The Lipid Hypothesis

The lipid hypothesis states that elevated plasma cholesterol, more specifically, LDL cholesterol, has a causal role in the development of coronary heart disease and other cardiovascular diseases. This hypothesis has been debated for over 150 years. Cholesterol was first discovered in bile and in the gallstones by Poulletier de la Salle in 1769 and rediscovered by Michel Eugene Chevreul in 1815. The latter coined the name “cholesterine” which was shown to be present in bilestones.

In 1856, Rudolf Virchow observed inflammatory changes associated with atherosclerotic plaque growth within the arterial wall. He termed this condition “endo-arteritis chronica deformans.” Around 1910, Adolf Windaus began his study of cholesterol and identified its presence in bile and other tissues. He showed that cholesterol increases during pregnancy and decreases during diseased states. Windaus was awarded the Nobel Prize in chemistry in 1928 for studies on this “constitutions of sterols and their connection with other substances appearing in nature.” The proposed structure of cholesterol described in 1928 by Heinrich Wieland, which had four ring structures, was subsequently shown to be wrong. The correct formula was published by Wieland and Bain in 1932. In the meantime, the Russian scientist Nikolai Anichkov showed that a high cholesterol diet was responsible for cholesterol in atherosclerotic lesions of arteries. The degree of atheromatous involvement was related to the amount of cholesterol uptake, published in 1913. Anichkov was also the first to describe the foam cell, a lipid macrophage in arterial tissue which he called cholesterinesterphagozyten.

In the 1920s a Frenchman Michel Macheboeuf first described lipoproteins as complexes between lipid and proteins circulating in blood. Konrad Bloch and Feodor Lynen received the Nobel Prize for the discovery of the synthetic pathway of cholesterol. In 1938, Carl Muller first observed the concomitant presence of xanthoma, hypercholesterolemia, and coronary artery disease. This was the first publication describing the linkage between plasma cholesterol levels in humans and cardiovascular disease. Muller was the first to identify familial hypercholesterolemia which was present in these families. It was marked by tendon xanthoma. It was also suggested that occurrence in heart disease in families should direct attention to this disorder. In 1959, HMG-CoA Reductase, which catalyzed the conversion of HMG CoA to mevalonic acid, was shown to be the rate limiting step in cholesterol biosynthesis. In 1949, John Gofman, a biophysicist working at the University of California, Berkeley, used ultracentrifugation separate plasma lipoproteins by floatation, based on their density. Gofman described the atherogenic potential of LDL particles and showed that in patients with familial hypercholesteremia, the cholesterol elevation was all in the LDL and IDL fractions. In the 1950s, Ancel Keys showed that cardiovascular mortality rates in populations around the world were linked to serum cholesterol levels and dietary patterns, including the proportion of calories consumed of saturated fat. Then the ongoing Framingham HEART study, initiated in 1948, identified major risk factors for coronary heart disease, mainly serum cholesterol (later shown to be LDL cholesterol), hypertension, and cigarette smoking. Later, the Framingham Study included diabetes as a risk factor and high levels of HDL cholesterol as protective.  Clinical trial evidence in support of the lipid hypothesis emerged in the 1970s, with the Lipid Research Clinic—Coronary Prevention Trial (LRC-CPPT). In 3,806 males with hypercholesterolemia, after 7.4 years, there was a 12.6% reduction in cholestyramine compared with the placebo group, resulting in a 19% reduction in coronary artery events.

A great advance was the discovery of the LDL receptor, which helped elucidate the mechanisms of cholesterol regulation, by Michael Brown, MD, and Joseph Goldstein, MD, in 1974. Another major turning point was the isolation of a competitive inhibitor of 3-hydroxy-3-methyl-glutaryl-COA reductase from the fungus Penicillium citrinum in 1976 by Akira Endo, PhD, who was working at the Sankyo Co. The substance, called compactin or mevastatin, was the first statin to be administered to humans and was a competitive inhibitor of HMG CoA reductase, the rate limiting step in cholesterol biosynthesis. Sankyo terminated its development in 1980 because of suspected adverse effects in dogs. However, Merck decided to pursue the development of another statin, and lovastatin was approved by the Food and Drug Administration on September 1, 1987. 

The advent of statins ushered in a new era of preventive cardiology, but the lipid hypothesis still faced considerable skepticism during this time, particularly from leading British cardiologists. An investigative reporter named Thomas Moore published a long article in the 1989 issue of The Atlantic titled, “The Cholesterol Myth” stating that lowering your cholesterol is next to impossible with diet, and often dangerous with drugs - and it won’t make you live any longer. We now know that each of these claims were wrong. According to Moore, there was a conspiracy which was masterminded by the “cholesterol mafia”, including Scott Grundy, MD, PhD, John LaRosa, MD, Robert Levy, MD, Daniel Steinberg, MD, PhD, and myself.

During the 1990s, clinical trials with statins, beginning with the 4S study with simvastatin, provided the evidence needed to confirm the lipid hypothesis and silence the skeptics. Numerous trials were held – showing statin efficacy in men, women, the elderly, and patients with diabetes. By 2012, the evidence base had accumulated to the extent that a meta-analysis, published by Cholesterol Treatment Trialists, published pool data from 170,000 participants in 12 randomized trials. This study showed that, for every 39 mg/dL reduction in LDL-C, the risk for major vascular events is reduced by one-fifth, with no apparent lower threshold beyond which LDL-C ceases to be beneficial. After years of controversy, the lipid hypothesis was confirmed, which brought a new challenge to medicine – putting the evidence to practice. The NLA has made incredible progress towards this challenge. The field of lipidology that lies ahead of us, building on advancements from previous studies as we continue to address the residual risk remaining after obtaining optimal LDL levels, is an exciting one.

Article By:

Antonio M. Gotto Jr., MD, DPhil, FNLA

President, National Lipid Association, 2019-2020

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