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

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.

 

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Summary of Results from a Trial of a Novel Selective PPARɑ Modulator, Pemafibrate, on Lipid and Glucose Metabolism in Patients with Type 2 Diabetes and Hypertriglyceridemia1

Summary of Results from a Trial of a Novel Selective PPARɑ Modulator, Pemafibrate, on Lipid and Glucose Metabolism in Patients with Type 2 Diabetes and Hypertriglyceridemia

By Kristen N Smith, PhD, RD, LD; Mary R Dicklin, PhD; Kevin C Maki, PhD

 Background:

Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of death in persons with type 2 diabetes2 and the incidence of cardiovascular events is elevated in patients with type 2 diabetes compared with those without diabetes.3,4 Abnormalities in lipid metabolism often accompany type 2 diabetes mellitus and are associated with insulin resistance, including:

  • Elevated triglyceride (TG) levels with delayed clearance of TG-rich lipoproteins from the circulation;
  • Reduced high-density lipoprotein cholesterol (HDL-C) levels;
  • An increased proportion of small, dense low-density lipoprotein (LDL) particles.

Several large-scale clinical trials, including the Collaborative Atorvastatin Diabetes Study (CARDS) and a Cholesterol Treatment Trialists’ (CTT) meta-analysis, have shown that effective management of dyslipidemia through LDL cholesterol (LDL-C)-lowering therapy with statins results in reduced cardiovascular risk in patients with diabetes.5,6 Other studies in people with diabetes have also identified risk factors for developing coronary heart disease including the Japan Diabetes Complication Study (JDCS), which noted high LDL-C and TG levels as risk factors, and the UK Prospective Diabetes Study (UKPDS), which showed that high LDL-C and low HDL-C are associated with elevated cardiovascular disease risk.7,8

Studies with fibrates have shown the expected decreases in TG and increases in HDL-C, but have shown inconsistent results regarding reductions in ASCVD risk in patients with type 2 diabetes. A meta-analysis completed by our group9 showed evidence that fibrates and other drugs that primarily lower TG and TG-rich lipoproteins (omega-3 fatty acid concentrates and niacin) reduce ASCVD events in participants with elevated TG, particularly if also accompanied by low HDL-C.

Pemafibrate (K-877) is a novel selective peroxisome proliferator-activated receptor alpha (PPARɑ) modulator approved for the treatment of dyslipidemia.10 Ishibashi et al. performed a dose-finding phase 2 trial of pemafibrate in patients with atherogenic dyslipidemia (elevated TG and low HDL-C) and noted significant reductions in TG and increases in HDL-C with rates of adverse events (AEs) similar to placebo. Because type 2 diabetes and atherogenic dyslipidemia often coexist, many of the patients who receive treatment with pemafibrate (once approved for marketing) are expected to also have type 2 diabetes. This summary reports on the initial 24-week treatment period for a Phase III clinical trial comparing the effects of pemafibrate and placebo in patients with elevated TG and type 2 diabetes. The primary end point of the study was the percentage change in fasting serum TG level from baseline to the end point of 24 weeks. Secondary endpoints included the percentage changes or changes from baseline in fasting and postprandial lipid-related and glycemic parameters. The primary safety end points were the incidence rates of AEs and adverse drug reactions after the study drug usage.

 Methods:

This was a multicenter, placebo-controlled, randomized, double-blind, parallel group study that was completed in 34 medical institutions in Japan from February 20, 2014 through April 30, 2015. Subjects were eligible for the study if they met the following criteria:

  • Men and postmenopausal women age ≥20 years;
  • Type 2 diabetes with glycated hemoglobin (HbA1c) ≥6.2% and TG ≥150 mg/dL (1.7 mmol/L);
  • ≥12 weeks of dietary or exercise guidance before the first screening visit.

This study included participants who were randomly assigned to receive twice daily placebo (n = 57), 0.2 mg/day pemafibrate (n = 54), or 0.4 mg/day pemafibrate (n = 55) for 24 weeks. Pemafibrate is available in 0.1 mg tablets.

 Results:

Fasting serum TG significantly decreased by ~45% with pemafibrate compared with placebo (p<0.001, see table).

 

 

Fasting TG, mg/dL, mean ± standard deviation

 

Baseline

Week 24

Placebo

  284.3 ± 117.6

240.0 ± 92.2

0.2 mg/day pemafibrate

240.3 ± 93.5

129.0 ± 71.5

0.4 mg/day pemafibrate

260.4 ± 95.9

135.8 ± 71.2

Percentage changes in fasting serum TG levels from baseline to 24 weeks were -10.8% (p < 0.01), -44.3% (p < 0.001) and -45.1% (p <0.001) for placebo, 0.2 mg/day and 0.4 mg/day, respectively. The pemafibrate groups also had significantly reduced levels of non-HDL-C, remnant lipoprotein cholesterol, apolipoprotein (Apo) B100, Apo B48 and Apo C3, and significantly increased HDL-C and Apo A1 levels. LDL-C was not significantly affected by treatment with pemafibrate. The 0.2 mg/day pemafibrate group had significant reductions in homeostasis model assessment (HOMA)-insulin resistance scores compared with placebo, but no significant alterations vs. placebo were seen in fasting plasma glucose, fasting insulin, glycoalbumin or HbA1c. Rates of AEs and adverse drug reactions were similar between the two pemafibrate groups and the placebo group.

 Comment:

This is the first report of long-term (24 weeks) efficacy and safety of pemafibrate in subjects with type 2 diabetes and hypertriglyceridemia. In this study, which was conducted in Japan, pemafibrate lowered TG levels by ~45%, which was apparent within the first month of the treatment period and maintained over the entire treatment period. An ASCVD event trial with pemafibrate commenced enrollment in 2017, the Pemafibrate to Reduce Cardiovascular Outcomes by Reducing Triglycerides in Patients with Diabetes (PROMINENT) trial, and is expected to complete in 2022 (https://clinicaltrials.gov/ct2/show/NCT03071692).

References:

  1. Araki E, Yamashita S, Arai H, et al. Effects of pemafibrate, a novel selective PPARalpha modulator, on lipid and glucose metabolism in patients with type 2 diabetes and hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial. Diabetes Care. 2018;41(3):538-546.
  2. Tancredi M, Rosengren A, Svensson AM, et al. Excess mortality among persons with type 2 diabetes. N Engl J Med. 2015;373(18):1720-1732.
  3. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction. N Engl J Med. 1998;339(4):229-234.
  4. Mulnier HE, Seaman HE, Raleigh VS, et al. Risk of myocardial infarction in men and women with type 2 diabetes in the UK: a cohort study using the General Practice Research Database. Diabetologia. 2008;51(9):1639-1645.
  5. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet. 2004;364(9435):685-696.
  6. Cholesterol Treatment Trialists C, Kearney PM, Blackwell L, et al. Efficacy of cholesterol-lowering therapy in 18,686 people with diabetes in 14 randomised trials of statins: a meta-analysis. Lancet. 2008;371(9607):117-125.
  7. Sone H, Tanaka S, Tanaka S, et al. Serum level of triglycerides is a potent risk factor comparable to LDL cholesterol for coronary heart disease in Japanese patients with type 2 diabetes: subanalysis of the Japan Diabetes Complications Study (JDCS). J Clin Endocrinol Metab. 2011;96(11):3448-3456.
  8. Turner RC, Millns H, Neil HA, et al. Risk factors for coronary artery disease in non-insulin dependent diabetes mellitus: United Kingdom Prospective Diabetes Study (UKPDS: 23). BMJ. 1998;316(7134):823-828.
  9. Maki KC, Guyton JR, Orringer CE, Hamilton-Craig I, Alexander DD, Davidson MH. Triglyceride-lowering therapies reduce cardiovascular disease event risk in subjects with hypertriglyceridemia. J Clin Lipidol. 2016;10(4):905-914.

10.       Ishibashi S, Yamashita S, Arai H, et al. Effects of K-877, a novel selective PPARalpha modulator (SPPARMalpha), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis. 2016;249:36-43.

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