What are the LDL‑C targets and treatment goals recommended in the 2025 American College of Cardiology (ACC) cholesterol‑management guidelines?

LDL-C Management Goals in the 2025 ACC/AHA ACS Guidelines

The 2025 ACC/AHA guidelines for acute coronary syndrome recommend achieving an LDL-C < 55 mg/dL as the primary treatment goal, with high-intensity statin therapy initiated before hospital discharge and addition of non-statin agents (ezetimibe, PCSK9 inhibitors, or bempedoic acid) when LDL-C remains ≥ 70 mg/dL on maximally tolerated statin therapy. 1

Primary LDL-C Target

• The goal is LDL-C < 55 mg/dL for all ACS patients. 1, 2, 3 This represents the most aggressive evidence-based target for patients at extremely high cardiovascular risk.

• No specific percentage reduction target is mandated, though achieving ≥ 50% reduction from baseline is considered optimal when baseline LDL-C allows. 1, 4 The 2025 guideline notably does not specify treatment targets based on percentage reduction alone, departing from earlier approaches. 1

• There is no lower safety threshold—patients achieving LDL-C levels as low as 53 mg/dL or even < 25 mg/dL demonstrate continued cardiovascular benefit without safety concerns. 1, 2, 4

Treatment Algorithm Based on LDL-C Levels

At Hospital Discharge

• Initiate high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) before discharge in all ACS patients (Class I). 1, 3

• Concurrent addition of ezetimibe 10 mg at discharge may be considered (Class IIb) to accelerate achievement of LDL-C goals, particularly in extremely high-risk patients. 1, 2

At 4-8 Week Follow-Up

Reassess lipid profile and adjust therapy according to the following algorithm: 1

LDL-C < 55 mg/dL on maximally tolerated statin

• Continue high-intensity statin therapy without de-escalation (Class I). 1 Do not reduce statin intensity even when LDL-C falls to very low levels, as benefit persists without safety concerns. 1, 2

LDL-C 55-69 mg/dL on maximally tolerated statin

• Adding ezetimibe 10 mg daily is reasonable (Class IIa). 1, 3 This provides an additional 15-25% LDL-C reduction. 1, 2, 3

• Prioritize ezetimibe addition in high-risk subgroups: patients with diabetes mellitus (who derive 5.5% absolute risk reduction over 7 years), elderly patients, those with polyvascular disease, or prior heart failure. 2

LDL-C ≥ 70 mg/dL on maximally tolerated statin

• Add ezetimibe 10 mg daily (Class I, Level A). 1, 2, 3 This is a mandatory recommendation, not optional.

• Reassess LDL-C 4-8 weeks after adding ezetimibe. 1

LDL-C ≥ 70 mg/dL despite maximally tolerated statin + ezetimibe

• Add a PCSK9 inhibitor (evolocumab, alirocumab, or inclisiran) (Class I). 1, 3 PCSK9 inhibitors provide an additional 50-60% LDL-C reduction and reduce major adverse cardiovascular events by approximately 15% over 2-3 years. 1, 3

• Greater absolute benefit occurs when PCSK9 inhibitors are started closer to the ACS event, so do not delay initiation. 1, 3

Management of Statin-Intolerant Patients

• Non-statin lipid-lowering therapy is mandatory (Class I) for statin-intolerant patients. 1, 3

• Bempedoic acid is the preferred option with outcomes data, reducing major adverse cardiovascular events by 13% in the CLEAR Outcomes trial. 1, 3 Bempedoic acid provides 15-25% LDL-C reduction. 1, 3

• Combination bempedoic acid + ezetimibe achieves approximately 35% LDL-C reduction. 1, 3

• PCSK9 inhibitors are safe and well-tolerated in statin-intolerant patients, though outcome data as monotherapy are not yet available. 1, 3

• A minimum of 2 statins should be attempted (including at least one at the lowest approved daily dose) before declaring statin intolerance. 1

Key Differences from Prior Guidelines

• The 2025 guideline does not specify LDL-C treatment targets or percentage reduction goals in the traditional sense, focusing instead on maximizing therapy based on achieved LDL-C levels. 1 This contrasts with the 2023 AHA/ACC chronic coronary disease guideline, which recommends ≥ 50% LDL-C reduction. 1

• The < 55 mg/dL goal is more aggressive than the previous < 70 mg/dL threshold used in earlier secondary prevention guidelines. 1, 4

• Upfront combination therapy (statin + ezetimibe at discharge) is now a Class IIb recommendation, representing a paradigm shift toward earlier intensive LDL-C lowering rather than stepwise escalation. 1, 2, 3

Critical Safety Monitoring

• Monitor for elevated uric acid levels and gout with bempedoic acid. 1, 3

• Check liver function tests with bempedoic acid. 1, 3

• No safety concerns exist for achieving very low LDL-C concentrations (< 55 mg/dL or even < 25 mg/dL). 1, 2, 3, 4

Common Pitfalls to Avoid

• Do not de-escalate high-intensity statin therapy during follow-up in patients tolerating treatment, even when LDL-C falls to very low levels. 1, 2, 3 The benefit of high-intensity statins after ACS is independent of baseline LDL-C concentration. 1

• Do not delay ezetimibe in diabetic ACS patients with LDL-C ≥ 70 mg/dL, as they achieve the greatest absolute benefit (5.5% reduction over 7 years). 2

• Do not assume lack of benefit in patients with baseline LDL-C < 70 mg/dL—the IMPROVE-IT trial demonstrated consistent benefit even in the 50-<70 mg/dL stratum. 2

• Do not accept suboptimal LDL-C levels—only 22% of very high-risk secondary prevention patients in Europe meet LDL-C targets < 55 mg/dL, and another 22% receive no lipid-lowering therapy at all. 3, 4 Approximately 20% of ACS patients experience a recurrent cardiovascular event within 24 months, underscoring the need for aggressive early LDL-C lowering. 3

• Do not use the Friedewald equation for LDL-C calculation in patients with levels < 70 mg/dL or elevated triglycerides, as it significantly underestimates LDL-C; use the Martin/Hopkins method instead. 4

Evidence Quality

• The 2025 ACC/AHA guideline represents the most current and comprehensive evidence-based approach to ACS lipid management. 1, 3 The recommendations are based on high-quality randomized controlled trials including IMPROVE-IT (ezetimibe), FOURIER and ODYSSEY OUTCOMES (PCSK9 inhibitors), and CLEAR Outcomes (bempedoic acid). 1, 2, 3

• Cardiovascular event rates are substantially higher in patients with recent ACS (within 12 months) than those with chronic coronary disease, with 1-year rates of cardiovascular death, MI, and ischemic stroke estimated at 10-15%. 1 This justifies the more aggressive LDL-C targets and earlier combination therapy approach.