Every once in a while some brave investigator charts a new course for modern medicine. For various reasons this one is not likely to become the new paradigm and supplant the reigning cholesterol theory of heart disease. But a recently published landmark paper posits a long overlooked hypothesis which gleans evidence from statin cholesterol-lowering drugs themselves. It convincingly points those health practitioners who embrace science over commercial gain in a direction away from cholesterol as a measure of arterial health.
11Leo R Zacharski MD, a medical and scientific board member of The Iron Disorders Institute, writes a seminal paper entitled “THE STATIN-IRON NEXUS: ANTI-INFLAMMATORY INTERVENTION FOR ARTERIAL DISEASE PREVENTION in the April issue of The American Journal of Public Health.
Even with all of the resounding evidence presented by Dr. Zacharski and colleagues, the cholesterol theory of heart disease is so ingrained it will be next to impossible to get an estimated 25 million statin drug users to cease their lipid-lowering medications. Without their statin pills they would feel like they are a sitting duck for a sudden mortal heart attack.
All is not well in statin drug land, however. A leading cardiologist now points out that there is a 1 in 200 risk of getting diabetes on a statin, while only two in 200 heart attacks, heart surgeries, or other types of heart problems are prevented.
Don’t anticipate abandonment of statin drugs
However, even with recent revelations that statin drugs increase the risk for diabetes by up to 20%, and the risk for muscle damage by 10% and are liver toxins that may also bring on mental confusion, physicians and pharmaceutical companies hold sway over a naïve patient population that craves a number to chart their success in maintaining healthy coronary arteries and reduction of the most feared event – a sudden mortal heart attack.
Harvard physician John Abramson, author of OVERDOSED AMERICA, has noted that the ten largest clinical trials of statin drugs did not significantly lower mortality rates among healthy individuals using statin drugs for prevention. If the revelation that statin drugs don’t reduce death rates hasn’t shaken Americans from using statin drugs, nothing else will. Even a false assurance calms imagined fears.
Statin drugs were never efficacious
The cholesterol theory of heart disease gained traction in the 1970s with the introduction of the first cholesterol-lowering statin drug, Mevacor. And even though Mevacor did not significantly reduce cholesterol to lower coronary artery disease mortality rates, the FDA never flinched in allowing it to remain on the market.
More powerful statin drugs were introduced, but they had to make sure they weren’t too liver toxic as they are designed to inhibit a key liver enzyme that is required to produce cholesterol. Even today, stronger statin drugs do not appreciably reduce death rates from heart disease among healthy individuals. But there is no turning back.
Whether cholesterol reduction is an intentional misdirection to maintain a certain level of disease for physicians to treat, or it is part of a covert population control agenda as some have imagined, even patent expiration of every statin drug will not likely cause modern medicine to abandon its central mantra – to reduce circulating levels of cholesterol.
Iron over fat
That’s enough throwing tomatoes at cholesterol drugs. What Dr. Zacharski postulates is the “rust” theory of heart disease. The idea was first aired by the late Dr. Jerome L. Sullivan III in 1981. Dr. Sullivan observed that young women who have low iron levels because of monthly menstrual blood losses simply didn’t have heart attacks.
Instead of measuring circulating cholesterol levels, Dr. Zacharski would have Americans chart their iron storage number – their ferritin levels. A healthy range would fall between 20-50 nanograms per milliliter of blood.
Statin drugs point to iron, not cholesterol
The scientific rationale that Dr. Zacharski presents is that statin drugs promote health unrelated to their proposed ability to reduce lipids (cholesterol). Indeed, statin drugs modestly reduce stored iron levels as measured by ferritin in patients with advanced cardiovascular disease, kidney disease and diabetes. Reduction of stored iron (ferritin) via blood donation(phlebotomy) has been shown to reduce all-cause mortality among patients with peripheral artery (lower leg) disease.
Dr. Zacharski shows that statin drug users have lower ferritin levels. Strikingly, whereas reduction of ferritin levels correlated with reduced mortality, an improvement in the HDL (good cholesterol) to LDL (bad cholesterol) ratio had no effect.
While statin drugs do reduce cholesterol synthesis by the liver and ferritin levels, these mechanisms were independent of each other. Iron reduction produces better outcomes (fewer heart attacks), regardless of statin drug use, “which suggests iron reduction rather than altered lipid status is the more powerful – or possibly the sole – contributor to improved outcomes,” says the Statin-Iron Nexus report.
Statin drugs also work in part by their demonstrated ability to activate an endogenous (internal) antioxidant known as heme oxygenase, an iron controlling enzyme also demonstrated by red wine and the red wine molecule resveratrol. The wine-drinking French exhibit a very low mortality rate for coronary artery disease (~90 per 100,000) compared to North Americans (~200 per 100,000).
Statins also inhibit hepcidin, a hormonal regulator of iron distribution. Hepcidin is also inhibited by iron chelation (key-lay-shun).
The statin/iron nexus
Dr. Zacharski notes that statins intersect with iron controlling interventions (example: blood-letting) or dietary iron control (example: Mediterranean diet) to inhibit buildup of arterial plaque whereas the provision of supplemental iron increases plaque.
Males benefit from reduction of iron stores more so than females because they have no physiological mechanism to control iron as do females via monthly menstruation. Peak iron storage levels are exhibited in males between the ages of 30-70 years, the age span when males benefit most from iron reduction.
Putting it into practice
Whereas statin drugs are costly, Dr. Zacharski suggests prospective trials be launched to demonstrate the ability of iron reduction in high-risk populations (diabetics, those individuals with existing heart disease) to reduce arterial disease and mortality “without the need for universal drug treatment.” The Mediterranean diet is given as a population-wide model and bloodletting as an intervention.
Donation of a unit of blood reduces iron load by about 250 milligrams compared against a few thousand excess milligrams of stored iron in middle-aged males. Repeated blood donation over time may be a clinical way of addressing iron excess without the need for drugs and their accompanying side effects.
It is not anticipated the phlebotomists will prevail over the pharmacologists in this matter (the pharmaceutical sector of the stock market would plunge with news statin drugs were about to be unseated as the most profitable selling class of prescription drugs of all time), and doctors would not be expected to diminish their status to embrace a technology that the ancients practiced, albeit bloodletting was performed prior to Hippocrates in the 5th century B.C.
It is worth noting that the first article in the inaugural issue of the New England Journal of Medicine and Surgery, in January 1812, was a treatise on treatment of angina pectoris (chest pain) via bloodletting by John Warren.
Maybe the science has come full circle, but modern medicine is ruled by commercial gain, not science. The invasion of commercialism in the practice of medicine was bemoaned over a decade ago. Pharmaceutical marketing has now become a pervasive practice in medicine that even conflict of interest laws may not abate.
Still, with the landmark paper on the Statin-Iron Nexus, Dr. Leo Zacharsky may have removed the practice of bloodletting from the Museum of Quackery.
Can you imagine a day when 25 million Americans line up for scheduled bloodletting sessions rather than taking daily statin pills? Some enterprising fellow opening up a chain of bloodletting outlets called Heme Health. That would be phleboto-mania. Back to reality.
Phlebotomy in a doctor’s office is said to cost $200-400. Bi-annual phlebotomy for 25 million statin drug users would cost ~$10-20 billion a year, compared to $26 billion a year for statin drugs. Thousands of lives would be saved as it is believed phlebotomy would reduce cardiac mortality and over-all mortality. The overall cost of medical care would plunge as diabetesand obesity rates would also predictably fall.
Indeed, high ferritin levels are associated with nearly a six-fold increase in the risk for an acute heart attack. That is a 600% increase compared to cholesterol reduction via a statin drug that reduces the risk for a non-mortal heart attack by a mere ~30%.
To the point, Dr. Zacharski and colleagues report that higher mean ferritin levels (132 nanograms per milliliter) were found among subjects with peripheral artery disease who died than those who didn’t (86 nanograms per milliliter). Iron control is truly a life and death issue. Cholesterol is not.
As a final comparison, cholesterol reduction may modestly, in 1 in 200 healthy subjects, reduce the risk for a non-mortal heart attack over a 5-year period (zero healthy adults are helped by being saved from a mortal heart attack taking statin drugs, and zero avoid sudden cardiac death even among subjects with acute heart problems). Looking at it this way, it appears cholesterol control via statin drugs is an inappropriate practice fraught with potential side effects that poses medical ethical problems. But statin drugs bring patients to doctors’ offices, the phlebotomy needle may chase them away.
None the less, Dr. Zacharsky has planted his flag. The scientific territory has been conquered.