What medications are recommended to reduce coronary atherosclerosis in adults (≥18 years) with established coronary artery disease or high cardiovascular risk?

Medications to Reduce Coronary Atherosclerosis

All adults with established coronary artery disease should receive high-intensity statin therapy (atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily) targeting LDL-C <55 mg/dL, with immediate addition of ezetimibe 10 mg if LDL-C remains ≥70 mg/dL, followed by PCSK9 inhibitors if targets are still not met. 1, 2, 3

Core Medication Classes

High-Intensity Statins (First-Line)

• Atorvastatin 40–80 mg daily or rosuvastatin 20–40 mg daily are the only true high-intensity statin regimens that achieve ≥50% LDL-C reduction and reduce major cardiovascular events by approximately 20–30% for each 39 mg/dL LDL-C decrease. 2, 3, 4

• High-intensity statins lower LDL-C to approximately 62–79 mg/dL and reduce cardiovascular death, myocardial infarction, and stroke more effectively than moderate-intensity regimens. 2, 3

• Every 38.7 mg/dL (1 mmol/L) reduction in LDL-C lowers cardiovascular event risk by approximately 28%, demonstrating a clear dose-response relationship. 3

• Start high-intensity statin therapy before hospital discharge in all patients with acute coronary syndrome or established coronary disease, as early initiation markedly increases long-term adherence and target achievement. 5

Ezetimibe (Second-Line Add-On)

• Add ezetimibe 10 mg daily when LDL-C remains ≥70 mg/dL on maximally tolerated statin therapy, providing an additional 15–25% LDL-C reduction beyond statin monotherapy. 1, 2, 5

• The International Lipid Expert Panel recommends immediate addition of ezetimibe at baseline in extremely high-risk patients (recent ACS, recurrent events) rather than waiting for statin response, to accelerate LDL-C lowering during the vulnerable early period. 1, 2

• Ezetimibe blocks intestinal cholesterol absorption via the NPC1L1 protein and demonstrated a 7% relative risk reduction in major cardiovascular events over 6 years in the IMPROVE-IT trial when added to moderate-intensity statins post-ACS. 2, 5

• The combination of high-intensity statin plus ezetimibe is more effective and better tolerated than up-titrating statin doses alone. 2

PCSK9 Inhibitors (Third-Line Add-On)

• Add a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) when LDL-C remains ≥70 mg/dL despite maximally tolerated statin plus ezetimibe, providing an additional 50–60% LDL-C reduction. 2, 5

• PCSK9 inhibitors reduce major adverse cardiovascular events by approximately 15% over 2–3 years, with greater absolute benefit when started closer to the acute coronary event. 5

• Inclisiran offers twice-yearly dosing (after initial and 3-month injections), which may improve adherence compared to more frequent injection schedules required for evolocumab and alirocumab. 1, 2

• Access to PCSK9 inhibitors varies significantly by country; many reimbursement policies require documented failure of statin plus ezetimibe before approval. 1

Bempedoic Acid (Alternative for Statin-Intolerant Patients)

• Bempedoic acid 180 mg daily is the preferred non-statin agent for patients who cannot tolerate statins, reducing LDL-C by 15–25% and lowering major cardiovascular events by 13% in the CLEAR Outcomes trial. 5

• The fixed-dose combination of bempedoic acid 180 mg plus ezetimibe 10 mg achieves approximately 35% LDL-C reduction and should be initiated immediately in statin-intolerant patients. 5

• Monitor serum uric acid and liver function tests when using bempedoic acid, as it can increase gout risk. 5

Treatment Algorithm

Step 1: Initiate High-Intensity Statin

• Start atorvastatin 40–80 mg or rosuvastatin 20–40 mg daily before hospital discharge or at diagnosis. 2, 3, 5
• Measure baseline liver enzymes before starting therapy. 3
• For Asian patients, initiate rosuvastatin at 5 mg once daily due to increased plasma concentrations. 4

Step 2: Assess LDL-C at 4–6 Weeks

• Re-measure lipid panel 4–6 weeks after initiating therapy to guide further treatment. 2, 5

Step 3: Add Ezetimibe if LDL-C ≥70 mg/dL

• Add ezetimibe 10 mg daily to the high-intensity statin regimen. 2, 5
• In extremely high-risk patients (recent MI, recurrent events, diabetes with CAD), consider adding ezetimibe upfront at discharge rather than waiting for statin response. 1, 2

Step 4: Add PCSK9 Inhibitor if LDL-C ≥70 mg/dL Despite Statin + Ezetimibe

• Introduce evolocumab, alirocumab, or inclisiran after 4–6 weeks if LDL-C remains elevated. 2, 5
• Earlier initiation yields greater absolute cardiovascular benefit. 5

Step 5: Continue Therapy if LDL-C <55 mg/dL

• Do not de-escalate statin intensity in patients tolerating therapy, even when LDL-C falls below 55 mg/dL or to very low levels (<25 mg/dL). 5
• Very low LDL-C levels have no identified safety concerns and retain cardiovascular benefit. 5

Target LDL-C Goals

• All patients with established coronary artery disease should achieve LDL-C <55 mg/dL with at least a 50% reduction from baseline. 1, 2, 3, 5

• This represents the most aggressive evidence-based target for extremely high-risk individuals and is more stringent than the prior <70 mg/dL threshold. 5

• For patients experiencing recurrent cardiovascular events within 2 years, consider an even more aggressive target of <40 mg/dL. 5

• Only approximately 18–22% of very high-risk secondary prevention patients in Europe currently achieve LDL-C <55 mg/dL, highlighting widespread therapeutic inertia. 1, 2

Special Populations

Statin-Intolerant Patients

• Confirm true complete statin intolerance by objectively testing at least two different statins (including one at the lowest approved dose); true complete intolerance occurs in <3% of patients. 5

• Initiate bempedoic acid 180 mg plus ezetimibe 10 mg daily immediately once statin intolerance is confirmed. 5

• If LDL-C remains ≥70 mg/dL after 4–6 weeks, add a PCSK9 inhibitor. 5

• PCSK9 inhibitors are safe and well-tolerated in statin-intolerant patients, though outcome data for monotherapy are pending. 5

Patients with Severe Renal Impairment

• In patients with severe renal impairment (creatinine clearance <30 mL/min/1.73 m²) not on hemodialysis, start rosuvastatin at 5 mg once daily and do not exceed 10 mg once daily. 4

Elderly Patients (≥65 Years)

• Elderly patients experience similar relative risk reductions with statin therapy as younger patients, but because baseline event rates are higher, the absolute risk reduction is approximately twice as large. 3

• Do not assume elderly patients cannot benefit from aggressive lipid-lowering therapy; moderate-intensity statins still confer comparable relative risk reductions. 2

Common Pitfalls to Avoid

• Do not start with moderate-intensity statins (simvastatin 20–40 mg, pravastatin 40 mg, atorvastatin 10–20 mg) in patients with established coronary disease, as they provide suboptimal protection and achieve insufficient LDL-C reduction. 2, 3

• Do not add non-statin therapies before maximizing statin intensity, except when high-intensity statins are not tolerated. 2

• Do not accept LDL-C levels above 55 mg/dL in secondary prevention patients; achieving lower LDL-C confers additional event reduction. 3, 5

• Do not delay combination therapy in very high-risk individuals; upfront statin plus ezetimibe maximizes LDL-C lowering and improves adherence. 1, 2

• Do not unnecessarily up-titrate statin doses when adding ezetimibe is more effective and better tolerated. 2

• Do not de-escalate statin therapy during follow-up in patients tolerating treatment, even when LDL-C falls to very low levels. 5

• Do not assume all PCSK9 inhibitors are contraindicated when a patient is allergic to one agent; alirocumab, evolocumab, and inclisiran have different molecular structures. 5

• Do not postpone lipid-lowering treatment while conducting multiple statin trials; once complete intolerance is confirmed, start non-statin therapy promptly. 5

Safety Monitoring

• Monitor hepatic transaminases before and during treatment, particularly when combining ezetimibe with statins; consecutive elevations ≥3× upper limit of normal occurred in 1.3% of combination therapy patients versus 0.4% with statin alone. 2

• Atorvastatin 80 mg is associated with a 3.3% incidence of >3-fold transaminase elevation versus 1.1% with pravastatin 40 mg. 2

• Myopathy risk remains <0.1% at guideline-recommended doses; serious muscle injury is rare. 2

• No safety concerns have been identified for achieving very low LDL-C concentrations (<55 mg/dL or even <25 mg/dL). 5