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Diabetes Medication

Comparing Type II Diabetes Pills: Metformin and the Insulin Secretagogues

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.

This article is based on an earlier version of my article published by HealthCentral.

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  • MJBooker at

    Hello. I have been diagnosed as a diabetic, and have been monitoring my blood glucose levels. I was given Metformin to help control my levels. recently I am finding my levels have been up and down. I have made a few changes, one of them being no coffee and no sugars. I noticed a significant drop in blood sugar readings. My problem now is when taking Metformin I am having serious issues with heart burn. I quit the metformin and in about 5 days the gastric and esophageal burn has gone away. I restart Metformin and the gastric burn is back. I have tried many different types of otc meds to try and control the burn, no effect. I am on my 5th day of no Metformin and the burn is gone. I have advised my dr, all they have to say is take anti acids. Why is the metformin causing this painful acid burn?

    • David Mendosa at

      That’s an interesting question, MJ! I have never heard that metformin can cause heartburn. But we are all different, which is a great thing in its own way too! Maybe you should work with your doctor to switch to another effect diabetes drug, like one of the GLP-1 receptor agonists (like Bydureon, Victoza, or Trulicity). Or even better, start eating very few carbohydrates. That’s what I did beginning in 2007, and of course I don’t have ANY side effects from my low-carb diet.

  • Maneeshi Trivedi at

    Have any studies been conducted to study the effect on fatty liver cell of the type 2 diabetes drug – metformin? For instance, for a person with fatty liver what is the maximum allowed metformin dose? As we all know that all drugs load the liver to varying extents, especially metformin which metabolises in the liver. In some cases, taking of BP drugs such as amlodipine (trade name ISTIN) over a long term can lead to diabetes 2 for which metformin can be prescribed. It is a catch-22 situation some patients can find themselves in.

    • David Mendosa at

      Dear Maneeshi,

      Yes indeed! Metformin does help reverse fatty liver disease. You can get much more information with a Google search using these terms:

      fatty liver metformin

      The key is actually reducing your blood glucose level to normal. That means down to an A1C level of less than 6.0