https://orcid.org/0000-0002-3189-6204
Abstract
Reduction of low-density lipoprotein cholesterol (LDL-C) decreases cardiovascular mortality and morbidity. Bempedoic acid represents a promising novel lipid-modifying agent for patients who cannot reach guideline recommended LDL-C goals or statin-intolerant patients, but data on safety and cardiovascular outcomes are limited. We therefore aimed to systematically review randomized controlled trials investigating bempedoic acid vs. placebo in patients with hyperlipidaemia.
A systematic search on the databases PubMed, Web of Science, and Embase until 20 March 2023 was performed. All randomized trials comparing bempedoic acid (180 mg daily) with placebo in patients with an indication for lipid-lowering therapy were included. As a primary endpoint, we analysed three-point major adverse cardiovascular events (MACEs) consisting of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. The analysis was carried out using the odds ratio (OR) as the outcome measure. Due to the expected heterogeneity across studies, a random-effects model was fitted to the data.
Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria. In total, these trials included 18 200 patients (9765 on bempedoic acid, 8435 on placebo). Bempedoic acid significantly reduced MACEs compared with placebo (OR 0.84 [95% confidence interval (CI) 0.76–0.96]; P < 0.001; I2 = 0%). The endpoint reduction was driven by a lower rate of non-fatal MI, whereas bempedoic acid had no significant effect on stroke (OR 0.86 [95% CI 0.69–1.08]; P = 0.20, I2 = 0%) and all-cause mortality (OR 1.19 [95% CI 0.73–1.93]; P = 0.49; I2 = 18%).
Bempedoic acid reduced non-fatal MI in patients with hyperlipidaemia, whereas it had no significant effect on stroke and all-cause mortality.
Introduction
Lowering low-density lipoprotein cholesterol (LDL-C) in patients with hyperlipidaemia is of utmost importance to reduce the risk of future major adverse cardiovascular events (MACEs).
Current guidelines recommend the treatment of patients with atherosclerotic cardiovascular disease (ASCVD) with a high-dose statin or the highest tolerated statin dose to achieve the recommended LDL-C goals.1,2 In primary and secondary prevention for patients at very high cardiovascular risk, an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.4 mmol/L (<55 mg/dL) are recommended, and for patients at high cardiovascular risk, an LDL-C reduction of ≥50% from baseline and an LDL-C goal of <1.8 mmol/L (<70 mg/dL) are recommended. If LDL-C goals cannot be achieved, a combination of the highest tolerated statin dose with ezetimibe is recommended. In secondary prevention and for patients with familial hyperlipidaemia (FH), the establishment of a PCSK9 inhibitor is recommended in addition to this combination, if LDL-C reduction is still insufficient.3
However, due to factual or—more frequently—subjectively perceived adverse musculoskeletal effects, many patients refuse or stop statin therapy. Accordingly, there is a need for alternative oral LDL-C lowering agents. In recent years, bempedoic acid has increasingly become the focus of clinical studies. Its mechanism of action is similar to statins as bempedoic acid inhibits ATP citrate lyase, which plays a role in the cholesterol synthesis pathway upstream to 3-hydroxy-3-methylglutaryl coenzyme A reductase, which is inhibited by statins.4 However, as a prodrug bempedoic acid is dependent on biotransformation by acyl–coenzyme A synthetase 1 in order to exert its pharmacological effects. Since acyl–coenzyme A synthetase 1 is present in hepatocytes but not in myocytes, bempedoic acid acts only in the liver and cannot cause musculoskeletal side effects.4–8
In this regard, bempedoic acid represents a promising approach to reduce LDL-C in statin-intolerant patients. Meanwhile, several randomized controlled clinical trials analysed the efficacy and safety of bempedoic acid as single therapy and as part of established lipid-lowering therapies, especially in statin-intolerant patients.4,6–21
These studies demonstrated a significant effect of bempedoic acid on LDL-C reduction and only few side effects, in particular gout, cholelithiasis and small increases in serum creatinine, uric acid, and hepatic-enzyme levels. Recently, a large randomized trial showed a lower risk of MACE with bempedoic acid vs. placebo in statin-intolerant patients.13
In order to further analyse the benefits and potential risks of bempedoic acid in hypercholesterolaemia patients, we performed a systematic review and meta-analysis of randomized clinical trials of bempedoic acid.
Methods
Reference search and study selection
The present analysis was performed following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The review protocol was registered in PROSPERO (ID: CRD42023414470). A systematic search on the main databases PubMed, Web of Science, and Embase until 20 March 2023 was performed. The following mesh terms and keywords were used: (bempedoic acid OR ETC-1002 OR ESP55016 OR ESP-55 016) AND (hypercholesterolemia OR hyperlipidaemia OR dyslipidaemia OR low-density lipoprotein cholesterol). Article bibliographies were additionally screened and relevant articles were added to the review process. All randomized trials comparing bempedoic acid (at a starting dose of 180 mg daily) with placebo in patients with an indication for LDL-C lowering therapy were included. The risk of bias in the eligible trials was independently evaluated using the revised Cochrane Collaboration's tool.22
Furthermore, we only included studies published in English and performed in humans. Two investigators independently screened all retrieved references by title and abstract, and checked references of full-text articles for other relevant studies and trials. Data extraction from full-text articles was performed independently by two investigators via a predefined data-recording form. Data on author, year of publication, number of participants, data on study drugs, endpoints, and patient characteristics were extracted.
Endpoints
As a primary endpoint, we analysed three-point MACEs consisting of cardiovascular death, non-fatal myocardial infarction (MI), or non-fatal stroke. As secondary endpoints, we investigated all-cause death, MI, stroke, and adverse events.
Statistical analysis
The analysis was carried out using the odds ratio as the outcome measure. Due to the expected heterogeneity across studies, a random-effects model was fitted to the data. The amount of heterogeneity (i.e. Tau2) was estimated using the DerSimonian–Laird estimator.23 In addition to the estimate of Tau2, the Q-test for heterogeneity (Chi2) and the I2 statistic are reported. Studentized residuals and Cook's distances were used to examine whether studies may be outliers and/or influential in the context of the model. Studies with a studentized residual larger than the 100 × (1–0.05/(2 × k))th percentile of a standard normal distribution were considered potential outliers (i.e. using a Bonferroni correction with two-sided α = 0.05 for k studies included in the meta-analysis). Studies with a Cook's distance larger than the median plus six times the interquartile range of Cook's distances were considered to be influential. Assessment of publication bias was not possible based on the low number (<10) of included studies.
Additional meta-regression analyses for MACE and MI using mean LDL change were performed. The analysis was carried out using R (version 4.2.2; R Core Team, 2020) and the ‘metafor’ package (version 4.0.0).23
Results
Out of 258 manuscripts, 10 manuscripts fulfilled the inclusion criteria, as depicted in Figure 1.7,8,10,11,13,17–21 In total, these trials included 18 200 patients (9765 on bempedoic acid, 8435 on placebo). A summary of the study characteristics is provided in Table 1. All 10 studies were judged to be of overall moderate to high quality (Table 2).
PRIMSA flowchart presenting the study identification and selection process.
| First author and year of publication | Patient cohort | Study duration | Treatment group | Control group | Background therapy | Baseline LDL-C | Primary endpoint | LDL-C reduction |
|---|---|---|---|---|---|---|---|---|
| Ballantyne et al. (2018)10 | Statin intolerance with LDL ≥100 mg/dL | 12 weeks | Bempedoic acid | Placebo | Ezetimibe 10 mg daily | 126.6 mg/dL | LDL-C change | −28.5% |
| Goldberg et al. (2019)8 | Atherosclerotic cardiovascular disease and/or HeFH with LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid-modifying therapy allowed | 120.4 mg/dL | LDL-C change | −15.1% at week 12 |
| Laufs et al. (2019)11 | Hyperlipidaemia (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) with statin intolerance | 24 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 157.6 mg/dL | LDL-C change | −21.4% at week 12 |
| Ray et al. (2019)7 | Atherosclerotic cardiovascular disease and/or HeFH and LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 103.2 mg/dL | Clinical safety | −16.5% at week 12 |
| Lalwani et al. (2019)21 | Hypercholesteremia (LDL-C 100-220 mg/dL on high-intensity statins, 115-220 mg/dL on moderate- or low-intensity statins) | 4 weeks | Bempedoic acid | Placebo | Atorvastatin 80 mg o.d. | 86 mg/dL vs. 71 mg/dL | LDL-C change | −13.0% |
| Ballantyne et al. (2020)19 | High cardiovascular risk due to overt cardiovascular disease, FH, or multiple risk factors (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) | 12 weeks | Bempedoic acid, | stable background statin therapy | 149.8 mg/dL | LDL-C change | −36.2% | |
| Rubino et al. (2021)18 | Hyperlipidaemia without cardiovascular disease | 6 weeks | Bempedoic acid, ezetimibe 10 mg o.d., atorvastatin 20 mg o.d. | Placebo | None | 154.8 mg/dL | LDL-C change | −63.6% |
| Rubino et al. (2021)20 | Hypercholesterolemia (LDL-C above 70 mg/dL while on PCSK-9 inhibitors) | 2 months | Bempedoic acid | Placebo | PCSK-9 inhibitor therapy | 102.1 mg/dL vs. 104.1 mg/dL | LDL-C change | −27.5% |
| Bays et al. (2021)17 | T2DM and hyperlipidaemia | 12 weeks | Bempedoic acid, ezetimibe 10 mg o.d. | Placebo | None | 142.6 mg/dL | LDL-C change | −38.8% |
| Nissen et al. (2023)13 | High risk for cardiovascular disease or overt cardiovascular disease with statin intolerance | Median 40.6 months | Bempedoic acid | Placebo | Low-dose statins allowed; other background lipid-modifying therapy allowed | 139.0 mg/dL | four-component MACE | −21.7% at 6 months |
| First author and year of publication | Patient cohort | Study duration | Treatment group | Control group | Background therapy | Baseline LDL-C | Primary endpoint | LDL-C reduction |
|---|---|---|---|---|---|---|---|---|
| Ballantyne et al. (2018)10 | Statin intolerance with LDL ≥100 mg/dL | 12 weeks | Bempedoic acid | Placebo | Ezetimibe 10 mg daily | 126.6 mg/dL | LDL-C change | −28.5% |
| Goldberg et al. (2019)8 | Atherosclerotic cardiovascular disease and/or HeFH with LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid-modifying therapy allowed | 120.4 mg/dL | LDL-C change | −15.1% at week 12 |
| Laufs et al. (2019)11 | Hyperlipidaemia (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) with statin intolerance | 24 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 157.6 mg/dL | LDL-C change | −21.4% at week 12 |
| Ray et al. (2019)7 | Atherosclerotic cardiovascular disease and/or HeFH and LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 103.2 mg/dL | Clinical safety | −16.5% at week 12 |
| Lalwani et al. (2019)21 | Hypercholesteremia (LDL-C 100-220 mg/dL on high-intensity statins, 115-220 mg/dL on moderate- or low-intensity statins) | 4 weeks | Bempedoic acid | Placebo | Atorvastatin 80 mg o.d. | 86 mg/dL vs. 71 mg/dL | LDL-C change | −13.0% |
| Ballantyne et al. (2020)19 | High cardiovascular risk due to overt cardiovascular disease, FH, or multiple risk factors (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) | 12 weeks | Bempedoic acid, | stable background statin therapy | 149.8 mg/dL | LDL-C change | −36.2% | |
| Rubino et al. (2021)18 | Hyperlipidaemia without cardiovascular disease | 6 weeks | Bempedoic acid, ezetimibe 10 mg o.d., atorvastatin 20 mg o.d. | Placebo | None | 154.8 mg/dL | LDL-C change | −63.6% |
| Rubino et al. (2021)20 | Hypercholesterolemia (LDL-C above 70 mg/dL while on PCSK-9 inhibitors) | 2 months | Bempedoic acid | Placebo | PCSK-9 inhibitor therapy | 102.1 mg/dL vs. 104.1 mg/dL | LDL-C change | −27.5% |
| Bays et al. (2021)17 | T2DM and hyperlipidaemia | 12 weeks | Bempedoic acid, ezetimibe 10 mg o.d. | Placebo | None | 142.6 mg/dL | LDL-C change | −38.8% |
| Nissen et al. (2023)13 | High risk for cardiovascular disease or overt cardiovascular disease with statin intolerance | Median 40.6 months | Bempedoic acid | Placebo | Low-dose statins allowed; other background lipid-modifying therapy allowed | 139.0 mg/dL | four-component MACE | −21.7% at 6 months |
o.d. = once daily; LDL-C = low-density lipoprotein cholesterol; MACEs = major adverse cardiovascular events; T2DM = type 2 diabetes mellitus.
| First author and year of publication | Patient cohort | Study duration | Treatment group | Control group | Background therapy | Baseline LDL-C | Primary endpoint | LDL-C reduction |
|---|---|---|---|---|---|---|---|---|
| Ballantyne et al. (2018)10 | Statin intolerance with LDL ≥100 mg/dL | 12 weeks | Bempedoic acid | Placebo | Ezetimibe 10 mg daily | 126.6 mg/dL | LDL-C change | −28.5% |
| Goldberg et al. (2019)8 | Atherosclerotic cardiovascular disease and/or HeFH with LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid-modifying therapy allowed | 120.4 mg/dL | LDL-C change | −15.1% at week 12 |
| Laufs et al. (2019)11 | Hyperlipidaemia (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) with statin intolerance | 24 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 157.6 mg/dL | LDL-C change | −21.4% at week 12 |
| Ray et al. (2019)7 | Atherosclerotic cardiovascular disease and/or HeFH and LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 103.2 mg/dL | Clinical safety | −16.5% at week 12 |
| Lalwani et al. (2019)21 | Hypercholesteremia (LDL-C 100-220 mg/dL on high-intensity statins, 115-220 mg/dL on moderate- or low-intensity statins) | 4 weeks | Bempedoic acid | Placebo | Atorvastatin 80 mg o.d. | 86 mg/dL vs. 71 mg/dL | LDL-C change | −13.0% |
| Ballantyne et al. (2020)19 | High cardiovascular risk due to overt cardiovascular disease, FH, or multiple risk factors (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) | 12 weeks | Bempedoic acid, | stable background statin therapy | 149.8 mg/dL | LDL-C change | −36.2% | |
| Rubino et al. (2021)18 | Hyperlipidaemia without cardiovascular disease | 6 weeks | Bempedoic acid, ezetimibe 10 mg o.d., atorvastatin 20 mg o.d. | Placebo | None | 154.8 mg/dL | LDL-C change | −63.6% |
| Rubino et al. (2021)20 | Hypercholesterolemia (LDL-C above 70 mg/dL while on PCSK-9 inhibitors) | 2 months | Bempedoic acid | Placebo | PCSK-9 inhibitor therapy | 102.1 mg/dL vs. 104.1 mg/dL | LDL-C change | −27.5% |
| Bays et al. (2021)17 | T2DM and hyperlipidaemia | 12 weeks | Bempedoic acid, ezetimibe 10 mg o.d. | Placebo | None | 142.6 mg/dL | LDL-C change | −38.8% |
| Nissen et al. (2023)13 | High risk for cardiovascular disease or overt cardiovascular disease with statin intolerance | Median 40.6 months | Bempedoic acid | Placebo | Low-dose statins allowed; other background lipid-modifying therapy allowed | 139.0 mg/dL | four-component MACE | −21.7% at 6 months |
| First author and year of publication | Patient cohort | Study duration | Treatment group | Control group | Background therapy | Baseline LDL-C | Primary endpoint | LDL-C reduction |
|---|---|---|---|---|---|---|---|---|
| Ballantyne et al. (2018)10 | Statin intolerance with LDL ≥100 mg/dL | 12 weeks | Bempedoic acid | Placebo | Ezetimibe 10 mg daily | 126.6 mg/dL | LDL-C change | −28.5% |
| Goldberg et al. (2019)8 | Atherosclerotic cardiovascular disease and/or HeFH with LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid-modifying therapy allowed | 120.4 mg/dL | LDL-C change | −15.1% at week 12 |
| Laufs et al. (2019)11 | Hyperlipidaemia (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) with statin intolerance | 24 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 157.6 mg/dL | LDL-C change | −21.4% at week 12 |
| Ray et al. (2019)7 | Atherosclerotic cardiovascular disease and/or HeFH and LDL-C ≥70 mg/dL | 52 weeks | Bempedoic acid | Placebo | Background lipid- modifying therapy allowed | 103.2 mg/dL | Clinical safety | −16.5% at week 12 |
| Lalwani et al. (2019)21 | Hypercholesteremia (LDL-C 100-220 mg/dL on high-intensity statins, 115-220 mg/dL on moderate- or low-intensity statins) | 4 weeks | Bempedoic acid | Placebo | Atorvastatin 80 mg o.d. | 86 mg/dL vs. 71 mg/dL | LDL-C change | −13.0% |
| Ballantyne et al. (2020)19 | High cardiovascular risk due to overt cardiovascular disease, FH, or multiple risk factors (LDL-C ≥130 mg/dL in primary prevention; ≥100 mg/dL in HeFH or in secondary prevention) | 12 weeks | Bempedoic acid, | stable background statin therapy | 149.8 mg/dL | LDL-C change | −36.2% | |
| Rubino et al. (2021)18 | Hyperlipidaemia without cardiovascular disease | 6 weeks | Bempedoic acid, ezetimibe 10 mg o.d., atorvastatin 20 mg o.d. | Placebo | None | 154.8 mg/dL | LDL-C change | −63.6% |
| Rubino et al. (2021)20 | Hypercholesterolemia (LDL-C above 70 mg/dL while on PCSK-9 inhibitors) | 2 months | Bempedoic acid | Placebo | PCSK-9 inhibitor therapy | 102.1 mg/dL vs. 104.1 mg/dL | LDL-C change | −27.5% |
| Bays et al. (2021)17 | T2DM and hyperlipidaemia | 12 weeks | Bempedoic acid, ezetimibe 10 mg o.d. | Placebo | None | 142.6 mg/dL | LDL-C change | −38.8% |
| Nissen et al. (2023)13 | High risk for cardiovascular disease or overt cardiovascular disease with statin intolerance | Median 40.6 months | Bempedoic acid | Placebo | Low-dose statins allowed; other background lipid-modifying therapy allowed | 139.0 mg/dL | four-component MACE | −21.7% at 6 months |
o.d. = once daily; LDL-C = low-density lipoprotein cholesterol; MACEs = major adverse cardiovascular events; T2DM = type 2 diabetes mellitus.
Quality of studies according to the authors´ judgement
| Ballantyne et al.10 | Goldberg et al.8 | Laufs et al.11 | Ray et al.7 | Lalwani et al.21 | Rubino et al.18 | Rubino et al.20 | Ballantyne et al.19 | Bays et al.17 | Nissen et al.13 | |
|---|---|---|---|---|---|---|---|---|---|---|
| Bias arising from the randomization process |  | | | | | | | | | |
| Bias due to deviations from intended interventions | | | |  | | | | | | |
| Bias in measurement of the outcome | | | | | | | | | | |
| Bias due to missing outcome data | | | | | | | | | | |
| Bias in selection of the reported results | | | | | | | | | | |
| Ballantyne et al.10 | Goldberg et al.8 | Laufs et al.11 | Ray et al.7 | Lalwani et al.21 | Rubino et al.18 | Rubino et al.20 | Ballantyne et al.19 | Bays et al.17 | Nissen et al.13 | |
|---|---|---|---|---|---|---|---|---|---|---|
| Bias arising from the randomization process | | | | | | | | | | |
| Bias due to deviations from intended interventions | | | | | | | | | | |
| Bias in measurement of the outcome | | | | | | | | | | |
| Bias due to missing outcome data | | | | | | | | | | |
| Bias in selection of the reported results | | | | | | | | | | |
This table presents potential bias of all in the present meta-analysis, which included trials, as judged by the authors and in accordance with the revised Cochrane's Collaboration risk of bias assessment tool.22
Quality of studies according to the authors´ judgement
| Ballantyne et al.10 | Goldberg et al.8 | Laufs et al.11 | Ray et al.7 | Lalwani et al.21 | Rubino et al.18 | Rubino et al.20 | Ballantyne et al.19 | Bays et al.17 | Nissen et al.13 | |
|---|---|---|---|---|---|---|---|---|---|---|
| Bias arising from the randomization process | | | | | | | | | | |
| Bias due to deviations from intended interventions | | | | | | | | | | |
| Bias in measurement of the outcome | | | | | | | | | | |
| Bias due to missing outcome data | | | | | | | | | | |
| Bias in selection of the reported results | | | | | | | | | | |
| Ballantyne et al.10 | Goldberg et al.8 | Laufs et al.11 | Ray et al.7 | Lalwani et al.21 | Rubino et al.18 | Rubino et al.20 | Ballantyne et al.19 | Bays et al.17 | Nissen et al.13 | |
|---|---|---|---|---|---|---|---|---|---|---|
| Bias arising from the randomization process | | | | | | | | | | |
| Bias due to deviations from intended interventions | | | | | | | | | | |
| Bias in measurement of the outcome | | | | | | | | | | |
| Bias due to missing outcome data | | | | | | | | | | |
| Bias in selection of the reported results | | | | | | | | | | |
This table presents potential bias of all in the present meta-analysis, which included trials, as judged by the authors and in accordance with the revised Cochrane's Collaboration risk of bias assessment tool.22
Study durations ranged from 6 weeks to a median of 40.6 months. In four trials, the primary efficacy endpoint was % LDL-C change. In CLEAR Harmony, the primary endpoint was safety outcomes, and in CLEAR Outcomes, the primary endpoint included four-component MACEs comprising cardiovascular death, non-fatal MI, non-fatal stroke, and coronary revascularization. In two studies, more than two treatment arms were reported. Therefore, the results were pooled into two groups for analysis (bempedoic acid vs. no bempedoic acid).17,19
MACE
A total of five studies were included in the analysis.7,8,11,13,19 We could detect a significant difference between bempedoic acid (n = 669/9765) and placebo (n = 720/8435) [odds ratio (OR) 0.84 [95% confidence interval (CI) 0.76–0.96]; P < 0.001; Figure 2]. According to the Q-test, there was no significant amount of heterogeneity (Chi2 = 3.90, P = 0.42, Tau2 = 0.00, I2 = 0%). One study had a relatively large weight compared with the rest of the studies (i.e. ‘weight’≥3/k, so a weight at least three times as large as having equal weights across studies), and according to Cook's distances, it could be considered to be overly influential.13 According to meta-regression analysis, mean LDL change was not a significant predictor of future outcomes (P ≥ 0.05).
Forest plot for three-point MACEs including cardiovascular death, non-fatal MI, and non-fatal stroke.
All-cause death
A total of three studies were included in the analysis.7,8,13 We could not detect a significant difference between bempedoic acid (n = 453/9765) and placebo (n = 424/8435) (OR 1.19 [95% CI 0.73–1.93]; P = 0.49; Figure 3). According to the Q-test, there was no significant amount of heterogeneity in the true outcomes (Chi2 = 2.45, P = 0.29, Tau2 = 0.07, I2 = 18%). According to Cook's distances, none of the studies was overly influential.
Forest plot for all-cause death.
Myocardial infarction
A total of five studies were included in the analysis.7,8,11,13,19 We could detect a significant difference between bempedoic acid (n = 290/9765) and placebo (n = 359/8435) (OR 0.75 [95% CI 0.64–0.88]; P < 0.001; Figure 4). According to the Q-test, there was no significant amount of heterogeneity in the true outcomes (Chi2 = 2.82, P = 0.59, Tau2 = 0.00, I2 = 0%). One study had a relatively large weight compared with the rest of the studies (i.e. ‘weight’≥3/k, so a weight at least three times as large as having equal weights across studies), and according to Cook's distances, it could be considered to be overly influential.13 According to meta-regression analysis, mean LDL change was not a significant predictor of future outcomes (P ≥ 0.05).
Forest plot for MI.
Stroke
A total of four studies were included in the analysis.7,8,11,13 We could not detect a significant difference between bempedoic acid (n = 146/9765) and placebo (n = 162/8435) (OR 0.86 [95% CI 0.69–1.08]; P = 0.20; Figure 5). According to the Q-test, there was no significant amount of heterogeneity in the true outcomes (Chi2 = 0.67, P = 0.88, Tau2 = 0.00, I2 = 0%). One study had a relatively large weight compared with the rest of the studies (i.e. ‘weight’≥3/k, so a weight at least three times as large as having equal weights across studies).13 According to Cook's distances, none of the studies could be considered to be overly influential.
Forest plot for stroke.
Adverse events
Although only marginally, bempedoic acid was associated with an 11% increased relative rate of treatment discontinuation compared with controls (OR 1.11 [95% CI 1.01–1.23]; P = 0.03; I2 = 0%; Figure 6). Bempedoic acid was significantly associated with increased rates of hyperuricaemia, gout, elevated liver enzymes, and renal impairment (all P < 0.05, Supplementary material online, Figures S1–S4). In contrast, bempedoic acid was not associated with increases of creatine kinase, myalgia, or diabetes (all P > 0.5, Supplementary material online, Figures S5–S7).
Forest plot for adverse events leading to treatment discontinuation.
Discussion
Our meta-analysis demonstrates that bempedoic acid significantly reduced non-fatal MI in patients with hyperlipidaemia. However, bempedoic acid had no beneficial effect on all-cause mortality.
Cardiovascular disease remains the leading cause of death worldwide.24 Lipid-modifying therapy is one of the cornerstones to reduce cardiovascular risk in primary or secondary prevention.3 Although several lipoproteins have been associated with cardiovascular risk, only the reduction of LDL-C has consistently been associated with a reduction of mortality and morbidity. Therefore, the European Society of Cardiology has defined several risk categories with varying LDL-C treatment goals.2
Statins are the mainstay of lipid-modifying therapy, and depending on the agent, they are able to reduce LDL-C levels by ∼50% and also triglyceride levels to some extent.3 Also, several additional pleiotropic mechanisms have been proposed and statin therapy has been consistently demonstrated to reduce morbidity and even mortality.3 However, statins have been associated with several side effects, particularly with muscle symptoms and—very rarely—rhabdomyolysis.3 Reports have suggested that ∼50% of patients stop their statin therapy within 6 months and that only 20% of high-risk patients remain adherent to statins in the long run.25,26
Bempedoic acid has recently been introduced as a novel lipid-modifying agent for patients with moderate hyperlipidaemia who do not meet treatment goals despite maximally tolerated lipid-modifying therapy or in patients with statin intolerance. Bempedoic acid has moderate lipid-modifying potency and reduces LDL-C levels by 20–25% from baseline, with an overall good safety profile.16
The CLEAR Outcomes (Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients) trial included 13 970 patients with an indication to lipid-modifying therapy and clinically diagnosed statin intolerance or unwillingness to take a statin. The study participants were randomized to bempedoic acid vs. placebo. In line with our results, they could demonstrate a significant reduction of three-point MACE with a 15% relative risk reduction compared with placebo over a median follow-up period of 40.6 months.13 The effect on MACE reduction seen in our models and also by CLEAR Outcomes was predominantly the effect of a significant decrease of non-fatal MI.8,13 In our models, treatment with bempedoic acid resulted in a 25% relative risk reduction of future MI, basing on the results of CLEAR Wisdom and CLEAR Outcomes.8,13 Moreover, we have performed meta-regression analyses for MACE and MI using ‘mean LDL change’ as a continuous predictor. Although no significant association of LDL change and outcomes was detectable, this comes not as a surprise as the mean LDL change was similar throughout all included studies.7,8,10,11,13,17–21 However, we believe that treatment duration is most relevant for potential benefits seen with bempedoic acid treatment.
No significant effect or even a tendency of benefit regarding stroke and all-cause mortality was detectable for bempedoic acid in our analysis, similar to CLEAR Outcomes, CLEAR Wisdom, and CLEAR Harmony.7,8,13 This is a remarkable finding as the recent SAMSON trial (Side Effect Patterns in a Crossover Trial of Statin, Placebo, and No Treatment) demonstrated that the majority of muscle-related symptoms of statins, which have been associated with mortality benefits particularly in secondary prevention therapy, is the result of the nocebo effect.27 This fact was even acknowledged in the above-mentioned CLEAR Outcomes trial, in which patients and investigators had to provide confirmation that they were aware of the mortality benefits of statins.13 However, also the other ‘non-statin’ lipid-modifying agents ezetimibe and the PCSK-9 inhibitors had no beneficial effects on mortality.28–30
Despite the potent lipid-lowering effect of statins, a substantial number of patients do not meet the required LDL-C treatment goals, and bempedoic acid might be an effective adjunct to high-intensity statin therapy.31 While in CLEAR Outcomes only very low statin doses were allowed, CLEAR Harmony and CLEAR Wisdom also allowedsignificant statin doses with ∼50% of patients receiving high-intensity statin therapy.7,8,13 Of note, the lipid-modifying efficacy of bempedoic acid was similar in patients with low/moderate-intensity statins and in those with high-intensity statins.7,8 If the addition of bempedoic acid to potent statin therapy also reduces MACEs to a similar extent as seen in other trials remains to be studied in further clinical studies.28 Also, the triple combination of statins, ezetimibe, and bempedoic acid was associated with significantly lower LDL-C levels compared with either dual combination therapy alone, and might offer a benefit in patients with an indication for potent lipid-modifying therapy.19
Bempedoic acid is a well-tolerated drug with only few side effects. Of note, bempedoic acid was not associated with increases in creatine kinase, myalgias, or diabetes, known side effects of statins.7,10,11,32 This is of interest as CLEAR Harmony had indicated a benefit of bempedoic acid on the rates of subsequent diabetes.7 In contrary, in a post-hoc analysis of CLEAR Wisdom, bempedoic acid only demonstrated a marginal effect on glycemic control and had no impact on the rates of diabetes in both CLEAR Wisdom and CLEAR Outcomes, respectively.8,13 However, while bempedoic acid appears to have a neutral effect on glycemic control, statins have been associated with an increased incidence of diabetes in some studies.33–35
Bempedoic acid was associated with increased rates of hyperuricaemia and gout. Moreover, bempedoic acid was associated with renal impairment (either defined as a rise in creatinine or defined as a decrease of glomerular filtration rate) and hepatic enzymes, as previously reported.7,8,12,13 The most likely mechanism for this observation is a reduction in renal tubular excretion due to a renal transporter competition between bempedoic acid and creatinine.7 However, the rise of creatinine seen in CLEAR Outcomes was only marginal (0.05 ± 0.2 vs. 0.01 ± 0.2 mg/dL).13 Nevertheless, if the rates of renal impairment are associated with increased rates of hemodialysis, then they need to be addressed in further long-term observational trials.
Bempedoic acid is a viable option in patients with true statin intolerance, i.e. rhabdomyolysis or severe hepatopathy, or in the case of LDL-C levels above the treatment goal despite otherwise optimal lipid-modifying therapy. Whether bempedoic acid in addition to high-dose statins (with or without ezetimibe) is able to reduce cardiovascular events remains to be elucidated in further randomized clinical trials. Although ezetimibe and the PCSK-9 inhibitors are currently the preferred agents in addition to statins in a clinical routine due to their proven reduction of cardiovascular events,28–30 bempedoic acid might be an interesting additional option by replacing other lipid-lowering agents or in combination with those in order to reach the treatment goal early.36
The present investigation should be interpreted in light of the following limitations: First, we included results from trials with varying treatment durations, different enrolment criteria, and lipid-modifying background therapy. Moreover, like the majority of meta-analyses, we used published data only and did not investigate the effect of bempedoic acid at the patient level. However, we elaborated a thorough search strategy and screening, which is likely to have identified relevant studies from the most important medical databases.
Conclusion
Bempedoic acid reduced non-fatal MI in patients with hyperlipidaemia, whereas it had no significant effect on stroke and all-cause mortality. As bempedoic acid did not reduce mortality, it should primarily be prescribed in patients with a true contraindication to statins or those who do not reach treatment goals on otherwise optimal lipid-modifying therapy.
Funding
None.
Conflict of interest: D.M. and M.T. have nothing to declare. K.H. received lecture and consulting fees from Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, Daiichi Sankyo, Novartis, and Sanofi. T.G. received speaker/consulting fees from AstraZeneca, Amgen, Bayer, Boehringer-Ingelheim, Bristol Myers Squibb, Daiichi- Sankyo, Novartis, and Pfizer, and grant support from Boehringer-Ingelheim, Bristol Myers Squibb, Medtronic and Abbott.
Data availability
The data underlying this meta-analysis are available in the article and in its online supplementary material.
References
Author notes
These authors contributed equally to the manuscript.
