Low HDL—The Challenge

Introduction to Atherosclerosis

The atherosclerotic process occurs over time starting with damage to the endothelium via a number of risk factors such as hypertension, smoking, dyslipidemia, diabetes, aging, and various toxins. Lipids, including LDL, and inflammatory cells accumulate in the wall of the blood vessel with eventual fibrosis and calcification. As the blood vessel narrows, it may compromise oxygen delivery downstream resulting in symptoms such as angina when it affects the coronary arteries and claudication when it affects the peripheral arteries. Vulnerable plaques, with large lipid cores, inflammatory cells and a thin endothelial cap, are prone to rupture. Thrombi may form to seal off the rupture but may end up occluding the blood vessel depriving the downstream organ of oxygen and nutrients, leading to devastating consequences such as myocardial infarction or stroke.

LDL in the Atherosclerotic Plaque

The LDL that infiltrates the blood vessel becomes oxidized by oxygen free radicals, which are key inflammatory components, and which is a very important process in the promotion of atherosclerosis. In addition to the risk factors involved in the atherosclerotic process, several genes encoding for proteins and growth factors, such as monocyte chemoattractant protein I, and platelet derived growth factors have been identified, which promote the atherosclerotic process.⁵ The main type of cholesterol that leads to the formation of atherosclerotic plaque is LDL, which comes in part from a high cholesterol diet. LDL synthesis also occurs in the liver and depends on the enzyme 3-hydroxy-3-methylglutaryl-Co-enzyme A (HMG-CoA) reductase. The LDL level in the blood also depends on the number of LDL receptors on the hepatocytes. When there is an increase in the number of receptors, the receptors bind more LDL from the blood, thus decreasing serum levels of LDL. The receptors are also regulated by proprotein convertase subtilisin/kexin type 9 (PCSK9). Inhibition of this protein will increase LDL receptors, thus resulting in a decrease in LDL levels. While cholesterol esters are fat soluble, they cannot circulate in the blood as such; however, they are surrounded by a capsule of phospholipids and proteins, forming lipoprotein to circulate in the blood. They are divided into four categories: chylomicron transport triglycerides; very low density lipoprotein (VLDL), composed of triglyceride, cholesterol, and phospholipids; LDL, and HDL.⁶

HDL and Atherosclerosis

While LDL is an important risk factor for the development and progression of atherosclerosis, HDL protects blood vessels from developing that process. Initially in 1951, research studies found patients with documented CAD who had low levels of HDL. In 1977, it was very clear that low HDL was a risk factor for the development of atherosclerosis. In a review of the HDL hypothesis, it was reported that with an increase in the level of HDL by 1 mg/dL, there was a 2% to 3% decrease in the rate of atherosclerosis.⁷ HDL acts as an acceptor of cellular LDL, leading to reverse cholesterol transport (a process that moves cholesterol from blood vessels in peripheral tissues to the liver for excretion). In addition, HDL exerts other beneficial effects on blood vessel endothelium. It inhibits expression of endothelial adhesion molecules and also has antioxidant effects, both of which add to its value for the health of blood vessels.

Since HDL promotes the efflux of LDL from atherosclerotic plaques, it is very beneficial in protecting blood vessels from atherosclerotic disease. Its value is more pronounced when there is an elevation of serum LDL levels. The more LDL is available, the greater the need for HDL. Interestingly, in patients with Tangier disease, an inherited disorder characterized by a very low HDL and low LDL, the incidence of premature atherosclerosis is not a prominent occurrence in this disease. Thus, in patients with low LDL levels, the value and need for HDL is attenuated.⁸ To protect from the development of atherosclerotic disease, it is necessary to manage elevated LDL levels, while at the same time enhancing HDL production.

Management of Elevated LDL

Patients with elevated LDL levels should be advised to maintain a heart healthy diet as well as develop healthy lifestyle modifications. However, it was the discovery of HMG-CoA reductase inhibitors and their role in controlling LDL synthesis that led to the development of statins, which proved to be the backbone of cholesterol management and control of CAD.

In 1996, Sacks et. al. reported the results of the CARE (Cholesterol and Recurrent Events) study.⁹ A total of 4159 patients with total cholesterol of about 240 mg/dL and LDL of about 140 mg/dL, and who suffered myocardial infarction, were randomized to treatment of 40 mg pravastatin or placebo and were followed for 5 years. Those cholesterol levels were targeted in the study because they were considered average levels at that time. The frequency of coronary events, coronary revascularization, and strokes was less in the pravastatin group.⁹ In 1998, the LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) study group reported pravastatin also showed reduced mortality from coronary heart disease as well as total mortality at 6 years of follow up after starting pravastatin.¹⁰

Statins work to lower LDL primarily by inhibiting the enzyme HMG-CoA reductase, which is responsible for cholesterol synthesis in the liver. There are other pharmacologic agents used to treat high LDL, besides statins, that have different mechanisms of action. Ezetimide blocks the cholesterol absorption in the small intestine. The mechanism of PCSK9 inhibitors prevent the degradation of LDL receptors on the surface of hepatocytes. Bempedoic acid interferes with cholesterol synthesis in the liver.

With time, it was clear that the goals for cholesterol levels were not optimal, which led to testing more intensive therapy for cholesterol control. Cannon et al.,¹¹ in 2004, published the results of the PROVE-IT study. They enrolled 4162 patients with acute coronary syndromes who were randomized to treatment with 40 mg of pravastatin daily or 80 mg of atorvastatin (a more potent statin) daily. Patients were followed for 2 years. At the conclusion of the study, LDL in the pravastatin group was 95 mg/dL, versus 62 mg/dL in the atorvastatin group. This level of 62 mg/dL was associated with a decrease in composite end points of myocardial infarction, need for revascularization, and death from any cause. Thus, the level of 62 mg/dL achieved with 80 mg of atorvastatin was associated with less composite end points when compared with a weaker statin (pravastatin.) The IMPROVE-IT study randomized 18,144 patients with acute coronary syndrome to either 40 mg simvastatin daily or a combination of 40 mg simvastatin plus 10 mg of ezetimibe.¹² While statins alone or in combination with ezetimibe may increase liver enzymes in some patients or cause myopathy, there was no statistically significant difference between treatment and control groups. Although studies showed cardiac benefit in the treatment groups, it also confirmed safety in the treatment groups.^11,12 The group that received both simvastatin plus ezetimibe achieved LDL levels of 53.7 mg/dL, which provided additional benefits to cardiovascular events at median follow up of 6 years.

For patients who do not achieve the recommended targets despite statin therapy or do not tolerate statins, there are other options that can be utilized. Ezetimide can be added, as shown in the IMPROVE-IT study.¹² Monoclonal antibodies that inhibit PCSK9, such as evolocumab¹³ and alirocumab,¹⁴ result in marked reduction of LDL with significant benefits for cardiovascular events. There was no statistically significant difference in side effects between treatment groups, except in rare occurrence of injection site reactions.^13-16 More recently, inclisiran, which is a small interfering RNA molecule that reduces the production of PCSK9 protein in the liver, injected twice yearly, showed similar benefits.^15,16 In clinical trials, bempedoic acid was shown to reduce LDL cholesterol by 17%–28% following 12 weeks of therapy.¹⁷ These new innovations can result in very low levels of LDL, substantially below recommended target levels, without any significant side effects.

Management of Low HDL

Since 1950, it has become clear there is an inverse relationship between HDL level and the risk of developing CAD.¹⁸ Low HDL is an important risk factor for development of CAD, independent of the level of LDL.¹⁹ HDL is a nanoparticle capable of mediating multiple functions on different biologic systems.²⁰ The function of HDL is not just protection from atherosclerosis, since it is present in multiple atherosclerotic free species. The main mechanism by which HDL removes LDL from blood vessels is through the reverse cholesterol transport pathway. HDL combines with LDL from atherosclerotic plagues and macrophages, returns it to the liver, where it is then eliminated from the body. In addition, HDL molecules have anti-inflammatory, antioxidant, and vasodilator properties, which all add to the clear benefit of HDL.²¹ The normal level of HDL in men over 20 years-of-age is 40 mg/dL or higher. In women over 20 years-of-age, it is 50 mg/dL or higher. The level of HDL is important for the protection of blood vessels, yet the function of HDL is equally important. Many types of HDL exist. In general, the lighter, larger size molecule is HDL₂, and its main function is reverse cholesterol transport. The smaller molecule is called HDL₃, and its main function is anti-inflammatory in nature. If a person develops autoimmune disease, infection, diabetes, or chronic kidney disease, the HDL particle function will decrease, with less blood vessel protection.¹⁸

While in general the higher HDL level, the fewer cardiac events in most patients, there is some evidence that some patients with a very high HDL level may not necessarily show any cardiac benefit. Chen et al.²² studied the effect of HDL on patients following percutaneous coronary angioplasty. They followed 7284 patients for a mean of 4 years after coronary angioplasty. The patients were divided into three groups according to HDL level: < 25 mg/dL, 25-60 mg/dL, and > 60 mg/dL. While the higher level of HDL was protective and associated with fewer cardiac events and less mortality, a very low level (< 25 mg/dL) or a level higher than 60 mg/dL was associated with higher risk and higher mortality. The exact mechanism is not clear, but it may be related to the fact that when patients have a very high level (> 70 mg/dL in men or > 90 mg/dL in women), the functionality of HDL particles may be diminished.

There are clear racial differences for the value of HDL. Over a 10-year period, follow up of 23,901 normal individuals was performed in the REGARDS (Reasons for Geographic and Racial Differences in Stroke) study cohort, and while low HDL level was a clear risk factor for a white population, it did not significantly increase cardiac risk in a black population.²³

It seems the value of HDL is more pronounced in patients with elevated LDL. In two uncommon congenital diseases, Tangier disease and lecithin cholesterol acyl transferase (LCAT) deficiency disease, the HDL is markedly diminished, and LDL is low as well.²⁴ Follow up of these patients showed there was a low risk for premature atherosclerosis. Thus, while low HDL level is a clear risk factor in patients with elevated LDL, this may not be the case in the presence of low LDL.

HDL, in addition to reverse cholesterol transport, has other functions that are protective to the blood vessels, mainly anti-inflammatory and antioxidant properties.^25-28 These are mainly mediated by HDL₃. The higher the HDL, the lower the high-sensitivity C-reactive protein (hs-CRP) and fibrinogen, and the lower the mortality. The antioxidant effect prevents blood vessel damage by oxygen free radicals. The treatment of low HDL is discussed in the following paragraphs.

Treatment of Low HDL

There are general measures that improve HDL, yet with attenuated effect. Changes in lifestyle, controlling acute metabolic syndrome with reducing insulin resistance, and improving diabetes may result in some increase in HDL.¹⁸ Life style changes should be considered in most patients.

Regular endurance exercise is effective in increasing HDL level, and it is most important in patients with low HDL and elevated triglycerides.²⁹ Exercise duration – not frequency – is an important factor in the rise of HDL. In a meta-analysis by Kodama et al.,³⁰ every 10 minutes of prolongation of exercise was associated with a rise in HDL of 1.4 mg/dL Exercise not only increases the number of HDL particles, but also its functionality. Exercise enhances reverse cholesterol transport and potentiates anti-inflammatory and antioxidative effects.³¹

Smoking cessation will likely increase HDL by 5%–10%, an important measure of priority in the management of low HDL.¹⁸ Moderate alcohol consumption raises HDL level by increasing the transport rate of apolipoprotein A-I and A-II.³² The deferential effect on various subfractions of HDL is controversial and is not yet resolved.

Niacin

Many decades ago several studies tested the value of niacin in patients with significantly higher cholesterol compared to today’s standards.³³ A total of 2531 patients were randomized to clofibrate, niacin, or placebo. Niacin showed an increase in HDL by only 6%, with some benefit in cardiac events.

In 2011, the AIM-HIGH study was reported. It randomized 3414 patients with dyslipidemia to extended release niacin or placebo.³⁴ All patients initially received simvastatin plus ezetimide to lower their LDL cholesterol to a mean of 62 mg/dL. There was no benefit of adding extended release niacin to patients after 2 years of therapy. Thus, while there was some benefit of niacin when LDL was elevated, no benefit was observed in patients with controlled LDL.

Statins and HDL

The role of statins in lowering LDL level is well established and accepted in the guidelines for management of dyslipidemia. Statins may also result in a small increase in HDL. In most studies, HDL increases after statin therapy by about 5%–10%. The full mechanism by which this occurs is not completely clear, but at least in part, it may be secondary to a decrease in the rate of cholesteryl ester transfer protein (CETP) flow of cholesterol from the molecule of HDL.³⁵ The STELLAR trial was an open label, 6-week trial to compare the effect of pravastatin, simvastatin, atorvastatin, and rosuvastatin on LDL and HDL.³⁶ Rosuvastatin was associated with the greatest increase in HDL level, up to 10% increase, as compared with other statins. The increase in HDL level was independent of the degree of decrease in LDL.³⁷ Thus, patients should receive statins not only to improve their LDL levels, but also to improve and elevate their HDL levels.

Cholesteryl Ester Transfer Protein Inhibitors

Cholesteryl ester transfer protein (CETP) inhibitors decrease HDL transfer, resulting in an increase in the number of HDL particles. In a study by Schwartz et al.,³⁸ the authors suggested this increase in HDL levels by CTEP inhibitors might have a therapeutic potential and reduce CAD. They tested the CTEP inhibitor dalcetrapid in a study of 15,871 patients with a recent acute coronary syndrome who were randomized to either the drug or placebo and were followed for 31 months. While the HDL did increase significantly in the dalcetrapid group, the primary end point of cardiovascular death, nonfatal myocardial infarction, unstable angina, cardiac arrest, and stroke were similar between the active treatment group and the placebo. Dalcetrapib increased patients’ blood pressure and increased the degree of inflammation, which may have neutralized any potential benefit.³⁸

The ACCELERATE trial tested the CTEP inhibitor evacetrapib in patients with high risk vascular disease.³⁹ Despite a significant rise in HDL level at 3 months of evacetrapib therapy, there was no clinical benefit, and it seemed the increase in HDL particles was not associated with any increase in functionality of the particles. The only CETP inhibitor with some benefit in patients at high risk for CAD was anacetrapib, yet after 4 years of therapy, the magnitude of benefit was still quite limited.⁴⁰ This drug was dropped by the company and is no longer being developed. Thus, despite more than a decade of development in CETP inhibitor drugs, there does not appear to be any significant potential in the management of low HDL.

Apolipoprotein A₁ infusions

Apolipoprotein A₁ infusion increases cholesterol efflux from the vascular system. It was logical to try the infusion in high risk patients following acute myocardial infarction. Gibson et al.⁴¹ conducted a double blind, placebo controlled trial in 18,219 patients who presented with acute myocardial infarction within 5 day after the first medical contact to receive either four weekly infusions of 6 gm of human apolipoprotein A₁ or placebo. All patients were very high risk and had multi-vessel CAD. Study end points were a composite end point of myocardial infarction, stroke, or death at 90 days of follow up. At randomization, the baseline LDL level was 84 mg/dL, and HDL level was 39 mg/dL. There was no significant difference in the primary endpoint between the active treatment group and the placebo group in this study of a cohort with low LDL levels. It was another negative study utilizing an active pharmacologic agent to enhance the function of HDL.⁴¹

Other Medications

Many studies described the effect of the omega III fatty acids, eicosapentaenoic and docosahexaenoic acid on lipids. Their main effect is on triglycerides, but they minimally increase HDL. Clinical studies showed minimal benefit, and the studies were not always consistent. Only icosapent ethyl (Vascepa®) has shown a clear benefit on cardiovascular outcome when combined with diet and lifestyle modification.⁴² The benefit of icosapent ethyl may be due to its lowering of triglycerides.