Chapter Update: Therapeutic Interventions to Increase HDL-C and its Impact on Cardiovascular Risk Modification

Multiple observational studies have found an inverse relationship between highdensity lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD).^1-3 The cumulative mechanism(s) by which HDL-C is associated with reduction in CVD is/are intricate and multifactorial.² Pharmacologic approaches to increase HDL-C have been successful, but the studies assessing the cardio protective effect(s) of these interventions often has been conflicting and is debatable.⁴ The Adult Treatment Panel (ATP) III report also has recognized the ambiguity of cardiovascular benefits associated with increasing HDL-C without addressing low-density lipoprotein cholesterol (LDL-C) and, hence, mostly have targeted LDL-C with additional recommendations for lowering HDL-C as secondary targets.⁵ After appropriately lowering LDLC, residual risk still exists and it is then that targeting HDL-C to try to eliminate residual risk.⁶

HDL-C scavenges excess cholesterol from peripheral vascular macrophages and transports it back to the liver for elimination in the bile. This process is known as "reverse cholesterol transport."^1-3 Apolipoprotein (Apo) A1 is the functional unit of HDL-C that controls its ability to efflux cholesterol from the periphery.^2,7 HDL-C also possesses anti-inflammatory, anti-oxidant and anti-thrombotic properties.³ It prevents endothelial damage and slows atherosclerotic plaque formation³. Once HDL-C scavenges cholesterol from the periphery, it is converted to cholesterol ester by lecithincholesterol acyltransferase. The cholesteryl ester transfer protein (CETP) mediates the bidirectional and equimolar distribution of cholesterol esters along with triglycerides between lipoproteins and fuels reverse cholesterol transport.⁸ Inhibition of CETP in humans is known to increases HDL-C, something learned from studies of genetic polymorphism in which genetic mutation decreases the quantity or activity of CETP.4 This evidence has given rise to a novel class of drugs called CETP inhibitors. Niacin and fibric acid derivatives also are known to increases HDL-C levels. The mechanism via which niacin increases HDL-C is not well established, but studies have shown that niacin works via G-protein-coupled receptors to exert its action.⁹ Fibrates activate transcription of peroxisome proliferator-activated receptors that induce transcription of Apo A1 and Apo A2. They also decrease the production of Apo C-III and stimulate lipolysis by increasing the activity of lipoprotein lipase.¹⁰

Torcetrapib was the first CETP inhibitor to be investigated. It increased HDL-C by 72% and decreased LDL-c by 24.9% when administered in combination with atorvastatin.¹¹ However, torcetrapib increased production of aldosterone and cortisol, which was speculated to have influenced electrolyte abnormalities and elevation in blood pressure, causing an increase in morbidity and mortality—93 deaths in the torcetrapib group versus 59 in the atorvastatin-only group). As a result, the trial had to be terminated.^4,6,11 After termination of the trial, reports of all-cause death and cardiovascular events during follow-up were similar in both groups.¹¹ Dalcetrapib is a CETP modulator and second in this class after torcetrapib to be discontinued for futility.⁴ Dalcetrapib caused anticipated physiological changes of raising HDL-C by 31% to 40% with minimal decreases in LDL-C.⁴ Dalcetrapib is less potent and so did not elevate HDL-C as much as torcetrapib did. It also did not have as many significant adverse effects as torcetrapib.4 However, it failed to show meaningful efficacy in patients with CVD.⁴ Two more drugs, evacetrapib and anacetrapib, are currently being investigated. Evacetrapib also has shown a significant dose-dependent increase in HDL-C—up to 128.8 %—while decreasing LDL-C and triglycerides at highest dosage without any adverse effects.¹² Results from the DEFINE—Determining the Efficacy and tolerability of CETP INhibition with Anacetrapib¹³—trial of anacetrapib showed a 138% increase in HDL-C and a 40% decrease in LDL-C in patients on anacetrapib and statin compared to placebo.⁶ No significant changes in morbidity and mortality were noted, including adverse effects.⁶ The phase III trial known as REVEAL—Randomized EValution of the Effects of Anacetrapib through Lipid-modification¹⁴—is on the way to investigate whether a therapeutic increase in HDL-C is protective against cardiovascular events.

CETP inhibitors such as anacetrapib and evacetrapib have shown reduction in LDL-C not seen in dalcetrapib, along with a significant increase in HDL-C. They also don’t have any of the adverse effects seen with torcetrapib, but they have yet to be proven to be cardio protective in a clinical trial. They also have shown a significant LDL-C-lowering effect that may make it difficult to conclude how much of the benefit is the result of a decrease in LDL-C versus an increase in HDL-C. A study in Japanese-American men with genetically inactivating CETP mutation showed an increased risk of CVD in men with an HDL-C range from 41 to 60. It was thought likely to be the result of a negative impact on the role of CETP as a contributor in reverse cholesterol transport making CETP deficiency a positive risk factor for CVD.⁸ Men with HDL-C greater than 60 in this study had relatively lower CVD, which was attributed to the possible artheroprotective effect of elevated HDL-C resulting from increase reverse transport.⁸ Apo-B containing molecules such as LDL-C and VLDL also are involved in transporting cholesterol back to the liver, and inhibiting CETP would impede the transfer of cholesterol ester to these particles and negatively impact reverse cholesterol transport.¹⁵ These observations make it important to further investigate the role of CETP in reverse cholesterol transport.

Therapeutic use of niacin in its chemical form, nicotinic acid, has been shown to increase HDL-C and decrease LDL-C, VLDL and triglycerides levels in a dosedependent manner. The ARBITER 6-Halts trial showed a significant decrease in carotid intima-medial thickness as a potential benefit of niacin’s HDL-Cincreasing effect in patients with atherosclerotic disease who were on statin monotherapy.¹⁶ A more recent study, the AIM-High trial, concluded that niacin showed no additional benefit in patients with optimum LDL-C levels, regardless of the increase in HDL-C and reduction in triglycerides.¹⁷ Another large multi-center randomized trial, known as HPS2-Thrive and coordinated by University of Oxford, compared extended-release niacin 2 grams plus laropiprant 40 milligrams versus placebo in patients with pre-existing occlusive vascular disease who were treated with a statin.¹⁸ Laropiprant does not have an effect on HDL-C levels. When added to extended-release niacin, though, it reduces the incidence of flushing and, thus, makes the drug more tolerable. The results of this trial showed no meaningful reduction in cardiovascular events in patients in whom LDL-C was optimally managed with statin therapy.¹⁸

Apo-A1, the functional unit of HDL-C, regulates its ability to mobilize cholesterol from peripheral macrophages. A rare mutation in Apo-A1 known as "APO-A1 Milano" is characterized by elevated levels of Apo-A1 activity with extremely low levels of HDL-C.^7,19 Some people carrying this mutation are thought to be free of CVD, irrespective of lifestyle. This mutation is associated with a rapid increase in the efflux capacity, which ramps up reverse cholesterol transport. In animal studies, this effect is seen within 48 hours.⁷ This evidence supports the importance of HDL-C quality over quantity. Further investigation of the components of HDL-C and their dynamics is important to understanding its role in reverse transport.

What we currently know about HDL-C, its role in atherosclerosis and effects of HDL-C modulation is just the tip of an iceberg, and any definitive conclusion based on current evidence is premature. There is a discrepancy between the observation that people with low HDL-C are at higher risk of CVD and the evidence that raising HDL-C does not offer incremental protection. This evidence begs the question: If the LDL-C level is optimum, would exceptionally high HDL-C levels confer any cardio protective benefit? Is there any specific sub-group that would benefit from HDL-C-lowering therapy?

Future studies will be able to give us some direction and may be answer some of these critical questions.

Disclosure statement: Dr. Lokhandwala has no disclosures to report. Dr. Dhoble has no disclosures to report.