Triumph of the Heart: The Story of Statins (英語) ハードカバー – 2009/4/3
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Over 25 million people in the U.S. alone have benefited from statins―such drugs as Lipitor, Zocor, Crestor, Pravachol, and other cholesterol-lowering medicines―in preventing stroke, heart attack, and other forms of coronary heart disease. But how did these remarkable, life-saving drugs come into being? In Triumph of the Heart, Dr. Jie Jack Li, a medicinal chemist and expert on drug discovery, tells for the first time the fascinating story of statins. Drawn from interviews with many scientists involved in the discovery and development of these drugs, the book illuminates the human side of science by revealing the role played by persistence, luck, and sudden insight that characterize major discoveries. For scientists in the drug industry, health care professionals, students of medicine, and all those intrigued by the basic human drive to explore and discover, Triumph of the Heart offers a compelling view of one of the most important drug discoveries of our time.
This book offers valuable insights into the way a drug company goes about building a platform for a potential "blockbuster". (Lancet)
You do not need to be a chemist or scientist to understand this book. It is easy to read, engaging and educational. (Laura Strachan, Nursing Standard)
Negative ratings seem to have been motivated not by evaluation of the content of the book for what it proposes to be, but rather in response to an individual's adverse reaction to a particular statin (or, on a subject I choose to pass over, more general issues of the commentators with the idea of employment in / profit from healthcare-directed activities in this society). While the first of these motivations can lead us to sympathize, it should not be mistaken for the basis of a review about a book on the manner by which a class of molecules was discovered and developed.
That there have been therapeutic agents that were neither efficacious nor safe, but were nevertheless brought to the public will not be disputed. Absent actual corruption, that mistakes have been made in drug development will also not be disputed. Corrupt practices should be prosecuted, and incompetence should be exposed and corrected.
Even so, for each drug on market---whether heinous as those, or all but entirely safe and so therapeutically invaluable contributions: Health care consumers must realize that that there will always be some cases within a population where the efficacy of a prescribed medicine is not "normal" or the safety is unacceptable. This also cannot be disputed. Medical research is about behaviors (of drugs, pathogens, toxins, processes, etc.) <bold> in populations </bold> of organisms. The <ital> practice </ital> of medicine—and so each of our personal experiences with medicines and medical practitioners—is not a matter of populations, but of the behavior of the medicine in <bold> an individual, us or our loved one, within the population </bold>. Each of us are but one, and are almost certainly not one whose experience was considered in bringing the drug or other therapy forward. Even had we participated in the trial for the agent or device, our experience would have had to aggregate with other individual experiences to rise to a level for it, whether poor efficacy or adverse event, to become detectable and significant in the studies that brought the therapy forward. (This is the very nature of clinical trials, and why statisticians are their unsung heroes.)
If one does not accept the very nature of science in medical research (its statistical basis and the implications of the same), and the role of medical research in producing all medical agents, devices, and procedures, then one should simply not participate in use of any of these. Even when the process is entirely free from all corruption, it remains simply what it is, the practice of studying things on populations, to inform their use by individuals. Many, many academicians and professionals are devoted to improving the process, with regard to specific products, but also in general. But one cannot have it both ways---making use of therapies, but denying their very nature and inherent risks. Blanket condemnations of process, motivation, etc. based on individual stories of failed therapy (anecdotal information) help little in allowing us to arrive at the truth of the matter.
With regard to the matter of the statins in biomedical understanding and medical practice—this is a matter for cardiology and research experts.
I will cite but one recent review (Cochrane) to make clear that the negativism of other book reviewers appearing in response to Dr Li's book is not shared by the preponderance of experts. Writing in 2013, Fiona Taylor of the London School of Hygiene and Tropical Medicine, in "Statins For the Primary Prevention of Cardiovascular Disease" ([...]), states that "Reducing high blood cholesterol, a risk factor for cardiovascular disease (CVD)… in people with and without a past history of CVD is an important goal of pharmacotherapy. Statins are the first-choice agents. Previous reviews of the effects of statins have highlighted their benefits in people with CVD. The case for primary prevention was uncertain when the last version of this review was published… and in light of new data an update of this review is required… Authors' Conclusions: Reductions in all-cause mortality, major vascular events and revascularisations were found with no excess of adverse events among people without evidence of CVD treated with statins."
Does this make statins right for all, or for any one person? No, individual decisions are made by the ones involved, in consultation with the medical experts that they consult---not by Amazon books, or reviewers, or commentators. As the Mayo Clinic website notes, while statins have been "shown to be effective in lowering cholesterol, [and] may have other potential benefits" the site also notes that "doctors are far from knowing everything about statins" and the role of cholesterol, and the best way for clinicians to respond to individual cases. As that site and any should indicate, translating the population-based conclusions of research studies to the needs of the individual is a matter between each and their physicians.
This said, ON TO THE BOOK, which actually regards a discovery process---specifically, the process of modern, small-molecule pharmaceutical discovery. Dr Li chooses for his subject a wonderful and clearly successful case study, that of the development of biological understanding around the target processes against which the statins are directed, and then, specifically, and in historical and scientific detail, the discovery of this class of small molecule agents. (The phrase small-molecule is used here to differentiate this class of drugs from "biologics," for instance agents that are antibodies.) Li elaborates on this case study with his usual enthusiasm and quality of thought and production. That Li believes in the positive role of pharmaceutical agents such as these, and the process for discovering them, is clear; if one vociferously opposes this view, then there is likely no need for 220 pages of self-flagellation.
I for one am very happy for the energy that this author has shown in bringing this and other chemical subjects before a broader audience---he is one of very few that has made chemistry a component of popular science writing. I am sure he will be unaffected by stray one star comments, and am very happy for this as well. May he continue to find that energy for years to come. May readers evaluate material for what it proposes to be, and so for what it is worth, and not as an easy springboard for philosophical rejection of a mainstay of modern life based on personal experience.
It seems more likely that cholesterol is only harmful if modified (1-5), and although the total/HDL ratio appears to be one of the best predictors of cardiovascular outcomes (6-9), cholesterol markers tend to be poor predictors in the elderly (8,10-13). Furthermore, low cholesterol is often associated with higher mortality (14-34), or worse cause-specific outcomes (35,36). Of course, it does not mean that these associations are casual, as correlation does not imply causation.
In trials, hormones, sPLA2 inhibitors, fibrates, niacin, CETP inhibitors, and ezetimibe all fail to lower CV/CHD death and total mortality despite "improving" numerous lipid markers (37-41,85). There were also other trials using different treatments, but these were not supportive either (42), although some are misinterpreted to be. Many diet interventions have lowered cholesterol but failed to lower outcomes (43-50), whereas other trials have resulted in similar reductions in cholesterol (51-53) or none at all (54-56), but have looked far more promising. In fact, the two most successful dietary trials had no reduction in cholesterol at all (54-56).
All this data considered so far suggests that cholesterol levels are irrelevant. Do statins change this? The answer is no. Considering that statins possess a ton of pleiotropic effects (that seem to keep growing), it may be important to recognize that "cholesterol-lowering and statin therapy are different scientific entities" (57). Nevertheless, the evidence for statin use is not as strong as Dr. Li claims it to be:
There is controversy with regard to statin use in primary prevention, and many trials are of poor quality, resulting in uncertainty as to whether statins should be used this population (58), and the small reduction in mortality is likely due to bias (59). There is no credible evidence that statins benefit diabetics (60,61), intensive statin therapy in secondary prevention patients fails to lower CHD death and total mortality (62,63), the only non-truncated trial in hypertensive patients was a failure (64), statins have failed to lower CHD death, CV/cardiac death, and total mortality in kidney patients (65-68), failed to lower coronary events, CV/cardiac death, and total mortality in heart failure patients (69,70), failed to lower CV death and total mortality in aortic stenosis patients (71), and failed to lower CV/cardiac death and total mortality in stroke patients (72). The elderly should also be cautious since the only randomized trial done on the elderly found no effect on total mortality, thanks to an increase in cancer deaths (73).
It should also be taking into consideration that the lack of transparency is a major problem (74-78), and statin trials should be viewed with a skeptical eye, especially earlier trials (79).
A few other things should be mentioned. Both the PROVE-IT (80) and MIRACL trials (81) cited in the book were both driven by soft endpoints (more susceptible to bias), and the statins had no significant effects on heart attacks or mortality outcomes. Dr. Li cites the CARE trial as a Lipitor trial, but it was really a Pravachol trial (82). The book refers to cholesterol targets, but the recent ACC/AHA cholesterol guidelines focus more on overall risk rather than cholesterol levels (83), since there was never any credible evidence for targets (84).
In conclusion, statins are not by any means "wonder drugs", and look rather useless if all is taken into consideration. Whatever credibility the pharmaceutical industry had in the beginning is long gone, and many trials seem to be conducted for marketing purposes. Although the story of statins is interesting, I cannot recommend this book.
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