Bempedoic Acid: for Whom and When

Lipid-lowering therapy remains a mainstay in the preventive approach to coronary disease. Reductions in circulating lipid fractions, particularly total cholesterol and low-density-lipoprotein cholesterol (LDL-C), have been responsible for a definite improvement in the primary preventive care of high-risk patients and more so in the post-cardiovascular (CV) event care [1, 2]. More recent guidelines indicate the opportunity of reducing LDL-C to very low levels to achieve optimal atherosclerotic cardiovascular benefit [3, 4]. However, although the percentage of US adults taking high-intensity statin therapy following MI increased substantially between 2011 and 2019, a retrospective cohort study of 601,934 US patients with established atherosclerotic cardiovascular disease (ASCVD) showed gaps in appropriate statin use (only 50.1% of patients were using a statin), especially among younger patients, women, and those with noncoronary ASCVD [5]. Gaps between clinical guidelines and clinical practice have been also reported in the DA VINCI study evaluating patients in primary and secondary care across Europe [6] with even higher statin non-adherence in Central and Eastern Europe [7]. Specifically, many patients to whom statins are prescribed do not adhere to therapy, namely, 30% or more within 1 year of initiation [8], raising the risk of ASCVD [9]. Interestingly, a simulation study showed that improving adherence to statins by 50% (from 50 to 75%) would prevent twice as many additional deaths compared to a strategy of lowering the CV threshold (from a 20 to a 15.5% 10-year risk of ASCVD) with statins [10].

Overall, although statin treatment is safe and the ASCVD benefit far outweighs the risk of any adverse effects [11], safety concerns particularly related to muscle side effects are among the most significant determinants of poor statin adherence [12]. Considering that RCTs evaluating statins and combination of statins with ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies have shown that what matters most is how much, when and for how long the LDL-C reduction is achieved, rather than how it is achieved, the use of lipid-lowering therapies associated with reduced muscular side effects can definitely improve the success of treatment. Thus, since combination lipid-lowering therapy should be considered as first-line strategy in very high-risk patients, in those who are statin intolerant, the first step of any regimen could include ezetimibe and (PCSK9)–targeted therapy (if available) or ezetimibe and bempedoic acid [13]. The addition of ezetimibe to simvastatin has led to a 7.2% lower rate of major vascular events and PCSK9 inhibitors to a 15% lower risk, and the outcome trial with bempedoic acid (CLEAR OUTCOMES) is eagerly awaited (the recruitment for the study was already stopped and the estimation study completion time is by December 2022). It will continue until 1620 patients experience the primary endpoint, with a minimum duration of treatment of 36 months. Until then and based on the phase 3 clinical trials and pooled analyses, it is only possible to give clinical insights on safety and efficacy of bempedoic acid and to understand to whom it should be prescribed.

In view of the general preference of patients for the use of oral agents, either given alone or added to statins in order to achieve better LDL-C lowering, the newly available bempedoic acid has raised interest and appears to have significant ASCVD potential either when used alone or when added to statins in order to achieve improved LDL-C reduction [14].

ASCVD incidence and mortality rates are declining in many European countries, but it is still a major cause of morbidity and mortality. As stated in the recent 2021 ESC guidelines on CV disease prevention in clinical practice, getting to ultimate LDL-C goals in high- and very-high risk patients is of fundamental value [51]. In these patients, a combination therapy will be needed in approximately 80% of patients to deal with the new LDL-C targets [52]. Considering that statins plus ezetimibe allow achieving the most frequently reported LDL-C targets in roughly ≥ 50% of patients, at least one-third of high-/very high–risk patients will require use of a third oral therapy or an injectable therapy [53]. However, dealing with this aspect has economic implications. Statins and ezetimibe are available at a relatively low cost (roughly 100 euros/year), whereas the annual cost, e.g., of PCSK9 inhibitors is around 5000–7000 euros/year. In this scenario, although the cost-effectiveness of bempedoic acid in different countries will depend on the different healthcare systems, drug pricing (in the USA, it is now about US$300–400/month) and populations within each country [23], a simulation study in a contemporary cohort of coronary artery disease patients concluded that addition of bempedoic acid to lipid lowering medications would (1) reduce the projected need for a PCSK9 inhibitor (roughly 25%) resulting in lower medication expenditure and (2) be particularly favourable in patients with full statin intolerance [54]. Thus, in this scenario, the use of bempedoic acid could fall within the therapeutic lipid-lowering algorithm proposed by the Guidelines being at the same time cost-effective. The combination therapy with ezetimibe seems the most promising also on the view of a secondary analysis of the IMPROVE-IT study reporting that adding ezetimibe to statin consistently reduced the risk for CV events in post-acute MI patients irrespective of baseline LDL-C values, supporting the use of intensive lipid-lowering therapy with ezetimibe even in patients with baseline LDL-C < 70 mg/dL [55].

Overall, based on available studies, the Polish guidelines decided to recommend bempedoic acid (and its combination with ezetimibe) in selected groups of patients with lipid disorders (Table 4) [56••].

Before proceeding to any further consideration, we believe it is important to give an overview on real-life data, although from a single site. Prescription of bempedoic acid to 73 patients showed that at 3-, 6- and 12-month LDL-C fell by 36.7%, 31% and 20.3%, respectively, with > 20% achieving LDL-C < 70 mg/dL, some patients achieving an over 70% LDL-C reduction [57]. However, a high rate of discontinuation was observed (32.8%), primarily related to musculoskeletal complaints, most likely linked to the concomitant use of low-intensity statins. As in the case of statins [58], the considerable inter-individual variability in LDL-C response is a likely consequence of genetic polymorphisms modulating, in this case, ACLY, on which we have limited information, although reduced function variants of the enzyme are associated with a clear lowering of CV risk.

A single case has been described with statin intolerance and poor response to PCSK9 antagonists, achieving optimal LDL-C response with bempedoic acid. A 29-year-old male with documented heterozygous frameshift deletion mutation in exon 3 of the LDL-receptor presented a moderate reduction in LDL-C with atorvastatin (80 mg/day), followed by severe skin lesions, lymphadenopathy, eosinophilia and abnormal liver functions test [59]. When started on alirocumab 150 mg Q2W added to an immunosuppressant regimen, LDL-C remained elevated (139–250 mg/dL). At this point, addition of BA (180 mg/day) led to a dramatic lowering of LDL-C to 51 mg/dL and, at a later evaluation, to 39 mg/dL. The patient had no significant side effects [59].

Bempedoic acid as a monotherapy or in combination can provide a valuable choice in a number of conditions. Bempedoic acid may be of value for patients who have statin intolerance (or not willing to use statins) with high doses or high-intensity agents (atorvastatin, rosuvastatin), in which case the addition of either bempedoic acid alone or in combination with minimal statin doses may again be adequate to reach target levels [43].

An important advantage of bempedoic acid alone or of the combination with ezetimibe (in secondary prevention) is the significant reduction of the inflammatory marker hsCRP, unfortunately still seldom monitored in clinical laboratories. However, a very large UK study in 102,337 patients with suspected coronary syndromes and divided into hsCRP quartiles (hsCRP < 2 mg/L (n = 38,390), 2 to 4.9 mg/L (n = 27,397), 5 to 9.9 mg/L (n = 26,957) and 10 to 15 mg/L (n = 9593) clearly indicated a stepwise rise in risk with mild elevations, just up to 15 mg/L, being a clinically meaningful prognostic marker beyond troponin with potential utility in selecting patients for treatments targeting inflammation [60]. CRP is associated with a rise of CV risk, and in the classical JUPITER study with rosuvastatin, a clear link was shown between hsCRP reduction and lower reinfarction incidence. As the absolute risk increased with increasing hsCRP, the absolute risk reduction associated with rosuvastatin within JUPITER was also greatest among those with the highest entry hsCRP levels [40]. Reduction of hsCRP with bempedoic acid ranges between 18 and 35%, being greater in patients with baseline values ≥ 2 mg/L compared with baseline hsCRP < 2 mg/L and not influenced by background statin intensity [61]. This significant feature of bempedoic acid, whose mechanism is as yet not clarified, is certainly a guide to the choice of this agent or of a combination in secondary prevention patients not adequately treated with statins or with statin intolerance.

Prescription of bempedoic acid may be useful upon the observation of statin-associated muscular side effects, which may be observed in 9.1% of statin-treated patients [11]. In this case, an agent associated with a very low risk of these symptoms appears attractive. Indeed, although statin-associated side effects are noted at a much lower frequency in clinical trials, they are far more prevalent in routine practice, and unfortunately play a major role in drug discontinuation [12, 62]; an oral treatment with a molecule of satisfactory tolerability and ease of use, not requiring injection, is certainly appealing to both doctors and patients. The extensive knowledge on bempedoic acid mechanism, metabolism and side effects has led to an improved understanding of the potential benefits of this agent and offers a possible alternative to cardiologists and clinical practitioners somewhat worn out today by the occurrence of the muscular side effects of statins. Additionally, it needs to be emphasized, that it may be a second lipid-lowering agent (after statins) with properties to reduce inflammatory biomarkers, with the potential to reduce inflammation-related residual cardiovascular risk.

However, in spite of this promising landscape, issues pertaining to medication access and affordability have to be considered, e.g. clinician-level barriers, or failure to initiate a new therapy [57]. Simply writing a prescription may not be sufficient to initiate treatment with novel branded drugs [63]. Optimizing medication access can be overwhelming and time consuming for providers and necessitates a multi-disciplinary team approach. Medication adherence is inversely linked to medication cost in cardiovascular patients [64].

The very large CLEAR OUTCOMES Trial, predicted to terminate before the end of 2022, will bring definite light on the efficacy of bempedoic acid on cardiovascular outcomes. This trial has randomized 14,014 patients and will test the superiority of bempedoic acid vs placebo in preventing major cardiovascular events (MACE: cardiovascular death, nonfatal myocardial infarction, nonfatal stroke or coronary revascularization) in patients with (i) established ASCVD or at high risk of developing ASCVD, (ii) documented statin intolerance and (iii) an LDL-C ≥ 100 mg/dL on maximally tolerated lipid-lowering therapy. The trial will continue until 1620 patients will experience a primary endpoint, with minimum treatment duration of 36 months with projected median treatment exposure of 42 months [65]. In the meantime, we can rely on data generated by using the SMART (Second Manifestations of ARTerial disease) prediction model that estimated the baseline 10-year risk of three-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction and non-fatal stroke) in patients with ASCVD who were enrolled in the CLEAR phase 3 RCTs [66, 67]. Ten-year event risk reduction was 3.3% in statin-treated and 6.0% in statin-intolerant patients [67]. Thus, the absolute benefits seem to be greater among patients with higher predicted risk and higher baseline LDL-C levels as currently being studied in the ongoing CLEAR Outcomes trial. Furthermore, data of a Mendelian randomization study, in which ACLY genetic variants mimicking the effects of ATP citrate lyase inhibitors, were tested concluded that ACLY variants associated with decreased LDL-C were associated with a reduction of 17.7% in the risk of major CV events (OR, 0.823; 95% CI, 0.78–0.87) and of 19.4% in the risk of MI (OR = 0.806; 95% CI, 0.76 to 0.86; P = 6.4 × 10 − 12) for each 10 mg/dL LDL-C lowering [68].