Diabetes Drugs: Sulfonylureas

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Editor’s Note: This is the seventh post in our miniseries about diabetes drugs. Tune in on September 25 for the next installment.

sulfonylureasSulfonylureas were among the first oral medicines available for the treatment of Type 2 diabetes. They were discovered by accident in France by a researcher who was working on drugs for typhoid fever. Animals that were given sulfonylureas displayed unusual behaviors and were found to have hypoglycemia (low blood glucose). It was quickly recognized that these drugs could be used for the treatment of diabetes.

The first sulfonylurea became available in 1955. (Notably, metformin was also discovered in a French laboratory and became available in France in 1959, but as I mentioned in a previous post, it was not available in the United States until 1995.) Despite the many new diabetes therapies that have been discovered over the past 50 years, metformin and sulfonylureas are still two of the initial choices for treatment. (For further reading on the early development of these and other diabetes drugs, click here.) Medicines in the sulfonylurea class include chlorpropamide (brand name Diabinese), glyburide (DiaBeta, Glynase, Micronase), glipizide (Glucotrol), glipizide extended-release (Glucotrol XL), and glimepiride (Amaryl).

Insulin is found in small packets inside the beta cells of the pancreas. The release of these packets is set off by rising calcium concentrations inside the cells. Sulfonylureas trigger a rise in calcium, and the subsequent release of insulin, by inhibiting the action of a protein that brings potassium molecules into the cells. The result of this inhibition is a change in the charge (or voltage) of the cells’ membranes, which allows calcium to enter the cells.

Since sulfonylureas work by stimulating the pancreas to release insulin, they are only useful in people with Type 2 diabetes whose beta cells still produce insulin. Additionally, although sulfonylureas stimulate the release of insulin, they do not reduce insulin resistance, a common feature of Type 2 diabetes.

Because sulfonylureas have been available since the 1950’s, they have a long history of clinical use. These medicines are considered to be a core treatment, in combination with metformin, when metformin, diet, and exercise alone are not sufficient for controlling blood glucose. (Another therapy considered in this case is the addition of insulin to metformin.) Sulfonylureas have gone through several steps of development and are categorized as first-, second-, or third-generation drugs. The main difference between the generations is how well they bind to the sulfonylurea receptor, with each progressive generation binding more tightly and thus requiring a lower dose to bring about the same amount of insulin secretion.

Sulfonylureas have a substantial effect on HbA1c (an indicator of blood glucose control over the previous 2–3 months) levels, working faster than many other oral medicines and resulting in average HbA1c reductions of roughly 1.5%. As was shown in the “A Diabetes Outcome Progression Trial,” or ADOPT, which followed people with Type 2 diabetes for five years, these medicines result in reductions in fasting blood glucose and HbA1c levels in the first several months of use. Unfortunately, the effects of the sulfonylureas were not sustained over the five-year trial period. ADOPT also indicated that sulfonylureas increase how well the beta cells of the pancreas function early on in the course of therapy, but again, this effect was shown to decline over the five-year period studied. (Given that the insulin-producing beta cells acted upon by sulfonylureas tend to decrease in function and number as diabetes progresses, the decline in these effects is not surprising.)

Sulfonylureas have a number of side effects, the most prominent of which is weight gain (roughly four pounds, on average). These drugs can also cause hypoglycemia, which can be severe and long lasting. Because sulfonylureas are eliminated from the body by the kidneys, decreased kidney function may lead to increased blood levels of the medicine, with a subsequent increased risk of side effects. Certain drugs such as fluconazole (Diflucan) may interfere with the metabolism of sulfonylureas, leading to an increased level of sulfonylureas in the blood.

Click here for other installments of “Diabetes Drugs.”

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