April 28, 2015

Statins: Sugar-Coating the Truth






A priest, a rabbi, and a cardiologist walk into a bar.

No, that’s not it…

Why did the cholesterol cross the road?

Nope, that’s not it either…

Did you hear the one about statins and increased risk for type 2 diabetes?

YES! That’s the one I meant. Only, this isn’t a joke.

Statin drug use is now associated with an increased risk for developing type 2 diabetes. Is this just fearmongering headlines, or is there really something to it?
  

At some point, I will write another post (or two or three) about the myriad horrible effects of statin drugs. Today, I’d like to focus on one specific unintended consequence of our insanely misguided and biochemically ridiculous “war on cholesterol.” (It seems like most of my readership is already pretty familiar with how important cholesterol is to just about every single thing the body does. If you’re new here, I’m sorry that this news might shock and/or confuse you. Like I said, I’ll cover the nuts & bolts of it some other time. For now, suffice it to say that if you’ve found my blog because you’ve come to realize that everything we thought we knew about saturated fat, low calorie diets, and things like that, is completely backward, just know that the same is true for cholesterol. Bottom line: cholesterol is the single most misunderstood, maligned, and wrongfully accused nutrient in all of health science.)

Okay. Recently, a study came out that indicated a significant increase in the risk of developing type 2 diabetes among male statin users, ages 45-73. (Not just statistically significant, but clinically significant, meaning it actually matters in the real world, and not just to eggheads in labs looking for grant money to fund their next study.[Just kiddin', researchers. You know I love ya! My blog wouldn't exist without you.]) The first thing to know is that this shouldn’t surprise anyone. It’s kind of old news, actually. It’s been known for a few years now that this is a possibility. It’s not a huge possibility, but the association between statin drug treatment and developing T2D is strong enough that even the U.S. Food and Drug Administration (FDA) acknowledges that statins may result in elevated blood glucose and hemoglobin A1c. The highly respected Mayo Clinic (one of the premier medical institutions in the U.S., for those of you who’ve never heard of it) also lists “increased blood sugar or type 2 diabetes among the potential side-effects of statins. (Also: liver damage, muscle damage, digestive problems, and neurological side-effects, but move along! Nothing to see here! FFS…)

Now, before we get into why drugs that lower cholesterol might have an effect on blood sugar, let’s dissect the study a little further.

According to the authors, compared to subjects not taking statins, those receiving statin therapy had a 46% increased risk for type 2 diabetes during the 6-year follow-up, with the risk specified as dose-dependent for those taking simvastatin and atorvastatin. (Meaning, the higher the dose, the greater the risk for developing the dreaded diabeetus.) Among the men receiving statin treatment, insulin sensitivity was decreased by 24% and insulin secretion decreased by 12% compared to individuals not being treated with statins, with these effects also being dose-dependent for simvastatin and atorvastatin.

Out of a total of 8,749 subjects, 625 received new diagnoses of type 2 diabetes. Here's how it broke down:

Total subjects: 8,749
Total new T2D diagnoses after 6-yr follow up: 625

Subjects not taking statins: 6,607
Non-statin takers who developed diabetes: 386 (5.84%)

Total taking statins: 2,142
Statin-takers who developed diabetes: 239 (11.16%)

However, at baseline (that is, the start of the study) compared to subjects who did not receive diabetes diagnoses during the follow-up years, the group of people who became diabetic were older, more overweight, less physically active, had lower HDL levels, higher fasting blood glucose and HbA1c, higher triglycerides, worse response to an oral glucose tolerance test, and had a greater percentage of smokers. So these subjects were at greater risk for developing type 2 diabetes (or metabolic syndrome, or heart disease, or just plain dropping dead) regardless of whether they were taking a statin or not. This doesn’t negate a potential role for statins in contributing even further to the risk for diabetes, but I want to be intellectually honest here and point out that these subjects were already at a higher risk.

BUT: according to the researchers, even when they controlled for these factors—however it was they managed to do that—the subjects treated with statins still had a greater risk for developing diabetes. (Don’t ask me about controlling, and p-values, confidence intervals, and blah, blah, blah. I know only enough statistics to make me dangerous.)


Yes, Virginia, There Is a Connection


Now that I’ve done my due diligence, let’s see why there’s a correlation between statin use and risk for diabetes. Again, we’re trying to determine if there’s a plausible biochemical or physiological mechanism that might explain this. I refuse to participate in nonsense like, “Meat rots in the colon,” which has no scientific basis whatsoever. If I’m saying something damning about a pharmaceutical drug that tens of millions of people take every day (and which I rail against in my book), then I had darn well better back it up with some actual facts, right?  So here goes.

The link between statins and diabetes can be summed up in two words: prenylated proteins. If you have no idea what these things are, and you’ve never heard the term “prenylation,” you’re not alone. I can almost guarantee most doctors who prescribe statins on a daily basis have never heard this term, either. And that is a disaster, Here’s why:

“Statin” is a generic term for drugs that inhibit the enzyme HMG CoA reductase. HMG CoA reductase works its biochemical job very early on in a long, complex pathway called the mevalonate pathway. (You can see just how long and complex it is in this nifty diagram by Chris Masterjohn, PhD. All I can say is, when it comes to cholesterol, this dude knows his stuff.)

And here’s a diagram, with pertinent items circled for our learning convenience:

Image by Sav vas (Own work) [CC0], via Wikimedia Commons

First, look for “STATINS,” in the purple box toward the top left. Notice how high up in the pathway they exert their effects. Second, look for cholesterol, waaaay down at the bottom, circled in green. The key thing to understand about this is, statins don’t only block the production of cholesterol. They block production of everything else that’s supposed to get produced along the way, too.

Before we proceed to the diabetes connection, let’s look way down at the bottom again. You’ll see “ubiquinones” circled in yellow. I’m generalizing here, but think of “ubiquinones” as coenzyme Q10, which is an essential molecule involved in the mitochondrial electron transport chain. (As detailed in this post from the cancer series. Yeah…if you’re thinking that statins could maybe, just possibly also increase cancer risk, since they disrupt the synthesis of something required for healthy mitochondrial function, I can’t confirm for certain that you’re right, but let’s just say I’m giving you a virtual high-five. I swear, you can’t make this stuff up…)


The Statin-Diabetes Link


Now, let’s get back to diabetes and that weird “prenylated proteins” thing. Down toward the bottom of the mevalonate pathway diagram (again, the end of a pathway that statins disrupt much earlier), you will see three things circeled in red: farnesyl-PP, geranylgeranyl-PP, and prenylated proteins. You don’t need to understand exactly what these things are. For our purposes of learning the physiological mechanism by which statins might increase risk for diabetes, it’s enough to know that these compounds are required for glucose-stimulated secretion of insulin by the pancreatic beta-cells. Yes, the cells that secrete insulin need these prenylated proteins in order to function properly. Finally, we’re getting somewhere!

I managed to dig up some studies that establish a connection between farnesyl-PP, geranylgeranyl-PP, and “G proteins” that help beta-cells do their job. (From what I can understand of the studies, these “G proteins” are involved in getting the beta-cells to secrete insulin in response to rising blood glucose. Just like an insulin receptor, they have to be translocated (moved) from where they’re produced inside the cell, over to the cell membrane. And what triggers them to do this is the prenylation step, which requires farnesyl-PP and geranylgeranyl-PP. No prenylation --> no translocation of G proteins --> no secretion of insulin. (And in case anyone doesn’t see the final connection here: no secretion of insulin means blood glucose stays elevated for longer than it should, leading to chronic hyperglycemia, elevated hemoglobin A1c, and quite possibly an eventual diagnosis of type 2 diabetes. Nice, huh?)


Additional Important “Stuff”
(¡Muy Importante!)


Two more things:

This is Human Body 101.
Why does the average statin-shilling 

cardiologist have NO CLUE?
  1. What statin drugs do is block the endogenous synthesis of cholesterol. (That is, the cholesterol our bodies produce inside us.) They have no effect on the cholesterol we get from foods. So while somoene on a statin who eats a lot of cholesterol-rich foods might be able to overcome the laundry list of heinous side effects of statins that come about due to depletion of cholesterol, they can not ameliorate the effects that are due to depletion of some other compound way at the bottom of that pathway. (This is why everyone on a statin should be taking a CoQ10 supplement.)
  2. Statins don’t completely, 100% block the mevalonate pathway. They are called HMG CoA reductase inhibitors, not HMG CoA reductase stoppers, or nullifiers. So the pathway still goes forward, but not as much as it is supposed to. So some cholesterol, and some CoQ10, and some prenylated proteins still get manufactured—just not as much as the body likely needs. (Think about it: if cholesterol production were completely shut down by statins, and someone taking a statin was following an extremely low-cholesterol diet…you know the type…vegan; egg-whites only; margarine; skinless white meat chicken, etc.—they would probably drop dead in short order, since we need cholesterol for every single cell and mitochondrial membrane in our body. And nerve function. And brain function. And synthesis of testosterone, estrogen, progesterone, cortisol, aldosterone, vitamin D, and more. But I digress. I’ll save that rant for when I write in more detail about cholesterol someday.)


Regardless of whether statins block this pathway or merely “inhibit” it, now you can see that there is, in fact, a physiological mechanism by which these drugs might very well increase someone’s risk for diabetes.


P.S. If you are interested in totally geeking out on this stuff, you should check out this paper. Here’s the abstract, which is incredible in its forthright condemnation of statins in causing rhabdomyolysis. (That’s a fancy word for “muscle destruction,” which, you’ll recall from way back at the beginning of this post, the FDA and Mayo Clinic both recognize as a side effect of statin use.)

(Emphasis below is mine.)
Abstract: Rhabdomyolysis is a rare, but serious complication of statin therapy, and represents the most severe end of the spectrum of statin-induced myotoxicity. We report a case where coenzyme Q10 facilitated recovery from statin-induced rhabdomyolysis and acute renal failure, which had initially persisted despite statin cessation and haemodialysis. This observation is biologically plausible due to the recognised importance of coenzyme Q10 in mitochondrial bioenergetics within myocytes, and the fact that statins inhibit farnesyl pyrophosphate production, a biochemical step crucial for coenzyme Q10 synthesis. 

(In case you didn't quite catch the biggie up there, way beyond even the muscle damage -- STATIN INDUCED ACUTE RENAL FAILURE?! HELLO!! Know what that means? Youll have the lowest cholesterol in the dialysis ward! Congratulations!!)

P.P.S. If you want to geek out even further, all you really need to do is read the awesome title of another paper: The alteration of protein prenylation induces cardiomyocyte hypertrophy through Rheb-mTORC1 signalling and leads to chronic heart failure. (Yes, the alteration of protein prenylation can lead to heart failure. I said it before, and I can’t help saying it again: You can’t make this stuff up! Modern medicine is SO FREAKING BACKWARD. There is NO part of human health that statin drugs do not compromise.)







Remember: Amy Berger, M.S., NTP, is not a physician and Tuit Nutrition, LLC, is not a medical practice. The information contained on this site is not intended to diagnose, treat, cure, or prevent any medical condition.

9 comments:

  1. Please continue this series :D

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  2. Showed this great piece to a friend that is still on statins, but thinking twice. Hope it works !!!

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  3. Here can you get a free copy of uffe Ravnskovs book http://www.ravnskov.nu/CM http://www.ravnskov.nu/cholesterol.htm

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  4. One of the worst attempts of sounding like someone is a expert but failing terribly. Yes cholesterol is a important part of our biochemistry, thats a given but its when you have to much of a particular type is when you block your arteries and its statins that block this type.
    If you look at recorded blood plasma levels over the last 40 yrs in the US. They have increased in line with the increase in cardiac mortality and our shift in poor diet. Also its so easy to prove that ldl chol is a killer all cadavers in the US over 50 yrs of age have some such deposits. As has biopsies of live patients during stenting procedures.

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    1. Suggest you do a bit more reading. Ben Goldacre's book title is relevant here 'I think you'll find it's a bit more compicated than that'

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    2. There is no strong connection between LDL levels and CHD or morbidity and there is no connection between circulating levels and indications of atherosclerosis in almost any method of determining this you care to use. Framingham/MRFIT and lots of other gold-seal studies suggest a very slight tendency in people under 50 but the reverse for people over 50. Natural LDL cholesterol is protective and you are MUCH better having high cholesterol levels than lower in old age. Most people admitted to cardiac wards have low or normal cholesterol, ie 75%. LDL when oxidized is a different story as oxidized LDL has receptors on the endothelium which don't exist for non oxidized LDL. Oxidation of LDL seems to be a phenomenon associated with high triglycerides and low HDL which may be diet derived, ie high refined carb input. LDL in its natural form has been around forever but only very recently associated with CHD, in fact heart attacks were virtually unknown prior to the early 1900s.

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  5. High five, Amy! I watched my mother completely deteriorate as the result of Lovastatin medication for several years. That stuff destroyed her memory and her muscles. Doctors just kept writing it off as old age, but you'll never convince me of that. I've been on this soapbox ever since, and have purchased several books on the subject. And the list of books exposing statins and the whole cholesterol myth is getting longer every day. My personal fav- How Statin Drugs Really Lower Cholesterol and Kill You One Cell at a Time by the Yosephs. All the deception is exposed that brought this poison to the market.

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  6. Great post! thanks. Why does the average cardiologist have no clue? Well, whatever good intentions they had entering med school was probably long lost by the time they start practicing. After 4 yrs med school (cirirculum decided by big pharma), 1-7 residency (again drugs are the cure), $250K in debt, starting their careers in their prime, maybe starting a family also, who would have time to research or know anything outside what they have just learned? Doctors are just soldiers for the pharmaceutical industry. Drug reps are foot soldiers, doctors are graded up to generals depending on their specialty, I guess oncologist on top or surgeons.

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