About this tool

This educational tool estimates expected LDL-C reduction from any combination of lipid-lowering therapies. Enter the patient's untreated baseline LDL-C, select a goal aligned with their cardiovascular risk category, and build a regimen on the right. The predicted LDL-C updates in real time as the regimen changes.

Predictions are based on population-mean reductions from landmark clinical trials and meta-analyses. Individual response varies based on adherence, genetics, hepatic function, and concurrent therapies.

For educational reference only. Not intended for clinical decision-making.

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.

• < 40 mg/dL — Very high-risk patients with a recurrent ASCVD event within two years on maximally tolerated statin therapy.
• < 55 mg/dL — Established ASCVD (prior MI, acute coronary syndrome, ischemic stroke, symptomatic peripheral artery disease), severe chronic kidney disease, or familial hypercholesterolemia with additional risk factors.
• < 70 mg/dL — High-risk patients including diabetes with target organ damage, a severely elevated single risk factor, or subclinical atherosclerosis (elevated coronary artery calcium score or plaque on imaging without a clinical event).
• < 100 mg/dL — Moderate-risk primary prevention patients with elevated cardiovascular risk factors but no detected plaque or established atherosclerosis.

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: ~22% 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.

Two FDA-approved mechanisms target this pathway. They are not used together — combining them provides no additional benefit because they act on the same pathway.

Monoclonal antibodies (PCSK9 inhibitors):

• Evolocumab (Repatha) and Alirocumab (Praluent) — fully human antibodies that bind circulating PCSK9 protein
• Expected reduction: ~55–60% additional LDL-C lowering
• Dosing: Subcutaneous injection every 2 or 4 weeks

siRNA therapy:

• 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
• ~14% 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

References

Guidelines

• Mach F, et al. 2019 ESC/EAS Guidelines for the Management of Dyslipidaemias. Eur Heart J. 2020;41(1):111–188.
• Visseren FLJ, et al. 2021 ESC Guidelines on Cardiovascular Disease Prevention in Clinical Practice. Eur Heart J. 2021;42(34):3227–3337.
• Grundy SM, et al. 2018 AHA/ACC/Multisociety Guideline on the Management of Blood Cholesterol. Circulation. 2019;139(25):e1082–e1143.
• Lloyd-Jones DM, et al. 2022 ACC Expert Consensus Decision Pathway on the Role of Nonstatin Therapies for LDL-C Lowering. J Am Coll Cardiol. 2022;80(14):1366–1418.

Statin efficacy

• Jones PH, et al. STELLAR trial: comparison of efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses. Am J Cardiol. 2003;92(2):152–160.
• Nicholls SJ, et al. VOYAGER meta-analysis: meta-analysis of comparative efficacy of increasing dose of atorvastatin versus rosuvastatin versus simvastatin. Am J Cardiol. 2010;105(1):69–76.

Ezetimibe

• Cannon CP, et al. IMPROVE-IT: ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. 2015;372(25):2387–2397.

PCSK9 inhibitors (monoclonal antibodies)

• Sabatine MS, et al. FOURIER: evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713–1722.
• Schwartz GG, et al. ODYSSEY OUTCOMES: alirocumab and cardiovascular outcomes after acute coronary syndrome. N Engl J Med. 2018;379(22):2097–2107.

Inclisiran (siRNA)

• Raal FJ, et al. ORION-9: inclisiran for the treatment of heterozygous familial hypercholesterolemia. N Engl J Med. 2020;382(16):1520–1530.
• Ray KK, et al. ORION-10 and ORION-11: two phase 3 trials of inclisiran in patients with elevated LDL cholesterol. N Engl J Med. 2020;382(16):1507–1519.

Bempedoic acid

• Ray KK, et al. CLEAR Harmony: safety and efficacy of bempedoic acid added to maximally tolerated statins. N Engl J Med. 2019;380(11):1022–1032.
• Nissen SE, et al. CLEAR Outcomes: bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med. 2023;388(15):1353–1364.