INTRODUCTION:

The medical disease known as hyperlipidemia is characterised by an increase in the blood's lipid profile and/or lipoprotein levels in any or all cases. Additionally, it is known as hyperlipoproteinemia and hypercholesterolemia¹. Important coronary heart disease (CHD) risk factors include abnormalities of different cholesterol lipoprotein lipids, such as high total cholesterol, low density lipoprotein (LDL) cholesterol, very low density lipoprotein (VLDL) cholesterol and triglycerides, and low high density lipoprotein (HDL) cholesterol.² Hyperlipidaemia, or elevated plasma lipid levels, specifically total cholesterol, triglycerides, and LDL, as well as a decline in HDL, are known to cause atherosclerosis to stall in its development.

Numerous problems, including heart attack, coronary artery syndrome, stroke, atherosclerosis, myocardial infarction, and pancreatitis, are caused by hyperlipidemia. The 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor statin effectively limit hepatic cholesterol formation and sufficiently reduce LDL-C by up to 50% from the baseline³. As alternatives to statins, bile acid-binding resins, fibrates, niacin, and ezetimibe have been approved for the treatment of dyslipidemia⁴.

The most frequent side effects of statins include asymptomatic increases in hepatic transaminases and muscle-related adverse events, which can range from myalgia to the extremely rare but potentially fatal condition known as rhabdomyolysis. Additionally, current research indicates that taking high doses of statins may make people more susceptible to developing type 2 diabetes⁵.

Esperion Therapeutics is developed bempedoic acid, a brand-new non-statin oral antihyperlipidemic medication, to treat hypercholesterolemia. Bempedoic acid has been licenced in the USA (February 2020) and the EU (April 2020) as monotherapy and as a fixed dose combination with ezetimibe, based on encouraging results from the phase III CLEAR clinical trial programme⁶.

Bempedoic Acid:

Bempedoic acid is an alpha, omega-dicarboxylic acid that is pentadecanedioic acid which is substituted by methyl groups at positions 2 and 14, and by a hydroxy group at position 8.

Molecular formula:

C₁₉H₃₆O₅

Molecular weight:

Molecular weight is 344.5 grams per mole.

Chemical Structure:

IUPAC name:

8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid.

Mechanism of action:

Bempedoic acid serves as a product that is converted to ETC-1002-CoA and ESP15228-CoA by the enzyme very long chain acyl-CoA synthetase 1 (ACSVL1)⁷. Through a two-step thioesterification reaction, acyl coenzyme A (CoA) synthetase (ACS) enzymes catalyse the activation of free fatty acids (FFAs) to CoA esters. A number of anabolic and catabolic lipid metabolic pathways, such as de novo complex lipid production, free fatty acid -oxidation, and lipid membrane remodelling, involve the participation of activated FFAs⁸.

Adenosine triphosphate citrate lyase is inhibited by the activated form of bempedoic acid, ETC-1002-CoA. (ACL). ACL is a crucial metabolic enzyme that is positioned upstream of HMG-CoA reductase and connects the liver's production of fatty acids and cholesterol to the breakdown of glucose.⁹Acetyl-CoA, a crucial building block for the biosynthesis of endogenous fatty acids and cholesterol, is produced by ACL by catalysing the conversion of citric acid into this compound in the cytoplasm¹⁰.Thus To enhance LDL-C clearance, bempedoic acid inhibits ACL, lowers cholesterol production, and upregulates lipoprotein receptors. Compared to HMG-CoA reductase, which is also found in skeletal muscle, very long chain acyl-CoA synthetase 1 is mostly found in the liver⁷.

Bempedoic acid stands out due to the fact that, in contrast to statins, it does not prevent the synthesis of cholesterol in skeletal muscle. Skeletal muscle lacks the enzyme necessary to convert bempedoic acid to ETC-1002-CoA¹¹.

Pharmacokinetics:

After 7 days of daily 180 mg oral bempedoic acid administration, steady state concentration is reached. After 3.5 hours, bempedoic acid concentrations in blood plasma are at their greatest¹².

The volume of distribution of bempedoic acid is 18 L. Plasma protein binding for bempedoic acid and its active metabolite is extremely high (99.3 and 99.2%, respectively). The half-life of Bempedoic acid is 15–24 h¹²

Aldehyde-ketone reductase can also convert bempedoic acid, however acyl glucuronide is mostly responsible for this metabolic process¹³. One oral intake of 240 mg bempedoic acid resulted in approximately 70% of the dose being eliminated through urine and 30% through faeces, with less than 5% of the dose remaining unaltered¹³.

There is no need to change the dose because the pharmacokinetics of bempedoic acid have been examined in patients with normal hepatic function as well as those with mild to severe hepatic impairment¹⁴. Patients with significant hepatic impairment have not been studied when given bempedoic acid. Based on the finding that aminotransferase increases are asymptomatic and reversible whether bempedoic acid treatment is continued or stopped, experts understand that bempedoic acid can be used in patients with mild to moderate hepatic impairment^13,14.

Therapeutic Uses:

Hypercholesterolaemia:

As an adjunct to diet and maximally tolerated statin therapy in adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who need further lowering of LDL-C, bempedoic acid received its first approval in the USA (as monotherapy on February 21, 2020, and in combination with ezetimibe on February 26, 2020).

In the 52-week randomised double-blind phase III CLEAR Harmony trial, patients with atherosclerotic cardiovascular disease and/or heterozygous familial hypercholesterolemia who were receiving maximally tolerated statins experienced significantly lower LDL-C levels with bempedoic acid 180 mg once daily compared to placebo (NCT02666664; designed to test safety and efficacy)¹⁵.

In a double-blind phase III trial (NCT03337308), bempedoic acid and ezetimibe at a fixed dose effectively reduced LDL-C when added to maximally tolerated statin therapy in patients with hypercholesterolemia and high cardiovascular disease risk¹⁶.

Adverse effects and Contraindications:

In the phase III CLEAR Harmony and CLEAR Wisdom trials, adverse reactions that occurred in 2% of patients receiving bempedoic acid and with a higher incidence than in placebo recipients included upper respiratory tract infection (occurring in 4.5% of bempedoic acid recipients vs. 4.0% of placebo recipients), muscle spasms (3.6% vs. 2.3%), hyperuricaemia (3.5% vs. 1.1%), back pain (3.3% vs. 2.2%), abdominal pain¹⁷.

Tendon Rupture:

Compared to placebo, bempedoic acid was found to be associated with an increased risk of tendon rupture (0.5% vs 0%). Tendon rupture may occur more frequently in patients over 60 years of age, in those taking corticosteroid or fluoroquinolone drugs, in patients with renal failure, and in patients with previous tendon disorders.

Discontinue Bempedoic acid immediately if the patient experiencesjoint pain, swelling or inflammation which are indications of tendon rupture.

Gout:

Elevated blood uric acid may lead to the development of gout. Compared to placebo, bempedoic acid was found to be associated with an increased risk of tendon rupture (1.5% vs 0.4%)

Benign Prostatic Hyperplasia:

Bempedoic acid was associated with an increased risk of benign prostatic hyperplasia (BPH) or prostatomegaly in men with no reported history of BPH (1.3% vs 0.1%).

Atrial Fibrillation:

Bempedoic acid was associated with an imbalance in atrial fibrillation (1.7% vs 1.1%)^11,17.

Table: Summary for Bempedoic acid^11,17,18

Alternative name	ESP-55016, ETC-1002
Chemical Name	8-Hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
Class	Antihyperlipidaemics, dicarboxylic acids
Mechanism of action	Inhibition of Adenosine triphosphate citrate lyase (ACL)
Pharmacokinetics	Steady state concentration: 180 mg orally for 7 days. Vd: 18L, Plasma protein binding: High (99%), T1/2: 15-24 hrs Metabolism: Via acyl glucuronidation Excretion: 70% through urine and 30% through faeces
Therapeutic Uses	Hypercholesterolemia, Hypelipdaemia
Adverse effects	Most frequent: Upper respiratory tract infection, muscle spasms, hyperuricaemia, back pain, abdominal pain Rare: Tendon rupture, benign prostatic hyperplasia or prostatomegaly, atrial fibrillation, gout

CONCLUSION:

In addition to considerably lowering LDL cholesterol levels, bempedoic acid added to maximally tolerated statin medication did not result in a greater incidence of total adverse events compared to placebo. Bempedoic acid was shown in clinical studies to dramatically lower LDL-C, non-HDL-C, and apo B levels. Hyperuricemia and tendon rupture are two serious adverse effects (AEs) related with bempedoic acid use, while the majority of AEs were mild to moderate in intensity.

REFERENCES:

1. Amit G, Vandana S, Sidharth M. Hyperlipidemia: An Updated Review. Inter J of Biopharma & Toxicol Res; 2011, 1:81-89.

2. Rajeev Gupta, Ravinder S. Rao, AnoopMisra, Samin K Sharma. Recent trends in epidemiology of dyslipidemias in India. Indian Heart Journal 69, 2017, 382–392.

3. Koo BK. Statin for the primary prevention of cardiovascular disease in patients with diabetes mellitus. Diabetes Metab J, 2014, 38:32-4.

4. Ridker PM. LDL cholesterol: controversies and future therapeutic directions. Lancet 2014; 384:607-17.

5. Dirk Moßhammer, ElkeSchaeffeler, Matthias Schwab &Klaus Mörike, Mechanisms and assessmentof statin-related muscularadverse effects. British Journal of ClinicalPharmacology. 78:3, 2014, 454-466

6. Anthony Markham, Bempedoic Acid: First Approval, Drugs. 80(7), 2020, 747-753.

7. Nexletol. Package insert. Esperion Therapeutics, Inc; 2020. Revised February 2020. Accessed April 11, 2020. https:// www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s 000lbl.pdf

8. Christine M. Roche, b Harvey W. Blanch, et al. Physiological Role of Acyl Coenzyme A Synthetase Homologs in Lipid Metabolism in Neurosporacrassa. Eukaryotic Cell, Volume 12 Number 9. 2013, 1244 –1257.

9. Lemus HN, Mendivil CO. 2015 Adenosine triphosphate citrate lyase: Emerging target in the treatment of dyslipidemia. J ClinLipidol. (3), 2015, 384-9

10. Barter PJ, Rye KA. (2016) New Era of Lipid-Lowering Drugs. Pharmacol Rev. 68(2), 2016, 458-5.

11. Bempedoic acid: Clinical study protocol 1002-048, a randomized, double-blind, placebo-controlled, parallel group, multicenter study to evaluate the efficacy and safety of bempedoic acid (etc-1002) 180 mg/day as add-on to ezetimibe therapy in patients with elevated LDL-C on low dose or less than low dose statins. Esperion Therapeutics, Inc, Amendment 2, 10 February 2017

12. Nguyen D, Du N, Sulaica EM, Wanat MA. A review of bempedoic acid: a new drug for an old problem. Ann Pharmacother. 2020, 55:1060028020941083

13. U. S. Food and Drug Administration. NEXLETOL (bempedoic acid) tablets, for oral use. (cited 2020March 20). Available from. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211616s000lbl.pdf

14. Nilemdo. Summary of product characteristics. last updated 28 Jan 2021,, www.ema.europa.eu/en/medicines/human/EPAR/nilemdo

15. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med.;380(11), 2019, 1022–32

16. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J PrevCardiol. 2019:2047487319864671

17. Esperion Therapeutics Inc. NEXLETOL (bempedoic acid): US prescribing information. 2020. https://www.acces sdata.fda.gov/drugs atfda docs/label /2020/21161 6s000 lbl.pdf. Accessed 24 Feb2020.

18. Anthony Markham, Bempedoic Acid: First Approval, ADISINSIGHT REPORT, Springer Nature Switzerland AG 2020

Received on 29.09.2022 Modified on 15.10.2022

Asian J. Pharm. Res. 2023; 13(1):68-70.

DOI: 10.52711/2231-5691.2023.00013