How should I evaluate and manage a patient with persistently low high‑density lipoprotein (HDL) and high low‑density lipoprotein (LDL) cholesterol?

Evaluation and Management of Persistent Low HDL and High LDL

For patients with persistently low HDL and high LDL cholesterol, initiate high-intensity statin therapy (atorvastatin 40-80 mg or rosuvastatin 20-40 mg daily) as first-line treatment, targeting LDL-C <100 mg/dL for high-risk patients or <70 mg/dL for very high-risk patients, with HDL-C serving as a risk marker rather than a treatment target. 1, 2

Initial Risk Stratification and Assessment

Determine cardiovascular risk category immediately:

• Very high-risk patients (documented cardiovascular disease, diabetes mellitus, moderate-to-severe chronic kidney disease, or 10-year cardiovascular death risk ≥5%): Target LDL-C <70 mg/dL (1.8 mmol/L) or achieve ≥50% reduction from baseline 1, 2

• High-risk patients (≥2 risk factors or 10-year risk 5-10%): Target LDL-C <100 mg/dL (2.6 mmol/L) or achieve ≥50% reduction from baseline 1, 2

• HDL-C thresholds for increased risk: <40 mg/dL in men, <45-50 mg/dL in women 2, 1

Assess for secondary causes before initiating therapy:

• Evaluate thyroid function, glucose control, renal function, and hepatic function 2
• Review medications that may worsen lipid profiles 2
• Screen for metabolic syndrome (waist circumference >102 cm in males/>88 cm in females, triglycerides ≥150 mg/dL, blood pressure ≥130/85 mmHg, fasting glucose ≥110 mg/dL) 2

Lifestyle Modification (Concurrent with Pharmacotherapy)

Implement aggressive dietary changes immediately:

• Reduce saturated fat to <7% of total energy intake and cholesterol to <200 mg/day 3
• Add plant stanols/sterols at 2 g/day (expected LDL reduction of 8-29 mg/dL) 3
• Increase soluble fiber to 10-25 g/day (expected ~2.2 mg/dL LDL reduction per gram) 3
• Smoking cessation and increased physical activity (both improve HDL-C) 4, 2

Pharmacological Treatment Algorithm

Step 1: High-Intensity Statin Monotherapy

Initiate immediately for LDL-C ≥130 mg/dL or based on risk category:

• Atorvastatin 40-80 mg daily OR rosuvastatin 20-40 mg daily 3, 2
• Expected LDL-C reduction: 50-60% 3
• Expected HDL-C increase: 5-7% (modest) 3
• Reassess lipid profile after 4-6 weeks 3

Important caveat: While statins modestly increase HDL-C, their primary benefit is through LDL-C reduction, not HDL-C elevation 5, 4

Step 2: Add Ezetimibe if LDL-C Goal Not Achieved

If LDL-C remains above target on maximally tolerated statin:

• Add ezetimibe 10 mg daily 3, 2
• Expected additional LDL-C reduction: 15-20% 3
• Reassess after 4-6 weeks 3

Step 3: Consider PCSK9 Inhibitors for Persistent Elevation

For very high-risk patients with LDL-C ≥70 mg/dL despite statin plus ezetimibe:

• PCSK9 monoclonal antibodies (evolocumab or alirocumab) are preferred as initial PCSK9 inhibitor based on demonstrated cardiovascular outcomes benefits 2
• Inclisiran may be considered for patients with poor adherence to PCSK9 mAbs or inability to self-inject 2
• Bempedoic acid represents an additional option for very high-risk patients 2, 1

Step 4: Addressing Persistent Low HDL-C

Critical distinction: Low HDL-C is a risk marker, not a treatment target 4, 6

If HDL-C remains <40 mg/dL (men) or <50 mg/dL (women) AND triglycerides ≥150 mg/dL after achieving LDL-C goal:

• Consider adding fibrate (gemfibrozil or fenofibrate) OR niacin, but only after careful consideration of safety concerns 6, 2
• Caution with fibrates: Risk of myopathy when combined with statins, increased serum creatinine, and cholelithiasis 6, 7
• Caution with niacin: Risk of elevated blood glucose (6.4% vs 4.5% placebo), diabetes mellitus (3.6% vs 2.2% placebo), flushing (up to 88% of patients), and hepatotoxicity 7, 6

Important evidence gap: Recent trials have not demonstrated cardiovascular benefit from pharmacologically raising HDL-C, despite epidemiological associations 4, 1

Monitoring Strategy

Follow-up schedule:

• Reassess lipid profile 4-6 weeks after initiating or adjusting therapy 3
• Monitor hepatic aminotransferases before starting statins 3
• Check creatine kinase only if musculoskeletal symptoms develop 3
• Once stable on therapy, monitor lipids annually 3

Common Pitfalls to Avoid

Do not delay combination therapy in very high-risk patients: The 2024 guidelines emphasize early aggressive treatment rather than sequential monotherapy titration 1

Do not target HDL-C pharmacologically: HDL-C elevation through drugs has not shown cardiovascular benefit; focus remains on LDL-C reduction 4, 1

Do not ignore residual risk: Approximately 60% of high-risk patients have residual dyslipidemia despite achieving LDL-C targets, particularly low HDL-C (40% in women, 33% in men) and elevated triglycerides 8, 9

Do not overlook metabolic syndrome: Patients with diabetes or metabolic syndrome are more likely to have abnormal HDL-C (28.9% vs 16.4%) and triglycerides (44.9% vs 29.5%) despite normal LDL-C 8

Special Considerations

For patients with familial hypercholesterolemia (baseline LDL-C ≥190 mg/dL):

• Target LDL-C <55 mg/dL with ≥50% reduction 2
• Consider referral to lipid specialist 2
• May require ezetimibe, PCSK9 inhibitors, or LDL apheresis 2

For patients with combined dyslipidemia (low HDL-C and high triglycerides):

• Non-HDL cholesterol (total cholesterol minus HDL-C) becomes secondary target, with goal 30 mg/dL higher than LDL-C goal 2, 1
• Non-HDL-C may be a better predictor of cardiovascular risk than LDL-C alone in these patients 1, 2