LDL-C lowering is the cornerstone of ASCVD prevention. This section summarizes interpretation thresholds, risk-based goal categories, and the lipid-lowering drug classes — statins, ezetimibe, PCSK9 pathway therapies, and bempedoic acid — modeled in the LDL Predictor.

LDL-C status interpretation

Reference ranges for untreated LDL-C in adults (NCEP ATP III / ACC/AHA).

Average untreated LDL-C in U.S. adults is ~115 mg/dL.

LDL-C goal categories

Thresholds align with the ESC/EAS 2019 dyslipidaemia guidelines and the 2021 prevention update. Select the category matching the patient's clinical risk profile.

ACC/AHA 2018/2022 guidelines emphasize ≥50% LDL-C reduction over strict numerical targets, but these thresholds are widely used in U.S. clinical practice as well.

Statins (HMG-CoA reductase inhibitors)

Statins are the foundation of LDL-C-lowering therapy. They competitively inhibit HMG-CoA reductase, the rate-limiting enzyme of hepatic cholesterol synthesis. Depletion of intracellular cholesterol upregulates LDL-receptor expression on hepatocytes, increasing clearance of circulating LDL-C.

Intensity classification (ACC/AHA)

• High (≥50% LDL-C reduction): atorvastatin 40–80 mg, rosuvastatin 20–40 mg
• Moderate (30–49%): atorvastatin 10–20, rosuvastatin 5–10, simvastatin 20–40, pravastatin 40–80, pitavastatin 1–4 mg
• Low (<30%): simvastatin 10, pravastatin 10–20, lovastatin 20 mg

Rule of 6

Each doubling of a statin dose yields only ~6% additional LDL-C reduction. This diminishing return makes maximal titration alone inefficient when substantial further lowering is required — combination therapy with non-statin agents typically provides greater incremental benefit than continued dose escalation.

Ezetimibe (Zetia)

Ezetimibe selectively inhibits the NPC1L1 transporter on the brush border of small intestinal enterocytes, blocking absorption of dietary and biliary cholesterol. The resulting drop in hepatic cholesterol delivery upregulates LDL-receptor expression, producing additional LDL-C lowering on top of statin therapy.

• Expected reduction: ~18% additional LDL-C lowering when added to a statin
• Dosing: 10 mg orally once daily
• Use case: Adjunct when LDL-C goal is not met on maximally tolerated statin; also useful in statin-intolerant patients as monotherapy or with bempedoic acid

The IMPROVE-IT trial demonstrated that adding ezetimibe to simvastatin reduced cardiovascular events in post-ACS patients, establishing it as a guideline-supported add-on therapy.

PCSK9 pathway therapies

PCSK9 (proprotein convertase subtilisin/kexin type 9) is a circulating protein that binds hepatic LDL receptors and targets them for lysosomal degradation. Inhibiting PCSK9 — by neutralizing the circulating protein or by preventing its synthesis — preserves LDL receptors, increases LDL-C clearance, and substantially lowers circulating LDL-C.

Four FDA-approved agent types target this pathway. They are not used together: combining them provides no additional benefit because they act on the same pathway.

PCSK9 Inhibitor (monoclonal antibodies)

• Evolocumab (Repatha) and Alirocumab (Praluent): fully human antibodies that bind circulating PCSK9 protein
• Expected reduction: ~60–63% additional LDL-C lowering
• Dosing: Subcutaneous injection every 2 or 4 weeks

Oral PCSK9 Inhibitor (small molecule)

• Enlicitide decanoate (Lipfendra): the first oral PCSK9 inhibitor — a macrocyclic peptide that binds circulating PCSK9, the same target as the antibodies, but delivered as a once-daily tablet
• Expected reduction: ~56% additional LDL-C lowering (CORALreef AddOn)
• Dosing: One 20 mg tablet once daily on an empty stomach; no cardiovascular-outcomes data yet (CORALreef Outcomes ongoing)

PCSK9-Binding Protein

• Lerodalcibep (Lerochol): a small PCSK9-binding protein fused to human serum albumin — roughly a tenth the size of an antibody, which is what allows one low-volume monthly injection without refrigeration
• Expected reduction: ~56% additional LDL-C lowering at week 52 (LIBerate-HR); 94% of treated patients reached a ≥50% reduction at one year
• Dosing: One 300 mg subcutaneous injection once monthly, self-administered; room-temperature stable up to 3 months. No cardiovascular-outcomes data yet (LIBerate-CVD ongoing)

PCSK9 Synthesis Inhibitor (siRNA)

• Inclisiran (Leqvio): small interfering RNA that silences hepatic PCSK9 mRNA, blocking protein production upstream
• Expected reduction: ~50% additional LDL-C lowering (time-averaged)
• Dosing: Subcutaneous injection at baseline, 3 months, then every 6 months — only twice yearly maintenance dosing

These therapies are typically reserved for patients with established ASCVD or familial hypercholesterolemia who haven't reached LDL-C goal on maximally tolerated statin plus ezetimibe. Prior authorization is commonly required.

Bempedoic acid (Nexletol)

Bempedoic acid is a prodrug activated only in the liver by ACSVL1, an enzyme not expressed in skeletal muscle. The active metabolite inhibits ATP-citrate lyase, an enzyme upstream of HMG-CoA reductase in the cholesterol synthesis pathway. The liver-specific activation eliminates the risk of statin-associated muscle symptoms — making it a useful option in statin-intolerant patients.

Expected reduction depends on context

• ~21% additional LDL-C lowering as monotherapy in statin-intolerant patients
• ~17% additional lowering when added to background statin therapy

The reduced effect on a statin reflects compensatory upregulation of ATP-citrate lyase by the statin itself, partially offsetting bempedoic acid's mechanism. This is built into the predictions in this tool — the reduction adjusts automatically based on whether a statin is selected.

• Dosing: 180 mg orally once daily
• Use case: Statin-intolerant patients or additional LDL-C lowering when goals aren't met on standard therapy