Koutaro Yokote1,2, Shizuya Yamashita3, Hidenori Arai4, Eiichi Araki5, Mitsunori Matsushita6, Toshiaki Nojima7, Hideki Suganami7, Shun Ishibashi8. 1. Department of Endocrinology, Hematology and Gerontology, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan. kyokote@faculty.chiba-u.jp. 2. Department of Diabetes, Metabolism and Endocrinology, Chiba University Hospital, 1-8-1 Inohana, Chuo-ku, Chiba-shi, Chiba, 260-8670, Japan. kyokote@faculty.chiba-u.jp. 3. Rinku General Medical Center, 2-23 Ohrai-kita, Rinku, Izumisano-shi, Osaka, 598-8577, Japan. 4. National Center for Geriatrics and Gerontology, 7-430 Morioka-cho, Obu-shi, Aichi, 474-8511, Japan. 5. Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto-shi, Kumamoto, 860-8556, Japan. 6. Medical Affairs Department, Kowa Company, Ltd, 3-4-14 Nihonbashi-honcho, Chuo-ku, Tokyo, 103-8433, Japan. 7. Clinical Data Science Department, Kowa Company, Ltd, 3-4-14 Nihonbashi-honcho, Chuo- ku, Tokyo, 103-8433, Japan. 8. Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke-shi, Tochigi, 329-0498, Japan.
Abstract
BACKGROUND:Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnormalities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. METHODS: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo-controlled trials that examined the effects of daily pemafibrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafibrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. RESULTS: The study population was 1253 patients randomized toplacebo (n = 298) or pemafibrate 0.1 mg/day (n = 127), 0.2 mg/day (n = 584), or 0.4 mg/day (n = 244). Participant mean age was 54.3 years, 65.4 % hadBMI ≥ 25 kg/m2, 35.8 % had type 2 diabetes, and 42.6 % had fatty liver. Fasting glucose, fasting insulin, and HOMA-IR decreased significantly in all pemafibrate groups compared to placebo. The greatest decrease was for pemafibrate 0.4 mg/day: least square (LS) mean change from baseline in fasting glucose - 0.25 mmol/L; fasting insulin - 3.31 µU/mL; HOMA-IR - 1.28. ALT, γ-GT, ALP, and total bilirubin decreased significantly at all pemafibrate doses vs. placebo, with the greatest decrease in the pemafibrate 0.4 mg/day group: LS mean change from baseline in ALT - 7.6 U/L; γ-GT - 37.3 U/L; ALP - 84.7 U/L; and total bilirubin - 2.27 µmol/L. Changes in HbA1c and AST did not differ significantly from placebo in any pemafibrate groups in the overall study population. The decreases from baseline in LFTs and glucose metabolism markers except for HbA1c were notable among patients with higher baseline values. FGF21 increased significantly in all pemafibrate groups compared to placebo, with the greatest increase in the pemafibrate 0.4 mg/day group. Adverse event rates were similar in all groups including placebo. CONCLUSIONS: In patients with hypertriglyceridemia, pemafibrate can improve glucose metabolism and liver function, and increase FGF21, without increasing adverse event risk.
RCT Entities:
BACKGROUND: Increased risk of cardiovascular events is associated not only with dyslipidemias, but also with abnormalities in glucose metabolism and liver function. This study uses pooled analysis to explore the in-depth effects of pemafibrate, a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) already known to decrease elevated triglycerides, on glucose metabolism and liver function in patients with hypertriglyceridemia. METHODS: We performed a post-hoc analysis of six phase 2 and phase 3 Japanese randomized double-blind placebo-controlled trials that examined the effects of daily pemafibrate 0.1 mg, 0.2 mg, and 0.4 mg on glucose metabolism markers and liver function tests (LFTs). Primary endpoints were changes in glucose metabolism markers and LFTs from baseline after 12 weeks of pemafibrate treatment. All adverse events and adverse drug reactions were recorded as safety endpoints. RESULTS: The study population was 1253 patients randomized to placebo (n = 298) or pemafibrate 0.1 mg/day (n = 127), 0.2 mg/day (n = 584), or 0.4 mg/day (n = 244). Participant mean age was 54.3 years, 65.4 % had BMI ≥ 25 kg/m2, 35.8 % had type 2 diabetes, and 42.6 % had fatty liver. Fasting glucose, fasting insulin, and HOMA-IR decreased significantly in allpemafibrate groups compared to placebo. The greatest decrease was for pemafibrate 0.4 mg/day: least square (LS) mean change from baseline in fasting glucose - 0.25 mmol/L; fasting insulin - 3.31 µU/mL; HOMA-IR - 1.28. ALT, γ-GT, ALP, and total bilirubin decreased significantly at allpemafibrate doses vs. placebo, with the greatest decrease in the pemafibrate 0.4 mg/day group: LS mean change from baseline in ALT - 7.6 U/L; γ-GT - 37.3 U/L; ALP - 84.7 U/L; and total bilirubin - 2.27 µmol/L. Changes in HbA1c and AST did not differ significantly from placebo in any pemafibrate groups in the overall study population. The decreases from baseline in LFTs and glucose metabolism markers except for HbA1c were notable among patients with higher baseline values. FGF21 increased significantly in allpemafibrate groups compared to placebo, with the greatest increase in the pemafibrate 0.4 mg/day group. Adverse event rates were similar in all groups including placebo. CONCLUSIONS: In patients with hypertriglyceridemia, pemafibrate can improve glucose metabolism and liver function, and increase FGF21, without increasing adverse event risk.
Authors: Enzo Bonora; Stefan Kiechl; Johann Willeit; Friedrich Oberhollenzer; Georg Egger; James B Meigs; Riccardo C Bonadonna; Michele Muggeo Journal: Diabetes Care Date: 2007-02 Impact factor: 19.112
Authors: N Sarwar; P Gao; S R Kondapally Seshasai; R Gobin; S Kaptoge; E Di Angelantonio; E Ingelsson; D A Lawlor; E Selvin; M Stampfer; C D A Stehouwer; S Lewington; L Pennells; A Thompson; N Sattar; I R White; K K Ray; J Danesh Journal: Lancet Date: 2010-06-26 Impact factor: 202.731