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Statins, Early History problems such as animal side effects,

Animal studies are a very good indicator for potential side effects in humans:  Animal studies are such a good indicator and given the significant number of animal side effects, the FDA and other regulatory bodies were reluctant to approve these drugs for hypercholesterolemia. After 8 years of review they were approved for a very limited use for familial hypercholesterolemia. The drug doesn’t work for lower levels of cholesterol as to end points MI and deaths, though it lowers the level of cholesterol.  If it did the FDA wouldn’t have taken 8 years for approval.  (Today’s FDA is more PhARMA friendly thanks to Congressional legislation.) What happened once approved was a result of marketing science. 

The original studies are done on animals to find out if a drug is effective and safe.  These are PhARMA funded, they own the results, and as part of normal business do not published unfavorable results or simply delete those portions from the journal article.    Others, like this review are written by the manufacturer, in this case Merck.  The article mentions the side effects and then concludes that they don’t occur in “human therapeutic doses.”  A large body of evidence contradicts this rosy conclusion.  It is very disappointing that the top tier journal Nature published this article, which is a sales pitch for Lipitor, dressed up as a review of the research. (see the published summation below to dispel doubt)  For example the effects upon testosterone and CoQ10 are not mentioned—though there is significant literature on their suppression by Lipitor and other statins.  

There are some good animal studies.  Animal studies are inexpensive, thus a number of them of them are part of graduate work supervised by a professor, and are published. 


Taken from the entire article to point out 1). This is a in house Merck article selling their product etc.  Still there are some interesting sections.  TWO KEY POiNTS:  Approved for familial hypercholesterolemia and significant animal side effects. 


Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors

Lovastatin: a difficult beginning


Author affiliations

Merck Research Laboratories, Rahway, New Jersey 07065, USA.
Email: jonathan_tobert@merck.com

In April 1980, after animal safety studies had been performed, Merck began clinical trials of lovastatin in healthy volunteers. Lovastatin was shown to be dramatically effective for lowering LDL cholesterol in healthy volunteers, with no obvious adverse effects18, 19. However, this promising start was soon to be interrupted. Clinical trials with compactin had been proceeding, but for reasons that have never been made public (but which were believed to include serious animal toxicity) the trials were stopped by Sankyo in September 1980. Because of the close structural similarity between compactin and lovastatin, Merck promptly suspended clinical studies with lovastatin, and initiated additional animal safety studies. The future of the drug seemed extremely doubtful. However, in 1982 some small-scale clinical investigations in very high-risk patients resumed outside Merck. Bilheimer and Grundy in Dallas, Texas, and Illingworth in Portland, Oregon asked Merck for lovastatin to test its effect in selected small groups of patients with severe heterozygous FAMILIAL HYPERCHOLESTEROLAEMIA (FH) (Box 1) refractory to existing therapy. They observed dramatic reductions in LDL cholesterol20, 21 with very few adverse effects. Later, Thompson in London found that lovastatin considerably enhanced the hypolipidaemic effect of apheresis in patients with heterozygous FH22. 



Familial hypercholesterolaemia  [notice that Merck is using the surrogate lowering cholesterol instead of the endpoints prevent deaths and MI.]

After the additional animal safety studies with lovastatin revealed no toxicity of the type believed to be associated with compactin, Merck decided, in 1983, to re-initiate the clinical development programme, initially in patients at very high risk of myocardial infarction. Because of concerns about patient safety, this was a difficult decision, reached only after prolonged internal debate. Not withstanding the excellent tolerability to date in relatively small short-term studies, it was quite possible that more experience in a large number of patients treated chronically, as well as long-term animal toxicology studies, would yield a poor safety profile, including potential carcinogenicity. This would prohibit the development of lovastatin, or at best limit its use to a few ultra-high-risk patients — the 'ORPHAN DRUG' scenario.

In randomized, double-blind Phase IIb placebo-controlled studies started in 1984 (TIMELINE), lovastatin was as effective in patients with heterozygous FH23 and patients with CHD and non-familial hypercholesterolaemia24 as it had been in healthy volunteers19. These effects were confirmed in larger Phase III studies, in which lovastatin produced much greater reductions in LDL cholesterol than the control agents cholestyramine25 and probucol26, with very few adverse effects. The effects of lovastatin in the Phase IIb studies are shown in Fig. 2.

Effect of lovastatin by time and dose on plasma cholesterol in Phase IIb studies in patients with familial hypercholesterolaemia (FH), and high-risk hypercholesterolaemic patients without FH. Bid, twice daily; qpm, once daily in the evening.  Lovastatin produced a profound reduction of apolipoprotein-B-containing lipoproteins, especially LDL cholesterol and, to a lesser extent, plasma triglycerides, and a small increase in HDL cholesterol. Observed tolerability continued to be excellent, with very few patients withdrawing from treatment due to adverse effects. In November 1986, Merck applied for regulatory approval of lovastatin. In February 1987, a US FDA advisory panel fully considered the various safety issues arising out of the animal toxicology studies discussed below and the clinical results summarized above. The panel voted unanimously for the approval of the drug, and FDA approval was obtained on 31 August 1987 (TIMELINE). Lovastatin had patent protection only in certain other countries, all of which later granted approval.


SIDE EFFECTS ANIMALS:  Statins produce significant toxicity at high doses in a variety of animal species. These effects include increases in hepatic transaminases, atypical focal hyperplasia of the liver, squamous epithelial hyperplasia [ORGAN ENLARGEMENT] of the rat fore-stomach (an organ not present in man), cataracts, vascular lesions in the central nervous system (CNS), skeletal muscle toxicity, testicular degeneration and, although the statins are clearly not genotoxic, tumours of the liver and other sites (details can be found in the product circulars of the individual statins). It has been shown, where it has been practical to conduct the experiment, that these effects can be prevented by administering mevalonate 29,30, the product of the reaction catalysed by HMG-CoA reductase.  This indicates that these toxic effects are mostly, if not entirely, attributable to extreme inhibition of the enzyme at high doses 29.  So Merck, and the regulatory agencies considering the marketing application submitted by Merck, were faced with a wide range of animal toxicological effects, as well as the history of compactin and the known central role of the cholesterol biosynthesis pathway in many physiological processes, including the production of steroids and cell membranes.  [Since the toxicity of the very similar in structure compactin, whose toxicity in animal studies resulted from it not being tested clinically, that the same occurred for Lovastin, but Merck went forward. Compactin was withdrawn from the market for ]   Fortunately, except for rare cases of myopathy and marked but asymptomatic increases in hepatic transaminases, none of the adverse effects found in animals occur at human therapeutic doses.” Nature Reviews Drug Discovery 2, 517-526 (July 2003) | doi:10.1038/nrd1112

Author’s affiliations: A. Tolbert, Merck Research Laboratories, Rahway, New Jersey 07065, USA.


  • Studies in the 1950s and 1960s led to the formulation of the lipid hypothesis, which proposed that elevated low-density lipoprotein (LDL) cholesterol was causally related to coronary heart disease (CHD) and that reducing it would reduce the risk of myocardial infarction and other coronary events.
  • 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase, the rate-limiting enzyme in the cholesterol biosynthetic pathway, was an attractive target in the search for drugs to reduce plasma cholesterol concentrations.
  • Compactin and lovastatin, natural products with a powerful inhibitory effect on HMG-CoA reductase, were discovered in the 1970s, and taken into clinical development as potential drugs for lowering LDL cholesterol.
  • However, in 1980, trials with compactin were suspended for undisclosed reasons (rumoured to be related to serious animal toxicity). Because of the close structural similarity between compactin and lovastatin, clinical studies with lovastatin were also suspended, and additional animal safety studies initiated.
  • In 1982 some small-scale clinical investigations of lovastatin in very high-risk patients were undertaken, in which dramatic reductions in LDL cholesterol were observed, with very few adverse effects. After the additional animal safety studies with lovastatin revealed no toxicity of the type thought to be associated with compactin, clinical studies resumed.
  • Large-scale trials confirmed the effectiveness of lovastatin. Observed tolerability continued to be excellent, and lovastatin was approved by the US FDA in 1987.
  • Lovastatin at its maximal recommended dose of 80 mg daily produced a mean reduction in LDL cholesterol of 40%, a far greater reduction than could be obtained with any of the treatments available at the time. Equally important, the drug produced very few adverse effects, was easy for patients to take, and so was rapidly accepted by prescribers and patients. The only important adverse effect is myopathy/rhabdomyolysis. This is rare and occurs with all HMG-CoA reductase inhibitors.
  • Several other HMG-CoA reductase inhibitors, now widely known as statins, subsequently became available for prescription: simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin and rosuvastatin.
  • The mechanism of the reduction in LDL cholesterol by statins is now known not to be simply reduction in cholesterol biosynthesis. Induction of the LDL receptor is crucial to their effectiveness.
  • Although the basic lipid hypothesis had been validated by the late 1980s, the movement towards treating hypercholesterolaemia was questioned because overviews of trials of treatments from the pre-statin era suggested that although CHD events might be reduced, survival was not improved.
  • However, large-scale, long-term trials published during the last decade, such as the Scandinavian Simvastatin Survival Study (4S, 1994), The Long-Term Intervention With Pravastatin in Ischaemic Disease (LIPID, 1998) and the Heart Protection Study (HPS, 2002) with simvastatin, have now provided unequivocal evidence of a reduction in all-cause mortality.
  • In 2001, cerivastatin was withdrawn by its manufacturer due to an excessive risk of rhabdomyolysis.
  • In HPS the risk of serious cardiovascular events was reduced by simvastatin regardless of LDL-cholesterol level.

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