Comparing Metformin and the Insulin Secretagogues

Patient Expert

When people with type 2 diabetes could take a pill instead of insulin to help us control our diabetes, smiles must have appeared on many faces. The pill was tolbutamide, and in the mid-1950s it became the first of the sulfonylurea class of drugs.

But that was more than half a century ago. Meanwhile, we now have choices of pills we can use. In fact, we now have nine other classes of oral diabetes medication plus several combinations.

The sulfonylureas force the beta cells in the pancreas to pump out the insulin that our body makes there. That’s why we call these drugs insulin secretagogues. For years many of us have been concerned that they will eventually burn out whatever beta cells we have left.

About a dozen years ago I voiced this suspicion to Edward S. Horton, who was then the director of clinical research at the Joslin Diabetes Center in Boston. In reply he told me that we have no evidence for this belief.

“You are not whipping the beta cells to death,” he said. “There is evidence that the beta cells do fail gradually over time. But there is no evidence that drugs hasten the process. I know that it is a popular conception that people have, but it is not true.”

The lack of evidence isn’t the evidence of lack, and ever since then I’ve wondered about the long-term use of any of the insulin secretagogues. We still have no evidence about beta cell burnout one way or the other. But now for most of the insulin secretagogues we have evidence of something worse. Heart disease.

A huge study of 107,806 people in Denmark compared the prevalence of heart attacks and strokes suffered by people who took insulin secretagogues and metformin. The European Heart Journal published the results of the study online this afternoon. The European Society of Cardiology, which publishes that journal, made an advance copy of the full study available to me. It, or at least the abstract of it, should be available on its website soon.

The study followed every adult living in Denmark who took either an insulin secretagogue or metformin between 1997 and 2006. Taking most insulin secretagogues was associated with a greater risk of death from any cause and a greater risk of heart attacks or strokes and a greater risk of death from these cardiovascular disease.

This was true both for people who had already had a heart attack and for people who didn’t. Those who had not already had a heart attack had a fifth to a third higher risk of death from any cause if they were taking one of these insulin secretagogues. Among those who had already had a heart attack the risk was a third to a half higher.

Still, two insulin secretagogues didn’t show any difference from metformin. One of these, gliclazide, which is available in Canada but not in the U.S., is a second-generation sulfonylurea. The other is repaglinide, a meglitinide rather than a sulfonylurea. Sold in the U.S. as Prandin, doctors rarely prescribe it here, probably because it is less effective than other choices.

Unlike all of those drugs, metformin works to combat insulin resistance by increasing the action of insulin on insulin receptors. That reduces blood glucose in the liver, muscles, and fat.

The new study is the first one ever to compare the insulin secretagogues with metformin. If anyone reading this is still taking one of these older drugs, the take-home message isn’t to stop taking it on your own. Instead, discuss your options with your doctor.