Therapeutic potential of selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) for management of patients with atherogenic dyslipidemia

By Heather Nelson Cortes, PhD and Kevin C Maki, PhD

 

Atherosclerotic cardiovascular disease (ASCVD) is associated with a significant public health burden around the world.  It is further exacerbated by chronic lifestyle-related diseases, such as visceral obesity, type 2 diabetes mellitus (T2D) and non-alcoholic fatty liver disease.  The morbidity and mortality of ASCVD is particularly high in low- and middle- income countries, which also have the largest number of people with obesity and diabetes.1-3  In these populations atherogenic dyslipidemia is a significant unmet clinical need.  Elevated plasma triglycerides (TG), with or without low levels of high-density lipoprotein cholesterol (HDL-C), are modifiable ASCVD risk factors, especially in insulin resistant conditions such as T2D.4

 

Some current ASCVD prevention guidelines recommend peroxisome proliferator-activated receptor alpha (PPARα) agonists (e.g., fibrates) for management of hypertriglyceridemia after statins.5  Unfortunately, these PPAR-α agonists have low potency and limited selectivity for PPARα.  They also have pharmacokinetic interactions and other side effects, including an increased risk of myopathy with gemfibrozil in combination with statin and reversible elevation in serum creatinine with fenofibrate, as well as liver enzyme elevation.6-9  Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα), which has a unique receptor-cofactor binding profile to identify the most potent molecules with PPARα-mediated effects while limiting unwanted side effects, has recently been developed.

 

Given the clear need for new therapeutic options for ASCVD, the Joint Consensus Panel from the International Atherosclerosis Society and the Residual Risk Reduction Initiative reviewed the scientific literature to help to determine if it is possible for pemafibrate to improve upon the beneficial lipid effects and safety profile demonstrated for PPARα agonists.10  In a randomized, double-blind clinical trial of 33 patients with atherogenic dyslipidemia, pemafibrate led to markedly decreased TG-rich lipoprotein levels and significantly increased concentrations of HDL-C, apolipoprotein (apo) A-I and apo-A-II, as well as improved markers of HDL function including pre-beta-HDL, smaller HDL particles (HDL3), and increased macrophage cholesterol efflux capacity.11  A pooled analysis of phase II/III studies showed that pemafibrate therapy over 12-24 weeks led to significant improvements in liver function tests (alanine aminotransferase, gamma glutamyl transferase, bilirubin).12  Also, unlike fenofibrate, pemafibrate did not elevate serum creatinine for up to 52 weeks in patients with or without pre-existing renal dysfunction.13  In general, the studies conducted to date have demonstrated that pemafibrate is well tolerated, especially with regard to renal and hepatic function, and that it may help in the management of atherogenic dyslipidemia, particularly by lowering elevated TG-rich lipoproteins and remnant cholesterol levels that are common in overweight patients with T2D.10

 

This Joint Consensus Panel concluded that pemafibrate, a SPPARMα agonist, represents a novel therapeutic class, distinct from fibrates according to its pharmacological activity, with a safe hepatic and renal profile.10  The Panel also recognized that the ongoing Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial of 10,000 patients with T2D, elevated TG, and low levels of HDL-C will help to determine if pemafibrate can be safely used to reduce residual cardiovascular risk.

 

References

  1. Joseph P, Leong D, McKee M, et al. Reducing the global burden of cardiovascular disease. Part 1: the epidemiology and risk factors. Circ Res. 2017;121:677–94.
  2. World Health Organization. Fact sheet. Obesity and overweight. http:// www.who.int/news-room/fact-sheets/detail/obesity-and-overweight. Accessed 21 Jan 2019.
  3. NCD Countdown 2030 collaborators. NCD Countdown 2030: worldwide trends in non-communicable disease mortality and progress towards Sustainable Development Goal target 3.4. Lancet. 2018;392:1072–88.
  4. Varbo A, Freiberg JJ, Nordestgaard BG. Remnant cholesterol and myocardial infarction in normal weight, overweight, and obese individuals from the Copenhagen General Population Study. Clin Chem. 2018;64:219–30.
  5. Piepoli MF, Hoes AW, Agewall S, et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37:2315–81.
  6. Davidson MH. Statin/fibrate combination in patients with metabolic syndrome or diabetes: evaluating the risks of pharmacokinetic drug interactions. Expert Opin Drug Saf. 2006;5:145–56.
  7. Mychaleckyj JC, Craven T, Nayak U, et al. Reversibility of fenofibrate therapy-induced renal function impairment in ACCORD type 2 diabetic participants. Diabetes Care. 2012;35:1008–14.
  8. Davis TM, Ting R, Best JD, et al. Effects of fenofibrate on renal function in patients with type 2 diabetes mellitus: the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Study. Diabetologia. 2011;54:280–90.
  9. Hedrington MS, Davis SN. Peroxisome proliferator-activated receptor alpha-mediated drug toxicity in the liver. Expert Opin Drug Metab Toxicol. 2018;14:671–7.
  10. Fruchart J-C, 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;18:71.
  11. Yamashita S, Arai H, Yokote K, et al. Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J Clin Lipidol. 2018;12:1267–79.
  12. Matsuba I, Matsuba R, Ishibashi S, et al. Effects of a novel selective peroxisome proliferator-activated receptor-α modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. J Diabetes Investig. 2018;9:1323–32.
  13. Yokote K, Yamashita S, Arai H, et al. A pooled analysis of pemafibrate Phase II/III clinical trials indicated significant improvement in glycemic and liver function-related parameters. Atheroscler Suppl. 2018;32:155.

 

Photo by Lucas Vasques

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