Glycemic Control For Fun And Litigation

The first piece I posted on blood glucose hysteria examined the less-than-stellar scientific evidence behind the notion of tight glycemic control. Many readers—doctors and patients alike—wrote in, and virtually all of the correspondence was favorable. Thus, we follow up with a look at the devastating pitfalls of certain diabetes oral meds.

The latest bad news concerns one more of the ill-fated thiazolidinediones (TZDs). This class of drugs was introduced in the late 1990s, and includes Avandia, Actos, and Rezulin. TZDs are PPAR-gamma agonists, meaning that they activate peroxisome proliferator-activated receptors, especially the “gamma” receptor. Such activation affects certain metabolic processes, and among other things, insulin resistance is reduced.

Rezulin—notoriously fast-tracked by FDA—was withdrawn from the market in 2000, in the wake of scores of liver failures and deaths. Pfizer, the manufacturer, was on the hook for upwards of $750 million in damages. At the time, Dr. Janet Woodcock, director of FDA’s drug evaluation center, said that Avandia and Actos, “[O]ffer the same benefits as Rezulin without the same risk. We are now confident that patients have safer alternatives.”

The next to fall would be Avandia, taken off the market in 2011, after being suspected of increasing the risk of heart attacks. GlaxoSmithKline, the manufacturer, has already paid out more than $200 million in settlements. This leaves Actos, and it is noted that the 2007 study promoting further inquiry into Avandia was paid for by Takeda, manufacturer of Actos. Conflict of interest anyone?

Alas, Actos’ day would also come. Early on, the drug was implicated in increased risk for bladder cancer, and was taken off the market in France and Germany in 2011. Yet, the FDA approved a generic version in 2012, after issuing its own bladder cancer warning on the proprietary drug in 2011! Yes, you read that correctly. Nonetheless, the lawsuits began to pile up for Takeda.

Fast forward to April 7, 2014. Takeda and its partner Eli Lilly & Co. were ordered to pay a combined $9 billion in punitive damages after a federal court jury found they hid the cancer risks of Actos. The extreme damages derive from Takeda’s systematic efforts to destroy incriminating e-mails and other documents—going back many years. Leave it to canny plaintiff’s attorneys to still be able to find a smoking gun.

It seems that in 1993, Takeda was negotiating with Upjohn (now owned by Pfizer) to partner with them on the development of Actos. Based on correspondence obtained from Upjohn, its president declined, expressing concerns over Actos’ “margin of safety.” Takeda replied, asking Upjohn to change its reason to Actos not showing sufficient glucose reduction.

Ironically, earlier this year, Takeda stopped development of another diabetes drug when research linked it to liver damage.

Needless to say, this entire matter stinks to high heaven. Although the three proprietary drugs differ in chemical structure, their mode of action is essentially identical, and associating one with liver damage, the next with heart issues, and the final one with bladder cancer could have more to do with the luck of the draw than anything more definitive. Indeed, the science behind the Avandia withdrawal is the most suspect—and not only because there were contradicting studies.

Heart attacks (myocardial infarctions) are not a particularly useful endpoint when studying an anti-diabetes drug. The majority of type 2 diabetics, and thus the majority of those taking the drug, are overweight, which is itself a key risk factor for MI’s. Moreover, it is likely that a significant number of these patients would emphasize drug therapy over lifestyle change. As such, you are looking at a cohort of overweight people, who, yes, are more inclined to MI’s. I daresay that this finding could be duplicated with Rezulin, Actos, insulin, and even metformin—the so-called safest of all the oral diabetes drugs.

At any rate, the thiazolidinediones are now 0 for 3. Perhaps the worst part of this is that—as we pointed out last week—the need for glycemic control with strong drugs in type 2’s is dubious at best.

You might also ask what the FDA was doing when it approved these drugs, or why it is held harmless when its approved drugs go sour. Heck, you could go even further. Inasmuch as the FDA could be instantly replaced with a random board of experts from academia and the private sector, you might well ask why the FDA exists at all.

16 responses to “Glycemic Control For Fun And Litigation

  1. What a minefield these drugs are – when in doubt leave them alone.

  2. Point#1: The ‘null hypothesis’ would be, “we can handle this without pharmaceuticals”, and that is a reasonable position to take in medical decision-making. And no, you don’t have to believe in a ‘pharma-conspiracy’ to take that position. A dietary intervention will have fewer side-effects than a drug, unless it’s a really great drug.

    Point #2: Everybody hates mass-tort lawyers, except, of course, when they like them.

  3. Why do we need “oral medications” anyway? Insulin works in Type 1 diabetics–and the desire to avoid taking insulin might motivate Type 2 diabetics to alter lifestyles to avoid injections. That being said, the cost of Type 2 diabetics who don’t change lifestyles and develop complications is very high. Yes, we can often handle this without drugs, but we won’t.

  4. I have heard people with Type 2 diabetes say that they would rather die than so drastically change their diet. So they don’t change their diet, and then they die.

    • I knew a person who said that. She went into the hospital for some routine procedure and was told she would have to go on insulin thereafter. She died. Did she will herself to die? Don’t know. It was very strange. You’re correct though–no change in habits leads to death over time, usually following complications from the diabetes.

      • I could have worded my posting a little better. I did not mean to imply that they died immediately. The ones I have known, who had been put on insulin injections, lived normally for about three years, eating their normal foods, and then their kidneys started failing, and then after about a year of dialysis they would die. However, the ones I have known that did that were usually in their 50’s, and none ever got past 62. And they all refused to change anything in their lifestyle, just taking more or less insulin to match what they were eating. I have heard of other diabetics that lived many years taking insulin, but the ones I am mentioning are ones that I knew personally.

  5. I want to dispel one myth about diabetics. As a 15yr type 2, I have attended many informational meetings with others similarly afflicted. They’re not all fat. In fact, there are a helluva lot of skinny type 2’s

    • Very true, Jerry. Being overweight increases your chances, it seems, but being skinny does not remove all chance. (Kind of like cholesterol–people with normal levels still had heart attacks…) Plus, diabetes seems more prevelant in groups no one used to look at–adults of normal weight, Type1 showing up in adulthood, not just childhood, etc. Looks like we don’t understand as much as we though about this disease.

    • @Jerry–

      Fat type 2’s comprise around 80-85% of the total. There are also many cases in which people have a single instance of elevated glucose and are forever branded as “type 2.”

      It has become very convenient for Big Pharma and others to conflate type 1 and type 2 nasty consequences—to scare people even in the absence of actual data.

      There is a growing group of docs who question whether there is really even such a disease as type 2 diabetes. After all, beyond arbitrary glucose values (that have been drastically lowered over the last 40 years), this is a “disease” without any other defined symptoms.

      • While I agree that the glucose numbers that are acceptable have been lowered to a ridiculous level, Type 2 diabetes does seem to have other symptoms, though they are vague. This is why Type 2 diabetics have so many complications–they go undiagnosed for years. I agree that ONE test should never label a person diabetic. There’s the A1C that measures longer blood sugar levels–like two months. That’s a better indicator (note I did not say diagnosis). With the home meters available today, there’s no reason to take just one reading–and with the meters, people can tell what’s elevating their blood sugars as far as food and activity go (assuming there is correlation). And, just as with high blood pressure, people should probably not jump right into medication until the numbers stay high. The whole glycemic index and obsession with A1c’s of 5.0 (that’s “normal”) may be doing far more harm than good. Maybe everything does not have to be “near normal” for everyone.

        • @Reality–

          Here’s a thought: What if these “complications” are actually caused by aggressive glycemic control? I mean, if the drugs can cause all sorts of mayhem, what about all those classical so-called complications?

          • I suppose that’s possible, though some I have known developed the complications before receiving treatment. Eye doctors often recognize Type 2 diabetes by the damage done to the eye–while the patient has no idea he is diabetic.
            Now, as for “aggressive glycemic control”–I had to stop reading diabetes blogs because these persons were so depressed. They ate no carbohydrates and were willing to pass out to achieve that elusive 5.0 A1c. It seemed insane to me. I’ve been diabetic for a very long time and had I been told that my A1c had to be 5, to eat no carbs (that’s what diabetics tried before insulin was discovered), and was totally obsessed day and night with glucose measurements, I probably would have hated the disease also. I certainly think the “depression” comes from the patient being given goals that are very unrealistic.

            • @Reality–

              Let me be more specific. In a fat type 2, this insulin resistance is an adaptation to excessive weight. Thus, an internal feedback mechanism is already in effect. I suppose that a “complication” can now occur, based on messed-up insulin function, but this is collateral damage to the worse problem of gaining more and more weight.

              I have searched the literature endlessly and have never seem anything on skinny type 2’s and their complications.

              The complications (especially to fatties) are probably iatrogenic. They take insulin, which causes weight gain, they get more fat, and are more insulin resistant, so they take more insulin, gain more weight, etc. Non-insulin therapy notoriously has side effects. Bottom line is that it is not wise to play around with hormones, as your body will adapt to what you are TRYING to do.

              The complications are likely caused by impaired insulin function, that can best be reset (or close to it) by losing weight.

              Note that all the studies extant compare “moderate” glycemic control with aggressive glycemic control, but anyone on control has an endpoint of complications.

              Cortisol (stress) is hyperglycemic, and in some people (including me) it is drastically hyperglycemic—35 to 40 points or more, under stress. Paradoxically, going hypo RAISES blood pressure—quite a bit.

              One size does not fit all. Many folks would do better controlling their stress level, than blood pressure or A1C with drugs.

  6. Michael:
    I understand some of what you’re saying. How does taking insulin cause weight gain? Other than from low blood sugars and eating more to compensate. I get that bodies try to compensate for what the person tries to do–the tighter the doctors tried to make my blood sugar control, the more erratic it became. So, yes, it’s like my body did not like what was being done to it.
    Interesting point on Type 2 and weight–don’t think I’ve seen any studies on normal versus overweight Type 2.
    I agree that people would be better of if they could control their stress level, but people seem much happier to swallow a pill than actually take action to reduce stress. I suppose the question is how to get people to take control of their own health and stop depending on doctors to do everything for them using a pill.
    Your examples are interesting–stress raises blood sugar in some people, hype raises blood pressure (prednisone is a real nightmare for diabetics as it really messes with blood sugars–sends them through the roof). In others, the reaction seems the opposite. We are not all alike, even if doctors want us to be.

    • @Reality–

      Insulin causes weight gain in type 2’s by forcing glucose into the cells. Simple as that. You are right: Everyone is not the same, and the body’s own glycemic control is extremely complex. God knows what happens when it also has to fend off exogenous agents.

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