New York, NY - There is no shortage of cholesterol news to begin the new year, especially with questions deriving from the Effect of Combination Ezetimibe and High-Dose Simvastatin vs Simvastatin Alone on the Atherosclerotic Process in Patients with Heterozygous Familial Hypercholesterolemia (ENHANCE) trial. Now, an editorial published over the weekend in the New York Times questions the cholesterol hypothesis, specifically that current medical practice is focusing inappropriately on LDL cholesterol rather than on the lipoproteins that carry the "bad" cholesterol. [1]

The opinion piece, titled "What's cholesterol got to do with it?" by Gary Taubes, author of Good Calories, Bad Calories: Challenging the Conventional Wisdom on Diet, Weight Control, and Disease, zeroes in on the Vytorin (ezetimibe/simvastatin, Merck/Schering-Plough Pharmaceuticals) storm, using the current controversy as a launching pad to question the clinical importance of lowering LDL cholesterol.

"The idea that cholesterol plays a key role in heart disease is so tightly woven into modern medical thinking that it is no longer considered open to question," writes Taubes. "This is the message that emerged all too clearly from the recent news that the drug Vytorin had fared no better in clinical trials than the statin therapy it was meant to supplant."

In light of these findings from the ENHANCE trial, many cardiologists, writes Taubes, said that "the result implied nothing about their assumption that LDL cholesterol is dangerous, only about whether it is always medically effective to lower it.

"But this interpretation is based on a long-standing conceptual error embedded in the very language we use to discuss heart disease," he writes. "It confuses the cholesterol carried in the bloodstream with the particles, known as lipoproteins, that shuttle that cholesterol around. There is little doubt that certain of these lipoproteins pose dangers, but whether cholesterol itself is a critical factor is a question that the Vytorin trial has most definitely raised. It's a question that needs to be acknowledged and addressed if we're going to make any more headway in preventing heart disease."

In his article, Taubes provides a brief history, noting that in the 1950s researchers suspected that lipoproteins, carriers of cholesterol, might play a bigger role in cardiovascular disease. However, measuring these lipoproteins was difficult and expensive, while cholesterol testing was relatively easy to order up for any doctor.

By the 1960s, scientists were able to measure the cholesterol inside the different types of lipoproteins—high-density, low-density, and very-low-density lipoproteins. Studies later showed that cholesterol in LDL was a marginal risk factor, leading to the concept that LDL carries bad cholesterol and HDL carries good cholesterol. HDL and LDL later became "good" and "bad" cholesterol, losing sight of the idea that the causal agent in cardiovascular disease might be abnormal lipoproteins, writes Taubes.

The results with statin drugs, which lower LDL cholesterol and prevent MI, have led many to believe that lowering LDL prevents heart disease. However, statins have other pleiotropic effects, including lowering the number of low-density and very-low-density lipoproteins in the blood, including the smallest, densest, and most noxious form of LDL, writes Taubes. Moreover, the ENHANCE study with Vytorin, as well as data on estrogen therapy and torcetrapib, all of which lower LDL cholesterol, have failed to show a benefit, he writes.

"If the evidence continues to challenge the role of cholesterol, then rethink it, without preconceptions, and consider what these other pathways in cardiovascular disease are implying about cause and prevention," writes Taubes. "A different hypothesis may turn out to fit the facts better and one day help prevent considerably more deaths."

With questions surrounding the mortality benefits of statins and the importance of lowering LDL cholesterol being asked in the media, some high-profile cardiologists also get in on the act in the January 29, 2008 issue of Circulation, with Drs H Robert Superko (St Joseph's Translational Research Institute, Atlanta, GA) and Spencer King III (Emory University School of Medicine, Atlanta, GA) [3] debating the effectiveness of lowering LDL to reduce cardiovascular risk and suggesting that new strategies are necessary. Taking an opposing stand is Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas), who argues for the promise of LDL-lowering therapy in primary and secondary prevention [4].

According to Superko and King, a danger for the future health of patients lies in assumptions that cholesterol reduction alone can stem the tide of coronary heart disease. They argue that "this is not enough" and state that the "well-meaning focus on LDL-cholesterol reduction has deflected interest in other therapeutic aspects of lipoprotein treatment that provide equal or greater benefit."

They also point to the many clinical trials with monotherapy showing a consistent 25% reduction in cardiovascular events. This relative risk reduction, they suggest, obscures the fact that 25% is simply insufficient.

To support their argument, Superko and King point to the PROVE-IT trial, a comparison of high-dose atorvastatin vs pravastatin 40 mg, suggesting that while the relative 16% reduction in clinical events is laudable, 22.4% of patients treated with atorvastatin 80 mg still experienced a clinical event. These events occurred despite LDL cholesterol being lowered to 62 mg/dL. The NNT also remains too high in monotherapy trials, write Superko and King, but combining LDL lowering with therapies to raise HDL cholesterol could reduce the NNT. In addition, as has been shown in different trials, combining LDL-lowering with HDL-raising therapy can actually regress atherosclerosis, whereas monotherapy with LDL-lowering drugs alone can't.

According to Grundy, however, whether raising HDL by pharmacological intervention will reduce cardiovascular risk remains to be proven, noting that the science in this area is still "in the arena of speculation."

He writes that LDL is a cause of atherosclerotic cardiovascular disease and that lowering it will reduce the risk, as has been shown by the past 20 years of research. Intensive LDL-lowering therapy, even in the presence of atherosclerosis, can reduce the risk of clinical events 40% to 50%, and not 25% as suggested by Superko and King, although he concedes there is still a residual risk of 50% to 60%. Reducing cigarette smoking and understanding the contribution of metabolic syndrome to clinical events as well as various arterial wall factors can help reduce this residual risk, writes Grundy.