February 20, 2004

Three inhaled insulin trials begin at VUMC

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Josh Cooper, clinical trials coordinator at the ASAP Clinic, demonstrates the inhaled insulin nebulizer for patient Kathleen Hayslip. Photo by Anne Rayner

Three inhaled insulin trials begin at VUMC

Vanderbilt University Medical Center researchers are studying a new inhaled form of insulin in three separate clinical trials. If proven effective, the new form of insulin, which is delivered to patients as an aerosolized powder via the lungs, could cut in half the number of insulin injections for a certain population of diabetics.

With the disease fast reaching epidemic proportions, diabetes currently affects over 18 million people in the United States alone. An estimated 60 million Americans suffer from elevated glucose levels, a pre-diabetic condition suggesting numbers of those affected by the disease will explode in the coming years.

Diabetics who receive insulin typically self-administer several shots daily. Type 1 diabetics typically take one dose of long-acting insulin in the evening, accompanied by several doses of short-acting insulin throughout the day. Insulin-dependent type 2 diabetics often follow a similar insulin regimen.

Some new types of quick-acting insulin, developed in the mid-1990’s, can be prescribed for either shortly before, or in some instances even immediately after meals to maintain blood sugar levels after food consumption.

A new inhaled, rapid-acting, dry-powder form of insulin, currently called Exubera, is being tested to replace injections of short-acting insulin.

“All preliminary studies done elsewhere show inhaled insulin is effective,” said Dr. Stephen Davis, the Rudolph H. Kampmeier Professor of Medicine, chief of the Division of Diabetes, Endocrinology and Metabolism, and principal investigator on one of VUMC’s three trials of Exubera. “Additionally, the patient satisfaction scores from these studies are very high.”

For diabetics who receive insulin up to four times a day, that can represent as many as 1460 injections a year. And that number doesn’t include the number of skin pricks diabetics must endure to draw blood samples for monitoring of blood sugar levels. Some diabetics may require more than four daily insulin injections.

Kathleen Hayslip, a 57-year-old insulin-dependent type 2 diabetic who also suffers from asthma, thinks having a more convenient way to receive the drug would be a tremendous benefit. While saying that living with diabetes isn’t the worst thing in the world, Hayslip resents how labor-intensive it is to be insulin-dependent, and says the disease can rob diabetics of some of the spontaneity of life.

“I would be more prone to take the dose of insulin I need at the appropriate time if it was easier to do,” Hayslip said. “I hate to admit it, but I don’t always do that.”

Hayslip cites difficulties diabetics face such as having to calculate and inject insulin doses ahead of mealtime. “If I’m at a restaurant and decide to have something different to eat than I originally calculated, then I have to consider my insulin,” she said. “When I’m around family or close friends I’m OK, otherwise in a social setting I feel self-conscious about injecting. Then there can be sanitary issues while out in public with trying to find a clean, private place to inject.”

Other than a cure for the disease, the holy grail of diabetes research is the ongoing search for more effective, less painful, methods to administer insulin and monitor blood sugar levels.

According to Dr. John Murray, associate professor of Medicine and Pharmacology and the Elizabeth and John Murray associate professor of Asthma, Sinus and Allergy Program, who is principal investigator on two of VUMC’s inhaled insulin studies, the concept of delivering inhaled insulin to diabetics through the lungs has been around for decades.

“The whole concept of nebulized, or airway-delivered, insulin has been around for 75 years. In addition to insulin delivered by injection, insulin was originally delivered by inhalation shortly after its discovery back in the 1920s,” said Murray. “There was a lot of variation in delivery, such as not being able to control the dose back then, so it never went anywhere.”

Murray says that drug companies began to look at delivering insulin by inhalation again in the 1980s and 1990s, which led to the development of Exubera and new nebulizer technology to administer accurate dosing.

The Diabetes Control and Complications Trial (DCCT), a landmark national trial headed by former VUMC faculty member Dr. Oscar Crofford, professor of Medicine emeritus, forever changed the way diabetics are taught to manage their disease. The DCCT led to proof that diabetics who receive insulin several times daily, and most closely manage their blood sugar levels day-in and day-out, suffer far fewer serious complications associated with diabetes.

Emphasis is now placed on tight control over blood sugar levels, which is achieved by exactly when, and how much, insulin is delivered. Therefore there is an ever-greater need for more convenient methods of delivery.

“Diabetics need to take insulin before they eat to appropriately manage blood glucose levels. One of the problems with this approach is that it can be inconvenient for people to inject themselves midday,” Murray said. “Another problem is that diabetics usually need to take their injections before eating to reach peak level. That can be inconvenient, or hard to remember. One of the advantages of Exubera is that it is as fast as quick-acting insulin getting into a person’s system.”

The inhaled form of insulin now being tested at VUMC in late Phase III trials is close to gaining broad-market FDA approval. But one of the remaining questions is the effectiveness of this form of insulin in patient populations who suffer from respiratory complications.

Murray’s two inhaled insulin studies, being conducted through the Asthma Sinus Allergy Prevention (ASAP) Research program, are seeking oral medication-dependent or insulin-dependent diabetic adults, ages 18-75, who suffer from either COPD (chronic obstructive pulmonary disease including chronic bronchitis and emphysema) or asthma.

Both of Murray’s studies will look at several variables — whether insulin control can be maintained over time, whether fluctuations in the patient’s pulmonary disease alters insulin control, and whether giving insulin through the lungs in this patient population might have an adverse effect on the lungs themselves.

“One of the questions is that if you’re giving insulin by inhalation, are you going to have variability in absorption from a normal person to someone with lung disease, and is that variability going to change with the state of the disease?” Murray said. VUMC’s other inhaled insulin study currently under way is being conducted through the division of Diabetes, Endocrinology and Metabolism by Dr. Stephen Davis and Dr. Deanna Aftab Guy, instructor of Pediatrics in the division of Pediatric Endocrinology.

Davis and Aftab Guy are seeking adult patients with type 2 diabetes who are currently on oral medications, who have difficulty maintaining appropriate blood sugar levels.

“We are looking for diabetic adults, ages 35-80, currently on two oral medications with an average blood sugar level of 180, and whose diabetes is poorly controlled,” said Aftab Guy. “Participants must also be less than 130 pounds overweight.”

Ideal participants for the adult type 2 study would be at the point in the disease process their diabetes will soon require switching from oral medications to insulin.

“We think inhaled insulin will be particularly appealing, especially to type 2 diabetics,” said Davis. “Over 50 percent of type 2 diabetics eventually need to receive insulin. Most people would prefer not to inject it.”

All three studies are conducted on an outpatient basis. Participants will receive a thorough history and physical prior to enrollment. Participants in Murray’s two studies will undergo a thorough evaluation of lung function and will have pulmonary function closely monitored throughout the study. All participants will receive free medications and blood glucose monitoring supplies for the duration of the studies.

“We are very hopeful, and early results with this method of insulin delivery are very encouraging,” said Davis.

For information about the asthma or COPD and inhaled insulin studies, please contact ASAP Research at 936-5764. For information about the adult type 2 inhaled insulin study contact Dr. Deanna Aftab Guy at 936-1824.