Atherogenic Dyslipidemia

Definition, Etiology, PathogenesisTop

A combination of:

1) High triglyceride (TG) levels: ≥1.7 to 5.6 mmol/L (150-500 mg/dL).

2) Low high-density lipoprotein cholesterol (HDL-C) levels: <1 mmol/L (40 mg/dL) in men, <1.2 mmol/L (45 mg/dL) in women (or <1.3 mmol/L [50 mg/dL] in the case of coexisting metabolic syndrome).

3) Abnormal (small, dense) low-density lipoprotein (LDL) particles (not typically measured in practice).

Insulin resistance plays a major role in the development of atherogenic dyslipidemia in metabolic syndrome and type 2 diabetes mellitus.

Clinical Features and DiagnosisTop

There are no typical symptoms. Overweight/obesity or type 2 diabetes mellitus may coexist. Diagnosis is based on TG and HDL-C levels. LDL-C levels are moderately increased; patients with significantly increased LDL-C are diagnosed with mixed (familial) hyperlipidemia.

TreatmentTop

General Principles

1. Aim at normalization of the LDL-C level.

2. Currently there are no specific target concentrations for TG and HDL-C (lack of clinical trials). A desirable TG concentration of <1.7 mmol/L (150 mg/dL) is suggested. Pharmacotherapy is recommended in patients at high risk for cardiovascular disease if TG levels are >2.3 mmol/L (200 mg/dL) despite nonpharmacologic treatment.

Nonpharmacologic Management

1. Reduction of body weight by appropriate diet and exercise.

2. Dietary modification is aimed at reducing TG and increasing HDL-C levels. This also includes restricted intake of carbohydrates (particularly simple carbohydrates).

3. Increased physical activity.

4. Limiting alcohol consumption to reduce TG levels. Abstinence is recommended in patients with a TG level ≥5.6 mmol/L (500 mg/dL).

5. Control of diabetes.

6. Decreasing tobacco consumption.

Pharmacotherapy

Agents and dosage: see Table 2 in Hypercholesterolemia.

1. Statins:

1) In patients with high LDL-C, high TG, and low HDL-C levels, start with a statin.

2) In patients who have achieved the target LDL-C level but continue to have TG ≥1.7 mmol/L (150 mg/dL), HDL-C <1 mmol/L (40 mg/dL), or both, exclude secondary dyslipidemia (see Hypercholesterolemia) and evaluate compliance. If this does not result in adequate improvements, you may try adding a fibrate or nicotinic acid.

2. Fibrates should be used in patients with high TG or low HDL-C levels and LDL-C at the target level. In patients with a TG concentration ≥5.6 mmol/L (500 mg/dL), start with a fibrate (prevention of pancreatitis) and then add a statin when necessary.

Contraindications: Severe chronic kidney disease (do not use fenofibrate in patients with a glomerular filtration rate [GFR] <50 mL/min/1.73 m2 or gemfibrozil in patients with a GFR <15 mL/min/1.73 m2), liver failure, cholelithiasis, pregnancy, and breastfeeding.

Major adverse effects: Increased serum alanine aminotransferase (ALT); myopathy; gastrointestinal complaints such as dyspepsia, abdominal pain, diarrhea, bloating. If the ALT or aspartate aminotransferase (AST) level is >3 × upper limit of normal (ULN), discontinue the fibrate. The risk of serious complications, especially myopathy, is increased in the case of combination treatment with a fibrate and a statin (not as increased with fenofibrate). When using such treatment, be especially cautious and warn the patient about muscle complaints; if such complaints occur, measure the creatine kinase (CK) level (an increase in CK >3 × ULN is an indication for treatment discontinuation). Do not combine gemfibrozil (not used in many countries) with a statin because of the risk of adverse effects.

3. Nicotinic acid is rarely used because of disturbing adverse effects, which include flushing, pruritus, paresthesias, and nausea (these are less frequent with sustained-release formulations used alone).

Contraindications: Gout, active liver disease, acute myocardial infarction, peptic ulcer disease, pregnancy, breastfeeding, diabetes mellitus (only for crystalline nicotinic acid).

4. Addition of eicosapentaenoic acid (EPA) to statin therapy (2 g bid), especially in patients with hypertriglyceridemia, further reduces the cardiovascular events in very high risk patients.Evidence 1High Quality of Evidence (high confidence that we know true effects of the intervention). Bhatt DL, Steg PG, Miller M, et al; REDUCE-IT Investigators. Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia. N Engl J Med. 2019 Jan 3;380(1):11-22. doi: 10.1056/NEJMoa1812792. Epub 2018 Nov 10. PMID: 30415628.