# Nonstatin Lipid-Lowering Therapy -- ACC/AHA 2018

## When to Consider Nonstatin Therapy

Nonstatin agents are considered as add-on therapy to maximally tolerated statin when LDL-C reduction goals are not met. The guideline emphasizes that statin therapy is the foundation of cholesterol management, and nonstatin agents are reserved for specific clinical scenarios.

## Ezetimibe

### Mechanism
- Ezetimibe inhibits intestinal cholesterol absorption at the brush border of the small intestine via the Niemann-Pick C1-Like 1 (NPC1L1) protein.
- LDL-C reduction: 13--20% when added to statin therapy.

### Indications

- **Very high-risk ASCVD with LDL-C >= 70 mg/dL on maximally tolerated statin:** Adding ezetimibe is reasonable (Class IIa, Level of Evidence B-R).
- **Non-very-high-risk ASCVD with LDL-C >= 70 mg/dL on maximally tolerated statin:** Adding ezetimibe is reasonable (Class IIa, Level of Evidence B-R).
- **Severe hypercholesterolemia (LDL-C >= 190 mg/dL) with LDL-C >= 100 mg/dL on maximally tolerated statin:** Adding ezetimibe is reasonable (Class IIa, Level of Evidence B-R).
- **Statin intolerance:** Ezetimibe monotherapy is reasonable as an alternative when statins cannot be tolerated (Class IIa, Level of Evidence B-R).

### Dosing
- **Ezetimibe:** 10 mg orally once daily, with or without food.
- Can be co-administered with any statin; no dose adjustment needed.
- No significant drug interactions with most statins.

### Evidence Base
- IMPROVE-IT trial: In post-ACS patients, simvastatin 40 mg + ezetimibe 10 mg reduced cardiovascular events compared with simvastatin 40 mg alone (median LDL-C 54 mg/dL vs 70 mg/dL; absolute risk reduction 2.0% over 7 years).

## PCSK9 Inhibitors

### Mechanism
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are monoclonal antibodies that bind circulating PCSK9, preventing LDL receptor degradation, thereby increasing LDL receptor recycling and LDL-C clearance.
- LDL-C reduction: 50--60% when added to statin therapy.

### Available Agents and Dosing

| Agent | Dose | Route | Frequency |
|---|---|---|---|
| **Alirocumab** | 75 mg (may increase to 150 mg if additional LDL-C reduction needed) | Subcutaneous injection | Every 2 weeks |
| **Evolocumab** | 140 mg | Subcutaneous injection | Every 2 weeks |
| **Evolocumab** | 420 mg | Subcutaneous injection | Once monthly |

### Indications

- **Very high-risk ASCVD with LDL-C >= 70 mg/dL on maximally tolerated statin PLUS ezetimibe:** Adding a PCSK9 inhibitor may be considered (Class IIb, Level of Evidence A).
- **Severe hypercholesterolemia (LDL-C >= 190 mg/dL) with LDL-C >= 100 mg/dL on maximally tolerated statin PLUS ezetimibe with multiple factors increasing risk:** A PCSK9 inhibitor may be considered (Class IIb, Level of Evidence B-R).
- **Heterozygous familial hypercholesterolemia (HeFH):** In patients not achieving adequate LDL-C reduction on maximally tolerated statin + ezetimibe, a PCSK9 inhibitor may be considered (Class IIb, Level of Evidence B-R).
- **Homozygous familial hypercholesterolemia (HoFH):** Evolocumab is FDA-approved; limited efficacy in receptor-negative HoFH.

### Evidence Base
- FOURIER trial (evolocumab): Reduced cardiovascular events (HR 0.85) in patients with stable ASCVD on statin therapy. Median LDL-C achieved: 30 mg/dL.
- ODYSSEY Outcomes trial (alirocumab): Reduced cardiovascular events (HR 0.85) in post-ACS patients on statin therapy. Median LDL-C achieved: 38 mg/dL.
- Long-term safety beyond 3 years is uncertain.
- At mid-2018 list prices, PCSK9 inhibitors have low cost-effectiveness (exceeding $150,000 per QALY); a 70--85% price reduction would be needed to meet the conventional threshold of < $150,000/QALY.

## Other Nonstatin Agents

### Bile Acid Sequestrants
- **Agents:** Colesevelam 3.75 g/day, cholestyramine 4--16 g/day, colestipol 2--16 g/day.
- LDL-C reduction: 15--30%.
- May be considered in patients intolerant to both statins and ezetimibe, or as add-on therapy in severe hypercholesterolemia (Class IIb, Level of Evidence C-LD).
- Common side effects: gastrointestinal (bloating, constipation).
- May increase triglycerides; avoid when triglycerides >= 300 mg/dL. Contraindicated when triglycerides >= 500 mg/dL.

### Icosapent Ethyl (EPA)
- The 2018 guideline was published before the full results of the REDUCE-IT trial (2019). At the time of publication, omega-3 fatty acids had not demonstrated cardiovascular benefit in statin-treated patients.

### Fibrates
- Do not add fibrate therapy to statin therapy for the purpose of further reducing ASCVD events (Class III: No Benefit, Level of Evidence A).
- Exception: Consider for severe hypertriglyceridemia (>= 500 mg/dL) to reduce pancreatitis risk.
- **Do not combine gemfibrozil with any statin** due to increased rhabdomyolysis risk (Class III: Harm, Level of Evidence B-R). Fenofibrate may be used with caution.

### Niacin
- Do not add niacin to statin therapy for the purpose of further reducing ASCVD events (Class III: No Benefit, Level of Evidence A).
- Evidence: AIM-HIGH and HPS2-THRIVE trials showed no incremental cardiovascular benefit.

## Nonstatin Therapy Decision Algorithm

For patients who require therapy beyond maximally tolerated statin:

1. **Assess current LDL-C on maximally tolerated statin therapy.**
2. **If LDL-C remains above threshold (>= 70 mg/dL for very high-risk ASCVD; >= 100 mg/dL for severe hypercholesterolemia):**
   - Add ezetimibe 10 mg/day.
   - Recheck lipid panel in 4--12 weeks.
3. **If LDL-C remains above threshold on statin + ezetimibe:**
   - Consider PCSK9 inhibitor (alirocumab or evolocumab) in very high-risk ASCVD or severe hypercholesterolemia with additional risk factors.
   - Discuss cost, injection route, and long-term safety with patient.
4. **If statin completely intolerant:**
   - Ezetimibe monotherapy.
   - Consider bile acid sequestrant if additional LDL-C reduction needed.
   - Consider PCSK9 inhibitor for very high-risk patients unable to tolerate any statin.

## Monitoring Nonstatin Therapy

- Recheck fasting lipid panel 4 to 12 weeks after adding or adjusting any nonstatin agent.
- Assess adherence to both statin and nonstatin therapy at each visit.
- For PCSK9 inhibitors: no routine laboratory monitoring beyond lipid panel is required.
- For ezetimibe: no additional monitoring beyond lipid panel is required.
- For bile acid sequestrants: monitor triglycerides; discontinue if triglycerides rise > 500 mg/dL.

## Limitations

- PCSK9 inhibitor long-term safety (> 3 years) data were not available at the time of guideline publication.
- Cost-effectiveness of PCSK9 inhibitors was low at 2018 list prices; subsequent price reductions may improve value.
- The guideline does not recommend specific absolute LDL-C targets; instead, it uses percentage reduction from baseline and threshold-based escalation.
- Icosapent ethyl (Vascepa) was not fully evaluated in this guideline; subsequent evidence (REDUCE-IT, 2019) supports its use in hypertriglyceridemia with ASCVD.
