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Sulfonylurea’s Potentially Harmful to the Heart

Apr 26, 2002

A study suggests that sulfonylurea oral diabetes medications may be linked to increased risk of coronary artery spasms. >These findings will be published in the July 15th issue of the Journal of Clinical Investigation and were summarized in a press release by The University of Chicago Hospitals & Health System.

Diabetes is a disorder in the body’s ability to use blood sugar (glucose). Glucose is the main source of energy for the human body. It is taken from the starches and sugars that people eat. Normally, the body’s tissues can absorb the glucose and use it for energy with the help of insulin. Insulin is a hormone produced in the pancreas (an organ next to the stomach) that is normally secreted when glucose levels are high. Patients with Type 2 diabetes do manufacture insulin, sometimes even more so than necessary, but for some reason their bodies reject and/or do not detect it, resulting in what the body perceives as a deficiency. This insulin blockage is due to cell abnormalities of unknown cause in the liver and muscles.

There are different oral medications to help patients with diabetes to stabilize their blood sugars. The sulfonylurea drugs help the body to produce more insulin and to use the insulin more efficiently.

In the past few decades, studies have suggested that patients on sulfonylurea drugs were more likely to have cardiovascular problems but the reasons were unclear.

So they began working with McNally, a specialist in cardiovascular genetics. McNally fitted the gene-altered mice with portable heart monitors, which revealed that they had elevated blood pressure and frequent cardiac "episodes." About 50 times a day the mice had severe angina attacks, caused by spasms of their coronary arteries, which cut off the blood supply to the heart.

These repeated spasms, which lasted for several minutes, were often lethal. By the age of 30 weeks, 65 percent of male mice and 35 percent of females had died.

The spasms were caused by the missing receptor, the same one that is targeted by the sulfonylureas.

Sulfonylureas induce the pancreas to release insulin by blocking this receptor. Blocking the receptor inhibits a potassium channel on the cell surface. When this channel is closed, potassium ions build up in the cell, which eventually triggers the cell to open its calcium ion channels. Calcium flows in, which signals the cell to secrete insulin.

Unfortunately, a similar receptor exists on the smooth muscle cells that surround arteries, regulating flow through these vessels. The researchers found that mice without the receptor, had no functional potassium channels in their smooth muscle, leading to calcium influx and contraction of the smooth muscle cells that surround arteries.

Drugs that block calcium channels reduced the frequency of coronary episodes.

"We found that this receptor plays a pivotal role in the regulation of blood pressure and vascular tone," said McNally. "The absence of the smooth muscle potassium channels promotes episodes of vascular spasm. Since the sulfonylureas work the same way, effectively closing these channels, we believe that they can increase susceptibility to vasospasm and therefore present a significant risk to diabetic patients. Since diabetic patients are already facing an increased risk of cardiovascular disease, this is a further insult to their vessels."

These gene-altered mice also provide an animal model of the disease known as Prinzmetal’s angina, which is caused by is coronary artery spasm. Unlike typical angina — chest pain during exertion — Prinzmetal’s nearly always occurs when a person is at rest.

"The good news," adds McNally, "is that this study provides us with a new way to study Prinzmetal’s angina and suggests a molecular target for new drugs to treat hypertension and vasospasm."

"This study, even though it involved mice, argues that from now on we should think twice, or maybe more than twice, about using sulfonylureas, particularly if other options are available," said Dr. Elizabeth McNally, a cardiologist at the University of Chicago and lead researcher of the study.