R3i Editorials

February 2021
Does SPPARMα offer new opportunities in metabolic syndrome and NAFLD?
Prof. Jean-Charles Fruchart, Prof. Michel Hermans, Prof. Pierre Amarenco

We are in the midst of an epidemic of metabolic disease. Already the metabolic syndrome, as defined by a joint statement from expert groups 1, affects about one-third of the adult world population 2. In the 21st century, lower- and middle-income countries will face a greater burden of disease, fuelled by increasing urbanisation, adoption of Westernised diet, and sedentary lifestyles 3. Obesity (i.e., body mass index ≥30 kg/m2) has reached epidemic levels worldwide, worsening all features of the metabolic syndrome 4. Accompanying the escalation in metabolic syndrome and type 2 diabetes prevalence is an increase in non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease worldwide, which poses a substantial challenge for individuals and societies at large 5. Furthermore, obesity and impaired metabolic health are not only risk factors for non-communicable diseases such as type 2 diabetes mellitus and cardiovascular disease, but also are associated with a high risk of severe COVID-19 6.

Dyslipidemia characterised by elevated triglycerides (TG) and low plasma levels of high-density lipoprotein cholesterol (HDL-C) is a common feature of these metabolic diseases. Visceral obesity drives metabolic changes, leading to overproduction of hepatic very low-density lipoproteins (VLDL), and reduction in catabolism of TG-rich lipoproteins. Cholesterol contained within these lipoproteins is usually referred to as remnant cholesterol.

There is accumulating evidence for the atherogenicity of remnant cholesterol 7. Indeed, this month’s Focus report highlights new data from the PREDIMED study, showing a link between remnant cholesterol and risk for incident cardiovascular disease among high-risk primary prevention individuals with prevalent obesity 8. Baseline remnant cholesterol ≥30 mg/dL, which equated to the 75th percentile of the cohort, identified individuals at high risk of a cardiovascular event independent of low-density lipoprotein cholesterol levels. Those who also had atherogenic dyslipidemia, i.e., both elevated TG and low HDL-C levels, had a 44% increase in the risk of incident cardiovascular events 8.

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) concept may offer new opportunities for managing atherogenic dyslipidaemia associated with the metabolic syndrome, and related metabolic disease 9. The latest SPPARMα, pemafibrate, has shown efficacy in managing elevated TG in patients with or without low HDL-C, including among patients with type 2 diabetes, lowering remnant cholesterol by ~50% (10). The effects of treatment were sustained for up to 52 weeks, together with improvement in fasting insulin and inflammation, and a favourable safety profile to date (10). Moreover, there are also preliminary data from both preclinical models and pilot clinical studies to suggest possible benefit in NAFLD (11-13).

These are promising data for this SPPARMα, with a profile of favourable activity on lipid metabolism, insulin sensitivity and inflammation. PROMINENT will provide important answers to the fundamental question: does targeting atherogenic dyslipidemia in type 2 diabetes patients translate to reduction in cardiovascular events? The future offers tantalising possibility for reducing the burden of metabolic disease.

References

  1. Alberti KG, Eckel RH, Grundy SM, et al. Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 2009;120:1640–45.
    2. O’Neill S, O’Driscoll L. Metabolic syndrome: a closer look at the growing epidemic and its associated pathologies. Obes Rev 2015;16:1–12.
    3. Lenzi A. Why urbanisation and health? Acta Biomed 2019;90:181-183.
    4. Roth GA, Mensah GA, Johnson CO, et al. Global burden of cardiovascular diseases and risk factors, 1990-2019: Update from the GBD 2019 Study. J Am Coll Cardiol 2020;76:2982-3021.
    5. Younossi Z, Anstee QM, Marietti M, Hardy T, Henry L, Eslam M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Nat Rev Gastroenterol Hepatol. 2018;15:11-20.
    6. Stefan N, Birkenfeld AL, Schulze MB. Global pandemics interconnected – obesity, impaired metabolic health and COVID-19. Nat Rev Endocrinol 2021;doi: 10.1038/s41574-020-00462-1.
    7. Sandesara PB, Virani SS, Fazio S, Shapiro MD. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk. Endocr Rev 2019;40:537-57.
    8. Castañer O, Pintó X, Subirana I, et al. Remnant cholesterol, not LDL cholesterol, is associated with incident cardiovascular disease. J Am Coll Cardiol 2020 ;76:2712-24.
    9. Fruchart JC, Hermans MP, Fruchart-Najib J, Kodama T. Selective peroxisome proliferator-activated receptor alpha modulators (SPPARMα) in the metabolic syndrome: is pemafibrate light at the end of the tunnel? Curr Atheroscler Rep 2021;231:3.
    10. Yamashita S, Arai H, Yokote K, et al. Efficacy and safety of pemafibrate, a novel selective peroxisome proliferator-activated receptor α modulator (SPPARMα): pooled analysis of phase 2 and 3 studies in dyslipidemic patients with or without statin combination. Int J Mol Sci. 2019;20:5537.
    11. Honda Y, Kessoku T, Ogawa Y, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep 2017;7:42477.
    12. Sasaki Y, Asahiyama M, Tanaka T, et al. Pemafibrate, a selective PPARα modulator, prevents non-alcoholic steatohepatitis development without reducing the hepatic triglyceride content. Sci Rep 2020; 10:7818.
    13. Seko Y, Yamaguchi K, Umemura A, et al. Effect of pemafibrate on fatty acid levels and liver enzymes in non-alcoholic fatty liver disease patients with dyslipidemia: A single-arm, pilot study. HepatolRes2020;50: 1328–36.