By David Pineles, MD
Peer Reviewed
With the implementation of the ACC/AHA guidelines on assessment of cardiovascular risk, HMG-CoA reductase inhibitors, commonly known as statins, will become one of the most prescribed medications in history [1]. Dr. John Ioadnnidis, in an article published in JAMA in February 2014, estimated that under the new guidelines approximately 1 billion people worldwide would qualify to be prescribed a statin [2]. With such a large number of individuals taking this medication, it begs the question: where did statins come from?
The story begins with famous German pathologist Rudolf Virchow. In the mid-19th century, Virchow discovered that cholesterol was found in the arterial walls of individuals that died from vaso-occlusive diseases such as myocardial infarction [3]. In 1913, Russian pathologist Nikolai Anitschkow, the first person to describe foam cells [4], in a brilliant study, demonstrated cholesterol’s role in the development of atherosclerosis. He showed that rabbits who were fed varying amounts of cholesterol developed early (fatty streaks) and advanced (atheromatous plaques) arterial lesions, similar to the atherosclerosis seen in humans [5]. However, despite these findings, physicians remained skeptical of a causal link between cholesterol and coronary artery disease (CAD) because most patients with CAD have plasma cholesterol levels not much different than the general population. They felt that atherosclerotic lesions were an incidental part of the degenerative changes of arteries [6].
This sentiment mostly continued until the Framingham Heart Study [7] and the Seven Country Studies [8] in the 1950’s demonstrated the correlation between high plasma cholesterol levels and CAD. Later investigations established that the association with CAD was attributable mainly to low-density lipoprotein (LDL) cholesterol, whereas high-density lipoprotein (HDL) cholesterol is inversely correlated with CHD (coronary heart disease) mortality. [9] From this, the “lipid hypothesis” was born, which proposed that elevated LDL cholesterol was causally related to coronary disease and that reducing it would reduce the risk of myocardial infarction and other coronary events.
Our story now takes us to 1970’s Tokyo, Japan. It was here that Dr. Akira Endo made a discovery that would change the face of cardiovascular medicine. During this period, the biosynthetic pathway of cholesterol production had already been elucidated. And several pharmaceutical companies had failed to find a chemical which would inhibit a crucial enzyme that controls the rate limiting step in the synthesis of cholesterol, HMG-CoA reductase. Dr. Endo, who was born on a farm in Northern Japan and was taught by his grandfather about the fungi that grew there, had a hypothesis [10]. Fungi use ergosterol rather than cholesterol for synthesis of their cell walls. Endo posited that perhaps a fungus exists which produces a chemical that inhibits HMG-CoA reductase, thereby depriving nearby bacteria of cholesterol without damaging its own cell wall. In August 1973, after testing 6,000 fungal broths, Endo discovered compactin (ML236B or mevastatin), an HMG-CoA reductase inhibitor, in the fermentation broth of the fungus Penicillium citrinum [11]. Animal trials [12] and later clinical trials [13] of compactin demonstrated good effect in lowering plasma cholesterol levels.
Then, in 1978, Alberts, Chen and others at Merck discovered a potent inhibitor of HMG-CoA reductase in a fermentation broth of Aspergillus terreus and named this compound mevinolin (later named lovastatin) [14]. Following numerous animal studies and clinical trials in the 1980’s, lovastatin demonstrated great promise in dramatically lowering LDL cholesterol without adverse effects [15]. Subsequently, lovastatin gained FDA approval in August 1987.
Although the main mechanism of statins to inhibit HMG-CoA reductase was understood, it was not until the work of Drs. Brown and Goldstein in the 1970’s that allowed us to fully comprehend how this class of medication lowers cholesterol. Working with tissue samples from people afflicted with familial hypercholesterolemia, Brown and Goldstein elucidated the cell-surface LDL receptor and demonstrated that inhibition of HMG-CoA reductase stimulates the upregulation of hepatic LDL receptors via downstream intracellular pathways thereby lowering the concentration of plasma LDL cholesterol [16]. In fact, this breakthrough was so monumental that Brown and Goldstein were awarded the Nobel Prize in Medicine in 1985.
Despite the proven success of these novel lipid-lowering agents, the adoption of statins into medical practice was initially slow in the late 1980’s and early 1990’s. Opponents to statins challenged that 1) the clinical trials were mainly limited to middle-aged men and generalization to women and the elderly was questionable, and 2) the trials to date indicated that although coronary heart disease events were reduced, survival had not been shown to improve [9]. This sentiment would change in April 1994, when the results of the Scandinavian Simvastatin Survival Study were published. In this landmark double-blinded, randomized, multi-center study, 4,444 patients with coronary heart disease were randomized to receive either simvastatin or placebo and followed for five years. The authors demonstrated an astonishing 30% reduction in all-cause mortality with simvastatin treatment [17].
Following the proven success and safety of statins, pharmaceutical companies began to take note. The next statin variant to hit the market was simvastatin (a semisynthetic derivative of lovastatin) in 1988, which differs from lovastatin by an additional methyl group side chain [18]. Then came pravastatin (derived from compactin by biotransformation) in 1991, fluvastatin (synthetic) in 1994, atorvastatin (synthetic) in 1997, and rosuvastatin (synthetic) in 2003 [9]. The development of statin variants was not without hiccups though. In August 2001, Cerivastatin (introduced in 1998) was withdrawn from the market due to reports of fatal rhabdomyolysis. Of the large number of reported cases of rhabdomyolysis in patients taking cerivastatin, 50 were fatal [19]. It is still unclear why cerivastatin is so myotoxic.
Coronary artery disease remains one of the leading causes of death in the Western World [20]. As stated above, statins have been shown to lower plasma levels of cholesterol and decrease overall mortality related to coronary artery disease. Although statins have become a staple of physicians’ armamentarium in the fight against coronary artery disease, we must appreciate its humble beginnings with such individuals as Akira Endo. It is truly amazing how the hard work and diligence of the few can have such a positive impact on the lives of many.
Commentary by Muhamed Saric, MD, PhD Associate Professor, Department of Medicine, Clinical Director, Non-Invasive Cardiology NYU Langone Medical Center
In this article, the authors demonstrate that medical discoveries don’t just happen but result from a hard work of many scientists. Remembering their names gives a humanistic perspective to often abstract concepts. The article describes key points in our understanding of the role of cholesterol metabolism in the pathophysiology of atherosclerosis and subsequent developed of statin, the most important drugs in primary and secondary prophylaxis of atherosclerosis. Although the presence of cholesterol-laden plaques was known to the 19th century histopathologists, including Virchow and Anitschkow, the causal role of cholesterol blood levels was not elucidated until the post-World War II epidemiologic studies in the New England community of Framingham.
It then took decades to develop effective cholesterol-lowering agents in the form of statins. Thee biochemists play the key role in elucidating the cholesterol metabolism and the role of statins in inhibition of cholesterol synthesis: Akira Endo of Japan, and Michael Brown and Joseph Goldstein of the United States. Thanks to their work, numerous heart attacks, strokes and deaths have been prevented.
Dr. David Pineles is a Gastroenterology fellow at NYU Langone Health
Peer reviewed by Muhamed Saric, MD, Cardiologist, NYU Langone Health
Image courtesy of Wikimedia Commons
References
1. Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published online November 12, 2013]. Circulation. https://www.ahajournals.org/doi/abs/10.1161/01.cir.0000437741.48606.98
2. Ioannidis JA. More Than a Billion People Taking Statins? Potential Implications of the New Cardiovascular Guidelines. JAMA. 2014;311(5):463-464.
3. Virchow, Rudolf (1856). Gesammelte Abhandlungen zur wissenschaftlichen Medizin. Vierteljahrschrift für die praktische Heilkunde (Germany: Staatsdruckerei Frankfurt). Phlogose und Thrombose im Gefäßsystem.
4. Daniel Steinberg. In Celebration of the 100th Anniversary of the Lipid Hypothesis of Atherosclerosis. Journal of Lipid Research 54.11 (2013): 2946–2949. PMC. Web. 23 Dec. 2015.
5. Finking G, Hanke H. Nikolaj Nikolajewitsch Anitschkow (1885-1964) established the cholesterol-fed rabbit as a model for atherosclerosis research. Atherosclerosis. 1997;135(1):1-7.
6. Steinberg D, Gotto AM. Preventing coronary artery disease by lowering cholesterol levels: fifty years from bench to bedside. JAMA. 1999;282(21):2043-50. https://www.ncbi.nlm.nih.gov/pubmed/10591387
7. Dawber T, Gilcin F, et al. National Heart Institute, National Institutes of Health, Public Health Service, Federal Security Agency, Washington, D. C., Epidemiological Approaches to Heart Disease: The Framingham Study Presented at a Joint Session of the Epidemiology, Health Officers, Medical Care, and Statistics Sections of the American Public Health Association, at the Seventy-eighth Annual Meeting in St. Louis, Mo., November 3, 1950
8. Keys A, Taylor HL, Blackburn H, et al. Coronary Heart Disease among Minnesota Business and Professional Men Followed Fifteen Years. Circulation 28:381-95 (Sept 1963)
9. Tobert JA. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov. 2003;2(7):517-26. https://www.ncbi.nlm.nih.gov/pubmed/12815379
10. Peter Landers. How one scientist intrigued by molds found first statin. Wall Street Journal. January 9, 2006.
11. Endo A, Kuroda M, Tsujita Y. ML-236A, ML-236B, and ML-236C, new inhibitors of cholesterogenesis produced by Penicillium citrinium. J Antibiot. 1976;29(12):1346-8.
12. Tsujita, Y, Kuroda, M, Tanzawa, K, et al. Hypolipidemic effects in dogs of ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Atherosclerosis 32, 307–313 (1979).
13. Mabuchi, H. et al. Effect of an inhibitor of 3-hydroxy-3- methyglutaryl coenzyme A reductase on serum lipoproteins and ubiquinone-10-levels in patients with familial hypercholesterolemia. N Engl J Med. 305, 478–482 (1981).
14. Alberts AW, et al. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc. Natl Acad. Sci. 77, 3957–3961 (1980). https://www.ncbi.nlm.nih.gov/pubmed/6933445
15. Tobert JA, Bell GD, Birtwell J, et al. Cholesterol-Lowering Effect of Mevinolin, an Inhibitor of 3-Hydroxy-3-Methylglutaryl-Coenzyme a Reductase, in Healthy Volunteers. Journal of Clinical Investigation 69.4 (1982): 913–919.
16. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232(4746):34-47.
17. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet. 1994;344(8934):1383-9.
18. Valdir Cechinel-Filho. Plant bioactives and drug discovery: principles, practice, and perspectives. Hoboken, N.J.: John Wiley & Sons. 2012, p. 104.
19. Raine, JM Withdrawal of cerivastatin (Libobay) by Bayer PLC. (Department of Health, Medicines Control Agency, London, 2001).
20. Roger VL, Go AS, Lloyd-jones DM, et al. Heart disease and stroke statistics–2012 update: a report from the American Heart Association. Circulation. 2012;125(1):e2-e220.