Bempedoic Acid: From Guidelines to the Real World

Abstract

Atherosclerotic cardiovascular disease remains the global leading cause of mortality. Hypercholesterolemia is a major, yet mostly insufficiently controlled, cardiovascular risk factor. Guideline-recommended lipid-lowering therapies (LLT) are underutilized, leading to low rates of low-density lipoprotein cholesterol (LDL-C) goal attainment. Poor adherence and intolerance to statins contributed to the need for developing non-statin lipid-lowering drugs. Their role increased following the concept of upfront combination LLT in patients unlikely to reach their LDL-C goal on statin monotherapy. Bempedoic acid emerged as a generally safe, efficient, and cost-effective strategy to lower LDL-C and cardiovascular risk in high- and very-high-risk individuals unable or unwilling to take statins. This updated review 1) outlines the basic pharmacology of bempedoic acid, 2) summarizes the results of clinical trials and real-world studies evaluating the efficacy and safety of bempedoic acid in the treatment of dyslipidemias, and 3) discusses the various current guidelines on the use of bempedoic acid in clinical practice.

INTRODUCTION

Cardiovascular diseases (CVDs), particularly ischemic heart disease, remain the global leading cause of mortality.¹ Elevated low-density lipoprotein cholesterol (LDL-C) accounts for ~20% of the cardiovascular disability-adjusted life years, exerting a large impact on the development of atherosclerotic cardiovascular disease (ASCVD).² The prevalence of dyslipidemias ranges from 30%–40% in Asia to nearly 50%–60% in Europe, while hypercholesterolemia, defined as total cholesterol (TC) of ≥200 mg/dL to ≥240 mg/dL, is found in approximately 25% of the global population.³,⁴ Following arterial hypertension and dietary patterns, hypercholesterolemia is predicted to remain the predominant contributor to CVDs in the years 2025–2050.⁵ Each 1% decline in LDL-C levels is equivalent to ~1% lower CVD risk.⁶ The aim of the primary and secondary CVD prevention is to diminish cumulative exposure to high LDL-C and to reach risk-based LDL-C target values early in life.⁷

Real-world approaches do not always align with evidence-based strategies. Statins, the first-line drugs recommended to effectively lower LDL-C and CVD risk, are underutilized.⁸ In a recent analysis from the United States, statins were prescribed to roughly 59%, 54%, and 44% of patients with ASCVD, diabetes, and dyslipidemia, respectively.⁸ In the European DA VINCI study, only 22% of primary-prevention patients and 42% of those with established ASCVD were treated with a high-intensity statin.⁹ Although the combination lipid-lowering therapy (LLT), comprising a statin, ezetimibe, and/or a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor—either a PCSK9 monoclonal antibody (mAb) or inclisiran—is associated with improved LDL-C control, its implementation among high- and very-high-risk patients across Europe reached roughly 26%, as demonstrated in the SANTORINI study.¹⁰ Correspondingly, the rates of LDL-C goal attainment in Central and Eastern Europe amounted to 24%,¹¹ and ranged from 28% to 41% in Western Europe.¹²,¹³,¹⁴,¹⁵

The awareness of dyslipidemia does not exceed 50%.¹⁶,¹⁷ Nearly 40% of eligible patients reject or disrupt statin therapy,¹⁸ although lacking statin adherence is associated with a higher risk of death, stroke, and myocardial infarction (MI).¹⁹ As widespread misinformation and insufficient patient education trigger fear of statin side effects,²⁰ over 50% of statin-associated muscle symptoms result from the drucebo effect,²¹ and even 95% of patients who report myalgia at first may pursue statin therapy.²² The prevalence of statin intolerance amounts to roughly 9.1%, but remains below 7% when diagnosed according to the criteria of the International Lipid Expert Panel (ILEP) and the European Atherosclerosis Society (EAS).²³ Nonetheless, affected individuals, particularly women, suffer from frequent muscle symptoms leading to severe pain in 43% of the cases.²⁴ Three-quarters of statin-intolerant patients fail to meet their LDL-C goal,²⁵ whereas the use of a greater number of lipid-lowering drugs is associated with higher LDL-C decrements, but not with further impairment of the quality of life.²⁶

Non-statin lipid-lowering drugs are necessary to reduce LDL-C and CVD risk in statin-intolerant or non-adherent patients, and in those who cannot reach their LDL-C goal on statin monotherapy, both in primary and secondary prevention settings.²⁷ The concept of upfront combination LLT in preference to high-intensity statin monotherapy reinforced add-on non-statin drugs in high- and very-high-risk patients.²⁸ Bempedoic acid, formerly referred to as ETC-1002, emerged as a generally safe, efficient, and cost-effective add-on to ezetimibe and PCSK9 inhibitors in high- and very-high-risk individuals unable or unwilling to take statins.²⁹ It has been approved in Europe for the management of primary hypercholesterolemia and mixed dyslipidemia, either as monotherapy or in combination with other lipid-lowering drugs, as well as for the reduction of CVD risk in high- and very-high risk patients.³⁰ Based on evidence published by November 2025, this updated review 1) outlines the basic pharmacology of bempedoic acid, 2) summarizes the results of clinical trials and real-world studies evaluating the efficacy and safety of bempedoic acid in the treatment of dyslipidemias, and 3) discusses the various current guidelines on the use of bempedoic acid in clinical practice.

BASIC PHARMACOLOGY

Pharmacological effects of bempedoic acid are illustrated in Fig. 1. Bempedoic acid is administered as an oral prodrug, subsequently converted into active bempedoyl-coenzyme A (CoA) through very-long-chain acyl-CoA synthetase-1.³¹ As ASCVL1 is expressed in the liver but not in skeletal muscles,³² the risk of muscle-related adverse events appears to be lower compared to statins.³³ Following activation in the liver, bempedoic acid suppresses cholesterol biosynthesis by inhibiting adenosine triphosphate citrate lyase (ACL), which precedes 3-hydroxy-3-methylglutaryl-CoA reductase targeted by statins.³⁴ In preclinical models, ACL inhibition with bempedoic acid upregulated the expression of LDL receptors, reduced the concentration of circulating LDL-C, and diminished the development of atherosclerotic lesions.³⁵,³⁶,³⁷ Genetic variants mimicking ACL inhibition were associated with lower LDL-C levels and lower CVD risk.³⁸

Fig. 1. Pharmacological effects of bempedoic acid. Created with BioRender.com.

LDLR, low-density lipoprotein receptor; LDL-C, low-density lipoprotein cholesterol; HMGR, 3-hydroxy-3-methylglutaryl coenzyme A reductase; HMG-CoA, 3-hydroxy-3-methylglutaryl coenzyme A; CoA, coenzyme A; FFA, free fatty acids; ASCVL1, very-long-chain acyl-CoA synthetase-1; ACL, adenosine triphosphate citrate lyase; AMPK, adenosine monophosphate-activated protein kinase.

In addition to its effect on ACL, bempedoic acid directly activates adenosine monophosphate-activated protein kinase (AMPK), which suppresses gluconeogenesis and lipogenesis while facilitating fatty acid oxidation.³⁹ Preclinical studies demonstrated that bempedoic acid counteracts intimal hyperplasia and cardiac remodeling.⁴⁰,⁴¹,⁴²,⁴³ In a high-fat diet-induced non-alcoholic fatty liver disease model, bempedoic acid prevented weight gain, optimized blood glucose, downregulated profibrotic pathways, lowered hepatic TC and triglycerides (TG), and reduced disease activity.⁴⁴,⁴⁵ In a mouse model of non-alcoholic steatohepatitis, bempedoic acid combined with glucagon-like peptide-1 receptor agonist, liraglutide, exerted additive benefits in the reduction of hepatic steatosis, fibrosis, and hepatocellular ballooning.⁴⁶ Recent studies reported that the anti-steatotic effects of bempedoic acid are independent of ACL, but may be attributable to the activation of AMPK or peroxisome proliferator-activated receptor α.⁴⁷,⁴⁸

CLINICAL TRIALS

1. Lipid-lowering effect in phase two clinical trials

The design and results of the phase two randomized controlled trials with bempedoic acid are summarized in Table 1.⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴,⁵⁵,⁵⁶,⁵⁷ On top of background statin therapy, bempedoic acid decreased LDL-C by 24% compared to 4% decline observed in the placebo group after 12 weeks.⁵⁰ Alongside LDL-C reductions, bempedoic acid significantly lowered TC, non-high-density lipoprotein cholesterol (non-HDL-C), apolipoprotein B (apoB), and LDL particle number, while increasing HDL particle number. HDL-C, TG, and lipoprotein(a) [Lp(a)] did not change substantially. The shift towards a less atherogenic lipid profile was accompanied by significant reductions in high-sensitivity C-reactive protein (hsCRP). No meaningful changes in glycemic markers were reported in a trial dedicated to hypercholesterolemic subjects with type 2 diabetes.⁵² Bempedoic acid was efficient, safe, and well-tolerated when added to a statin,⁵⁰,⁵⁴ ezetimibe,⁵³,⁵⁵ or a PCSK9 mAb.⁵⁶ Fixed-dose combination (FDC) of bempedoic acid and ezetimibe reduced LDL-C to a greater extent than ezetimibe alone or placebo (−38.8% vs. −19.2% vs. 0.9%, p<0.001), facilitating the attainment of LDL-C <70 mg/dL (38.9% vs. 5.4% vs. 0.0%, p<0.001) within 12 weeks in patients with hypercholesterolemia and type 2 diabetes on no statin.⁵³

Table 1. Efficacy of bempedoic acid in phase two clinical trials⁴⁹,⁵⁰,⁵¹,⁵²,⁵³,⁵⁴,⁵⁵,⁵⁶,⁵⁷ .

Trials	Population	LDL-C reduction	Other effects on lipids and inflammation markers
NCT01262638	LDL-C: 130–220 mg/dL; TG <400 mg/dL (n=177)	−26.6% at week 12 with 120 mg BA	TC: −17.1%; non-HDL-C: −23.0%; apoB: −22.1%; LDL: −20.7%; HDL: +7.3%; Lp(a): +6.0%*
NCT02072161	LDL-C: 115–220 mg/dL; TG ≤400 mg/dL (n=134)	−24.3% at 12 weeks with 180 mg BA	TC: −15.3%; non-HDL-C: −16.6%; apoB: −17.2%; LDL: −21.3%; HDL: +10.1%
NCT01751984	LDL-C: 100–270 mg/dL; TG <400 mg/dL; statin intolerance (n=56)	−32.0% at week 8 with 60, 120, 180, and 240 mg BA, two weeks each	TC: −22.2%; non-HDL-C: −25.4%; apoB: −19.7%; hsCRP: −42.0%*
NCT01607294	LDL-C ≥100 mg/dL; type 2 diabetes (n=60)	−42.9% at day 29 with 80 and 120 mg BA, two weeks each	TC: −25.1%; non-HDL-C: −32.0%; hsCRP: −41.0%*
NCT03531905	LDL-C: 100–220 mg/dL; type 2 diabetes (n=179)	−38.8% at week 12 with FDC 180 mg BA + 10 mg ezetimibe	TC: −27.3%; HDL-C: −5.1%; non-HDL-C: −33.0%; apoB: −27.5%; hsCRP: −25.3%*
NCT02659397	LDL-C: 100–220 mg/dL; TG ≤400 mg/dL (n=68)	−13.0% at day 29 with 180 mg BA + 80 mg atorvastatin	TC: −5.7%; non-HDL-C: −7.4%; apoB: −9.0%; hsCRP: −34.6%*
NCT03051100	LDL-C: 130–189 mg/dL (n=63)	−63.6% at week 6 with 180 mg BA + 20 mg atorvastatin + 10 mg ezetimibe	TC: −47.1%; non-HDL-C: −60.0%; apoB: −53.5%; TG: −27.4%; hsCRP: −47.7%*
NCT03193047	LDL-C ≥160 mg/dL (n=59)	−27.5% at month 2 with 180 mg BA + PCSK9 mAb	TC: −17.0%; non-HDL-C: −23.0%; apoB: −21.8%; hsCRP: −34.4%*
	LDL-C: 130–220 mg/dL; TG ≤400 mg/dL; Japanese (n=188)	−21.3% at week 12 with 180 mg BA	TC: −13.6%; HDL-C: −7.3%; non-HDL-C: −16.0%; apoB: −12.5%

Data are presented as the least-square mean percent change (unless otherwise indicated) in LDL-C from baseline with the corresponding differences in secondary parameters (p<0.05 vs. placebo). Key trial characteristics are presented in bold.

LDL-C, low-density lipoprotein cholesterol; TG, triglycerides; BA, bempedoic acid; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; apoB, apolipoprotein B; LDL, low-density lipoprotein (particle number); HDL, high-density lipoprotein (particle number); Lp(a), lipoprotein(a); hsCRP, high-sensitivity C-reactive protein; FDC, fixed-dose combination; PCSK9, proprotein convertase subtilisin/kexin type 9; mAb, monoclonal antibody.

^*Median percent change.

2. Lipid-lowering effect in phase three clinical trials

The design and efficacy measures of the phase three randomized controlled trials with bempedoic acid are summarized in Table 2.⁵⁸,⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵ The CLEAR Tranquility⁵⁸ and the CLEAR Serenity⁵⁹ trials examined the use of bempedoic acid in hypercholesterolemic subjects with statin intolerance. In the former, bempedoic acid added to ezetimibe lowered the mean LDL-C from 129.8 mg/dL at baseline to 96.2 mg/dL at week 12.⁵⁸ The LDL-C reduction was substantial from the first follow-up visit after four weeks. Although the LDL-C-lowering effect was independent of baseline LDL-C, body mass index (BMI), age, race, sex, or history of diabetes, greater LDL-C reductions were observed in participants treated with non-statin lipid-lowering drugs or who received no LLT compared with those on a low- or very-low-dose statin (−34.7% vs. −20.5%). Similar results were reported in the CLEAR Serenity trial.⁵⁹ In both trials, LDL-C reductions were accompanied by decreases in TC, non-HDL-C, apoB, and hsCRP, whereas the impact on HDL-C, TG, and Lp(a) seemed negligible.⁵⁸,⁵⁹

Table 2. Efficacy of bempedoic acid in phase three clinical trials⁵⁸,⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵ .

Trials	Population	LDL-C reduction	Other effects on lipids and inflammation markers
CLEAR Tranquility (NCT03001076)	LDL-C ≥100 mg/dL; statin intolerance (n=269)	−23.5% at week 12 with 180 mg BA + 10 mg ezetimibe	TC: −15.1%; HDL-C: −7.3%; non-HDL-C: −18.4%; apoB: −14.6%; hsCRP: -32.5%*
CLEAR Serenity (NCT02988115)	LDL-C ≥130 mg/dL for healthy group; LDL-C ≥100 mg/dL for ASCVD/FH group; statin intolerance (n=345)	−23.6%† at week 12 with 180 mg BA	TC: −16.1%†; non-HDL-C: −19.0%†; apoB: −15.5%†; hsCRP: −25.4%*
NCT03337308	LDL-C ≥130 mg/dL for high-risk group; LDL-C ≥100 mg/dL ASCVD/FH group; Max. tolerated LLT (n=301)	−36.2% at week 12 with FDC 180 mg BA + 10 mg ezetimibe	TC: −26.4%; non-HDL-C: −31.9%; apoB: −24.6%; hsCRP: −35.1%*
CLEAR Wisdom (NCT02991118)	LDL-C ≥70 mg/dL; ASCVD and/or FH; Max. tolerated LLT (n=779)	−15.1% at week 12 with 180 mg BA	TC: −9.9%; HDL-C: −6.4%; non-HDL-C: −10.8%; apoB: −9.3%; hsCRP: −18.7%*
CLEAR Harmony (NCT02666664)	LDL-C ≥70 mg/dL; ASCVD and/or FH; Max. tolerated LLT (n=2,230)	−16.5%† at week 12 with 180 mg BA	TC: −10.3%†; non-HDL-C: −11.9%†; apoB: −8.6%†; hsCRP: −22.4%*
CLEAR Harmony OLE (NCT03067441)	Completed CLEAR Harmony trial (n=1,462)	−14.2%† at week 130 with 180 mg BA	TC: −9.3%†; non-HDL-C: −10.8%†; apoB: −7.0%†; hsCRP: −18.1%*
CLEAR Outcomes (NCT02993406)	LDL-C ≥100 mg/dL; ASCVD or high risk; statin intolerance (n=13,970)	−21.7%† at month 6 with 180 mg BA	hsCRP: −22.2%*
CLEAR-J	LDL-C > target despite stable LLT; Japanese (n=96)	−25.3% at week 12 with 180 mg BA	TC: −16.4%; non-HDL-C: −20.3%; apoB: −18.1%; hsCRP: −26.6%‡

Data are presented as the least-square mean percent change (unless otherwise indicated) in LDL-C from baseline with the corresponding differences in secondary parameters (p<0.05 vs. placebo). Key trial characteristics are presented in bold.

LDL-C, low-density lipoprotein cholesterol; BA, bempedoic acid; TC, total cholesterol; HDL-C, high-density lipoprotein cholesterol; apoB, apolipoprotein B; hsCRP, high-sensitivity C-reactive protein; ASCVD, atherosclerotic cardiovascular disease; FH, familial hypercholesterolemia; LLT, lipid-lowering therapy; FDC, fixed-dose combination; OLE, open-label extension; LDL, low-density lipoprotein.

^*Median percent change; ^†Mean percent change; ^‡Between-group difference.

The CLEAR Wisdom⁶¹ and CLEAR Harmony⁶² trials evaluated the efficacy and safety of bempedoic acid in patients at high CVD risk. The mean LDL-C in participants treated with bempedoic acid decreased from 119.4 mg/dL at baseline to 97.6 mg/dL at week 12 in the CLEAR Wisdom trial,⁶¹ and from 103.6 mg/dL to 84.4 mg/dL in the CLEAR Harmony trial.⁶² The LDL-C-lowering effect was more pronounced in women than in men (−22.3% vs. −17.4%, p=0.03) in the latter,⁶¹ while no differences between subgroups were identified in the former trial.⁶² In the pooled analysis of the CLEAR trials, including 3,623 subjects, 12-week placebo-adjusted reductions in LDL-C (−21.2% vs. −17.4%, p=0.044), TC (−13.8% vs. −10.5%, p=0.012), non-HDL-C (−17.3% vs. −12.1%, p=0.003), and apoB (−16.0% vs. −11.3%, p=0.004) were significantly higher in women vs. men with ASCVD and/or heterozygous familial hypercholesterolemia (HeFH) treated with a statin.⁶⁶

Considering other subgroups of the CLEAR trials, a secondary analysis of participants with baseline hsCRP ≥2 mg/L revealed that improvements in lipid profiles were independent of changes in hsCRP.⁶⁷ LDL-C reductions were also independent of glycemic control at baseline.⁶⁸ Although patients with hemoglobin A1c (HbA1c) ≥6.5% were more likely to achieve HbA1c <6.5% when treated with bempedoic acid compared to the placebo (hazard ratio [HR], 1.47; p=0.032), HbA1c decreased by roughly −0.12% (p<0.0001) and −0.06% (p=0.0004) in diabetic and prediabetic subjects, respectively. Among 217 patients with HeFH, the mean 12-week LDL-C reduction reached −23.4% compared to −16.2% in those without HeFH.⁶⁹ Given the higher baseline LDL-C (172.8 mg/dL vs. 102.6 mg/dL), patients with HeFH achieved their LDL-C goals less frequently than those without HeFH (9.4% vs. 30.4% for LDL-C <70 mg/dL; 2.9% vs. 6.1% for LDL-C <55 mg/dL). In a post hoc multivariable analysis, the predictors of ≥30% LDL-C reduction comprised lack of statin therapy, use of ezetimibe, history of diabetes, female sex, and high hsCRP at baseline.⁷⁰

Significant decreases in LDL-C, TC, non-HDL-C, apoB, and hsCRP observed at week 12 of the CLEAR Harmony trial persisted through week 78 of the Open-Label Extension phase.⁶³ The greatest LDL-C reductions in the high-risk population were obtained by adding FDC of bempedoic acid and ezetimibe to a maximally tolerated statin.⁶⁰ LDL-C <70 mg/dL was achieved by 31.3% of patients treated with FDC within 12 weeks, compared to the placebo (0.0%, p<0.001), ezetimibe (10.0%, p≤0.002), and bempedoic acid alone (6.1%, p≤0.003). The advantage was also evident among patients without background statin therapy, as the mean 12-week LDL-C reduction reached −26.6% in those treated with bempedoic acid alone and −38.8% in those who received FDC.⁷¹

3. Cardiovascular outcome trial (CLEAR Outcomes)

The CLEAR Outcomes trial demonstrated that the LDL-C-lowering effect of bempedoic acid translates into cardiovascular benefits.⁶⁴,⁷² The trial included 13,970 participants unable or unwilling to take statins who either had experienced a cardiovascular event (69.9%) or were at high CVD risk (30.1%). At 6 months, the mean baseline LDL-C of 139 mg/dL decreased to 107 mg/dL in the treatment group and to 136 mg/dL in the placebo group. During the median follow-up of 40.6 months, the rate of the primary efficacy endpoint, the four-component composite of cardiovascular death, coronary revascularization, nonfatal stroke, or nonfatal MI, was significantly lower in those treated with bempedoic acid compared to the placebo (11.7% vs. 13.3%; HR, 0.87; p=0.004). Similar trend was observed for the key secondary efficacy endpoints, the three-component composite of cardiovascular death, nonfatal stroke or nonfatal MI (8.2% vs. 9.5%; HR, 0.85; p=0.006), fatal or nonfatal MI (3.7% vs. 4.8%; HR, 0.77; p=0.002), and coronary revascularization (6.2% vs. 7.6%; HR, 0.81; p=0.001), but not for cardiovascular or all-cause death, and fatal or nonfatal stroke.

For a given LDL-C reduction, bempedoic acid diminished the risk of the first major vascular event to a similar extent as statins (HR, 0.75 vs. 0.78 for bempedoic acid and statins, respectively, per 1 mmol/L [38.67 mg/dL] LDL-C decrement).⁷³ The magnitude of risk reduction increased with the number of major cardiovascular events (HR, 0.87; p=0.004 for the first; HR, 0.74; p<0.001 for the second; HR, 0.69; p=0.02 for the third; HR, 0.51; p=0.02 for the fourth event).⁷⁴ Among 4,206 (30%) high-risk primary-prevention patients enrolled in the CLEAR Outcomes trial, the rate of the four-component primary end point was significantly lower in the treatment compared to the placebo group (5.3% vs. 7.6%; HR, 0.70; p=0.002).⁷⁵ There was no interaction between the efficacy endpoint and sex, glycemic control, or BMI.⁷⁶,⁷⁷,⁷⁸ The risk of four- and three-component endpoints did not differ between the subgroups of participants who reported statin side effects.⁷⁹ However, those with a history of statin-associated muscle symptoms alone or in combination with non-muscle symptoms, whether treated with bempedoic acid or placebo, more frequently experienced muscle symptoms during the trial and more frequently disrupted treatment due to these events.

4. Safety in phase three clinical trials

The incidence of adverse events in the phase three randomized controlled trials with bempedoic acid is presented in Table 3.⁵⁸,⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵ Bempedoic acid, whether alone or in combination with other lipid-lowering drugs, was safe and well-tolerated, even in statin-intolerant patients. Most treatment-emergent adverse events were classified as mildly or moderately intense, and not linked or unlikely linked to the study drug. The most frequent adverse events comprised musculoskeletal symptoms, infections of the urinary tract and the respiratory system, as well as gastrointestinal disorders. There was no disproportion in the incidence of adverse events between the treatment and placebo groups when analyzed according to system-organ class.

Table 3. Safety of bempedoic acid in phase three clinical trials⁵⁸,⁵⁹,⁶⁰,⁶¹,⁶²,⁶³,⁶⁴,⁶⁵ .

Trials	Serious AEs	Discontinuation due to AEs	Muscle-related AEs	New-onset or worsening DM	Gout	Uric acid increase (mg/dL)	Creatinine increase (mg/dL)	CK >5 × ULN	ALT/AST >3 × ULN
CLEAR Tranquility (NCT03001076)	2.8% vs. 3.4%	6.1% vs. 5.7%	3.3% vs. 3.4%	1.1% vs. 2.3%	0%	+0.6 vs. ---	---	---	1.1% vs. 0.0%
CLEAR Serenity (NCT02988115)	6.0% vs. 3.6%	18.4% vs. 11.7%	12.8% vs. 16.2%	2.1% vs. 4.5%	1.7% vs. 0.9%	+0.68 vs. 0.0	---	0%	1.7% vs. 0.0%
NCT03337308	9.4% vs. 2.4%*	8.2% vs. 4.9%*	7.1% vs. 7.3%*	---	0%	+0.6 vs. −0.1*	+0.02 vs. −0.01*	0%	1.2% vs. 0.0%*
CLEAR Wisdom (NCT02991118)	20.3% vs. 18.7%	10.9% vs. 8.6%	2.9% vs. 3.1%†	6.9% vs. 7.4%	2.1% vs. 0.8%	+0.6 vs. +0.1	+0.05 vs. +0.01	0.0% vs. 0.4%	1.1% vs. 0.8%
CLEAR Harmony (NCT02666664)	14.5% vs. 14.0%	10.9% vs. 7.1%	13.1% vs. 10.1%	3.3% vs. 5.4%	1.2% vs. 0.3%	+0.73 vs. −0.06	+0.02 vs. −0.02	0.5% vs. 0.1%	0.5% vs. 0.1%
CLEAR Harmony OLE (NCT03067441)	20.8% vs. 19.7%‡	7.1% vs. 9.1%‡	8.4% vs. 8.7%‡	5.4% vs. 5.9%‡	2.5% vs. 2.8%‡	+0.9 vs. +0.9‡	0.0 vs. +0.1	0.4% vs. 0.0%	0.4% vs. 0.8%‡
CLEAR Outcomes (NCT02993406)	25.2% vs. 24.9%	10.8% vs. 10.4%	15.0% vs. 15.4%	5.5% vs. 6.3%§	3.1% vs. 2.1%	+0.76 vs. −0.03	+0.05 vs. +0.01	0.6% vs. 0.6%	1.2% vs. 0.8%‖
CLEAR-J	0%	2.1% vs. 2.1%	0.0% vs. 4.2%¶	0%	0%	+0.73 vs. +0.11	+0.04 vs. +0.01	0%	2.1% vs. 0.0%

Data are presented as percent of participants who experienced selected adverse events. Uric acid and creatinine increases are presented as means. Comparisons are presented for the bempedoic acid vs. placebo group unless otherwise indicated.

AE, adverse event; DM, diabetes mellitus; CK, creatine kinase; ULN, upper limit of normal; ALT, alanine aminotransferase; AST, aspartate aminotransferase.

^*Fixed-dose combination of bempedoic acid and ezetimibe vs. placebo; ^†Myalgia only; ^‡Treatment with bempedoic acid for ≤130 weeks vs. ≤78 weeks; ^§New-onset diabetes in patients with normoglycemia at baseline; ^‖Alanine aminotransferase only; ^¶Pain in extremity only.

New-onset or worsening diabetes tended to occur in the treatment group less often than in the placebo group. Muscle-related adverse events, with myalgia being the most common, occurred with comparable frequency in both groups. Elevations in liver enzymes >3-fold the upper limit of normal were more frequently reported during treatment with bempedoic acid than with the placebo. Tendon rupture was uncommon and occurred in patients with other risk factors, such as statin use.⁸⁰ Unlike previous trials, the CLEAR Outcomes trial reported a higher rate of cholelithiasis in those who received bempedoic acid compared to the placebo (2.2% vs. 1.2%).⁶⁴ Anemia occurred in 4.7% of CLEAR Outcomes participants treated with bempedoic acid and in 3.9% of those treated with the placebo.⁸¹ The mean hemoglobin decreases in the treatment group reached −0.36±0.85 g/dL at month 6 and −0.6±1.1 g/dL at month 36, yet the pathophysiology of this effect remains unclear.

Renal events were more frequent in patients treated with bempedoic acid compared to the placebo (11.5% vs. 8.6%), with declines in estimated glomerular filtration rate (eGFR) being the most common (3.6% vs. 2.9%).⁶⁴,⁸¹ Renal failure (1.1% vs. 0.9%) and acute kidney injury (1.1% vs. 1.0%) affected the treatment and placebo groups with comparable frequency. Mean elevations in creatinine during treatment with bempedoic acid reached roughly 0.05±0.2 mg/dL at month 6 and 0.07±0.2 mg/dL at month 36, while blood urea nitrogen increased by 1.9±5.2 mg/dL and 2.3±5.8 mg/dL, respectively. Changes in creatinine most likely resulted from the bempedoic acid-induced inhibition of the organic anion transporter 2 (OAT2) in the renal tubules.⁸¹,⁸² They were stable over time and comparable between patients with eGFR ≥90, 60–90, and <60 mL/min/1.73m².⁸¹,⁸³ In four CLEAR trials, mild increases in creatinine (0.048 mg/dL vs. −0.002 mg/dL) emerged within the first four weeks and returned to baseline after treatment discontinuation.⁸⁰ Therefore, minimal, reversible increases in creatinine and decreases in eGFR observed during treatment with bempedoic acid do not reflect renal damage and are of no clinical relevance. Nonetheless, given limited experience, additional monitoring for adverse reactions may be prudent in patients with eGFR <30 mL/min/1.73 m² or end-stage renal disease on dialysis.³⁰

Due to the renal OAT2 inhibition, bempedoic acid increases uric acid alongside creatinine.⁸¹ Elevations in uric acid during treatment with bempedoic acid reached 0.76±1.2 mg/dL at month 6 and 0.52±1.5 mg/dL at month 36.⁸¹,⁸⁴ Hyperuricemia (10.9% vs. 5.6%) and gout (3.1% vs. 2.1%) were more frequently reported in the treatment group than in the placebo group. However, among patients with no history of gout and normal uric acid at baseline, the incidence of gout was similar in the two groups. It was also lower with the concomitant use of uric acid-lowering medications. The cardiovascular benefits of bempedoic acid were comparable between patients with and without prior gout. In clinical practice, bempedoic acid should be discontinued when hyperuricemia occurs along with symptoms of gout.³⁰

REAL-WORLD DATA

The European prospective, non-interventional MILOS study confirmed the efficacy and safety of bempedoic acid, administered alone or in FDC with ezetimibe, in the management of primary hypercholesterolemia and mixed dyslipidemia in real-world settings.⁸⁵ The baseline patient characteristics and efficacy measures in the MILOS cohorts from Italy, Belgium, the United Kingdom, Austria, and Germany are presented in Table 4.⁸⁶,⁸⁷,⁸⁸,⁸⁹,⁹⁰,⁹¹,⁹²,⁹³ While the proportion of primary-prevention patients differed from 21% in Germany⁹¹,⁹²,⁹³ to 70% in Belgium,⁸⁷ most study participants were at high or very high CVD risk. Treating physicians tended to underestimate CVD risk, since the percentage of very-high-risk individuals increased from 78% to 90% when the risk was assessed centrally.⁹³ Lipid-lowering drugs were underused in all cohorts, with 25%–50% of patients receiving no LLT at baseline. The mean LDL-C reduction at week 8 ranged from nearly −23% in Italy⁸⁶ and Belgium⁸⁷ to −30% in the United Kingdom.⁸⁸ Considering long-term effectiveness, the mean LDL-C reduction reached −27% and −30% after one and two years, respectively, in the German cohort.⁹¹,⁹² The use of bempedoic acid, with or without other lipid-lowering drugs, allowed for a 7-fold increase in the rate of LDL-C goal attainment, especially in high- and very-high-risk patients. The safety and tolerability of bempedoic acid in the MILOS study were in line with those reported in previously published randomized controlled trials.

Table 4. Baseline patient characteristics and efficacy of bempedoic acid in the MILOS study⁸⁶,⁸⁷,⁸⁸,⁸⁹,⁹⁰,⁹¹,⁹²,⁹³ .

Cohorts		Italy (n=1,310)	Belgium (n=375)	UK (n=236)	Austria (n=200)	Germany (n=973)
Baseline characteristics
	Age (yr)	66.0	65.8	65.2	64.8	64.9
	Male	59.2%	65.3%	46.2%	49.5%	61.9%
	HeFH	11.1%	8.3%	14.4%	13.5%	13.1%
	Diabetes	15.1%	25.6%	22.0%	24.0%	24.2%
	Primary prevention	42.3%	30.7%	69.9%	48.0%	20.9%
	Secondary prevention	57.7%	69.3%	30.1%	52.0%	79.1%
	LDL-C (mg/dL)	110.7*	112.5†	139.4‡	138.6§	121.4‖
Cardiovascular risk category
	Low	2.9%	1.3%	8.5%	2.5%	0.8%
	Moderate	14.7%	8.8%	31.7%	16.5%	3.9%
	High	29.2%	17.3%	39.3%	35.0%	28.4%
	Very high	53.2%	72.0%	20.5%	46.0%	66.9%
Lipid-lowering therapy at baseline
	None	33.1%	24.0%	41.5%	50.5%	34.5%
	Statin alone	16.9%	16.5%	20.3%	10.5%	27.2%
	Ezetimibe alone	7.5%	10.7%	18.6%	5.0%	9.2%
	Statin+ezetimibe	25.7%	36.3%	8.1%	21.5%	21.2%
	PCSK9i alone	7.0%	1.3%	3.4%	8.0%	3.7%
	PCSK9i combination	5.3%	4.0%	2.5%	1.0%	2.0%
Follow-up
	Duration	8 wk	8 wk	8 wk	1 yr	2 yr
	LDL-C reduction	−22.6%*	−22.7%†	−30.0%‡	−28.0%§	−30.3%‖
LDL-C goal attainment by risk category (vs. baseline)
	Overall	37.2% vs. 7.1%*	33.7% vs. 5.0%†	44.8% vs. 7.5%‡	36.0% vs. 13.2%§	35.3% vs. 4.9%‖
	Low/moderate	67.6% vs. 20.3%	92.9% vs. 7.1%	85.7% vs. 21.4%	Not reported	55.0% vs. 20.0%
	High	28.6% vs. 7.5%	26.7% vs. 0.0%	47.1% vs. 2.9%	Not reported	32.5% vs. 5.6%
	Very high	32.1% vs. 2.7%	23.6% vs. 5.6%	10.5% vs. 5.3%	Not reported	35.2% vs. 3.6%

Data are presented as percent of participants. Age, baseline LDL-C, and LDL-C reduction are presented as means.

HeFH, heterozygous familial hypercholesterolemia; LDL-C, low-density lipoprotein cholesterol; PCSK9i - proprotein convertase subtilisin/kexin type 9 inhibitor.

^*n=855; ^†n=101, ^‡n=67, ^§n=114, ^‖n=451.

Similar efficacy and safety data for bempedoic acid were described in single-center studies from Italy.⁹⁴,⁹⁵ In a three-center analysis from the United Kingdom, 33% of 216 patients discontinued bempedoic acid due to muscle pain (43%), lack of effectiveness (16%), and gastrointestinal adverse events (15%).⁹⁶ However, the likelihood of discontinuation increased with the number of lipid-lowering drug groups not tolerated in the past, suggesting the drucebo effect. During a 3-month real-world observation, patients treated with bempedoic acid displayed no changes in eGFR calculated from serum creatinine and/or cystatin C.⁹⁷ A safety analysis from the United States found no association between bempedoic acid and tendon rupture or tendinopathies.⁹⁸ The Austrian COR Lipid Registry showed that dual LLT with a high-intensity statin and ezetimibe initiated during hospitalization for percutaneous coronary intervention, followed by addition of bempedoic acid or a PCSK9 inhibitor after 4–6 weeks, allows for achieving LDL-C <55 mg/dL in up to 97% of patients with acute coronary syndrome (ACS).⁹⁹ In the LAI-REACT study comprising 122 ACS patients, immediate initiation of triple LLT with high-intensity rosuvastatin, ezetimibe, and bempedoic acid during index hospitalization reduced LDL-C by nearly 60% after one week.¹⁰⁰ However, in the recent Spanish ES-BempedACS trial, initiation of bempedoic acid within 72 hours of ACS did not improve the proportion of patients achieving LDL-C <55 mg/dL after 8 weeks compared to the standard dual LLT of a high-intensity statin and ezetimibe (59.4% vs. 53.1%; p=0.376).¹⁰¹ Further studies are required to confirm the magnitude of the additional LDL-C reduction when bempedoic acid is combined with a high-intensity statin, given that both drugs act on the same cholesterol synthesis pathway.

In the years 2020–2022 in Germany, bempedoic acid was primarily utilized as an add-on to first-line LLT.¹⁰² In contrast to other LLT regimens, patients treated with bempedoic acid experienced LLT modifications more often, whereas bempedoic acid was terminated earlier than statins, ezetimibe, and PCSK9 inhibitors (median time to termination 0.6 vs. 1.45 vs. 1.04 vs. 2.45 years, respectively). Between 2022 and 2024, the prescription of bempedoic acid for patients with ACS across Europe increased from 3% to 5% at discharge, and from 1% to 6%–10% at follow-up.¹⁰³ By the end of 2022, bempedoic acid was ordered by roughly 2.4% of LLT providers in the United States, while 51% of the initial bempedoic acid prescriptions were dispensed by only 10% of physicians with the highest LLT prescription volume.¹⁰⁴ Thirty-one percent of participants prescriptions were not approved by an insurer, and 12% were not filled.¹⁰⁵ In the United States from 2020 to 2022, the annual expenditures on bempedoic acid and its FDC with ezetimibe increased from 215,499 USD to 2,164,050 USD and from 141,578 USD to 2,504,577 USD, respectively.¹⁰⁶ When bempedoic acid was added to a statin and ezetimibe in a German simulation cohort, PCSK9 inhibitors were necessary to achieve the LDL-C goal in 43% less patients, which lowered annual LLT expenses by nearly 36%.¹⁰⁷ An Australian simulation demonstrated that bempedoic acid is cost-effective in approximately 16% of primary-prevention statin-intolerant patients, mainly in those with LDL-C ≥155 mg/dL and systolic blood pressure ≥140 mmHg.¹⁰⁸

CLINICAL PRACTICE GUIDELINES

Current recommendations on the use of bempedoic acid in clinical practice are summarized in Fig. 2.¹⁰⁹,¹¹⁰,¹¹¹,¹¹² The 2025 Focused Update of the 2019 European Society of Cardiology and EAS guidelines for the management of dyslipidemias propose to use non-statin lipid-lowering drugs that improve cardiovascular outcomes, i.e., ezetimibe, bempedoic acid, and PCSK9 mAb, either as monotherapy or in combination, when LDL-C target values cannot be reached on a maximally tolerated statin.¹⁰⁹ To achieve the LDL-C goal, bempedoic acid is recommended in statin-intolerant patients, and should be considered in high- and very-high-risk patients unable to meet the LDL-C goal despite taking a maximally tolerated statin. Given the hsCRP-lowering effect, the ILEP suggested that the use of bempedoic acid may be reasonable in patients with concomitant LDL-C and hsCRP elevations.¹¹² As bempedoic acid does not increase HbA1c, it may also be considered an add-on to a statin in high- and very-high-risk patients with prediabetes, diabetes, or metabolic syndrome to diminish the risk of new-onset or worsening diabetes during LLT.¹¹²

Fig. 2. Recommendations on the use of bempedoic acid in clinical practice.¹⁰⁹,¹¹⁰,¹¹¹,¹¹² .

Data are presented as follows: Class I (green), ‘is recommended’; Class IIa (yellow), ‘should be considered’; Class IIb (orange), ‘may be considered’; Level A (dark blue), high-quality evidence; Level B (medium blue), moderate-quality evidence; Level C (light grey), limited evidence.

LDL-C, low-density lipoprotein cholesterol; ACS, acute coronary syndrome; ASCVD, atherosclerotic cardiovascular disease; HeFH, heterozygous familial hypercholesterolemia; hsCRP, high-sensitivity C-reactive protein.

^*Ezetimibe, bempedoic acid, alirocumab, evolocumab; ^†Ezetimibe, bempedoic acid, alirocumab, evolocumab, inclisiran.

The integrated recommendations of two ILEP position papers and an expert opinion paper on the use of LLT, particularly bempedoic acid, are presented in Fig. 3.¹¹²,¹¹³,¹¹⁴ The authors offer the convincing argument that the upfront combination of a statin and ezetimibe is advisable to prevent therapeutic inertia and delayed goal attainment in individuals requiring >50% LDL-C reduction, since high-intensity statin monotherapy decreases LDL-C by 50%.¹¹²,¹¹³,¹¹⁴ Following the rule of ‘the earlier, the lower, the better,’ patients with baseline LDL-C ≥160 mg/dL or partial statin intolerance may benefit from immediate triple LLT.¹¹²,¹¹³,¹¹⁴ Average LDL-C reductions that can be expected on different LLT regimens comprising bempedoic acid are presented in Fig. 4.¹⁰⁹

Fig. 3. Lipid-lowering therapy algorithm by cardiovascular risk proposed by expert opinion papers.¹¹²,¹¹³,¹¹⁴ Created with BioRender.com.

LDL-C, low-density lipoprotein cholesterol; HIS, high-intensity statin; EZE, ezetimibe; BA, bempedoic acid; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor.

^*If pharmacological intervention is necessary.

Fig. 4. Average low-density lipoprotein cholesterol reductions on lipid-lowering therapy regimens comprising bempedoic acid.¹⁰⁹ Created with BioRender.com.

BA, bempedoic acid; EZE, ezetimibe; HIS, high-intensity statin; PCSK9 mAb, proprotein convertase subtilisin/kexin type 9 monoclonal antibody.

The updated European guidelines highlight the need for prompt and potent LDL-C reduction in patients with ACS.¹⁰⁹ Immediate combination of a maximally tolerated statin and non-statin drugs that improve cardiovascular outcomes should be considered in treatment-naïve patients hospitalized for ACS.¹⁰⁹,¹¹⁰ In patients after ACS who were already treated with a maximally tolerated statin, LLT intensification with any lipid-lowering drug with confirmed cardiovascular benefits, i.e., ezetimibe, bempedoic acid, or PCSK9 mAb, selected based on required additional LDL-C reduction, is recommended.¹⁰⁹ Therefore, the use of bempedoic acid in patients after ACS is clearly suggested.

CONCLUSIONS

Bempedoic acid lowers the risk of major cardiovascular events in statin-intolerant patients at high and very high CVD risk. As bempedoic acid seems to counteract inflammation and metabolic dysfunction, its use may expand beyond lipid disorders. The current European guidelines suggest the use of bempedoic acid to reach LDL-C target values in both statin-tolerant and statin-intolerant patients. In clinical practice, bempedoic acid is primarily utilized in high- and very-high-risk individuals who require additional LDL-C reduction. The efficacy and safety of bempedoic acid in real-world settings are similar to those observed in the CLEAR trials. Altogether, bempedoic acid is an efficacious lipid-lowering drug with a good safety profile and confirmed cardiovascular benefits, mainly used as part of the combination LLT to achieve LDL-C goals and to prevent cardiovascular events.