By Duane Graveline, MD, MPH
The fact that statin drugs have multiple effects has only recently been recognized. First marketed as reductase inhibitors, statins are far more than that. It is no wonder doctors are confused about this class of drugs.
Twenty years ago when Merck first began to market Mevacor, we hailed them as giving us our first real tool for cholesterol reduction. After two decades of use of the earlier cholesterol lowering drugs, we welcomed these reductase inhibitors.
None of us really bothered to pick up our dusty biochemistry books and research just what reductase inhibition was all about. We were too busy treating sick people and had complete faith in the pharmaceutical industry to develop safe and effective medications without our personal intervention. I was not yet retired then and speak from 23 years of clinical experience. Only later did the consequences of our ignorance manifest themselves.
“These are reductase inhibitors,” the drug reps loudly proclaimed. “They block the synthesis of cholesterol.” After 30 years of brainwashing by the drug companies, food industry and our entire medical system about the evils of the cholesterol in whole milk, eggs and butter, we were ready for this major advance in treatment and so began the multi-billion dollar statin industry.
Skeptics like Paul Dudley White (who became President Eisenhower's personal physician after the president had suffered a heart attack), Uffe Ravnskov, author of The Cholesterol Myths and Kilmer McCully, author of The Homocysteine Revolution, were swept aside. We had no idea that these statins worked by blocking our vital mevalonate pathway.
That statins worked by reductase inhibition, we knew, but the fact that this reductase step lay at the very beginning of this mevalonate pathway was cunningly omitted by the drug companies. They did not say that statins would damage our mevalonate pathway, they just did not talk about it.
At least five critical metabolic functions in addition to cholesterol synthesis are carried in this pathway. When a statin reduces synthesis of cholesterol by 40%, it is, at the same time, reducing our synthesis of CoQ10, dolichols, selenoproteins, Rho, glutathione and normal phosphorylation by similar substantial amounts. This is the cause of the thousands of side effect reports. It has taken years to discover this—a simple bit of biochemical detective work that drug company researchers and, no doubt, management knew from the beginning.
The beginning of reductase inibition was actually during the time period from 1973 to 1980 when four researchers, Michael Brown, Joseph Goldstein, Jerry Faust and Akira Endo, had already jointly discovered most of the control mechanisms at work in the mevalonate pathway. Their earliest work published in the Journal of Biological Chemistry, 1973, revealed that compactin, the first reductase inhibitor to be conceived, actually increased reductase.
Compactin, the first statin, is also known as mevastatin or ML236B. Later work demonstrated that this increased reductase could not be suppressed simply by adding cholesterol to cultured cells. Additional non-cholesterol biochemicals like CoQ10, dolichols and mevalonate had to be added to restore normal function.
It was Akira Endo who first coined the phrase “the cells must adapt or die” to describe this effect of compactin because cells need both cholesterol and non-cholesterol mevalonate-based products to grow and replicate. A logical interpretation of this excess reductase response to reductase inhibition, is that this enhancement of the reductase enzyme is an indicator of just how critical this biochemical stepping stone known as reductase actually is. The life of the cell is absolutely dependent upon it.
This reductase enhancement with the use of statins is a biological protective response to ensure the continued synthesis of these vital substances regardless of threats to the synthetic pathway. After 1985, for reasons unknown to me, these researchers will only report statin-associated runaway reductase as secondary to cellular deprivation of cholesterol, and say NOTHING of the non-cholesterol products that are contributing.
To document that Merck was well aware of the potential of their statin, Mevacor, to block the synthesis of other biochemicals on the mevalonate pathway, they filed for two patents in 1990 with the US Patent Office for the addition of CoQ10 to Mevacor. Merck said as justification for this, "for the reduction of the anticipated inflammation to come."
Their patents No. 4,929,437 and No. 4,933,165 were granted but never acted upon. CoQ10 was never added to Merck's statins and their knowledge of the potential side-effect of CoQ10 blockade and depletion was never included in any patient or physician information sheets.
In 2001, Julian Whitaker's petition to the U.S. Food and Drug Administration (FDA) for CoQ10 supplementation with statin use, was side-tracked due to lack of support from the College of Cardiology who at that time did not understand the mechanism of action of CoQ10 in modulating statin associated myopathy. So statins inevitably continued to impair the synthesis of CoQ10.
“But statins lower cholesterol,” was the response when challenged. Even many doctors joined this chorus. In other words, side effects are the price we pay for cholesterol reduction and relative freedom from premature cardiovascular death and debility. Sounds good, but then we learned from such men as Ora Shovman, author of “The anti-inflammatory and immunomodulatory effects of statins,” that statins work in heart attack prevention not by cholesterol reduction but by their powerful anti-inflammatory action. Atherosclerosis is an inflammatory response, he informed us. Cholesterol lowering is irrelevant.
Shovman also taught us that there were two major critical pathways of statin influence on atherogenesis—anti-atherosclerotic and anti-thrombotic. The evolution of an atherosclerotic lesion involves four cell types subject to manipulation by statin drugs: endothelial cells, smooth muscle cells, macrophages and lymphocytes. Following plaque disruption statins may influence thrombosis through platelet inhibition, coagulation factors and fibrinolysis.
Our minds were whirling. Abruptly we learned that statins have two major and unrelated effects: 1) the well-known reduction of cholesterol synthesis via mevalonate pathway inhibition, now known to be irrelevant and even harmful and 2) reduction of cardiovascular risk by multiple anti-inflammatory and immunomodulatory effects, mediated, in part, by the inhibition of a ubiquitous transcriptase known as nuclear factor-kB, common to our entire immuno-defense system.
This is what I call a two-edged sword. On one side of the blade, the anti-inflammatory side, we cut premature cardiovascular deaths in high risk males; on the other side, the cholesterol lowering side, we promote a terrible legacy of side effects and disability by the combined inhibition of cholesterol, CoQ10 and dolichols and other vital biochemicals.
So we are left with a class of drugs that cause both good and bad. There just might be a middle of the road course of action in that most of the side effects from statin drugs are based upon excess mevalonate blockade. This is largely a function of dosage used.
Because of the false fixation on the enemy cholesterol, doctors have been using cholesterol lowering dosages of statin from the very beginning. Yet, what benefit there is from statins comes from their anti-inflammatory role with nuclear factor-kB inhibition being a major mechanism of action.
Evidence exists that much lower doses are adequate for this novel, pleiotrophic effect of statins. It is time to study this yet to be proven option, then once and for all prove or disprove the need for statins to continue to be dosed at cholesterol lowering levels.
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor