Another Drug That Lowers Blood Glucose in Prediabetes   (March 27, 2011)

One might think that it's pretty obvious that if you give someone who has elevated blood glucose a drug designed to lower blood glucose, that the blood glucose level will probably go down. That's the logic behind all the diabetes medications -- they lower blood glucose in people with diabetes. But what if the person taking the diabetes drug doesn't have diabetes?

It's been well-recognized that some diabetes drugs will lower blood glucose (BG) in anyone taking them, even if the person's BG level is perfectly normal. That's true of the sulfonylurea (SU) drugs, and for insulin. If someone without diabetes accidentally (or deliberately) takes a SU drug or insulin, their blood glucose will fall below normal. Other diabetes drugs are generally thought to have little if any ability to lower blood glucose below normal in people who have normal blood glucose. Several classes of diabetes drugs, including metformin and the thiazolidinediones (Actos/pioglitazone and Avandia/rosiglitazone) are unlikely to cause low glucose levels in people with normal BG levels.

What about people with slightly-elevated blood glucose levels, that are higher than normal but not quite high enough to be diagnostic of diabetes? Folks with this situation are described as having "impaired glucose tolerance" (IGT) and are frequently called "prediabetic" because it's commonly believed that their blood glucose levels will eventually go up with the passage time, so that they eventually will have high enough BG levels to be labeled as having diabetes. Would drugs that work to lower BG in people with diabetes work to lower elevated BG in people with prediabetes? After all, the cut-point to distinguish prediabetes from "real" diabetes is arbitrary: It has been set as 126 mg/dl when fasting -- so if someone is consistently 126 or higher, they have diabetes; if consistently just below 126, they are prediabetic. It seems likely that whether someone is just over 126, or just under 126, that diabetes medications should work to lower BG. And if someone with prediabetes is given a glucose-lowering drug, and it lowers the BG, then one could say the drug has "prevented" diabetes. Or if you prefer, one could alternatively say that using the drug has masked the development of diabetes.

There are several studies showing that giving diabetes drugs to people with prediabetes do indeed lower BG levels (and "prevent" -- or mask, or delay -- the onset of diabetes).

In a study published almost a decade ago in 2002, called the Diabetes Prevention Program (DPP), researchers demonstrated that giving the diabetes drug, metformin, to patients with IGT would reduce the risk of developing diabetes, although diet and exercise worked even better.

The same year, another diabetes drug, acarbose, was also reported to prevent progression to diabetes (STOP-NIDDM Trial).

In a study published in 2006, another drug (Avandia/rosiglitazone) was shown to reduce the risk of developing type 2 diabetes by 62 percent compared to placebo (DREAM - Diabetes REduction Assessment with ramipril and rosiglitazone Medication).

The question of whether diabetes drugs work to lower BG levels and "prevent" diabetes has been answered yet another time in a study published this month in the New England Journal of Medicine, Pioglitazone for Diabetes Prevention in Impaired Glucose Tolerance. In this study, 602 patients with impaired glucose tolerance were randomly assigned to receive either Actos (pioglitazone) or placebo for three years; both the patients and the study physicians unaware of whether the patient received one or the other. The results are totally unsurprising: the patients getting placebo tended to progress to having "real" diabetes; and those on Actos frequently had lowered glucose levels on followup. HDL ("good") cholesterol rose, and LDL ("bad") cholesterol levels decreased with Actos; blood pressure also dropped, as did the thickness of the walls of the carotid arteries. However, Actos was associated with "significant" weight gain (8.6 vs. 1.7 pounds with placebo) and edema (in 12.9% vs. 6.4% of the patients).

Should people with impaired glucose tolerance nag their physicians to start Actos to help prevent (or more likely, delay) prediabetes from turning into diabetes? The manufacturer of Actos probably thinks so -- after all, they funded the study. And one of their researchers is quoted as saying "If someone is at high risk, then I would, in addition to trying to get them to lose weight and exercise, recommend medication, and personally, I favor pioglitazone. If you can really lose 30 pounds -- or whatever it is you need to lose -- then you might be able to discontinue the medication."

But others would say that giving an expensive drug that is associated with weight gain, and that has a risk of causing edema, is pretty foolish  if there are other ways to handle the situation. and indeed there are: weight loss through meal planning and exercise, and perhaps adding metformin (which is a very inexpensive drug as it's available as a generic).

But all this discussion about lowering BG, or preventing it from rising to the level that's diagnostic of diabetes, misses an important point: lowering blood glucose is probably not the best way to assess whether it's worthwhile for someone with IGT/prediabetes to be treated with drugs. Much more relevant, and as of yet, unknown, is whether the drug decreases the risk of life-threatening cardiovascular events such as heart attacks and strokes. None of the studies of diabetes drugs in prediabetes have shown that giving these drugs decreases the future cardiovascular risk -- the studies are simply too short in duration to assess whether these drugs influence the rates of heart attacks and strokes. And one of the drugs, Avandia/rosiglitazone, actually increases the risk of cardiovascular events in people with diabetes, and consequently has been severely restricted in its availability. 

It will be important to fully understand the cardiac risk of glucose-lowering drugs in people with prediabetes before these drugs should be routinely recommended to "prevent" diabetes.