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Bempedoic Acid: An Emerging Therapy for Uncontrolled Low-Density Lipoprotein (LDL) Cholesterol
Akshyaya Pradhan1, Monika Bhandari1, Pravesh Vishwakarma1
1Department of Cardiology, King George's Medical University, Lucknow 226003, India.
Insights
Bempedoic acid effectively lowers LDL cholesterol, offering a new option for patients with atherosclerotic cardiovascular disease (ASCVD) who don't reach goals with statins alone. This novel agent shows cardiovascular benefits with fewer muscle side effects than statins.
Area of Science:
- Cardiology and Lipidology
- Pharmacology of novel lipid-lowering agents
Background:
- Atherosclerotic cardiovascular disease (ASCVD) poses a significant global health burden, particularly in developing nations like India, due to high dyslipidemia prevalence.
- Low-density lipoprotein cholesterol (LDL-C) is a primary driver of ASCVD; statins are first-line therapy but face challenges like muscle symptoms, glycemic issues, and treatment goal attainment.
- Emerging therapies like PCSK-9 inhibitors and inclisiran are effective but limited by administration route and cost, creating a need for alternative lipid-lowering strategies.
Purpose of the Study:
- To evaluate bempedoic acid, a novel ATP citrate lyase (ACL) inhibitor, as a lipid-lowering agent for patients with dyslipidemia and ASCVD.
- To assess bempedoic acid's efficacy in lowering LDL-C, both as monotherapy and in combination with other agents, and its impact on cardiovascular outcomes.
- To investigate bempedoic acid's safety profile, particularly regarding muscle-related symptoms and glycemic control, compared to placebo and existing therapies.
Main Methods:
- Analysis of data from the CLEAR trials, a series of four randomized controlled trials involving over 4000 patients with ASCVD.
- Assessment of bempedoic acid's LDL-C lowering efficacy in statin-naïve patients and those on existing statin therapy.
- Evaluation of the CLEAR Outcomes trial, a cardiovascular outcome trial assessing major adverse cardiovascular events (MACE) over 40 months.
Main Results:
- Bempedoic acid demonstrated significant LDL-C reduction (22-28% in statin-naïve, 17-18% with statins) by inhibiting ACL upstream of statins.
- Combination therapy with ezetimibe resulted in synergistic LDL-C reduction (39%), with no adverse effects on glycemic parameters and a reduction in hsCRP.
- The CLEAR Outcomes trial showed a 13% reduction in MACE over 40 months; increased uric acid and gout incidence were noted as potential side effects.
Conclusions:
- Bempedoic acid offers a valuable new therapeutic option for managing dyslipidemia and reducing ASCVD risk, particularly for patients not achieving LDL-C goals with statins.
- Its unique mechanism of action, minimal muscle-related side effects, and demonstrated cardiovascular benefits make it a significant addition to the lipid-lowering armamentarium.
- While generally well-tolerated, monitoring for potential increases in uric acid and gout is advised.
Abstract:
Atherosclerotic cardiovascular disease (ASCVD) is a silent epidemic, which is progressing relentlessly across the globe. Developing countries such as India have a high prevalence of dyslipidemia and consequently a huge burden of coronary artery disease (CAD) and ASCVD. Low-density lipoprotein is regarded as the primary culprit in the genesis of ASCVD, and statins are the first line therapy for LDL-C lowering. Statin therapy has unequivocally demonstrated the benefit of lowering LDL-C in patients across the spectrum of CAD and ASCVD. Muscle symptoms and worsening of glycemic homeostasis could be challenges with statin therapy, especially with the use of high doses. A large fraction of patients are also unable to achieve their LDL goals with statins alone in clinical practice. Moreover, LDL-C goals have become aggressive over years, necessitating a combination of lipid lowering therapies. PCSK-9 inhibitors and Inclisiran have emerged as robust and safe lipid-lowering agents, but parenteral administration and high cost precludes their widespread use. Bempedoic acid is a novel lipid-lowering agent working upstream of statins by inhibiting the enzyme ATP citrate lyase (ACL). The drug produces an average LDL lowering of 22-28% in statin-naïve patients and 17-18% when given to preexisting statin users. Because skeletal muscles lack the ACL enzyme, there is minimal risk of muscle-related symptoms. In combination with ezetimibe, the drug synergistically reduced LDL-C by 39%. Moreover, the drug has no adverse effect on glycemic parameters and lowers hsCRP (inflammation) like statin. The series of four randomized CLEAR trials, involving >4000 patients, have shown consistent LDL lowering across the spectrum of ASCVD patients with or without background therapy. The large and only cardiovascular outcome trial of the drug (CLEAR Outcomes) has recently demonstrated a 13% reduction of MACE at 40 months. Rise in levels of uric acid (four times) and acute gout (three times) are more common compared to placebo with the drug, owing to competitive renal transportation by OAT 2. In a nutshell, Bempedoic acid represents a value addition to the inventory of dyslipidemia management.
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