Bempedoic Acid: How Will It Shape the Future Lipid-Lowering Landscape? Mode of Action, Evidence, and Clinical Use Free

In 1985, the Nobel Prize for Medicine and Physiology was awarded to Drs. Joseph Goldstein and Michael Brown for the detection of the low-density lipoprotein (LDL) receptor in the coated pits of the cell membrane, e.g., of hepatocytes. This discovery turned out to be crucial in removing circulating LDL particles from the blood and thereby reducing the atherosclerosis risk with ultimate reduction of the myocardial infarction and stroke incidence.

Four major steps emerged to allow for successful therapy [1].

• 1.

  Intracellular cholesterol de novo synthesis should be reduced.

• 2.

  This is a signal for the cell to synthesize more LDL receptors and send them to the cell surface.

• 3.

  More LDL receptors at the cell surface enable the cell to import more LDL particles from blood and increase the cellular level of cholesterol toward a satiety level.

• 4.

  The result is a lower concentration of LDL particles in the blood with reduced attack to the arterial wall.

This principle was first proven in all its steps by statins. Statins reduce the activity of the key enzyme of endogenous cholesterol synthesis, HMG-CoA-reductase, as shown in Figure 1 [2]. An increase in hepatic LDL receptors is a secondary action and not the mode of action of statins and other established cholesterol-lowering drugs.

The second drug with proven cardiovascular benefit was ezetimibe. Ezetimibe, primarily acting at the gut level, ultimately also lowers LDL-cholesterol and therefore is an attractive drug for combinations with statins and bempedoic acid (BA).

Next, it was discovered that Proprotein Convertase Subtilisin/Kexin type 9 (PCSK9) reduces LDL receptor numbers by inducing their catabolism intracellularly together with the bound LDL particle. With inhibition of PCSK9, more LDL receptors survive and can recycle to the cell surface [3]. Last, BA came into the game. Very similar to the statins, this drug reduces intracellular cholesterol de novo synthesis (shown in Fig. 1).

At this point, it should be mentioned that the successful way described above consistently proved to be anti-atherosclerotic. CETP inhibitors are not available at this point and while an event reduction followed LDL-C reduction, the effect was modest.

BA differs pharmacologically from statins in two specific aspects: first, the synthesis of cholesterol is inhibited at an earlier step, at the ATP-citrate lyase level. Second, BA is a pro-drug and is converted to active coenzyme A form by very long-chain acyl-CoA synthetase in the liver [4].

Different from statins, BA is a precursor molecule that has to be activated. Because the activating enzyme is not expressed in muscle tissue, the active molecule derived from BA is not present in the muscle cell and therefore principally cannot induce muscle problems. Generally, this difference is considered as an advantage over statins. The absence of the molecule in the skeletal muscle promises to be a protection against muscle side effects.

As can be seen from Table 1, BA is only moderately effective in lowering LDL-C. As a mono-substance, the drug reduces LDL-C by around 20% from untreated baseline [5]. This is in the same order of magnitude as is observed with ezetimibe, and less than with moderate-intensity statins. High-intensity statins, PCSK9 antibodies, and siRNA are 2–3 times more effective than BA. Therefore, the initial expectations of endpoint reduction were moderate.

One of the first steps of the drug evaluation was aimed to prove safety and clinical efficacy in LDL-C lowering. Therefore, a research program was set up to analyze the LDL-C reduction and safety in various patient profiles. The major steps of this program are summarized in Table 2. BA treatment was compared to placebo treatment on top of high- and moderate-statin treatment in the trials CLEAR Harmony and CLEAR Wisdom [6, 7]. LDL-C reduction in statin-intolerant patients was analyzed in CLEAR Serenity and CLEAR Tranquility trials [8, 9]. In a pooled analysis of those 4 double-blind, placebo-controlled randomized clinical trials, LDL-C reduction was higher in statin-intolerant patients (approx. 24,5%; placebo controlled) compared to the patients who received BA on top of high- and moderate-intensity statins (approx. 17,8%; placebo controlled) [5]. Efficacy of the fixed-dose combination on top of maximum tolerated statin therapy was tested in another phase III trial. This demonstrated an LDL-C reduction of 38% (placebo corrected) [10]. In those trials, BA was associated with an acceptable safety profile. The published data demonstrate that the combination of all 3 lipid-lowering therapies is additive to each other.

Interestingly, BA not only reduced LDL-C, but also hsCRP. At the moment, it is still unclear if the hsCRP reduction (18–27% vs. placebo) has a clinical effect or not [5].

A good body of knowledge of a beneficial action of BA comes from the CLEAR-OUTCOMES trial published in March 2023 at the annual Meeting of the American College of Cardiology (ACC) and simultaneously published [11]. This study focused on statin-intolerant patients. Because statin intolerance is more often observed in women than in men, this study is a rare example of including a high proportion of women (48.1%). Altogether 13,970 patients were randomized to BA or placebo, the median patient follow-up was 40.6 months and was terminated when the predefined endpoint was met.

The primary endpoint was the time to first occurrence of a composite of death from cardiovascular causes, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization (4-component major adverse cardiovascular events [MACE]). Relative risk reduction was 13%, the absolute risk reduction was 1.6%, and thus the number needed to treat was 63 patients over the 40.6 months. During the study, the COVID pandemic leads to additional drop-in treatments in some placebo patients, but the results were positive anyway.

From CLEAR OUTCOMES, we have now firm evidence that BA reduces cardiovascular events. The selection of endpoints focuses on hard endpoints which are required for a modern outcome trial (cardiovascular mortality, nonfatal MI, and stroke, respectively), but as a composite also includes the weaker endpoint of coronary revascularization [12].

In the paper by Nissen et al. [11], in the secondary prevention patients, MACE 3 (excluding coronary interventions or strokes) showed a 15% event reduction, and for MACE 4 (including those two) reduction was 13%. Possibly the most significant reduction was that of fatal and nonfatal MI (−23%).

Perhaps more interesting data come from the primary prevention substudy [13] where the risk reductions were more dramatic: MACE 4 was reduced by 30% and the MI fatal/nonfatal by 39%. These recently presented data require publication as a full article, the reason for the difference between primary and secondary prevention is not clear at the time of this writing. We should not forget that the distinction between primary and secondary prevention is somewhat arbitrary. It distinguishes between patients with and without an endpoint like myocardial infarction; but both settings have in common that they aim at reducing atherosclerotic development.

Subgroup analysis of the CLEAR-OUTCOMES trial also demonstrated a benefit for BA in primary prevention [14], total events analysis [15], and diabetes mellitus [13], which again underlines the effect of LDL-C reduction.

BA is marketed in Europe as mono-drug (Nilemdo^®) and also as fixed-dose combination with Ezetimibe (Nustendi^®). BA has been approved for use in adults with primary hypercholesterolemia (heterozygous familial and non-familial) or mixed dyslipidemia, as an adjunct to diet [16].

• In combination with a statin or statin with other lipid-lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin, or

• Alone or in combination with other lipid-lowering therapies in patients who are statin-intolerant, or for whom a statin is contraindicated.

Major differential characteristics of BA versus PCSK9 inhibitors are given in Table 3 [17].

Here, we present the case of a patient with a clear indication for lowering LDL in secondary prevention. A 60-year-old man presented with non-STEMI, thus he was in the very high-risk category with an LDL-C goal <55 mg/dL (1.4 mmol/L) according to the recent ESC/EAS Guidelines [18]. A comprehensive risk factor assessment of the patient revealed a severely elevated LDL-C level of 215 mg/dL (5.6 mmol/L).

Expanded risk factor evaluation showed again a high LDL-C level of 225 mg/dL (5.82 mmol/L) and an Lp(a) level of 164 nmol/mL. No other notable risk factors were identified. Initial treatment was started with atorvastatin 80 mg and ezetimibe 10 mg. Because of suspected statin intolerance, he was referred to the lipid clinic. Upon admission in September 2018, his LDL-C level was 100 mg/dL (2.59 mmol/L). As per guidelines, the LDL goal level of <55 mg/dL (1.42 mmol/L) was not achieved; hence, therapy with evolocumab was initiated. Due to ongoing muscle pain, atorvastatin was switched to rosuvastatin 20 mg in combination with ezetimibe 10 mg. In October 2018, due to reported persistent and dissimilated muscle pain, he discontinued the intake of rosuvastatin and ezetimibe. Subsequent laboratory analyses revealed an LDL level of 123 mg/dL (3.18 mmol/L). After an additional 3 weeks on evolocumab, LDL remained elevated at 123 mg/dL. Therefore, the recommendation was made to add ezetimibe. By December 2018, the LDL level had decreased to 98 mg/dL (2.53 mmol/L). The suggestion at this point was to initiate a very low dose of atorvastatin 10 mg to approach the target LDL-C. Unfortunately, atorvastatin again induced muscle pain, leading to the termination of the therapy of atorvastatin and also ezetimibe by the patient. After another month, the LDL level measured 81 mg/dL (2.09 mmol/L). After a year of PCSK9 inhibitor therapy, the LDL-C was 101 mg/dL (2.61 mmol/L).

The next subsequent admission occurred one and a half years later, in April 2022, while still on evolocumab therapy, with an LDL-C level of 88 mg/dL (2.28 mmol/L). BA was now available and combined with ezetimibe into the regimen. A month later, the patient reported good tolerance, and finally, the LDL levels reached the target of 44 mg/dL (1.14 mmol/L). The LDL-progression over time is shown in Table 1. The percentage of achievable LDL-C reductions with different drug classes are given in Table 4 [19]. A similar patient case has been reported recently [20], and our findings are consistent with two lately published articles [21, 22].

As of 2022, BA was approved in the USA, Switzerland, the European Union, and the United Kingdom as an adjunct to diet and maximally tolerated statin therapy to treat adults with established ASCVD or heterozygous familial hypercholesterolemia who are not at the recommended LDL-C goal [23, 24]. In phase 3 clinical trials, BA was well tolerated in hypercholesterolemic patients unable to take statins. BA alone lowered LDL-C by a mean of 26.5%, and, in combination with ezetimibe, by an average of 39.2% [25].

A meta-analysis published in May 2023 [26], covering data from 16,978 patients, confirmed the safety data from individual trials and underlined the efficacy of BA in reducing a 5-point MACE (cardiovascular death, myocardial infarction, nonfatal stroke, hospitalization due to unstable angina, and coronary revascularization). Here, it should be mentioned that a 5-point MACE endpoint is not uniformally accepted because only the first three event types are considered hard endpoints that are not influenced by physician decision [12].

Again, in May 2023, Jialal and Olatunbosun [27] commented in an Editorial on CLEAR OUTCOMES and concluded that BA is particularly valuable in statin-intolerant patients, both in the primary and secondary prevention setting. They also emphasized further advantages, like lowering of hsCRP which may have influenced outcomes positively, and absence of worsening glycemia or new-onset diabetes.

The long-term discussion on the relative value of LDL-C versus CRP reduction has recently been fostered by an article by Ridker et al. [28]. These authors investigated three studies (PROMINENT; REDUCE-IT; STRENGTH) in which patients already receiving statins in addition received a fibrate or omega-3-fatty acids. The data support the view that in statin-treated patients the CRP is the stronger predictor of future events than the already treated LDL-C. In contrast, CLEAR-OUTCOMES included patients not taking statins and are thus fundamentally different. Moreover, the inclusion criteria of LEAR-OUTCOMES were lipids and not inflammatory markers, and BA is licensed as a lipid-lowering drug and not as an inflammatory drug. However, the debate whether CRP or LDL-C mainly translates more into the clinical cardiovascular benefit cannot be proven by data of a randomized clinical trial like CLEAR OUTCOMES that tests an intervention lowering both, LDL-C and hsCRP.

The above-stated advantage on glycemia was confirmed by a post hoc analysis from phase 3 trials [29]; more negative effects are a slightly increased cholelithiasis rate and elevated uric acid level over placebo, which may call for caution (whatever it means) in patients with gout and perhaps cholelithiasis [27].

Shapiro et al. [30] extended the safety findings in an analysis of patients with and without the metabolic syndrome. Ballantyne et al. [31] summarized that above-average declines in LDL-C could be anticipated from the following factors: female sex, absence of statin intake, diabetes history, use of ezetimibe, and high hs-CRP; in general, a decline comparable to moderate- to high-intensity statins was concluded by these authors.

When the effects of BA were compared between men and women in pooled analyses from phase 3 trials, women had significantly greater placebo-corrected reductions than men: 21 versus 17%; the p value was 0.044 and there were comparable safety data [32]. Because of the only marginal p value and almost identical safety records, sex-specific effects should not be overemphasized.

For clinical use, a major question is how BA compares to PCSK9 inhibition (PSK9i) by monoclonal antibodies. BA has a smaller effect on LDL-C lowering than PCSK9i but adds the positive reduction of hsCRP which is not altered by PCSK9i. BA as an oral drug has to be ingested daily, the antibodies only every 2–4 weeks by s.c. injection. A double or triple oral combination with a statin and ezetimibe is feasible and offers an LDL-C reduction of a similar magnitude than PCSK9i.

A common approach is that patients in secondary prevention, whose LDL-C at baseline or under statins is more than 50% above goal are candidates for PSCK9i, while those who are closer to the goal could get BA primarily. However, this approach is more based on common sense than on outcome data.

The effect on LDL-C is lower when BA is used on top of other therapies. The additional reduction in a combination therapy is a common observation may be based on several factors, like lower dose of the other single component, lower substrate availability, and limited capacity to enhance the number or function of the LDL receptors. Moreover, it should not be forgotten that percentage values are often misused for such a comparison. It is better to use an absolute reduction of LDL-C in mmol/L or mg/dL. This has been exemplified by the CTTC equation, first published in Lancet 2005 [33], where the best fit to predict the outcome (relative reduction of events) was the absolute LDL-C reduction.

On the basis of the current knowledge, it appears prudent to answer the above question as follows.

• BA is excellently tolerated over 2.5 years [34].

• BA has consistent efficacy over 2.5 years in patients with heterozygous familial hypercholesterolemia as well as with ASCVD [34].

• BA is useful for statin-treated patients that are not at the LDL-C goal.

• In the statin-intolerant patients, BA has evidence of benefit, particularly also in women.

• BA is best used in combination with ezetimibe.

• The use in primary as well as in secondary prevention is justified.

• BA, even in combination with ezetimibe, does not promise to bring largely elevated LDL-C to goal.

• In an oral triple combination with a high-intensity statin, LDL-C reductions in the range of two-thirds can be achieved.

Based on these observations, BA alone and in combination with ezetimibe is excellent for the treatment of patients who are not at goal after either statin therapy or – if statins are not tolerated – after PCSK9-reducing therapy. The effect in the described individual patient was stronger than expected. This underlines the experience that relative LDL-C reduction by BA like with other lipid-lowering drugs can vary widely from the published average.

The authors wish to thank Dr. Cornelia Malin for excellent assistance in the preparation of the manuscript.

Ethical approval with regard to the Case Report was not required in accordance with local/national guidelines. Written informed consent was obtained from the patient for publication of the details of the medical case.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

H.D.: scientific concept and preparation of the manuscript A.M.: provision of patient case.