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Journal of Atherosclerosis and Thrombosis logoLink to Journal of Atherosclerosis and Thrombosis
. 2026 May 23;33(8):1015–1024. doi: 10.5551/jat.66057

Perspectives on Bempedoic Acid, ATP-citrate lyase inhibitor: Targeting Lipid Metabolism and Inflammation

Ryuki Kitamoto 1, Yuki Morikawa-Isogai 1, Hitoshi Shimano 2
PMCID: PMC13447979  PMID: 42178228

Abstract

Bempedoic acid is a novel oral low-density lipoprotein cholesterol (LDL-C)–lowering agent that selectively inhibits ATP-citrate lyase (ACL), an enzyme located upstream of 3-hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase in the cholesterol biosynthesis pathway. Inhibition of ACL suppresses acetyl-CoA production, leading to reduced cholesterol synthesis and increased hepatic expression of LDL receptors, which lowers circulating LDL-C. Clinical trials have demonstrated an approximately 20% reduction in LDL-C when bempedoic acid is used in combination with statins. To offer a new perspective on the underlying mechanism, we reviewed the literature examining the LDL-C–lowering effects of bempedoic acid based on Michaelis-Menten kinetics. This framework helps explain why adding bempedoic acid to statin therapy may result in a synergistic increase in LDL-C reduction, greater than from increasing the statin dose alone. In animal studies, reductions observed in both hepatic and plasma triglyceride (TG) levels have been attributed to suppressed fatty acid synthesis due to decreased acetyl-CoA availability following ACL inhibition. Additionally, bempedoic acid has been shown to lower high-sensitivity C-reactive protein (hs-CRP) and inflammatory cytokines, suggesting potential anti-inflammatory and anti-lipotoxic effects. These findings support broader metabolic benefits of bempedoic acid, particularly in conditions such as obesity and fatty liver with hypercholesterolemia. In this review article, we outline the synergistic effects of bempedoic acid with statins, and its potential metabolic benefits based on the mechanism of action of bempedoic acid, and discuss its prospective role in future lipid management strategies.

Keywords: Bempedoic acid, ATP-citrate lyase, Acetyl-CoA, Dyslipidemia, Inflammation

Introduction: Future Preventive Strategies for Cardiovascular Protection

Since the introduction of statins several decades ago, the guiding principle of atherosclerotic cardiovascular disease (ASCVD) prevention through treatment of dyslipidemia has been based on lowering circulating low-density lipoprotein cholesterol (LDL-C) via upregulation of LDL receptors (LDLR), in accordance with sterol feedback regulation 1 , 2) . The subsequent introduction of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors has further increased the efficacy of LDLR-mediated LDL-C lowering, but this fundamental principle remains valid. At the same time, insufficient reduction of ASCVD has increasingly focused attention on the management of residual risk. In addition to inadequate control of LDL-C, factors such as insufficient management of triglycerides (TG) including remnant lipoproteins, chronic inflammation, and elevated lipoprotein(a) have been identified as contributors to suboptimal ASCVD reduction and are now recognized as key components of residual risk 3) . When existing treatments prove insufficient, therapeutic approaches are needed that target alternative sites of action, beyond the conventional pathways for clearing remnant lipoproteins and LDL. It is also essential to improve comorbid conditions that contribute to residual risk, such as diabetes and metabolic dysfunction-associated steatohepatitis (MASH). Achieving these new therapeutic goals is expected to contribute not only to the prevention of ASCVD, but also to organ protection as an extended objective of lipid management.

Bempedoic acid is a novel oral LDL-C–lowering agent. It inhibits ATP-citrate lyase (ACL), a key enzyme that is involved in both the cholesterol and fatty acid biosynthesis pathways. ACL directly generates acetyl coenzyme A (acetyl-CoA), an energy hub molecule that reflects nutritional status 4) . Inhibiting this enzyme depletes acetyl-CoA, thereby shifting metabolism toward reduced synthesis of both cholesterol and fatty acids. In the CLEAR-Outcomes trial, which involved patients with statin intolerance at high risk of ASCVD, long-term administration of bempedoic acid significantly reduced the incidence of the primary endpoint, MACE-4, compared with placebo at the median follow-up of 40.6 months 5) . Such high-risk ASCVD populations commonly present with comorbidities beyond elevated LDL-C, including diabetes, obesity, and MASH 6 , 7) . For the comprehensive management of these conditions, ACL represents a promising therapeutic target.

Based on these considerations, this article discusses the expectations and challenges associated with the entry of bempedoic acid into the Japanese market.

Part 1: Mechanism of Action of Bempedoic Acid

What is Bempedoic Acid?

Bempedoic acid is a novel, small-molecule, developed as an oral LDL-C–lowering agent. Large-scale international clinical trials have demonstrated that bempedoic acid reduces LDL-C levels in hypercholesterolemic patients with statin intolerance or inadequate statin response 8 - 10) . This agent was approved in the United States and some European countries in 2020 and became available in Japan in 2025.

The Mechanism of Action and Studies Investigating Efficacy of Bempedoic Acid ( Fig.1 )

Fig.1. Why bempedoic acid is expected to provide a synergistic effect with statins.

Fig.1. Why bempedoic acid is expected to provide a synergistic effect with statins

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A) Differences in the Sites of Action of Statins and Bempedoic Acid in Hepatocytes

Within the cholesterol biosynthesis pathway in hepatocytes, statins and bempedoic acid each competitively inhibit their respective target enzymes. This process decreases the production of cholesterol synthesis precursor molecules and ultimately upregulates LDLR expression, leading to the uptake of circulating LDL-C into the cells (green arrows: effects of statins; pink arrows: effects of bempedoic acid).

B) Enzyme reaction velocity in response to changes in competitive inhibitor concentrations-Michaelis-Menten Kinetics

The effects of varying the concentration of each competitive inhibitor are evaluated under conditions where enzyme and substrate concentrations are assumed to remain constant.

• stage I: A large amount of free enzyme is present, and the speed of the reaction between the enzyme and the competitive inhibitor increases relatively quickly.

• stage II, III: As the number of enzyme-inhibitor complexes increases, the speed of the reaction decreases.

After statin dose escalation, the reaction corresponds to stage II or beyond, where the reaction with the target enzyme becomes slower. When bempedoic acid is added to statin therapy, the reaction begins at stage I, allowing for a rapid interaction with the target enzyme. In addition, by inhibiting ACL, acetyl-CoA is decreased, which reduces the supply of HMG-CoA used downstream by HMGCR. This shifts the statin-HMGCR interaction out of the saturated zone of the Michaelis-Menten curve, allowing higher statin effects to provide synergistic suppression of cholesterol synthesis. As a result cholesterol is more effectively reduced by combining bempedoic acid with statins than by statin dose escalation alone.

TCA: tricarboxylic acid; ACSVL: very long-chain acyl-CoA synthetase; ACL: ATP-citrate lyase; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A; HMGCR: HMG-CoA reductase; LDLR: LDL receptors; LDL: low-density lipoprotein.

Bempedoic acid is an ACL inhibitor that lowers LDL-C, primarily by inhibiting cholesterol synthesis in the liver. In the cholesterol biosynthesis pathway, ACL is an enzyme upstream of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGCR), the enzyme inhibited by statins. The ACL-inhibiting activity of bempedoic acid requires its conversion to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1 (ACSVL1). Because ACSVL1 is highly expressed in the liver but not in most peripheral tissues (including skeletal muscles), bempedoic acid is considered to act in a liver-specific manner. Similar to the well-known feedback mechanism of HMG-CoA reductase inhibition, ACL inhibition suppresses the cholesterol biosynthesis pathway, leading to increased density and activity of hepatic LDLR, enhanced clearance of LDL particles from the bloodstream, and a reduction in serum LDL-C levels 11) ( Fig.1A ) .

In Mendelian randomization analyses, single nucleotide polymorphisms in the ACL gene region associated with LDL-C reduction were shown to be linked with a decreased risk of ASCVD. This effect was equivalent to that of HMGCR gene mutations, which mimic the efficacy of statins 12) . Based on these findings, a causal relationship was predicted between ACL inhibition and clinical benefits similar to those seen with statins, even prior to interventional trials. In several rodent models, bempedoic acid reduced markers of cholesterol biosynthesis, improved serum lipid profiles, and suppressed the progression of diet-induced atherosclerosis 11 , 13) . These results are considered to support the clinical efficacy of bempedoic acid.

Part 2: Why may Bempedoic Acid be Effective as an Add-on to Statins?

Japanese Phase 2 and Phase 3 trials and a long-term safety study have demonstrated efficacy and safety comparable to those of international clinical trials 5 , 8 , 10 , 14 - 18) . Subgroup analyses showed approximately 20% LDL-C reduction with bempedoic acid in patients with inadequate statin response.

In the “Guidelines for the Prevention of Atherosclerotic Cardiovascular Diseases 2022”, published by the Japan Atherosclerosis Society, LDL-C management target values are set according to each patient’s ASCVD risk, and statins are recommended as first-line therapy 19) . If the effect is insufficient, administration of the maximum tolerated dose of statins is recommended, based on a substantial body of evidence accumulated to date. When increasing the statin dose, it is common practice to double the dose within the approved range. However, the resulting LDL-C reduction is rarely proportional to the dose increase; in clinical practice, the additional effect is often only a few percentage points. This phenomenon, sometimes referred to as the “6% rule of statins” 20) , has been documented in studies of atorvastatin and rosuvastatin. Although statins and bempedoic acid inhibit the same cholesterol biosynthesis pathway, the LDL-C–lowering effects differ between statin dose escalation and the addition of bempedoic acid to background statin therapy in patients with inadequate statin response. Below, we consider these differences from both the biochemical and kinetic perspectives.

First, from a biochemical perspective, intracellular hepatic cholesterol levels are tightly regulated by sterol regulatory element-binding protein 2 (SREBP-2). When statins inhibit cholesterol synthesis via competitive inhibition of HMGCR, SREBP-2-driven transcription is activated, increasing the expression of enzymes in the cholesterol synthesis pathway, such as HMGCR and ACL, and thereby counteracting the inhibitory effect. At the same time, LDLR expression is upregulated, enhancing clearance of LDL-C from plasma. The net result is a new equilibrium in which intracellular cholesterol levels remain essentially stable, while circulating LDL-C falls due to increased LDLR-mediated uptake. However, prolonged SREBP-2 activation also induces PCSK9, which promotes LDLR degradation. Thus, statin dose escalation increases both LDLR expression (accelerator) and PCSK9 levels (brake), eventually limiting further hepatic LDL-C uptake 21) .

Next, we discuss our new hypothesis regarding the “6% rule” and the synergistic effect of bempedoic acid from the perspective of Michaelis-Menten kinetics ( Fig.1B ) . This model originally describes the relationship between enzyme activity and substrate concentration 22 , 23) . As substrate concentration increases, reaction velocity rises until the enzyme’s active sites are saturated, beyond which further increases have minimal effect. The same principle applies to competitive inhibition: increasing inhibitor concentration enhances inhibition up to a saturation point, after which a plateau is reached. Increasing the statin dose brings the drug closer to its maximum inhibitory capacity, so the relationship between dose and HMG-CoA response is no longer a linear dose-response curve but reaches a plateau region on the Michaelis-Menten curve ( Fig.1B ) . Once a substantial fraction of HMGCR is occupied, further dose increases yield diminishing returns. Initial statin therapy shifts the system to a new equilibrium; dose escalation moves it again, but the magnitude of change is constrained by saturation effects and the compensatory regulation described above. This ceiling effect is not unique to statins and has also been observed in dose-finding studies of bempedoic acid 24) .

Two main factors may explain the observed synergistic effect of bempedoic acid. First, the reaction between bempedoic acid and ACL is thought to begin at the initial phase of Michaelis-Menten kinetics, allowing for a rapid interaction with the target enzyme ACL. Second, by inhibiting an enzyme upstream of HMGCR, bempedoic acid lowers the concentration of HMG-CoA, which is the substrate for HMGCR, the statin target. This changes the relative competitive balance between HMGCR and statin, and mitigates the saturation limitation described by Michaelis-Menten kinetics and enhances the efficacy of statins. This clear synergistic effect likely reflects the advantage of inhibiting different enzymes within the same linear cholesterol biosynthesis pathway. In summary, rather than increasing the statin dose to further inhibit HMGCR, targeting a different enzyme in the pathway, such as ACL, may result in greater LDL-C reduction. This concept is supported by a randomized controlled trial (RCT) conducted in Italy, in which patients with inadequate statin response were assigned either to statin dose escalation or to bempedoic acid added to ongoing statin therapy. After 12 weeks, LDL-C levels fell by 8% in the statin escalation group versus 23% in the combination group 25) . In summary, adding bempedoic acid to statins suppresses cholesterol synthesis more efficiently than simply increasing the statin dose.

Part 3: The Potential of Bempedoic Acid

Bempedoic Acid Attenuates Lipotoxicity by Reducing Acetyl-CoA, a Key Metabolic Substrate ( Fig.2 )

Fig.2. Bempedoic acid reduces the level of acetyl-CoA as a metabolic substrate and helps to decrease lipotoxicity.

Fig.2. Bempedoic acid reduces the level of acetyl-CoA as a metabolic substrate and helps to decrease lipotoxicity

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A) Physiological status

In an energy-abundant state, SREBP1c is induced, leading to increased ACL activity and enhanced conversion of citrate into acetyl-CoA. The resulting elevation in acetyl-CoA, a common substrate for both cholesterol and triglyceride synthesis pathways, promotes the synthesis of both lipid classes. Increased triglyceride synthesis in the liver exacerbates lipotoxicity, with hepatic steatosis linked to phenotypes such as inflammation and fibrosis. These pathologies, mediated by lipotoxicity, are commonly involved in organ damage such as obesity, atherosclerosis, type 2 diabetes, and MAFLD/MASH.

B) Effects of bempedoic acid

Following administration of bempedoic acid under energy-rich conditions, ACL is inhibited, leading to reduced production of acetyl-CoA, which is a central substrate for both triglyceride and cholesterol synthesis pathways. This suppression attenuates the biosynthesis of both lipid classes, initiating a reduction in lipid accumulation and thereby mitigating lipotoxicity.

Additionally, bempedoic acid may indirectly promote mitochondrial fatty acid β-oxidation via activation of CPT-1, the mitochondrial fatty acid transporter. This activation may result from reduced levels of malonyl-CoA, a potent CPT-1 inhibitor, which in turn may arise from decreased acetyl-CoA availability.

Beyond its ACL-dependent effects, bempedoic acid may also exert ACL-independent actions, such as activating PPARs, thereby promoting fatty acid β- or ω-oxidation, potentially via a direct mechanism, though the exact molecular basis has not yet been elucidated (*).

Overall, by reducing lipotoxicity, bempedoic acid may help prevent organ damage associated with hepatic steatosis, inflammation, and fibrosis.

SREBP: sterol regulatory element-binding protein; SRE: sterol regulatory element; CiC: citrate carrier; TCA: tricarboxylic acid; ACL: ATP-citrate lyase; OAA, oxaloacetate; HMGCS: 3-hydroxy-3-methylglutaryl coenzyme A synthase; HMGCR: HMG-CoA reductase; ACC: acetyl-CoA carboxylase; CPT-1: carnitine palmitoyltransferase 1, FASN: fatty acid synthase; ACSS: acyl-CoA short-chain synthetases; NADP: nicotinamide adenine dinucleotide phosphate oxidized form; NADPH: nicotinamide adenine dinucleotide phosphate reduced form; PPP: pentose phosphate pathway; TG: triglyceride; MAFLD: metabolic dysfunction-associated fatty liver disease; MASH: metabolic dysfunction-associated steatohepatitis, PPARs: peroxisome proliferator-activated receptors.

Bempedoic acid dose-dependently suppressed the production of multiple metabolites, including acetyl-CoA generated by ACL, and transiently increased levels of citrate, which is the substrate of ACL 26) . ACL is a cytosolic enzyme that cleaves citrate into oxaloacetate and acetyl-CoA, a common substrate for the de novo synthesis of cholesterol and fatty acids 27) . The reduction of acetyl-CoA as a key substrate in cellular nutrient metabolism is considered one of the distinctive effects of bempedoic acid. Lipogenesis is achieved through the formation of malonyl-CoA by the enzyme acetyl-CoA carboxylase (ACC), followed by the synthesis of fatty acids and TGs. In this section, we will explore the significance of bempedoic acid-induced suppression of lipotoxicity.

The accumulation of visceral fat due to obesity and the deposition of ectopic fat in conditions such as fatty liver are known to promote the progression of atherosclerosis and increase the risk of myocardial infarction (MI) and angina. These conditions are collectively referred to as lipotoxicity and are characterized by increased visceral and ectopic fat accumulation and adipocyte dysfunction and inflammation, as well as by adipokine dysregulation and insulin resistance 28) ( Fig.2A ) .

When LDLR knockout mice were fed a high-fat diet, which induced increases not only in plasma LDL-C and TG but also in hepatic cholesterol and hepatic TG, but those increases were suppressed by the administration of bempedoic acid. In addition, bempedoic acid suppressed the hepatic expression of the C-C motif chemokine ligand 3 (CCL3) and nitric oxide synthase 2 (NOS2) genes, which are markers of proinflammatory macrophages (M1). It also suppressed the expression of tumor necrosis factor (TNF), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), C-C motif chemokine ligand 2 (CCL2), and NOS2 genes in atherosclerotic lesions of the aorta. Furthermore, in aortic lesions, bempedoic acid suppressed the accumulation of cholesteryl esters, resulting in a 44% reduction in lesion size 13) . Similar findings have been reported in several other studies 11 , 29 , 30) , suggesting that the reduction in acetyl-CoA via ACL inhibition by bempedoic acid attenuates lipotoxicity, and indicating the efficacy of suppressing atherosclerosis. These findings suggest that bempedoic acid, acting as a potential anti-inflammatory and anti-atherogenic agent, reduces TG-rich lipoproteins including VLDL and the expression of inflammatory cytokines, both of which are known to contribute to plaque inflammation and formation.

These findings suggest that the resolution of lipotoxicity by bempedoic acid is likely mediated through the suppression of lipogenesis, although enhanced lipid degradation may also play a role 26 , 31 , 32) ( Fig.2B ) . Bempedoic acid may also target key regulators of TG metabolism and atheroma inflammation; further clinical evidence is needed.

In clinical practice, a subgroup analysis from the CLEAR-Outcomes trial showed that obese patients treated with bempedoic acid had a significantly reduced risk of MACE-4 compared with the placebo group, consistent with the results of the overall analysis. In addition, the bempedoic acid group lost weight during the study period 33) . Obesity and hypercholesterolemia are risk factors for ASCVD, and these data demonstrate that bempedoic acid may have beneficial effects on both.

However, although bempedoic acid has demonstrated the effects of reducing ASCVD, no data are yet available regarding its impact on human aortic lesions. In clinical practice, a meta-analysis of clinical trials of bempedoic acid showed no reduction in plasma TG levels 34 , 35) . This apparent contradiction may be due to fundamental differences in TG metabolism between mice and humans. In humans, plasma TG levels are predominantly regulated by lipoprotein lipase (LPL) activity, whereas mice are characterized by rapid and vigorous very-low-density lipoprotein (VLDL) turnover driven by a high influx of free fatty acids from adipose tissue 36 , 37) . This metabolic feature normally results in very low plasma VLDL levels in mice. Under conditions of obesity, metabolic stress, or energy surplus, the metabolic load of free fatty acids is further amplified, accompanied by enhanced hepatic de novo lipogenesis. Consequently, both plasma and hepatic metabolic states in mice provide a favorable context for observing the metabolic benefits of bempedoic acid. In pathophysiological mouse models resembling metabolic dysfunction-associated fatty liver disease (MAFLD) and/or MASH, bempedoic acid was reported to reduce plasma and hepatic TG levels and liver fibrosis and improve MASH 38) . In humans, we speculate that the strong dependence of human plasma TG levels on LPL activity may mask potential favorable effects of bempedoic acid on TG metabolism when assessments are limited to circulating TG concentrations alone.

As emerging clinical evidence, findings from a single-center prospective cohort study in patients with hypercholesterolemia showed that 12 weeks of bempedoic acid treatment resulted in significant reductions in liver controlled attenuation parameter (CAP) and liver stiffness (LS) 39) . Because these indices are established markers of hepatic fat content and fibrosis, the findings suggest that bempedoic acid may reduce intrahepatic TG accumulation and improve fatty liver, even in the absence of detectable changes in circulating TG levels.

Although direct evaluation of organ-specific metabolism in humans remains challenging, obese and diabetic patients are known to exhibit increased hepatic lipogenesis 40 , 41) . Future clinical studies that evaluate bempedoic acid or ACL inhibition leading to reduced acetyl-CoA, a central metabolic hub, should therefore focus on these metabolically dysregulated populations, in whom the therapeutic impact on lipid metabolism may be more apparent. Additional data generation following the launch of bempedoic acid in Japan is eagerly anticipated.

The Significance of Controlling both Cholesterol and Inflammation in Treatment

The aforementioned results from mouse studies showing suppression of plaque formation also suggest that bempedoic acid provides anti-inflammatory effects, potentially another feature of this agent. While no human studies have yet been conducted to elucidate the underlying mechanisms, the clinical effect of lowering plasma hs-CRP has been consistently demonstrated across multiple trials 17 , 42) . Anti-inflammatory effects achieved through hs-CRP suppression are known to reduce ASCVD risk independently of LDL-C reduction 43 , 44) .

In a Japanese primary prevention cohort, complications correlated with elevated hs-CRP levels included hypertension, diabetes, obesity, hypercholesterolemia, metabolic syndrome, and smoking 45) . Because bempedoic acid offers both LDL-C–lowering and anti-inflammatory effects, it may be an appropriate treatment option for patients with hypercholesterolemia and these additional comorbidities when LDL-C control is insufficient even at the maximum tolerated statin dose. A meta-analysis on the hs-CRP–lowering effects of lipid-lowering agents found that bempedoic acid achieved hs-CRP reductions similar to those observed with statins 46) . If hs-CRP reduction is considered to result from steps downstream in the cholesterol biosynthesis pathway, this could explain the similar effects observed with statins and bempedoic acid. In addition, administration of bempedoic acid suppressed the expression of inflammatory marker genes associated with the M1 (pro-inflammatory) macrophage phenotype in the liver, suggesting that this mechanism may contribute to the observed reduction in hs-CRP 13 , 47) . In this context, it may be worth considering whether bempedoic acid’s unique ability to lower acetyl-CoA contributes to its anti-inflammatory effect. Regarding other mechanisms, when human primary monocyte-derived macrophages (MDMs) were exposed to bempedoic acid, an increase in adenosine monophosphate-activated protein kinase (AMPK) phosphorylation was observed, which correlated with a reduction in the production of pro-inflammatory cytokines and chemokines 48) . Notably, unlike hepatocytes, bempedoic acid was not detected in its CoA-conjugated form in human primary MDMs, suggesting that the unmodified form of bempedoic acid is responsible for AMPK activity in these cells. Therefore, it is plausible that the anti-inflammatory effects of bempedoic acid may be mediated via these mechanisms.

Closing

In this review, we analyzed the current clinical findings on bempedoic acid from a mechanistic perspective and considered future directions for its use.

Highlights

1) Bempedoic acid is a novel oral LDL-C–lowering agent that selectively inhibits ACL in the liver. Inhibition of ACL suppresses cholesterol synthesis, enhances LDLR activity, and consequently lowers circulating LDL-C.

2) Based on the Michaelis-Menten model, co-administration of bempedoic acid with a statin offers more efficient inhibition of cholesterol synthesis than simply increasing the statin dosage. The additional LDL-C–lowering effect is approximately 6% with statin dose escalation, compared with about 20% when the initial statin dose is combined with bempedoic acid.

3) The reduction in acetyl-CoA through ACL inhibition by bempedoic acid may help improve lipid metabolism and inflammation associated with obesity, fatty liver, and hypercholesterolemia, potentially contributing to the suppression of aortic atherogenesis.

With the accumulation of real-world clinical experience, it is hoped that the types of patients and disease conditions best suited for bempedoic acid—as well as optimal combination therapies—will come into clearer focus. In addition to the Phase 3 trials have already been conducted in Japan, further ASCVD outcome evidence specific to Japanese patients will need to be established for clinical guidelines to offer appropriate recommendations regarding bempedoic acid use. It is also important to clarify whether the effects of bempedoic acid on reduction of ASCVD are due solely to LDL-C reduction or are also influenced by anti-inflammatory effects. In addition, the roles of TG and remnant lipoproteins in ASCVD risk reduction remain an important topic for future investigation.

Among the various pathophysiological effects observed with ACL inhibition in preclinical studies, the most pronounced improvements appear to occur under conditions of hepatic steatosis. This suggests that bempedoic acid may help improve metabolic abnormalities in patients with obesity, diabetes, MAFLD, and MASH. Given that these conditions are all associated with elevated ASCVD risk, such effects would likely contribute additional benefit beyond LDL-C lowering alone. Because the acetyl-CoA molecule plays a central role in energy metabolism, reductions in acetyl-CoA may not only reflect improvements in substrate-level metabolism, but could also influence longevity and aging through epigenetic mechanisms, such as suppressing the acetylation of both chromatin and metabolic genes in the nucleus 49) . Furthermore, the reduction in acetyl-CoA may suppress protein acetylation more broadly, affecting nuclear targets such as transcription factors, cofactors, and histones, as well as non-nuclear proteins involved in energy metabolism, including the citrate carrier (CiC) 50) . These post-translational modifications may mediate part of bempedoic acid’s metabolic and anti-inflammatory effects. This is one reason why ACL inhibitors are referred to as calorie restriction mimetics 4) . In long-term follow-up studies of ASCVD outcomes, this broader perspective will be essential for fully understanding the potential of bempedoic acid in a therapeutic context. Meanwhile, there are a few reports that the effects of bempedoic acid could be partially ACL-independent. Bempedoic acid ameliorate Western diet-mediated hepatic steatosis in both WT and liver ACL knockout mice, and this apparent independence from ACL could be related to activation of PPARs 31) . Another potential mechanism has been reported based on bempedoic acid-induced changes in the microbiome 51) . These ACL-independent mechanisms are currently at the initial research stage, awaiting further investigation. The potential effects of bempedoic acid and the mechanisms associated with them are gradually being elucidated, and it is hoped that bempedoic acid will contribute further to meeting unmet clinical needs in the future.

Acknowledgements

The authors wish to thank EDIT, Inc. (Tokyo, Japan) for translation into English, which was funded by Otsuka Pharmaceutical Co., Ltd., in accordance with Good Publication Practice guidelines (https://www.ismpp.org/gpp-2022).

Notice of Grant Support

None.

Conflicts of Interest

RK and YI are employees of Otsuka Pharmaceutical Co., Ltd. HS has received honoraria from Kowa Company, Ltd., clinical research funding from Parexel International Inc., and scholarship grants from Mitsubishi Tanabe Pharma Corporation and Life Scan Japan.

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