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Bempedoic Acid for the Treatment of Dyslipidemia

Bempedoat acid, a new class of oral medication, is thought to have the potential to treat dyslipidemia. Dyslipidemia is a risk factor for cardiovascular and cerebrovascular disease. During this time, the drug of choice for dyslipidemia, especially in patients with high levels of low-density lipoprotein (LDL), is a statin drug group. However, many patients are unable to tolerate statins. Scientific evidence reports that 29% of patients experience intolerance to statins, and muscle disorders cause more than 90% of these intolerance events.

Bempedoic Acid for the Treatment of Dyslipidemia
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Limitations of the current Management of Dyslipidemia

Atherosclerotic cardiovascular disease (ASCVD), including myocardial infarction and ischemic stroke, has a high mortality rate. Research has shown that increasing LDL is one of the main risk factors of ASCVD. A decrease in LDL of 1 mmol / L (equivalent to 40 mg/dl) can reduce the risk of ASCVD by 22%. Therefore, the management of dyslipidemia, especially elevated LDL levels, is important.

Statins have long been the preferred treatment for reducing LDL cholesterol levels. Statins work by inhibiting 3-hydroxy-3-Methylglutaryl coenzyme A reductase (HMG CoA reductase), thereby inhibiting cholesterol biosynthesis, increasing LDL receptor expression, and increasing LDL catabolism.

At high-intensity doses, statins are very effective in reducing LDL levels. However, many patients cannot tolerate statin administration, mainly due to muscle disorders. This intolerance causes many patients to be nonadherence and stop statin therapy without the doctor's instructions.

In recent years, the development of the management of dyslipidemia using PCSK9 monoclonal antibodies has continued. PCSK9 monoclonal antibodies work by preventing LDL receptor binding with PCSK9, thereby preventing degradation and increasing LDL clearance. Various studies have reported its efficacy, but the administration of this agent through subcutaneous injection makes it more invasive and has quite a high price.


Action Mechanism of Bempedoat Acid

Bempedoic acid is an inhibitor of the ATP-citrate lyase molecule, a component of the cholesterol biosynthetic pathway that works upstream of HMG CoA. Bempedoic acid is a prodrug that requires activation by the enzyme Acyl-CoA synthetase 1 (ACL 1), which is only present in the liver. This activity will increase the LDL receptor's regulation and increase LDL clearance.

ACL1 is not in skeletal muscles. Therefore, although Bempedoic acid works in the same pathway as statins, the mechanism of action of Bempedoic acid can prevent the musculoskeletal side effects that often occur in statin use.


Efficacy of Bempedoic Acid in the Management of Dyslipidemia

The combined CLEAR researchers (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) sought to evaluate the efficacy and safety of Bempedoic acid in the management of dyslipidemia.

CLEAR Harmony clinical trial tried to assess the Bempedoic acid's effect in patients who get statins in the maximum tolerable dose range. The study involved 2230 patients, of whom 1488 received Bempedoic acid and 742 received placebos. The results showed a decrease in LDL cholesterol levels with a mean of 19.2 mg / dL at 12 weeks, and this effect lasted until 52 weeks.

The researchers stated that there were no significant differences in general side effects between the two study groups. However, the side effects that caused patients to stop therapy were higher in the Bempedoic acid group. The incidence of gout was also reported to be higher in patients who get Bempedoic acid.

The CLEAR Wisdom study attempts to evaluate the effect of Bempedoic acid in reducing LDL levels in patients with high cardiovascular risk and who have been taking maximal lipid-lowering drugs.

The study involved 779 patients, of which 522 received Bempedoic acid, and 257 received the placebo. The study found a mean decrease in LDL levels of 122.8 mg/dl in patients receiving Bempedoic acid and 97.6 mg/dl in the placebo group.

This study concluded that Bempedoic acid is effective in reducing LDL levels in patients who do not respond adequately to lipid-lowering therapy compared to placebo. In this study, side effects also were obtained are nasopharyngitis (5.2%), urinary tract infections (5%), and hyperuricemia (4.2%).

Meanwhile, the CLEAR Serenity study seeks to evaluate the effects of Bempedoic acid in patients who are unable to tolerate low-dose statin therapy. The study involved 345 patients who were randomized to a ratio of 2: 1 to get Bempedoic acid 180 mg or placebo.

The study reported a mean decrease in LDL levels of 21.4% in the Bempedoic acid group. This study also found a decrease in total cholesterol (14.8%), apolipoprotein B (15%), and high sensitivity C reactive protein (24.3%). Myalgia side effects were found in 4.7% of patients who received Bempedoic acid and 7.2% of patients who received a placebo. Other side effects reported in this study were arthralgia (6%), hypertension (4.3%), fatigue (3.4%), urinary tract infections (3.4%), back pain (3.0%), bronchitis (2.6%), and muscle spasms (4.3%).

At present, CLEAR Outcomes (Evaluation of Major Cardiovascular Events in Patients With) study, or at High Risk for, Cardiovascular Disease Who Are Statins Intolerant Treated With Bempedoic Acid or Placebo), which evaluates the efficacy of Bempedoic acid in reducing the risk of cardiovascular events in patients intolerant of statins.


Conclusion
Until now, the management of dyslipidemia, especially in reducing levels of low-density lipoprotein, is done by administering statins. However, many patients cannot tolerate long-term statin consumption due to complaints of muscle disorders.

Bempedoic acid is a new class of drugs, that is thought to increase LDL receptor regulation and increase LDL clearance. Various studies that have been published by joint CLEAR researchers (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) report that Bempedoic acid has good efficacy in reducing LDL levels. However, this drug is also reported to cause various side effects such as gout, arthralgia, and hypertension. Various studies are still ongoing to evaluate the efficacy and safety of Bempedoic acid in the management of dyslipidemia.


References
1. Laufs U, Banach M, Mancini GBJ, Gaudet D, Bloedon LT, Sterling LR, et al. Efficacy and Safety of Bempedoic Acid in Patients With Hypercholesterolemia and Statin Intolerance. JAHA, 2019 Apr 2; 8(7). Available from: https://www.ahajournals.org/doi/10.1161/JAHA.118.011662
2. Stroes ES, Thompson PD, Corsini A, et al. European Atherosclerosis Society Consensus. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology, and Management. Eur Heart J. 2015; 36:1012–1022
3. Penson P, McGowan M, Banach M. Evaluating bempedoic acid for the treatment of hyperlipidemia. Expert Opinion on Investigational Drugs. 2017 Feb;26(2):251–9.
4. Feng X, Zhang L, Xu S, Shen A. ATP-citrate lyase (ACLY) in lipid metabolism and atherosclerosis: An updated review. Progress in Lipid Research. 2020 Jan;77:101006.
5. Mao J, Blumenthal RS, Martin SS. Bempedoic Acid, the Next LDL Cholesterol-Lowering Medication to Join the Arsenal? Insights From the CLEAR Wisdom Trial. Expert Analysis. American College of Cardiology, 2019. https://www.acc.org/latest-in-cardiology/articles/2019/05/03/10/20/bempedoic-acid-the-next-ldl-cholesterol-lowering-medication-to-join-the-arsenal
6. Ray KK, Bays HE, Catapano AL, Lalwani ND, Bloedon LT, Sterling LR, et al. Safety and Efficacy of Bempedoic Acid to Reduce LDL Cholesterol. N Engl J Med. 2019 Mar 14;380(11):1022–32.
7. Bilen O, Ballantyne CM. Bempedoic Acid (ETC-1002): an Investigational Inhibitor of ATP Citrate Lyase. Curr Atheroscler Rep. 2016 Oct;18(10):61.
8. Goldberg AC, Leiter LA, Stroes ESG, Baum SJ, Hanselman JC, Bloedon LT, et al. Effect of Bempedoic Acid vs Placebo Added to Maximally Tolerated Statins on Low-Density Lipoprotein Cholesterol in Patients at High Risk for Cardiovascular Disease: The CLEAR Wisdom Randomized Clinical Trial. JAMA. 2019 Nov 12;322(18):1780.

9. US National Library of Medicine. Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo (CLEAR Outcomes). Clinical Trials Gov, 2020. https://clinicaltrials.gov/ct2/show/NCT02993406

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