THE HDL CHOLESTEROL CONUNDRUM

THE HDL CHOLESTEROL CONUNDRUM 

The role of High-density lipoprotein (HDL) cholesterol in the development of atherosclerosis and cardiovascular (CV) morbidity and mortality has long been recognized. Epidemiological studies have demonstrated an inverse relationship between HDL cholesterol and CV events. HDL is incorporated in the calculation of the 10-yr ASCVD risk in patients who have never had coronary disease. A high HDL usually predicts a lower risk and for this reason, is called GOOD CHOLESTEROL. In addition, low HDL is usually associated with obesity, high triglycerides (TG), hypertension, and elevated blood sugar, a condition called metabolic syndrome and is associated with a higher risk of coronary disease. The exception to this is if you were born in Northern Italy with a mutation of the ApolipoproteinA-1 Milano, the major protein in HDL. Despite having high TG, the population with this mutation have very little coronary disease.

For the last 15 yrs, multiple randomized controlled trials have attempted to improve clinical outcomes by raising HDL cholesterol and have failed to achieve any significant results. The studies of niacin and fibrates have shown that HDL can be raised modestly but had no clinical impact on cardiovascular events. ILLUMINATE studied torcetrapib, a CETP inhibitor that can raise HDL cholesterol by 72% and reduce LDL by 25%. Torcetrapib vs placebo was given for 12 months in patients with a high risk of ASCVD. Surprisingly, the study showed an increase in cardiovascular mortality secondary to off-target effects like raising blood pressure and aldosterone and lowering potassium.

QUALITY OVER QUANTITY AND THE ROLE OF HDL CHOLESTEROL.

The primary function of HDL is to take cholesterol from the vascular system and transport it to the liver to be excreted by the biliary system. This is called reverse cholesterol transport or cholesterol efflux. By removing cholesterol from macrophages inside the arterial wall, it is thought to be atheroprotective by enhancing endothelial function and promoting the repair of the vascular wall. It may also have an anti-oxidant and anti-inflammatory action on the vessel wall preventing blood monocytes from entering the wall of the arteries.

HDL function is not easy to measure in clinical practice and for this reason, it is not performed. A fluorescence-labeled reagent (BODIPY cholesterol) measures the ABCA1-mediated efflux or the macrophage-mediated efflux. The Dallas Heart Study of patients without CAD found that high cholesterol efflux was associated with less risk of ASCVD events. Low cholesterol efflux has been related to the worst outcomes in patients with CAD, particularly after an acute coronary event.

HOW CAN WE INCREASE THE FUNCTION OF HDL CHOLESTEROL?

ApoA-1 lipoprotein is the primary functional component of HDL cholesterol. CSL112 is a plasma-derived apoA-1 lipoprotein reconstituted into disk-shaped lipoprotein particles with phosphatidylcholine and stabilized in sucrose. CSL112 is infused intravenously over a period of 2 hours and has been demonstrated to increase plasma apoA-1 and increase the ABCA1-dependent cholesterol efflux. In AEGIS-1, over 1500 patients, 7 days post MI, were infused on a weekly interval over a period of 1 month and tolerated the procedure very well. AEGIS-II is a phase 3 clinical trial currently enrolling patients post-MI and will evaluate clinical outcomes after the same infusion protocol of CSL112.

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