No cholesterol is good cholesterol

Two head-to-head studies have found that HDL has no effect on plaque and that LDL targets need to be lower

By Katherine Addleman

Current thinking about so-called good and bad cholesterol could be turned on its head if two new studies are anything to go by. The studies have shown, to an unprecedented degree, the enormous impact of 'bad' low-density lipoprotein (LDL) cholesterol on mortality, and the comparative irrelevance of 'good' high-density lipoprotein (HDL) cholesterol as a protective factor in cardiovascular disease. For years, the HDL boosters have pointed to results from large trials like the Framingham Heart Study, which showed that it was heart-protective and could even cancel out high levels of LDL. That assumption is now on the ropes.

The studies compared high-dose atorvastatin treatment with a more moderate dose of pravastatin. The results from the REVERSing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial appeared in the Journal of the American Medical Association in March. The study randomized 502 stable coronary heart disease (CHD) patients to either pravastatin or atorvastatin and measured the progression of atherosclerosis in their coronary arteries. Changes in plaque volume were monitored over a period of 18 months. Atherosclerosis progressed in the pravastatin group, but actually dropped in the aggressive atorvastatin group. Analysis of lipids showed that LDL had decreased significantly with atorvastatin compared with pravastatin. C-reactive protein was 5.2% lower with pravastatin, but a whopping 36.4% less with atorvastatin therapy. It didn't seem to matter whether HDL was high or low, nor did it seem to play any role at all in plaque growth.

The second trial, Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE-IT-TIMI 22), is in the April 8 issue of the New England Journal of Medicine. This study was designed to show that standard lipid-lowering with an

LDL target of 2.59mmol/L using pravastatin was just as beneficial as intensive LDL-lowering to around 1.81mmol/L with high-dose atorvastatin. Over 4,000 patients hospitalized for acute coronary syndrome were randomized to receive one drug or the other. To everyone's astonishment, including lead author Dr Christopher P Cannon, the study proved just the opposite.

The study found that intense atorvastatin treatment significantly reduced the risk of death from CHD, myocardial infarction (MI), and urgent revascularization by 25%. With pravastatin, patients reached a median LDL level of 2.46mmol/L while the atorvastatin patients' levels dropped to 1.60mmol/L after just two years. In both trials and with both treatments, adverse effects were minor. A number of Canadian research groups in Saskatchewan and Quebec took part in the PROVE-IT study.

These findings have rocked the foundations of conventional wisdom about cholesterol, calling into question established guidelines, which now recommend an optimal benefit threshold for LDL of less than 2.59mmol/L. Physicians will have to think again about targets for lowering LDL, and whether HDL is protecting their patients after all. Cardiologist Dr Gregory Curnew of the Hamilton General-McMaster University Lipid Research Clinic agrees. "Lower is better for LDL. PROVE-IT is the first of a series of landmark trials that has already changed my practice of lipid management in high-risk patients," he says. "For my very high-risk patients, the target LDL is 1.5!"