How to Increase HDL in Homozygous Familial Hypercholesterolemia
In patients with homozygous familial hypercholesterolemia (HoFH), focus on aggressive LDL-lowering rather than targeting HDL elevation, as the primary therapeutic goal is reducing LDL-cholesterol to prevent premature atherosclerotic cardiovascular disease; however, LDL apheresis may secondarily increase HDL levels by up to 2-fold as LDL is removed. 1, 2
Primary Treatment Strategy: LDL Reduction Takes Priority
The most recent international guidelines 3, 4 make clear that HDL is not a treatment target in HoFH—the focus must be on lowering LDL-cholesterol to <1.8 mmol/L (<70 mg/dL) if atherosclerotic cardiovascular disease is present, or <2.5 mmol/L (<100 mg/dL) without ASCVD 3. This is critical because:
- HoFH patients have severely elevated LDL-cholesterol (typically >10 mmol/L or >400 mg/dL untreated) 4
- The overwhelming cardiovascular risk comes from LDL, not low HDL
- Evidence-based therapies that reduce mortality and morbidity in HoFH target LDL reduction 3, 4
The HDL Paradox in HoFH: A Secondary Benefit
While you cannot directly and effectively raise HDL in HoFH through conventional means, LDL apheresis produces a beneficial side effect of increasing HDL cholesterol:
- When LDL is removed via apheresis, plasma HDL can increase up to 2-fold above baseline 2
- This HDL elevation persists between apheresis treatments and improves the HDL:LDL ratio 2
- The mechanism involves removing the metabolic burden of excess LDL, allowing HDL metabolism to normalize 5
Specific Treatment Algorithm for HoFH
Step 1: Immediate Initiation (at diagnosis, ideally by age 2)
- High-potency statin at maximally tolerated dose
- Ezetimibe 10 mg daily
- Consider bile acid sequestrants (colesevelam) if tolerated 3
Step 2: Add Within 8 Weeks if LDL Goals Not Met
- PCSK9 inhibitor (evolocumab or alirocumab) in patients without biallelic LDLR null mutations—continue only if ≥15% additional LDL reduction achieved 3, 6
Step 3: LDL Apheresis (by age 3-8 years)
- Initiate lipoprotein apheresis when LDL goals are not achieved with maximal medication 1, 3
- Perform weekly or biweekly 1
- This is the intervention that will secondarily raise HDL 2
Step 4: Novel Therapies for Refractory Cases
- Lomitapide (microsomal triglyceride transfer protein inhibitor)—works independently of LDL receptors 7, 8, 4
- Evinacumab (angiopoietin-like 3 inhibitor)—effective even in null-null LDLR mutations 4, 6
Why Traditional HDL-Raising Strategies Fail in HoFH
Do not use niacin or fibrates primarily to raise HDL in HoFH—the evidence does not support this approach:
- The 2013 ACC/AHA guidelines 9 explicitly state that adding niacin or fibrates to statin therapy for low HDL has not shown ASCVD event reduction (AIM-HIGH and ACCORD trials were futile)
- In HoFH specifically, the metabolic derangement is so severe that HDL-raising medications have minimal effect 5
- Low HDL in FH patients is often secondary to insulin resistance and visceral obesity—address these through lifestyle modification 5
Lifestyle Interventions (Adjunctive Only)
While lifestyle changes alone are insufficient in HoFH, they may modestly improve HDL:
- Weight loss if visceral obesity present 5
- Increased physical activity 10
- Smoking cessation 11
- Moderate alcohol consumption (1-2 drinks daily) raises HDL by ~12%, but this is not recommended as a therapeutic strategy in HoFH given other risks 12
Critical Pitfalls to Avoid
Do not delay LDL apheresis while attempting to raise HDL with medications—apheresis should begin by age 8 at the latest 1, 3
Do not combine statins with gemfibrozil—use fenofibrate if a fibrate is absolutely necessary, and only with careful monitoring for myopathy 10, 11
Do not use niacin aggressively in HoFH patients who also have diabetes or insulin resistance, as it significantly worsens glycemic control 10, 11
Do not treat to an HDL target—the 2012 European guidelines 1 and 2016 ESC/EAS guidelines 13 explicitly state there is insufficient evidence for HDL as a treatment target
The Bottom Line
In HoFH, HDL elevation is not achievable through conventional HDL-raising therapies and should not be a treatment goal. The evidence-based approach is maximal LDL reduction through combination pharmacotherapy and LDL apheresis, which will secondarily improve HDL levels and the HDL:LDL ratio 2. Any attempt to specifically raise HDL with fibrates or niacin diverts attention from the life-saving priority of aggressive LDL lowering and lacks evidence for reducing cardiovascular events in this population 9.