R3i Editorial

The failure of HPS2-THRIVE has been much debated. However, it is now time to take a step back for a balanced analysis, as discussed in this month’s Focus article.

The Residual Risk Reduction Initiative (R3i) believes that recent trials with niacin highlight two key points. First, trials aimed at investigating therapeutic options for reducing residual risk clearly need to be relevant to the intended target patient population. Second, when considering data from both niacin trials, HPS2-THRIVE and AIM-HIGH, it is clear that there are unresolved issues about the use of niacin to reduce residual cardiovascular risk. Not only was there a lack of benefit, but there was also significant harm associated with niacin plus statin combination therapy.(1-3) Exacerbation of diabetes complications, and indeed the significant increase in new-onset diabetes, is a major disadvantage in the treatment of patients with insulin resistance phenotype and/or comorbidities commonly associated with atherogenic dyslipidemia.

As already discussed, the only outcomes evidence to date for therapeutic options in this setting is from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) Lipid trial with fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARα) agonist, specifically in patients with type 2 diabetes and atherogenic dyslipidemia (the combination of elevated triglycerides and low high-density lipoprotein cholesterol [HDL-C]).(4) However, it is acknowledged that fenofibrate is a comparatively weak agonist of PPARα Consequently, efficacy is modest due to the need to balance the risks versus-benefits of treatment.

Will improving PPARα selectivity provide better balance?

Given that PPARα plays a key role in the regulation of lipid homeostasis, this nuclear receptor is a highly logical target in individuals with cardiometabolic disease. Thus, one line of activity has been directed to the improving the selectivity and hence potency of PPARα agonists. The selective PPARα modulator (SPPARMα) K-877 is one such agent, currently in phase II clinical development. Studies in animal models of obesity show that the triglycerides-lowering efficacy of K-877 is about 1000-fold greater than that of fenofibrate.(5) In patients with atherogenic dyslipidemia (triglycerides ≥200 mg/dL or 2.3 mmol/L and HDL-C ≤50/55 mg/dL or 1.29-1.42 mmol/L), treatment with K 877 (100-µg twice daily) was superior to fenofibrate 100 mg daily for lowering triglycerides and raising HDL-C. Importantly, the adverse effects profile with K-877 showed no evidence of any deleterious effects on markers of renal or hepatic function.(6) Further analyses also indicate that K-877 appears to suppress the postprandial increase in remnant cholesterol (non-fasting total cholesterol minus HDL-C minus LDL-C), recently shown to be a major risk factor for ischemic heart disease.(7) These early findings clearly warrant further development of this novel SPPARMα agonist.

There are also two other types of PPAR receptors: PPARδ (also called PPARβ) and PPARγ. As the latter targets include genes involved in obesity and insulin resistance, this would suggest that dual PPARα/γ agonists may offer potential in the management of patients with cardiometabolic disease. Until recently the development of such dual agonists has been plagued by safety issues, including detrimental effects on cardiovascular and renal outcomes, as well as weight gain.(8-10) The most recent dual PPARα/γ agonist - aleglitazar - may offer new potential, with studies showing enhanced effects on glucose homeostasis (versus pioglitazone), as well as improved lipid-modifying efficacy (versus fenofibrate).(11,12)

The R3i believe that the development of novel selective PPARα modulators (either as single or dual PPAR agonists) signals real promise for addressing the burden of residual vascular risk, against a background of increasing cardiometabolic disease. We look forward to results of ongoing trials with great anticipation.

References

1. HPS2-THRIVE Collaborative Group. HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment. Eur Heart J 2013; online ahead of print 27 February 2013.
2. HPS2-THRIVE Trial website: http://www.thrivestudy.org/
3. 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.
4. 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.
5. Takizawa T. K-877, a highly potent and selective PPARα agonist, improves dyslipidemia and atherosclerosis in experimental animal models . Atheroscler Suppl 2012; 12:Abstr 787.
6. Ishibashi S, Arai H, Yamashita S, Araki E, Yamada N. Benefical effects of K-877, a potent and highly selective PPARα agonist, on plasma lipoprotein profile in patients with atherogenic dyslipidemia. Atheroscler Suppl 2012; 12:Abstr 525.
7. Varbo A, Benn M, Tybjærg-Hansen A, Jørgensen AB, Frikke-Schmidt R, Nordestgaard BG. Remnant cholesterol as a causal risk factor for ischemic heart disease. J Am Coll Cardiol 2013;61:427-36.
8. Nissen SE, Wolski K, Topol EJ. Effect of muraglitazar on death and major adverse cardiovascular events in patients with type 2 diabetes mellitus. JAMA 2005;294:2581-6.
9. Hamren B, Ohman KP, Svensson MK et al. Pharmacokinetic-pharmacodynamic assessment of the interrelationships between tesaglitazar exposure and renal function in patients with type 2 diabetes mellitus. J Clin Pharmacol 2012;52:1317-27.
10. Rosenson RS, Wright RS, Farkouh M, Plutzky J. Modulating peroxisome proliferator-activated receptors for therapeutic benefit? Biology, clinical experience, and future prospects. Am Heart J 2012; 164:672-80.
11. Henry RR, Lincoff AM, Mudaliar S et al. Effect of the dual peroxisome proliferator-activated receptor-alpha/gamma agonist aleglitazar on risk of cardiovascular disease in patients with type 2 diabetes (SYNCHRONY): a phase II, randomised, dose-ranging study. Lancet 2009;374:126-35.
12. Herz M, Gaspari F, Perico N et al. Effects of high dose aleglitazar on renal function in patients with type 2 diabetes. Int J Cardiol 2011;151:136-42.