Aspirin and Diabetes – Good for the Heart?

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In my last post I set the stage for talking about aspirin in the context of diabetes. There is quite a lot to talk about. Let’s start with heart disease. People with diabetes are at a much greater risk of developing various forms of heart disease. This is the case for both type I and type II. One study, analyzing aspirin usage in a US diabetic population, estimated that approximately 14% of their study population had a heart attack, 11% had a stroke, and 8% experience angina. Over 70% of them had one or more risk factors elevating their relative risk from 2 to 4 times that of a non-diabetic person.  Since it has been known for some time that low dose aspirin decreases the risk of stroke, the ADA has been promoting its use for diabetic patients for a number of years. By low dose I mean really low dose. Think of an aspirin tablet. Bayer Aspirin, for example, is 300 mg. You might take as many as 3 tablets to get a decent response but you will probably take at least 1 tablet. If you were taking this drug on a low dose regimen you would cut the tablet in 4 and take a quarter tab per day. The mechanism by which low dose aspirin makes this happen is quite interesting and worth a paragraph or three.

Stroke is caused by blood clots which get stuck in capillaries and block the flow of nutrients to critical brain regions. The cell which initiates clotting is called the platelet. Platelets, for some reason, do not have nuclei. They are actually pinched off pieces of a larger cell called a megakaryocyte. Since they only live for about 10 days I guess they don’t need it but this lack of a nucleus does have some consequences. The nucleus is the place where DNA is found and, of course, DNA is the template for making new proteins. No DNA…no new proteins. The cell is stuck with what it had upon birth.

Aspirin is a member of a class of drugs called NonSteroidal AntiInflamatory Drugs (NSAIDs). It is unique among this class of drugs (which includes Advil and Aleve) in that it is the only one that binds covalently to its target. Things that bind covalently form new chemical bonds with their target so that they are permanently attached. Advil and other members of this family use electrical charge interactions to stick to their target but the interaction is quite temporary. Indeed most of the drugs that we take bind to their target in this temporary fashion. We use the fancy name: competitive antagonist to describe them. As long as the concentration of drug is reasonably high in a tissue, some of that drug will be bound to its target receptor and the receptor will stay inhibited. As the drug level falls due to metabolism or other things, the drug falls off of the receptor and the receptor becomes active again until your next dose. When aspirin binds to its target it does so permanently. Thus when aspirin levels fall in the tissue, the drug does NOT come off of the receptor. It stays bound until the receptor gets degraded.

Aspirin’s target is an enzyme called cyclooxygenase (COX). COX is instrumental in converting a component of the cell membrane (arachadonic acid) into inflammatory signaling molecules called prostaglandins. I have always found it fascinating that the cell “mines” the plasma membrane for resources just like we mine the surface of the earth. The plasma membrane (which acts like the “skin” of the cell – separating outside from inside) is made up of long carbon chains called fatty acids. Other enzymes harvest the fatty acid called arachadonic acid and send it to COX which then folds it into the appropriate shape and then sends it on its way to another set of enzymes that further process what has become an inflammatory signaling molecule. When aspirin binds to COX it shuts down the enzyme. Since prostaglandins are very short lived (we measure their lifespan in seconds) aspirin quickly causes a complete depletion of these signals. Platelets use prostaglandins as part of its complex machinery to initiate clotting. Now, if platelets had nuclei, they would simply make more COX thus requiring that we take a great deal of aspirin to keep them inhibited. However, because they lack nuclei, we only need to take a very small amount of aspirin to keep them in check. Since most other cells in the body have nuclei they will simply make more COX. In particular, I want to focus on the cells of the stomach. One of the chief adverse effects of chronic usage of these drugs is ulcers or general GI bleeding. Prostaglandins play an important role in balancing stomach acid production and so patients on chronic therapies often present with bleeding in the stomach or intestines. In the presence of low amounts of aspirin, the cells of the stomach can usually make enough extra COX to avoid this problem. Thus low dose aspirin therapy is a unique and safe way to keep this aspect of heart disease under control.

Given what I just said one would expect that all diabetes patients would be taking low dose aspirin. Surprisingly, this is not the case. In the study I mentioned above, only 20% of patients take low dose aspirin on a regular basis. This may not be a bad thing.

Given the genetic diversity of the human race it perhaps is not surprising that when it comes to preventing clotting, some folks are aspirin resistant. While this is not completely understood, when one looks at a diagram of all the ways in which a platelet can be activated it is pretty apparent that prostaglandin production is not the only way to activate these cells. One possibility is that in resistant folks, other signaling pathways are genetically dominant giving the platelet other avenues when the prostaglandin pathway is shut down. What is more surprising is that people with diabetes are more likely to develop GI bleeds and are also more likely to show some degree of aspirin resistance than the general population. As a matter of fact, we have known for more than 30 years that the blood of people with diabetes will clot much more readily in a laboratory test than blood from non-diabetic people. More recently, studies have shown that the rate of aspirin resistance is about 50% higher than in the non-diabetic population.

Diabetes is not the only condition associated with resistance to aspirin mediated clotting inhibition. It seems that obesity creates pretty much the same condition. Given the association between obesity and diabetes we can see that these risk factors are tightly linked. To what extent life style choice interacts with genetics, at present, is a matter of heated debate.

More recently the results of a couple of larger clinical trials have been published (click here for a review) which have called the benefits of aspirin for people with diabetes into question. Since the possibility of GI bleeds is increased along with the possibility of resistance, the risk/benefit ratio needs to be looked at carefully. People who already have problems with GI events when taking NSAIDs should be especially careful. The relative benefit has been estimated at 10 to 15% less chance of having a cardiac event if you are an at risk patient (that is if you have one or more risk factors for cardiovascular disease).

Perhaps this would be a good point to mention another way to lower the risk of cardiac disease. Exercise….

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