Dyslipidemia

Dyslipidemia refers to abnormal quantity or quality of plasma lipids/lipoproteins that increases the risk of atherosclerotic cardiovascular disease (ASCVD), pancreatitis, and other metabolic complications.

It includes:

• Elevated LDL cholesterol (LDL-C)
• Elevated triglycerides (TG)
• Low HDL cholesterol (HDL-C)
• Elevated lipoprotein(a) [Lp(a)]
• Mixed lipid abnormalities

Classification of Dyslipidemia

1. According to Lipid Abnormality

2. Primary vs Secondary

Primary (Genetic)

Due to inherited defects in lipoprotein metabolism.

Examples:

1. Familial hypercholesterolemia (FH)
2. Familial combined hyperlipidemia
3. Familial dysbetalipoproteinemia
4. Familial hypertriglyceridemia
5. Chylomicronemia syndrome

Secondary Dyslipidemia

Much more common.

Drugs Causing Dyslipidemia

Increase LDL/TG

1. Thiazides
2. Beta blockers
3. Corticosteroids
4. Estrogens
5. Retinoids
6. Antiretrovirals
7. Atypical antipsychotics
8. Cyclosporine
9. Tacrolimus
10. Protease inhibitors

Lipoprotein Physiology

Exogenous Pathway

Dietary fat → intestine → chylomicrons → TG delivery → remnant uptake by liver.

Endogenous Pathway

Liver secretes VLDL → IDL → LDL.

LDL delivers cholesterol to tissues.

Reverse Cholesterol Transport

HDL removes cholesterol from peripheral tissues and returns it to liver.

Lipoproteins

Apolipoproteins

Pathogenesis of Atherosclerosis

LDL and Endothelial Injury

• Elevated LDL penetrates arterial intima → oxidation → inflammation.
• Macrophages ingest oxidized LDL → foam cells → fatty streaks → plaques.

Major Atherogenic Particles

1. LDL
2. Non-HDL cholesterol
3. ApoB-containing lipoproteins
4. Lp(a)
5. Remnant cholesterol

Clinical Manifestations

Most patients are asymptomatic.

Manifestations

Atherosclerotic Disease

1. Coronary artery disease
2. Stroke
3. Peripheral arterial disease

Hypertriglyceridemia Manifestations

1. Acute pancreatitis
2. Eruptive xanthomas
3. Lipemia retinalis

Cholesterol Deposition

Familial Hypercholesterolemia (FH)

Genetic defect causing markedly elevated LDL.

Usually due to:

• LDL receptor mutation
• ApoB mutation
• PCSK9 gain-of-function mutation

Types

Clinical Features

1. Premature CAD
2. Tendon xanthomas
3. Arcus cornealis
4. Family history of premature ASCVD

Diagnosis

Dutch Lipid Clinic Criteria

Uses:

• LDL level
• Family history
• Xanthomas
• Genetic testing

Hypertriglyceridemia

Causes of Hypertriglyceridemia

Primary

1. Familial hypertriglyceridemia
2. Familial combined hyperlipidemia
3. LPL deficiency

Secondary

1. Diabetes
2. Obesity
3. Alcohol
4. Hypothyroidism
5. Pregnancy
6. CKD
7. Drugs

Risk of Pancreatitis

Major risk when TG >500 mg/dL, especially >1000 mg/dL.

Mechanism:

• Chylomicron excess
• Free fatty acid toxicity
• Pancreatic ischemia

Lipoprotein(a) [Lp(a)]

LDL-like particle with Apo(a).

Independent risk factor for:

1. Premature ASCVD
2. Aortic stenosis

Usually genetically determined.

Evaluation of Dyslipidemia

History

1. Family history premature CAD
2. Diabetes
3. Smoking
4. Alcohol
5. Diet
6. Physical activity
7. Drug history
8. Pancreatitis history

Examination

1. BMI
2. Waist circumference
3. Xanthomas
4. Xanthelasma
5. Corneal arcus
6. Peripheral pulses
7. BP

Laboratory Evaluation

Lipid Profile

LDL Calculation

Friedewald Formula

LDL-C=Total Cholesterol−HDL-C−5TG

Not reliable if:

• TG >400 mg/dL
• Nonfasting severe hyperTG

Additional Tests

Secondary Cause Workup

ASCVD Risk Assessment

MAJOR ASCVD RISK SCORES USED WORLDWIDE

RISK ENHANCERS 

Used when risk is borderline/intermediate.

CORONARY ARTERY CALCIUM (CAC) SCORE

Used when decision about statin is uncertain.

Interpretation

HOW TO ASSESS ASCVD RISK 

Step 1 — Identify Major High-Risk Groups

If present → no calculator needed:

• Clinical ASCVD
• LDL ≥190
• Diabetes age 40–75

These usually warrant statins directly.

Step 2 — Calculate 10-Year Risk

Use:

• PCE (USA)
• SCORE2 (Europe)
• QRISK3 (UK)

Step 3 — Look for Risk Enhancers

Especially in:

• Borderline risk
• Intermediate risk

Step 4 — Consider CAC Score

If still uncertain.

Targets of Therapy

Non-HDL Cholesterol

Formula

Non-HDL Cholesterol=Total Cholesterol−HDL Cholesterol

Useful in:

• Hypertriglyceridemia
• Diabetes
• Obesity

Management of Dyslipidemia

Lifestyle Therapy

Foundation of treatment.

Diet Therapy Recommendations

1. Reduce saturated fat

2. Eliminate trans fat
3. Increase fiber

Types of Fiber

Recommended Intake

4. Mediterranean diet/DASH Diet
5. Reduce refined carbohydrates
6. Weight reduction
7. Reduce alcohol

Exercise

• ≥150 min/week moderate aerobic exercise or ≥75 min/week vigorous intensity
• Resistance training 2–3 times/week

Weight Loss

5–10% weight reduction significantly lowers TG.

Smoking Cessation

Improves HDL and reduces ASCVD risk.

Pharmacotherapy

The major contemporary guidelines used worldwide are:

• ACC/AHA Dyslipidemia Guidelines
• ESC/EAS Dyslipidemia Guidelines
• ADA Standards of Care in Diabetes
• NICE Lipid Guidelines

The basic principle in all guidelines:

• Higher ASCVD risk → earlier and more intensive LDL lowering
• Statins remain first-line therapy
• Nonstatins are added when LDL targets are not achieved or statin intolerance exists

1. PRIMARY PREVENTION — WHEN TO START STATINS

A. LDL-C ≥190 mg/dL (≥4.9 mmol/L)

Indication

Start statin regardless of calculated risk.

Guideline Recommendation

• High-intensity statin immediately
• Consider familial hypercholesterolemia

Examples

• Atorvastatin 40–80 mg
• Rosuvastatin 20–40 mg

LDL Goal

• ≥50% LDL reduction
• Often target LDL <100 mg/dL

B. DIABETES MELLITUS

Age 40–75 Years + Diabetes

Start statin even if baseline LDL is normal.

Diabetes Risk Enhancers

• Long duration diabetes
• Albuminuria
• CKD
• Retinopathy
• Neuropathy
• ABI <0.9
• Smoking
• Hypertension

LDL Goals

• Most diabetics: LDL <70 mg/dL
• Very high risk: LDL <55 mg/dL

C. PRIMARY PREVENTION BASED ON 10-YEAR ASCVD RISK

ACC/AHA Risk Categories

2. SECONDARY PREVENTION (ESTABLISHED ASCVD)

Clinical ASCVD Includes

• Prior MI
• Stroke/TIA
• PAD
• Angina
• Coronary revascularization
• Symptomatic carotid disease

Recommendation

LDL Goals

6. WHEN TO ADD EZETIMIBE Indications

LDL Thresholds for Addition

Dose-Ezetimibe 10 mg daily

LDL Reduction-~15–25%

7. WHEN TO ADD PCSK9 INHIBITORS Indications

Drugs-Evolocumab,Alirocumab

LDL Thresholds

LDL Reduction-50–65%

8. BEMPEDOIC ACID — WHEN USED

LDL Reduction

• 15–25%

9. FIBRATES — INDICATIONS

Drugs

• Fenofibrate
• Gemfibrozil

Main Indications

Important

• Fenofibrate preferred with statin
• Avoid gemfibrozil + statin (myopathy risk)

10. OMEGA-3 FATTY ACIDS / ICOSAPENT ETHYL

Indications

Benefit

Reduces CV events in high-risk patients.

11. LIPOPROTEIN(a) [Lp(a)] RELATED INDICATIONS

Elevated Lp(a)

• Strong ASCVD risk enhancer
• Favors earlier statin initiation
• Consider aggressive LDL lowering

Current guidelines advise at least one lifetime measurement of Lp(a).

Statins-First-line drugs.

Mechanism:

• Inhibit HMG-CoA reductase
• Increase LDL receptors
• Reduce hepatic cholesterol synthesis

12. HYPERTRIGLYCERIDEMIA — WHEN TO TREAT if TG 150–499 mg/dL

First-line

• Lifestyle
• Statin if ASCVD risk elevated

TG ≥500 mg/dL

Goal-Prevent pancreatitis

Drugs