July 30, 2012

Sulfonylureas Cause Higher Mortality Risk

Alvin Powers, MD, of Vanderbilt University in Nashville, TN, who was not involved in the study, was brave enough to make this statement, "We don't know enough about those drugs [sulfonylureas]." I thought as long as these had been around, they should have had more than enough information, but when it comes to oral diabetes medications, apparently there is still a lot to learn even when they are now in generic.

The study compared data from a large retrospective cohort study of metformin to three commonly prescribed sulfonylurea drugs. The three drugs were glipizide, glyburide, and glimepiride. The discovery was a little shocking when diabetes patients had a 50 percent higher risk of death compared to patients on metformin. The study, which was funded by drug company Astra Zeneca shows that apparently the sulfonylureas are more a cause for concern.

This is speculation on my part, but I feel that doctors just don't cover the side effects in sufficient detail. They don't emphasize the warning that these drugs cause low blood glucose by themselves (hypoglycemia) and if you skip a meal, skip the medication. This alone could be causing part if not much of the increase in mortality. Patients that do not understand the dangers of hypoglycemia will not take the care that needs to be taken. This is also an area that the certified diabetes educators seem to gloss over.

I also hope this will give researchers cause for concern and not to stack so many oral medications. Many researchers that think the larger the oral diabetes medications cocktail, the greater glycemic control there should be. Some researchers may continue to stack oral medications and fail to report adverse medication events until the adverse events become so great like they did on the ACCORD study.

Findings, like this study, presented at medical meetings are typically considered preliminary until published in a peer-reviewed journal. However, this could still cause "enormous clinical implications." Apparently, sulfonylureas have been considered safe and effective. Now we will need to see if the FDA will require a label warning.

Cost cannot be a distinguishing factor, as all three sulfonylurea drugs are available in inexpensive generic forms. Metformin offers an alternative to sulfonylureas as first-line oral therapy for diabetes and also is available as a generic.

An enterprise-wide electronic health record (EHR) system was used to conduct the retrospective study of diabetic patients who started treatment with one of the sulfonylureas or metformin from Oct. 24, 1998 to Oct. 12, 2006. The search produced records for 23,915 patients. About half (12,774) started treatment with metformin, followed by glipizide (4,325), glyburide (4,279), and glimepiride (2,537). All patients were adults treated in outpatient clinics. Investigators excluded patients using insulin, other injectable diabetes medications, or multiple oral drugs for diabetes.

The patients had a median follow-up of 2.2 years and 2,546 patients died. This was verified by the EHR or Social Security Death Index. This is how patients treated with a sulfonylurea had a mortality hazard ratio of 1.50 compared with metformin.

Because recent reports suggested sulfonylurea risk varied in patients with coronary artery disease (CAD), investigators conducted a separate analysis of 2,721 patients with a history of CAD. As compared with metformin, patients who started treatment with glyburide had a 38% increase in the mortality hazard (HR 1.38), and there was a 41% increased risk in patients started on glipizide (HR 1.41). Only glimepiride was not associated with an increased mortality hazard versus metformin.

Dr. Minisha Sood, also an endocrinologist at Lenox Hill, said that sulfonylureas may fare worse than metformin because they may "interfere" with cardiovascular processes that strengthen and protect heart tissue making it more resilient should a cardiac event occur.

"What's interesting about this study is that all three sulfonylureas examined led to increased mortality rates vs. metformin in the entire cohort study, which included patients without coronary artery disease," Sood added. "Does this mean that we shouldn't be prescribing sulfonylureas at all? I think prospective trials are needed to answer that question, so the jury is still out."

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