual cardiovascular risk. We wait with eager anticipation for the results of PROMINENT.

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 Suppl 10:1K–34K.
2. Bhatt DL, Steg PG, Miller M et al. Cardiovascular risk reduction with icosapent ethyl for hypertriglyceridemia. N Engl J Med 2019;380:11-22.
3. Baum SJ, Scholz KP. Rounding the corner on residual risk: Implications of REDUCE-IT for omega-3 polyunsaturated fatty acids treatment in secondary prevention of atherosclerotic cardiovascular disease. Clin Cardiol 2019. doi: 10.1002/clc.23220. [Epub ahead of print]
4. Jun M, Foote C, Lv J et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 2010;375:1875-84.
5. Lewis JS, Jordan VC. Selective estrogen receptor modulators (SERMs): mechanisms of anticarcinogenesis and drug resistance. Mutat Res 2005;591:247–63.
6. Fruchart JC. Selective peroxisome proliferator-activated receptor α modulators (SPPARMα): the next generation of peroxisome proliferator-activated receptor α-agonists. Cardiovasc Diabetol 2013;12:82
7. Fruchart JC, Santos RD, Aguilar-Salinas C et al. The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation. Cardiovasc Diabetol 2019;18(1):71.
8. Choi HD, Shin WG, Lee JY, Kang BC. Safety and efficacy of fibrate-statin combination therapy compared to fibrate monotherapy in patients with dyslipidemia: a meta-analysis. Vascul Pharmacol 2015;65-66:23-30.
9. Pradhan AD, Paynter NP, Everett BM, et al. Rationale and design of the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) study. Am Heart J 2018;206:80–93.
10. 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.
11. Schwartz GG, Steg PG, Szarek M et al. Alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med 2018;379:2097–107.