Earlier and More Aggressive LDL Lowering, or Better Approaches for Targeting High-Risk Individuals?

A new review by three renowned experts in cardiology suggests that efforts to treat elevated cholesterol levels are not exploiting the full potential of cholesterol-lowering strategies, and current approaches to treatment are simply doing "too little, too late. [1]" The evidence, say these experts, is strong enough to support even more aggressive use of lipid-lowering therapies and to intervene at earlier stages in the development of atherosclerosis. Writing in the August 5, 2008 issue of Circulation, Drs Daniel Steinberg, Christopher Glass, and Joseph Witztum (all from the University of California, San Diego [UCSD]) point out that the National Institutes of Health (NIH) now recognizes that for individuals at high risk, treatment to LDL-cholesterol levels <70 mg/dL is better than previously recommended targets of <100 mg/dL. The researchers suggest, however, that treating to LDL-cholesterol levels to between 40 and 60 mg/dL confers even more benefit.

"With combination therapy, it is now possible to reach these low LDL goals; they are not unrealistic," write Steinberg, Glass, and Witztum. "Yet, most patients outside specialty clinics are not reaching those goals, in part because of poor compliance but also in part because practitioners are still hesitant to be more aggressive. There continue to be concerns about safety and side effects, despite the wealth of evidence that they are not serious problems in the vast majority of patients."

In terms of clinical management, adults with existing coronary heart disease or multiple risk factors should strive to lower their LDL-cholesterol levels to <50 mg/dL. In fact, the authors write that on the basis of the accumulated evidence, it "would be reasonable to recommend that an 'ideal' LDL-cholesterol level should be defined as <50 mg/dL."

Can You do Better Than Simply Lowering LDL Cholesterol?

Commenting on the proposals of the UCSD researchers, Dr Prediman Shah (Cedars-Sinai Health Center, Los Angeles, CA) told heartwire that he agrees with many of their arguments, especially that earlier and more aggressive treatment in childhood and adolescence, specifically through lifestyle modifications, might be the way to further reduce cardiovascular events from atherosclerosis.

"The problem with that approach, however, is a practical one," said Shah. "We won't be around to see the benefits of those interventions begun in childhood. It will take 30 or 40 or 50 years to establish the usefulness of those strategies, even though such benefits seem reasonable and plausible. While it is still a worthwhile goal, what do we do with the millions of people who have disease and need something done now?"

In their paper, Steinberg, Glass, and Witztum point out that atherosclerosis is often well under way by the time an individual is 30 years old, with fatty-streak lesions evident but asymptomatic and clinically nonthreatening. They argue, however, that intervention should not be deferred until later years--with treatment catching up to the disease--but rather started early because atherosclerosis is a single disease entity that evolves over time. If the disease is a continuum, then treating these fatty streaks will prevent or slow the progression of later, clinically significant lesions.

"Why not slow things down early in the game?" they ask. By eliminating age from risk-prediction models, this would be one way to encourage earlier intervention in patients with high-risk profiles, they add.

Although a long-range plan focusing on prevention at a very early age is appropriate, Shah said there exists a sizable challenge in the current patient population where statin therapy alone is only modestly effective in reducing cardiovascular events. Researchers need to look to other paradigms of management that are applicable now or those next-generation therapies on the horizon within the next five or seven years, such as HDL-based or immunomodulation therapies. Steinberg, Glass, and Witztum agree that these therapies might one day be used alongside cholesterol-lowering agents, but there are ample existing data that show statins and other agents have not been utilized to their full potential and can be put to work to further decrease the risks of hypercholesterolemia.

What About apoB and Other Markers of Risk?

On the proposed push toward an ideal LDL-cholesterol target of <50 mg/dL, Dr Allan Sniderman (McGill University, Montreal, QC) told heartwire that this is an extreme and overly simplistic approach to managing elevated cholesterol levels and the risk of coronary heart disease. Clinicians simply are unable to get patients to such a low treatment target, and in trying to do so, will be prescribing too much medication for too many people. Instead, said Sniderman, the focus should be on using technology to more precisely identify at-risk individuals who would benefit from lower LDL-treatment targets.

Sniderman is a proponent of measuring apolipoprotein B (apoB), as it is a surrogate of the number of atherogenic particles, including very low-density cholesterol (VLDL) and LDL cholesterol, rather than LDL cholesterol, which is a surrogate for the cholesterol concentration of the LDL particle. He believes that Steinberg, Glass, and Witztum are wrong in declaring war on LDL cholesterol and the existing treatment targets.

"I think we would end up using all of the resources in healthcare in a frantic way," said Sniderman. "I think we should try to identify ways in which to make society healthier, but in medical terms, I think we need better ways to identify high-risk people. They don't mention apoB, which is unfortunate, because I don't think there is much doubt that apoB identifies high-risk people more precisely than LDL cholesterol. That's not really debatable at this point. Why wouldn't we use better technology to identify fewer people to treat?"

The American Diabetes Association (ADA) and American College of Cardiology (ACC), said Sniderman, have begun to recognize the value of apoB as a marker of cardiovascular risk, and with the price of the assay coming down, it should start to be used more frequently as a means of identifying high-risk patients. "It's the same biology, just more precise," he said. "So why wouldn't we want to do better, target the patients better? The real benefit comes from making sure you are treating the high-risk patient and get them down to a low level."

Like Steinberg, Glass, and Witztum, Sniderman agrees that at present, short-term strategies based on 10-year risk models result in treating people too late. "Because of the effects of exposure, if we can identify the high-risk person earlier, then we can make very substantial changes in outcome by intervening moderately earlier in life," he said.

Steinberg D, Glass CK, Witztum JL. Evidence mandating earlier and more aggressive treatment of hypercholesterolemia. Circulation 2008; 118: 672-677. Abstract

Reviewed by Ramaz Mitaishvili, MD

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