The Success Story of LDL Cholesterol Lowering

Abstract

Abstract:We can look back at >100 years of cholesterol research that has brought medicine to a stage where people at risk of severe or fatal coronary heart disease have a much better prognosis than before. This progress has not come about without resistance. Perhaps one of the most debated topics in medicine, the cholesterol controversy, could only be brought to rest through the development of new clinical research methods that were capable of taking advantage of the amazing achievements in basic and pharmacological science after the second World War. It was only after understanding the biochemistry and physiology of cholesterol synthesis, transport and clearance from the blood that medicine could take advantage of drugs and diets to reduce the risk of atherosclerotic diseases. This review points to the highlights of the history of low-density lipoprotein-cholesterol lowering, with the discovery of the low-density lipoprotein receptor and its physiology and not only the development of statins as the stellar moments but also the development of clinical trial methodology as an effective tool to provide scientifically convincing evidence. (Circ Res. 2016;118:721-731.

Attenuation of Atherosclerosis by 3,4-Dihydroxy-Hydrocinnamic Acid in Rabbits by Partial Inhibition of ACAT

“…HMG-CoA reductase is best known for catalyzing a rate-limiting step in cholesterol biosynthesis and its inhibitors are the most effective class of drugs for lowering serum cholesterol concentrations [9]. A previous report showed that 3,4-DHHCA acts as inhibitor of HMG-CoA reductase in a rat model [19].…”

“…These atherosclerotic processes are controlled by two key enzymes that regulate cholesterol metabolism, 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase and acyl-CoA: cholesterol acyltransferase (ACAT) [8,9]. HMG-CoA reductase is the rate-controlling enzyme in cholesterol production.…”

“…Since inhibition of HMG-CoA reductase can decrease the plasma lipid level, statins such as atorvastatin, simvastatin, rosuvastatin, and lovastatin have been widely used as therapeutic agents for atherosclerosis [9,10]. ACAT is an intracellular enzyme that converts cholesterol to cholesteryl esters (CEs).…”

Therapeutic strategies for atherosclerosis and atherothrombosis: Past, present and future

“…This inspired Morrison to initiate the first clinical trial in 1946, resulting in initial evidence that a low cholesterol diet can protect against atherosclerosis-related mortality (7). In 1955, niacin (nicotinic acid) was found to be an effective agent to lower cholesterol (LDL), while at the same time increasing high-density lipoproteins (HDL) (8). Niacin remained a widely used drug, although its exact mechanism of action is still not well understood and its beneficial influence on lipid profiles not matched by effects on cardiovascular risk in clinical trials (9)(10)(11)(12)(13).…”

“…However, over the last years a debate has arisen around the increased risk of diabetes due to statin treatment, which has been shown to be 9 % in a meta-analysis (18). Until recently, statin treatment had remained unrivalled for lack of adequate alternatives (8). One notable exception was recently provided by the IM-PROVE-IT study, which showed that ezetimibe resulted in an additional 6.4 % reduction in major clinical outcome and 16 % LDL reduction on top of statins vs statins alone (19).…”