Angry Toxicologist

Cutting to chase for those of you who want a quick answer: we don’t know, there aren’t enough people to study yet. There are hints, though.

Ezetimibe is commonly used in combination with a statin as Vytorin to reduce heart disease in patients. It doesn’t work all that well. I should say, it decreases cholesterol fine but whether that leads to less overall heart disease isn’t conclusive (latest study released today says maybe a little). Of course that study found an increase in cancer in those taking the drug. However, another analysis released today found that cancer deaths were increased but cancer cases were decreased (both were on the verge of stastical significance). Based on that reverse finding alone, it seems that not much is happening here, or if there is, not much. Animal studies show nothing that would indicate a problem.

This seems like a bit of ho hum but think about what this means for drug approval for a second. This drug was approved in 2002. It’s 2008 and we don’t really know if it decreases death an disease. This is the problem with approving on surrogate markers – that’s where the FDA says “well, you don’t know if it reduces heart disease but you know it decreases cholesterol and those are known to be related so good enough”. Sadly, this is very common with many types of drugs. The problems with this approach are four-fold (at least):

One, there may be a diluted association. For instance, if there is a certain amount that arterial plaque has to be lowered to effect risk and the drug lowers cholesterol a little bit which in turn effects plaque, by the time you look at an overall effect, it may be tiny or insignificant. Even if it exists, it may be so small as to not outweigh the risks from taking the drug.

Two, the surrogate may not be a causal factor, it may be a good marker. Take markers for cancer such as PSA for prostate cancer. Generally as the PSA level goes up that means the cancer is getting worse. However, the marker isn’t causing the cancer. Therefore, a drug that lowers PSA isn’t necessarily curing the cancer, only lowering the marker. This is like putting a picture of a empty highway infront of a traffic camera and concluding that there is no traffic today.

Three, the more assocaitions you make the more likely you are wrong. This is similar to one but isn’t talking about the magnitude of the effect but the likely you are plain old wrong. If each association has a uncertainty of 5% or so and you are using a couple of links, the possibility that the drug has nothing to do with the disease increases dramatically.

Four, if you don’t do a large study to figure out if it works, then you find out less about the toxicity; cancer for one among many.

On the other hand, if you do a big ol’ study, it takes longer to get the drug to market. I say FDA shouldn’t use surrogates unless there either aren’t any treatments available at all, or the new drug show a drastic improvement above the existing treatment. Of course, if the later is true, the study wouldn’t take as long so it could probably be limited to the former exemption.

Starting to wonder under what ‘good enough’ method the drugs you take got approved? So am I…

Comments

  1. #1 Ahcuah
    September 2, 2008

    This is a subject near and dear to my heart (pun intended).

    Without treatment, my cholesterol level is around 300mg/dL. Lipitor lowers that to around 260, but I may have had some muscle pain related to the Lipitor.

    On the other hand, every three years, I get one of those heart x-rays that looks for plaque. Result: no plaque at all. My doctor says she’s never seen that in a man my age (and just once in a woman). So, somehow, I’ve had ridiculously high cholesterol for a long time without any plaque build-up (I’m not complaining).

    Adding Zetia to the mix lowers the level down to 160. But, as you point out, at what cost, and what is really going on?

  2. #2 Anna
    September 2, 2008

    Statins are simply bads news. I’ve got gobs of family members on them who shouldn’t be (especially the women, for which there is no evidence of benefit). I also prefer the EBT coronary artery scans (worth every penny to pay for OOP if insurance doesn’t cover). I like the preventive approach outlined by Dr. Davis at the Heart Scan Blog (disclaimer: no affiliation or connections, other than as a reader). The heart disease industry is a giant moneymaker and is centered around treating the disease when it becomes acute adn life-threatening, rather than doing the *right* things to prevent CVD – eliminate wheat/grains & excessive starches and reduce all sugars (beware of so-called “natural” sugars) to minimum (to keep insulin levels low); reduce excessive omega 6 fatty acids (grains, grainfed animal products, industrial seed oils); consume natural fats from foods, including saturated fats – rich sources of important fat soluble vitamins; reduce/minimize highly unstable PUFAs (esp. industrial oils); reduce industrial foods (neary anything in a package/consume more foods that come in minimal packaging (foods our great-ancestors ate – that means home-prepared meals!); maintain strength and lean muscle tone with weight bearing exercise; and get enough Vitamin D3 through either prudent sun exposure and/or D3 supplements.

    My younger sister, in her early 30s, had extremely high cholesterol levels (500-600+ with “cholesterol rashes) after the birth of her final child. She was convinced to halt breastfeeding when her daughter was only 3 months old and go on statins. Her doctor didn’t investigate why a young woman’s cholesterol levels would suddenly go so whacky; he just Rx’d the drug du jour.

    I’m not a doctor, but after being diagnosed with hypothyroidism two years ago (but probably had it for a decade or more) and learning quite a bit about thyroid conditions, I have a strong suspicion that my sister’s high cholesterol levels were due to a post-partum flare-up of hypothyroidism, perhaps auto-immune Hashimoto’s (thyroid disorders are more common in women, more common during periods of hormonal change, and often have a strong family history). Hypothyroidism often raises cholesterol levels, too.

    The only thing that worries me about cholesterol is not having enough. Truly. Ok, I suppose I would worry if my LDL was the dangerous numerous, small dense (associated with grain and sugar consumption) kind instead of the large, fluffy kind (associated with low carb and saturated fat consumption). For those curious about this “contrary” view, check out Peter’s Hyperlipid blog for a some great interprations of the research (often very technically challenging for those of us with a minimal biochemisty base- but well worth the effort to slog through) – disclaimer: not connected, affiliated with Hyperlipid either, jsut a reader).

  3. #3 Phil Boncer
    September 4, 2008

    It is always a balancing act, a risk/benefit calculation (and necessarily almost always made with incomplete information).

    There is certainly a risk to approving a drug too soon, but there is also a risk and a cost to holding up one that might well be able to do some people some good.

    So you’re almost always essentially taking your best educated guess, from the data reasonably available, as to the likelihood of help vs. the likelihood of significant harm, knowing that sometimes you’ll guess wrong.

    Until we understand biology a hell of a lot better than we do now (mostly, I think, this will happen with the decoding of the proteome), that’s about the best we’ve got.

    Any drug will have significant biological effects; that’s why they are selected. And of course thos effects will be complex and interconnected, and certainly then there will be “side” effects beyond the desired one. This will probably never be avoidable.

    PhilB

  4. #4 Acai
    September 6, 2008

    arterial plaque has to be lowered to effect risk I doubt that it will help enough to reduce the cancers effect.

  5. #5 Anna
    September 7, 2008

    Most of the analysis I’ve seen on statins is that it takes treating about 100 men under the age of 65 *with diagnosed CVD/prior heart attacks) to prevent even one heart attack. There’s no data showing a benefit to men over the age of 65 or without prior history of heart disease.

    The stats aren’t readily available for women because the major statin studies have focussed on men. There’s little hard data to suggest that statins benefit women, who statistically seem to be protected from cancer and dementia with higher cholesterol levels.

    That’s a lot of treating with a very expensive, potentially debilitating drug with very, very little benefit, IMO, especially when one considers that statins are intended to be taken for the rest of one’s life if one can manage to tolerate/pay for them ( ka-ching! for Pfizer and Merck, etc.), the huge expense (to the person, to an insurance co, or to a govt program), and a massive amount of people putting up on with debilitating side effects while hoping they are the one lucky person (they nearly always aren’t informed enough to know the actual odds and think everyone who takes statins is protected from MI).

    Folks might think some muscle weakness (or memory loss or cancer) is a small price to pay for protection from a heart attack. Um, the heart is a muscle and it weakens on statins, too. Not good.

    Since statins block the enzymatic pathway also involved in the production of Co-Enzyme Q10 (very important), which is necessary for healthy heart muscle, the risk of heart failure is increased if one’s doctor fails to make sure the patient is also taking an adequate dose of Co-EQ-10 with their statin (many don’t even mention it).

    It’s ironic isn’t it, that attempting to avoid an MI might result in congestive heart failure instead? CHF is not a nice way to go, either.

    Then there’s the lack of benefit from all cause mortality with statins. Or a possibility of increased cancer risk.

  6. #6 NM
    September 21, 2008

    The analyses in the NEJM by Peto et al indicate that the observation in the earlier trial was due to chance.

    So, currently, it appears that there’s no solid evidence that vytorin causes cancer.

  7. #7 zay?flama
    December 7, 2008

    There is certainly a risk to approving a drug too soon, but there is also a risk and a cost to holding up one that might well be able to do some people some good.

  8. #8 Dan
    December 20, 2008

    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. However, ince 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 personís lifespan, if one is on any particular statin medication for their lipid management over another, others have conclusion. 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 perhaps at this time with the evidence that exists regarding statins.
    Abstract etiologies for those who choose to prescribe statin drugs on occasion for unindicated reasons , such as reducing CRP levels, or for Alzheimerís treatment, or anything else not involved with LDL reduction may 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, according to many.
    Statins as a particular class of drugs that seem to in fact 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 they also have the ability to stabilize coronary artery plaques, which prevents myocardial infarctions. Statins also decrease thrombus formation as well as modulate inflammatory responses (CRP). For those patients with dyslipidemia who are placed on a statin, the effects of that statin on reducing a patientís LDL level can be measured with the efficacy of the statin 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 presently.
    As stated previously, 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, comparatively speaking. 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 patientís bloodstream.

    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 patientís 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. What that ideal LDL level is may have yet to be empirically determined.
    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, regarding the high cholesterol issue.
    Dietary management should be the first consideration in regards to correcting lipid dysfunctions,

    Dan Abshear

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    January 3, 2009

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  10. #10 cetq
    January 15, 2009

    super Statins are simply bads news. I’ve got gobs of family members on them who shouldn’t be (especially the women, for which there is no evidence of benefit). I also prefer the EBT coronary artery scans (worth every penny to pay for OOP if insurance doesn’t cover). I like the preventive approach outlined by Dr. Davis at the Heart Scan Blog (disclaimer: no affiliation or connections, other than as a reader). The heart disease industry is a giant moneymaker and is centered around treating the disease when it becomes acute adn life-threatening, rather than doing the *right* things to prevent CVD – eliminate wheat/grains & excessive starches and reduce all sugars (beware of so-called “natural” sugars) to minimum (to keep insulin levels low); reduce excessive omega 6 fatty acids (grains, grainfed animal products, industrial seed oils); consume natural fats from foods, including saturated fats – rich sources of important fat soluble vitamins; reduce/minimize highly unstable PUFAs (esp. industrial oils); reduce industrial foods (neary anything in a package/consume more foods that come in minimal packaging (foods our great-ancestors ate – that means home-prepared meals!); maintain strength and lean muscle tone with weight bearing exercise; and get enough Vitamin D3 through either prudent sun exposure and/or D3 supplements.

    thanks

  11. #11 cet
    January 15, 2009

    Statins are simply bads news. I’ve got gobs of family members on them who shouldn’t be (especially the women, for which there is no evidence of benefit). I also prefer the EBT coronary artery scans (worth every penny to pay for OOP if insurance doesn’t cover). I like the preventive approach outlined by Dr. Davis at the Heart Scan Blog (disclaimer: no affiliation or connections, other than as a reader). The heart disease industry is a giant moneymaker and is centered around treating the disease when it becomes acute adn life-threatening, rather than doing the *right* things to prevent CVD – eliminate wheat/grains & excessive starches and reduce all sugars (beware of so-called “natural” sugars) to minimum (to keep insulin levels low); reduce excessive omega 6 fatty acids (grains, grainfed animal products, industrial seed oils); consume natural fats from foods, including saturated fats – evet super rich sources of important fat soluble vitamins; reduce/minimize highly unstable PUFAs (esp. industrial oils); reduce industrial foods (neary anything in a package/consume more foods that come in minimal packaging (foods our great-ancestors ate – that means home-prepared meals!); maintain strength and lean muscle tone with weight bearing exercise; and get enough Vitamin D3 through either prudent sun exposure and/or D3 supplements.

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    This seems like a bit of ho hum but think about what this means for drug approval for a second. This drug was approved in 2002. It’s 2008 and we don’t really know if it decreases death an disease. This is the problem with approving on surrogate markers – that’s where the FDA says “well, you don’t know if it reduces heart disease but you know it decreases cholesterol and those are known to be related so good enough”. Sadly, this is very common with many types of drugs. The problems with this approach are four-fold (at least):

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