Cardiovascular Risk Reduction with Nonstatin Therapies

Introduction to Cardiovascular Risk Reduction

The American College of Cardiology recommends a lower LDL-C threshold of ≥55 mg/dL (or non-HDL-C ≥85 mg/dL) for considering nonstatin therapies in very high-risk patients, reflecting evidence that individuals achieving LDL-C <55 mg/dL experience lower event rates than those with higher levels 2
For patients with clinical ASCVD at very high risk on maximally tolerated statin therapy with LDL-C ≥70 mg/dL, adding ezetimibe reduces major adverse cardiovascular events (MACE) 1
There appears to be no LDL-C level below which cardiovascular benefit ceases—lifelong very low LDL-C levels (15-30 mg/dL) in patients with genetic conditions and in clinical trials show lower ASCVD incidence without adverse effects 2

For every 1% reduction in LDL-C levels, relative risk for major coronary events is reduced by approximately 1%, and this relationship holds even for LDL-C levels below 100 mg/dL 3
Recent trials did not identify a threshold LDL-C level below which no further reduction in risk occurs 4
Reducing LDL-C by 30% starting at 100 mg/dL produces another 20-30% lowering in relative risk for coronary heart disease 4

Very high-risk characteristics include history of multiple major ASCVD events 5, recent acute coronary syndrome (within 2 years) 3, and baseline LDL-C ≥190 mg/dL with clinical ASCVD 5
For these patients, intensive LDL lowering to <70 mg/dL (and consideration of <55 mg/dL) is supported by outcomes data, not arbitrary number-chasing 1, 2, 6

Confirm the patient is on maximally tolerated high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) 5
Assess adherence to medications and lifestyle modifications 5, 2
If the patient has clinical ASCVD at very high risk AND LDL-C ≥55 mg/dL (or non-HDL-C ≥85 mg/dL), consider adding nonstatin therapy 2
If the patient has clinical ASCVD (not very high risk) AND LDL-C ≥70 mg/dL, consider adding ezetimibe 1

PCSK9 monoclonal antibodies can be beneficial to further reduce MACE risk (Class 2a recommendation) 1
Bempedoic acid may be considered as an alternative or addition 2
Inclisiran may be considered for patients with poor adherence to PCSK9 mAbs (twice-yearly dosing), but cardiovascular outcomes trials are pending 7

Assess lipid response 4-12 weeks after adding therapy, then every 3-12 months 5
Continue monitoring adherence to lifestyle modifications and medications 5, 2
Apolipoprotein B (apoB) testing provides superior assessment of residual cardiovascular risk in statin-treated patients compared to LDL-C alone, particularly in those with elevated triglycerides or low HDL-C 8
If apoB is elevated despite LDL-C near target, this indicates residual risk and should prompt discussion about add-on therapy 8