What is the comparison between statins (HMG-CoA reductase inhibitors) and Nexletol (bempedoic acid) for cholesterol management?

Comparison of Statins vs. Nexletol (Bempedoic Acid) for Cholesterol Management

Statins remain the first-line therapy for cholesterol management due to their proven cardiovascular benefits, while bempedoic acid (Nexletol) is an effective alternative for statin-intolerant patients, providing LDL-C reduction of 15-24% compared to statins' 30-50% reduction. 1, 2

Mechanism of Action

• Statins inhibit HMG-CoA reductase, the rate-limiting enzyme in cholesterol synthesis, leading to upregulation of LDL receptors and enhanced clearance of LDL particles from circulation 3, 4
• Bempedoic acid inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway, which reduces hepatic cholesterol production through a different mechanism 5, 6
• Both medications ultimately reduce endogenous cholesterol production, but through different targets in the same metabolic pathway 5

Efficacy in LDL-C Reduction

• High-intensity statin therapy achieves approximately 50% reduction in LDL-C levels, while moderate-intensity statin regimens achieve 30-49% reductions 1
• Bempedoic acid lowers LDL-C by approximately 15-24% when used alone, making it less potent than statins 1, 2, 6
• When combined with ezetimibe, bempedoic acid can achieve up to 40% LDL-C reduction, approaching the efficacy of moderate-intensity statins 5

Cardiovascular Outcomes

• Statins have robust evidence from multiple large clinical trials showing 24-37% relative risk reduction in cardiovascular events 7, 4
• The CLEAR Outcomes trial demonstrated that bempedoic acid reduced major adverse cardiovascular events (MACE-4) by 13% compared to placebo in statin-intolerant patients 1, 2
• In patients with diabetes, bempedoic acid showed a 17% reduction in MACE-4 events 1
• For primary prevention, bempedoic acid resulted in a 30% reduction in primary composite outcome compared to placebo 1

Safety Profile and Tolerability

• Statins are generally well-tolerated but can cause muscle-related adverse effects (myalgia, myopathy, rhabdomyolysis) in some patients 1, 8
• Bempedoic acid is activated primarily in the liver and not in skeletal muscle, which limits muscle-related adverse effects commonly associated with statins 1, 6
• This unique activation mechanism makes bempedoic acid particularly valuable for patients who experience statin-associated muscle symptoms 1, 6

Clinical Applications and Guidelines

First-Line Therapy

• Statins remain the first-line therapy for most patients requiring cholesterol management due to their established cardiovascular benefits and extensive clinical experience 1
• For patients with established ASCVD, high-intensity statin therapy is recommended 1
• For primary prevention in patients over 40 years with diabetes, moderate-intensity statin therapy is recommended 1

Alternative for Statin-Intolerant Patients

• Bempedoic acid is indicated for patients who cannot tolerate statins or for whom statins are inadequately effective 1, 2
• It can be used as monotherapy or in combination with other lipid-lowering therapies in statin-intolerant patients 2, 5
• The combination of bempedoic acid with ezetimibe provides an additional 19% reduction in LDL-C beyond bempedoic acid alone 1

Combination Therapies

• When LDL-C goals are not achieved with maximally tolerated statin therapy, adding ezetimibe can provide additional LDL-C reduction 1
• The IMPROVE-IT trial showed that adding ezetimibe to simvastatin led to a 6.4% relative benefit and 2% absolute reduction in major adverse cardiovascular events 1
• Bempedoic acid can be used in combination with ezetimibe for patients who cannot tolerate statins 1, 5
• Statin plus fibrate combination therapy has not shown improvement in cardiovascular outcomes and is generally not recommended 1

Special Populations

• For patients with diabetes and established ASCVD, high-intensity statin therapy is recommended 1
• In statin-intolerant patients with diabetes, bempedoic acid showed a 17% reduction in major adverse cardiovascular events 1
• For patients with heterozygous familial hypercholesterolemia (HeFH), both statins and bempedoic acid are effective options, with bempedoic acid serving as an alternative when statins are not tolerated 2, 5

Practical Considerations and Pitfalls

• Statin intolerance should be carefully evaluated before switching to alternative therapies, as many patients can tolerate a different statin, lower dose, or alternate-day dosing 1
• When transitioning from statins to bempedoic acid, patients should be informed about the potentially lower LDL-C reduction compared to high-intensity statins 1, 2
• Combination therapy with bempedoic acid and ezetimibe should be considered to maximize LDL-C reduction in statin-intolerant patients 1, 5
• Dietary modifications remain important even when on lipid-lowering medications, as they may have additive effects on cholesterol reduction 1, 3

Decision Algorithm for Cholesterol Management

1. For patients without contraindications to statins:

   • Start with appropriate intensity statin based on risk profile 1
   • If LDL-C goal not achieved, consider adding ezetimibe 1

2. For patients with statin intolerance:

   • Try alternative statin, lower dose, or alternate-day dosing 1
   • If still intolerant, consider bempedoic acid with or without ezetimibe 1, 2

3. For patients with partial statin intolerance (can tolerate only low-dose statin):

   • Continue maximum tolerated statin dose and add bempedoic acid 1, 2