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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