Non–High-Density Lipoprotein Cholesterol and Guidelines for Cholesterol Lowering in Recent History

Stanley S. Levinson, PhD


Lab Med. 2020;51(1):14-23. 

In This Article

The National Cholesterol Education Program (NCEP) and the Development of its Guidelines

The idea that cholesterol was a cause of coronary disease has been supported by a wealth of evidence from experimental animal models, epidemiological studies, genetic studies, and strongly suggestive human clinical trials. However, through the years, for various reasons, this idea was rejected by many scientists.[4] An article published by Anitschkow and Chalatow[5] in 1913 proposed a central role of hypercholesterolemia in atherogenesis. Yet, only in 2017 did a consensus statement from the European Atherosclerosis Society note that LDLC was not only a biomarker but a definitive cause of coronary disease. This statement was based on evidence from inherited disorders, prospective epidemiological studies, Mendelian randomization studies, and randomized control trials (RCTs).[6]

Anitschkow was a careful experimentalist.[4] He described lipid droplets, cholesterol accumulation, and white blood cell accumulation in the artery tissue, as well as conversion of the fatty streak to fibrous plaque. One reason that the findings of Antischow were not taken seriously was because he worked with rabbits, which have low-density lipoprotein (LDL) metabolism similar to that of humans, whereas later investigators worked with rodents, which have different LDL metabolism compared with humans. Also, the prevalent view of atherosclerosis was generally accepted to be that it accompanies aging, and there was a rigid preconceived notion that only aging and not cholesterol was responsible (for a brief discussion of the work of Antischow, see reference[4]). Even today, some investigators[7] doubt the cholesterol hypothesis and claim that most, if not all, evidence implicating cholesterol as a cause of atherosclerosis is faulty.

The first guidelines recommending treatments for lowering cholesterol, called the Adult Treatment Panel (ATP), were released by the NCEP in 1988.[8] These defined target values for LDLC range from less than 130 mg per dL to 160 mg per dL or less, according to estimated coronary risk. The many events in the history of cholesterol are described by Steinberg in a series of reviews.[9–12] The discovery of a defective gene in familial hypercholesterolemia and the identification of the LDL receptor in the 1970s by Goldstein and Brown[13–15] were among many milestones in the history of cholesterol and were major finding in its understanding. However, the development of the first ATP guidelines was probably dependent on 2 other milestones.

The first such milestone is the Coronary Primary Prevention Trial (CPPT).[16] This trial, conceived in the early 1970s and completed in the early 1980s, was a double-blinded RCT that enrolled 3806 men who were followed up for an average of 7.4 years. These men had to consume packets of sandy cholestyramine—a bile-acid sequestrant that lowers LDLC—or a similar gritty placebo 3 times per day. Although the compliance was poor overall, causing the lowering of cholesterol to be much less than was expected, the treated group showed a statically significant 19% reduction in coronary events. Thus, it was apparent that heart disease could be reduced by lowering cholesterol. However, there was no simple way to lower it until Akira Endo identified a substance in mold that could inhibit cholesterol synthesis—the second milestone.

Week after week for 2 years, Endo and his associates assayed more than 6000 substances to finally find a substance called compactin that inhibited cholesterol synthesis at the HMG-CoA reductase step—this was the first statin.[12] In 1978, Endo, along with Goldstein, Brown, and colleagues,[17] published an article showing the large effect of statins on cells. At the time, there was great concern that intensive cholesterol lowering could lead to cancer. Despite this, the drug company Merck & Co, Inc.[12] went on to identify and support clinical trials for another statin—lovastatin—that was to become the first commercially available statin. Thus, by 1988, when the ATP I was released, it seemed clear that lowering LDLC could reduce coronary disease and that taking statins were an effective, innocuous way to lower LDLC.

The ATP I guidelines were followed by ATP II and ATP III in 1994 and 2002. These guidelines affirmed the approach of ATP I and set a new LDLC goal of 100 mg per dL or less as optimal and the target for the highest risk groups.[18,19] It designated persons with diabetes (mellitus) as among the highest-risk group, identified persons with multiple risk factors for more-intense treatment, and introduced the idea that persons with metabolic syndrome should be considered for intensified therapeutic lifestyle changes. The 2002 guidelines,[19] which were endorsed by the AHA and the American Diabetes Association,[20] indicated that for patients with triglycerides between 200 mg per dL and 500 mg per dL, non-HDLC could be a secondary target, whereas for patients with triglyceride levels greater than 500 mg per dL, triglycerides should be lowered and then LDLC should be treated until the patient reaches the goal value, with non-HDLC as a secondary target. Likewise, the guidelines from the European Atherosclerosis Society[21,22] indicated that non-HDLC may be substituted for LDLC in assessing risk in patients with elevated triglycerides, especially when associated with diabetes mellitus, kidney disease, or metabolic syndrome.