ABSTRACT
The introduction of statin therapy into clinical practice has revolutionized the management of lipid disorders and, at a stroke, silenced the critics of cholesterol management as a means to vascular disease prevention. Yamamoto et al.1 and Mabuchi et al.2 were the first to take their courage in both hands and apply Endo’s discovery (see Chapter 3) of the progenitor statin, compactin, to hypercholesterolaemic men. Their initiative paved the way for a raft of clinical trials (see Chapters 7 and 8) which tied statin therapy to virtually guaranteed lipid-lowering efficacy with a negligible side-effect profile. Contrary to the jaundiced expectations of some, there was no increased risk of cancer or of the likelihood of dying of accidental, suicidal or violent death. On the contrary, statins were the first lipid-lowering agents which, within the framework of a clinical trial, actually extended life by mechanisms which probably go beyond cholesterol reduction alone and which favourably affect blood flow through all major arterial conduits, including the coronary, cerebral and peripheral vessels. In fact the benefits of statins are so impressive that some enthusiasts have been emboldened to write that they ‘are to atherosclerosis what penicillin was to infectious disease’3 Taking that analogy one step further might lead us to wonder whether statins represent the pinnacle of our needs as far as cholesterol lowering is concerned. If antibiotics have taught us anything it must surely be that nature is not as easily tamed as we might imagine. But, does atherosclerosis share the pleiotropic features that characterize infections? Advances in experimental pathology suggest that it may do4 and some have implied from these findings that cholesterol lowering with statin therapy might not be the whole answer to atherosclerosis and vascular disease prevention, arguing that if it were, coronary events would have been eliminated in the published trials rather than ‘merely’ reduced by 30-50%. The flaw in this logic is of course that no clinical trial can truly reflect the multifaceted biology of real life and to eliminate a disease which crucially depends on the insidious tissue accumulation of cholesterol over a lifetime would probably require action over a longer timespan than is dictated by the exigencies of trial design. However, there is another more cogent reason why we should gain comfort from continuing lipid-lowering drug development. The primary pharmacological action of statins (see Chapter 4) is to promote the physiological clearance of low-density lipoprotein (LDL) from the circulation via its specific high-affinity receptor located particularly on hepatocyte membranes. However, the practising cardiologist will quickly point out that the majority of dyslipidaemic patients admitted to the coronary care unit usually exhibit raised plasma cholesterol and triglyceride levels rather than hypercholesterolaemia alone. This
combined hyperlipidaemia results from over-production of triglyceride-rich very lowdensity lipoprotein (VLDL) particles coupled with defective catabolism of LDL. While the statins were specifically designed to deal with the latter problem, their ability to lower plasma triglyceride levels is much more limited. Head-to-head comparisons of the statins show that, at best, they can be expected to lower triglyceride by no more than about 20%, their efficacy perhaps being greater at higher triglyceride values. In an attempt to address this issue, the pharmaceutical industry has embarked on a series of investigations aimed at limiting the hepatic elaboration and secretion of triglyceride-rich lipoproteins.
