What are the newer lipid-lowering medications and their mechanisms of action?

Newer Lipid-Lowering Medications and Their Mechanisms of Action

The newer lipid-lowering medications include PCSK9 inhibitors (evolocumab, alirocumab), ezetimibe, bempedoic acid, and inclisiran, with PCSK9 inhibitors providing the most potent LDL-C reduction (50-60%) and proven cardiovascular mortality benefit. 1

PCSK9 Inhibitors (Evolocumab, Alirocumab)

Mechanism of Action

• PCSK9 inhibitors are human monoclonal antibodies that bind to and inactivate the PCSK9 enzyme, preventing degradation of LDL receptors and increasing the number of LDL receptors available to clear circulating LDL-C from the bloodstream. 1, 2

Clinical Efficacy

• PCSK9 inhibitors reduce LDL-C by 50-60% when added to statin therapy, with the FOURIER and ODYSSEY OUTCOMES trials demonstrating approximately 15% relative risk reduction in major cardiovascular endpoints. 1
• These agents are FDA-approved for adults with established atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia who require additional LDL-C lowering beyond maximally tolerated statin therapy. 1

Dosing and Administration

• Evolocumab: 140 mg subcutaneously every 2 weeks or 420 mg subcutaneously once monthly. 1
• Alirocumab: 75 mg subcutaneously every 2 weeks (can increase to 150 mg every 2 weeks if needed), or 300 mg subcutaneously every 4 weeks. 1

Safety Profile

• The EBBINGHAUS trial confirmed that evolocumab use on top of statin therapy is not associated with cognitive deficits, addressing a major safety concern. 1
• Generally well-tolerated with injection site reactions being the most common adverse effect (2-4% with evolocumab/alirocumab). 1

Ezetimibe

Mechanism of Action

• Ezetimibe inhibits the Niemann-Pick C1-Like 1 (NPC1L1) protein in the small intestine, blocking cholesterol absorption and providing a complementary mechanism to statins which reduce hepatic cholesterol synthesis. 1, 3

Clinical Efficacy

• Ezetimibe provides 15-25% additional LDL-C reduction when added to statin therapy. 1
• The IMPROVE-IT trial demonstrated that adding ezetimibe to moderate-intensity statin therapy in patients with recent acute coronary syndrome reduced the composite endpoint of cardiovascular death, nonfatal MI, unstable angina requiring hospitalization, coronary revascularization, or nonfatal stroke over 6 years of follow-up. 1
• Patients achieving LDL-C levels <30 mg/dL at 1 month had the lowest rate of cardiovascular events over 6 years with similar safety profiles, providing reassurance for aggressive LDL-C lowering. 1

Dosing and Administration

• 10 mg orally once daily, with or without food. 1
• Take either 2 hours before or 4 hours after bile acid sequestrants if used in combination. 1

Adherence Benefits

• Fixed-dose combination ezetimibe/statin formulations improve adherence by reducing pill burden, which is particularly important after acute coronary events when patients are often prescribed multiple medications. 1

Bempedoic Acid

Mechanism of Action

• Bempedoic acid is an ATP-citrate lyase inhibitor that reduces cholesterol synthesis in the liver, providing an alternative mechanism for patients who cannot tolerate statins. 1, 4
• Unlike statins, bempedoic acid is a prodrug that requires activation by very-long-chain acyl-CoA synthetase-1 (ACSVL1), an enzyme present in the liver but not in skeletal muscle, potentially explaining its better tolerability profile. 5

Clinical Efficacy

• Bempedoic acid reduces LDL-C by approximately 17-18% when added to maximally tolerated statin therapy. 5
• The cardiovascular outcomes trial (Trial 1) demonstrated reduction in major adverse cardiac events (MACE) in adults with established CVD or at high risk for CVD over 3.5 years. 5

Dosing and Administration

• 180 mg orally once daily. 5

Safety Considerations

• Not recommended in patients with moderate to severe hepatic impairment. 1
• Monitor hepatic transaminases before and during treatment when used with concomitant statin therapy. 1
• Cases of myopathy and rhabdomyolysis have been reported, though less common than with statins alone. 1

Inclisiran (siRNA Therapy)

Mechanism of Action

• Inclisiran is a small interfering RNA (siRNA) that targets PCSK9 messenger RNA in hepatocytes, reducing PCSK9 production and increasing LDL receptor availability. 1, 4

Clinical Efficacy

• Inclisiran provides sustained LDL-C reduction of approximately 50% with dosing only twice yearly after initial loading doses. 1

Dosing Advantage

• The major advantage of inclisiran is its convenient dosing schedule: initial dose, second dose at 3 months, then every 6 months thereafter, which may significantly improve long-term adherence. 1

Guideline-Recommended Treatment Algorithm

For Very High-Risk Patients (Secondary Prevention, Recent ACS)

• Start with high-intensity statin immediately; if LDL-C remains >55 mg/dL (1.4 mmol/L), add ezetimibe as the next step. 1, 3
• If LDL-C remains elevated despite maximally tolerated statin plus ezetimibe, add a PCSK9 inhibitor to achieve target LDL-C <55 mg/dL (1.4 mmol/L). 1, 3
• For patients with recurrent cardiovascular events, target LDL-C <40 mg/dL (1.0 mmol/L). 1

For Extremely High-Risk Patients

• The 2024 International Lipid Expert Panel recommends upfront combination therapy with high-intensity statin plus ezetimibe (double therapy) or even triple therapy including PCSK9 inhibitor for extremely high-risk patients to minimize lifetime LDL-C exposure. 1, 3

For Statin-Intolerant Patients

• Use bempedoic acid as an alternative or add-on therapy, as it does not cause muscle-related side effects due to lack of activation in skeletal muscle. 1, 5, 4
• Ezetimibe can be combined with bempedoic acid in patients who cannot tolerate any statin therapy. 3

Common Pitfalls to Avoid

• Do not unnecessarily up-titrate statin doses when adding ezetimibe is more effective and better tolerated for achieving LDL-C goals. 3
• Do not delay adding non-statin therapies in very high-risk patients; the stepwise approach of "watch and wait" increases lifetime LDL-C exposure and cardiovascular risk. 1, 4
• Do not overlook fixed-dose combinations, as they significantly improve adherence compared to multiple separate pills. 1
• Avoid assuming all patients need to reach the same LDL-C target; higher-risk patients require more aggressive targets (<55 mg/dL for very high-risk, <40 mg/dL for recurrent events). 1

Cost-Effectiveness Considerations

• PCSK9 inhibitors are expensive and should be prioritized for secondary prevention in very high-risk patients who have not achieved LDL-C goals on maximally tolerated statin plus ezetimibe. 1, 6
• Maximizing oral lipid-lowering therapy (statin plus ezetimibe, potentially plus bempedoic acid) before adding PCSK9 inhibitors is cost-effective and may reduce the need for monoclonal antibody therapy. 1