By Duane Graveline, MD, MPH
On October 12th 2015, drug company Eli Lilly said it was halting a 12,000-patient study of its drug, evacetrapib, an oral cholesterol lowering medication.
In earlier studies, the treatment cut "bad" LDL cholesterol by 30 to 35 percent and doubled the levels of "good" HDL cholesterol. But the influence on cholesterol levels did not ultimately improve patients' health, dashing hopes for this approach to treating heart disease.
Merck's anacetrapib is now the only drug in this novel class, known as CETP inhibitors, that remains in late-stage trials and on the basis of lack of effectiveness of Lilly's product, I would say its chances for success are slim.
Not only is this new CETP inhibitor class of drug no better than statins they are not as good. And with the terrible side effect profile of statins the good they do is moderate to minimal at best making this a pharmaceutical write-off.
CETP (cholesteryl ester transfer protein) inhibitors suppress the process whereby HDL cholesterol is transferred to LDL and VLDL. This causes a drop in serum LDL and VLDL and a consequent rise in HDL.
This improvement in lipid profiles, it was believed, would be of great benefit in reducing the risk of cardiovascular disease. But so far, this has not happened. Lower LDL and higher HDL has been of no benefit to the patients in the clinical trials.
In 2006, trials of Pfizer’s CETP inhibitor, torcetrapib, were halted. Not only was no clicnical benefit observed, but patients taking torcetrapib along with atorvastatin (Lipitor) had a 60% higher rate of death compared to those taking atorvastatin alone. Hoffman - LaRoche’s CETP inhibitor, dalcetrapib, also raised HDL levels. But development of this drug was halted in 2012 "due to a lack of clinically meaningful efficacy."
From my perspective, as someone who has closely followed the statin era for over 15 years, drug companies have failed to accept that cholesterol is not the problem. This end product of the mevalonate pathway is one of our most important biochemicals, particularly with respect to brain function where it is mandatory for both the formation and function of our memory synapses.
Additionally, the mevalonate pathway is critical for the synthesis of coenzyme Q10 and dolichols, two other biochemicals also vital to cell function. So when statins are used the end result is not just inhibition of cholesterol alone but also coenzyme Q10 and dolichol as well which play a major role in the development of such adverse reactions as diabetes, myopathy and peripheral neuropathy.
The benefit of statin use on the process of atherosclerosis has nothing to do with cholesterol. It has to do with the inflammation underlying atherosclerosis mediated by a completely different pathway known as nuclear factor kappa B (NF-κB), an effect of statins discovered only a few years ago.
This intracellular transcriptase is carried in an inert form in all nucleated cells. When triggered by such things as statins, viruses, bacteria, various fungi and certain chemicals it is converted into the active form which passes into the nucleus of the cell where it exerts its effect on the inflammatory process by DNA change.
Suppression of inflammation is the mechanism by which statins help a few people who are heart attack and stroke prone. How modest and partial this effect is can be observed by reviewing the US Food and Drug administration’s (FDA) data. Despite being “proteceted” by statins, FDA\'s MedWatch reported 35,042 heart attacks and 13,713 strokes during the time period 1997-2012.
As long as pharmaceutical researchers remain dedicated to cholesterol causality, they will find only disappointment.
However, we have learned that the benefit of statins to inhibit atherosclerosis via the nuclear factor kappa B anti-inflammatory mechanism can be triggered by remarkably small doses of statins suggesting the possibility that a statin dose too small to block the mevalonate pathway might be sufficient to trigger this nuclear factor kappaB mechanism and indeed this appears to be the case.
We now have abundant evidence that a statin dose too small to inhibit one’s cholesterol is still sufficient for anti-inflammatory benefit. Thousands of high risk people intolerant to statins in the usual doses could be managed in this manner suggesting the dosing schedules we have used from the very beginning have been wrong. It is the blocking of the mevalonate pathway that has given all the trouble.
Duane Graveline MD MPH
Former USAF Flight Surgeon
Former NASA Astronaut
Retired Family Doctor