What is the role of Nexletol (bempedoic acid) in managing hypercholesterolemia?

Nexletol (Bempedoic Acid) in Managing Hypercholesterolemia

Bempedoic acid (Nexletol) is indicated to reduce the risk of myocardial infarction and coronary revascularization in adults unable to take recommended statin therapy, and as an adjunct to diet for LDL-C reduction in adults with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH). 1

Mechanism of Action

Bempedoic acid works through a novel mechanism compared to other lipid-lowering therapies:

• Inhibits adenosine triphosphate-citrate lyase (ACL), an enzyme upstream of HMG-CoA reductase in the cholesterol biosynthesis pathway 1
• Requires activation by very long-chain acyl-CoA synthetase 1 (ACSVL1), which is primarily expressed in the liver 2
• This liver-selective activation provides an advantage for patients with statin-associated muscle symptoms 2
• Reduces LDL-C by decreasing cholesterol synthesis and upregulating LDL receptors 1

Efficacy

Bempedoic acid demonstrates significant lipid-lowering effects:

• Reduces LDL-C by approximately 15-25% when added to maximally tolerated statin therapy 2
• Provides up to 38% additional LDL-C reduction when combined with ezetimibe 2
• Lowers non-HDL cholesterol, total cholesterol, and apolipoprotein B 2
• Reduces high-sensitivity C-reactive protein (hs-CRP) by approximately 24.3%, indicating anti-inflammatory effects 2

Cardiovascular Outcomes

The CLEAR Outcomes trial demonstrated significant cardiovascular benefits:

• 13% reduction in the composite outcome of four-point major adverse cardiovascular events compared with placebo 2
• Greater benefit in primary prevention (30% reduction) compared to secondary prevention 2
• 17% reduction in major adverse cardiovascular events in patients with diabetes 2

Clinical Indications

Bempedoic acid is particularly valuable in specific patient populations:

• Adults with established cardiovascular disease (CVD) or high risk for CVD events who are unable to take recommended statin therapy 1
• Patients with primary hyperlipidemia, including heterozygous familial hypercholesterolemia (HeFH) 1
• Statin-intolerant patients, due to its liver-selective activation which avoids muscle-related side effects 2
• Patients who have not achieved ≥50% LDL-C reduction and LDL-C <70 mg/dL on maximally tolerated statin therapy 2

Dosing and Administration

• Available as 180 mg tablets for once-daily oral administration 1
• Can be taken with or without food 1
• Available as monotherapy or in fixed-dose combination with ezetimibe 2
• No dosage adjustment necessary for mild or moderate renal or hepatic impairment 1

Safety Profile

Bempedoic acid is generally well-tolerated with some considerations:

• Does not cause the muscular adverse reactions associated with statins 3
• Potential side effects include elevated uric acid levels and tendon disorders 2
• Limited experience in patients with severe renal impairment (eGFR < 30 mL/min/1.73 m²) 1
• Not studied in patients with end-stage renal disease receiving dialysis 1
• Not studied in patients with severe hepatic impairment (Child-Pugh C) 1

Place in Therapy

Bempedoic acid offers an important option in the lipid management algorithm:

• May be considered after ezetimibe or PCSK9 inhibitors in the treatment algorithm 2
• Particularly valuable for patients who cannot tolerate adequate doses of statins or any statin therapy 4
• Serves as an adjunct to diet and maximally tolerated statin therapy for adults with HeFH or established ASCVD requiring additional LDL-C lowering 2
• Provides a well-tolerated and effective therapeutic option for lipid lowering, both as monotherapy and in combination with other lipid-lowering agents 3

Practical Considerations

• Higher cost than generic statins and ezetimibe 2
• Once-daily dosing improves convenience and potential adherence 1
• No significant drug-food interactions, increasing flexibility in administration 1
• Safe for use in older adults with no dosage adjustments required 1

Bempedoic acid represents an important addition to the lipid-lowering armamentarium, particularly for patients who cannot achieve adequate LDL-C reduction with statins alone or who experience statin intolerance.