Then and Now | ATP III Versus IV: Lipid-Lowering Paradigm Shifts with New Guidelines

By Scott M. Grundy, MD, PhD

The ACC and the American Heart Association (AHA) recently released new guidelines for treatment of high blood cholesterol1 that were originally designed to serve as the next iteration of the 2002 Adult Treatment Panel III (ATP III) report of the National Cholesterol Education Program.2 Recently, the National Heart Lung and Blood Institute (NHLBI) discontinued developing clinical guidelines and instead provided its evidence review to the ACC and AHA, who transformed NHLBI's evidence reviews into treatment guidelines that constitute a new paradigm for cholesterol management.

The most recent guideline update process, started several years ago by the so-called "ATP IV" panel, followed the "rules" for guideline development from the Institute of Medicine (IOM). The IOM emphasized "evidence-based medicine" in guideline development; in other words, recommendations should be based mainly on evidence obtained by randomized clinical trials (RCTs). This contrasted with the ATP III panel, which emphasized RCTs, but also used epidemiological data, genetic and metabolic studies, and in vivo and in vitro investigations.

Both sets of guidelines stress the value of lifestyle intervention, although the ACCF/AHA guidelines do so without RCT evidence. They did apply the evidence-based rules to drug therapy, where recommendations focus on statins, which have the strongest RCT evidence, and largely discount other lipid-lowering drugs because of insufficient RCT studies.

Low-Density Lipoproteins and Atherosclerotic Cardiovascular Disease

ATP III identified elevated LDL as a major cause of atherosclerotic cardiovascular disease (ASCVD), a relationship seen most dramatically in patients with familial hypercholesterolemia, where premature atherosclerosis commonly occurs absent all other risk factors. While animal studies and human epidemiology also demonstrate that a high LDL causes atherosclerosis, RCTs teach us that the more LDL falls through intervention, the greater the ASCVD risk reduction. Congruence of these different lines of evidence makes LDL the centerpiece of ATP III, and the panel concluded that any modality that lowers LDL will proportionately reduce coronary heart disease (CHD) risk.

Although acknowledging that LDL-lowering could be beneficial, the ACC and AHA—reflecting the IOM paradigm—make LDL irrelevant to guideline development. Instead statins secured the linchpin of their recommendations. By moving away from the connection between LDL and ASCVD risk and focusing on the efficacy of particular drugs per se, ATP IV departs markedly from previous cholesterol guidelines; this will continue as long as RCTs are the sole basis of these guidelines.

The new guidelines have abandoned LDL targets of therapy in favor of treating with a dose of statin. But is the achieved risk reduction adequate? ATP III helps the clinician answer this crucial question via the LDL goal, but the new guidelines are agnostic on this point. In addition, the approach of the new guidelines makes cholesterol management quite different from the established clinical method of managing risk factors by setting therapeutic goals.

Secondary Prevention

ATP III and its 2005 update3 set an LDL of <100 mg/dL for high-risk patients, especially those with established ASCVD; this group also includes patients with diabetes and a 10-year risk >20%. For those considered to be at very high risk (i.e., ASCVD + multiple risk factors), a goal of <70 mg/dL was considered reasonable (which includes most patients with ASCVD). While high-intensity statins lower LDL to near 70 mg/dL on average, ATP III allowed for the addition of a second LDL-lowering drug in patients not reaching that goal.

ACCF/AHA guidelines recommend high-intensity statins in patients with established ASCVD; non-statin drugs are not explicitly recommended and thus patients with a high baseline LDL likely will not receive the full benefit of LDL-lowering.

Primary Prevention

Both sets of guidelines carried out 10-year risk assessment to guide drug therapy. ATP III recommended considering drug therapy when 10-year risk for CHD was ≥10%; ACCF/AHA set a threshold for statin drugs at 7.5% for ASCVD. Even ≥5% risk was considered a therapeutic option for statin therapy. For higher-risk patients, ATP III permitted drug therapy at LDL >100 mg/dL, whereas ACCF/AHA starts statins at LDL >70 mg/dL. The latter value is supported by the more recent results of the JUPITER trial,4 which showed efficacy in patients with LDL <100 mg/dL. The ACCF/AHA's reduction of both the projected 10-year risk threshold and the drug initiation level of LDL will expand statin use beyond ATP III recommendations.

Older and Middle-Aged Persons

Since risk increases with age, the number of people of advancing age eligible for statins will grow progressively. Age becomes the dominant factor in the ACCF/AHA algorithm, where eventually everyone becomes statin eligible—most men in their 60s and more women in their 70s. Without a better means of risk assessment, unnecessary treatment will be common in older persons with little atherosclerosis. For those who are middle aged, ACCF/AHA guidelines are similar to ATP III except that persons with lower risk and lower LDL will qualify for statin therapy. To account for over-prediction of risk by the ACCF/AHA algorithm, a 10-year threshold for statin therapy in the range of 10–15% seems reasonable.

Despite similarities, ATP III and the ACCF/AHA guidelines are fundamentally different. Backed by decades of research, ATP III is based on the concept that lowering atherogenic lipoproteins will prevent ASCVD; thanks to an IOM paradigm, the ACCF/AHA guidelines feel more like statin treatment instructions. They also give lip service to lifestyle intervention and make risk assessment based on older data that may not be suitable for the current US population. Because they depend entirely on RCTs, the ACCF/AHA guidelines are not universally considered to be comprehensive cholesterol guidelines. ATP III remains useful for guiding the physician's clinical judgment.


1. Archer E, Lavie CJ, McDonald SM, et al. Mayo Clin Proc. 2013;88(12):1368-77.
2. O'Keefe JH, Patil HR, Lavie CJ, et al. Mayo Clin Proc. 2012;87(6):587-95.
3. O'Keefe JH, Lavie CJ. Heart. 2013;88(9):516-19.
4. Ridker PM, Danielson E, Fonseca FA, et al. N Engl J Med. 2008;359:2195-207.

Scott M. Grundy, MD, PhD, is a professor at University of Texas Southwestern Medical Center in Dallas. He was chair of the Third Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III).

Keywords: Life Style, National Heart, Lung, and Blood Institute (U.S.), Atherosclerosis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Evidence-Based Medicine, National Academies of Science, Engineering, and Medicine, U.S., Health and Medicine Division, Primary Prevention, Lipoproteins, LDL, Judgment, Secondary Prevention, Risk Assessment, ACC Publications, CardioSource WorldNews

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