Thursday, February 21, 2008

ACCORD and ADVANCE

I previously discussed the "surprising" negative results of the ACCORD trial, designed to test the effects of intensive blood glucose control in Type II diabetics. The media was full of statements to the effect that "don't panic, lower blood in Type II diabetics sugar is good", which seems a no-brainer. I suggested that the increased insulin dosage received by the intervention group could explain the increased mortality, due to various known effects of insulin, especially on cardiovascular health.

The ADVANCE Study is even bigger than ACCORD, but with the same essential goals. It's essentially a drug trial (really two drugs, one for blood pressure and one for blood sugar). After the ACCORD results, the ADVANCE investigators quickly trotted out a press release noting that their preliminary results saw no adverse effects in the treatment group. The difference between ACCORD and ADVANCE? ADVANCE did not treat with insulin, but rather with the drug Diamicron MR, from the class of sulfonylurea drugs. Sulfonylurea drugs work by increasing the insulin production of the pancreas, so in the coarsest sense, both ACCORD and ADVANCE are treating blood sugar by increasing insulin. But Diamicron MR has some other effects which may be protective against heart attack. We also don't know how much extra insulin was provided/created in ACCORD vs. ADVANCE. And for whatever it's worth (not much, really) Diamicron MR is helping the pancreas to fulfill it's natural function in response to blood sugar variations, so there may be some difference compared to just dumping exogenous insulin into a patient's blood. But that's hand-waving at this point.

ADVANCE has yet to publish its results, so we don't know whether the treatment was ultimately beneficial or not, only that there is currently no evidence of adverse effects of the treatment. I personally believe both ADVANCE and ACCORD are treating the wrong thing. Type II diabetes is fundamentally the result of insulin resistance. High blood sugar is a symptom. If you can reduce insulin resistance, the blood sugar will follow.

Drugs like Metformin can increase insulin sensitivity. But what causes insulin resistance in the first place? There are multiple hypotheses, but the simplest one which seems to fit the facts is consumption of refined carbohydrates. Refined carbohydrates rapidly increase blood sugar, requiring the pancreas to output large quantities of insulin. Insulin stays high in the blood well after the sugar has been forced into the cells, so insulin receptors continue to be bombarded, and this constant overstimulus likely results in down-regulation of cellular insulin receptors. Insulin performs other more powerful functions beyond blood sugar control, and it is logical to believe that cells adapt their insulin response to the ambient insulin level in order to maintain reasonable allostasis. There is considerable evidence both anecdotal and clinical that patients can restore insulin sensitivity (more or less) by simply removing the stimulus of refined carbohydrates and other "high glycemic" foods from the diet. The medical community seems to have forgotten the old chestnut:
Patient: Doctor, it hurts when I do this.
Doctor: Then don't do that.

If eating carbohydrates increases insulin and leads to insulin resistance, then don't eat carbohydrates. Now, this is easier said than done. The higher your insulin, the more deranged your metabolism, and that derangement is such that it creates major sugar cravings, because insulin resistant cells can't effectively get energy from the blood. A diabetic's cells think the body is in danger of dying from starvation. The body tends to do what it can to avoid death, like sending signals to the brain to get some sugar and get it NOW. So Type II diabetic's might require some level of drug intervention to help get their metabolism back on track, but the focus of the treatment needs to be curing the cause of the disease (insulin resistance) and not simply alleviating symptoms.


2 comments:

Cindy Moore said...

Good post. I've long believed that insulin resistance is a defense mechanism. Makes no sense to me to feed someone they have trouble metabolizing and then giving them drugs to help them metabolize it!

Dr Bernstein has been treating Type 2s with insulin.....but also a low carb diet. His rationale is to allow the pancreas to rest and allow you to preserve the function you still have. Dr B has had great success, the difference is the diet.

I'm starting to wonder if they'll ever "get it".

bryony said...

I completely agree. The fact that drugs are valued on the basis of their ability to lower a surrogate marker instead of their ability to reduce mortality is preposterous.