Efficacy and safety of Pemafibrate administration in patients with dyslipidemia: A Systematic Review and Updated Meta-analysis of Randomized Controlled Trials. 

Efficacy and safety of Pemafibrate administration in patients with dyslipidemia: A Systematic Review and Updated Meta-analysis of Randomized Controlled Trials. | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and safety of Pemafibrate administration in patients with dyslipidemia: A Systematic Review and Updated Meta-analysis of Randomized Controlled Trials. Mohammed A. Elbahloul, Ammar Elgadi, Hossam Fayed, Mohamed Ramadan, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4486419/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: Patients with dyslipidemia are at risk for cardiovascular diseases. Lowering levels of lipid decreases morbidity. Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that works better at lowering serum triglycerides. Methods: Clinical trials investigating the effect of pemafibrate on lipid biomarkers in patients with dyslipidemia were searched in PubMed, Ovid Medline, SCOPUS, Web of Science (WOS), and the Cochrane Library from inception till December 31, 2023. The data were pooled as mean difference, odds ratio (OR), and 95% confidence interval (CI). Results: 14 clinical trials were eligible involving 12451 patients showed favorable triglyceride level change (MD: -49.60 [-62.64, -36.55] P<0.00001) for pemafibrate compared to placebo. Pemafibrate showed a significant increase in HDL-C levels (MD: 14.57 [10.14, 19.01] P<0.00001) but showed a concurrent increase in LDL-C levels (MD: 10.99 [6.10, 15.88] P <0.00001). It also showed non-HDL-C, total cholesterol level, Apo B, Apo C-II, and Apo C-III to be significantly reduced in pemafibrate groups. Also, in pemafibrate groups, hepatic adverse events were reported less frequently than in placebo groups. No significant difference was found in the frequency of total adverse effects, adverse drug reactions, or serious adverse events between the pemafibrate and placebo groups. Conclusion: Pemafibrate improved the overall lipid biomarkers compared to placebo groups, demonstrating a significant reduction in triglycerides, non-HDL-C, and total cholesterol while increasing in HDL-C. Moreover, there was no significant difference in adverse effects. Pemafibrate other fibrates dyslipidemia Lipid biomarkers adverse events. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction Dyslipidemia refers to the abnormal changes in lipid composition in the bloodstream ( 1 ). Over the previous 30 years, the prevalence of dyslipidemias has increased globally ( 2 ). It is considered one of the main risk factors for cardiovascular disease (CVD) with growing evidence of hypertriglyceridemia as an independent risk factor for CVD ( 3 ). The number of deaths from CVD grew from 12.1 million in 1990 to 18.6 million in 2019 ( 4 ). Previous studies have shown that lipid-lowering drugs greatly reduce CHD morbidity and optimizing lipid levels is crucial for preventing CVD ( 5 , 6 ). Currently, fibrates represent the most significant medication class in combating dyslipidemia. Statins aid in lowering low-density lipoprotein cholesterol (LDL), but they have little effect on serum triglyceride or HDL levels; fibrates are needed in these cases ( 7 ). The recently emerging evidence supports the therapeutic value of fibrates in the control of cardiovascular risk ( 8 ). Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that works better in lowering serum triglycerides (TG) and raising HDL-C. It also exhibited improved liver and kidney function test values, while accessible fibrates showed worsening of those test findings. It can also be taken in along with statins. Moreover, pemafibrate can be taken safely in patients even if they have reduced renal function ( 9 , 10 ). We believed that by combining and analyzing all the previous clinical trials and research, we could obtain highly relevant results regarding the safety and efficacy of administering pemafibrate, so this study aimed to investigate the efficacy and safety of pemafibrate administration in patients with dyslipidemia. Materials and methods This study was structured according to the Cochrane Handbook's guidelines for systematic reviews and meta-analysis ( 11 ) and reporting items for systematic review and meta-analysis (PRISMA-P statement) ( 12 ). We registered our study protocol in Prospero with ID: CRD42024509332 Literature search strategy Databases including PubMed, Ovid Midline, SCOPUS, Web of Science (WOS), and Cochrane Library were searched till December 31, 2023, using the following terms: ("Pemafibrate" OR "selective peroxisome proliferator-activated receptor α modulator" OR “Peroxisome proliferator-activated receptor alpha” OR "PPARα" OR “PPARalpha” OR "peroxisome proliferator-activated receptor alpha ") AND ("Hypertriglyceridemia" OR "High TG" OR” High Triglyceride" OR “dyslipidemia” OR “Dyslipoproteinemia” OR “low HDL" OR "High LDL" OR "High cholesterol" OR Hyperlipemia OR Hyperlipidemia OR Lipidemia OR Lipemia OR “Elevated Cholesterol” OR Hypercholesteremia OR Hyperlipoproteinemia OR Hyperchylomicronemia). Study selection We included studies that met the following PICOs criteria: (P) patient with resistant dyslipidemia (I) pemafibrate (C) placebo or other fibrates (O) changes in lipid biomarkers "triglyceride levels, HDL-C level, LDL-C level, cholesterol level, VLDL, and Apolipoprotein B'' (S) Clinical trials. Conversely, we excluded ( 1 ) studies not in English; ( 2 ) non-human studies; ( 3 ) instances of duplicated literature; and ( 4 ) study designs other than clinical trials, including guidelines, systematic reviews, meta-analyses, case reports, case series, conference abstracts, letters to the editor, author opinion papers, editorials, and review articles lacking original data. Two authors screened independently the title and abstract to include relevant studies using the Rayyan review tool ( 13 ), then the full-text screening was conducted to confirm the eligibility of the included studies. In cases of conflicts, another third author arbitrated between the two authors. Data extraction and Quality assessment We extracted the characteristics of each study using a predefined Excel sheet: (Author, year of publication, study design, study country, total sample size, number and dose of each study arm, and follow-up duration). Also, patients’ baseline characteristics were listed as follow: (age, sex, body mass index (BMI), number of patients with comorbidities (Type 2 diabetes, hypertension), number of subjects taking Any Statin and biomarkers (triglyceride levels, HDL-C level, LDL-C level, total cholesterol level, HbA1c). Efficacy and safety outcomes data. In the case of a study comparing placebo with more interventions, we consider it as different studies sharing the same placebo group. The quality of the included RCTs was evaluated using the Cochrane Risk of Bias tool (version 2) ( 14 ). Randomization process, deviation from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result are the five domains that the ROB tool assessed. Each domain of the included studies was assessed as low risk, some concerns, or high risk. Statistical analysis The statistical analysis was performed with RevMan version 5.3 software. Continuous outcomes were pooled as mean difference (MD) and 95% confidence interval (CI) while dichotomous outcomes were pooled as odds ratio (OR) and 95% CIs. The random-effects model was used for analysis and I 2 and Chi-square tests were used to detect the heterogeneity (I 2 > 50 indicates significant heterogeneity) Results Search results and Characteristics of included study: Our search on the databases retrieved 5961 studies, 11 RCTs were included ( 15 ),( 16 ), ( 17 ),( 18 ),( 19 ),( 20 ),( 21 ),( 22 ),( 23 ),( 24 ), ( 25 ) with a total population of 12451 patients with further details can be found in PRISMA flow diagram ( Fig. 1 ) . The characteristics of the 11 studies are summarized in Table 1. Pemafibrate was administered at different doses (0.0025, 0.05, 0.1, 0.2, and 0.4) mg. The compression group was placebo and other fibrates. The follow-up duration ranged from 8 weeks to 182.5 weeks, whole studies were conducted in Japan except two studies, one was conducted in 9 European countries ( 17 ) and another one was conducted in 24 countries ( 18 ). We summarized the baseline characteristics of the patients in Supplementary Table 1 Risk of bias and quality assessment All the included studies reported a low overall risk of bias except for three studies. Matsuba et al ( 20 ) showed a high risk for deviation from the intended intervention and some concerns for selection of reported results, Nakamura et al ( 21 ) showed a high risk of bias for randomization process and deviation from the intended intervention while ishibashi et al ( 22 ) reported a high risk of bias for missing outcome data and some concerns for selection of reported result. ( Fig. 2 ) The pooled studies for each outcome did not exceed 10 studies, and according to Egger et al ( 39 ), publication bias is not reliable for less than 10 pooled studies. So, we were unable to report the existence of publication bias by Egger’s test for funnel plot asymmetry. Outcomes 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, I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 31%), (MD: 22.62 [17.65, 27.59] P < 0.00001 with considerable heterogeneity I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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, I 2 = 80%), (P < 0.00001, I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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; I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 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 I 2 = 52%) and (MD: -2.73 [-9.75, 4.30] P = 0.45 with no heterogeneity I 2 = 0) (Supplementary file: Fig. S29, S30) . Safety Total adverse effects No significant difference was found in the frequency of total adverse effects between the pemafibrate groups and placebo groups (OR: 0.83 [0.64, 1.08] P = 0.17 with no heterogeneity I 2 = 0%; Fig. 5 ). However, the least doses to cause side effects were 0.05 mg and 0.1 mg which may be clinically significant. Furthermore, no significant difference between pemafibrate and other fibrates (OR: 0.79 [0.61, 1.03]; P = 0.08 with no heterogeneity I 2 = 0%; Fig. 6 ). Adverse drug reactions Regarding the frequency of Adverse drug reactions, there was no significant difference between Pemafibrate and placebo groups (OR: 0.95[0.59, 1.54] P = 0.84) (Supplementary file: Fig. S31) . However, Pemafibrate is found to produce significantly fewer adverse drug reactions than other fibrates (OR: 0.51 [0.31, 0.82] P = 0.006 with no heterogeneity I 2 = 0%) (Supplementary file: Fig. S32) . Serious Adverse events No significant difference was found between pemafibrate groups and placebo groups regarding the frequency of Serious adverse events (OR: 1.06 [0.98, 1.14] P = 0.18 with no heterogeneity I 2 = 0%), Musculoskeletal adverse events (OR: 1.29 [0.60, 2.78] P = 0.51 with moderate heterogeneity I 2 = 47%), or Rhabdomyolysis (OR: 0.49 [0.17, 1.42] P = 0.19 with minimal heterogeneity I 2 = 22%) (Supplementary file: Fig. S33, S34, S35) . Same goes when comparing pemafibrate to other fibrates, no significant difference in Serious adverse events (OR: 2.01[0.81, 4.99] P = 0.13 with no heterogeneity I 2 = 0%), Musculoskeletal adverse events (OR: 0.53 [0.10, 2.93] P = 0.47 with no heterogeneity I 2 = 0%) or Rhabdomyolysis (OR: 0.56 [10.18, 1.71] P = 0.31 with no heterogeneity observed I 2 = 0%) %) (Supplementary file: Fig. S36, S37, S38) . Hepatic adverse events were reported less in pemafibrate groups than in placebo groups, and results were of statistical significance (OR: 0.80 [0.67, 0.96] P = 0.02 with no heterogeneity observed I 2 = 0%) (Supplementary file: Fig. S39) , moreover, pemafibrate was ahead of other fibrates regarding less hepatic adverse events (MD: 0.28 [0.14, 0.56] P = 0.0003 with minimal heterogeneity I 2 = 24%) (Supplementary file: Fig. S40) . Liver function tests Our analysis showed pemafibrate was significantly associated with less frequency of abnormal liver enzymes compared to placebo: AST being more than upper limit (OR: 0.60[0.38, 0.93]; P = 0.02 with no heterogeneity I 2 = 0%), ALT being more than upper limit of normal (OR: 0.52 [0.35, 0.78]; P = 0.001 with no heterogeneity I 2 = 0%) and GGT being more than upper limit of normal (OR: 0.15[0.05, 0.45]; P = 0.0008 with no heterogeneity I 2 = 0%) (Supplementary file: Fig. S41_S43) . When compared to other fibrates, pemafibrate also showed significantly less frequency of AST being more than the upper limit of normal (OR: 0.16 [0.07, 0.37] P < 0.0001 with minimal heterogeneity I 2 = 28%) and ALT being more than the upper limit of normal (OR: 0.44 [0.20, 0.94] P = 0.03 with no heterogeneity I 2 = 0%) (Supplementary file: Fig. S44, S45) . Creatine kinase and creatinine level Results showed creatine kinase levels more than the upper limit of normal to be less frequent in pemafibrate groups than in placebo groups (OR: 0.36 [0.15, 0.85] P = 0.02 with no heterogeneity) (Supplementary file: Fig. S46) . And less frequent in Pemafibrate groups compared to other fibrate groups (OR: 0.49 [0.14, 1.75] P = 0.27 with no heterogeneity observed I 2 = 0%) (Supplementary file: Fig. S47) . More frequency of increased Creatinine was reported in pemafibrate groups compared to placebo groups but was of no statistical significance (OR: 1.43 [0.45, 4.52] P = 0.54 with no heterogeneity) (Supplementary file: Fig. S48) , however, when compared to other fibrates, pemafibrate shows a significant less frequent increase in creatinine (OR: 0.34 [0.13, 0.92] P = 0.03 with moderate heterogeneity I 2 = 49%) (Supplementary file: Fig. S49) Discussion Our meta-analysis showed the changes in TG levels to be statistically significant. Also, the drug was better than other fibrates in lowering TG levels. The drug also significantly lowers the levels of non-HDL cholesterol and total cholesterol levels more than placebo or other fibrates. Pemafibrate is also shown to increase levels of HDL-C more than placebo, or other fibrates. It is however shown to increase the levels of LDL-C more than placebo, and other fibrates. The last dose to cause elevation of LDL-C is pemafibrate at 0.4 mg. Pemafibrate is mainly designed to lower serum TG levels and many previous studies have proven that finding, our meta-analysis result further contributes to this finding. The mechanism of action of fibrates has also been demonstrated in several previous studies, one way by which the drug lowers serum TG levels is that it decreases hepatic TG production. Fibrates also increase hepatic HDL-C synthesis and stimulate reverse cholesterol transport. They also stimulate lipolysis and increase the uptake of fatty acids. The drug exerts all these effects by acting as an agonist on PPARs especially PPAR-alpha, which are nuclear receptors that play a role in the regulation of lipid metabolism ( 26 ). One explanation for LDL-C elevation associated with pemafibrate is that the effect of lipolysis by pemafibrate on VLDL-C results in the formation of IDL-C which subsequently increases the levels of LDL-C which contains apo-B lipoproteins gathered from VLDL-C catabolism ( 27 , 28 ). Although the increase of LDL-C by pemafibrate appears to be clinically safe, Elevation of LDL-C requires more investigation, a previous study demonstrated that elevated LDL-C levels especially sdLDL-C particles rapidly undergo modifications such as oxidization, desialylation, glycation, and electronegative LDL, making them highly atherogenic and increase the risk of ASCVD ( 29 ). Apart from increasing LPL activity and lipolysis, Lowering TG levels is also accompanied by a decrease in apoC-III which in turn decreases the inhibitory effect on LPL which also increases lipolysis ( 26 ). Being a PPAR-alpha agonist, fibrates increase the expression of apo A-1 and A-II which are major components of HDL increasing their serum levels ( 30 ) A previous meta-analysis ( 31 ) ALT, GGT, and AST levels were reduced in pemafibrate groups. The reason for this is not well understood, however, some experimental studies on animals demonstrated that the effect might be due to decreased apoptosis of hepatocytes and decreased hepatic fibrosis ( 32 , 33 ). The authors of the PROMINENT trial which is a huge trial included in our meta-analysis that was conducted in 24 countries also contributed to the fact that Pemafibrate improves liver functions. Their trial also found that changes were non-significant in pemafibrate group regarding cardiovascular events when compared to placebo. They further informed us about a second ongoing pemafibrate trial to evaluate histological markers of liver fibrosis. Pemafibrate is also shown to significantly increase HOMA-IR levels than placebo or other fibrates, suggesting an improvement in insulin resistance, in turn, significantly lower values of FBG were found in pemafibrate groups in our meta-analysis. It is believed that that effect might be due to the decreased amounts of free fatty acids along with a decrease in inflammatory cytokines and oxidative stress ( 34 , 35 ). No significant difference in adverse effects when comparing pemafibrate to placebo or other fibrates, however, low doses of pemafibrate 0.05mg and 0.1mg are shown to cause fewer side effects, this suggests that an increase in pemafibrate dose might be associated with a slightly higher frequency of AE. Although the overall risk for AE is minimal, this relationship requires more investigation. Significant low levels of creatine kinase were also found in pemafibrate groups. Also, significantly low levels of AST, ALT, ALP, and GGT were found in pemafibrate groups. It is also worth noting that pemafibrate increases creatinine levels to a lesser extent than other fibrates. Pemafibrate in humans is mainly excreted by the biliary route ( 9 ). Like some other fibrates, Serum creatinine was more in pemafibrate groups than placebo groups with no statistical significance, some think it might be safe on kidneys as the biliary route is the main route for the drug excretion ( 36 ). Our analysis also showed that pemafibrate elevates serum creatinine to a lesser extent than other fibrates with a significant difference along with a significant reduction in eGFR in pemafibrate groups than placebo groups which also contributed to the previous finding. However, only four of the included trials reported the change in serum creatinine levels which implies the need for further investigation. We found that CK levels being more than the upper limit of normal less in pemafibrate groups when compared to both placebo and other fibrates, however, it is previously reported that myopathy and Rhabdomyolysis can both be adverse effects of fibrates especially when combined with statins ( 37 , 38 ). Limitations of the study First, the majority of the studies included were conducted in Japan except for two multi-center studies therefore the results cannot be generalized to all populations, Second, some of the included RCTs were of short durations which makes it harder to assess the long-term efficacy and safety of the drug. Third, the availability of a small number of RCTs may limit proper assessment. Moreover, the lack of individual patient data hinders our ability to investigate further other important outcomes. Therefore, we call for more RCTs to be conducted on different populations in an attempt to investigate the effects of pemafibrate in a generalized manner with also a long-term follow-up to assess its long-term safety and applicability. Conclusion Our meta-analysis investigated the efficacy and safety of pemafibrate compared to placebo and other fibrates in patients with dyslipidemia. Pemafibrate demonstrated a significant improvement in the overall lipid profiles, reducing the levels of triglycerides, VLDL-C, non-HDL-C, and total cholesterol and increasing HDL-C levels but considering increasing LDL-C levels which needs more investigations. Abnormal liver enzymes were less frequent with pemafibrate. Moreover, there was no significant difference in adverse effects, adverse drug reactions, serious adverse events, and rhabdomyolysis. Declarations Ethics approval and consent to participate: Not required as it is a systematic review. Consent for publication: All authors reviewed and agreed on the final version of the manuscript. Availability of data and material: All data are available and attached. Competing interests: The authors declare that they have no competing interests. Funding: No funding received. Acknowledgments: None . References Raja V, Aguiar C, Alsayed N, Chibber YS, ElBadawi H, Ezhov M, et al. Non-HDL-cholesterol in dyslipidemia: Review of the state-of-the-art literature and outlook. Atherosclerosis [Internet]. 2023 Oct;383:117312. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0021915023052334 Pirillo A, Casula M, Olmastroni E, Norata GD, Catapano AL. Global epidemiology of dyslipidaemias. Nat Rev Cardiol [Internet]. 2021 Oct 8;18(10):689–700. Available from: https://www.nature.com/articles/s41569-021-00541-4 Reiner Ž. Hypertriglyceridaemia and risk of coronary artery disease. Nat Rev Cardiol [Internet]. 2017 Jul 16;14(7):401–11. 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Available from: https://www.bmj.com/lookup/doi/10.1136/bmj.d5928 Arai H, Yamashita S, Yokote K, Araki E, Suganami H, Ishibashi S. Efficacy and Safety of Pemafibrate Versus Fenofibrate in Patients with High Triglyceride and Low HDL Cholesterol Levels: A Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial. J Atheroscler Thromb [Internet]. 2018 Jun 1;25(6):521–38. Available from: https://www.jstage.jst.go.jp/article/jat/25/6/25_44412/_article Araki E, Yamashita S, Arai H, Yokote K, Satoh J, Inoguchi T, et al. Efficacy and safety of pemafibrate in people with type 2 diabetes and elevated triglyceride levels: 52‐week data from the PROVIDE study. Diabetes, Obes Metab [Internet]. 2019 Jul;21(7):1737–44. Available from: https://dom-pubs.pericles-prod.literatumonline.com/doi/10.1111/dom.13686 Ginsberg HN, Hounslow NJ, Senko Y, Suganami H, Bogdanski P, Ceska R, et al. Efficacy and Safety of K-877 (Pemafibrate), a Selective PPARα Modulator, in European Patients on Statin Therapy. Diabetes Care [Internet]. 2022 Apr 1;45(4):898–908. Available from: https://diabetesjournals.org/care/article/45/4/898/144603/Efficacy-and-Safety-of-K-877-Pemafibrate-a Das Pradhan A, Glynn RJ, Fruchart JC, MacFadyen JG, Zaharris ES, Everett BM, et al. Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk. N Engl J Med [Internet]. 2022 Nov 24;387(21):1923–34. Available from: http://www.nejm.org/doi/10.1056/NEJMoa2210645 Ishibashi S, Arai H, Yokote K, Araki E, Suganami H, Yamashita S. Efficacy and safety of pemafibrate (K-877), a selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia: Results from a 24-week, randomized, double blind, active-controlled, phase 3 trial. J Clin Lipidol [Internet]. 2018 Jan;12(1):173–84. Available from: https://linkinghub.elsevier.com/retrieve/pii/S193328741730466X Matsuba I, Matsuba R, Ishibashi S, Yamashita S, Arai H, Yokote K, et al. 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. J Diabetes Investig [Internet]. 2018 Nov 26;9(6):1323–32. Available from: https://onlinelibrary.wiley.com/doi/10.1111/jdi.12845 Nakamura A, Kagaya Y, Saito H, Kanazawa M, Sato K, Miura M, et al. Efficacy and Safety of Pemafibrate Versus Bezafibrate to Treat Patients with Hypertriglyceridemia: A Randomized Crossover Study. J Atheroscler Thromb [Internet]. 2023 May 1;30(5):63659. Available from: https://www.jstage.jst.go.jp/article/jat/30/5/30_63659/_article Ishibashi S, Yamashita S, Arai H, Araki E, Yokote K, Suganami H, et al. Effects of K-877, a novel selective PPARα modulator (SPPARMα), in dyslipidaemic patients: A randomized, double blind, active- and placebo-controlled, phase 2 trial. Atherosclerosis [Internet]. 2016 Jun;249:36–43. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0021915016300727 Araki E, Yamashita S, Arai H, Yokote K, Satoh J, Inoguchi T, et al. 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. Diabetes Care [Internet]. 2018 Mar 1;41(3):538–46. Available from: https://diabetesjournals.org/care/article/41/3/538/36634/Effects-of-Pemafibrate-a-Novel-Selective-PPAR Yamashita S, Arai H, Yokote K, Araki E, Suganami H, Ishibashi S. Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J Clin Lipidol [Internet]. 2018 Sep;12(5):1267-1279.e4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S193328741830268X Nakajima A, Eguchi Y, Yoneda M, Imajo K, Tamaki N, Suganami H, et al. Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator‐activated receptor α modulator (SPPARMα), versus placebo in patients with non‐alcoholic fatty liver disease. Aliment Pharmacol Ther [Internet]. 2021 Nov 16;54(10):1263–77. Available from: https://onlinelibrary.wiley.com/doi/10.1111/apt.16596 Katsiki N, Nikolic D, Montalto G, Banach M, Mikhailidis DP, Rizzo M. The Role of Fibrate Treatment in Dyslipidemia: An Overview. Curr Pharm Des [Internet]. 2013 Apr 1;19(17):3124–31. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1381-6128&volume=19&issue=17&spage=3124 Sigurdsson G, Nicoll A, Lewis B. Conversion of very low density lipoprotein to low density lipoprotein. A metabolic study of apolipoprotein B kinetics in human subjects. J Clin Invest [Internet]. 1975 Dec 1;56(6):1481–90. Available from: http://www.jci.org/articles/view/108229 Berneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res [Internet]. 2002 Sep;43(9):1363–79. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0022227520328005 Ivanova EA, Myasoedova VA, Melnichenko AA, Grechko A V., Orekhov AN. Small Dense Low-Density Lipoprotein as Biomarker for Atherosclerotic Diseases. Oxid Med Cell Longev [Internet]. 2017;2017:1–10. Available from: https://www.hindawi.com/journals/omcl/2017/1273042/ DUVAL C, MULLER M, KERSTEN S. PPARα and dyslipidemia. Biochim Biophys Acta - Mol Cell Biol Lipids [Internet]. 2007 Aug;1771(8):961–71. Available from: https://linkinghub.elsevier.com/retrieve/pii/S138819810700114X Ida S, Kaneko R, Murata K. Efficacy and safety of pemafibrate administration in patients with dyslipidemia: a systematic review and meta-analysis. Cardiovasc Diabetol [Internet]. 2019 Dec 21;18(1):38. Available from: https://cardiab.biomedcentral.com/articles/10.1186/s12933-019-0845-x Honda Y, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Fujita K, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep [Internet]. 2017 Feb 14;7(1):42477. Available from: https://www.nature.com/articles/srep42477 Cindoruk M, Kerem M, Karakan T, Salman B, Akin O, Alper M, et al. Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study. BMC Gastroenterol [Internet]. 2007 Dec 28;7(1):44. Available from: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-7-44 Kaur J, Reddy K, Balakumar P. The Novel Role of Fenofibrate in Preventing Nicotine- and Sodium Arsenite-Induced Vascular Endothelial Dysfunction in the Rat. Cardiovasc Toxicol [Internet]. 2010 Sep 7;10(3):227–38. Available from: http://link.springer.com/10.1007/s12012-010-9086-7 Boden G, Chen X, Ruiz J, White J V, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest [Internet]. 1994 Jun 1;93(6):2438–46. Available from: http://www.jci.org/articles/view/117252 Blair HA. Pemafibrate: First Global Approval. Drugs [Internet]. 2017 Oct 19;77(16):1805–10. Available from: http://link.springer.com/10.1007/s40265-017-0818-x Alsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates*. Am J Cardiol [Internet]. 2004 Oct;94(7):935–8. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0002914904009506 Milionis H, Moutzouri, Kei, Elisaf. Management of dyslipidemias with fibrates, alone and in combination with statins: role of delayed-release fenofibric acid. Vasc Health Risk Manag [Internet]. 2010 Jun;525. Available from: http://www.dovepress.com/management-of-dyslipidemias-with-fibrates-alone-and-in-combination-wit-peer-reviewed-article-VHRM Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ [Internet]. 1997 Sep 13;315(7109):629–34. Available from: https://www.bmj.com/lookup/doi/10.1136/bmj.315.7109.629 Table Table 1 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Suplementerytables.docx suplementayfigures.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4486419","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":318457064,"identity":"19a393b2-fff2-4665-8195-4b5b241d267b","order_by":0,"name":"Mohammed A. 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tool (version 2)\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/3bdbdd71b5cb2fe099477270.jpg"},{"id":60446633,"identity":"04974a4d-b9cf-4eb8-b67d-1b37ac87f6d6","added_by":"auto","created_at":"2024-07-16 21:55:52","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":120393,"visible":true,"origin":"","legend":"\u003cp\u003eforest plot presenting MD for the effect of pemafibrate VS placebo on TGs\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/8ae371bf5dc939bde94559ea.jpg"},{"id":60447499,"identity":"954c8831-0e29-4517-9b4b-f141a9b02735","added_by":"auto","created_at":"2024-07-16 22:03:52","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":115834,"visible":true,"origin":"","legend":"\u003cp\u003eforest plot presenting MD for the effect of pemafibrate VS other fibrates on TGs\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/e14a56c7578f34c3dfd9290c.jpg"},{"id":60446639,"identity":"cf61e88b-bf7d-4695-8d92-263aa8bc1bc5","added_by":"auto","created_at":"2024-07-16 21:55:52","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":123234,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot presenting OR for effect of pemafibrate VS placebo on total AEs.\u003c/p\u003e","description":"","filename":"5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/36fc5c4c1b55d5e0e8f63a15.jpg"},{"id":60447505,"identity":"acbbd415-c81c-4e20-850f-40460abfa8f3","added_by":"auto","created_at":"2024-07-16 22:03:52","extension":"jpg","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":115963,"visible":true,"origin":"","legend":"\u003cp\u003eForest plot presenting OR for effect of pemafibrate VS other fibrates on total AEs.\u003c/p\u003e","description":"","filename":"6.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/c0c7c5e1f3cb00547f06378b.jpg"},{"id":61955799,"identity":"71adf4bf-f317-4fb1-beb2-617f44058f84","added_by":"auto","created_at":"2024-08-07 13:34:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1352293,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/b00b3e77-5774-40e5-8179-0e3129949841.pdf"},{"id":60446637,"identity":"72583479-1d6e-4c24-9959-7b8f3a1d13cf","added_by":"auto","created_at":"2024-07-16 21:55:52","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":22986,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/3e8e613246bfdc02b9ac8b2d.docx"},{"id":60446636,"identity":"4f8c7220-f9fc-49bf-8362-9bd9deaea09a","added_by":"auto","created_at":"2024-07-16 21:55:52","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":56009,"visible":true,"origin":"","legend":"","description":"","filename":"Suplementerytables.docx","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/399fbece8301a781585ebfd0.docx"},{"id":60446638,"identity":"2d858b44-9b4a-40f7-a677-4a3640b05229","added_by":"auto","created_at":"2024-07-16 21:55:52","extension":"docx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":1581980,"visible":true,"origin":"","legend":"","description":"","filename":"suplementayfigures.docx","url":"https://assets-eu.researchsquare.com/files/rs-4486419/v1/d66c1c6d730a2374e2e60681.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and safety of Pemafibrate administration in patients with dyslipidemia: A Systematic Review and Updated Meta-analysis of Randomized Controlled Trials. ","fulltext":[{"header":"Introduction","content":"\u003cp\u003eDyslipidemia refers to the abnormal changes in lipid composition in the bloodstream (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Over the previous 30 years, the prevalence of dyslipidemias has increased globally (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). It is considered one of the main risk factors for cardiovascular disease (CVD) with growing evidence of hypertriglyceridemia as an independent risk factor for CVD (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). The number of deaths from CVD grew from 12.1\u0026nbsp;million in 1990 to 18.6\u0026nbsp;million in 2019 (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePrevious studies have shown that lipid-lowering drugs greatly reduce CHD morbidity and optimizing lipid levels is crucial for preventing CVD (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Currently, fibrates represent the most significant medication class in combating dyslipidemia. Statins aid in lowering low-density lipoprotein cholesterol (LDL), but they have little effect on serum triglyceride or HDL levels; fibrates are needed in these cases (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The recently emerging evidence supports the therapeutic value of fibrates in the control of cardiovascular risk (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePemafibrate is a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that works better in lowering serum triglycerides (TG) and raising HDL-C. It also exhibited improved liver and kidney function test values, while accessible fibrates showed worsening of those test findings. It can also be taken in along with statins. Moreover, pemafibrate can be taken safely in patients even if they have reduced renal function (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe believed that by combining and analyzing all the previous clinical trials and research, we could obtain highly relevant results regarding the safety and efficacy of administering pemafibrate, so this study aimed to investigate the efficacy and safety of pemafibrate administration in patients with dyslipidemia.\u003c/p\u003e"},{"header":"Materials and methods","content":"\u003cp\u003eThis study was structured according to the Cochrane Handbook's guidelines for systematic reviews and meta-analysis (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e) and reporting items for systematic review and meta-analysis (PRISMA-P statement) (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). We registered our study protocol in Prospero with ID: CRD42024509332\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search strategy\u003c/h2\u003e \u003cp\u003eDatabases including PubMed, Ovid Midline, SCOPUS, Web of Science (WOS), and Cochrane Library were searched till December 31, 2023, using the following terms: (\"Pemafibrate\" OR \"selective peroxisome proliferator-activated receptor α modulator\" OR \u0026ldquo;Peroxisome proliferator-activated receptor alpha\u0026rdquo; OR \"PPARα\" OR \u0026ldquo;PPARalpha\u0026rdquo; OR \"peroxisome proliferator-activated receptor alpha \") AND (\"Hypertriglyceridemia\" OR \"High TG\" OR\u0026rdquo; High Triglyceride\" OR \u0026ldquo;dyslipidemia\u0026rdquo; OR \u0026ldquo;Dyslipoproteinemia\u0026rdquo; OR \u0026ldquo;low HDL\" OR \"High LDL\" OR \"High cholesterol\" OR Hyperlipemia OR Hyperlipidemia OR Lipidemia OR Lipemia OR \u0026ldquo;Elevated Cholesterol\u0026rdquo; OR Hypercholesteremia OR Hyperlipoproteinemia OR Hyperchylomicronemia).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStudy selection\u003c/h2\u003e \u003cp\u003eWe included studies that met the following PICOs criteria: (P) patient with resistant dyslipidemia (I) pemafibrate (C) placebo or other fibrates (O) changes in lipid biomarkers \"triglyceride levels, HDL-C level, LDL-C level, cholesterol level, VLDL, and Apolipoprotein B'' (S) Clinical trials. Conversely, we excluded (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e) studies not in English; (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e) non-human studies; (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) instances of duplicated literature; and (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e) study designs other than clinical trials, including guidelines, systematic reviews, meta-analyses, case reports, case series, conference abstracts, letters to the editor, author opinion papers, editorials, and review articles lacking original data. Two authors screened independently the title and abstract to include relevant studies using the Rayyan review tool (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e), then the full-text screening was conducted to confirm the eligibility of the included studies. In cases of conflicts, another third author arbitrated between the two authors.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and Quality assessment\u003c/h2\u003e \u003cp\u003eWe extracted the characteristics of each study using a predefined Excel sheet: (Author, year of publication, study design, study country, total sample size, number and dose of each study arm, and follow-up duration). Also, patients\u0026rsquo; baseline characteristics were listed as follow: (age, sex, body mass index (BMI), number of patients with comorbidities (Type 2 diabetes, hypertension), number of subjects taking Any Statin and biomarkers (triglyceride levels, HDL-C level, LDL-C level, total cholesterol level, HbA1c). Efficacy and safety outcomes data. In the case of a study comparing placebo with more interventions, we consider it as different studies sharing the same placebo group. The quality of the included RCTs was evaluated using the Cochrane Risk of Bias tool (version 2) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Randomization process, deviation from the intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result are the five domains that the ROB tool assessed. Each domain of the included studies was assessed as low risk, some concerns, or high risk.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe statistical analysis was performed with RevMan version 5.3 software. Continuous outcomes were pooled as mean difference (MD) and 95% confidence interval (CI) while dichotomous outcomes were pooled as odds ratio (OR) and 95% CIs. The random-effects model was used for analysis and I\u003csup\u003e2\u003c/sup\u003e and Chi-square tests were used to detect the heterogeneity (I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;\u0026gt;\u0026thinsp;50 indicates significant heterogeneity)\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eSearch results and Characteristics of included study:\u003c/h2\u003e \u003cp\u003eOur search on the databases retrieved 5961 studies, 11 RCTs were included (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e),(\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e), (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e),(\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e),(\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e),(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e),(\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e),(\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e),(\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e),(\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e), (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e) with a total population of 12451 patients with further details can be found in PRISMA flow diagram \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e. The characteristics of the 11 studies are summarized in Table\u0026nbsp;1. Pemafibrate was administered at different doses (0.0025, 0.05, 0.1, 0.2, and 0.4) mg. The compression group was placebo and other fibrates. The follow-up duration ranged from 8 weeks to 182.5 weeks, whole studies were conducted in Japan except two studies, one was conducted in 9 European countries (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e) and another one was conducted in 24 countries (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). We summarized the baseline characteristics of the patients in Supplementary \u003cb\u003eTable\u0026nbsp;1\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eRisk of bias and quality assessment\u003c/h2\u003e \u003cp\u003eAll the included studies reported a low overall risk of bias except for three studies. Matsuba et al (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e) showed a high risk for deviation from the intended intervention and some concerns for selection of reported results, Nakamura et al (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) showed a high risk of bias for randomization process and deviation from the intended intervention while ishibashi et al (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e) reported a high risk of bias for missing outcome data and some concerns for selection of reported result. \u003cb\u003e(\u003c/b\u003eFig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e\u003cb\u003e)\u003c/b\u003e\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe pooled studies for each outcome did not exceed 10 studies, and according to Egger et al (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e), publication bias is not reliable for less than 10 pooled studies. So, we were unable to report the existence of publication bias by Egger\u0026rsquo;s test for funnel plot asymmetry.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eOutcomes\u003c/h2\u003e \u003cdiv id=\"Sec11\" class=\"Section3\"\u003e \u003ch2\u003eEfficacy\u003c/h2\u003e \u003cp\u003eChange of triglyceride level %\u003c/p\u003e \u003cp\u003eWe 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\u0026thinsp;\u0026lt;\u0026thinsp;0.00001; Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). The overall results showed high heterogeneity (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;99%). Results also showed that Pemafibrate significantly reduced TG levels more than other fibrates (MD: -7.05 [-10.96, -3.14]; P\u0026thinsp;=\u0026thinsp;0.0004 with high heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;89%; Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eChange in LDL-C\u003c/p\u003e \u003cp\u003eRegarding 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\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with substantial heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;82%) \u003cb\u003e(Supplementary file: Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e)\u003c/b\u003e. 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\u0026thinsp;=\u0026thinsp;0.07 with no heterogeneity observed I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. \u003cspan refid=\"MOESM2\" class=\"InternalRef\"\u003eS2\u003c/span\u003e)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eChange in HDL-C\u003c/p\u003e \u003cp\u003eRegarding 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\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with high heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;98%) \u003cb\u003e(Supplementary file: Fig. S3)\u003c/b\u003e. The drug is also shown to increase levels of HDL-C more than other fibrates (MD: 3.13 [0.71, 5.54] P\u0026thinsp;=\u0026thinsp;0.01 with high heterogeneity results I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;91%) \u003cb\u003e(Supplementary file: Fig. S4)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eChange in Non-HDL-C\u003c/p\u003e \u003cp\u003eRegarding 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\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with high heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;90%) \u003cb\u003e(Supplementary file: Fig. S5)\u003c/b\u003e. The same goes for VLDL-C with (MD: -48.16 [-62.16, -34.13]; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with high heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;92%) \u003cb\u003e(Supplementary file: Fig. S7)\u003c/b\u003e. 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\u0026thinsp;=\u0026thinsp;0.11 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;23%) \u003cb\u003e(Supplementary file: Fig. S6)\u003c/b\u003e whereas pemafibrate significantly reduces VLDL-C levels when compared to other fibrates (MD: -12.37 [-16.35, -8.38] P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with moderate heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;33%) \u003cb\u003e(Supplementary file: Fig. S8)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eTotal cholesterol level\u003c/p\u003e \u003cp\u003eWhen 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\u0026thinsp;=\u0026thinsp;0.03 with substantial heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;81%) \u003cb\u003e(Supplementary file: Fig. S9)\u003c/b\u003e. 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\u0026thinsp;=\u0026thinsp;0.40 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S10)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eChange in Apo proteins (A-1, A-II, B, B48, C-II, C-III)\u003c/p\u003e \u003cp\u003eRegarding 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\u0026thinsp;=\u0026thinsp;0.14) with significant heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;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\u0026thinsp;=\u0026thinsp;0.03 with significant heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;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\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;31%), (MD: 22.62 [17.65, 27.59] P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with considerable heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;84%) respectively. When compared to other fibrates, pemafibrate significantly increases the levels of Apo A-I (MD: 1.79 [0.54, 3.04] P\u0026thinsp;=\u0026thinsp;0.005 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;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\u0026thinsp;=\u0026thinsp;0.19 with significant heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;89%) \u003cb\u003e(Supplementary file: Fig. S11_S16)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eOur analysis also revealed statistically significant lower levels of ApoB48 in pemafibrate groups (MD: -68.03 [-78.10, -57.96]; P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;3%) \u003cb\u003e(Supplementary file: Fig. S17)\u003c/b\u003e. Pemafibrate also significantly reduces ApoB48 values more than other fibrates (MD: -11.29 [-16.70, -5.88] P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;18%) \u003cb\u003e(Supplementary file: Fig. S18)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eRegarding 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\u0026thinsp;=\u0026thinsp;0.0001), (MD: -34.73 [-39.86, -29.60] P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001) respectively. Both results showed significant heterogeneity (P\u0026thinsp;\u0026lt;\u0026thinsp;0. 0001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;80%), (P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001, I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;73%) respectively \u003cb\u003e(Supplementary file: Fig. S19, S20)\u003c/b\u003e. Pemafibrate also reduces the values of Apo C-III more than other fibrates (MD: -6.24 [-11.84, -0.65] P\u0026thinsp;=\u0026thinsp;0.03 with substantial heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;72%) \u003cb\u003e(Supplementary file: Fig. S21)\u003c/b\u003e\u003c/p\u003e \u003cp\u003eChange in RemL-C\u003c/p\u003e \u003cp\u003eRegarding 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\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S22)\u003c/b\u003e. Pemafibrate also reduces RemL-C values more than other fibrates with a significant difference (MD: -12.95 [-16.92, -8.98] P\u0026thinsp;\u0026lt;\u0026thinsp;0.00001 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S23)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003ePemafibrate is shown to significantly reduce the values of HOMA-R than in placebo groups with (MD -0.78 [-1.12, -0.43]; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001; I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0% indicating no heterogeneity) \u003cb\u003e(Supplementary file: Fig. S24)\u003c/b\u003e. No significant difference was found when comparing the effect of pemafibrate with other fibrates (MD: -0.06 [-0.39, 0.27]; P\u0026thinsp;=\u0026thinsp;0.74 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S25)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eOur analysis showed that pemafibrate significantly reduced the levels of FBG compared to placebo groups (MD: -3.65 [-5.54, -1.77]; P\u0026thinsp;=\u0026thinsp;0.0001 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;9%) \u003cb\u003e(Supplementary file: Fig. S26)\u003c/b\u003e. The same goes for levels of fasting insulin (MD: -3.65 [-5.54, -1.77]; P\u0026thinsp;=\u0026thinsp;0.0001 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;9%) \u003cb\u003e(Supplementary file: Fig. S27)\u003c/b\u003e. Changes in HBA1C values showed a minimal significant increase in pemafibrate group (MD: 0.10 [0.01, 0.20] P\u0026thinsp;=\u0026thinsp;0.03 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) (\u003cb\u003eSupplementary file: Fig. S28)\u003c/b\u003e. 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\u0026thinsp;=\u0026thinsp;0.48 with moderate heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;52%) and (MD: -2.73 [-9.75, 4.30] P\u0026thinsp;=\u0026thinsp;0.45 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0) \u003cb\u003e(Supplementary file: Fig. S29, S30)\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eSafety\u003c/h2\u003e \u003cp\u003eTotal adverse effects\u003c/p\u003e \u003cp\u003eNo significant difference was found in the frequency of total adverse effects between the pemafibrate groups and placebo groups (OR: 0.83 [0.64, 1.08] P\u0026thinsp;=\u0026thinsp;0.17 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). However, the least doses to cause side effects were 0.05 mg and 0.1 mg which may be clinically significant. Furthermore, no significant difference between pemafibrate and other fibrates (OR: 0.79 [0.61, 1.03]; P\u0026thinsp;=\u0026thinsp;0.08 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%; Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eAdverse drug reactions\u003c/p\u003e \u003cp\u003eRegarding the frequency of Adverse drug reactions, there was no significant difference between Pemafibrate and placebo groups (OR: 0.95[0.59, 1.54] P\u0026thinsp;=\u0026thinsp;0.84) \u003cb\u003e(Supplementary file: Fig. S31)\u003c/b\u003e. However, Pemafibrate is found to produce significantly fewer adverse drug reactions than other fibrates (OR: 0.51 [0.31, 0.82] P\u0026thinsp;=\u0026thinsp;0.006 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S32)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eSerious Adverse events\u003c/p\u003e \u003cp\u003eNo significant difference was found between pemafibrate groups and placebo groups regarding the frequency of Serious adverse events (OR: 1.06 [0.98, 1.14] P\u0026thinsp;=\u0026thinsp;0.18 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), Musculoskeletal adverse events (OR: 1.29 [0.60, 2.78] P\u0026thinsp;=\u0026thinsp;0.51 with moderate heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;47%), or Rhabdomyolysis (OR: 0.49 [0.17, 1.42] P\u0026thinsp;=\u0026thinsp;0.19 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;22%) \u003cb\u003e(Supplementary file: Fig. S33, S34, S35)\u003c/b\u003e. Same goes when comparing pemafibrate to other fibrates, no significant difference in Serious adverse events (OR: 2.01[0.81, 4.99] P\u0026thinsp;=\u0026thinsp;0.13 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), Musculoskeletal adverse events (OR: 0.53 [0.10, 2.93] P\u0026thinsp;=\u0026thinsp;0.47 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) or Rhabdomyolysis (OR: 0.56 [10.18, 1.71] P\u0026thinsp;=\u0026thinsp;0.31 with no heterogeneity observed I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) %) \u003cb\u003e(Supplementary file: Fig. S36, S37, S38)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eHepatic adverse events were reported less in pemafibrate groups than in placebo groups, and results were of statistical significance (OR: 0.80 [0.67, 0.96] P\u0026thinsp;=\u0026thinsp;0.02 with no heterogeneity observed I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S39)\u003c/b\u003e, moreover, pemafibrate was ahead of other fibrates regarding less hepatic adverse events (MD: 0.28 [0.14, 0.56] P\u0026thinsp;=\u0026thinsp;0.0003 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;24%) \u003cb\u003e(Supplementary file: Fig. S40)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eLiver function tests\u003c/p\u003e \u003cp\u003eOur analysis showed pemafibrate was significantly associated with less frequency of abnormal liver enzymes compared to placebo: AST being more than upper limit (OR: 0.60[0.38, 0.93]; P\u0026thinsp;=\u0026thinsp;0.02 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%), ALT being more than upper limit of normal (OR: 0.52 [0.35, 0.78]; P\u0026thinsp;=\u0026thinsp;0.001 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) and GGT being more than upper limit of normal (OR: 0.15[0.05, 0.45]; P\u0026thinsp;=\u0026thinsp;0.0008 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S41_S43)\u003c/b\u003e. When compared to other fibrates, pemafibrate also showed significantly less frequency of AST being more than the upper limit of normal (OR: 0.16 [0.07, 0.37] P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 with minimal heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;28%) and ALT being more than the upper limit of normal (OR: 0.44 [0.20, 0.94] P\u0026thinsp;=\u0026thinsp;0.03 with no heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S44, S45)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eCreatine kinase and creatinine level\u003c/p\u003e \u003cp\u003eResults showed creatine kinase levels more than the upper limit of normal to be less frequent in pemafibrate groups than in placebo groups (OR: 0.36 [0.15, 0.85] P\u0026thinsp;=\u0026thinsp;0.02 with no heterogeneity) \u003cb\u003e(Supplementary file: Fig. S46)\u003c/b\u003e. And less frequent in Pemafibrate groups compared to other fibrate groups (OR: 0.49 [0.14, 1.75] P\u0026thinsp;=\u0026thinsp;0.27 with no heterogeneity observed I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;0%) \u003cb\u003e(Supplementary file: Fig. S47)\u003c/b\u003e.\u003c/p\u003e \u003cp\u003eMore frequency of increased Creatinine was reported in pemafibrate groups compared to placebo groups but was of no statistical significance (OR: 1.43 [0.45, 4.52] P\u0026thinsp;=\u0026thinsp;0.54 with no heterogeneity) \u003cb\u003e(Supplementary file: Fig. S48)\u003c/b\u003e, however, when compared to other fibrates, pemafibrate shows a significant less frequent increase in creatinine (OR: 0.34 [0.13, 0.92] P\u0026thinsp;=\u0026thinsp;0.03 with moderate heterogeneity I\u003csup\u003e2\u003c/sup\u003e\u0026thinsp;=\u0026thinsp;49%) \u003cb\u003e(Supplementary file: Fig. S49)\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur meta-analysis showed the changes in TG levels to be statistically significant. Also, the drug was better than other fibrates in lowering TG levels. The drug also significantly lowers the levels of non-HDL cholesterol and total cholesterol levels more than placebo or other fibrates. Pemafibrate is also shown to increase levels of HDL-C more than placebo, or other fibrates. It is however shown to increase the levels of LDL-C more than placebo, and other fibrates. The last dose to cause elevation of LDL-C is pemafibrate at 0.4 mg. Pemafibrate is mainly designed to lower serum TG levels and many previous studies have proven that finding, our meta-analysis result further contributes to this finding. The mechanism of action of fibrates has also been demonstrated in several previous studies, one way by which the drug lowers serum TG levels is that it decreases hepatic TG production. Fibrates also increase hepatic HDL-C synthesis and stimulate reverse cholesterol transport. They also stimulate lipolysis and increase the uptake of fatty acids. The drug exerts all these effects by acting as an agonist on PPARs especially PPAR-alpha, which are nuclear receptors that play a role in the regulation of lipid metabolism (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eOne explanation for LDL-C elevation associated with pemafibrate is that the effect of lipolysis by pemafibrate on VLDL-C results in the formation of IDL-C which subsequently increases the levels of LDL-C which contains apo-B lipoproteins gathered from VLDL-C catabolism (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Although the increase of LDL-C by pemafibrate appears to be clinically safe, Elevation of LDL-C requires more investigation, a previous study demonstrated that elevated LDL-C levels especially sdLDL-C particles rapidly undergo modifications such as oxidization, desialylation, glycation, and electronegative LDL, making them highly atherogenic and increase the risk of ASCVD (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). Apart from increasing LPL activity and lipolysis, Lowering TG levels is also accompanied by a decrease in apoC-III which in turn decreases the inhibitory effect on LPL which also increases lipolysis (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Being a PPAR-alpha agonist, fibrates increase the expression of apo A-1 and A-II which are major components of HDL increasing their serum levels (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eA previous meta-analysis (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) ALT, GGT, and AST levels were reduced in pemafibrate groups. The reason for this is not well understood, however, some experimental studies on animals demonstrated that the effect might be due to decreased apoptosis of hepatocytes and decreased hepatic fibrosis (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e, \u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The authors of the PROMINENT trial which is a huge trial included in our meta-analysis that was conducted in 24 countries also contributed to the fact that Pemafibrate improves liver functions. Their trial also found that changes were non-significant in pemafibrate group regarding cardiovascular events when compared to placebo. They further informed us about a second ongoing pemafibrate trial to evaluate histological markers of liver fibrosis.\u003c/p\u003e \u003cp\u003ePemafibrate is also shown to significantly increase HOMA-IR levels than placebo or other fibrates, suggesting an improvement in insulin resistance, in turn, significantly lower values of FBG were found in pemafibrate groups in our meta-analysis. It is believed that that effect might be due to the decreased amounts of free fatty acids along with a decrease in inflammatory cytokines and oxidative stress (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e, \u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eNo significant difference in adverse effects when comparing pemafibrate to placebo or other fibrates, however, low doses of pemafibrate 0.05mg and 0.1mg are shown to cause fewer side effects, this suggests that an increase in pemafibrate dose might be associated with a slightly higher frequency of AE. Although the overall risk for AE is minimal, this relationship requires more investigation. Significant low levels of creatine kinase were also found in pemafibrate groups. Also, significantly low levels of AST, ALT, ALP, and GGT were found in pemafibrate groups. It is also worth noting that pemafibrate increases creatinine levels to a lesser extent than other fibrates.\u003c/p\u003e \u003cp\u003ePemafibrate in humans is mainly excreted by the biliary route (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). Like some other fibrates, Serum creatinine was more in pemafibrate groups than placebo groups with no statistical significance, some think it might be safe on kidneys as the biliary route is the main route for the drug excretion (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e). Our analysis also showed that pemafibrate elevates serum creatinine to a lesser extent than other fibrates with a significant difference along with a significant reduction in eGFR in pemafibrate groups than placebo groups which also contributed to the previous finding. However, only four of the included trials reported the change in serum creatinine levels which implies the need for further investigation.\u003c/p\u003e \u003cp\u003eWe found that CK levels being more than the upper limit of normal less in pemafibrate groups when compared to both placebo and other fibrates, however, it is previously reported that myopathy and Rhabdomyolysis can both be adverse effects of fibrates especially when combined with statins (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e, \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations of the study\u003c/h2\u003e \u003cp\u003eFirst, the majority of the studies included were conducted in Japan except for two multi-center studies therefore the results cannot be generalized to all populations, Second, some of the included RCTs were of short durations which makes it harder to assess the long-term efficacy and safety of the drug. Third, the availability of a small number of RCTs may limit proper assessment. Moreover, the lack of individual patient data hinders our ability to investigate further other important outcomes. Therefore, we call for more RCTs to be conducted on different populations in an attempt to investigate the effects of pemafibrate in a generalized manner with also a long-term follow-up to assess its long-term safety and applicability.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur meta-analysis investigated the efficacy and safety of pemafibrate compared to placebo and other fibrates in patients with dyslipidemia. Pemafibrate demonstrated a significant improvement in the overall lipid profiles, reducing the levels of triglycerides, VLDL-C, non-HDL-C, and total cholesterol and increasing HDL-C levels but considering increasing LDL-C levels which needs more investigations. Abnormal liver enzymes were less frequent with pemafibrate. Moreover, there was no significant difference in adverse effects, adverse drug reactions, serious adverse events, and rhabdomyolysis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate:\u003c/strong\u003e Not required as it is a systematic review.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication:\u0026nbsp;\u003c/strong\u003eAll authors reviewed and agreed on the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material:\u0026nbsp;\u003c/strong\u003eAll data are available and attached.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u0026nbsp;\u003c/strong\u003eNo funding received.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eNone\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRaja V, Aguiar C, Alsayed N, Chibber YS, ElBadawi H, Ezhov M, et al. 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Available from: https://diabetesjournals.org/care/article/41/3/538/36634/Effects-of-Pemafibrate-a-Novel-Selective-PPAR\u003c/li\u003e\n\u003cli\u003eYamashita S, Arai H, Yokote K, Araki E, Suganami H, Ishibashi S. Effects of pemafibrate (K-877) on cholesterol efflux capacity and postprandial hyperlipidemia in patients with atherogenic dyslipidemia. J Clin Lipidol [Internet]. 2018 Sep;12(5):1267-1279.e4. Available from: https://linkinghub.elsevier.com/retrieve/pii/S193328741830268X\u003c/li\u003e\n\u003cli\u003eNakajima A, Eguchi Y, Yoneda M, Imajo K, Tamaki N, Suganami H, et al. Randomised clinical trial: Pemafibrate, a novel selective peroxisome proliferator‐activated receptor \u0026alpha; modulator (SPPARM\u0026alpha;), versus placebo in patients with non‐alcoholic fatty liver disease. Aliment Pharmacol Ther [Internet]. 2021 Nov 16;54(10):1263\u0026ndash;77. Available from: https://onlinelibrary.wiley.com/doi/10.1111/apt.16596\u003c/li\u003e\n\u003cli\u003eKatsiki N, Nikolic D, Montalto G, Banach M, Mikhailidis DP, Rizzo M. The Role of Fibrate Treatment in Dyslipidemia: An Overview. Curr Pharm Des [Internet]. 2013 Apr 1;19(17):3124\u0026ndash;31. Available from: http://www.eurekaselect.com/openurl/content.php?genre=article\u0026amp;issn=1381-6128\u0026amp;volume=19\u0026amp;issue=17\u0026amp;spage=3124\u003c/li\u003e\n\u003cli\u003eSigurdsson G, Nicoll A, Lewis B. Conversion of very low density lipoprotein to low density lipoprotein. A metabolic study of apolipoprotein B kinetics in human subjects. J Clin Invest [Internet]. 1975 Dec 1;56(6):1481\u0026ndash;90. Available from: http://www.jci.org/articles/view/108229\u003c/li\u003e\n\u003cli\u003eBerneis KK, Krauss RM. Metabolic origins and clinical significance of LDL heterogeneity. J Lipid Res [Internet]. 2002 Sep;43(9):1363\u0026ndash;79. 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Available from: https://cardiab.biomedcentral.com/articles/10.1186/s12933-019-0845-x\u003c/li\u003e\n\u003cli\u003eHonda Y, Kessoku T, Ogawa Y, Tomeno W, Imajo K, Fujita K, et al. Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, improves the pathogenesis in a rodent model of nonalcoholic steatohepatitis. Sci Rep [Internet]. 2017 Feb 14;7(1):42477. Available from: https://www.nature.com/articles/srep42477\u003c/li\u003e\n\u003cli\u003eCindoruk M, Kerem M, Karakan T, Salman B, Akin O, Alper M, et al. Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study. BMC Gastroenterol [Internet]. 2007 Dec 28;7(1):44. Available from: https://bmcgastroenterol.biomedcentral.com/articles/10.1186/1471-230X-7-44\u003c/li\u003e\n\u003cli\u003eKaur J, Reddy K, Balakumar P. The Novel Role of Fenofibrate in Preventing Nicotine- and Sodium Arsenite-Induced Vascular Endothelial Dysfunction in the Rat. Cardiovasc Toxicol [Internet]. 2010 Sep 7;10(3):227\u0026ndash;38. Available from: http://link.springer.com/10.1007/s12012-010-9086-7\u003c/li\u003e\n\u003cli\u003eBoden G, Chen X, Ruiz J, White J V, Rossetti L. Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest [Internet]. 1994 Jun 1;93(6):2438\u0026ndash;46. Available from: http://www.jci.org/articles/view/117252\u003c/li\u003e\n\u003cli\u003eBlair HA. Pemafibrate: First Global Approval. Drugs [Internet]. 2017 Oct 19;77(16):1805\u0026ndash;10. Available from: http://link.springer.com/10.1007/s40265-017-0818-x\u003c/li\u003e\n\u003cli\u003eAlsheikh-Ali AA, Kuvin JT, Karas RH. Risk of adverse events with fibrates*. Am J Cardiol [Internet]. 2004 Oct;94(7):935\u0026ndash;8. 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Available from: https://www.bmj.com/lookup/doi/10.1136/bmj.315.7109.629\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Pemafibrate, other fibrates, dyslipidemia, Lipid biomarkers, adverse events.","lastPublishedDoi":"10.21203/rs.3.rs-4486419/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4486419/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003ePatients with dyslipidemia are at risk for cardiovascular diseases. Lowering levels of lipid decreases morbidity. Pemafibrate is a selective peroxisome proliferator-activated receptor α modulator (SPPARMα) that works better at lowering serum triglycerides.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Clinical trials investigating the effect of pemafibrate on lipid biomarkers in patients with dyslipidemia were searched in PubMed, Ovid Medline, SCOPUS, Web of Science (WOS), and the Cochrane Library from inception till December 31, 2023. The data were pooled as mean difference, odds ratio (OR), and 95% confidence interval (CI).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e 14 clinical trials were eligible involving 12451 patients showed favorable triglyceride level change (MD: -49.60 [-62.64, -36.55] P\u0026lt;0.00001) for pemafibrate compared to placebo. Pemafibrate showed a significant increase in HDL-C levels (MD: 14.57 [10.14, 19.01] P\u0026lt;0.00001) but showed a concurrent increase in LDL-C levels (MD: 10.99 [6.10, 15.88] P \u0026lt;0.00001). It also showed non-HDL-C, total cholesterol level, Apo B, Apo C-II, and Apo C-III to be significantly reduced in pemafibrate groups. Also, in pemafibrate groups, hepatic adverse events were reported less frequently than in placebo groups. No significant difference was found in the frequency of total adverse effects, adverse drug reactions, or serious adverse events between the pemafibrate and placebo groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003ePemafibrate improved the overall lipid biomarkers compared to placebo groups, demonstrating a significant reduction in triglycerides, non-HDL-C, and total cholesterol while increasing in HDL-C. Moreover, there was no significant difference in adverse effects.\u003c/p\u003e","manuscriptTitle":"Efficacy and safety of Pemafibrate administration in patients with dyslipidemia: A Systematic Review and Updated Meta-analysis of Randomized Controlled Trials. 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