By Duane Graveline, M.D., M.P.H.
In 2003, Law and others reported in the British Medical Journal (BMJ) the remarkable effects of low dose statins on both LDL cholesterol and ischemic heart disease reduction (1).
One would have thought this comprehensive meta-analysis would have shaken the very foundation of the medical community with respect to dosing strategy of statin drugs, yet all that was heard was an inaudible "ho-hum" as if nothing had registered.
The authors of this study reported that reductions in LDL cholesterol ( in the 164 trials observed ) were 2.8 mmol/L ( 60% ) with rosuvastatin ( Crestor® ) 80 mg/day, compared with 1.8 mmol/L ( 40% ) with rosuvastatin 5 mg/day, all from pretreatment LDL cholesterol concentrations of 4.8 mmol/L. In my world, cholesterol reduction is of negligible importance but it was the effect of 5 mg Crestor on reduction of ischemic heart disease that caught my full attention.
In the 58 trials where the effect of statins on ischemic heart disease was studied, Law reported that for every LDL cholesterol reduction of 1.0 mmol/L, the risk of IHD ( Ischemic heart disease ) events was reduced by 11% in the first year of treatment, 24% in the second year, 33% in year three to five, and by 36% thereafter.
Law worded his report as if to suggest the reduction of LDL cholesterol was somehow causative of the IHD risk reduction, which it is not. He just as easily and far more accurately could have worded his report to read: The risks of IHD events were reduced substantially by the use of 5 mg of Crestor daily.
Law predicted that after several years a reduction of 1.8 mmol/L of LDL cholesterol would reduce IHD events by an estimated 61%, which, according to his data, is the same as saying that the dosage of 5 mg of Crestor would after several years reduce IHD events by an astounding 61%.
His results from the same 58 trials, corroborated by results from the nine cohort studies, showed that lowering LDL cholesterol decreases all strokes by 10% for a 1 mmol/L reduction and 17% for a 1.8 mmol/L reduction or that 5 mg Crestor decreases all strokes by a factor of 17%.
Why are high doses of statins being used, with their terrible legacy of side effects, when doses of one-sixteenth the amount can achieve 60% of the benefit and the highly desirable benefit of very few significant side effects?
Although the medical community may have ignored Law's BMJ paper, the results astounded me. I am very impressed that rosuvastatin 5 mg daily, one sixteenth the size of the 80 mg dose, can give 61% of the ischemic heart disease risk reduction and 17% of the stroke risk reduction.
I can think of no stronger case for the consideration of low dose statins by primary care physicians than this paper by Law. Obviously further studies were needed to define low dose response relationships, but this was an excellent start.
In 2002, Shovman had identified the pleiotropic effects of statins ( multiple effects independent of cholesterol reduction ) in a study titled Antiinflammatory and immunomodulatory properties of statins (2).
In my opinion, this is the crux of the matter and nuclear factor-kappaB (NF-κB) inhibition is felt to be the mechanism for the anti-inflammatory and immunomodulatory properties that somehow lead to benefit in cardiovascular disease control.
Some authors feel that inhibition of NF-κB is part of the consequence of reductase inhibition, placing NF-kB in the same context as CoQ10, dolichols and prenylation. Yet I can see no justification for this opinion in any of the studies I have reviewed thus far.
Barnes is the most commonly cited authority(3) but even he fails to demonstrate its link to statin drug use or more specifically to reductase inhibition. What then is the relationship between statin drug use and NF-κB?
Barnes describes NF-κB as "a ubiquitous transcription factor that, by regulating the expression of multiple inflammatory and immune genes, plays a critical role in host defense and in chronic inflammatory diseases."
Others describe NF-κB in much the same terms. Rather than be synthesized anew, as is true for members of the mevalonate pathway cascade, Barnes refers to NF-κB as "present in the cytoplasm of cells in an inactive form complexed to an inhibitory protein, IκB". He further adds that, "many extracellular stimuli, including viruses, oxidants, inflammatory cytokines and immune stimuli, activate NF-κB."
In light of this documentation of NF-κB's nature I submit that the inhibition of NF-κB by statin drugs is another pleitrophic property of statins independent of that of mevalonate inhibition.
Furthermore I add that it may be possible to provoke this property independently of mevalonate blockade effect. Doses of statins so small that they have no effect on reductase may be sufficient to trigger NF-κB inhibition.
Perhaps many of the anti-inflammatory and immunomodulatory properties of current statin dosing are masked by the adverse consequences of CoQ10, dolichol and prenylation inhibition? It will take only a few studies to establish this.
Hilgendorff already has demonstrated persistance of anti-inflammation with low doses of statins. In his 2003 paper titled, "Statins differ in their ability to block NF-κB activation in human blood monocytes"(4), Hilgendorff laid the concept for the low dose statin in his use of inflammation as a marker of statin effect.
Starting with extremely low concentrations of statin solutions, Hilgendorff found surprisingly robust anti-inflammation, as measured by NF-κB inhibition in human monocytes, even at the lowest dilution of statins and only minimal increases in effect as concentrations were increased.
Although Hilgendorff was primarily focused on the differing degrees of anti-inflammatory potency, his identification of at least 70 percent anti-inflammatory potency even at the weakest levels of statin strengths (0.001microM compared with his peak level of 5 microM ) impressed me greatly. He already had most of the effect at his very first dilution lending credence (but still not proof) to my low dose hypothesis.
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor
3. Barnes PJ. Nuclear Factor kappaB -molecules in focus. Internat J Biochem & CellBiol. 29(6); 867-70. June 1997
4. Hilgendorff A.and others. Statins differ little in their ability to block NF-κB activation in human blood monocytes. Internat J Clin and Therapeut 41(9); 397-401, 2003
Updated October 2011