- ACRONYMS AND DEFINITIONS
- ADA - American Diabetes Association
- AHA - American Heart Association
- CVD - Cardiovascular disease
- HDL - High density lipoprotein
- IDL - Intermediate density lipoprotein
- LDL - Low density lipoprotein
- NCEP ATP III - National Cholesterol Education Program Adult Treatment Panel III
- NHLBI - National Heart, Lung, and Blood Institute
- RCT - Randomized controlled trial
- VLDL - Very low density lipoprotein
- PHYSIOLOGY
- Cholesterol
- Cholesterol is a fatty compound found in all animals
- It is used by the body to make cell walls, bile acids, and various hormones
- The body acquires the cholesterol it needs by either making it (80%) or absorbing it (20%) from the diet
- Most cholesterol is made in the liver
- Cholesterol is transported through the bloodstream by molecules called lipoproteins (LDL, HDL, VLDL, IDL)
- Cholesterol and disease
- When cholesterol levels are too high, LDL molecules can deposit cholesterol in the walls of arteries
- This can lead to the formation of plaques, a process called atherosclerosis
- As plaques thicken, they can obstruct blood flow and lead to coronary artery disease, peripheral artery disease, and strokes
- Plaques may also promote the formation of clotted blood (a thrombus)
- A thrombus can break off of a plaque and plug arteries downstream. This causes sudden heart attacks and strokes
- CHOLESTEROL SCREENING RECOMMENDATIONS
- See cholesterol screening recommendations for a review of guidelines from professional organizations
- MEASURING CHOLESTEROL LEVELS
- Overview
- Cholesterol is measured from a blood sample
- The AHA 2018 guidelines state that for adults not on lipid-lowering therapy, both fasting and nonfasting lipid profiles are acceptable. If the triglyceride level comes back > 400 mg/dl, a fasting profile should be obtained. [30]
- The most widely used method for measuring cholesterol levels is presented below
- The standard lipid profile includes the following:
- Total cholesterol
- LDL
- HDL
- Triglycerides
- Non-HDL = Total cholesterol - HDL
- Total Cholesterol
- Total cholesterol is measured directly in the blood sample
- The total cholesterol value is used to calculate LDL, but it is not used in most cholesterol guidelines
- Individual total cholesterol measurements may vary by a median of 4.9% between measurements
- High Density Lipoprotein (HDL)
- HDL is measured directly in the blood sample
- Individual HDL measurements may vary by a median of 6.9% between measurements
- Triglycerides
- Triglycerides are measured directly in the blood sample
- Individual triglyceride measurements may vary by a median of 23.5% between measurements
- Low Density Lipoprotein (LDL)
- LDL is measured indirectly
- Taking one-fifth of the triglycerides approximates the amount of VLDL in the sample
- IDL is not accounted for separately. It is included in the amount of LDL.
- LDL cannot be calculated if triglyceride levels are > 400 mg/dl
- Individual LDL measurements may vary by a median of 6.5% between measurements [21]
- LDL is calculated using the following formula:
- LDL = Total cholesterol - HDL - 1/5 (Triglycerides)
- LOW DENSITY LIPOPROTEIN (LDL)
- Physiology
- LDL is a lipoprotein molecule that transports cholesterol in the bloodstream to various tissues in the body
- LDL can deposit cholesterol into the artery wall and promote atherosclerosis
- Association with heart disease
- LDL cholesterol is a proven risk factor for heart disease
- A meta-analysis in the Lancet looked at the risk for heart disease outcomes across a large number of trials
- The study calculated the risk of various outcomes for differences in LDL cholesterol levels
- The analysis found the following:
- For every 39 mg/dl decrease in LDL cholesterol, a person's relative risk of overall mortality decreases by 10%
- For every 39 mg/dl decrease in LDL cholesterol, a person's relative risk of a major vascular event decreases by 22% [22]
- Risk factors for high LDL
- Diet
- Diets high in saturated fatty acids and trans fatty acids tend to raise LDL levels
- Diets high in dietary cholesterol can raise LDL levels
- Physical inactivity
- Obesity
- Genetics (family history)
- LDL concentrations persistently > 190 mg/dl typically have a strong genetic component
- Familial hypercholesterolemia (FH)
- Familial hypercholesterolemia is a syndrome caused by genetic mutations in one of three cholesterol-related genes: low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9)
- Patients with FH will typically have LDL cholesterol levels ≥ 190 mg/dl
- In one study, FH was found in ∼ 1.8% of patients who had an LDL ≥ 190 mg/dl [29]
- Hypothyroidism
- Low thyroid levels raise LDL
- The NCEP ATP III recommends that any patient with LDL > 160 mg/dl be screened for hypothyroidism
- Kidney disease
- Various kidney diseases (nephrotic syndrome, etc) have been associated with elevated LDL levels
- Obstructive liver disease
- Medications
- HIV protease inhibitors
- Progesterones
- Antipsychotics (Zyprexa®, Risperdal®, etc.)
- Corticosteroids
- Anabolic steroids [5]
- Venlafaxine (Effexor®) [25]
- Short stature [28]
- LDL cholesterol goals
- In 2013, the focus of cholesterol treatment guidelines shifted from specific LDL goals to statin therapy goals
- See cholesterol treatment guidelines for a review of treatment recommendations from various professional organizations
- Treatment
- Weight loss
- Studies have shown a weight loss of 5 - 10% of body weight reduces LDL by 15% on average (see diet and weight loss below) [21]
- Diet
- Reduce dietary fats and dietary cholesterol (see diet and weight loss below)
- Exercise
- Medications
- Statins - most common treatment
- Niacin
- Fibrates
- Ezetimibe
- PCSK9 inhibitors
- Bile acid sequestrants
- HIGH DENSITY LIPOPROTEIN (HDL)
- Physiology
- HDL is a lipoprotein molecule that transports cholesterol in the bloodstream
- HDL transports cholesterol back to the liver for metabolism and it is protective against atherosclerosis
- Association with heart disease
- A number of observational studies have consistently shown that low HDL levels are associated with a higher risk for heart disease
- Despite this observation, medications that raise HDL levels (ex. niacin, fibrates) have not been shown to decrease the risk of heart disease. Additionally, genetic variants that are associated with high HDL levels have not been found to be protective.
- A property of HDL cholesterol called "cholesterol efflux capacity" has recently been studied. Cholesterol efflux capacity is the amount of cholesterol that can be transported from macrophages (often found in atherosclerotic plaque) to HDL cholesterol for transport back to the liver. A recent study looked at the association of cholesterol efflux capacity with incident CVD in a cohort of adults who were free of CVD at baseline. That study is detailed below [26, 27]
- STUDY
- A study published in the NEJM followed 2924 adults who were free of cardiovascular disease at baseline
- A number of CVD risk factors including HDL cholesterol efflux capacity and HDL levels were measured at baseline. HDL cholesterol efflux capacity is the amount of cholesterol that can be transported from macrophages (often found in atherosclerotic plaque) to HDL cholesterol for transport back to the liver.
- Baseline characteristics: Median age - 42 years | Black - 49% | Median LDL - 104 mg/dl | Median HDL - 47 mg/dl
- The primary outcome was a composite of nonfatal heart attack, nonfatal stroke, coronary revascularization, or death from cardiovascular causes. Follow-up was a median of 9.4 years.
- Results:
- NOTE: Hazard Ratios (HR) are expressed as comparisons of quartile 4 (highest capacity) to quartile 1 (lowest capacity)
- In a model adjusted for traditional CVD risk factors, HDL levels were not significantly associated with the primary outcome (HR 0.80, 95%CI 0.47 - 1.37)
- In a model adjusted for traditional CVD risk factors, HDL cholesterol efflux capacity was strongly associated with the primary outcome (HR 0.30, 95%CI 0.18 - 0.50)
- Cholesterol efflux capacity was not strongly correlated with traditional risk factors or other lipid levels
- Self-reported weekly exercise activity and alcohol intake explained 3% of the variance in cholesterol efflux capacity and 35% of the variance in the HDL cholesterol level [26]
- Findings: Cholesterol efflux capacity, a new biomarker that characterizes a key step in reverse cholesterol transport, was inversely associated with the incidence of cardiovascular events in a population-based cohort.
- Risk factors for low HDL
- Elevated triglycerides
- Obesity
- Physical inactivity
- Cigarette smoking
- Very high carbohydrate intake (defined as > 60% of calories)
- Type 2 diabetes
- Medications - beta blockers, anabolic steroids, progesterones
- Genetics (family history) [5]
- HDL cholesterol goals
- Low HDL (< 40 mg/dl in men | < 50 mg/dl in women) is considered a risk factor for CVD
- The AHA cholesterol treatment guidelines incorporate HDL levels into their recommendations
- See cholesterol treatment guidelines for a review of treatment recommendations from various professional organizations
- Treatment for low HDL cholesterol
- Exercise
- In studies, exercise raises HDL an average of 2.5 mg/dl
- The threshold for a significant increase in HDL was 120 minutes of exercise per week
- HDL increase was only associated with exercise sessions that lasted 30 minutes or longer
- More frequent sessions or more strenuous sessions did not have a significant effect [1]
- Smoking cessation
- Stopping smoking causes HDL to rise [24]
- Alcohol
- Moderate alcohol intake (1 - 6 drinks a week) is associated with increased levels of HDL cholesterol
- One drink a day has been shown to increase HDL by an average of 4 mg/dl in one study [2,3]
- Weight Loss
- Weight loss of 5 - 10% body weight has been shown to increase HDL by 8 - 10% [21]
- Medications
- TRIGLYCERIDES
- Physiology
- Triglycerides are compounds made up of three fatty acids joined together
- Triglycerides are formed when fatty acids are absorbed in the intestine after the ingestion of fat-containing foods
- Triglycerides are used by cells for energy, and they are stored as fat in the liver and fat tissue when their energy is not needed
- Triglycerides are also a large part of the molecules (chylomicrons, VLDL, IDL, LDL, HDL) that are used to transport cholesterol
- Association with heart disease
- Because high triglycerides are often associated with other risk factors for heart disease (ex. low HDL levels, high LDL levels, high IDL, high VLDL levels, and insulin resistance), it has been difficult to determine if they are an independent risk factor for heart disease
- Studies that have evaluated a link between high triglycerides and heart disease have been conflicting [4,21]
- At this time, triglycerides can be viewed as an indicator that someone is most likely at increased risk for heart disease, even though the triglycerides themselves may not be the cause
- Very high triglycerides (> 1000 mg/dl) are a risk factor for developing pancreatitis
- Risk factors for high triglycerides
- Obesity
- Physical inactivity
- Smoking
- Excessive alcohol intake
- Very high carbohydrate diets (> 60% of total calories)
- Type 2 diabetes
- Kidney failure
- Medications - antipsychotics, corticosteroids, protease inhibitors, beta blockers, estrogens
- Genetic factors (family history) [5]
- Triglyceride goals
- Treatments for high triglycerides
- NOTE: Patients with triglyceride levels > 1000 mg/dl should begin medications immediately because they are at increased risk of pancreatitis
- Weight loss
- Weight loss of 5 - 10% of body weight leads to 20% reduction in triglycerides
- For every kilogram (2.2 pounds) of weight loss - triglycerides decrease by 1.5 mg/dl [21]
- Exercise
- Tobacco cessation
- Avoid excessive alcohol
- Avoid high carbohydrate intake (> 60% of calories)
- Replacing regular carbohydrates with fiber appears to help [21]
- Fish oil
- Medications
- VERY LOW DENSITY LIPOPROTEIN (VLDL)
- VLDL is a molecule that transports triglycerides and cholesterol from the liver to various tissues of the body
- VLDL is estimated by taking 1/5 of the fasting triglyceride number
- Some advanced cholesterol profiles can measure VLDL directly
- VLDL is thought to have the same atherosclerosis-promoting properties as LDL [5]
- See Cholesterol transport illustration
- VLDL, IDL, and LDL, are related in the following manner:
- VLDL molecule → releases free fatty acids → IDL molecule → releases free fatty acids → LDL molecule
- INTERMEDIATE DENSITY LIPOPROTEIN (IDL)
- IDL is formed when VLDL releases some of its free fatty acids to body tissues
- IDL is thought to have the same atherosclerosis-promoting properties as LDL
- On a standard cholesterol profile, IDL is not listed separately
- IDL is included as part of the LDL cholesterol
- When IDL releases free fatty acids, it becomes LDL [20,21]
- See Cholesterol transport illustration
- VLDL, IDL, and LDL, are related in the following manner:
- VLDL molecule → releases free fatty acids → IDL molecule → releases free fatty acids → LDL molecule
- CHYLOMICRONS
- Chylomicrons are molecules that transport triglycerides and cholesterol absorbed from the intestine
- Chylomicrons release free fatty acids to muscle and fat tissue before they are eventually taken up by the liver
- They are made up of 80 - 95% triglycerides
- Chylomicrons are not included on the standard cholesterol panel
- Chylomicrons are normally only present in the blood after a person consumes a meal with fat
- Patients with very high triglyceride levels (> 500 mg/dl) typically have chylomicrons in their blood even when they are fasting
- Fasting blood chylomicrons are usually related to genetic defects in lipoprotein metabolism [5,21]
- NON-PRESCRIPTION TREATMENT
- Diet and weight loss
- Diet and weight loss can have a significant effect on cholesterol levels
- The table below shows potential reductions in LDL cholesterol from diet changes and weight loss
| Measure | Potential reduction of LDL |
|---|---|
| Reduce intake of saturated and trans fat | 8 - 10% |
| Reduce cholesterol intake | 3 - 5% |
| Increase fiber intake (increase 5 - 10 grams a day) | 3 - 5% |
| Consume 2 grams of plant sterols a day (see below) | 6 - 15% |
| Weight Loss (lose 10 pounds) | 5 - 8% |
| POTENTIAL CUMULATIVE REDUCTION | 20 - 30% |
- Dietary supplements
- Calcium - in studies, the effects of calcium supplements on cholesterol have been mixed [15,16,17,18]
- Fiber - 5 - 10 grams of viscous (soluble) fiber a day has been shown to decrease LDL levels by about 5% [5]
- Fish oil - fish oil lowers triglycerides, but it does not have a meaningful effect on LDL [31]
- Garlic - in trials, garlic has not been proven in any form (raw or powdered) to lower cholesterol [11,12,31]
- Guggulipid - guggulipid is a tree extract that has been touted to lower cholesterol. However, some studies have shown that it can actually raise cholesterol, and its use is discouraged. [9]
- Nuts - daily consumption of an average of 67 grams (about 2 ounces) of nuts (most commonly walnuts and almonds) has been shown to lower LDL levels by an average of 7.4% and triglycerides by 10.2%. [13]
- Plant Sterols - plant sterols are available in pill form and have been added to a number of foods, including margarine (Benecol®, Promise activ®), orange juice (Minute Maid Heart Wise®), and yogurt (Promise activ®). In studies, daily intakes of 2-3 grams have been shown to lower LDL levels by 4 - 15%. [5,31]
- Policosanol - policosanol is a plant extract derived from sugar cane that has been touted to lower LDL and raise HDL. A randomized trial published in JAMA found it had no effect on cholesterol. [PMID 16705107]
- Red Yeast Rice - some brands of red yeast rice contain the active component of the drug lovastatin (referred to as "monacolin K" in red yeast rice products). In studies, red yeast rice at doses of 2.4 - 3.6 grams daily has been shown to lower LDL levels by 7 - 21%. [8,31]
- Soy - high consumption of soy foods (25 - 40 grams/day) has a small effect on LDL levels (3% reduction) and triglycerides (6% reduction) [7]
- Tea - in one trial, a theaflavin-enriched green tea extract was shown to lower LDL levels by 16.4% compared to placebo [PMID 12824094]
- STUDY
- Design: Randomized open-label trial (N=74, Length = 12 weeks) in adults with high cholesterol
- Exposure: Simvastatin 40 mg/day vs Intensive education + Fish oil 3 grams twice daily + Red yeast rice 2.4 - 3.6 grams/day
- Primary outcome: Percentage change in low-density lipoprotein cholesterol (LDL-C)
- Results:
- Simvastatin: LDL decrease 39.6%, Triglycerides decrease 9.3%
- Diet/fish oil/red yeast rice: - LDL decrease 42.4%, Triglycerides decrease 29%
- Findings: Lifestyle changes combined with ingestion of red yeast rice and fish oil reduced LDL-C in proportions similar to standard therapy with simvastatin
- STUDY
- Design: Randomized controlled trial (N=46, Length = 4 weeks) in adults with high cholesterol
- Exposure: Diet low in saturated fat vs Diet low in saturated fat + lovastatin 20 mg/day vs Diet with plant sterols (1g/1000 kcal) + Fiber (9.8 g/1000 kcal) + Almonds (14 g/1000 kcal)
- Primary outcome: Lipid and C-reactive protein levels at weeks 0, 2, and 4
- Results:
- Low-fat diet: LDL decrease 8%, C-reactive protein decrease 10%
- Diet + lovastatin: LDL decrease 31%, C-reactive protein decrease 33%
- Plant sterols/fiber/almonds: LDL decrease 28.6%, C-reactive protein decrease 28%
- Findings: In this study, diversifying cholesterol-lowering components in the same dietary portfolio increased the effectiveness of diet as a treatment of hypercholesterolemia.
- ADVANCED CHOLESTEROL PANELS
- Overview
- A number of labs offer "advanced" cholesterol panels
- At this time, there is no evidence advanced cholesterol panels offer any meaningful information beyond the standard cholesterol profile
- Measurements on these panels often include:
- Apolipoproteins - receptor molecules on the surface of LDL and HDL
- LDL and HDL particle size
- Chylomicrons
- Lipoprotein(a), Lp(a) - a large glycoprotein attached to a LDL-like particle
- Professional guidelines:
- The AHA and the ACC do not currently recommend performing advanced cholesterol panels [23]
- BIBLIOGRAPHY
- 1 - PMID 17533202
- 2 - PMID 19640960
- 3 - PMID 10591709
- 4 - PMID 19436658
- 5 - PMID 12485966
- 6 - USPSTF recommendation statement on cholesterol screening
- 7 - Balk et al, Effects of Soy on Health Outcomes. Agency for Healthcare Research and Quality. July 2005.
- 8 - PMID 19528562
- 9 - PMID 12915429
- 10 - PMID 16705107
- 11 - PMID 17325296
- 12 - PMID 9634262
- 13 - PMID 20458092
- 14 - PMID 12824094
- 15 - PMID 17209177
- 16 - PMID 17928806
- 17 - PMID 12791622
- 18 - PMID 10664640
- 19 - PMID 21193627
- 20 - PMID 9133510
- 21 - PMID 21502576
- 22 - PMID 21067804
- 23 - PMID 21098428
- 24 - PMID 8047525
- 25 - Venlafaxine PI
- 26 - PMID 25404125
- 27 - PMID 22607825
- 28 - PMID 25853659 height and CAD
- 29 - PMID 27050191 - Familial hypercholesterolemia study
- 30 - PMID 30423391 - PMID 2018 AHA/ACC Guideline on the Management of Blood Cholesterol: Executive Summary, J Am Coll Cardiol, (2018)
- 31 - PMID 36351465 - Comparative Effects of Low-Dose Rosuvastatin, Placebo and Dietary Supplements on Lipids and Inflammatory Biomarkers, J Am Coll Cardiol (2022)