Article Figures & Data
Figures
- Figure 1
Practical approach to the addition of nonstatin therapy.
aIndividual LDL-cholesterol target based on patient risk profile.
bNo current cardiovascular outcome data.
LDL = low-density lipoprotein; PCSK9 = proprotein convertase subtilisin/kexin type 9
Tables
Agent Mechanism Dosing Cost Expected lowering of LDL cholesterol Major prescribing considerations Ezetimibe7,10–15 Inhibition of intestinal cholesterol absorption leads to increased synthesis of LDL receptors and increased LDL cholesterol clearance Daily oral medication $ Monotherapy: 15%–19%
With statin therapy: 13%–25%Generally well tolerated (avoid in hepatic dysfunction)
Low cost
Available in combination with simvastatin
Often first-line recommended nonstatin for lowering LDLAlirocumab, evolocumab7,16–19 Monoclonal antibodies bind to PCSK9 protein, reducing destruction of LDL receptors and increasing LDL cholesterol clearance Subcutaneous injection every 2–4 weeks $$$ Monotherapy: 50%
With statin therapy: 54.7%–70%Substantially more LDL-lowering than oral options
Requires ongoing injections
Risk of site reactions
Variable insurance coverage may result in high costBempedoic acid7,8,20–22 Inhibition of ATP citrate lyase leads to a reduction in cholesterol biosynthesis, leading to an increase in LDL receptors and to increased LDL cholesterol clearance Daily oral medication $$ Monotherapy: 17.2%–26.5%
With statin therapy: 16.5%–18%
With ezetimibe: 25%–35%Generally well tolerated
No muscle-related side effects
Relatively high cost and variable coverage (may need prior authorization)
Available as combination therapy with ezetimibeInclisiran7,23–26 Inhibits translation of PCSK9 via RNA interference, reducing destruction of LDL receptors and increasing LDL cholesterol clearance Subcutaneous injection every 6 months $$$ Monotherapy: limited data
With statin therapy: 39.7%–52.3%Twice-yearly dosing may be convenient and desirable
High cost and variable coverage
Limited access (current ongoing cardiovascular outcomes trials ORION-4 and VICTORION-2P)Bile acid sequestrants7,27 Less intestinal bile acid absorption leads to an increase in cholesterol converted to bile acid, which leads to an increase in LDL receptors and LDL cholesterol clearance Daily oral medication $ Monotherapy: 15%
With statin therapy: additional 10%–16%Unpalatable agents with gastrointestinal side effects
Cardiovascular outcome data older and weaker than other options
Not recommended by guidelines to lower LDL cholesterolATP = adenosine triphosphate; LDL = low-density lipoprotein; ORION = A Randomized Trial Assessing the Effects of Inclisiran on Clinical Outcomes Among People With Cardiovascular Disease; PCSK9 = proprotein convertase subtilisin/kexin type 9; VICTORION = A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial, Assessing the Impact of Inclisiran on Major Adverse Cardiovascular Events in Participants With Established Cardiovascular Disease
Trial Intervention Study population, prevention goal Composite primary outcome Major findings IMPROVE-IT 201512 Simvastatin plus ezetimibe vs simvastatin only 18,144 patients with recent acute coronary syndrome and LDL cholesterol 50–125 mg/dL
Secondary preventionCardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization Simvastatin + ezetimibe combination reduced primary end point at 7 years (32.7% vs 34.7%)
Driven primarily by myocardial infarction and stroke
No mortality effectFOURIER 201718 Evolocumab plus statin vs statin alone 27,564 patients with ASCVD and LDL cholesterol ≥ 70 mg/dL despite statin use
Secondary preventionCardiovascular death, myocardial infarction, stroke, unstable angina, or coronary revascularization Evolocumab reduced primary end point at 2.2 years (9.8% vs 11.3%)
Driven by myocardial infarction, stroke, need for revascularization
No mortality effectODYSSEY 201819 Alirocumab + statin vs statin alone 18,924 patients with recent acute coronary syndrome and elevated lipids despite statin use
Secondary preventionCardiovascular death, myocardial infarction, stroke, or unstable angina Alirocumab reduced primary end point at 2.8 years (9.5% vs 11.1%)
No significant mortality benefitCLEAR 20238 Bempedoic acid vs placebo 13,970 patients with ASCVD or at high risk and unable to take statins
Primary and secondary preventionCardiovascular death, myocardial infarction, stroke, or coronary revascularization Bempedoic acid reduced primary end point at 40.6 months (11.7% vs 13.3%)
No significant effect on fatal or nonfatal stroke, cardiovascular death, or all-cause mortalityASCVD = atherosclerotic cardiovascular disease; LDL = low-density lipoprotein
