HDL-Cholesterol's Role in Coronary Artery Disease

Summarized by Robert W. Griffith, MD
March 5, 2007

Summary

For the first time it's been shown that lowering low-density lipoprotein cholesterol (LDL-C) and raising high-density cholesterol (HDL-C) at the same time, through statin medication, is associated with a reduction in the degree of degenerative artery changes (atherosclerosis).

Introduction

There's plenty of evidence that lowering raised levels of the 'bad' cholesterol - low-density lipoprotein cholesterol (LDL-C) - prevents atherosclerotic¹ cardiovascular disease. High-density lipoprotein cholesterol (HDL-C) is the 'good' cholesterol, and it's regarded as protective against cardiovascular problems. However, there are no data showing the relationship between raising HDL-C and a reduction in cardiovascular atherosclerosis.

A team of researchers at the Cleveland Clinic have just reported on the effects of satins on cholesterol levels and the degree of atherosclerosis in the Journal of the American Medical Association. They used pooled data from four large clinical trials involving 177 centers in the USA, North America, Europe, and Australia. Here's a summary of the reported findings.

What was done

The 4 clinical trials evaluated the changes over time in the degree of coronary atherosclerosis, using intravascular ultrasound.² All the ultrasound image analyses were done at a core site (the Cleveland Clinic), and all blood analyses were conducted at two central reference laboratories. The patients were treated with either a moderate dose of pravastatin, a high dose of atorvastatin, a high dose of rosuvastatin, a calcium blocker, an ACE inhibitor, an experimental lipid-lowering drug, or a placebo. The studies lasted 18 or 24 months, with blood sampling every 3 to 6 months, and ultrasound done at the start and the end of each study.

What was found

Out of over 3,500 patients in the 4 studies, 1455 were given statins and had assessment of the changes in the amount of their atherosclerosis. Their average age was 58; 73% were men; the average body mass index (BMI) was 30; 24% were smokers; 76% had high blood pressure; and 19% were diabetic. The lipid values and the atheroma volumes varied from study to study, as one study was aimed at treating high cholesterol, another at treating high blood pressure, and so on. Results from the studies were pooled for analysis.

The average LDL-C levels dropped under statins from 124.0 to 87.5 mg/dL (-23%); average HDL-C levels increased from 42.5 to 45.1 mg/dL (+7.5%); and the LDL-C to HDL-C ratio dropped from 3.0 to 2.1 (-27%).

There was a 0.5% increase in the percentage atheroma volume, from 39.7% to 40.1%; however, the average total atheroma volume decreased by 2.4 cu mm.

The reduction in atherosclerotic changes was clearly dependent, not only on the reduction in LDL-C, but also the increase in HDL-C. This is shown in the table:

LDL-C Level	% Change in HDL-C	Change in total atheroma
below 87.5 mg/dL	above 7.5%	- 8.8 cu mm
below 87.5 mg/dL	below 7.5%	- 2.8 cu mm
above 87.5 mg/dL	above 7.5%	+ 0.3 cu mm
above 87.5 mg/dL	below 7.5%	+ 2.1 cu mm

In a further analysis, an LDL-C ratio of less than 2.0 during treatment was associated with a reduction in total atheroma, while a ratio of more than 2.0 was linked to an increase in atheroma.

Although clinical events - such as heart attack, stroke, or cardiac death - were recorded during the study, there were no significant differences in the rates of these events in the different groups shown in the table.

What the findings mean

It must be emphasized that this study provided no evidence that reducing HDL-C and simultaneously raising HDL-C confers a reduction in clinical events, such as heart attack or stroke. However, the results show quite conclusively that the lipid changes that were produced by statin administration were associated with slowing or even reversal of the development of atheroma. While lowering LDL-C has been known to have this effect, the role of raising HDL-C is shown here for the first time. The greatest benefit was seen in those patients who had LDL-C levels below 87.5 mg/dL (2.3 mmol/L) and HDL-C levels 7.5% above their baseline level.

Statins increase HDL-C levels by around 5% to 15%, as a rule. The recently-dropped drug torcetrapib increased them by 50% to 60%. It was clearly hoped that torcetrapib would have pronounced effects on atherosclerosis, and reduce cardiovascular clinical events dramatically. Unfortunately serious adverse events in a large-scale study (15,000 patients) were more frequent in the torcetrapib + statin group than in the statin-alone group.

There will be follow-up drugs to torcetrapib, but it will take a long time to see if they have a similar side-effect profile. In the meantime, physicians can turn to older favorites once commonly used to influence lipid levels, including raising HDL-C: nicotinic acid (vitamin B3, sold as Niacin^®), and gemfibrazol (Lopid^®). These don't have the same dramatic effect as torcetrapib, and they may have some unpleasant side effects in some patients, but perhaps it's worth it to stop or reverse atherosclerosis. Your doctor can advise you on this.

Source

• Statins, high-density lipoprotein cholesterol, and regression of coronary atherosclerosis. SJ. Nicholls , EM. Tuzco, I. Sipahi,  et al. , JAMA, 2006, vol. 297, pp. 499--508

Footnotes
1. Atherosclerosis is a condition in which fatty material collects along the walls of arteries, called 'atheroma'; it thickens, hardens, and may eventually block the arteries. The atheroma plaque deposits make the artery less flexible; they can also break apart, causing pieces to move through the artery, causing a stroke or heart attack, depending on where they end up blocking the artery.
2. Intravascular ultrasound is a medical imaging methodology using a specially designed catheter with a miniaturized ultrasound probe attached to its distal end. The proximal end is attached to computerized ultrasound equipment. It allows one to see from inside blood vessels outwards, visualizing the endothelium (inner wall).

Related Links
Cholesterol: Size Does Matter (1)
Cholesterol: Size Does Matter (2)
What is Atheroma?

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