R3i Editorial

Peroxisome proliferator-activated receptor alpha (PPAR?) agonists – fibrates – are perhaps the best option among available agents for managing atherogenic dyslipidaemia, a key contributor to lipid-related residual cardiovascular risk.¹ However, this benefit is not without downsides, notably the potential for elevation in serum creatinine and liver enzymes, as well as precautions for their use in renal disease. To counter these effects, it has been proposed that modifying the receptor–cofactor binding profile of the PPAR ligand may result in improved potency and tissue selectivity, and at the same time limit potentially deleterious adverse effects.² This selective peroxisome proliferator-activated receptor modulator alpha (SPPARM?) concept has been much lauded. Pre-clinical studies have shown that improved PPAR? selectivity and potency (more than 2,500-fold compared with fenofibrate) with the first in class SPPARM? K-877 (pemafibrate) resulted in enhanced triglyceride lowering and elevation in high-density lipoprotein cholesterol (HDL-C), compared with fenofibrate.^3-5

Do these pre-clinical data translate to the clinic?

This month’s Focus report highlights data from the first published phase II trial with this novel agent that bear out the SPPARM? concept.⁶ This trial from Japan investigated the effects of K-877 in the patient population most likely to derive benefit, i.e. patients with type 2 diabetes and atherogenic dyslipidaemia, i.e. elevated triglycerides (?200 mg/dl and <500 mg/dl) and low HDLC (<55 mg/dl in women and <50 mg/dl in men). The study was primarily conducted to investigate the dose-ranging response in triglyceride lowering with K-877 (0.025, 0.05, 0.1 or 0.2 mg twice daily), and compare this with placebo and fenofibrate 100 mg once daily. As discussed in the report, treatment with K 877 resulted in significant benefit in both lowering triglycerides (by up to 43%) and raising HDL-C (by up to 21%) over this dose range, with an apparent plateau in response at the two highest doses. There was also benefit on other apoB-containing atherogenic lipoproteins, including very low-density lipoprotein cholesterol, remnant cholesterol, and on apoCIII, with maximal reduction from baseline of 48%, 50% and 34%, respectively. Incidentally, K-877 also improved the activity of fibroblast growth factor 21 (FGF 21), a metabolic regulator with insulin-sensitizing activity,⁷ although this did not translate to reduction in body weight or improvement in glucose tolerance at the doses tested.

Importantly, the adverse event profile with K 877 was similar to that observed with placebo, with no evidence to suggest an increase in the frequency of adverse events with increasing dosage. Compared with fenofibrate 100 mg daily, there was a lower frequency of liver enzyme elevation, and no increase in serum creatinine.

Next steps?

Clearly, this is still early stages in the development of this novel pharmacotherapy. We do need to bear in mind that patients receiving lipid-modifying therapy (including statins) were excluded from this phase II trial. Larger phase III studies are needed to evaluate extended treatment with K-877 in the target patient population on best evidence-based treatment including a statin, against the recommended dose of fenofibrate (200 mg daily). Provided ongoing data remain favourable, the ultimate test will be whether the addition of K-877 reduces cardiovascular events in statin-treated type 2 diabetes patients with residual atherogenic dyslipidaemia at baseline. In the last 6 months, the PROMINENT (Pemafibrate to Reduce cardiovascular OutcoMes by reducing triglycerides IN diabetic patiENTs) cardiovascular outcomes trial with K-877 has been announced. This plans to recruit 10,000 high-risk diabetic patients with and without established cardiovascular disease worldwide.

Of course, the results of PROMINENT are some years ahead. It may be possible that this novel SPPARM? may offer new potential to address the high lipid-related residual cardiovascular risk that persists despite best available lipid-modifying therapy. We shall have to wait and see.

References

1. Sacks FM, Carey VJ, Fruchart JC. Combination lipid therapy in type 2 diabetes. N Engl J Med 2010;363:692-4.
2. Fruchart JC. Selective peroxisome proliferator-activated receptor ? modulators (SPPARM?): the next generation of peroxisome proliferator-activated receptor ?-agonists. Cardiovasc Diabetol 2013;12:82.
3. Yamazaki Y, Abe K, Toma T et al. Design and synthesis of highly potent and selective human peroxisome proliferator-activated receptor alpha agonists. Bioorg Med Chem Lett 2007;17:4689-93.
4. Raza-Iqbal S, Tanaka T, Anai M et al. Transcriptome analysis of K-877 (a Novel Selective PPAR? Modulator (SPPARM?))-regulated genes in primary human hepatocytes and the mouse liver. J Atheroscler Thromb 2015;22:754-72.
5. Masuda D, Kobayashi T, Nakaoka H et al. A novel potent and selective PPARalpha agonist, K-877, ameriolates the atherogenic profile of fasting and postprandial hypertriglyceridemia in mice. Eur Heart J 2014;35(Abstract Supplement): 904 [abstract].
6. Ishibashi S, Yamashita S, Arai H et al. Effects of K-877, a novel selective PPARa modulator (SPPARMa), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis 2016;249:36-43.
7. Bailey CJ, Tahrani AA, Barnett AH. Future glucose-lowering drugs for type 2 diabetes. Lancet Diabetes Endocrinol 2016;4:350-9.