It’s not exactly the tortoise versus the hare, but in the effort to get islet transplantation and a closed-loop artificial pancreas to the market, there seems to be a race.
At the November 2, 2001, Diabetes Technology Meeting in San Francisco, California, Christopher Saudek, MD, of Johns Hopkins University shared the following opinion:
“With all apologies to Dr. [James] Shapiro [of the Edmonton Protocol team, who pioneered islet transplants], a closed-loop artificial pancreas will be available before islet transplantation.”
In a later e-mail sent to Diabetes Health, Saudek explained that his observation stems from the major obstacles that still must be overcome before islet transplantation is generally available as a viable approach to treating diabetes.
“The most obvious of these [obstacles] are the need for a replenishable supply of islets for transplantation and the need for lifelong anti-rejection therapy for recipients,” says Saudek, who adds that an artificial pancreas also faces its share of obstacles. “I was simply stating my estimate that overcoming the obstacles in mechanical-device development could be quicker than in islet transplant development.”
At a banquet during the evening of November 2, 2001, Edmonton Protocol leader James Shapiro, MD, assistant professor of surgery and director of the clinical islet transplant program at the University of Alberta, rebutted Saudek’s prediction. Shapiro argued to the high-tech crowd that when you transplant islets, you are providing “750,000 tiny grains of sand,” with each grain made up of approximately 2,000 cells. When all these cells are working in synchrony, he added, they have their own self-replenishing power supply.
“The islet is essentially the perfect implantable device,” Shapiro told the crowd. “The islet is the most biocompatible glucose sensor ever made, and it doesn’t suffer from the same limitations that the artificial-pancreas devices do. The islet provides perfectly timed insulin release in response to meals without the risk of low blood glucose.”
Shapiro added that another advantage of the transplanted islet is that it has the entire “endocrine orchestra” controlling glucose.
“It has all the counter-regulatory hormones,” he said. “Not only does it secrete insulin, but it secretes glucagon and pancreatic polypeptide and other hormones that are designed to keep glucose in perfect balance. In addition, if it is rejected the whole graft can self-destruct. It doesn’t need to be surgically removed,” as an artificial pancreas would need to be.
People With Diabetes Speak Up
David Lytle of Greenbrae, California, a type 1 for 45 years and pump wearer for 11, was in attendance when Dr. Saudek made his comment. He agrees with Saudek about the promise of the artificial pancreas and cites as his reason the difficulty of obtaining sufficient islets to make the Edmonton Protocol a general reality.
“It would seem that the problems with implementing a closed-loop system will be solved long before enough islets become available to offer the Edmonton Protocol treatment on a general basis,” says Lytle. “It would appear that the Edmonton Protocol is a reality today based on performance, but it cannot be a viable solution on a general basis until the islet problem is solved.”
Lytle says that—hypothetically speaking—if both the Edmonton Protocol and the artificial pancreas were available tomorrow, he would still opt for the latter. “No anti-rejection medication is needed” with an artificial pancreas, he explains.
Deb, a type 1 from Burlington, Massachussetts, is also rooting for the artificial pancreas. She has qualms about the Edmonton Protocol: “To take anti-rejection drugs every day and deal with their side effects for the rest of my life seems like swapping one set of problems for another. Sometimes the devil you know is better than the devil you don’t.”
Sarah Jang, on the other hand, does not agree with Saudek and would prefer something like the Edmonton Protocol to a closed-loop system.
“I would prefer the Edmonton Protocol because it is not artificial,” says Jang, a type 1 from Berkeley, California. “What the [normally functioning] human body does is really amazing. I would find it hard to believe any current technology could 100 percent replicate the ‘miracle’ of the human body.”
Tracy Engeleiter, a type 1 from Costa Mesa, California, believes that widely available islet transplantation will be a reality before a closed-loop artificial pancreas because of the Edmonton Protocol’s positive results in recent years.
“I think perfecting an artificial pancreas and the checks and balances involved in making sure that it is functioning perfectly will take much longer than gauging the results of islet transplantation,” says Engeleiter. “To me, the Edmonton Protocol seems more of an actual cure, as it ‘fixes’ my pancreas, whereas the artificial pancreas is essentially a transplant without having to wait for an organ donor. If both produce the same results, I guess I would rather go with the one that is least likely to cause problems.”
Kelsey Metcalf, a type 1 from Chandler, Arizona, who would rather see the Edmonton Protocol win the race, agrees that the artificial pancreas is leading around the final lap.
“There are too many unfortunate political and ethical barriers standing in the way of mass islet implementation,” she says.
The Industry Spin: The Artificial-Pancreas Camp
Marc C. Torjman, PhD, associate director of the Artificial Pancreas Center at Thomas Jefferson University in Philadelphia, believes the question of who will win the race is a difficult one to answer. While both approaches have major obstacles to overcome, he agrees that a closed-loop system might be closer to fruition than islet transplantation.
“The various approaches tried with islet transplantation are encouraging but still unable to offer a long-term solution for people with diabetes,” says Torjman. “The promising Edmonton technique requires islets from two donor pancreases per transplant with only about 3,000 pancreases available from cadaver donors each year. This is in contrast to the 30,000 new cases of type 1 diabetes reported in the United States alone each year.”
Torjman, like many Diabetes Health readers interviewed for this story, expressed concern about the need for anti-rejection drugs as part of the Edmonton technique.
“The long-term effects of these drugs are not well understood,” he says. “On the other hand, glucose sensors are becoming smaller and more reliable. Subcutaneous sensors like the Medtronic/MiniMed sensor have demonstrated reliable measurements but cannot remain under the skin for more than three days.”
Torjman says the development of a working glucose sensor has been an important first step in developing a working artificial pancreas, but he explains that a closed-loop system also requires a controller (an algorithm) to work in coordination with a sensor and an insulin pump.
“Progress is currently being made in that area, particularly since in vivo glucose sensor data can now be collected in patients,” he says. “What still needs to be developed is a more permanent insulin delivery system.”
The implantable insulin pump developed by Medtronic/MiniMed appears to be playing the leader-of-the pack role as far as artificial pancreases go.
According to Bob Murtfeldt, director of marketing and development for Medtronic/MiniMed, the integrated sensor and pump system has been implanted, with encouraging results, in both animals and humans who have diabetes. Murtfeldt told Diabetes Health that human trials using the implantable sensor and pump were conducted in early 2001 and announced at the American Diabetes Association scientific session in Philadelphia as well as at the European Association for the Study of Diabetes meeting in Glasgow, Scotland. (See sidebar on page 37.)
In addition, Murtfeldt says that an algorithm component is coming along. Medtronic/MiniMed is working on a number of them, one of which will be for a closed-loop application.
Murtfeldt agrees that a closed-loop artificial pancreas will be commercialized ahead of islet transplantation.
“Both programs are making exciting progress, and both have unique strengths and weaknesses, so to some extent they have been going in parallel paths,” says Murtfeldt. “But I just think the history with implantable medical devices is such that we’ll see commercial systems out ahead of islet systems.”
The Industry Spin: The Edmonton Protocol Camp
Shapiro, in a telephone interview with Diabetes Health, does not discount the possibility that, with significant advances in miniaturization, closed-loop systems can be improved. However, the lack of clinical data concerns him.
“There is still a lack of clinical data showing that closed-loop systems can maintain normal blood glucose for sustained periods of time,” he says. “Even though there has been major improvement in monitoring technology, the ability to maintain the functionality of these sensor systems long-term is far less than perfect.”
On the other hand, Shapiro cites “dramatic progress” in the past two years in terms of clinical outcomes of islet transplantation.
“The Edmonton Protocol was certainly one of the first to demonstrate success. [So far] we have transplanted 28 patients, and 96 percent of them have ongoing graft function with C-peptide production.”
Shapiro agrees with Saudek’s concern about the limited availability of islets for transplantation. He believes, however, that progress has been made in the past year in the ability to isolate a more successful number of islets from each pancreas.
So How Long Are We Supposed to Wait?
Torjman says that nothing on the immediate horizon looks like an ideal closed-loop system.
“However, I do see more encouraging signs of progress,” he allows. “For example, the Medtronic/MiniMed sensor and the GlucoWatch Biographer were recently approved for patient use, and valuable clinical experience is being gained from human trials with those devices.
“I am also very encouraged by the developments reported by Disetronic Medical Systems in Europe and the increasing research effort toward the development of control systems by industrial and academic scientists.”
Torjman ventures that, with more funding, we might see a preliminary type of closed-loop feedback system within the next five years.
Shapiro says there is nothing preliminary about islet transplantation—the results are already in.
“Islets are already being delivered [to people with diabetes],” he says. “In Edmonton, we have treated 28 patients. There are 50 new islet transplant centers opening up in the United States. There are 10 in England and 25 in Europe and the Far East.”
As with an artificial-pancreas system, however, Shapiro agrees that refinements still need to be made with islet transplantation.
“We will continue to make progress with safer anti-rejection therapies, and we will reach a point in the very near future where we can justify application of islet transplantation even in people who don’t have diabetic complications,” he says. “But we are still in the process of refining tailored anti-rejection therapies.”
Shapiro goes so far as to speculate that islet transplantation without steroids or anti-rejection drugs will become a reality.
“I think it is very possible and will happen over time,” he predicts. “The question is: which pathway? There are many different routes to the same end. Living donors will increase our availability. Maybe with the success of new anti-rejection protocols and without the use of steroids, I think we will be able to take one organ graft and maybe treat two patients, whereas today we need two organs to treat one patient. That would allow us to treat four times as many patients in a lot shorter time frame.”
In addressing the issue of limited islet supplies, Shapiro describes the past 12 months as a time of tremendous progress in the understanding of embryonic and adult stem-cell technology.
“There are cells available now that secrete human insulin and are responsive to glucose, but it is still. a long way away before those can be safely applied in humans.”
How Much Will We Pay?
So, hypothetically speaking, suppose that an artificial pancreas or an unlimited supply of islets becomes available very soon. What kind of costs would a person with diabetes be facing to utilize one of these therapies?
Murtfeldt says it is too early to be specific about the costs of a closed-loop artificial pancreas.
“Obviously, the healthcare system will have something to say about costs, as they will be paying for these systems,” he notes. “It is likely that they will reimburse costs for the artificial pancreas at some premium above current therapy (e.g., insulin pumps and glucose monitors) based upon improvements in patient outcomes in clinical trials.”
Susan Cannon from Anaheim Hills, California, whose daughter has type 1 diabetes, says she “would not hesitate to get a second mortgage on my house” in order to get her child an artificial pancreas as soon as one becomes available.
“I would not let my daughter take anti-rejection drugs,” she states. “Her diabetes is manageable enough without the terrible side effects of anti-rejection drugs. I would much rather have the closed-loop pump.”
Sara Falconer, a type 1 from New York City, says she would not empty out her piggy bank if the Edmonton Protocol were available tomorrow. However, she might do so for an artificial pancreas.
“I am not ready to exchange one drug that I know works [insulin] for something I don’t know [anti-rejection drugs]. Now, the artificial pancreas—maybe. If insurance covered it, I would be more likely to do it. However, I am not ready to trade what I know works for something that there isn’t 20 to 30 years of empirical evidence [to support].”
Mark Davies is the father of a 16-year-old boy with type 1. Regardless of which method first becomes available, he pledges that he would do anything in his financial power to provide his son with any solution that would offer normal glucose levels.
Shapiro notes that in Canada the Edmonton Protocol is already insured.
“In Canada, we don’t charge patients for an islet transplant,” he explains, although “there are costs to the patients related to the drugs they take afterward and costs for traveling to Edmonton to get the procedure. The anti-virals they take can get expensive.”
Shapiro feels sure that, someday, the United States will follow Canada’s lead and offer insurance coverage for the Edmonton Protocol.
Last year, “there were hundreds of billions of dollars spent in the United States on managing the complications of diabetes, and that doesn’t include the number of days of work missed,” he says.
Shapiro equates paying a lot of money up front for the Edmonton Protocol with the cost of getting a kidney transplant.
“It will be expensive for the first year, but every year thereafter it pays dividends enormously in terms of preventing complications.”
And Here They Come Down the Stretch
So perhaps it’s the bell lap, and the option leading as the two come down the stretch is anybody’s guess. Are we really only a few years away from a breakthrough that could possibly change the lives of people with diabetes? Or, as many people with diabetes worry, are these just the latest installments in a long line of cure promises?
Marc Torjman, while speculating that both techniques will be available to people with diabetes in the future, argues that having a choice between the two will be a good thing.
“Not every patient might be a good candidate for a particular technique, and it might therefore be advantageous to have [the other] treatment option available.”