What are the guidelines for screening and management of hypercholesterolemia in adults at high risk for cardiovascular disease?

Screening and Management for Hypercholesterolemia

Screening Recommendations

All adults should begin lipid screening at age 20 if risk factors are present (diabetes, family history of premature CVD, smoking, hypertension, obesity), or at age 35 for men and age 45 for women without risk factors, with repeat testing every 5 years. 1, 2

Who to Screen

• High-risk patients starting at age 20: Those with diabetes, family history of CVD before age 50 in male relatives or age 60 in female relatives, family history suggestive of familial hyperlipidemia, smoking, hypertension, or obesity 2, 1
• Average-risk men: Begin screening at age 35 1
• Average-risk women: Begin screening at age 45 1
• All adults aged 40-75: Should undergo comprehensive cardiovascular risk assessment 1, 2

Screening Intervals

• Every 5 years for patients without risk factors 2, 1
• Every 2 years for patients with risk factors present or lipid levels close to treatment thresholds 2, 1
• Within 4-12 weeks after initiating lipid-lowering therapy to assess response 1

What to Measure

A fasting lipid profile is the cornerstone and must include total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, and non-HDL cholesterol. 1, 2

• Total cholesterol and HDL can be measured non-fasting if fasting samples are unavailable, though fasting is preferred 2, 1
• LDL cholesterol requires fasting samples for accurate measurement 2
• Abnormal results must be confirmed with a repeated sample on a separate occasion, using the average of both results for risk assessment 2, 1
• Fasting blood glucose should be measured at the same intervals as lipid screening 1, 2

Risk Stratification and Treatment Targets

Very High-Risk Patients

Very high-risk patients (documented CVD, diabetes with CVD/CKD, moderate-to-severe renal disease, familial hypercholesterolemia) should target LDL-C <70 mg/dL (1.8 mmol/L) or achieve ≥50% reduction from baseline. 2, 3, 4

Very high-risk includes:

• Established cardiovascular disease 2, 3
• Diabetes mellitus with CVD or chronic kidney disease 2, 4
• Moderate to severe renal disease 2
• Familial hypercholesterolemia 2
• Acute coronary syndrome patients 2, 3

High-Risk Patients

High-risk patients (diabetes without CVD, multiple risk factors, 10-year ASCVD risk ≥20%) should target LDL-C <100 mg/dL (2.6 mmol/L) or achieve ≥50% reduction from baseline. 2, 3, 4

Moderate-Risk Patients

Moderate-risk patients should target LDL-C <130 mg/dL, with <100 mg/dL as a therapeutic option. 4

Risk Assessment Tools

• Calculate 10-year ASCVD risk using blood markers combined with age, sex, blood pressure, smoking status, presence of diabetes, and family history 1, 2
• Patients with ≥20% 10-year risk or diabetes are considered CHD risk equivalents requiring aggressive intervention 1, 2
• The Framingham tables or Pooled Cohort Equations can be used to calculate 10-year cardiovascular disease event risk 2, 3

Treatment Strategies

First-Line Therapy

Statins are the first-line treatment to reach LDL-C goals, with high-dose statins recommended for acute coronary syndrome patients regardless of initial LDL-C values. 2, 3, 5

• Statins lower LDL by 35-55% depending on type and dose 3
• High-intensity statins should be initiated immediately for patients with severe primary hypercholesterolemia (LDL-C ≥190 mg/dL) 4
• In the Scandinavian Simvastatin Survival Study, simvastatin 20-40 mg reduced total mortality by 30%, CHD mortality by 42%, and major coronary events by 34% 5

Combination Therapy

If LDL-C goal is not achieved with maximally tolerated statin monotherapy, add ezetimibe for an additional 15-20% reduction, followed by PCSK9 inhibitors for persistently elevated LDL-C in very high-risk patients. 3, 4

• The 2024 International Lipid Expert Panel advocates for upfront combination therapy in extremely high-risk individuals to improve adherence and effectiveness 3
• Combination therapy with a fibrate or nicotinic acid may be considered for high-risk patients with elevated triglycerides or low HDL-C 3

Treatment Intensity Requirements

When initiating lipid-lowering therapy in high or very high-risk patients, aim for at least 30-40% LDL-C reduction beyond dietary therapy. 2, 4

• Statins should be titrated to the highest recommended or tolerable dose to reach goal 4
• Only 30.3% of patients with definite/probable familial hypercholesterolemia on statins are taking a high-intensity statin, representing a major treatment gap 6

Special Populations

Familial Hypercholesterolemia

FH should be suspected in adults with LDL-C >190 mg/dL (>5 mmol/L) or children with LDL-C >150 mg/dL (>4 mmol/L), or those with CHD before age 55 in men or 60 in women. 2, 3

• Family cascade screening is recommended when an index case of FH is diagnosed 2
• FH patients should be treated with intense-dose statin, often in combination with ezetimibe 2
• In children, testing is recommended from age 5 years, or earlier if homozygous FH is suspected 2
• Despite high prevalence of cholesterol screening and awareness, only approximately 50% of adults with FH are on statin therapy 6

Diabetes Mellitus

In all patients with type 2 diabetes and CVD or CKD, the recommended goal for LDL-C is <70 mg/dL (<1.8 mmol/L). 2, 4

• In all patients with type 2 diabetes without CVD or additional risk factors, LDL-C <100 mg/dL (<2.6 mmol/L) is the primary goal 2
• In all patients with type 1 diabetes with microalbuminuria and/or renal disease, LDL-C lowering (at least 50%) with statins as first choice is recommended irrespective of baseline LDL-C 2
• High or borderline high total cholesterol is present in 70% of adults with diagnosed diabetes and 77% with undiagnosed diabetes 7

Older Adults

Treatment with statins is recommended for older adults with established cardiovascular disease, similar to younger patients. 3

• Screening may be appropriate in older persons who have never been screened, but repeated screening is less important after age 65 years because lipid levels are less likely to increase 2
• Simvastatin resulted in similar decreases in relative risk for total mortality, CHD mortality, and major coronary events in geriatric patients (≥65 years) compared with younger adults 5

Women

Women should begin screening at age 45 if no risk factors are present, or age 20 if risk factors exist. 1, 2

• Simvastatin significantly reduced the risk of major coronary events in women by 34% 5
• The average benefit of treating abnormal lipid levels in women may be smaller than in men of similar ages because of their lower rates of heart disease 2

Lifestyle Interventions

All patients, regardless of lipid levels, should receive counseling about a diet low in saturated fat and high in fruits and vegetables, regular physical activity, avoiding tobacco use, and maintaining a healthy weight. 2

• Reducing dietary saturated fat and weight loss can lower total cholesterol and LDL levels by as much as 10-20% in some persons, but the average effect is relatively modest (2-6% reduction) 2
• Although diet therapy is appropriate initial treatment for most patients, drugs are frequently needed to achieve therapeutic goals, especially in high-risk patients 2

Critical Implementation Gaps and Pitfalls

Despite available effective therapies, clinical practice goals are not met in up to 70% of patients, representing a major treatment gap. 3

Common Pitfalls to Avoid

• Delaying combination therapy: The 2024 guidelines emphasize early aggressive treatment rather than sequential monotherapy titration in very high-risk patients 3
• Undertreating young and uninsured patients: These groups are at highest risk for lack of screening and undertreatment 6
• Stopping screening in older adults: While repeated screening is less important after age 65, treatment decisions should still be based on overall cardiovascular risk 2
• Focusing solely on LDL-C: Non-HDL cholesterol may be a better predictor of cardiovascular risk than LDL alone, especially in patients with elevated triglycerides 3

Guideline Differences

The European Society of Cardiology/European Atherosclerosis Society guidelines are more aggressive with specific absolute LDL-C targets and broader use of combination therapy, while the American Heart Association/American College of Cardiology guidelines are more conservative, focusing on percentage reductions and incorporating cost-effectiveness considerations. 3

• The ESC/EAS approach recommends specific absolute LDL-C concentration targets plus percentage reductions and supports liberal use of PCSK9 inhibitors across broader patient groups 3
• The AHA/ACC approach emphasizes percentage reductions with statin intensity and reserves non-statin additions only for select very high-risk patients with specific LDL-C thresholds 3