Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis

Arrigo F G Cicero; Federica Fogacci; Adrian V Hernandez; Maciej Banach; on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP)

doi:10.1371/journal.pmed.1003121

. 2020 Jul 16;17(7):e1003121. doi: 10.1371/journal.pmed.1003121

Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis

Arrigo F G Cicero ^1,^*, Federica Fogacci ¹, Adrian V Hernandez ^2,³, Maciej Banach ^4,^5,^6,^*; on behalf of the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group and the International Lipid Expert Panel (ILEP)^¶

Editor: Anthony Wierzbicki⁷

PMCID: PMC7365413 PMID: 32673317

Abstract

Background

Bempedoic acid is a first-in-class lipid-lowering drug recommended by guidelines for the treatment of hypercholesterolemia. Our objective was to estimate its average effect on plasma lipids in humans and its safety profile.

Methods and findings

We carried out a systematic review and meta-analysis of phase II and III randomized controlled trials on bempedoic acid (PROSPERO: CRD42019129687). PubMed (Medline), Scopus, Google Scholar, and Web of Science databases were searched, with no language restriction, from inception to 5 August 2019. We included 10 RCTs (n = 3,788) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]). Effect sizes for changes in lipids and high-sensitivity C-reactive protein (hsCRP) serum concentration were expressed as mean differences (MDs) and 95% confidence intervals (CIs). For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method. Bempedoic acid significantly reduced total cholesterol (MD −14.94%; 95% CI −17.31%, −12.57%; p < 0.001), non-high-density lipoprotein cholesterol (MD −18.17%; 95% CI −21.14%, −15.19%; p < 0.001), low-density lipoprotein cholesterol (MD −22.94%; 95% CI −26.63%, −19.25%; p < 0.001), low-density lipoprotein particle number (MD −20.67%; 95% CI −23.84%, −17.48%; p < 0.001), apolipoprotein B (MD −15.18%; 95% CI −17.41%, −12.95%; p < 0.001), high-density lipoprotein cholesterol (MD −5.83%; 95% CI −6.14%, −5.52%; p < 0.001), high-density lipoprotein particle number (MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049), and hsCRP (MD −27.03%; 95% CI −31.42%, −22.64%; p < 0.001). Bempedoic acid did not significantly modify triglyceride level (MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189), very-low-density lipoprotein particle number (MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585), and apolipoprotein A-1 (MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290). Treatment with bempedoic acid was positively associated with an increased risk of discontinuation of treatment (OR 1.37; 95% CI 1.06, 1.76; p = 0.015), elevated serum uric acid (OR 3.55; 95% CI 1.03, 12.27; p = 0.045), elevated liver enzymes (OR 4.28; 95% CI 1.34, 13.71; p = 0.014), and elevated creatine kinase (OR 3.79; 95% CI 1.06, 13.51; p = 0.04), though it was strongly associated with a decreased risk of new onset or worsening diabetes (OR 0.59; 95% CI 0.39, 0.90; p = 0.01). The main limitation of this meta-analysis is related to the relatively small number of individuals involved in the studies, which were often short or middle term in length.

Conclusions

Our results show that bempedoic acid has favorable effects on lipid profile and hsCRP levels and an acceptable safety profile. Further well-designed studies are needed to explore its longer-term safety.

Maciej Banach and colleagues discuss the efficacy and safety of bempedoic acid, a drug that designed to lower LDL-C levels.

Author summary

Why was this study done?

Lowering low-density lipoprotein cholesterol (LDL-C) is effective for reducing cardiovascular events over time.
A number of phase II and phase III randomized controlled trials (RCTs) are already available showing encouraging results of bempedoic acid treatment on LDL-C.
We aimed to perform a systematic review and meta-analysis on the clinical evidence available to date to better define the efficacy and tolerability profile of treatment with bempedoic acid.

What did the researchers do and find?

In this analysis of bempedoic acid that included 10 randomized clinical trials (n = 3,788 patients) comprising 26 arms (active arm [n = 2,460]; control arm [n = 1,328]), we confirmed that bempedoic acid significantly reduced total cholesterol (by 15%), non-high-density lipoprotein cholesterol (by 18.2%), LDL-C (by 22.9%), low-density lipoprotein particle number (by 20.7%), apolipoprotein B (by 15.2%), and high-sensitivity C-reactive protein (hsCRP) (by 27%), while negatively affecting serum levels of high-density lipoprotein cholesterol (−5.8%) and high-density lipoprotein particle number (−3.2%).
Our results also confirmed that the therapy is overall safe and well tolerated, with no significant increase of serious adverse effects.

What do these findings mean?

The current meta-analysis demonstrates the multiple positive effects of bempedoic acid on lipid profile and hsCRP serum levels, as well as acceptable safety profile.
This could be relevant in a setting where statin intolerance is very frequent and the LDL-C target suggested by international guidelines for dyslipidemia management is hard to achieve with standard therapies.
An ongoing long-term cardiovascular outcomes trial will answer questions on the effect of bempedoic acid on cardiovascular events and mortality as well as on the drug’s safety issues.

Introduction

Cardiovascular diseases (CVDs) are still the leading cause of disability and death in developed countries [1]. As reported by Mendelian randomization studies, a lifetime reduction of low-density lipoprotein cholesterol (LDL-C) of 1 mmol/l might reduce the potential risk of atherosclerotic CVDs by over 50% [2]. Controlled clinical studies successfully showed a consistent relationship between the reduction of LDL-C and cardiovascular (CV) risk decrease [3], such that lipid-lowering therapy became a cornerstone in CV risk reduction.

Bempedoic acid (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; ETC-1002; Esperion Therapeutics, Ann Arbor, MI) is a first-in-class small-molecule inhibitor of ATP citrate lyase (ACLY), a key enzyme that supplies substrate for cholesterol and fatty acid synthesis [4]. ACLY is essential for growth and development, such that homozygous knockout (Acly⁻) in mice is embryonic lethal, indicating non-redundancy during development [5]. By inhibiting ACLY, bempedoic acid induces LDL receptor upregulation and stimulates the uptake of LDL particles by the liver, which contributes to reduction of LDL-C concentration in the blood [6]. Bempedoic acid is administered orally once a day, is quickly absorbed in the small intestine, and has a half-life ranging from 15 to 24 hours [7]. It is a prodrug that is activated by very-long-chain acyl-CoA synthetase 1, an enzyme that is synthesized only in the liver [8]. Even though bempedoic acid acts on the same pathway as statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors), the lack of the activating enzyme in skeletal muscle may prevent the muscular adverse effects associated with statins [8]. For this reason, bempedoic acid may represent a novel treatment to reach LDL-C goals for statin-intolerant patients [9].

A number of phase II and phase III randomized controlled trials (RCTs) are already available, showing encouraging effects of bempedoic acid treatment on LDL-C. Consequently, we aimed to perform a systematic review and meta-analysis of the clinical evidence available to date to better define its efficacy and tolerability profile.

Methods

The study is reported in accordance with the 2009 guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (S1 PRISMA Checklist) [10], and was registered in the PROSPERO database (registration code: CRD42019129687). Due to the study design (meta-analysis), neither institutional review board approval nor patient informed consent was required.

Search strategy

PubMed (Medline), Web of Science, Google Scholar, and Scopus databases were searched, with no language restriction, using the following search terms: (“Bempedoic acid” OR “ETC-1002”) AND (“Trial” OR “Study”) [Search terms: ((“Bempedoic acid”) AND Study) OR ((Bempedoic acid) AND Trial) OR (ETC-1002 AND Study) OR (ETC-1002 AND Trial))]. The wild-card term “*” was used to increase the sensitivity of the search strategy, which was limited to studies in humans. The reference lists of identified papers were manually checked for additional relevant articles. Additional searches for potential trials included the references of review articles on bempedoic acid, and the abstracts from selected scientific conferences on the subject of the meta-analysis. Literature was searched from inception to 5 August 2019.

All abstracts were screened by 2 reviewers (FF and AFGC) in an initial process to remove ineligible articles. The remaining articles were obtained in full-text and assessed again by the same 2 researchers, who evaluated each article independently and carried out data extraction and quality assessment. Disagreements were resolved by discussion with a third party (MB).

Study selection criteria

Original studies were included if they met the following criteria: (i) were a phase II or III RCT with either multicenter or single-center design, (ii) investigated the effect of bempedoic acid on plasma lipids or high-sensitivity C-reactive protein (hsCRP), (iii) tested the safety of bempedoic acid in short- and middle-term administration, and (iv) reported all the adverse events (AEs) that occurred during the treatment.

Studies that lacked a control-treated group for comparison with bempedoic acid were excluded.

Data extraction

Data abstracted from the eligible studies were the following: (i) study registration code; (ii) first author’s name; (iii) publication year; (iv) study phase; (v) main inclusion criteria and underlying disease; (vi) treatment duration; (vii) study arms; (viii) number of participants in the active and control group; (ix) age and sex of study participants, (x) baseline and outcome data of total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), very-low-density lipoprotein (VLDL), non-HDL-C, triglycerides (TGs), apolipoprotein (Apo) B, Apo A-1, and hsCRP; and (xi) discontinuation of treatment and AEs that occurred during the trials. Safety outcomes included: AEs, serious AEs, study-drug-related AEs, AEs leading to discontinuation of treatment, death, major adverse cardiac events, muscle-related AEs, arthralgia, gout, back pain, pain in extremity, pruritus, rash, new onset hypertension, headache, fatigue, dizziness, dyspepsia, abdominal pain, nausea, constipation, diarrhea, nasopharyngitis, sinusitis, cough, dyspnea, upper respiratory tract infection, bronchitis, urinary tract infection, vulvovaginal mycotic infection, new onset or worsening diabetes, neurocognitive disorders, vertigo, increase in blood creatinine level, decrease in glomerular filtration rate, creatine kinase (CK) elevation serum uric acid (SUA) elevation, and liver enzyme (transaminase and gamma-glutamyl transferase) elevation. All the verbatim terms for the AEs were coded to preferred term and System Organ Class with the use of the Medical Dictionary for Regulatory Activities (MedDRA).

Missing or unpublished data were sought by trying to contact authors or sponsors via e-mail, and, in cases of no response, repeated messages were sent. Data extraction and database typing were performed by 2 authors (AFGC and FF) and reviewed by a third author (MB) before the final analysis. Doubts were resolved by mutual agreement among the authors.

Risk of bias evaluation

A systematic evaluation of risk of bias in the included studies was performed using the Cochrane tool [11]. The items used were the following: adequacy of sequence generation, blinding, addressing of dropouts (incomplete outcome data), allocation concealment, selective outcome reporting, and other probable sources of bias [12]. Risk of bias assessment was performed by 2 reviewers (FF and AFGC) independently; disagreements were resolved by a consensus-based discussion. Each item was judged as high, low, or unclear risk of bias. A trial with high risk of bias in the randomization or blinding items was judged as having high risk of bias overall.

Data synthesis

All analyses were performed with Comprehensive Meta-Analysis (CMA) version 3 software (Biostat, Englewood, NJ) [13]. Changes in continuous outcomes were calculated for each study arm by subtracting the value at baseline from the one after intervention. All values were expressed as percent change from baseline. Standard deviations (SDs) of the mean differences (MDs) were obtained as follows, per Follmann and colleagues [14]: SD = √[SD_pre² + SD_post² − (2R × SD_pre × SD_post)], assuming a correlation coefficient (R) of 0.5. If the outcome measures were reported in the original articles as median and interquartile range (or 95% confidence interval [CI]), mean and SD values were obtained as described by Wan et al. [15]. In case standard error of the mean (SEM) was only reported as a dispersion measure, SD was estimated using the following formula: SD = SEM × √n, with n being the number of individuals. To handle the double-counting problem in trials comparing different treatments against a single control group, individuals within the control group were divided by the required comparisons.

Meta-analyses were conducted using a fixed-effect model or a random-effect model (using the DerSimonian–Laird method) and the generic inverse variance method based on the moderately low (<50%) or high (≥50%) inter-study heterogeneity, which was quantitatively assessed using the Higgins index (I²) [16]. Effect sizes for lipid and hsCRP changes were expressed as MDs and 95% CIs. For safety analyses, odds ratios (ORs) and 95% CIs were calculated using the Mantel–Haenszel method [17]. If 1 or more outcomes could not be extracted from a study, the study was removed from the analysis involving those outcomes. AEs were included in the analysis only if occurring in at least 2 of the selected clinical trials. The efficacy analysis was performed on the safety population; the analysis of safety data was based on the intention-to-treat population.

For the purpose of evaluating the influence of each study on the overall effect size, sensitivity analysis was conducted using the leave-one-out method (i.e., repeating the analysis after omitting 1 study at a time) [18]. Two-sided p-values ≤ 0.05 were considered statistically significant for all tests.

If statistical heterogeneity was detected, attempts to identify the sources of heterogeneity and potential publication biases were made through the visual inspection of Begg’s funnel plot asymmetry, and carrying out the Begg’s rank correlation test and Egger’s linear regression test [19]. The Duval and Tweedie “trim and fill” method was used to adjust the analysis for the effects of publication bias [20]. In case of a significant result, the number of potentially missing studies required to make the p-value non-significant was estimated by using the classical fail-safe N method as another marker of publication bias. Two-sided p-values ≤ 0.05 were considered statistically significant.

Results

Flow and characteristics of the included studies

We identified 248 published abstracts. Of these, 238 were excluded because they were not original articles. All the other 10 studies met the inclusion criteria and were carefully assessed and reviewed. On the basis of the established eligibility criteria, all 10 RCTs were included in the meta-analysis [9,21–29]. The study selection process is shown in Fig 1.

Fig 1 — Data were pooled from 10 trials comprising 26 treatment arms, which included overall 3,788 individuals, with 2,460 in the active arm and 1,328 in the control arm.

Eligible studies were published between 2013 and 2019. Follow-up periods ranged between 4 and 52 weeks, and several treatment schedules were tested. All trials were parallel and multicenter [9,21–26,28,29] or single-center [27]. Enrolled individuals were statin-intolerant individuals [9,21,24,28], patients with type 2 diabetes [21,27], or patients affected by hypercholesterolemia despite statin treatment [21–23,25,26,29]. The main characteristics of the selected studies are summarized in Table 1.

Table 1. Main characteristics of the selected studies.

Study	First author, year [reference]	Study design	Main inclusion criteria	Primary outcomes	Treatment duration	Study groups	Patients, n	Age (years), mean ± SD	Female, n (%)	Average change in LDL-C from baseline
NCT03337308	Ballantyne, 2019 [21]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III clinical study	≥18 years of age; high risk for CVD; LDL-C ≥ 2.4 mmol/l for ASCVD or HeFH patients and LDL-C ≥ 3.4 mmol/l for patients with multiple CVD risk factors; TGs < 5.6 mmol/l; maximally tolerated lipid-lowering therapy	Percent change in LDL-C	12 weeks	Bempedoic acid 180 mg/day and ezetimibe 10 mg/day	86	62.2 ± 9.5	44 (51.2%)	−36.2%
						Ezetimibe 10 mg/day	86	65.1 ± 8.4	43 (50.0%)	−23.2%
						Bempedoic acid 180 mg/day	88	65.2 ± 9.8	48 (54.5%)	−17.2%
						Placebo	41	65.4 ± 10.8	17 (41.5%)	+1.8%
NCT02659397	Lalwani, 2019 [22]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase II clinical study	18–70 years of age; BMI ≥ 18 kg/m² and ≤40 kg/m²; no history of CVD; treatment with atorvastatin 80 mg/day	Percent change in LDL-C from baseline to week 4; fold change in C_max from baseline to week 2; fold change in AUC from baseline to week 2	4 weeks	Bempedoic acid 180 mg/day	45	58 (10)^*	21 (51.2%)	−13.3%
NCT02659397	Lalwani, 2019 [22]				4 weeks	Placebo	23	58 (8)^*	10 (43.5%)	+9.2%
CLEAR Serenity (NCT02988115)	Laufs, 2019 [9]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III clinical study	Men and postmenopausal or surgically sterile women; ≥18 years of age; history of intolerance of ≥2 statins; LDL-C ≥ 3.4 mmol/l for primary prevention patients and ≥2.4 mmol/l for HeFH patients	Percent change in LDL-C from baseline to week 12	24 weeks	Bempedoic acid 180 mg/day	234	65.2 ± 9.7	133 (56.8%)	−23.6%^°
CLEAR Serenity (NCT02988115)	Laufs, 2019 [9]			Percent change in LDL-C from baseline to week 12	24 weeks	Placebo	111	65.1 ± 9.2	61 (55%)	−1.3%^°
CLEAR Harmony (NCT02666664)	Ray, 2019 [23]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III clinical study	Men and postmenopausal or surgically sterile women; ≥18 years of age; high CV risk; maximally tolerated lipid-lowering therapy; LDL-C ≥ 1.8 mmol/l	Overall safety, assessed according to the incidence of adverse events and changes in safety laboratory variables	52 weeks	Bempedoic acid 180 mg/day	1,487	65.8 ± 9.1	389 (26.1%)	−12.6%
CLEAR Harmony (NCT02666664)	Ray, 2019 [23]				52 weeks	Placebo	742	66.8 ± 8.6	213 (28.7%)	+1.1%
CLEAR Tranquility (NCT03001076)	Ballantyne, 2018 [24]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase III clinical study	≥18 years of age; history of intolerance to statin; low-dose statin therapy or no statin therapy; LDL-C ≥ 2.4 mmol/l	Percent change in LDL-C	12 weeks	Bempedoic acid 180 mg/day	181	63.8 ± 10.8	109 (60.2%)	−23.5%
CLEAR Tranquility (NCT03001076)	Ballantyne, 2018 [24]			Percent change in LDL-C	12 weeks	Placebo	88	63.7 ± 11.3	56 (63.6%)	+5.2%
NCT02072161	Ballantyne, 2016 [25]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase IIb clinical study	18–80 years of age; BMI ≥ 18 kg/m² and ≤45 kg/m²; statin therapy; LDL-C ≥ 3 mmol/l and ≤5.7 mmol/l; TGs ≤ 4.5 mmol/l	Percent change in LDL-C	12 weeks	Bempedoic acid 180 mg/day	45	57 ± 10	31 (69%)	−24.3%
						Bempedoic acid 120 mg/day	44	59 ± 9	26 (61%)	−17.3%
						Placebo	45	56 ± 10	22 (49%)	−4.2%
NCT01941836	Thompson, 2016 [26]	Multicenter, randomized, double-blind, controlled, parallel-group, phase IIb clinical study	18–80 years of age; LDL-C ≥ 3.4 mmol/l and ≤5.7 mmol/l; TGs ≤ 4.5 mmol/l; BMI ≥ 18 kg/m² and ≤45 kg/m²	Percent change in LDL-C	12 weeks	Bempedoic acid 180 mg/day and ezetimibe 10 mg/day	24	59 ± 9	13 (54.2%)	−48.2%
						Bempedoic acid 120 mg/day and ezetimibe 10 mg/day	26	59 ± 10	14 (54%)	−43.3%
						Ezetimibe 10 mg/day	99	60 ± 10	52 (51.5%)	−21.2%
NCT01607294	Gutierrez, 2014 [27]	Single-center, randomized, double-blind, placebo-controlled, parallel-group, phase II clinical study	Type 2 diabetes; low risk for CVD; 18–70 years of age; LDL-C ≥ 2.4 mmol/l; BMI ≥ 25 kg/m² and ≤35 kg/m²	Percent change in LDL-C	4 weeks	Bempedoic acid 80 mg/day for 2 weeks followed by bempedoic acid 120 mg/day for 2 weeks	30	55.3 ± 6.9	13 (43.4%)	−42.9%
NCT01607294	Gutierrez, 2014 [27]			Percent change in LDL-C	4 weeks	Placebo	30	56.0 ± 9.9	10 (33.3%)	−4.3%
NCT01751984	Thompson, 2015 [28]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase II clinical study	Men and postmenopausal or surgically sterile women; 18–80 years of age; history of intolerance ≥1 statin; LDL-C ≥ 2.4 mmol/l and ≤5.7 mmol/l; TGs < 4 mmol/l; BMI ≥ 18 kg/m² and ≤40 kg/m²	Percent change in LDL-C	8 weeks	Bempedoic acid 60 mg/day for 2 weeks followed by increasing dose at 2-week intervals to 120, 180, and 240 mg/day	37	64 ± 5	17 (46%)	−32.5%
NCT01751984	Thompson, 2015 [28]			Percent change in LDL-C	8 weeks	Placebo	19	60 ± 8	11 (58%)	−3.3%
NCT01262638	Ballantyne, 2013 [29]	Multicenter, randomized, double-blind, placebo-controlled, parallel-group, phase II clinical study	18–80 years of age; LDL-C ≥ 3.4 mmol/l and ≤5.2 mmol/l; TGs < 4.5 mmol/l; BMI ≥ 18 kg/m² and ≤35 kg/m²	Percent change in LDL-C	12 weeks	Bempedoic acid 120 mg/day	44	57 ± 10	19 (43%)	−26.6%
						Bempedoic acid 80 mg/day	44	59 ± 9	21 (48%)	−25.4%
						Bempedoic acid 40 mg/day	45	58 ± 9	26 (58%)	−17.9%
						Placebo	44	56 ± 10	13 (30%)	−2.1%

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*Expressed as median (standard deviation).

°After 12 weeks of treatment.

ASCVD, atherosclerotic cardiovascular disease; AUC, area under the curve; BMI, body mass index; C_max, peak plasma concentration; CV, cardiovascular; CVD, cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; TG, triglyceride.

Risk of bias evaluation

The studies reported sufficient information regarding sequence generation, allocation concealment, blinding of participants, personnel, and outcome assessment. Details of the risk of bias evaluation are reported in Table 2.

Table 2. Risk of bias evaluation of the studies according to Cochrane guidelines.

First author, year [reference]	Sequence generation	Allocation concealment	Blinding of participants, personnel, and outcome assessment	Incomplete outcome data	Selective outcome reporting	Other potential threats to validity
Ballantyne, 2019 [21]	L	L	L	H	U	U
Lalwani, 2019 [22]	L	L	L	L	L	L
Laufs, 2019 [9]	L	L	L	L	L	L
Ray, 2019 [23]	L	L	L	L	L	L
Ballantyne, 2018 [24]	L	L	L	L	L	L
Ballantyne, 2016 [25]	L	L	L	L	L	L
Thompson, 2016 [26]	L	L	L	L	L	L
Gutierrez, 2014 [27]	L	L	L	L	L	L
Thompson, 2015 [28]	L	L	L	L	L	L
Ballantyne, 2013 [29]	L	L	L	L	L	L

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H, high risk of bias; L, low risk of bias; U, unclear risk of bias.

Effect of bempedoic acid on selected laboratory parameters

Meta-analysis of available data showed that bempedoic acid significantly reduced TC (n = 3,485; MD −14.94%; 95% CI −17.31%, −12.57%; p < 0.001; I² = 76.1%) (Fig 2), non-HDL-C (n = 3,485; MD −18.17%; 95% CI −21.14%, −15.19%; p < 0.001; I² = 87.2%) (Fig 3), LDL-C (n = 3,483; MD −22.94%; 95% CI −26.63%, −19.25%; p < 0.001; I² = 77.3%) (Fig 4), LDL particle number (n = 441; MD −20.67%; 95% CI −23.84%, −17.48%; p < 0.001; I² = 0%) (Fig 5), Apo B (n = 3,402; MD −15.18%; 95% CI −17.41%, −12.95%; p < 0.001; I² = 81.4%) (Fig 6), HDL-C (n = 3,453; MD −5.83%; 95% CI −6.14%, −5.52%; p < 0.001; I² = 33.4%) (Fig 7), and hsCRP (n = 3,179; MD −27.03%; 95% CI −31.42%, −22.64%; p < 0.001; I² = 0%) (Fig 8). Furthermore, bempedoic acid had a barely detectable significant effect on HDL-C particle number (n = 271; MD −3.21%; 95% CI −6.40%, −0.02%; p = 0.049; I² = 43.3%) (Fig 9).

There were no significant effects on TGs (n = 2,954; MD −1.51%; 95% CI −3.75%, 0.74%; p = 0.189; I² = 15.1%) (Fig 10), VLDL particle number (n = 271; MD 3.79%; 95% CI −9.81%, 17.39%; p = 0.585; I² = 35.1%) (Fig 11), and Apo A-1 (n = 382; MD −1.83%; 95% CI −5.23%, 1.56%; p = 0.290; I² = 50.1%) (Fig 12). When the largest study (the CLEAR Harmony trial) [23] was excluded from the meta-analysis, all the effect sizes were similar (S1 Table). Furthermore, the effect sizes were robust in the leave-one-out sensitivity analysis (S1–S4 Figs) and not mainly driven by a single study.

Visual inspection of Begg’s funnel plots did not reveal any asymmetry, suggesting no publication bias for the effect of bempedoic acid on the investigated parameters (S6 Fig).

Duval and Tweedie’s “trim and fill” method yielded 1 potentially missing study on the left side of the plot for TC, increasing the effect size to −15.27% (95% CI −17.61%, −12.92%); 4 potentially missing studies on the left side of the plot for HDL-C, lowering the effect size to −5.88% (95% CI −6.18%, −5.57%); 1 potentially missing study on the right side of the plot for HDL particle number, lowering the effect size to −1.86% (95% CI −4.86%, 1.13%); 4 potentially missing studies on the left side of the plot for non-HDL-C, increasing the effect size to −20.15% (95% CI −23.73%, −16.57%); 3 potentially missing studies on the left side of the plot for LDL-C, increasing the effect size to −25.17% (95% CI −29.55%, −20.79%); 2 potentially missing studies on the left side of the plot for LDL particle number, lowering the effect size to −21.85% (95% CI −24.74%, −18.96%); 1 potentially missing study on the right side of the funnel for VLDL particle number, increasing the effect size to 8.55% (95% CI −4.01%, 21.11%); 2 potentially missing studies on the left side of the plot for Apo A-1, lowering the effect size to −3.77% (95% CI −7.33%, −0.21%); and 3 potentially missing studies on the right side of the plot for hsCRP, lowering the effect size to −25.69% (95% CI −29.89%, −21.48%). However, neither Begg’s rank correlation nor Egger’s linear regression confirmed the presence of publication bias for the analyses (p > 0.05 for all) (S2 Table).

The classic fail-safe N test suggested that the following number of studies with negative results would be needed to bring the estimated effect size for each outcome to a non-significant level: 2,280 studies for TC (p < 0.001 for the test), 838 studies for HDL-C (p < 0.001 for the test), 2 studies for HDL particle number (p = 0.017 for the test), 2,004 studies for non-HDL-C (p < 0.001 for the test), 2,053 studies for LDL-C (p < 0.001 for the test), 263 studies for LDL particle number (p < 0.001 for the test), 1,308 studies for Apo B (p < 0.001 for the test), and 188 studies for hsCRP (p < 0.001 for the test). The individual analyses are included in S3 Table.

Safety analysis

Bempedoic acid was positively associated with an increased risk of discontinuation of treatment (n = 3,731; OR 1.37; 95% CI 1.06, 1.76; p = 0.015; I² = 0%), elevated SUA (n = 569; OR 3.55; 95% CI 1.03, 12.27; p = 0.045; I² = 0%), elevated liver enzymes (n = 2,363; OR 4.28; 95% CI 1.34, 13.71; p = 0.014; I² = 0%), and elevated CK (n = 2,718; OR 3.79; 95% CI 1.06, 13.51; p = 0.04; I² = 0%), but it was strongly associated with a decreased risk of new onset or worsening diabetes (n = 2,498; OR 0.59; 95% CI 0.39, 0.90; p = 0.01; I² = 0%) (Fig 13).

These findings were robust in the leave-one-out sensitivity analyses (S6 Fig). However, when the data from the largest study (the CLEAR Harmony trial) [23] were excluded from the meta-analysis, the effect sizes for the safety outcomes lost their statistical significance (S1 Table).

The incidence of the other AEs did not differ between groups (S4 Table). Considering the reasons for treatment discontinuation in included trials that reported all or part of them (S5 Table), it was not possible to identify the responsible reasons of the effect size of Fig 6 (S7 Fig).

Visually, the funnel plot of standard error by log OR was slightly asymmetric only for risk of discontinuation of treatment. This asymmetry was imputed to 6 potentially missing studies on the right side of the funnel plot, increasing the estimated risk to 1.55 (95% CI 1.22, 1.97) (S8 Fig). The presence of publication bias for the analysis was confirmed by Egger’s linear regression (p = 0.005), but not by Begg’s rank correlation (p = 0.298). The classic fail-safe N test suggested that 1 study with a negative result would be needed to bring the estimated risk of CK elevation to a non-significant level (p = 0.042 for the test), and 2 studies with negative results would be needed to bring the estimated risk of transaminase elevation to a non-significant level (p = 0.021 for the test). The individual analyses are included in S6 Table.

Discussion

Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) represent the first-line treatment for dyslipidemia, being able to reduce LDL-C by 30%–50% and subsequently decrease the incidence of CV events [30]. Despite the highly favorable benefit/risk profile of statins, a large number of patients are statin intolerant or need additional lipid-lowering drugs to reach optimal LDL-C levels [3]. The current meta-analysis shows that bempedoic acid safely reduces LDL-C levels by about 23%, suggesting that it might be considered as an effective alternative or add-on therapy to statins or ezetimibe.

About 31%–49% or more of patients with hyperlipidemia do not achieve LDL-C goals with current lipid-lowering therapies [31,32], and more than half of patients stop statin treatment within 1 year of initiation [33]. Sixty percent of patients who discontinue statins report different symptoms of drug intolerance as the main reason for discontinuation [34]. Statin intolerance, usually characterized by myalgia, myositis, and/or myopathy, occurs in 2%–15% of users, the estimate being strongly variable in epidemiological and rechallenging studies [35,36]. Furthermore, large meta-analyses showed that statin treatment is associated with a 9%–13% increase in risk of developing diabetes [37]. However, scientifically unsupported concerns about statin safety spread by mass media lead to the formation of a negative image of these drugs and increase of their cessation rate [38].

Additional treatments of dyslipidemia include ezetimibe (second-line) and fenofibrate (third-line). Ezetimibe, in combination with statin therapy, lowers LDL-C by an additional 20% or so [39] and significantly reduces the risk of major adverse CV events, non-fatal myocardial infarction, and non-fatal stroke compared with statins alone, with less or no effect on fatal endpoints [40]. A simulation based on adding ezetimibe in a huge statin-treated cohort suggests that the percentage of patients with LDL-C > 1.8 mmol/l and >2.4 mmol/l would fall from 65% to 38% and from 25% to 12%, respectively [41].

Fibrates are less effective on LDL-C levels, with their main indication being moderate-to-severe hypertriglyceridemia, such that they are rarely used in cardiology settings. However, a large meta-analysis of 16,112 patients showed evidence for a protective effect compared to placebo for the primary composite outcome of non-fatal myocardial infarction, non-fatal stroke, and vascular death [42]. Besides, patients with very high baseline LDL-C level or very high or extreme global CV risk need additional lipid-lowering drugs to optimize the lipid profile [43], especially in light of the most recent international recommendations [44,45]. Monoclonal antibodies that target proprotein convertase subtilisin/kexin type 9 (PCSK9) have recently been demonstrated to dramatically reduce LDL-C level (even over 60%) in the majority of cases, while significantly reducing CV risk; however, their cost–benefit ratio is yet under discussion, and in many countries their use is limited due to strict reimbursement rules [46]. In this context, there is yet place for the development of new less-expensive, effective/safe lipid-lowering drugs.

By analyzing data from 10 phase II and phase III RCTs including a total of 3,788 patients, we confirmed that bempedoic acid significantly reduced TC (by 15%), non-HDL-C (by 18.2%), LDL-C (by 22.9%), LDL particle number (by 20.7%), Apo B (by 15.2%), and hsCRP (by 27%), while negatively affecting serum levels of HDL-C (−5.8%) and HDL particle number (−3.2%). These findings strengthen the unpowered data previously reported by Wang et al., based on only 625 patients [47]. These findings could also be quantitatively relevant, since they have usually been obtained when bempedoic acid is administered on top of an effective lipid-lowering treatment, with a quite good safety and tolerability profile.

Our results also confirmed that bempedoic acid therapy is overall safe and well tolerated, with no significant increase of serious AEs. However, an increase of drug discontinuation and elevations of SUA, transaminase, and CK were observed. The detailed analysis of the reasons for discontinuation (see S5 Table) reported in the available trials does not give any clear pattern that could explain the 37% increased risk of discontinuation of bempedoic acid in comparison to placebo; this issue, however, needs to be further investigated. As for the other adverse effects possibly related to bempedoic acid, it is important to emphasize that in the 4 trials where CK increase was reported, it was observed in only 16 patients (of 1,792 investigated; 0.9%), and only single patients had a repeated and confirmed CK elevation greater than 5 times the upper limit of normal. More data with longer follow-up are also necessary to confirm the risk of SUA increase with bempedoic acid (observed in only 3 trials, where SUA increase was observed in 18/354 [5%]), as well as the risk of transaminase increase (observed in 5 trials, where transaminase increase was observed in only 1.1% of patients [20/1,823] in active-treated group). It is also worth emphasizing that bempedoic acid, due to its mechanism of action, does not increase the risk muscle-related side-effects and significantly reduces the risk of worsening or new onset diabetes by about 40% (however, based only on 2 available studies)—AEs that might be relatively often observed in statin trials, especially for high- and very-high-risk patients requiring intense therapy.

In this context, bempedoic acid seems to be an interesting option as an overall safe drug to be easily associated to statins and ezetimibe. In particular, the drug will be marketed as monotherapy or in a single pill with ezetimibe for the management of statin-intolerant patients. Considering the different mechanism of action of bempedoic acid and ezetimibe, the high safety profile of both drugs, and the lack of interaction risk between them, it is expected that this association will be a relatively effective and safe lipid-lowering treatment.

The main limitation of this meta-analysis is related to the relatively small number of patients involved in the studies, which were often short or middle term, as well as their heterogeneity (including different populations that were investigated, i.e., patients with type 2 diabetes, hypercholesterolemia, or statin intolerance). Moreover, heterogeneity of effects is moderate to large across most of the biochemical outcomes. Data on decreased CV events and mortality are lacking for bempedoic acid as well [48].

In conclusion, the current meta-analysis demonstrates an acceptable safety profile and multiple positive effects of bempedoic acid on lipid profile and hsCRP serum levels.

Further data on the cost–benefit efficacy of bempedoic acid treatment will come from the CLEAR Outcomes study, a phase III, event-driven, randomised, multicenter, double-blind, placebo-controlled trial designed to evaluate whether treatment with bempedoic acid reduces the risk of CV events. The primary endpoint of the study is the effect of bempedoic acid on major adverse CV events (CV death, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization). The enrollment ended in November 2019 [49].

Supporting information

S1 PRISMA Checklist. PRISMA Checklist.

(DOC)

Click here for additional data file.^{(57.5KB, doc)}

S1 Data. Summary data for all included studies.

(XLS)

Click here for additional data file.^{(90.5KB, xls)}

S1 Fig. Forest plots showing leave-one-out for TC, non-HDL-C, and TG.

(TIF)

Click here for additional data file.^{(1.8MB, tif)}

S2 Fig. Forest plots showing leave-one-out for LDL-C, LDL particle number, VLDL particle number, and Apo B.

(TIF)

Click here for additional data file.^{(2.1MB, tif)}

S3 Fig. Forest plots showing leave-one-out for HDL-C, HDL particle number and Apo A-1.

(TIF)

Click here for additional data file.^{(1.5MB, tif)}

S4 Fig. Forest plots showing leave-one-out for hsCRP.

(TIF)

Click here for additional data file.^{(461.3KB, tif)}

S5 Fig. Funnel plots detailing publication bias in the studies reporting the effect of ETC-1002 treatment on serum lipids and hsCRP concentrations.

(TIF)

Click here for additional data file.^{(813.6KB, tif)}

S6 Fig. Plot showing leave-one-out sensitivity analysis for safety analysis.

(TIF)

Click here for additional data file.^{(4.3MB, tif)}

S7 Fig. Plot showing reasons for discontinuation to treatment as reported in the studies.

*Data referring to statin-intolerant patients; ^§ Data referring to statin-tolerant patients.

(TIF)

Click here for additional data file.^{(141.2KB, tif)}

S8 Fig. Funnel plot detailing publication bias in the safety analysis.

(TIF)

Click here for additional data file.^{(330.9KB, tif)}

S1 Table. Meta-analysis’ findings after excluding the CLEAR Harmony study.

(DOC)

Click here for additional data file.^{(38KB, doc)}

S2 Table. Begg’s rank correlation nor Egger’s linear regression tests.

(DOC)

Click here for additional data file.^{(39.5KB, doc)}

S3 Table. Classic fail-safe N results for the efficacy analyses.

(DOC)

Click here for additional data file.^{(30KB, doc)}

S4 Table. Adverse events occurred in at least 2 clinical trials.

AEs = Adverse events.

(DOC)

Click here for additional data file.^{(55KB, doc)}

S5 Table. Reasons of discontinuation to treatments as reported by the studies.

(DOC)

Click here for additional data file.^{(55KB, doc)}

S6 Table. Classic fail-safe N results for the safety analyses.

(DOC)

Click here for additional data file.^{(27KB, doc)}

Acknowledgments

The meta-analysis was prepared within the Lipid and Blood Pressure Meta-Analysis Collaboration (LBPMC) Group (http://www.lbpmcgroup.umed.pl).

The members of the International Lipid Expert Panel (ILEP) are F. Alnouri, F. Amar, A. G. Atanasov, G. Bajraktari, M. Banach, M. A. Bartlomiejczyk, B. Bjelakovic, E. Bruckert, A. Bielecka-Dabrowa, A. Cafferata, R. Ceska, A. F. G. Cicero, X. Collet, O. Descamps, N. Devaki, D. Djuric, R. Durst, M. V. Ezhov, Z. Fras, D. Gaita, S. von Haehling, A. V. Hernandez, S. R. Jones, J. Jozwiak, N. Kakauridze, N. Katsiki, A. Khera, K. Kostner, R. Kubilius, G. Latkovskis, G. B. J. Mancini, A. D. Marais, S. S. Martin, J. A. Martinez, M. Mazidi, D. P. Mikhailidis, E. Mirrakhimov, A. R. Miserez, O. Mitchenko, P. Moriarty, S. M. Nabavi, D. B. Panagiotakos, G. Paragh, D. Pella, P. E. Penson, Z. Petrulioniene, M. Pirro, A. Postadzhiyan, R. Puri, A. Reda, Ž. Reiner, J. Riadh, D. Richter, M. Rizzo, M. Ruscica, A. Sahebkar, N. Sattar, M. C. Serban, A. M. A. Shehab, A. B. Shek, C. R. Sirtori, C. Stefanutti, T. Tomasik, P. P. Toth, M. Viigimaa, D. Vinereanu, B. Vohnout, M. Vrablik, N. D. Wong, H. I. Yeh, J. Zhisheng, and A. Zirlik.

Abbreviations

ACLY: ATP citrate lyase
AE: adverse event
Apo: apolipoprotein
CI: confidence interval
CV: cardiovascular
CVD: cardiovascular disease
HDL-C: high-density lipoprotein cholesterol
hsCRP: high-sensitivity C-reactive protein
LDL-C: low-density lipoprotein cholesterol
MD: mean difference
OR: odds ratio
RCT: randomized controlled trial
SD: standard deviation
SUA: serum uric acid
TC: total cholesterol
TG: triglyceride
VLDL: very-low-density lipoprotein

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The authors received no specific funding for this work.

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PLoS Med. doi: 10.1371/journal.pmed.1003121.r001

Decision Letter 0

Adya Misra

24 Dec 2019

Dear Dr. Banach,

Thank you very much for submitting your manuscript "Efficacy and safety of bempedoic acid: a systematic review and meta-analysis of phase 2 and 3 randomized controlled trials" (PMEDICINE-D-19-03833) for consideration at PLOS Medicine.

Your paper was evaluated by a senior editor and discussed among all the editors here. It was also discussed with an academic editor with relevant expertise, and sent to independent reviewers, including a statistical reviewer. The reviews are appended at the bottom of this email and any accompanying reviewer attachments can be seen via the link below:

[LINK]

In light of these reviews, I am afraid that we will not be able to accept the manuscript for publication in the journal in its current form, but we would like to consider a revised version that addresses the reviewers' and editors' comments. Obviously we cannot make any decision about publication until we have seen the revised manuscript and your response, and we plan to seek re-review by one or more of the reviewers.

In revising the manuscript for further consideration, your revisions should address the specific points made by each reviewer and the editors. Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments, the changes you have made in the manuscript, and include either an excerpt of the revised text or the location (eg: page and line number) where each change can be found. Please submit a clean version of the paper as the main article file; a version with changes marked should be uploaded as a marked up manuscript.

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Please use the following link to submit the revised manuscript:

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Your article can be found in the "Submissions Needing Revision" folder.

To enhance the reproducibility of your results, we recommend that you deposit your laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. For instructions see http://journals.plos.org/plosmedicine/s/submission-guidelines#loc-methods.

Please ensure that the paper adheres to the PLOS Data Availability Policy (see http://journals.plos.org/plosmedicine/s/data-availability), which requires that all data underlying the study's findings be provided in a repository or as Supporting Information. For data residing with a third party, authors are required to provide instructions with contact information for obtaining the data. PLOS journals do not allow statements supported by "data not shown" or "unpublished results." For such statements, authors must provide supporting data or cite public sources that include it.

We look forward to receiving your revised manuscript.

Sincerely,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

-----------------------------------------------------------

Requests from the editors:

Title- please include a descriptor for bempedoic acid in the title such as “lipid lowering drug” or similar

At this stage, we ask that you include a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract. Please see our author guidelines for more information: https://journals.plos.org/plosmedicine/s/revising-your-manuscript#loc-author-summary

Abstract- in the background please provide a sentence about bempedoic acid use in humans in more accessible language. For example- has it been used to reduce LDL-c etc.

Abstract- methods and findings sections must be combined in PLOS Medicine style and the last sentence in this section should outline the limitations of your methodology

Abstract-please provide a sentence about the search, including dates and databases searched.

Abstract- please correct the typo in “mean differences”

Abstract- please provide 95% CI and p values for all the results reported in the abstract, not only the positive findings

Abstract- since you have investigated and reported on safety in the main manuscript, please include these findings in the abstract for greater transparency- in the methods, findings and conclusions sections

References- please use Vancouver style and provide references within square brackets throughout

Line 78- please revise to be more specific “showing and overall interesting impact of bempedoic acid on human lipid pattern”

Line 110- please elaborate “Studies that lacked a properly controlled design for bempedoic acid treatment were excluded”

Please revise “diabetics” to patients with type 2 diabetes. The same goes for hypercholestrolemics

Table 2- please provide annotations for all letters, L H and U.

Results- the effect on HDL particle number (p=0.049) cannot be described as “significant” along with those that were p<0.01. Please provide this result separately as it is so close to p=0.05

Please include a separate paragraph for the analysis on missing studies and the lowering of effect sizes. Please provide individual p values here along with the confidence intervals.

Line 243- “However, neither Begg’s rank correlation nor Egger’s linear

regression confirmed the presence of publication for the analyses (p>0·05 always)” please provide these analyses as supplementary information and please provide the exact p value instead of p>0.05

Please provide exact p values for the results on N tests and provide the individual analyses as supplementary information

Figure 1- several p values are p=0.000, please correct this to an appropriate p value of either p<0.001 or provide the exact p values if p>0.001. As pointed out by Reviewer 1, each meta-analysis should be provided in an individual figure for more precise plotting. You may choose to include some of these as supplementary figures as you see fit.

Figure 1 should be a flowchart of records screened in this study

Results- please include a sentence about the degree of heterogeneity observed and what was done to identify the sources of the heterogeneity.

Discussion- this sentence requires copyediting and a reference to support “Despite statins should be regarded as one of the major advances of modern preventive medicine, a large number of patients needs additional lipid lowering to reach the optimal LDL-C levels or is statin intolerant”

Discussion- it is unclear if this refers to the current submission? If so, this was not specifically studies in the SR/MA and should be removed “We showed that bempedoic acid might be such an effective alternative as an add-on to statins or ezetimibe or in monotherapy as it might reduce LDL-C levels by about 23% and inflammation level (hsCRP) by over 27% with acceptable overall tolerance”

Discussion focusses on statins and other treatments of dyslipidemia which should be provided in the introduction as a condensed paragraph. Please present and organize the Discussion as follows: a short, clear summary of the article's findings; what the study adds to existing research and where and why the results may differ from previous research; strengths and limitations of the study; implications and next steps for research, clinical practice, and/or public policy; one-paragraph conclusion.

Discussion- “Our results also confirmed that this therapy is overall safe and well tolerated, with no significant increase of serious adverse effects” this sentence is not supported by the results and must be revised to fully acknowledge the risk of discontinuation of treatment and other AEs as needed

Discussion- muscle related side effects were not studied in this SR/MA and therefore this sentence should be removed “It is also worth emphasizing that bempedoic acid, due to its mechanism of action, does not increase the risk muscle-related side effects and significantly reduce the risk of worsening or new onset diabetes by about 40% (however based only on two available studies), what might be relatively often observed in statin trials, especially for high and very high risk patients requiring intense therapy”

Discussion- a number of trials were short term or have not yet been completed. This should be included as a limitation more clearly

PRISMA checklist- please remove page numbers as these are likely to change and include sections or paragraphs

Supplementary information- Table S3 contains adverse events “general disorders” please include a more specific description.

Comments from the reviewers:

Reviewer #1: I confine my remarks to statisitical aspects of this paper

I have only a couple of minor points to fix before I can recommend publication.

Line 47 Insert "significant" between not and modify

Line 56 Instead of (or in addition to) ranks of causes, give the number dead or rate of death. Ranks have two problems in this context: 1) Something has to be the leading cause and 2) Ranks depend on how causes are divided up (is "cancer" one thing or many?)

Line 152 This is not the right format. It should be use the square root symbol, no parens is needed around the first two terms, the subscripts could be pre and post for brevity.

Line 153: On what basis was R = 0.5 chosen?

Table 2: What about H and U (in subscript)?

Figures: I can see why you did them this way, but I'd consdier a figure for each MA (so, figure 1 would be 3 figures); this would let you change the minima and maxima of the x-axis to allow more precise plotting. That would be 15 figures altogether, but the same ones, really. I'm not sure if that's better but I think it is. A simpler alterntative is to print them landscape instead of portrait

Peter Flom

Reviewer #2: The "Efficacy and safety of bempedoic acid: a systematic review and meta-analysis of phase 2 and 3 randomized controlled trials" is a systematic review and meta-analysis of ten studies, published between the years 2013 and 2019, including a total of 3788 subjects, with 2460 in the active-treated arm and 1328 in the control one. The main endpoint was the effect of bempedoic acid on lipid profile and high-sensitivity C-reactive protein (hsCRP) serum concentrations. For safety analyses, odds ratios (OR) and 95%CI were calculated using the Mantel-Haenszel method. According to this work, bempedoic acid significantly reduced total colesterol, non high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, LDL particle number, apolipoprotein B, HDL-cholesterol, and HDL-particle number. Bempedoic acid failed to modify triglycerides levels, very-low-density lipoprotein particle number and Apolipoprotein A-1. Secondary effects and possible causes of discontinuations were also exposed. The authors attempted a very ambitious work combining relevant literature regarding a novel drug that might play a significant role in dyslipidemia treatment in the future. The article shows several strenghts such as modern clinical relavance, an extended description of the statistical analysis, and that it serves as a generator of hypothesis for future inverstigations. The article structure should be improved along with clarification of some statements supporting results with scarce evidence.

A clearer structure separating main ideas by paragraphs are recommended highliting and separating the endpoints of efficacy and safety. The results concerning lipid profiles, hsCRP, are mixed and lost within the paragraphs, blended with other secondary endpoints.

According to the journal recommendations, systematic reviews registered in the PROSPERO database should provide the registry number in their abstract. State all authors´emails on the manuscript as well as author contributions. According to the journal publication guidelines, the corresponding author should have an ORCID ID adressed in the manuscript.

The writers are asked to indicate, within the methods section, if a review protocol exists, if and where it can be accessed, and, if so, provide a copy of the protocol as Supporting Information. Alternatively, the authors should include more information that clarifies and justifies their choice of methods. In line 121, the "adverse events" must be clearly stated, as so should be the "major cardiac adverse events" (death, heart failure...?) in line 122. When abstracting quantitative measures such as worsening diabetes or descrease in glomerular filtration rate, please describe how much change in levels is threshhold to categorize as an event.

With respect to the baseline characteristics of the evealuated studies summarized in table 1, the authors are off to a good start, however, it might be important to expose the main endpoints and results of the different studies.

In the results it might be usefull to highlight as to why exclude form the meta-analysis the data from the largest study (line 223, line 283).

With respect to the results shown in Table S2, there is a lot of data and the table fails to be comprehensible. May be pick those events with the most biological plausability.

While the discussion appears to be sound, the prioritization of ideas is unclear for it should start with a brief summary of the main findings, following journal recommendations, giving the reader a quick glance of the main take-home message. The discussion should give a concise insight and be tightly argued, supporting the main results of the metaanalysis with previous litarature, which is not elaborated in the discussion.

Only two comments of the effect of acid bempedoic are written about the hsCPR, mixed with the results concerning the lipid profile; a separate paragraph might emphasize the importance of this finding. A clarification as to if secondary causes of change in CPR levels where excluded is advised.

It would be interesting to explain the etiology of the CK increase in patients with bempedoic acid for it does not act on muscle tissue enzime pathways (lines 353-356 and later 361-362).

The authors aim to demonstrate an effect of bempedoic acid on diabetes, however, the data does not fully support this conclusion, specifically supported by two studies with biases of their own (figure 5, line 362).

Please explain the phrase "The detailed analysis of the discontinuation reasons reported in the available trials does not give any clear pattern, which could explain 37% risk increase of discontinuation of bempedoic acid in comparison to placebo" (line 350-352).

The authors should revise the language to improve readability, with emphasis in the discussion.

Reviewer #3: Standard meta-analysis of phase 2 & 3 studies of bempedoic acid for both efficacy and safety. Uses standard methodology with a systematic review and complete data synthesis. Early stage analysis given absence of significant additional data from on-going phase 3 studies and end-point studies.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. doi: 10.1371/journal.pmed.1003121.r002

Decision Letter 1

Adya Misra

6 Apr 2020

Dear Dr. Banach,

Thank you very much for re-submitting your manuscript "Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia:

a systematic review and meta-analysis of phase 2 and 3 randomized controlled trials" (PMEDICINE-D-19-03833R1) for review by PLOS Medicine.

I have discussed the paper with my colleagues and the academic editor and it was also seen again by xxx reviewers. I am pleased to say that provided the remaining editorial and production issues are dealt with we are planning to accept the paper for publication in the journal.

The remaining issues that need to be addressed are listed at the end of this email. Any accompanying reviewer attachments can be seen via the link below. Please take these into account before resubmitting your manuscript:

[LINK]

Our publications team (plosmedicine@plos.org) will be in touch shortly about the production requirements for your paper, and the link and deadline for resubmission. DO NOT RESUBMIT BEFORE YOU'VE RECEIVED THE PRODUCTION REQUIREMENTS.

In revising the manuscript for further consideration here, please ensure you address the specific points made by each reviewer and the editors. In your rebuttal letter you should indicate your response to the reviewers' and editors' comments and the changes you have made in the manuscript. Please submit a clean version of the paper as the main article file. A version with changes marked must also be uploaded as a marked up manuscript file.

Please also check the guidelines for revised papers at http://journals.plos.org/plosmedicine/s/revising-your-manuscript for any that apply to your paper. If you haven't already, we ask that you provide a short, non-technical Author Summary of your research to make findings accessible to a wide audience that includes both scientists and non-scientists. The Author Summary should immediately follow the Abstract in your revised manuscript. This text is subject to editorial change and should be distinct from the scientific abstract.

We expect to receive your revised manuscript within 1 week. Please email us (plosmedicine@plos.org) if you have any questions or concerns.

We ask every co-author listed on the manuscript to fill in a contributing author statement. If any of the co-authors have not filled in the statement, we will remind them to do so when the paper is revised. If all statements are not completed in a timely fashion this could hold up the re-review process. Should there be a problem getting one of your co-authors to fill in a statement we will be in contact. YOU MUST NOT ADD OR REMOVE AUTHORS UNLESS YOU HAVE ALERTED THE EDITOR HANDLING THE MANUSCRIPT TO THE CHANGE AND THEY SPECIFICALLY HAVE AGREED TO IT.

If you have any questions in the meantime, please contact me or the journal staff on plosmedicine@plos.org.

We look forward to receiving the revised manuscript by Apr 13 2020 11:59PM.

Sincerely,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

------------------------------------------------------------

Requests from Editors:

Title- Please revise title to “Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: a systematic review and meta-analysis”

Abstract

Methods and findings- please move this sentence earlier in the section “We included 10 RCTs (n=3788) comprising 26 arms [active arm (n=2460); control arm (n=1328)]”.

Exact p-values must be provided unless p<0.001

Conclusion- please begin with “our results show” or similar

Author summary

The section “why was this study done” does not clearly outline the need for this meta-analysis in plain language. Please add a sentence or two about why LDL-C treatment is important, for instance.

Please also revise “is hardly to achieve” to “is hard to achieve”

Data availability

The Data Availability Statement (DAS) requires revision. For each data source used in your study:

a) If the data are freely or publicly available, note this and state the location of the data: within the paper, in Supporting Information files, or in a public repository (include the DOI or accession number).

b) If the data are owned by a third party but freely available upon request, please note this and state the owner of the data set and contact information for data requests (web or email address). Note that a study author cannot be the contact person for the data.

c) If the data are not freely available, please describe briefly the ethical, legal, or contractual restriction that prevents you from sharing it. Please also include an appropriate contact (web or email address) for inquiries (again, this cannot be a study author).

References- please place the full stop after the square brackets

Line 105- “so that” should be revised to “such that”

Methods

Please provide detailed search terms used along with limiters such that the search may be replicated. This can be provided as an SI file. Please reference the full list of search terms in SI file xxx

Please also add a sentence noting that this manuscript is reported according to PRISMA guidelines and the checklist has been provided as SI file xx

Results

Line 371 onwards please provide exact p values, p<0.05 is not permitted

Line 413 should be revised to “…patients need additional lipid…”

Line 423 ought to say “criticism of statins in the media…”

Please ensure that you provide a clean version of the manuscript along with one that has tracked changes. The current PDF contains highlighted text which should be un-highlighted.

Comments from Reviewers:

Reviewer #1: The authors have addressed my concerns and I now recommend publication

Peter Flom

Reviewer #3: The authors have revised many aspecst of the manuscript satisfactorily.

The authors downplay the effectiveness, safety and significance of ezetimibe therapy. This is the second line after statins for treatment of LDL-C in all major guidelines (USA, Europe etc). Fibrates are very much a third line therapy and have minimal use in cardiology services being more comonly used in the management of hypertriglyceridemia. Indeed a formualtion bempedoic acid with ezetimibe is proposed for marketing. This section needs to be re-written and the safety and efficacy of the combination described.

Statin intolerance occurs in 1-2% of users in systematic rechallenge studies. The quoted figure of 20-30% was challenged and discredited by both US and European Society consensus groups on statin myopathy and intolerance as well as in reviews of statin tolerability. Indeed in the PCSK-9 statin intolerance studies about 15% of patients recruited on the basis of intolerance to 3 statins recorded myalgia on placebo treatment.

The authors state that 30% of patients did not achieve the 2009 US targets (LTAP study) but do not provide more up to date US or European data. There have been 2 iterations of guidelines since that date. The international DYSIS-2 (Gitt AK et al; Atherosclerosis. 2016 Dec;255:200 (n=57885 patints) and Ferriere J et al; Eur J Prev Cardiol. 2018 Dec;25(18):1966 ) study suggests 31-49% LDL-C target attainment in 2018. A simulation based on adding ezetimibe in this cohort suggests that the percentage of patients with LDL-C >1.8mmol/L (70mg/dl) and >2.4mmol/L (100 mg/dl) would fall from 65 to 38% and from 25 to 12%, respectively (De Ferrari GM et al. J Cardiovasc Med. 2018 Sep;19(9):485).

The statement about outcome trials is incorrect as is the statement about phase 3 studies. The authors should comment on the phase 3 CLEAR programme of trials on bempedoic acid https://www.esperion.com/pipeline/clinical-trials/ or through clinicaltrials.gov (with trial identifiers) which include descriptions of the 5 CLEAR trials comprising 3623 patients which follow standard protocols for phase 3 designs in the field of lipid-lowering established during the statin studies. Most of those trials are included in this meta-analysis (n=3543). Details of the CLEAR-outcomes study in phase 4 required for regulatory approval are available via the Esperion site and through clinicaltrials.gov. This study is now underway.

Any attachments provided with reviews can be seen via the following link:

[LINK]

PLoS Med. doi: 10.1371/journal.pmed.1003121.r003

Decision Letter 2

Adya Misra

9 Jun 2020

Dear Prof. Banach,

On behalf of my colleagues and the academic editor, Dr. Anthony Wierzbicki, I am delighted to inform you that your manuscript entitled "Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia:

a systematic review and meta-analysis" (PMEDICINE-D-19-03833R2) has been accepted for publication in PLOS Medicine.

PRODUCTION PROCESS

Before publication you will see the copyedited word document (in around 1-2 weeks from now) and a PDF galley proof shortly after that. The copyeditor will be in touch shortly before sending you the copyedited Word document. We will make some revisions at the copyediting stage to conform to our general style, and for clarification. When you receive this version you should check and revise it very carefully, including figures, tables, references, and supporting information, because corrections at the next stage (proofs) will be strictly limited to (1) errors in author names or affiliations, (2) errors of scientific fact that would cause misunderstandings to readers, and (3) printer's (introduced) errors.

If you are likely to be away when either this document or the proof is sent, please ensure we have contact information of a second person, as we will need you to respond quickly at each point.

PRESS

A selection of our articles each week are press released by the journal. You will be contacted nearer the time if we are press releasing your article in order to approve the content and check the contact information for journalists is correct. If your institution or institutions have a press office, please notify them about your upcoming paper at this point, to enable them to help maximize its impact.

PROFILE INFORMATION

Now that your manuscript has been accepted, please log into EM and update your profile. Go to https://www.editorialmanager.com/pmedicine, log in, and click on the "Update My Information" link at the top of the page. Please update your user information to ensure an efficient production and billing process.

Thank you again for submitting the manuscript to PLOS Medicine. We look forward to publishing it.

Best wishes,

Adya Misra, PhD

Senior Editor

PLOS Medicine

plosmedicine.org

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 PRISMA Checklist. PRISMA Checklist.

(DOC)

Click here for additional data file.^{(57.5KB, doc)}

S1 Data. Summary data for all included studies.

(XLS)

Click here for additional data file.^{(90.5KB, xls)}

S1 Fig. Forest plots showing leave-one-out for TC, non-HDL-C, and TG.

(TIF)

Click here for additional data file.^{(1.8MB, tif)}

S2 Fig. Forest plots showing leave-one-out for LDL-C, LDL particle number, VLDL particle number, and Apo B.

(TIF)

Click here for additional data file.^{(2.1MB, tif)}

S3 Fig. Forest plots showing leave-one-out for HDL-C, HDL particle number and Apo A-1.

(TIF)

Click here for additional data file.^{(1.5MB, tif)}

S4 Fig. Forest plots showing leave-one-out for hsCRP.

(TIF)

Click here for additional data file.^{(461.3KB, tif)}

S5 Fig. Funnel plots detailing publication bias in the studies reporting the effect of ETC-1002 treatment on serum lipids and hsCRP concentrations.

(TIF)

Click here for additional data file.^{(813.6KB, tif)}

S6 Fig. Plot showing leave-one-out sensitivity analysis for safety analysis.

(TIF)

Click here for additional data file.^{(4.3MB, tif)}

S7 Fig. Plot showing reasons for discontinuation to treatment as reported in the studies.

*Data referring to statin-intolerant patients; ^§ Data referring to statin-tolerant patients.

(TIF)

Click here for additional data file.^{(141.2KB, tif)}

S8 Fig. Funnel plot detailing publication bias in the safety analysis.

(TIF)

Click here for additional data file.^{(330.9KB, tif)}

S1 Table. Meta-analysis’ findings after excluding the CLEAR Harmony study.

(DOC)

Click here for additional data file.^{(38KB, doc)}

S2 Table. Begg’s rank correlation nor Egger’s linear regression tests.

(DOC)

Click here for additional data file.^{(39.5KB, doc)}

S3 Table. Classic fail-safe N results for the efficacy analyses.

(DOC)

Click here for additional data file.^{(30KB, doc)}

S4 Table. Adverse events occurred in at least 2 clinical trials.

AEs = Adverse events.

(DOC)

Click here for additional data file.^{(55KB, doc)}

S5 Table. Reasons of discontinuation to treatments as reported by the studies.

(DOC)

Click here for additional data file.^{(55KB, doc)}

S6 Table. Classic fail-safe N results for the safety analyses.

(DOC)

Click here for additional data file.^{(27KB, doc)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Efficacy and safety of bempedoic acid for the treatment of hypercholesterolemia: A systematic review and meta-analysis

Arrigo F G Cicero

Federica Fogacci

Adrian V Hernandez

Maciej Banach

Roles

Abstract

Background

Methods and findings

Conclusions

Author summary

Why was this study done?

What did the researchers do and find?

What do these findings mean?

Introduction

Methods

Search strategy

Study selection criteria

Data extraction

Risk of bias evaluation

Data synthesis

Results

Flow and characteristics of the included studies

Fig 1. Flow chart of the number of studies identified and included in the meta-analysis.

Table 1. Main characteristics of the selected studies.

Risk of bias evaluation

Table 2. Risk of bias evaluation of the studies according to Cochrane guidelines.

Effect of bempedoic acid on selected laboratory parameters

Fig 2. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of total cholesterol.

Fig 3. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of non-high-density lipoprotein (HDL) cholesterol.

Fig 4. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of low-density lipoprotein (LDL) cholesterol.

Fig 5. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of low-density lipoprotein (LDL) particle number.

Fig 6. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of apolipoprotein B.

Fig 7. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of high-density lipoprotein (HDL) cholesterol.

Fig 8. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of high-sensitivity C-reactive protein.

Fig 9. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of high-density lipoprotein (HDL) particle number.

Fig 10. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of triglycerides.

Fig 11. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of very-low-density lipoprotein (VLDL) particle number.

Fig 12. Forest plot displaying mean difference and 95% confidence intervals for the effect of bempedoic acid on plasma levels of apolipoprotein A-1.

Safety analysis

Fig 13. Forest plot comparing the risk of adverse events statistically associated with bempedoic acid treatment.

Discussion

Supporting information

Acknowledgments

Abbreviations

Data Availability

Funding Statement

References

Decision Letter 0

Adya Misra

Roles

Decision Letter 1

Adya Misra

Roles

Decision Letter 2

Adya Misra

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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