My adult patient’s hypercholesterolemia is not responding to statins—what’s next?

Faaiq N. Aslam; Mohamed G. Ibrahim; Razvan Chirila

doi:10.3949/ccjm.92a.24117

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Figure 1
Clinical approach to evaluating statin hyporesponsiveness.
Based on information from reference 5.

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TABLE 1

Nonstatin lipid-lowering agents

Lipid-lowering agent	Mechanism of action	LDL-C reduction	When to consider using
Ezetimibe	Inhibits cholesterol absorption in the small intestine	15%–22% (23%–25% in combination with a statin)	First-line agent if insufficient response seen with statins alone
PCSK9 inhibitor	Prevents PCSK9, an enzyme involved in the degradation of LDL receptors on liver cells, from binding to LDL receptors, reducing receptor degradation and, in turn, increasing LDL-C clearance	55%–65%¹³	Second-line agent if LDL-C targets are not met with statin and ezetimibe combination therapy Can be first line if > 25% reduction in LDL-C is required or patient is deemed very high risk^{^a}
Inclisiran	Small interfering RNA that binds to messenger RNA of PCSK9, limiting production of the enzyme	49.9%–52.3%	For patients deemed very high risk who are not achieving LDL-C targets on statins alone
Bempedoic acid	Decreases cholesterol synthesis in the liver by inhibiting adenosine triphosphate citrate lyase	16.5% (36.2% in combination with ezetimibe)	For patients deemed very high risk who are not achieving LDL-C targets on statins alone
Evinacumab	Monoclonal antibody that inhibits angiopoietin-like 3, a protein that reduces the activity of lipases involved in lipid hydrolysis, thus increasing lipid metabolism	47.1%	For patients with homozygous familial hypercholesterolemia
Lomitapide	Inhibits microsomal triglyceride transfer protein, which is involved in the assembly of apolipoprotein B and the production of very-low-density lipoprotein	25%–51%	For patients with homozygous familial hypercholesterolemia

↵^aVery high risk: history of either multiple major atherosclerotic cardiovascular disease (ASCVD) events or 1 major ASCVD event with multiple high-risk factors (age > 65, heterozygous familial hypercholesterolemia, history of prior coronary artery bypass grafting or percutaneous coronary intervention outside of a major ASCVD event, diabetes, hypertension, chronic kidney disease, smoking, persistent LDL-C elevation despite therapy with maximum statin and ezetimibe, congestive heart failure history).²
LDL = low-density lipoprotein; LDL-C = low-density lipoprotein cholesterol; PCSK9 = proprotein convertase subtilisin/kexin type 9
Based on information from reference 3.