Efficacy
Change of triglyceride level %
We conducted a subgroup analysis based on the dose of Pemafibrate. The overall effect estimates favor Pemafibrate on placebo regarding the change of TG level % (MD: -49.60 [-62.64, -36.55]; P < 0.00001; Fig. 3). The overall results showed high heterogeneity (P < 0.00001, I2 = 99%). Results also showed that Pemafibrate significantly reduced TG levels more than other fibrates (MD: -7.05 [-10.96, -3.14]; P = 0.0004 with high heterogeneity I2 = 89%; Fig. 4)
Change in LDL-C
Regarding the change in LDL-C, Test for overall effect showed a significant increase in LDL-C levels in pemafibrate groups than placebo groups (MD: 10.99 [6.10, 15.88] P < 0.00001 with substantial heterogeneity I2 = 82%) (Supplementary file: Fig. S1). Pemafibrate at the dose of 0.4 mg was the least to elevate LDL-C levels. When compared to other fibrates, the levels of LDL-C were also higher in pemafibrate groups however with no significant difference (MD: 2.55[-0.22, 5.33] P = 0.07 with no heterogeneity observed I2 = 0%) (Supplementary file: Fig. S2).
Change in HDL-C
Regarding the change in HDL-C, the test for overall effect shows HDL-C to be significantly higher in pemafibrate groups than in placebo groups (MD: 14.57 [10.14, 19.01]; P < 0.00001 with high heterogeneity I2 = 98%) (Supplementary file: Fig. S3). The drug is also shown to increase levels of HDL-C more than other fibrates (MD: 3.13 [0.71, 5.54] P = 0.01 with high heterogeneity results I2 = 91%) (Supplementary file: Fig. S4).
Change in Non-HDL-C
Regarding change in non-HDL-C, the test for overall effect shows non-HDL-C to be significantly reduced in pemafibrate groups compared to placebo groups (MD: -10.27 [-14.48, -6.05] P < 0.00001 with high heterogeneity I2 = 90%) (Supplementary file: Fig. S5). The same goes for VLDL-C with (MD: -48.16 [-62.16, -34.13]; P < 0.00001 with high heterogeneity I2 = 92%) (Supplementary file: Fig. S7). Results also showed non-HDL-C levels to be slightly reduced in Pemafibrate groups when compared to other fibrates with no significant difference (MD: -1.32 [-2.97, 0.32] P = 0.11 with minimal heterogeneity I2 = 23%) (Supplementary file: Fig. S6) whereas pemafibrate significantly reduces VLDL-C levels when compared to other fibrates (MD: -12.37 [-16.35, -8.38] P < 0.00001 with moderate heterogeneity I2 = 33%) (Supplementary file: Fig. S8).
Total cholesterol level
When analyzing the change in total cholesterol level, results showed them to be significantly reduced in pemafibrate groups than placebo groups (MD: -3.42 [-5.91, -0.93]; P = 0.03 with substantial heterogeneity I2 = 81%) (Supplementary file: Fig. S9). No significant difference was found when comparing the change in total cholesterol levels across both pemafibrate groups and other fibrates groups (MD: 0.59 [-0.79, 1.97]; P = 0.40 with no heterogeneity I2 = 0%) (Supplementary file: Fig. S10).
Change in Apo proteins (A-1, A-II, B, B48, C-II, C-III)
Regarding the change in Apo B, the test for overall effect showed a non-significant difference between pemafibrate and placebo groups (MD: 1.67 [-0.57, 3.91]; P = 0.14) with significant heterogeneity I2 = 65%). Results also showed that Apo B was higher in pemafibrate group than other fibrates group, changes were significant (MD: 4.59 [0.51, 8.68]; P = 0.03 with significant heterogeneity I2 = 83%). On the other hand, changes in Apo A-1, and Apo A-II were significantly higher in pemafibrate groups than in placebo groups (MD: 5.90 [4.33, 7.48] P < 0.00001 with minimal heterogeneity I2 = 31%), (MD: 22.62 [17.65, 27.59] P < 0.00001 with considerable heterogeneity I2 = 84%) respectively. When compared to other fibrates, pemafibrate significantly increases the levels of Apo A-I (MD: 1.79 [0.54, 3.04] P = 0.005 with minimal heterogeneity I2 = 16%) whereas no significant difference was found in the change of Apo A-II across pemafibrate arm and other fibrates arm (MD: 3.31 [-1.66, 8.29] P = 0.19 with significant heterogeneity I2 = 89%) (Supplementary file: Fig. S11_S16).
Our analysis also revealed statistically significant lower levels of ApoB48 in pemafibrate groups (MD: -68.03 [-78.10, -57.96]; P < 0.00001 with minimal heterogeneity I2 = 3%) (Supplementary file: Fig. S17). Pemafibrate also significantly reduces ApoB48 values more than other fibrates (MD: -11.29 [-16.70, -5.88] P < 0.0001 with minimal heterogeneity I2 = 18%) (Supplementary file: Fig. S18).
Regarding changes in Apo C-II and Apo C-III, results showed them to be significantly reduced in pemafibrate groups (MD: -16.85 [-25.34, -8.36] P = 0.0001), (MD: -34.73 [-39.86, -29.60] P < 0.00001) respectively. Both results showed significant heterogeneity (P < 0. 0001, I2 = 80%), (P < 0.00001, I2 = 73%) respectively (Supplementary file: Fig. S19, S20). Pemafibrate also reduces the values of Apo C-III more than other fibrates (MD: -6.24 [-11.84, -0.65] P = 0.03 with substantial heterogeneity I2 = 72%) (Supplementary file: Fig. S21)
Change in RemL-C
Regarding the change in RemL-C. Test of the overall effect revealed it to be reduced in pemafibrate groups with (MD of -73.03 [-81.87, -64.19]; P < 0.00001 with no heterogeneity I2 = 0%) (Supplementary file: Fig. S22). Pemafibrate also reduces RemL-C values more than other fibrates with a significant difference (MD: -12.95 [-16.92, -8.98] P < 0.00001 with no heterogeneity I2 = 0%) (Supplementary file: Fig. S23).
Pemafibrate is shown to significantly reduce the values of HOMA-R than in placebo groups with (MD -0.78 [-1.12, -0.43]; P < 0.0001; I2 = 0% indicating no heterogeneity) (Supplementary file: Fig. S24). No significant difference was found when comparing the effect of pemafibrate with other fibrates (MD: -0.06 [-0.39, 0.27]; P = 0.74 with no heterogeneity I2 = 0%) (Supplementary file: Fig. S25).
Our analysis showed that pemafibrate significantly reduced the levels of FBG compared to placebo groups (MD: -3.65 [-5.54, -1.77]; P = 0.0001 with minimal heterogeneity I2 = 9%) (Supplementary file: Fig. S26). The same goes for levels of fasting insulin (MD: -3.65 [-5.54, -1.77]; P = 0.0001 with minimal heterogeneity I2 = 9%) (Supplementary file: Fig. S27). Changes in HBA1C values showed a minimal significant increase in pemafibrate group (MD: 0.10 [0.01, 0.20] P = 0.03 with no heterogeneity I2 = 0%) (Supplementary file: Fig. S28). When comparing the effect of pemafibrate with other fibrates, no significant difference was found in FBG values and Fasting Insulin levels (MD: 0.71[-1.25, 2.67] P = 0.48 with moderate heterogeneity I2 = 52%) and (MD: -2.73 [-9.75, 4.30] P = 0.45 with no heterogeneity I2 = 0) (Supplementary file: Fig. S29, S30).