Cardiovascular disease (CVD) accounts for nearly half of all deaths in Europe. Despite the introduction of lower LDL-cholesterol (LDL-C) treatment targets, effective LDL-C control remains challenging. At the Advances in Medicine (AIM) 2025 meeting, Professor Andreas Schäfer from Hannover Medical School, Hannover, Germany, discussed unmet needs in LDL-C control across Europe and shared new clinical insights on bempedoic acid.
LDL-C treatment gaps in Europe
LDL-C treatment targets continue to change based on evolving evidence from the latest trials. The 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for management of dyslipidaemias recommended a goal of <1.4 mmol/L (<55 mg/dL) for very-high-risk patients with documented atherosclerotic cardiovascular disease (ASCVD) and <1.8 mmol/L (<70 mg/dL) for high-risk patients, along with a reduction of ≥50 percent from baseline LDL-C levels for both groups. [Eur Heart J 2020;41:111-188]
“These [latest] targets are nice but ambitious, and we don’t always achieve the previous ones [ie, the 2016 ESC/ EAS targets],” commented Schäfer.
The EUROASPIRE V survey, which evaluated implementation of dyslipidaemia management guidelines in 27 European countries, found that only 49.9 percent of patients with coronary heart disease received high-intensity lipid-lowering therapy, and most did not achieve the previous 2016 LDL-C target of <1.8 mmol/L. Another EU-wide observational study in 2020 showed that only 39 percent of patients with established ASCVD reached the previous 2016 target of <1.8 mmol/L, while only 18 percent met the latest goal of <1.4 mmol/L. [Atherosclerosis 2019;285:135-146; Eur Heart J 2020;41:111-188; Eur J Prev Cardiol 2020;28:1279-1289]
The gaps in LDL-C control persisted in the years following the 2019 guideline update. According to the multinational observational SANTORINI study (n=9,044), which evaluated clinical practice between 2020 and 2021, median LDL-C levels for both high-risk patients (2.4 mmol/L) and very-high-risk patients (2.0 mmol/L) were still above guideline-recommended goals across Europe. Notably, 73.1 percent of patients with ASCVD did not reach LDL-C targets, highlighting the overall suboptimal LDL-C control. [Lancet Reg Health Eur 2023:29:100624]
“We can make a difference by starting with potent treatment,” said Schäfer. “Using combination therapy can help patients achieve their treatment targets.”
CLEAR Outcomes: CV risk reduction with bempedoic acid
“Bempedoic acid, an ATP-citrate lyase [ACL] inhibitor, is involved in the hepatic cholesterol synthesis pathway. Unlike statins, it is activated only in the liver and not in skeletal muscle, so it is [less likely to] cause muscle pain,” noted Schäfer. “This offers statin-intolerant patients a chance to reach treatment targets through intensified therapy.” [JAMA Cardiol 2024;9:245-253]
A prespecified analysis of the CLEAR Outcomes trial assessed the effects of bempedoic acid on total cardiovascular (CV) events in 13,970 statin-intolerant patients. Compared with placebo, bempedoic acid significantly reduced the risk of four-component major adverse CV events (MACE-4: CV death, nonfatal MI, nonfatal stroke, or coronary revascularization) by 20 percent for total events (hazard ratio [HR], 0.80; 95 percent confidence interval [CI], 0.72–0.89; p<0.001), 13 percent for first event (HR, 0.87; 95 percent CI, 0.79–0.96; p=0.004), 26 percent for second event (HR, 0.74; 95 percent CI, 0.63–0.87; p<0.001), 31 percent for third event (HR, 0.69; 95 percent CI, 0.51–0.93; p=0.02), and 48 percent for the fourth or subsequent events (HR, 0.52; 95 percent CI, 0.31–0.88; p=0.02). [JAMA Cardiol 2024;9:245-253]
The efficacy of bempedoic acid was further illustrated in the trial’s subgroup analysis. The trial included 30 percent of patients without a prior CV event. In this primary prevention population, bempedoic acid was associated with an absolute risk reduction (ARR) of 2.3 percent in MACE-4 (HR, 0.70; 95 percent CI, 0.55–0.89; p=0.002) and 2.4 percent in MACE-3 (a composite of death from cardiovascular causes, nonfatal MI, or nonfatal stroke; HR, 0.64; 95 percent CI, 0.48–0.84; p<0.001) vs placebo over a median follow-up of 39.9 months. (Figure) [JAMA 2023;330:131-140]
The overall incidences of adverse events (AEs), serious AEs, and AEs leading to discontinuation of the trial regimen did not differ between the two groups.
In patients with peripheral artery disease, bempedoic acid demonstrated a 36 percent relative risk reduction and a 2.5 percent ARR in major adverse limb events (cumulative incidence, 5.8 vs 8.3 percent; HR, 0.64; 95 percent CI, 0.44– 0.93; p=0.018) vs placebo. [Bonaca MP, AHA 2024]
Based on the Cholesterol Treatment Trialists’ Collaboration methodology, the relationship between CV risk reduction and LDL-C lowering with bempedoic acid was similar to that of statins, with a 25 percent reduction in risk of first major vascular event per 1.0 mmol/L reduction in LDL-C demonstrated by bempedoic acid in CLEAR Outcomes. [J Am Coll Cardiol 2024;84:152-162]
Insights from HACOL-ACS trial
“With bempedoic acid gaining importance in LDL-C management, there remains a need for studies to provide up-to-date data on how many patients achieve guideline LDL-C targets with atorvastatin plus ezetimibe, and how the addition of bempedoic acid helps more patients reach their goals,” said Schäfer.
The ongoing HACOL-ACS (Hannover Cholesterol Lowering-ACS) trial aims to address these questions by assessing the effectiveness of bempedoic acid in patients who have had ST-elevation MI or non–ST-elevation MI. [EudraCT 2022-003526-50]
ESC recommendations for bempedoic acid
ESC’s 2024 guidelines for chronic coronary syndrome reinforce the recommendation for lipid-lowering treatment with an LDL-C goal of <1.4 mmol/L (<55 mg/dL) and a ≥50 percent reduction from baseline (class I, level A). [EurHeart J 2024;45:3415-3537]
Combination therapy with bempedoic acid is recommended in patients who are statin-intolerant and do not achieve treatment goal on ezetimibe (class I, level B). For patients already on the maximum tolerated dose of statin plus ezetimibe who fail to achieve their treatment goal, combination with bempedoic acid should be considered (class IIa, level C).