New National Cholesterol Guidelines
The Dual Challenge of Pragmatics and Science

by Diane Becker, RN, ScD, MPH

In 1993 with the advent of the National Cholesterol Education Program's Second Report of the Adult Treatment panel II (ATP II), 97 million adults in the United States were reported to have total cholesterol levels greater than 200 mg/dl. These numbers have not changed dramatically despite recommendations for diet and highly effective pharmacotherapy, although the average total cholesterol has fallen for both men and women in the US. Many health providers and health systems have not been particularly successful in applying the ATP II Guidelines. This has been attributed to the lack of encounter time, lack of reimbursement mechanisms, poor patient adherence, and lack of appropriate training and skills in dietary and even pharmacologic management. Although there has been a clear improvement in provider practice, the population has not received the benefits that could be achieved by effective application of the ATP II Guidelines. In the Spring of 2001, the new National Cholesterol Education Program Adult Treatment Panel III Report will be released, providing a powerful impetus for renewing efforts to improve lipid management and reduce the risk of both first and recurrent coronary disease events. The new Guidelines are evidence-based and represent an exhaustive expert review of all available contemporary trials and epidemiologic data. The genesis of national guidelines has provided a conundrum for the Panel relative to balancing the simplicity that would enable broad application of the Guidelines with the complexity of the emerging lipid science.

The primary "culprit" in the development of CHD has long been thought to be the LDL particle which contains 60 to 70 percent of the total serum cholesterol. For this reason, LDL cholesterol has become and remains the major target of treatment. The link between elevated LDL-C and CHD has been well established in epidemiologic studies, and the cascade of atherosclerosis, plaque formation, plaque instability and rupture, and the genesis of clinical CHD has been well documented. It appears that LDL-C levels below 100 mg/dl may be the "physiological" level at which atherogenesis does not occur and this fact has been the driving force behind recommendations that focus on LDL-C and on achieving levels below this in extremely high risk patients. In the United States, where the average LDL-C level is markedly above this, about a third of women and almost 50% of men will develop CHD in their lifetime while in societies where the average LDL-C levels are below 100 mg/dl, CHD is rare. Most convincing, however, is the powerful evidence that treating LDL-C and lowering levels to below 100 mg/dl, independent of the nature of the treatment, causes a marked decrement in CHD risk. Thus, the argument presented in ATP II focusing on LDL-C remains persuasive and may drive the new Guidelines as well. Goal levels vary as do cutpoints for initiating therapy based on the extent of risk.

The story is far more complex, however, and the emergence of information about atherogenic dyslipidemia or the atherogenic lipoprotein profile which includes moderate elevations of triglycerides, small dense LDL particles, and low HDL-C (the "lipid triad"), provides a case for approaching the management of lipids with far greater precision than that offered by an LDL-C centered model only. Atherogenic dyslipidemia is strongly associated with aggressive premature CHD and is part of a metabolic syndrome that also encompasses abdominal obesity, hypertension, insulin resistance or diabetes, and thrombogenic potential. How to integrate this complex information into treatment algorithms and retain the simplicity necessary to foster integration of the new Guidelines into clinical practice provides a major challenge to the Panel. The rapid advancement of lipid science has created new challenges about what to measure and how to interpret complex laboratory data. While it is unlikely that measuring subclasses or extending the paradigm to other aspects of lipoproteins will occur in ATP III, it remains possible that measuring entities such as LDL particle size and the number of LDL particles will become a part of lipid management in more sophisticated practices, guided by new data that are not quite ready for application to the entire population. One could then expect ATP IV to be even more complex.

Further complicating the picture is the clear evidence that not everyone with moderate elevations of LDL-C is at increased risk. Will global risk assessment using a calculated risk score make it possible to further tailor therapy and reserve aggressive lipid management for the highest risk populations? Ignoring what we know scientifically about the distribution of lipid-related CHD risk could result in many people being placed on pharmacotherapy who may not need it. Conversely, it could result in not enough people being placed on therapy. Global risk assessment has the desirable characteristic of targeting lipid management to the persons who will benefit most.

In addition, ATP II took a strong position on treating individuals with known vascular disease to goal levels of LDL-C < 100 mg/dl that were more aggressive than for individuals who had not yet experienced a coronary event. In the past decade, there has been strong scientific evidence that there are CHD risk equivalents, or clinical states that pose the same degree of lipid-related risk as does a prior CHD or vascular event. Yet, to ignore what the evidence has shown us about these risk equivalents in the interest of simplicity would be to obviate the necessity of science to drive our care paradigms and perhaps rob these high-risk people of optimal care.

Incorporating global risk assessment into recommendations for usual clinical practices may make the Guidelines quite complex as does the incorporation of different goal levels for an array of specific high risk conditions, but refining this position may serve the cause of lowering CHD risk in the US better than wholesale pharmacologic treatment of every person with a high cholesterol or of simply ignoring the degree of risk and seeking a middle ground for lipid management for all comers. Again, the challenge is the balance of simplicity with best practices that emanate from the best scientific knowledge we have available.

Thus, while the target for therapy is likely to remain LDL-C, there is increasing attention to optimizing therapy to assure concomitant attention to the potentially atherogenic potential of other lipoproteins. Current pharmacotherapy offers alternatives that at least partially address the effects of these atherogenic lipid profiles. Together with lifestyle modification, our current therapeutic armamentarium can play a major role in approaching other aspects of the metabolic derangement that appears to be associated with CHD. Further, better refining risk algorithms and risk equivalents will foster tailored therapy directed to the patients who will benefit most. Simplifying the Guidelines may appear at first blush to be highly desirable, but refining them based on science should be eminently appealing to practitioners who provide high quality care and whose practices involve infinitely more complex therapeutic paradigms than this. SELA's goal is to foster the opportunities to master the increasing complexity of lipid management and to take a leadership role in the translational end of the science of good health care delivery. The annual meeting will include a number of members of the NCEP ATP III Expert Panel and will address many of the complex scientific issues facing the Panel as they move into the refinement of a new set of Guidelines for the nation.

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