In a forthcoming study, online-published in Circulation December 15, 2008, we learn more about the potential effects of the differing mechanisms of action between statins (with a liver mechanism of action) and Zetia, or ezetimibe (with a gut mechanism of action). What we learn would suggest that one's actual LDL/HDL numbers may matter less than the way in which the cholesterol-lowering agent works -- that is, it may have "other effects" which are, as yet, not well-understood. And those "other effects" may actually be providing the bulk of the benefit historically-associated with those lower cholesterol numbers.
A good friend, and an expert -- will be along shortly, to give you more, but here is a snippet from Circulation:
. . . .By inhibiting 3-hydroxy-3- ethylglutaryl coenzyme A reductase, statins not only reduce cholesterol biosynthesis but also decrease the formation of isoprenoids, which are important for mediating signaling through the Rho-associated coiled-coil containing protein kinase (ROCK) pathway. Increased ROCK activity has been implicated in endothelial dysfunction and vascular inflammation. We hypothesize that ezetimibe [Zetia], which inhibits intestinal cholesterol absorption, may not exert similar cholesterol-independent or pleiotropic effects of statins and, when used with a lower dose of statin, have less effect on ROCK activity than a higher dose of statin. . . .
[The study's] results indicate that high-dose statin monotherapy exerts greater effects on ROCK activity and endothelial function, but not on C-reactive protein, than low-dose statin plus ezetimibe. These findings provide additional evidence of statin benefits beyond cholesterol lowering. . . .
Look for a much better analysis, over at Gooznews, shortly.
14 comments:
Condor,
Take a look at:
http://www.pharmalot.com/2008/12/us-should-lower-co-pays-to-save-money-study/#comment-384827
ISOPRENOIDS!
Right around the time of the finding of increased cancer in the Vytorin/Zetia study, FDA had a seminar by an outside oncologist from the University of Iowa on a short visit working at FDA on the role of ISOPRENOIDS in causing cancer.
Salmon
Condor,
You may want to search past comments and see if I mentioned isoprenoids and the cancer risk in the past. I think I may have.
Salmon
Found it. See:
http://shearlingsplowed.blogspot.com/2008/08/again-via-tip-from-pm-dod-to-share-data.html
Salmon
The person on minisabattical at FDA was Raymond Hohl, M.D. Ph.D.
C32-I GH
(319) 356-8110
raymond-hohl@uiowa.edu
Dept of Pharmacology Research Interests: Role of Isoprene Compounds in Cell Proliferation and Differentiation
It's strange that instead of being associated with the medical divisions at FDA he was on sabbatical with the Office of Translational Sciences where Bob Powell Fred's ex-VP from Pharmacia is deputy director and for whom it was just announced today that his group is looking at using computer simulations to approve things like the Vytorin/Zetia combination in the future.
See:
http://www.pharmalot.com/2008/12/drug-experiment-fda-eyes-simulated-studies/
Salmon
http://www.pharmalot.com/2008/12/bristol-myers-lays-off-more-employees/
Can S/P be far behind?
It isn't quantity it's the quality of the layoffs that's important. Say 5 or 6 people would really help a lot.
Lol, if you mean me, I'm more of a dilettante than an expert.
Marilyn not unless your real initials are FH or CC or ...
I've got to wonder about the original comment about layoffs though. What is this person trying to say? That SP will need to lay people off unless they hide the fact that the cancer issue with Vytorin/Zetia is a real concern.
This is as bad as some people saying that without preemption we have problems with overwarning, frivolous lawsuits, lack of new drug development, and layoffs. When there may be some real concerns. Seems like pure fearmongering to me.
To clarify:
S/P profits are down, probably going further down, stock is off~the Executive Team Management's policy has been to initiate a Productivity initiative i.e, downsizing.
Very similar to what BMS did last year and is now invoking~
So, with all the negativity around S/P-will they be next to add more to the unemployment roles?
And, yes-I agree-some significantly well placed restructuring at the EMT level would go a lot further than the large scale releases of the rank and file.
JMHO
To clarify:
S/P profits are down, probably going further down, stock is off~the Executive Team Management's policy has been to initiate a Productivity initiative i.e, downsizing.
Very similar to what BMS did last year and is now invoking~
So, with all the negativity around S/P-will they be next to add more to the unemployment roles?
And, yes-I agree-some significantly well placed restructuring at the EMT level would go a lot further than the large scale releases of the rank and file.
JMHO
JMHO thanks for the clarification.
In this light the original and FU comment seems reasonable to me. It's a shame that so many people have to be hurt by the people at the top. Both physically, psychologically, and economically.
In other news people may find the following thread on Pharmalot quite interesting.
http://www.pharmalot.com/2008/12/drug-experiment-fda-eyes-simulated-studies/
Facts Believed to be Associated With All Statin Medications:
Adverse events associated with the statin class of pharmaceuticals are thought to occur more often than they are reported- with high doses of statins prescribed to patients in particular. Since this class of drugs has existed for use for over 20 years, statins are considered safe and effective for enhancing the clearance of LDL noted to be elevated in the lipid profiles of patients.
Additionally, there is no reduction in cardiovascular morbidity or mortality, as well as an increase in a person’s lifespan, if one is on any particular statin medication for their lipid management. So caution should perhaps be considered if one chooses to prescribe such a drug for a patient if they are absent of dyslipidemia to a significant degree, or are under the belief that one statin medication provides a greater cardiovascular benefit over another. In other words, the health care provider should be assured that any statin therapy for their patients is considered reasonable and necessary if the LDL in their patients need to be reduced..
Abstract etiologies for those who prescribe statin drugs on occacsion , such as reducing CRP levels, or for Alzheimer’s treatment, or anything else not involved with LDL reduction is not appropriate prophylaxis at this point for any patient. All other benefits that appear to have favorable effects in such areas are speculative at this point, and require further research for disease states aside from dyslipidemia.
Several risk factors should determine if one is placed on statin therapy, and not just one particular reason. High LDL cholesterol is the apex of rationale for statin therapy, yet other risk factors of the patient should be examined and evaluated as well by their health care provider, perhaps- depending on the patient’s cardiovascular history to determine the appropriate dosage and strength of statin therapy for such patients as it relates to their present LDL level and the reduction that is needed.
Statins do decrease the risk of cardiovascular events significantly, it has been proven. This may be due to the fact that statins improve endothelial function as well as statins having the ability to stabilize coronary artery plaques, which prevents myocardial infarctions. Statins also decrease thrombus formation as well as modulate inflammatory responses. For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patient’s LDL level can be measured after about five weeks of therapy on a particular statin drug. Liver Function blood tests are recommended for those patients on continued statin therapy, and most are chronically taking statins for the rest of their lives to manage their lipid profile in regards to maintaining the suitable LDL level for a particular patient.
In regards to other uses of statins besides just LDL reduction, there is evidence to suggest that statins have other benefits besides lowering LDL, such as reducing inflammation (CRP) with patients on statin therapy, those patients with dementia or Parkinson's disease may benefit from statin medication, as well as those patients who may have certain types of cancer or even cataracts. Yet again, these other roles for statin therapy have only been minimally explored. Because of the limited evidence regarding additional benefits of statins, the drug should again be prescribed for those with dyslipidemia only at this time involving elevated LDL levels as detected in the patient’s bloodstream.
It appears those statins that are produced specifically by fermentation, such as Zocor and Pravachol, have less incidences of myopathy than the other synthetic statins that exist presently. This may possibly due to the fact that fermented statins are believed to be much more hydrophyllic, which may optimize safety for a patient on a statin medication. Regardless, the lower the dose, the better, with any pharmaceutical prescribed to a patient. All pharmaceuticals have side effects, or they would not be pharmaceuticals. Statin drugs are not an exception.
Yet overall, the existing cholesterol lowering recommendations or guidelines should be re-evaluated, as they may be over-exaggerated upon tacit suggestions from the makers of statins to those who create these current lipid lowering guidelines. This is notable if one chooses to compare these cholesterol guidelines with others in the past. The cholesterol guidelines that exist now are considered by many health care providers and experts to be rather unreasonable, unnecessary, and possibly detrimental to a patient’s health, according to others. Yet statins are beneficial medications for those many people that exist with elevated LDL levels that can cause cardiovascular events to occur because of this abnormality.
Finally, a focus on children and their lifestyles should be amplified so their arteries do not become those of one who is middle-aged, and this may prevent them from being candidates for statin therapy now and in the future.
Dietary management should be the first consideration in regards to correcting lipid dysfunctions,
Dan Abshear
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