Atherosclerotic cardiovascular disease (ASCVD), is a leading cause of mortality in Western Countries, accounting for approximately 18 million deaths per year worldwide, with more than four million of which in Europe alone (Guo et al., 2023). Several risk factors independently contribute to the onset of ASCVD, resulting in the increased probability of experiencing a cardiovascular event during the patient’s lifetime. Dyslipidemia and familial hypercholesterolaemia (FH) represents major risk factors for ACSVD since available epidemiological studies highlight the existence of log-linear relationship between plasma levels of low-density lipoprotein cholesterol (LDL-C) and ASCVD (Borén and Williams, 2016; Pećin et al., 2017; Ference et al., 2012; Holmes et al., 2015). Accordingly, LDL-C lowering strategies are pivotal for reducing ASCVD-related mortality (Silverman et al., 2016).

Statins are the first-choice drugs used in LDL-C lowering therapy. Statins’ pharmacodynamics (PD) rely on the competitive inhibition of hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase, associating with an average 30%–50% of LDL-C reduction, according to the different molecules, daily dosage and interindividual variability (Boekholdt et al., 2014). This translates to a 5-years average 22% reduction in major vascular events for each statin-associated 1 mmol/L LDL-C lowering (Baigent et al., 2010). Musculoskeletal disorders (MSD) are the most prevalent adverse drug reactions (ADR) associated with the use of statins, ranging from myalgia, with a reported prevalence of 10%–15%, with or without the increase of creatine kinase levels, to the rarest rhabdomyolysis, with a prevalence of 1-3 patients/100.000 per year (Bruckert et al., 2005; Davidson et al., 2006; Gupta et al., 2017). Statin-induced myopathy has been associated with decreased cell levels of ubiquinone, a component of the mitochondrial respiratory chain which is produced by the HMG-CoA pathway, resulting in impaired energy metabolism and cell death (Pallotti et al., 2021; Safitri et al., 2021). However, the impairment of protein prenylation, inhibition of complexes I and III of the electron transport chain, oxidative stress, downregulation of mitochondrial biogenesis, impairment of the insulin receptor/Akt/mTORC pathway and cytochrome c-related apoptosis pathways have also been involved in MSD onset (Bouitbir et al., 2020). Therapy discontinuation related to MSD, also known as “statins intolerance”, is a current clinical issue associated with their use. MSD are estimated to affect up to 27% of statin users, and up to 62% in those who discontinue the therapy (Cohen et al., 2012; Reith et al., 2022).

Other non-statin LDL-C lowering agents have been developed, among which bempedoic acid (BA) is one of the most recent, being approved for clinical use in the U.S. and in Europe in 2020. The PD of BA relies on the competitive inhibition of adenosine triphosphate–citrate lyase (ACL), an enzyme involved in cholesterol synthesis upstream of HMG-CoA reductase. The use of BA in mono-therapy is associated with an average LDL-C reduction by 18%–20% (Duarte Lau and Giugliano, 2023; Yasmin et al., 2024). Importantly, BA is a prodrug since it is activated by the hepatic enzyme very long-chain acyl-CoA synthetase-1 (ACSVL1), whose expression by skeletal muscle is reported as negligible (Zabielski et al., 2024). On this basis, the active form of BA is not detectable in skeletal muscle specimens and thus claimed as non-myotoxic (Ruscica et al., 2019). In addition, recent studies suggest BA as a possible agonist of monophosphate-activated protein kinase (AMPK), a master regulator of metabolism with different effects on energy homeostasis and sterol synthesis such as the inhibition of acetyl-CoA carboxylase (ACC) and HMG-CoA reductase (Clarke and Hardie, 1990; Foretz and Viollet, 2011; Pinkosky et al., 2016). BA is administered via the oral route and its current clinical indications are: i) in combination with a statin, or with a statin and other lipid-lowering therapies, in patients unable to achieve the target LDL-C levels with the maximally tolerated doses of either drugs ii) as monotherapy or in combination with other lipid-lowering therapies in patients intolerant to statins or when the use statin is contraindicated (Nissen et al., 2023).

Recent studies suggest a more complex scenario of BP-related ADRs, for which the occurrence of myalgia and gout appear as more frequent than that reported in available clinical trials (Laufs et al., 2019; De Filippo et al., 2023; Nissen et al., 2023; Bays et al., 2024). However, the frequency of Muscle-related ADR for BA in current clinical practice is under-investigated.

In this study, we aimed to evaluate the occurrence of ADRs reported for BA, particularly focusing on muscle-related ADRs, in comparison with those reported for the mainstay of statin drugs: atorvastatin (ATO). To this aim we adopted a Registry-based approach, using the European spontaneous reporting system to evaluate reported ADRs through disproportionality analysis.

In this study, we compared ADR reports between Bempedoic Acid and Atorvastatin, a widely used statin class representative. We provide evidence that the use of BA associates with a more than doubled occurrence of reports depicting musculoskeletal or gastrointestinal disorder compared to ATO. In addition, BA showed an increased occurrence of reports related to general disorders, administration site conditions and nervous system disorders, compared to ATO. However, BA reports were characterized by lower severity and more favourable clinical outcomes, in terms of both lower rate of fatality and higher rate of resolution or recovery.

BA is a recent cholesterol lowering drug currently indicated, in monotherapy or in combination, in patients unable to achieve LDL-C target levels or in patients with intolerance/contraindication for the use statins because of its low myo-toxic potential (De Filippo et al., 2023; Duarte Lau and Giugliano, 2023). Indeed, in line with its mechanism of action, available meta-analyses of randomized clinical trials strongly support a low risk of musculoskeletal disorders associated with BA or even lower than that observed in placebo-treated patients (Goyal et al., 2024; Sayed et al., 2024). Furthermore, the reported therapy discontinuation for muscle-related ADRs was rare in BA recipients (Ballantyne et al., 2016; Thompson et al., 2016; Ray et al., 2019). However, recent evidence suggest that the use of BA is not devoid of the risk of myopathy. In fact, by the use of the Food and Drug Administration-ADR repository reporting system, Li et al. showed that musculoskeletal and connective tissue disorders are the most reported issues in BA recipients, with a ROR of 6.08 (CI 5.13–7.18), followed by nervous system disorders and hepatobiliary disorders (Li et al., 2024). Notably, the reported outcome severity, such as disability, hospitalization and life-threatening events, showed a prevalence of 10.47%, 8.90% and 1.57%, respectively, with a generally worse prognosis than that observed in our results, despite a fairly comparable demographic composition. Importantly, data from Li et al. were based on a lower number of reports compared to those available from our investigation, respectively 735 vs. 2667 BA-only recipients, which may imply a disproportionate representation of more serious ADRs in the two databases (Li et al., 2024). In addition, reporting sources from Li et al. were evenly distributed among Unites States, Germany and United Kingdom, whilst our dataset derived mostly from the EU area.

In order to provide a representative term of comparison for ADRs, we used ATO as a reference mainstay of cholesterol-lowering therapy. Indeed, ATO is the most prescribed statin drug worldwide, highly effective in patients with non-familiar hypercholesterolemia and whose risk of withdrawals associated with ADRs did not differ from placebo-treated patients in short-term trials (Adams et al., 2015). Overall, we found that muscle-related adverse events were more frequently reported in BA-only recipients but with a milder pattern of symptoms severity and clinical outcome. Differently, reported ADRs in ATO-only recipients showed a more severe pattern, being more frequently associated with rhabdomyolysis, increased CPK levels and a non-zero prevalence of fatal cases. This evidence opens up to various interpretative hypotheses. As previously reported for statins, long term HMGR inhibition associates with reduced levels of CoQ10, leading to mitochondrial dysfunction and muscle cell death (Bouitbir et al., 2020; Zeng et al., 2025). On the other hand, AMPK/ACC and AMPK/HMGR pathways modulation by BA is likely dependent on the proportion of free BA which is not converted in the active form bempedoyl-CoA (Clarke and Hardie, 1990; Foretz and Viollet, 2011; Pinkosky et al., 2016). Since a limited fraction of the drug remains unconverted, this likely associates with a less severe myotoxic effect than the one exerted by statins. In line with this hypothesis, we showed that the prevalence of MR-PTs reporting in patients receiving both BA and ATO was of 68%, underlining a possible cumulative effect on muscle outcomes based on the shared branches of AMPK-mediated pathways.

Alternatively, it might be hypothesized that BA-reporting suffered of the “alert-bias”, namely a higher propensity to report an adverse event associated with its use (Moore et al., 2003; Pariente et al., 2007). According to available clinical trials, a favourable myotoxicity profile has been clearly suggested for BA and, being anticipated as a safer alternative to statins, this may have led to an over-attention and reporting of ADRs for this new marketed drug. This phenomenon is not uncommon for newly marketed drugs, for which this heightened vigilance trend tends to decline over time (Moore et al., 2003). Moreover, randomized clinical trials, whilst representing the reference investigation addressing drug efficacy, only describe limited scenario of the possible ADRs a drug may generate in settings of clinical practice, given the limited sample size and stringent inclusion criteria. In this frame, deriving from pharmacovigilance data, findings here presented are suggested to have clinical relevance, deserving to consider drug-related causes of muscle symptoms, particularly even when BA is used in combination with statins. However, it is important to interpret these results with caution, deserving further investigation through more targeted tolerability studies.

We acknowledge some limitations to our findings. First, reporting bias, as previously mentioned, is a matter of concern. In addition, we recognize the limit of the selection of ATO as the sole comparator. However, adding additional comparators would have increased the already existing reporting disproportion between the two drug classes, leading to a possible underestimation of BA reporting. In addition, data sourced exclusively from the EudraVigilance database, providing limited access to clinical data to be used as confounding factors, restricting the generalizability of the findings. This is the case of dose stages of ATO and BA, which are considered as optional data and are rarely reported, and the patient’s age which generally reported as prevalence of a categorical variable <1 month, 12–17 years and >18 years. These represent additional limits to our findings. However, with respect to the more strictly geographical aspect, it should be noted that nearly 56% of reports were from no-EU area, providing some wide representativeness of our findings. In addition, we provided subgroup analysis by sex, showing no significant clustering of ADRs.

Finally, inherent limitations of disproportionality analysis must be taken into account, including the lack of critical information such as treatment duration, comorbidities and dosage, which prevents a comprehensive assessment of the long-term safety profile of the medications and the impossibility to establish causal relationships between drug exposure and ADRs. Further studies are warranted to assess how future pharmacovigilance signals trends will influence the reporting of ADRs related to BA and to investigate additional comparators.

In conclusion by the use of a Registry-based study, we showed an increased reporting of musculoskeletal-related ADR in BA recipients compared to ATO, although characterized by a lower severity outcome. Further studies are required to address the biological and clinical basis of this evidence.