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Efficacy and Safety of Pemafibrate Administration in Patients With Ida et al. Cardiovasc Diabetol (2019) 18:38 https://doi.org/10.1186/s12933-019-0845-x Cardiovascular Diabetology ORIGINAL INVESTIGATION Open Access Efcacy and safety of pemafbrate administration in patients with dyslipidemia: a systematic review and meta-analysis Satoshi Ida*, Ryutaro Kaneko and Kazuya Murata Abstract Background: Using a meta-analysis of randomized controlled trials (RCTs), this study aimed to investigate the ef- cacy and safety of pemafbrate, a novel selective peroxisome proliferator-activated receptor α modulator, in patients with dyslipidemia. Methods: A search was performed using the MEDLINE, Cochrane Controlled Trials Registry, and ClinicalTrials.gov databases. We decided to employ RCTs to evaluate the efects of pemafbrate on lipid and glucose metabolism- related parameters in patients with dyslipidemia. For statistical analysis, standardized mean diference (SMD) or odds ratio (OR) and 95% confdence intervals (CIs) were calculated using the random efect model. Results: Our search yielded seven RCTs (with a total of 1623 patients) that satisfed the eligibility criteria of this study; hence, those studies were incorporated into this meta-analysis. The triglyceride concentration signifcantly decreased in the pemafbrate group (SMD, 1.38; 95% CI, 1.63 to 1.12; P < 0.001) than in the placebo group, with a reduc- tion efect similar to that exhibited− by fenofbrate.− Compared− with the placebo group, the pemafbrate group also showed improvements in high-density and non-high-density lipoprotein cholesterol levels as well as in homeostasis model assessment for insulin resistance. Furthermore, the pemafbrate group showed a signifcant decrease in hepa- tobiliary enzyme activity compared with the placebo and fenofbrate groups; and, total adverse events (AEs) were signifcantly lower in the pemafbrate group than in the fenofbrate group (OR, 0.60; 95% CI, 0.49–0.73; P < 0.001). In contrast, the low-density lipoprotein cholesterol level was signifcantly higher in the pemafbrate group than in the placebo (P 0.006) and fenofbrate (P < 0.001) groups. = Conclusions: The lipid profle signifcantly improved in the pemafbrate group than in the placebo group. In addition to the pemafbrate group having an improved lipid profle, which was comparable with that of the fenofbrate group, the AEs were signifcantly lower than in the fenofbrate group and an improvement in hepatobiliary enzyme activity was also recognized. However, we believe that actual clinical data as well as long-term efcacy and safety need to be investigated in the future. Keywords: Fibrate, Meta-analysis, Dyslipidemia, Pemafbrate, Adverse events, Lipid profle, Hepatobiliary enzyme activity *Correspondence: [email protected] Department of Diabetes and Metabolism, Ise Red Cross Hospital, 1-471-2, Funae, 1-Chome, Ise-shi, Mie 516-8512, Japan © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Ida et al. Cardiovasc Diabetol (2019) 18:38 Page 2 of 14 Background Trials Registry (from 1960), and ClinicalTrials.gov. Previous studies have demonstrated that lipid control is Te search strategy included terms of “(pemafbrate or important for preventing cardiovascular disease onset [1, selective peroxisome proliferator-activated receptor or 2]. In particular, the fnding that cardiovascular disease selective peroxisome proliferator-activated receptor or onset can be prevented by reducing low-density lipo- selective modulator of peroxisome proliferator-activated protein cholesterol (LDL-C) levels via statin administra- receptor or selective modulator of peroxisome prolif- tion [1] has achieved high clinical priority. However, the erator-activated receptor or selective PPAR or selective problem here is that the beneft of statin administration modulator of PPAR) AND (Randomized Controlled Trial to cardiovascular disease inhibition is only approximately or Controlled Clinical Trial or Randomized or Rand- 20%, the remaining 80% being residual risk [3]. Target omized or placebo or randomly or assigned).” We decided lipids for arteriosclerosis prevention, including triglycer- to include RCTs to evaluate the efect of pemafbrate ides (TG) and high-density lipoprotein cholesterol (HDL- on lipid and glucose metabolism-related parameters in C) except LDL-C, and hypertriglyceridemia and low patients with dyslipidemia. Te RCTs included compared HDL-C-emia are reportedly associated with cardiovas- pemafbrate with placebo and lipid-lowering drugs irre- cular disease onset [4]. As a drug against hyperTG-emia spective of the presence of diet/exercise therapy or the and low HDL-C-emia, a fbrate-system drug capable use of lipid-lowering drugs. Exclusion criteria included of strong TG-lowering and HDL-C-elevating actions is studies that were not RCT, research on animals, research being clinically used to activate peroxisome proliferator- without sufcient data to perform analysis, and cases activated receptor α (PPARα) [5]. Some meta-analyses of duplicate literature. In cases of difculty in interpre- have reported the possibility of the suppression of cardio- tation, the senior author decided to consult with other vascular disease development by fbrate administration reviewers (RK and KM). [6, 7]; this may be useful in remedying the residual risk of arteriosclerosis that cannot be sufciently controlled Data extraction and quality assessment by statin administration alone. However, manifestation We created a data extraction form describing the char- of side efects, such as hepatic disorder, kidney disorder, acteristics of the research included in each study (key or rhabdomyolysis, may be problematic for fbrate-type author’s name, publication year, study location, sam- drugs and may occasionally make it difcult to continue ple size, patient’s baseline information, basic treatment, administration [8, 9]. Tus, fbrate formulations are pres- and treatment duration). Continuous variables were ently considered problematic for wide-scale clinical use. expressed as the mean value, standard deviation, stand- Pemafbrate reportedly reduces TG, which is consid- ard error or 95% confdence intervals (CIs), and binary ered as a risk factor for the development of cardiovas- variables were expressed in terms of percentage (%). In cular diseases, or increases HDL-C levels. Furthermore, case of a study comparing one placebo group and two or pemafbrate is a PPARα modulator (SPPARMα) with more intervention groups, we treated it as two or more extremely high selectivity to PPARs subtypes, devel- studies sharing the placebo group. For quality evaluation, oped with the aim to reduce the occurrence of adverse we used Cochrane’s risk of bias tool [13]. We evaluated efects associated with fbrate-type drugs and as a drug low risk of bias, moderate risk of bias, and high risk of with fewer restrictions for use in patients with renal dis- bias related to six domains (random sequence generation, ease or for concomitant statin use [10]. Pemafbrate pos- allocation concealment, blinding of personnel and partic- sesses lipid-improving efects similar to those of existing ipants, blinding of outcome assessors, incomplete data, fbrate-type drugs; moreover, its side efects are equiva- and selective reporting). lent to those of the placebo [11, 12]. We considered that highly relevant results related to the efcacy and safety Statistical analysis of pemafbrate administration could be obtained via an As an indicator of the therapeutic efect, the diference integrated analysis of all these previous studies. Tere- between groups was assessed regarding the amount of fore, using a meta-analysis of randomized controlled tri- change of lipid and sugar metabolism-related markers als (RCTs), this study aimed to investigate the efcacy before and after treatment. Since studies used diferent and safety of pemafbrate administration in patients with units, we decided to analyze using standardized mean dyslipidemia. diference (SMD) and 95% CIs. As a safety evaluation index, analysis was performed using odds ratio (OR) Methods and 95% CIs related to total AEs, the increase in hepa- Study selection tobiliary enzyme activities [aspartate aminotransferase Te literature search was performed on November 1, (AST), alanine aminotransferase (ALT), and γ-glutamyl 2018, using MEDLINE (from 1960), Cochrane Controlled transpeptidase (γGTP) activities above the normal upper Ida et al. Cardiovasc Diabetol (2019) 18:38 Page 3 of 14 limit], kidney disorder (creatinine 1.5 mg/dL or more), satisfed the eligibility criteria of this study and were and creatine kinase (CK) increase (above the normal incorporated into the meta-analysis (Fig. 1) [11, 12, 17– upper limit). In cases where only the standard error or 21]. Te characteristics of these seven RCTs are sum- P-values were mentioned, the standard deviation was marized in Table 1. Te dose of pemafbrate in these calculated with reference to Altman and Bland [14]. In studies was 0.025, 0.05, 0.1, 0.2, or 0.4 mg/day. Te com- the absence of the standard deviation, it was calculated
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