Thursday, September 17, 2015

A Life on Drugs: We've Lost Sight of What's Important

We are at a place in our healthcare economy where a vast majority of American adults are on more than one chronic medications, with what seems like no hope of ever coming off of any of them. Of the more common kinds, HMG-CoA reductase inhibitors (statins) are high on that list, as are anti-hypertensives, anti-depressants and anti-anxiolytics, and many others. Frankly, we are not really taught about taking people off of these drugs in health care, since, more often than not, this isn't something we imagine taking place. Rather, once someone is put on a medication, the likely course of action is that the disease process will continue to progressively worsen, not improve to a point where they no longer need the support of the drug.

Now, I would gladly be one of the first people to stand up and tout the benefits of a well-studied pharmaceutical drug that has a proven track-record of eradicating some disease or another, particularly with respect to things like infectious microorganisms. The fact is, we need medicine like this. If we didn't have access to certain kinds - e.g. vaccines, antibiotics, etc. - or, if they were never invented, droves of people would still be dying of smallpox.

That said, I can think of many examples of prescription drugs which have either not been proven sufficiently well, prior to their institution, or simply have so many adverse events that the purported benefits of taking the drug may not outweigh the side effects. The example I feel most comfortable giving here, with respect to the latter, is of statins. It is my fervent belief that lifestyle diseases cannot be cured or well-treated with pharmaceuticals, but that environmental and lifestyle changes must be implemented intelligently and consistently if one is to hope to truly overcome it. If poor diet, awful sleep habits and sedentary behavior is the cause of someone's disease, I find it doubtful that pharmacological inhibition of the mevalonate pathway, as is the case with HMG-CoA reductase inhibitors, for instance, will be of much help, rather than addressing the fundamental concerns mentioned previously. (Other scenarios, such as certain genetic conditions that predispose to severe hyperlipidemia, like heterozygous familial hypercholesterolemia, may be quite a different story - although, it's worth pointing out that the causes of death in persons suffering from heterozygous-FH are multifactorial and amount to more than just "they've got too much cholesterol in their blood."[1]

Millions of people in the United States are currently taking statin drugs. One of the more popular varieties is atorvastatin. It has been postulated many times that, should someone suffer from what's called hyperlipidemia, or coronary artery disease (CAD), taking a statin, such as Lipitor, may serve to prolong their lifespan. But, I have to wonder, if this is truly the case, by how much? In other words, would it be worth it? Do the pros of taking the medication outweigh whatever cons exist?

It turns out this was studied by Ferket, et al., in 2012, in asymptomatic individuals with established, non-fatal coronary artery disease.[2] Here's what the authors had to say on the matter:

Two important caveats come to mind, for me:

1.) Their model estimated... "x." That doesn't mean someone else's model, predicated on different criteria, couldn't be made to estimate "y."

2.) It's also important to note that the study population they are referring to are people with stable disease and non-fatal atherosclerosis. These numbers might look a little different, should they have examined folks with unstable atherosclerotic disease. Possibly. But, again, I would wonder by how much.

Having prefaced with those two statements, I think this was an incredibly interesting study. All the more fascinating, because they seemed to have found a maximum lifespan increase in primary CVD prevention patients of roughly 0.7 years.

Let's assume that this result holds for a moment. Listed below are just a few of the well-documented adverse events associated with statin therapy, in the primary biomedical literature:

               - Short-term memory loss and cognitive impairment[3]
               - Worsened insulin resistance, or newly developed type 2 diabetes mellitus[4-5]
               - Severe muscle disease, including myositis and rhabdomyolysis[6-7]
               - Mitochondrial dysfunction[8]
               - Significant vascular calcification and arteriosclerosis[9]
               - Atherosclerosis and heart failure[10]

So, you tell me (because it may just be a thing of personal preference or philosophy); would it be worth it for you, to have just one more year of life, but to potentially suffer any one of a number of significant side effects in the process, or even develop other serious and debilitating diseases?

Moving along....

Years ago, there was yet another cholesterol-related drug in the clinical trial phases of testing, but was, it turned out, a miserable failure, because it was killing people.[11] Torcetrapib, a cholesteryl-ester transfer protein (CETP) inhibitor, was actually completely halted during the testing process, the clinical trials stopped in their tracks, because the deaths were piling up with a frequency that the FDA was uncomfortable with.

This led Tall and colleagues, among other researchers throughout the world, to question whether or not the cause of these deaths was the molecule in the drug, or the mechanism, itself.

In my opinion, all one must do to reach a conclusion here is to look at the aforementioned adverse events, when we inhibit cholesterol synthesis or mess with the mevalonate pathway, and it should be clear to us all: the problem seems to be with the evolutionarily conserved mechanisms we are messing with, not necessarily the molecules.

Now, in 2015, Big Pharma has its eye on another "big win" for preventing cardiovascular disease - still regarding cholesterol, mind you. Another mechanistic inhibitor, pharmacological PCSK9-inhibition. Where statins target synthesis, CETP-inhibitors attempt to block the transfer of cholesterol and triacylglycerols from lipoproteins to cells, PCSK9-inhibitors work to prevent certain strains of the enzyme proprotein convertase subtilisin/kexin type 9 (PCSK9), from downregulating or destroying LDL-receptors in the liver, which is the primary disposal site of excess LDL-particles from the blood.

What will the results of these experiments be, I wonder? It could be that this turns out to be a miracle drug for someone with advanced hyperlipoproteinemia. But, what, for example, do you suppose might happen to an otherwise healthy person when their overly eager health care provider prescribes the PCSK9-inhibitor as a first line of defense, in the primary prevention setting, not realizing that very low cholesterol is also quite dangerous. Hypocholesterolemia is associated with cognitive deficits, increased risks of cancer, and, most notably, a three-fold higher risk of hemorrhagic stroke. There is a reason that every single eukaryotic cell in the entire body synthesizes and requires cholesterol to some degree to exist healthfully.

Just today, I saw on Twitter a post from Nature Medicine regarding the membrane protein Nogo-B, which has recently been shown to have inhibitory effects on sphingolipid biosynthesis in murine models. How long do you suspect it will be before they've concocted a pharmaceutical drug designed to inhibit human sphingolipid biosynthesis, because of this new information? Whether that may turn out to be beneficial or harmful, I couldn't say. But that's not the point.

My point is that we've lost sight of what is most important in health care: quality of life. (In favor of "quantity of life.") In an attempt to halt one aspect of the progression of one disease, we have forsaken functional, positive health, well-being and quality of life, in the hopes for longevity, in the form of "delaying death."

This is not health. This is not what health care should be about. We can and should do better.


[1] Sijbrands, E. J., Westendorp, R. G., Lombardi, M. P., Havekes, L. M., Frants, R. R., Kastelein, J. J., & Smelt, A. H. (2000). Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia. Atherosclerosis, 149(2), 421-425.
[2] Ferket, B. S., van Kempen, B. J., Heeringa, J., Spronk, S., Fleischmann, K. E., Nijhuis, R. L., ... & Hunink, M. M. (2012). Personalized prediction of lifetime benefits with statin therapy for asymptomatic individuals: a modeling study.
[3] Galatti, L., Polimeni, G., Salvo, F., Romani, M., Sessa, A., & Spina, E. (2006). Short‐Term Memory Loss Associated with Rosuvastatin. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy, 26(8), 1190-1192.
[4] OHMURA, C., WATADA, H., HIROSE, T., TANAKA, Y., & KAWAMORI, R. (2005). Acute onset and worsening of diabetes concurrent with administration of statins. Endocrine journal, 52(3), 369-372.
[5] Koh, K. K., Quon, M. J., Han, S. H., Lee, Y., Kim, S. J., & Shin, E. K. (2010). Atorvastatin causes insulin resistance and increases ambient glycemia in hypercholesterolemic patients. Journal of the American College of Cardiology, 55(12), 1209-1216.
[6] McClure, D. L., Valuck, R. J., Glanz, M., & Hokanson, J. E. (2007). Systematic review and meta‐analysis of clinically relevant adverse events from HMG CoA reductase inhibitor trials worldwide from 1982 to present. Pharmacoepidemiology and drug safety, 16(2), 132-143.
[7] Manoukian, A. A., Bhagavan, N. V., Hayashi, T., Nestor, T. A., Rios, C., & Scottolini, A. G. (1990). Rhabdomyolysis secondary to lovastatin therapy. Clinical chemistry, 36(12), 2145-2147.
[8] Statin adverse effects: a review of the literature and evidence for a mitochondrial mechanism. Am J Cardiovasc Drugs. 2008; 8(6): 373-418. doi: 10.2165/0129784-200808060-00004.
[9] Auscher, S., Heinsen, L., Nieman, K., Vinther, K. H., Løgstrup, B., Møller, J. E., ... & Egstrup, K. (2015). Effects of intensive lipid-lowering therapy on coronary plaques composition in patients with acute myocardial infarction: assessment with serial coronary CT angiography. Atherosclerosis, 241(2), 579-587.
[10] Okuyama, H., Langsjoen, P. H., Hamazaki, T., Ogushi, Y., Hama, R., Kobayashi, T., & Uchino, H. (2015). Statins stimulate atherosclerosis and heart failure: pharmacological mechanisms. Expert review of clinical pharmacology, 8(2), 189-199.
[11] Tall, A. R., Yvan-Charvet, L., & Wang, N. (2007). The Failure of Torcetrapib Was it the Molecule or the Mechanism?. Arteriosclerosis, thrombosis, and vascular biology, 27(2), 257-260.

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