The ‘Highly Difficult Lipoprotein’
Believe it or not, optimism about HDL

ACCEL | Almost 4 decades ago, the Framingham Study reported that high-density lipoprotein cholesterol (HDL-C) was a protective factor against CHD1 and, about 25 years ago Badimon et al. demonstrated that intravenous infusion of HDL-C into cholesterol-fed rabbits caused regression of atherosclerotic lesions.2

Since then there have been many attempts to harness the potential of HDL as a therapeutic strategy since it seems to have several protective vascular effects:

  • promotes cholesterol efflux
  • has antioxidant properties
  • has antithrombotic properties
  • has anti-inflammatory properties
  • improves endothelial function
  • promotes endothelial repair
  • improves diabetic control.

Consequently, multiple pharmaceutical agents have been studied with the goal of increasing HDL-C. Niacin, the most widely used medication to raise HDL-C, increases HDL-C by 25% or more and was shown in multiple surrogate endpoint studies to reduce CV risk. However, two large randomized controlled trials of niacin, AIM-HIGH and HPS2-THRIVE, have shown that despite its effects on HDL-C, niacin does not decrease the incidence of CV events and may have significant adverse effects.

Studies of other classes of agents such as cholesteryl ester transfer protein (CETP) inhibitors have also shown that even dramatic increases in HDL-C do not necessarily translate to reduction in clinical events. One of the latest attempts was described by Barter and colleagues who reported the results of the CHI-SQUARE study (Can HDL Infusions Significantly Quicken Atherosclerosis Regression) study, which is the largest randomized clinical trial to date testing the efficacy of serial HDL infusions in patients with a recent ACS.3

In this case, the authors investigated the effects of an HDL-mimetic agent on atherosclerosis by IVUS and quantitative coronary angiography at baseline and 3 weeks in a prospective, double-blinded, randomized trial including 507 patients from 51 centers in the U.S., The Netherlands, Canada, and France. Patients received 6 weekly infusions of placebo or 3, 6, or 12 mg/kg CER-001. The primary efficacy parameter was the nominal change in total atheroma volume. Unfortunately, CER-001 infusions did not reduce coronary atherosclerosis as compared with placebo, making this the fourth study to fail to show significant improvement in atheroma volume versus placebo after infusion of HDL in humans with coronary artery atherosclerosis.

In an accompanying comment to the CHI-SQUARE results, Alan Fogelman, MD, FACC, David Geffen School of Medicine at the University of California Los Angeles, offered potential explanations for the Barter et al. results: HDL-C may be only a biomarker and not a causal agent; inflammation may have rendered apolipoprotein A-I (apoA-I) ineffective; doses used may be too low or not delivered frequently enough; HDL’s protective effect may occur outside of the arterial circulation; or measurements used may be too crude.4

Fogelman and colleagues recently reviewed the hypothesis that HDL is a suitable therapeutic target despite the CHI-SQUARE results. He notes that HDL-C “is not like other lipoproteins; it is much more complex. It is also probably too soon to determine if trying to harness the potential of HDL is wishful thinking or a sound strategy.”5 Recent studies suggest, for example, that HDL-C becomes modified in patients with CAD or ACS because of oxidative processes that result in alterations in its proteome composition (proteome remodeling) leading to HDL dysfunction. Therefore, Fogelman wrote that it will be important to demonstrate that novel drugs not only increase HDL-C plasma levels but also improve HDL function in patients at high CV risk.

‘Highly Difficult Lipoprotein’

Professor Philip Barter, MD, Director of the Centre for Vascular Research, University of New South Wales, Sydney, Australia, certainly concurs over the complex nature of HDL, which he calls the “highly difficult lipoprotein.” We noted above a number of potential protective properties of HDL-C, including perhaps improved diabetes control. This is based on evidence that lipid-free and lipid-associated apoA-I and apoA-II increase pancreatic beta cell insulin synthesis and secretion, suggesting that interventions that raise HDL-C levels may be beneficial in type 2 diabetes.

Barter and colleagues demonstrated this in the ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events) trial where treatment with torcetrapib improved glycemic control in atorvastatin-treated patients with type 2 diabetes mellitus.6 However, whether the beneficial effect of torcetrapib on glucose homeostasis was related to the increase in HDL concentration or to some other off-target activity of the drug is unclear. So, to date, there is no clinical trial evidence that increasing the level of HDL-C in people with diabetes translates into a reduction in CVD risk.

In June 2015, Barter and others published (online before print) the initial results of a study using another novel CETP inhibitor, TA-8995, in patients with mild dyslipidemia.7 They enrolled 364 patients and low-density lipoprotein cholesterol (LDL-C) was reduced by about 25% to 50%, depending on dose, and HDL-C was increased from about 75% to 179%, again depending on dosing. Barter, too, thinks just raising HDL-C is not enough and this new agent increases HDL-C function. He said, “It increases the ability of HDL to promote cholesterol efflux by about 50%.” TA-8995 was well tolerated and clearly has beneficial effects on lipids and apolipoproteins in patients with mild dyslipidemia, but a CVD outcomes trial is needed to determine whether these effects translate into a reduction of CV events.

“HDL is very, very complex,” said Barter. “At last count, there was something like 37 identifiable subpopulations that migrate in the HDL range.” The problem, he said, is we do not know which functions of HDL-C are clinically important and we certainly do not know which subpopulations are clinically important.

Nevertheless, “I have moved from being pessimistic about HDL, to being less pessimistic, to now actually having some optimism.”

Finally, what about non-HDL cholesterol? Growing evidence suggests that non-HDL-C is a better risk predictor than LDL, can be performed in a nonfasting state, and does not incur any additional costs to the health care system. Yet surveys suggest that physicians cannot calculate non–HDL-C levels when provided a standard lipid profile, and cardiologists were just as likely as primary care physicians to not understand the calculation or know the non–HDL-C goal of therapy.8 Non–HDL-C is simply calculated by subtracting HDL-C from total cholesterol.

Barter said non-HDL-C has been a better risk predictor when evaluated against LDL-C, but he understands the reluctance to embrace non-HDL-C due to concerns that a sudden shift away from concentrating on LDL may cause great confusion. Having said that, he quickly added that in the next 3 to 5 years, non-HDL-C will likely replace LDL as the chief measure of CV risk. Until then, it remains a secondary target and the goal should be a non-HDL-C of <130 mg/dL.


  1. Gordon T, Castelli WP, Hjortland MC, et al. Am J Med. 1977;62:707-14.
  2. Badimon JJ, Badimon L, Fuster V, et al. J Clin Invest. 1990;85:1234-41.
  3. Tardif JC, Ballantyne CM, Barter P, et al. Eur Heart J. 2014;35:3277-86.
  4. Fogelman AM. Eur Heart J. 2014;35:3248-9.
  5. Luscher TF, Landmesser U, von Eckardstein A, et al. Circ Res. 2014;114:171-82.
  6. Barter PJ, Rye KA, Tardif JC, et al. Circulation. 2011;124:555-62.
  7. Hovingh GK, Kastelein JJ, van Deventer SJ, et al. Lancet. 2015 Jun 2. [Epub ahead of print]
  8. Virani SS, Steinberg L, Murray T, et al. Am J Med. 2011;124:876-880.e2.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Lipid Metabolism, Nonstatins

Keywords: CardioSource WorldNews, Anti-Inflammatory Agents, Antioxidants, Cholesterol, Cholesterol, HDL, Diabetes Mellitus, Endothelium, Infusions, Intravenous, Lipoproteins, HDL

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