FDA Warns About Zocor And Muscle Damage

This is consistent with what I have been saying here and elsewhere for a long time.

Many lethal drug reactions are due to issues related to drug metabolites or drug metabolism, and can be exascerbated by drug interactions.

Increased risk for some of these reactions can be predicted by knowledge of drug metabolism and in some cases pharmacogenetics.

Knowledge of an individual's pharmacogenetics is not necessary for communicating risk information. Instead knowledge of the individual's ethnic background is often sufficient to indicate a higher probability of risk.

Companies and the FDA have known of this for years (in some cases nearly 20 years) and have been remiss in not including such information in labeling.

Companies often design their studies to avoid obtaining the appropriate information. This should preclude approval per the Food Drug and Cosmetics Act as it is a failure to perform 'reasonable studies' both in vivo and in vitro.

Failure to include such information in labeling in my opinion means the drug is misbranded.

Salmon

No reputable cardiologist that I know would prescribe 80 mg of simvastatin (approx. equivalent to 40 mg of atorvastatin). Anyone requiring that much cholesterol lowering should probaby be on a combination of simvastatin and ezitimibe. At least that's how my local cardiologists would approach it.

Vet - why not low dose statin and high dose niacin SR ? The "lipid hypothesis" has been largely discredited. Atherogenesis is more likely to be an inflammatory, oxidative, and hemorheologic/hemodynamic derangment. The statins have demonstrated a number of acute and subacute toxic effects and long-term pleiotropic toxicity. The toxicity is likely to be class-specific, not just drug-specific. In terms of efficacy, both zetia and vytorin fail to prevent plaque buildup. There is no need for new statins in the marketplace. Just one internist's (a generalist) opinion.

Where can a guy get some arugula around here? I haven't had arugula for eight weeks!

Todd

One of the problems, as Pharmavet's comments allude to, is that companies and the FDA frequently do not provide such information even when known until the issue is moot due to other reasons.

Salmon

This industry has gone to crap worse than I thought. In bringing attention this info to a Merck Rep, the reply with regard to in general all media articles (sans my own interpretation) was:

<>

Merck: Our Employees Care

F'ing waterheaded fraud.

That interpretation didn't copy and paste correctly above. Insert:

"I do not read them and have no interest in reading them."

The unemployment pool is filled with "interested" people while there are waterheads working half days and think that's the way it should be.

M. Black

Patrons, I would combine low dose statin and Niaspan if the patient had mixed dyslipidemia which many of these patients in fact do, especially combined with low HDL cholesterol. Based on the recent ACCORD data, I would favor a long-acting niacin over a fibrate. I'm not familiar with tolerability of OTC products, such as Slo-Niacin, but they sure are inexpensive.

I would also add that FDA needs to be aggressive on this one. I was working in the statin field during the Baycol disaster, where it took way too long to learn that there was really an unacceptably small window between the therapeutic dose and doses that caused rhabdomyolysis.

Lots of interesting stuff here--

--Think Salmon's opening comment right on target. I assume for the same reason, people of Asian descent are more likely to have problems with Plavix and a statin--the same CYP enzyme issue and slower metabolizing, I assume.

--re: dosing, _80_ mg. of Lipitor (which would be equivalent 160 of simva?) is being touted as by Pfizer and Pfriends as the way to go. Recent ACC presentation about it, but it's been around for a while. (A cardiologist recommended it to me. I passed.)

--re: Baycol, the evidence suggests Bayer knew early on that rhabdo was significantly more a problem than with other statins, and especially when combined with a fibrate. (Graham et. al study later suggested odds of rhabdo with that combo were something like 1 in 15 (!), as I recall).

It "took way too long," in significant part, because Bayer appears to have gone out of its way to delay reasonable appreciation of what it already had "very strong signals" about.

in above, should have been more specific. Most clearly relevant fibrate was "gemfib."

This is about high doses of statins, nothing new. This is a known effect with all statins at high dose, but not at the usual doses being prescribed.

To all, Please note that the warning as it relates to niacin is specific to Merck's investigational extended-release niacin and laropiprant combination product. It does NOT apply to Kos/Abbott's extended-release niacin products which have all been deemed safe and effective alone and in combination with statins, including simvastatin at doses up to 40mg (Niaspan, Advicor, and Simcor).

Patrons99

"The “lipid hypothesis” has been largely discredited. Atherogenesis is more likely to be an inflammatory, oxidative, and hemorheologic/hemodynamic derangment."

While I understand your thinking, the overwhelming evidence with statins, still shows LDL reduction to be the primary, evidenced based, marker for CV event reduction. All these proposed pleiotropic mechanisms look promising, but there is no human based, large scale studies that verify their impact and certainly no definite lab values that can be used to assure maximum benefit is being reached.

With statins, lower LDL gives better outcomes on CV events. That is not to say that there are side effects linked to higher dose statins.

doc - the "benefit" of statins that you describe in terms of an association between lower LDL and fewer CV events is far short of a showing of causality. Again, other mechanisms may be involved, e.g. inflammatory, oxidative, and hemorheologic. Furthermore, the "cost" of the statins in terms of adverse effects of LDL lowering is not typically being measured. Here are some links which may further the discussion:

An article titled, “Statin-Associated Memory Loss” and an article titled, “Cholesterol - Friend or Foe?” by Duane Graveline, M.D., M.P.H.

http://www.spacedoc.net/statin_associated_memory_loss.html

http://www.spacedoc.net/cholesterol_friend_or_foe.html

An article titled, “Cheerios Are a Drug? - Why Lower Cholesterol Anyway?” by Joel M. Kauffman, Ph.D.

http://www.spacedoc.net/cheerios_fda

doc and Patrons99,

I'm somewhat in the middle on the debate about lower LDL vs. other effects of statins relating to a CV benefit. While I'm not convinced that a given LDL level as a target makes sense (given the other unmeasured/ unmeasurable/nonspecific markers which may be at play), I am fairly convinced that unless the statin is taken with signficant regularity - adherence close to 80%, the "benefits" may not be apparent. (A former student did a great analysis on this question across several different medication categories - phenomenal work for a Master's thesis. I can cite the ref if anyone cares.) Since LDL reduction and adherence are correlated, I'm left wondering does the LDL reduction/benefit relationship actually relate to an adherence/benefit relationship which may be independent of actual degree of LDL lowering? In other words, is it possible that the "correct" primary outcome measure was the adherence rate to the med during the study, and not the LDL variable which was easily measured?

I am convinced that the only statins I would take (if I ever needed one) are simva, atora, and rosuva. I would not take ezetimibe which seems to offer no benefits other than making your lab values look pretty.

From what I've seen in the plans I've worked with (which required PAs for essentially anything but simva) - There has never been a great deal of use for simva 80mg. There really did not seem to be that many people whose physicians either thought that they needed a greater than 50% reduction in LDL from baseline, or who could not reach goal on simva (usually at a 40mg or lower dose). Or, maybe the docs just didn't want to have their nurses call for a PA (which only required less than 2 minutes on the phone, and possibly sending a fax of lab results - less time and effort than it takes to see a drug rep).

What we saw in one plan was a fair percentage of atorva 80mg users who were splitting pills in an effort to lower the patient copay (and shift more costs back to their self-insured drug plan). I wonder if some of the simva 80mg use may be due to pill-splitting too.

I don't expect that we will ever know the answer to my biggest question. That is: if one takes these medications for a period of time - say 2 years, then discontinues them, how long do the "benefits" on CV events last compared to patients who continue to take them?

I also wonder if anyone will publish a study relating to the effect of simva or atorva on CRP or other inflammatory markers. It seems to me that the makers of rosuva are looking to have it added to the water supply with the wording of their newest indication. I wonder this story got a little "help" from the team that does Crestor PR.

I won't comment on the desire to chemically manipulate HDL levels other than to continue to hold fast to the (archaic and unpopular)belief that the best treatment for "low HDL" is to get off the couch. Admittedly, easy for me to say as I'm in my mid 40s with essentially no risk for a CV event in the foreseeable future.

There is nothing unusual about rx'ing atora 80 mg. in secondary prevention. Many cardiologists now consider it "gold standard." There are a number of key studies, all of which are open to the usual questions re: comparators, length of time, etc. But it's not a rare rx.

M. Helm, MD - while neither of us is quite ready for a nursing home, the data seem clear that the lipid hypothesis fails completely in the elderly, and by inference, that the elderly should not be on a statin.

Dr Joel Kauffman's article (link above) cites some very interesting epidemiologic data as to lipid levels in men and women and all-cause mortality.

At the risk of straying slightly off-topic, perhaps all patients on statins should add daily CoQ10 and Vitamin D3 to their current medications, to mitigate statin toxicity. Telomere length appears to be related to ageing, HIV disease, Down syndrome, and cardiovascular disease. Higher Vitamin D3 levels appear to be associated with longer telomere length and better immune function.

See an article titled, “Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients” by Ahmed W, et al. in Translational Research 2009;153:11–16.

See a letter to the editor of JACC titled, “Coenzyme Q10 in Statin-Associated Myopathy” by Harvey Wolinsky on October 22, 2007.

http://content.onlinejacc.org/cgi/reprint/50/19/1911.pdf

See an article by Damjanovic AK, et al. titled “Accelerated telomere erosion is associated with a declining immune function of caregivers of Alzheimer's disease patients.” J Immunol. 2007 Sep 15. 179(6):4249-54. PMID: 17785865

See an article titled, “Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women” by J. Brent Richards, et al. on November 2007 issue of Am J. Clin Nutr. (Am J Clin Nutr. 2007 November; 86(5): 1420-1425).

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2196219/

See an article titled, “Telomere length, risk of coronary heart disease, and statin treatment in the West of Scotland Primary Prevention Study: a nested case-control study”, by Scott W. Brouilette, et al in The Lancet, Volume 369, Issue 9556, pages 107-114, on January 13, 2007.

http://www.thelancet.com/journals/lancet/article/PIIS0140-6736%2807%2960071-3/abstract

See an article titled, “Reduced telomerase activity in human T lymphocytes exposed to cortisol”, by Jenny Choi, et al in Brain Behav Immun. 2008 May; 22(4): 600-605. Doi:10.1016/j.bbi.2007.12.004.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2386249/pdf/nihms47250.pdf

On November 18, 2004, Dr. David Graham, associate director in the FDA’s Office of Drug Safety gave senate testimony that Crestor was one of five drugs with safety concerns. The drug causes muscle breakdown and renal failure. Now we hear the same warnings for Zocor.

The truth is that women don't benefit from Zocor, Crestor, Lipitor or any other statin drug for elevated cholesterol. There are no statin trials with even the slightest hint of a mortality benefit in women, and women should be told so.

In the elderly, a lower cholesterol level is associated wih higher mortality. This is demonstrated in many medical studies.

To read more: http://www.drdach.com/Cholesterol_Women_Dr_Dach.html

Jeffrey Dach MD

Dr Dach is probably correct. On the other hand, I point to a definitive study in men, which happens to be the landmark Lipid Research Clinics Coronary Primary Prevention Trial, published in JAMA in 1984. To me, the advantages of this trial were 1) large sample size, 2) sufficient length to show mortality benefit, 4) use of a single drug, whose only mechanism of action was to lower cholesterol, and 5) non-use of surrogate endpoints (e.g., IM wall thickness), which are of questionable predictive value anyway.

C:\Users\manowin\Documents\The Lipid Research Clinics Coronary Primary Prevention Trial Results I_ Reduction in Incidence of Coronary Heart Disease -- Lipid Research Clinics Program 251 (3) 351 -- JAMA.mht

http://jama.ama-assn.org/cgi/reprint/251/3/365

Reprinting link for first article:

http://jama.ama-assn.org/cgi/reprint/251/3/351

Patrons, you need to review the efficacy of statins in stroke prevention, which tends to be more prevalent in elderly with cornary disease.

http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020702s056lbl.pdf

http://www.neurologyreviews.com/aug06/statins.html

Vet - Thank you for the citation of the LR-CPPT JAMA article and the stroke prevention Neurology Reviews article. And thank you for helping us see the “big picture”. So, let’s talk briefly about the “big picture”.

Could the reduction of CHD incidence in the cholestyramine group have been mediated by a reduction in blood viscosity and zeta potential of blood? It seems to me that measuring serum lipid profiles is really just another use of a surrogate endpoint, and not a particularly good one at that. Again, these articles support an association, but fall far short of establishing a causal relationship. All-cause mortality, including stroke-related and cardiac-related deaths, and survival are the hard clinical endpoints which should be measured.

I agree with Dr Dach, “In the elderly, a lower cholesterol level is associated with higher mortality” and “There are no statin trials with even the slightest hint of a mortality benefit in women, and women should be told so.” The data suggest that women of any age and the elderly should not be on a statin.

See an article titled, “The red cell electrophoretic mobility in atherosclerotic and other individuals” by T.B. Begg, et al in the Journal of Atherosclerosis Research in 1966.

Journal of Atherosclerosis Research Volume 6, Issue 4, July-August 1966, Pages 303-312 doi:10.1016/S0368-1319(66)80042-X

See a book titled, “Blood viscosity, hyperviscosity & hyperviscosaemia” by Leopold Dintenfass in 1985.

http://books.google.com/books?id=b1h_dPnYJ48C&lpg=PR9&ots=yXMhHQBNvK&dq=%22zeta%20potential%22%20viscosity%20blood%20coronary%20heart%20disease&lr=&pg=PP1#v=onepage&q=%22zeta%20potential%22%20viscosity%20blood%20coronary%20heart%20disease&f=false

Least we fail to see the forest for all of the trees, I would encourage you to read an article titled “Cardiovascular Risks from Swine Flu Vaccines” by Dr Mae-Wan Ho of ISIS on 10/11/09.

http://www.i-sis.org.uk/CRSFV.php

As I stated recently, in another pharmalot thread, “This article could foretell a convergence between the hemorheologic-hemodynamic theory of atherogenesis and Andrew Moulden’s theory of microvascular ischemia, infarctions, and anoxia, as being the final common pathway of vaccine toxicity and many disease conditions.” Read “many disease conditions” to mean strokes, heart attacks, cancers, autoimmune diseases, and neurodegenerative conditions.

I must say, I'm impressed by the knowledge base of the physicians and scientists contributing to this discussion.

But the process question I have is, why aren't these outstanding uncertainties being explicitly resolved scientifically? If the statin business is a few billion a year or something, why are there not clinical trials at a few hundred million or something to resolve the ambiguity? For both clinical and economic reasons.

I don't know where the point of process failure is, but to have this conversation on a blog without a concomitant commitment by the key regulatory and clinical stakeholders to definitively resolve what works for which patient populations is incredulous.

And stupid... But that's just me talking.

Statins have been studied extensively fo over 25 years. There is a mountain of evidence that they are extremely valuable for prevention when used in the right patient population at the right doses. Yes, there are side effects, even toxicity at high doses for some of them, and drug-drug interactions. If docs are well-read and thoughtful, they will use prava and atorva in most patients, and avoid lova and simva. Rosuva should be reserved for those patients who can't achieve appropriate reductions with prava or atorva. Be smart!

Re: Dr. CV

Thanks. But you're talking Latin and I only read Greek. Or is this a Greek tragedy in a Latin translation?

Steve, I'll translate:

Rosuvastatin= Crestor Atorvastatin= Lipitor Simvasatatin=Zocor Pravastatin= Pravachol Lovastatin= Mevacor

No charge for the consult.

Re: pharmavet

Thanks.

So it is a Greek tragedy. Marketing obfuscation to maximize profit - some people die, some get better, and some get rich.

Only the ones who get rich are mostly indifferent to the ones who die or get better. As long as they get rich.

I appreciate the clarity...

same old, same old, fda are incompetent, drug companies corrupt, the US people suffer, the doctors, drug companies, fda employees, government employees benefit in cash (millions), while people die, who will stop this, obama ??????, i am not so sure- am not a republican:)

same old, same old critics and fear mongerers will always be exactly that So many on this blog selectively choose anecdotal or single studies by some unknown investigator to damn everything else for which there's tons of evidence.

Good to see that unconditional, close-minded critics and conspiracy-theorists have found a place to hang around together and feed each other's beliefs.

CV MD--Why do you put atorva and prava in a different category? More studies? Evidence of fewer AEs? I have the impression the former is true; had not heard the latter.

Or is it about interactions and solubility, and best two choices given those issues?

All on the LDL/statin debate, My thoughts were never to defend statins in all situations, I would advocate that for no drug or class.

Pleiotropic mechanisms may be important, but there are really no large scale prospective studies to show that positive link (especially which of the 20+ mechanisms people think are beneficial, really are) , there are however several large scale studies showing clear benefit of lower LDL with statins. 4S, PROVE-IT, WOSCOPS, etc. These were not powered to specifically look at elderly or women, but the outcomes are fairly impressive in terms of CV event reduction in regards to LDL reduction with statins.

Do statins have problems? Yes, as does ASA or any other medication, but have they been of benefit to many patients? Yes.

Interesting note, I know many MDs that give co-Q 10 with statins, but mainly because they think it will be of benefit.

A personalixed approach as extolled above by CV MD is the rational way to treat any patient.

Doc, I think we're on the same page here. Although cholestyramine (Questran, Colestipol) is a nasty drug to take, it's advantage is that it does not act by pleiotropic mechanisms, as do the statins. That is why I cited LRC-CPPT trial above in order to show a direct link between LDL-C lowering and reduced mortality from coronary heart disease using a non-pleiotropic drug.

JiM - IMO, combination of clear efficacy and cleanest safety, primarily based on absence of significant drug-drug interactions and lack of lipid solubility.

Thanks, CV. That's what I was guessing. atorva and prava are different in terms of lipid solubility, so you have those two options with best track record otherwise.

CV and Justice, I don't think many on this board understand the lipid solubility issue and how it relates to ubiquinones, potential for rhabdo, etc. Perhaps a lesson here would help.

Vet - how do you reconcile the LRC-CPPT study results with those of the WHO Clofibrate Study where "unlike the LRC-CPPT, this decline [in the overall incidence of major ischemic heart disease events] was confined to nonfatal myocardial infarction, whereas the incidence of fatal heart attack was similar in both treatment and control groups. Of concern in this study [the WHO Clofibrate Study] was the increased incidence in all-cause mortality in the clofibrate group, which became more significant during a four-year posttrial followup."

Also, see Table 4 - Other Cardiovascular Events, from the LRC-CPPT Study JAMA article, where there was apparently a 21% increased risk of definite or suspect atherothrombotic brain infarction.

Lastly, I wonder what effect, if any, clofibrate and cholestyramine treatment have on fat soluble vitamin levels, e.g. Vitamin D3 levels.

I have noticed a disturbing trend regarding drugs that seem to be pushed to market before the long-term effects can be fully discovered. I understand that this is more about the dosage amount than anything else but shouldn't care be taken by physician's and others to ensure that any serious side effects are discovered and addressed immediately. I just think that pharma companies are concerned about the bottom line and not the people involved.

Robert, the problem with statins and rhabdomyolysis is not that it is a long term effect but rather an extremely rare event in the first place. The incidence of fatal rhabdomyolysis associated with statin use is 0.15 cases/million prescriptions in the US. This means that 100 million scrips would have to be written to yield 15 fatal cases. Assuming 12 scrips/patient/year, this means that approximately 8.3 million patients would have to take a given statin for one year for those 15 cases to show up in the data. Even for the best crackerjack pharmacovigilance team that is still a very low incidence to try to detect.

http://www.medicine.ox.ac.uk/bandolier/booth/cardiac/statmusc.html

OII - You are looking at the rate for fatalities. Obviously the incidence of hospitalized cases of rhabdo would be substantially higher.

Laurie, the overwhelming majority of hospitalizations for rhabdomyolysis are not due to statin drugs. They are due to extreme exertion, wherein skeletal muscles break down and release myoglobin into the bloodstram. The myoglobin clogs up the kidneys leading to renal insufficiency and renal failure in fatal cases.

The most recent example was the case of 13 players from the University of Iowa who were hospitalized with nonfatal rhabdomyolysis after an extreme workout. Statin-associated rhabdomyolysis is more of a diagnosis of exclusion after the more common causes have been ruled out.

http://abcnews.go.com/Health/university-iowa-football-players-hospitalized-muscle-condition/story?id=12780810