Bezafibrate improves insulin resistance evaluated using the glucose clamp technique in patients with type 2 diabetes mellitus: a small-scale clinical study

Abstract

BackgroundBezafibrate is mainly used to treat hypertriglyceridemia. Studies have reported that bezafibrate also improves type 2 diabetes mellitus, but the mechanism has not been fully elucidated. We performed euglycemic hyperinsulinemic clamps (glucose clamp) and meal tolerance tests (MTT) to examine the effects of bezafibrate on insulin resistance in patients with type 2 diabetes mellitus.MethodsTwelve Japanese patients with type 2 diabetes mellitus and dyslipidemia (mean age: 59.5 years; fasting plasma glucose: 7.95 mmol/L; hemoglobin A1c [HbA1c]: 7.3%; body mass index: 26.5 kg/m2) underwent a glucose clamp and MTT before and after 12 weeks of treatment with 400 mg/day bezafibrate. The glucose infusion rate was measured during the glucose clamp. The patients took a test meal (460 kcal) in the MTT. Plasma glucose and immunoreactive insulin levels were measured at 0 (fasting), 30, 60, 120, and 180 min. Serum C-peptide immunoreactivity, serum lipids, and liver function markers were also measured during the MTT.ResultsBezafibrate significantly increased the mean glucose infusion rate from 5.78 ± 1.94 to 6.78 ± 2.52 mg/kg/min (p < 0.05). HbA1c improved from 7.30 ± 0.55% to 7.02 ± 0.52% (p < 0.05). In the MTT, fasting plasma glucose decreased from 7.95 ± 1.15 to 6.98 ± 1.07 mmol/L (p < 0.05). The area under the plasma glucose curve from 0 to 180 min decreased significantly from 29.48 ± 5.07 to 27.12 ± 3.98 mmol/h/L (p < 0.05), whereas immunoreactive insulin was unchanged. Furthermore, bezafibrate also significantly improved serum lipids, with decreases in triglyceride levels from 1.84 ± 0.88 to 1.14 ± 0.41 mmol/L (p < 0.05), low-density lipoprotein cholesterol levels from 3.56 ± 0.83 to 2.92 ± 0.55 mmol/L (p < 0.05), and remnant-like particle cholesterol levels decreased from 0.25 ± 0.16 to 0.14 ± 0.06 mmol/L (p < 0.05), and increases in high-density lipoprotein cholesterol levels from 1.50 ± 0.24 to 1.66 ± 0.29 mmol/L (p < 0.05).ConclusionsBezafibrate improved glucose intolerance and peripheral insulin resistance in these Japanese patients with type 2 diabetes mellitus and dyslipidemia. Therefore, bezafibrate could be used to treat insulin resistance in patients with type 2 diabetes mellitus and dyslipidemia.Trial registrationUniversity Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000012462.

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

“…Conclusive evidence regarding the effects of PPARα agonists on insulin sensitivity was not established. Bezafibrate decreased the HOMA‐IR and increased the PGU in patients with type 2 diabetes. This finding might be attributed to the low PPARα selectivity and partial PPARγ agonistic activity, albeit weak, of bezafibrate.…”

“…Additionally, PPARα agonists, also known as fibrates, stimulate FA oxidation, suppress FA and TG synthesis, and reduce plasma TG or TG‐rich lipoprotein levels. However, previous studies showed inconsistent results regarding the effects of PPARα agonists on glucose metabolism.…”

Effects of Pemafibrate, a Novel Selective PPARα Modulator, on Lipid and Glucose Metabolism in Patients With Type 2 Diabetes and Hypertriglyceridemia: A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial

“…In terms of glycemic parameters, the post hoc repeated-measures ANCOVA showed that pemafibrate decreased the fasting glucose, insulin, and HOMA-IR levels, although the prespecified analyses did not show a clear trend. The results of previous studies on the effects of PPARa agonists other than pemafibrate on IR were inconsistent (31)(32)(33)(34)(35). Pemafibrate has been suggested to improve IR in the hyperinsulinemic-euglycemic-clamp study (36) and pooled analyses of previous studies (37).…”

PPARαAgonist Fenofibrate Reduced the Secreting Load ofβ-Cells in Hypertriglyceridemia Patients with Normal Glucose Tolerance

“…It is worth mentioning that bezafibrate, another drug of fibrates, also displayed some beneficial effects on insulin resistance and glucose metabolism in patients with type 2 diabetes [ 35 ]. Different from fenofibrate, bezafibrate is a pan PPAR agonist and activates three PPAR subtypes including PPAR α , PPAR δ , and PPAR γ [ 36 ].…”