Our HEART UK update on HDL for health professionals
What is HDL?
High-density lipoprotein is one of the five major fat and protein particles (lipoproteins) whose role it is to enable blood fats (lipids), such as cholesterol and triglycerides, to be transported within the water-based bloodstream.
HDL is the smallest and densest of the lipoproteins, containing the highest proportion of protein to cholesterol. In a healthy individual, HDL normally carries about a quarter of the total amount of cholesterol in the blood, whereas most of the remainder is carried in LDL (low-density lipoprotein) particles. The HDL particle is made up of many proteins, the most important being one known as apolipoprotein A1 (Apo A1).
The main roles of HDL
HDL is best known for its protective role against cardiovascular disease (CVD – the cause of heart attack and stroke). It is commonly referred to as “good cholesterol” – however the “cholesterol” itself in the HDL does not and cannot protect against disease, but it is called "good cholesterol" as it is carried away from the peripheral tissues, including arteries, back to the liver for recycling or removal from the body. What is more important is HDL’s function, protein and composition. It is the particle itself that is thought to be protective because of its three main benefits/functions:
The 3 benefits of HDL:
1) HDL removes excess cholesterol from the tissues and arteries and returns it back to the liver for recycling and removal from the body. This is known as “reverse cholesterol transport”.
2) HDL also helps protects the artery walls against LDL cholesterol (an anti-inflammatory effect).
3) HDL has a positive anti-oxidant effect, which helps protect cells and important chemical messengers in the blood and tissues from being broken down.
HDL cholesterol levels
Women usually have higher HDL than men, and levels above 1.2mmol/L are considered healthy for women. In men, HDL levels above 1.1mmol/L are considered healthy.
Young boys and girls have similar HDL levels, but after puberty HDL levels decrease in men and remain lower than those in women for all subsequent age groups.
Currently, HEART UK’s specialists believe that HDL reaches its best protective capacity when HDL cholesterol is around 1.3-1.4mmol/L and that levels which are higher than this may not offer additional protection and should not be used as a justification to avoid LDL cholesterol-lowering therapy when indicated.
Previous studies showed that lower levels of HDL cholesterol are an additional risk factor for CVD (or heart attack and stroke) and higher levels were seen to be more protective. HDL cholesterol was inversely associated with adverse CVD events such a MI, stroke, CVD death and HDL was a modifiable risk factor for CVD. However, more recent data suggests that levels higher than 1.4mmol/L may not offer extra protection and certain clinical situations may be associated with a poorer outcome. Research analysis shows a “U-shaped curve” association between HDL cholesterol and adverse events including all-cause mortality, suggesting that at very high levels HDL cholesterol may be associated with increased cardiovascular events and all-cause death. Furthermore, recent research into ways to increase HDL cholesterol with medications in clinical trials for those with well-controlled LDL cholesterol levels has not shown a reduction in these adverse outcomes.
If someone has a lower level of HDL cholesterol it may be due to an underlying reason or medical condition. Rarely, very low HDL cholesterol is related to a genetic cause. Some of the potential causes are listed below.
In cigarette smoke, a chemical called acrolein appears to interfere with the normal functioning of HDL by changing the structure of its protein, Apolipoprotein A1. This damage may actually play a part in speeding up atherosclerosis because of the reduced ability for HDL to remove cholesterol from the artery wall. By stopping smoking, HDL levels can increase by up to 10% (provided weight gain is prevented).
When the body contains too much stored fat, particularly around the waistline (apple-shaped obesity), this interferes with the ability of insulin to regulate the blood sugar. This problem, known as insulin resistance can result in metabolic syndrome leading to a fatty liver, elevated blood pressure and type 2 diabetes. It also leads to characteristic changes in the pattern of fats in the blood (lipid profile) often referred to as “dyslipidaemia”. Typically there is a pattern of high triglycerides and low HDL cholesterol levels with normal or slightly high LDL cholesterol. The LDL particles also tend to be smaller and more toxic to artery linings.
Ways to increase HDL cholesterol
Losing weight and inches around waistline can help raise HDL cholesterol levels. Current guidance by the European Society of Cardiology found that for every 1kg decrease in body weight levels of HDL cholesterol were increased by 0.01mmol/L, and in the case of excess body weight, even modest weight reduction (5-10%) showed an improvement in lipid abnormalities.
Tangier disease is a very rare condition which causes complete absence or extreme deficiency of HDL cholesterol, and LDL cholesterol levels are also usually reduced. The cause of the condition is due to a mutation in a cell surface protein that has an important role in transporting cholesterol from cells to HDL particles, meaning when mutations are present the cell cannot transfer cholesterol to HDL particles.
ApoA1 deficiency: A rare lipoprotein metabolism disorder characterised biochemically by the complete absence of apolipoprotein AI and extremely low blood HDL cholesterol level.
Familial Combined Hyperlipidaemia (FCH): FCH is a fairly common condition believed to affect around 1 in every 100 people in the UK. Similar to diabetes and insulin resistance, people with FCH usually have high triglycerides and low HDL cholesterol but much higher LDL cholesterol. This pattern of abnormal blood fats is also influenced by diet and lifestyle.
Some medications can sometimes reduce HDL levels too. These include beta-blockers, thiazide diuretics, androgens, progestogens and anabolic steroids. However, none of these medications should be stopped without consultation with healthcare professionals, as any possible risk from slightly lowering HDL cholesterol is likely well outweighed by other benefits of the medications.
Diet: adopt a healthy diet. All fats should be used sparingly.
Exercise and activity: be more active. Recent evidence suggests that the duration of exercise, rather than the intensity, is the more important factor in raising HDL cholesterol but both have been shown to have positive benefits. Regular aerobic exercise can increase HDL cholesterol by about 5% within 2 months, improve your LDL levels and also lower triglycerides.
European Society of Cardiology guidelines (2019) state that aerobic physical activity such as 25-30km of brisk walking per week or equivalent may increase HDL cholesterol by 0.08-0.15mmol/L. Exercise time, exercise volume and exercise intensity all have an effect on exercise-induced changes in blood lipids. HDL cholesterol is the most sensitive to exercise. In order to reduce LDL cholesterol and TG levels more, it is necessary to increase the aerobic exercise intensity.
Medications to raise HDL
Most medications have only a limited effect on HDL cholesterol levels.
Statins reduce LDL cholesterol effectively and fibrates reduce triglycerides but only have a small effect on HDL cholesterol levels. In recent meta-analysis, HDL cholesterol levels varied with dose among respective statins, ranging from 1-10%, but this modest effect was thought to be unreliable in comparison to the marked statin mediated decrement in atherogenic apoB containing lipoproteins (LDL and non HDL cholesterol). Fibrates were shown to increase HDL cholesterol by up to 20% in long term interventional trials. Other medications like Ezetimibe and PCSK9 monoclonal antibodies may increase HDL cholesterol.
Recent clinical trials: These include trials of cholesterol ester transfer protein (CETP inhibitors), which lower the activity of the cholesterol ester transfer protein in the blood, which in turn reduces the amount of LDL cholesterol and increases the amount of HDL cholesterol. These trials have shown the greatest elevation in HDL cholesterol but did not show any improvement in CVD outcomes except for the REVEAL study. The REVEAL study, which used a CETP inhibitor, Anacetrapib, raised HDL by 104% and lowered LDL by 17%. This study showed a reduction in major coronary events by 9% over 4 years but this was thought to be the result of its non -HDL-C lowering (mostly LDL cholesterol) and not the result of the increase in HDL cholesterol. Therefore the drug has not been submitted for regulatory approval.
Currently, both the European Society of Cardiology (ESC) and the American Heart Association (AHA) state that there is a current lack of understanding of the relationship between the modality of raising HDL/ApoA-1 levels and a possible anti-atherogenic function of HDL particles.
Most healthcare professionals are taught that the higher the HDL cholesterol, the more protection it offers. However, some specialists are beginning to question this. HDL cholesterol levels above 1.4mmol/L may not provide extra protection and indeed this protection may depend on properties of HDL particles that are difficult to measure.
HDL cholesterol of 1.2mmol/L or above in women, 1mmol/L or above in men. HEART UK experts say the protective effect of HDL cholesterol appears to reach its maximum when levels are roughly 1.4mmol/L. Beyond this, higher levels of HDL may not provide additional protection and current research suggests levels in excess of 2.3mmol/L may behave more like LDL cholesterol, raising the risk of developing CVD and heart problems, particularly in women who are going through or are post-menopause.
Very high levels have been reported to speed up the development of atherosclerosis in some cases but the mechanism for this effect is unclear. This means the HDL particle in these circumstances does not do its normal job of clearing plaque.
Causes of high HDL
In the first instance, you should consider what may have caused a high HDL level. Here are some of the causes, some of which are reversible:
Lifestyle issues such as a diet high in saturated fats and excessive alcohol consumption can contribute to a higher level of HDL but high HDL cholesterol because of alcohol excess does not provide protection from cardiovascular disease (CVD). For both diet and lifestyle changes, including reducing alcohol intake for an agreed time period, such as 3 months, should be tried before rechecking levels to see if they are effective.
Medication: oral contraceptive pill or oestrogen replacement therapy, anti-convulsants.
Inheriting a high HDL: taking a family history to determine if HDL cholesterol is high due to an inherited cause. A family history of longevity is reassuring whereas a history of early cardiovascular disease may prompt a referral to a specialist and only they can decide if the high level of HDL cholesterol is relevant and decide whether other family members should be tested.
Japanese ancestry: some people with a Japanese ancestry have been found to have high HDL cholesterol levels due to a genetic deficiency of a protein CETP.
Menopause: data from clinical research suggested that the benefits of having high HDL cholesterol are reduced during the menopause as a result of changes in hormone levels. A study carried out by the University of Pittsburgh Graduate School of Public Health Pittsburgh found the normal fall in oestrogen associated with the menopause changed the quality of HDL and its function, and increases in HDL during menopause were actually associated with greater plaque build up independent of other factors such as body weight and levels of LDL cholesterol. They concluded that the quality and functionality of HDL particles may be altered during the menopausal transitional period, making it less effective in providing normal heart health benefits.
Hypothyroidism: people who have an underactive thyroid may also have high levels of HDL cholesterol due to a reduction in the hepatic lipase enzyme and decreased activity of CETP which results in the reduced transfer of cholesteryl esters from HDL to VLDL, thus increasing HDL cholesterol levels.
Acute infection/chronic inflammation: recent research has suggested HDL particles change their make up in circumstances such as acute infection or chronic conditions linked to inflammation such as rheumatoid arthritis but more work is needed to understand this. Other findings have suggested that high HDL cholesterol levels may be harmful to kidney dialysis patients by worsening inflammation and tissue damage.
Specialist recommendations for high HDL
- If there is a family history of early heart disease (i.e. below age 60) and HDL cholesterol is higher than average with no obvious underlying cause then ideally a referral to a specialist lipid clinic for further investigation and assessment should be made.
- If both total and HDL cholesterol are high (TC over 7.5 with HDL over 2.5mmol) then treatment decisions should be guided by levels of LDL cholesterol and non-HDL cholesterol level, rather than by the TC/HDL ratio, which may be misleading.
- Health professionals should encourage anyone with a high HDL cholesterol level to adopt a healthy diet and lifestyle and manage any other risk factors they might have. This is especially important in women prior to, during and following the menopause.
There are no medications that specifically target high HDL cholesterol and address possible CVD risk from this. In patients with high HDL cholesterol, lifestyle and diet should be modified and other traditional risk factors should be assessed and addressed, for example, obesity, high LDL cholesterol and blood pressure.
More research is needed to fully evaluate HDL function and composition to help develop strategies to prevent and treat heart disease.
Future research should study the effect of an intervention likely to improve HDL function, and how well the HDL particle is able to extract free cholesterol from cell rather than increasing circulating HDL cholesterol which has not been shown to be effective. The HDL particle is a complex lipoprotein and any intervention should address is dynamics and functionality on multiple levels.