For adult patients with atherosclerotic cardiovascular disease or high cardiovascular risk who are statin‑intolerant or need additional low‑density lipoprotein cholesterol lowering beyond maximally tolerated statins, what are the indications, dosing schedules, efficacy, and safety of inclisiran (small interfering RNA PCSK9 inhibitor) and bempedoic acid (ATP‑citrate lyase inhibitor)?

Novel LDL-Lowering Therapies: Inclisiran and Bempedoic Acid

Indications

Inclisiran (Small Interfering RNA PCSK9 Inhibitor)

Inclisiran is FDA-approved as adjunctive therapy to maximally tolerated statins in adults with clinical atherosclerotic cardiovascular disease (ASCVD) or heterozygous familial hypercholesterolemia requiring additional LDL-C lowering. 1

• Primary indication: Patients with ASCVD or heterozygous FH with LDL-C ≥70 mg/dL despite maximally tolerated statin therapy (≥55 mg/dL if multiple ASCVD events or very high-risk features) 2, 3
• Critical positioning: Inclisiran should be considered as a second-line alternative to PCSK9 monoclonal antibodies (evolocumab, alirocumab), NOT as first-line PCSK9 inhibitor therapy 3, 4, 5
• Specific scenarios favoring inclisiran over PCSK9 mAbs: Documented poor adherence to injectable PCSK9 mAbs, adverse effects from both available PCSK9 mAbs (evolocumab and alirocumab), or inability to self-inject medications 4, 5

Bempedoic Acid (ATP-Citrate Lyase Inhibitor)

Bempedoic acid is indicated as adjunct to diet and maximally tolerated statin therapy for adults with heterozygous familial hypercholesterolemia or established ASCVD requiring additional LDL-C lowering. 2, 6

• Primary role: Third-line therapy after statins and ezetimibe, or as an alternative in statin-intolerant patients 2
• Statin-intolerant patients: Bempedoic acid is particularly valuable because it does not cause myalgia (conversion to active form occurs only in liver, not skeletal muscle) 6
• Combination therapy: Can be combined with ezetimibe (fixed-dose combination available) for approximately 35% LDL-C reduction 2

Dosing Schedules

Inclisiran Dosing

Inclisiran is administered as 284 mg subcutaneous injection at baseline, 3 months, then every 6 months thereafter by a healthcare professional. 2, 1, 7

• Route: Subcutaneous injection only 1
• Administration: Must be given by healthcare professional (not self-administered) 5
• Loading phase: Initial dose at day 1, second dose at day 90 (3 months) 2
• Maintenance phase: Every 6 months after the 3-month dose 2, 1

Bempedoic Acid Dosing

Bempedoic acid is administered as 180 mg orally once daily. 6

• Route: Oral tablet 6
• Frequency: Once daily dosing 6
• Combination product: Bempedoic acid 180 mg + ezetimibe 10 mg fixed-dose combination available 2

Efficacy

Inclisiran Efficacy

Inclisiran reduces LDL-C by approximately 50% (49.9-52.3% placebo-corrected reduction) at 18 months in patients with ASCVD. 2, 8

• ORION-10 trial: 52.3% placebo-corrected LDL-C reduction at day 510 in US patients with ASCVD 2
• ORION-11 trial: 49.9% placebo-corrected LDL-C reduction at day 510 in international patients with ASCVD 2
• Comparative efficacy: Network meta-analysis demonstrates inclisiran provides comparable LDL-C reduction to alirocumab (mean difference: -1.93%) and evolocumab (mean difference: 2.00%), and superior reduction compared to ezetimibe (mean difference: -44.24%) and bempedoic acid 8
• Critical limitation: Cardiovascular outcomes data will not be available until 2026-2027 (ORION-4 and VICTORION-2P trials ongoing) 4, 5
• Exploratory cardiovascular data: In ORION-10 and ORION-11, non-adjudicated cardiovascular events occurred in 7.4-7.8% of inclisiran patients vs 10.2-10.3% of placebo patients, but these were exploratory endpoints only 2

Bempedoic Acid Efficacy

Bempedoic acid reduces LDL-C by approximately 15-25% as monotherapy and reduces major adverse cardiovascular events by 13% in statin-intolerant patients. 2, 6

• LDL-C reduction: Pooled analysis shows approximately 23% LDL-C reduction compared to placebo 2
• CLEAR Outcomes trial: In statin-intolerant patients (mean baseline LDL-C 139 mg/dL), bempedoic acid reduced LDL-C by 29 mg/dL and reduced MACE by 13% (hazard ratio 0.87) 2
• Combination therapy: Bempedoic acid + ezetimibe combination reduces LDL-C by approximately 35% 2
• Additional benefits: Reduces high-sensitivity C-reactive protein significantly 6

Safety Profile

Inclisiran Safety

Inclisiran demonstrates excellent tolerability with adverse event rates similar to placebo in clinical trials. 2, 7

• Overall safety: Proportions of patients experiencing adverse events and serious adverse events were similar between inclisiran and placebo groups 2
• Injection site reactions: Generally mild and transient 7
• Long-term safety: Found to be safe and tolerable in ASCVD patients across multiple trials 7
• No muscle-related adverse effects: Unlike statins, inclisiran does not cause myalgia 1

Bempedoic Acid Safety

Bempedoic acid has low rates of muscle-related adverse effects but increases risk of hyperuricemia, gout, gallstones, and abnormal liver function tests. 2, 6

• Muscle safety: Low rates of muscle-related adverse effects because active form only produced in liver, not skeletal muscle 2, 6
• Hyperuricemia and gout: Raises uric acid levels in subset of patients; increased rates of gout in CLEAR Outcomes trial 2
• Hepatotoxicity: Increased rates of abnormal liver function tests 2
• Gallstones: Increased incidence in clinical trials 2
• Monitoring required: Baseline and periodic monitoring of hepatic aminotransferases, creatine kinase, glucose, and creatinine recommended 2

Treatment Algorithm

Step-by-Step Approach for LDL-C Management

1. Initiate high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg) as first-line therapy. 2

2. If LDL-C remains ≥70 mg/dL (or ≥55 mg/dL in very high-risk patients) after 4-12 weeks on maximally tolerated statin, add ezetimibe 10 mg daily. 2, 4

3. Reassess LDL-C 4-12 weeks after adding ezetimibe. 2, 4

4. If LDL-C remains ≥70 mg/dL despite statin + ezetimibe, add PCSK9 monoclonal antibody (evolocumab 140 mg every 2 weeks or 420 mg monthly, OR alirocumab 75-150 mg every 2 weeks) as preferred PCSK9 inhibitor. 2, 3, 5

5. Consider inclisiran (284 mg at baseline, 3 months, then every 6 months) ONLY if:

• Documented poor adherence to PCSK9 mAbs 4, 5
• Adverse effects from both available PCSK9 mAbs 4, 5
• Inability to self-inject medications 4, 5

6. Consider adding bempedoic acid 180 mg daily as third-line therapy if LDL-C remains elevated despite statin, ezetimibe, and PCSK9 inhibitor, OR as alternative in statin-intolerant patients. 2, 4

Special Considerations for Statin-Intolerant Patients

For patients with documented statin intolerance (minimum 2 statins attempted, including at least 1 at lowest approved dose): 2

• First-line: Ezetimibe 10 mg daily 2
• Second-line: Add bempedoic acid 180 mg daily (or use bempedoic acid + ezetimibe combination) 2
• Third-line: Add PCSK9 mAb (evolocumab or alirocumab preferred) or inclisiran if adherence/injection concerns 2, 5
• Critical note: Bempedoic acid demonstrated 13% MACE reduction in CLEAR Outcomes trial specifically in statin-intolerant patients 2

Critical Caveats and Common Pitfalls

Inclisiran-Specific Pitfalls

Never combine inclisiran with PCSK9 monoclonal antibodies—there is no evidence or mechanistic plausibility for additional benefit, and inclisiran must replace (not supplement) PCSK9 mAbs. 4, 5

• Insurance authorization: Most payers require documented PCSK9 mAb failure before approving inclisiran; attempting to bypass this sequence results in coverage denial 5
• LDL-C threshold requirement: Patient must have LDL-C ≥70 mg/dL (or ≥55 mg/dL if very high-risk) on current therapy to qualify for inclisiran 3
• Documentation requirements: Must document ≥3 months of maximally tolerated statin therapy with specific statin name, dose, duration, and reason for discontinuation if not currently on statin 3
• Outcomes data gap: Unlike PCSK9 mAbs (which have proven cardiovascular outcomes benefits in FOURIER and ODYSSEY Outcomes trials), inclisiran lacks completed cardiovascular outcomes data until 2026-2027 3, 4, 5

Bempedoic Acid-Specific Pitfalls

Monitor for hyperuricemia, gout flares, and hepatotoxicity—bempedoic acid raises uric acid levels and increases risk of gout and abnormal liver function tests. 2

• Baseline testing: Measure hepatic aminotransferases, creatine kinase, glucose, and creatinine before starting therapy 2
• Gout risk: Patients with history of gout or elevated uric acid require careful monitoring 2
• Hepatic monitoring: Periodic liver function testing recommended, especially in patients with history of liver disease or excess alcohol use 2
• Gallstone risk: Increased incidence in clinical trials; counsel patients on symptoms 2

General Treatment Pitfalls

Do not de-escalate therapy once LDL-C goals are achieved—continue existing well-tolerated therapy rather than switching to unproven alternatives. 3

• Premature inclisiran use: Do not initiate inclisiran in patients already at LDL-C goal with current therapy, as this adds cost without proven cardiovascular benefit 3
• Skipping ezetimibe: Always optimize with ezetimibe before adding more expensive PCSK9 inhibitors 2, 4
• Inadequate statin trial: Ensure patient has received ≥3 months of maximally tolerated statin therapy before adding non-statin agents 3