(p. 30) Lipids and cardiovascular disease 

Atherosclerotic plaques were noted to contain waxy deposits (cholesterol) by Fallopius in 1575 and in 1914 Anitschkow showed that cholesterol feeding led to atherosclerosis in a rabbit. The results of early lipid- lowering trials such as the Coronary Drug Project (clofibrate; niacin; d-thyroxine and oestrogen), World Health Organization Clofibrate Trial, Lipid Research Clinics (cholestyramine), and Programme on Surgical Correction of Hyperlipidaemia (ileal bypass surgery) were unclear, with some therapies showing no benefit (d-thyroxine and oestrogen) and the rest giving reductions in cardiovascular disease (CVD) events but not total mortality within the trial period. In some cases, for instance with clofibrate, mortality increased. Later trials (e.g. Helsinki Heart Study) failed to clarify the situation. A cholesterol controversy arose stating that cholesterol reduction might reduce CVD but increase other causes of mortality. The identity of the LDL-receptor was clarified and a class of drugs designed to block the rate-limiting step in cholesterol synthesis (2-hydroxy-methyl-glutaryl (HMG)-CoA reductase inhibitors) and increase LDL clearance was discovered. It remained to determine what their effects were in clinical practice.

A landmark paper in this field should fundamentally influence medical practice by setting a new paradigm for diagnosis, treatment, or by defining audit standards for the effectiveness of diagnosis or treatment so that improvements in care can be introduced and managed equitably.