Mechanism of Action of Nonstatin Therapies

Summary

The experts discuss additional lipid-lowering options beyond statins for those unable to tolerate statins or reach LDL cholesterol targets on statins alone. Long-used options include ezetimibe, which reduces intestinal cholesterol absorption, typically lowering LDL around 20%. The newer agent bempedoic acid is a prodrug activated in the liver that, like statins, reduces cholesterol production and increases LDL receptor activity. It lowers LDL around 17% on top of statins and 24% in statin-intolerant patients.

The PCSK9 inhibitor monoclonal antibodies evolocumab and alirocumab powerfully reduce LDL through improved LDL receptor recycling and clearance. LDL drops approximately 60% on these injectable agents, reaching under 55 mg/dL in over 80% by 4 weeks when added to statins. These antibodies have demonstrated safety, efficacy, and a “legacy effect” with earlier initiation conferring later cardiovascular risk reduction advantages.

In summary, the experts review current and emerging non-statin agents for treating high cholesterol, including those add-on or alternative therapies for statin intolerance. The PCSK9 inhibitors stand out given their potency, rapid onset of action, favorable tolerability, and most importantly, evidence demonstrating lower cardiovascular event rates with their early and continued use over the long-term. Taken together, these newer agents provide tools to intensify lipid lowering therapy quickly to reach lower LDL targets.

This summary was AI-generated and edited for clarity and readability.