Lipid Disorders: General Considerations

DefinitionTop

Dyslipidemias are conditions in which plasma concentrations of lipids, lipoproteins, or triglycerides are considered abnormal/elevated based on the patient’s total cardiovascular disease (CVD) risk.

Total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) used to be measured in the fasting state after 12 to 14 hours after the last meal. Current guidelines suggest that lipid measurement could be done in a nonfasting state for the purpose of risk assessment and screening, but fasting measurements should be taken to assess TG levels or when TG levels are elevated (>4.6 mmol/L).

Low-density lipoprotein cholesterol (LDL-C) levels are usually calculated using the Friedewald formula:

LDL-C = TC – HDL-C – (TG/5 [mg/dL] or TG/2.2 [mmol/L])

The calculations are unreliable in patients with a TG level >4.6 mmol/L (400 mg/dL). The more recent proposal from the National Institutes of Health (NIH) represents a more accurate alternative, especially for estimating LDL-C levels:

LDL-C = TC/0.948 – HDL-C/0.971 – (TG/8.56 + [TG × non–HDL-C]/2140 – TG2/16,100) – 9.44

Note that the NIH equation is based on lipid measurements in mg/dL.

Non–high-density lipoprotein cholesterol (non–HDL-C):

Non–HDL-C = TC – HDL-C

Where: HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol.

Atherogenic dyslipidemia is variably defined as an elevation of TG level (>1.7 mmol/L), low HDL-C (<1 mmol/L in men and 1.3 mmol/L in women), and increased LDL-C and/or apolipoprotein B (ApoB) levels (a more direct measure of atherogenic lipoproteins). Treatment is usually directed at normalization of LDL-C and TG levels and control of additional risk factors (eg, diabetes, hypertension, smoking, obesity).

Metabolic syndrome: The co-occurrence of cardiovascular risk factors including central obesity (increased waist circumference), elevated blood pressure (BP) (>130 systolic, or > 85 diastolic, or on treatment), dyslipidemia (high TG (>1.7 mmol/L) and low HDL-C levels (<1.0 mmol/L in men and <1.3 mmol/L in women). Insulin resistance, including genetic predisposition, and obesity are major determinants in its development. The treatment includes control of individual components.

screeningTop

The screening for dyslipidemia in adults should include those with ≥1 of the following risk factors:

1) Men aged ≥40 years; women aged ≥40 years (or postmenopausal). Consider earlier screening in ethnic groups at increased risk such as South Asian or indigenous individuals.

2) Clinical evidence of atherosclerosis.

3) Abdominal aortic aneurysm.

4) Diabetes mellitus (particularly in individuals aged 40-75 years).

5) Arterial hypertension.

6) Current cigarette smoking.

7) Stigmata of dyslipidemia (corneal arcus, xanthelasma, xanthoma).

8) Family history of dyslipidemia.

9) Chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] ≤ 60 mL/min/1.73 m2 or albumin-creatinine ratio [ACR] ≥ 3 mg/mmol).

10) Obesity (body mass index [BMI] ≥ 30 kg/m2).

11) Inflammatory diseases (rheumatoid arthritis, systemic lupus erythematosus, psoriatic arthritis, ankylosing spondylitis, irritable bowel syndrome).

12) HIV infection.

13) Erectile dysfunction.

14) Chronic obstructive pulmonary disease (COPD).

15) History of hypertensive disorder of pregnancy.

16) Family history of premature CVD (men aged <55 years and women aged <65 years).

17) Hypothyroidism, hypercotisolemia.

Screening should include:

1) History and physical examination.

2) Standard lipid profile: TC, HDL-C, TG, LDL-C, non–HDL-C.

 3) Lipoprotein(a)—once in a lifetime, with initial screening. The increasing levels of lipoprotein(a), controlled mostly by genetic factors, are associated with level-dependent increase in CVD risk. Currently lipoprotein(a) level is not considered a specific target of therapy, as it may be slightly increased by statins and decreased by 20% to 30% by proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors (see Hypercholesterolemia).

The additional elements of screening for CVD risk may include fasting plasma glucose (FPG) or glycated hemoglobin (HbA_1c), eGFR, ApoB, ACR (if eGFR <60 mL/min/1.73 m², hypertension, or diabetes), and thyroid-stimulating hormone (TSH) (hypothyroidism is a common secondary cause of hypercholesterolemia).

principles of therapyTop

Nonpharmacologic Management

1. Reduction of body weight by appropriate diet and exercise in persons with obesity or overweight.

2. Dietary modification aimed at reducing TG and increasing HDL-C levels. This also includes restricted intake of carbohydrates (particularly simple carbohydrates). Decreasing saturated fat and increasing insoluble fiber intake can help decrease LDL-C levels.

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. Control of additional CVD risk factors: Decreasing tobacco consumption, BP control.

Pharmacologic Management

Detailed information on pharmacologic management: Table 1.

Aim at normalization of LDL-C level to target, depending on risk (see Hypercholesterolemia).

Currently there are no specific target concentrations for TG and HDL-C (relative lack of clinical trials). A desirable TG concentration of <1.7 mmol/L (150 mg/dL) is suggested. Pharmacotherapy is recommended in patients with fasting TG >10 mmol/L because of the risk of acute pancreatitis. Use of icosapent ethyl (IPE) and/or fibrates: see below.

1. Statins:

1) Statins and other drugs used in the treatment of hypercholesterolemia: see Hypercholesterolemia.

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

3) In patients who have achieved the target LDL-C level but continue to have TG ≥1.7 mmol/L (150 mg/dL), exclude secondary dyslipidemia (see Hypercholesterolemia) and evaluate compliance. If this does not result in adequate improvements, you may consider IPE in high-risk patients with moderate TG elevation and a fibrate in patients with very high TG level (certainly if >10 mmol/L).

2. Fibrates could be used in patients with high TG. They should be used in patients with fasting TG concentration ≥10 mmol/L (885 mg/dL) for the prevention of pancreatitis (statins could be added when necessary): see Hypertriglyceridemia.

Contraindications: Severe CKD (do not use fenofibrate in patients with eGFR <50 mL/min/1.73 m2 or gemfibrozil in patients with eGFR <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 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 creatine kinase (CK) levels (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. An addition of IPE 2 g bid to statin therapy in patients at high risk of CVD and hypertriglyceridemia (fasting TG between 1.52 and 5.63 mmol/L) should be consideredEvidence 1Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to imprecision and generalizability. 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. to reduce cardiovascular events, including mortality.

4. Nicotinic acid, is rarely used because of lack of CVD prevention in large randomized clinical trials and 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).

TablesTop