The clofibrate saga: a retrospective commentary

Abstract

IntroductionAfter many years of study clofibrate, the first of the fibrates, seemed in the 1960s, to be an effective means of lowering raised plasma cholesterol. It provided an opportunity for examining the key question of whether reduction of plasma cholesterol might lead to reduction in the incidence of coronary heart disease (CHD). While small secondary prevention trials looked promising, a large primary prevention trial (the WHO trial) carried out over 5.3 years on 15 745 men aged 30-59 years provided contradictory results with reduction in nonfatal myocardial infarction, less hypertension, no change in coronary mortality but an increase in non-cardiovascular mortality. Clofibrate also increased gall stone formation and the need for cholecystectomies. Clofibrate was not an appropriate drug to recommend for population control of CHD. It did, however, usher in other fibrates and foreshadowed successful statin trials.

Initial Evaluation of Fenofibrate for Efficacy in Aiding Smoking Abstinence

“…Clofibrate, the drug reducing nicotine reinforcement and related responses in animal models, noted earlier, 9 was removed from the US market due to adverse side effects. 30 Yet, other fibrates or PPAR-α agonists may still warrant testing for efficacy in smoking cessation. 10,31 In conclusion, because of the costs and time of medication development, the efficient use of resources requires that drugs unlikely to be clinically effective be so identified in Phase 2 testing as early as possible and dropped from further consideration.…”

Emerging Trends in Clinical Research With Implications for Population Health and Health Policy

“…Rose's preference for mass solutions and structural changes rather than pharmacotherapy was influenced by the risk‐benefit profile of the medications available at the time, particularly research demonstrating the adverse effects of the cholesterol‐lowering drug clofibrate . Clofibrate was one of the first cholesterol medications considered for mass prevention, but the World Health Organization's (WHO) landmark clofibrate trial demonstrated increased adverse events, especially a rise in noncardiac mortality . However, current therapies for cardiovascular prevention, such as statins, have more favorable risk‐benefit profiles and a relatively low cost.…”

Michael Francis Oliver

“…Oliver himself, writing 30 years later, conceded that the results had been "a great disappointment" and, in his words, set research into the cholesterol hypothesis back by more than 10 years. 3 Later research with statins showed very different results. Oliver changed his mind when the evidence changed, although it was not until the 1990s-when he was chairman of the data and safety monitoring committee of the landmark West of Scotland Coronary Prevention Study 4 -did he do what Fox described as a "U-turn."…”