Pemafibrate decreases triglycerides and small, dense LDL, but increases LDL-C depending on baseline triglycerides and LDL-C in type 2 diabetes patients with hypertriglyceridemia: an observational study

Abstract

Background Pemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated. Methods Pemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4–8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL. Results Pemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (− 3.8–19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96–3.26] vs. 3.36 [3.05–3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62–6.69] vs. 3.25 [2.64–3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391–0.450] vs. 0.354 [0.341–0.396], P < 0.0001) at baseline. Pemafibrate decreased LDL-MI in group I, and the differences between the groups disappeared. These results showed contradictory effects of pemafibrate on LDL-C levels, and these effects were dependent on the baseline levels of LDL-C and TGs. Conclusions Pemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.

Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion

“…Pema; pemafibrate, UC; unilateral common carotid artery occlusion, TG; triglyceride, TC; total cholesterol. Next, triglyceride (TG) and total cholesterol (TC) levels in the serum were examined (Figure 6B,C), as TG and TC levels have also been reported to be changed by administration of pemafibrate in various experimental models and clinical studies [31,[43][44][45]. Expectedly, we detected continuous decreases in serum TG levels and increases in serum TC levels in pemafibrate-administered UCCAO-operated mice in comparison with PBS-administered UCCAO-operated mice.…”

Triglyceride/low-Density-Lipoprotein Cholesterol (TG/LDL-C) Ratio is the Most Diagnostically Valuable Predictor for Increased Small, Dense LDL in Type 2 Diabetes Patients

“…In our previous study, it was found that type 2 diabetes patients with hypertriglyceridemia can be divided into two groups: those with relatively low LDL-C and those with normal or high LDL-C. In the former group, TGs and sd-LDL were also higher than those in the latter group, but there was no difference in non-HDL-C between the two groups (4.9 [4.0-5.4] mmol/L vs. 4.8 [4.5-5.2] mmol/L) [9]. Alternatively, the increase in TGs and decrease in LDL-C (calculated using Friedewald's formula) could have been synchronized [13,32], and the change in non-HDL-C might have been offset.…”

“…If so, calculated non-HDL-C, regardless of the LDL-C assay method used, will largely re ect the decline in buoyant LDL present in some type 2 diabetes patients, and it is estimated that the increase in non-HDL-C would not be as expected. The changes in LDL composition would affect the measurement of non-HDL-C and thus impair its clinical reliability, and these changes might also affect the relationship between non-HDL-C and sd-LDL [9]. In contrast, another lipid marker that indirectly compares the changes in sd-LDL and buoyant LDL (i.e., the TG/LDL-C ratio) seems to more accurately re ect the pathophysiology of dyslipidemia in type 2 diabetes patients.…”

“…A recent study evaluating the effect of pema brate on hypertriglyceridemia in type 2 diabetes reported that baseline LDL-C measured via the direct method and LDL fraction measured by polyacrylamide gel (PAG) electrophoresis decreased with increasing baseline sd-LDL [9]. Pema brate, a selective peroxisome proliferator-activated receptor alpha modulator, allows control of serum TG levels and sd-LDL, which were previously inadequate with conventional treatment [10,11].…”

“…Pema brate, a selective peroxisome proliferator-activated receptor alpha modulator, allows control of serum TG levels and sd-LDL, which were previously inadequate with conventional treatment [10,11]. In more than half of type 2 diabetes patients with hypertriglyceridemia, baseline LDL-C is relatively lower than after pema brate administration [9].…”