DOI: 10.1097/MOL.0b013e32805dfb58

,  

,  

PMID: 17353674

Issn Print: 0957-9672

Publication Date: 2007/04/01


Print

Therapy and clinic trials

Shihong Chen; Alan Rees

+ Author Information

Author Information: Department of Endocrinology, Shandong University, Jinan, China

    loading  Checking for direct PDF access through Ovid

Excerpt

We live in an era when the results of late-breaking clinical trials involving statin therapy seem to be presented at each and every major international conference leading to regular revision of clinical guidelines and concomitant reduction in target low-density lipoprotein (LDL) cholesterol levels. Such is the bewildering pace of development, it is sometimes possible to lose a sense of historical perspective on how revolutionary the impact of the introduction of 3-hydroxy- 3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors into clinical practice was in the last decade of the 20th century. Whilst the prescience of Anitschkow in 1913 when he confidently stated ‘There can be no atheroma without cholesterol’ eventually led to the epidemiological studies (pioneered by the Framingham Project) which confirmed the predisposition of raised circulating LDL cholesterol levels to coronary heart disease, the need therefore for effective cholesterol lowering drugs had been apparent for many years. The conflation of basic science and clinical medicine that occurred profitably in the 1970s and 1980s was important to the development of the statins. Goldstein and Brown gained the Nobel Prize in 1985 ‘For their discoveries concerning the regulation of cholesterol metabolism’ and Akiro Endo, a Japanese clinical scientist employed by the Sankyo Pharmaceutical Company in Tokyo, identified a fungal metabolite capable of blocking cellular cholesterol production by partial inhibition of the rate-limiting HMG CoA reductase enzyme. This discovery in turn led Akira Yamamoto et al. and Hiroshi Mabuchi et al. to apply this discovery to the management of hypercholesterolaemia in humans.
The historical perspective is eloquently described in Jim Shepherd's review entitled ‘Who should receive a statin these days? Lessons from recent clinical trials’ [1••]. He outlines the progress of basic laboratory science to the clinical trial evidence which has led to the statins ‘being the most successful cardiovascular drugs of all times’. The review charts the initial use of statins in the prevention of coronary artery disease and to their subsequent use in the prevention of cerebrovascular disease as well as peripheral vascular disease. In other words, disease in all the major arterial trees. The Landmark Trials which underpin the evidence base for statin therapy are described as well as the two large meta-analysis of aggregate data – the Pravastatin Pooling Project and the Cholesterol Treatment Trialists Collaboration.
Lipoprotein metabolism is the result of a complex network of many individual components. In a thematic review on patient-orientated research, Parhofer and Barrett review ‘What we have learned about VLDL and LDL metabolism from human kinetics studies’ [2••]. The review focuses on apolipoprotein (Apo) B metabolism focusing on selected clinically relevant conditions. In hypo-β-lipoproteinaemia, the rate of secretion is closely linked to the length of the truncated ApoB molecule. Conversely, in patients designated to have the metabolic syndrome, it is the substrate in the form of free fatty acids coupled to the state of insulin resistance which determines the hypersecretion of VLDL ApoB. This review underpins the premise that human lipoprotein kinetic studies can provide insight into the factors that control the secretion and catabolism of ApoB-containing lipoproteins.
Finally, with the recent publication of the Stroke Prevention by Aggressive Reduction in Cholesterol Levels study proving the efficacy of statins in the prevention of atheromatous stroke, it is important to retain a sense of perspective as to the relative contribution of various risk factors for ischaemic stroke. Hankey [3•] reviews the relative contribution of various traditional and new risk factors to the development of ischaemic stroke.
    loading  Loading Related Articles