Islet transplant improved long-term glycemic control

Insulin independence is not yet sustainable, but islet function still protected from severe hypoglycemia.

Issue: November 2006

A multicenter international trial found that islet transplantation using the Edmonton Protocol successfully restores endogenous insulin production and glycemic stability in patients with type 1 diabetes mellitus.

Long-term insulin independence, however, does not appear to be sustainable at this point.

“This is the first ever international multicenter trial of islet transplantation,” said A. M. James Shapiro, MD, PhD, director of the Clinical Islet Transplant Program at the University of Alberta in Edmonton, Canada. “It is a landmark trial. This is the beginning, not the end, of where islet transplantation is going to be.”

Prior to 2000, results with islet transplantation had been mixed, without consistently high rates of insulin independence or glycemic control among patients. A treatment protocol that proved successful in a small study in 2000 was named the Edmonton Protocol; this involved treatment with glucocorticoid-free immunosuppressive therapy combined with infusion of a mass of freshly prepared islets from two or more pancreases from deceased donors.

Study aims

The current study tests the reproducibility of this protocol across nine international centers, as well as the protocol’s ability to produce insulin independence and good glycemic stability in patients with type 1 diabetes and poor glycemic control. The results of the study were published in the New England Journal of Medicine.

Researchers screened about 2,000 potential patients, with only 149 fulfilling the initial criteria and 36 eventually enrolled in the study. All nine centers had at least three patients. Patients were an average of 41-years-old with an average diabetes duration of 27 years; they had an average BMI of 22. Almost all patients (n=35, 97%) had severe recurrent hypoglycemia, 20 (56%) patients had severe glycemic lability and 19 (53%) patients had progressive secondary complications of type 1 diabetes including neuropathy, retinopathy or nephropathy.

All 36 patients were enrolled between May 2001 and January 2003, with the primary end point (insulin independence with adequate glycemic control one year after the final transplantation) determined by June 2005. The researchers administered a total of 77 islet infusions, with 11 (31%) patients receiving one infusion, 9 (25%) patients receiving two infusions and 16 (44%) patients receiving three infusions.

Patients were followed for a median of 41 months (range = 37 to 50) after the first transplantation; 35 patients were evaluated after two years and 21 were evaluated after three or more years. All patients were given an immunosuppressive regimen involving daclizumab (Zenapax, Roche), sirolimus (Rapamune, Wyeth) and tacrolimus (Prograf, Astellas Pharma).

Results

One year after the final transplantation, 16 (44%) patients had reached the primary endpoint (five of these with one transplant, six with two transplants and five with three transplants). Ten (28%) patients had partial graft function and 10 patients had complete graft loss; four of the latter were due to primary nonfunction, two had early graft loss and four withdrew from further treatment.

“All [patients] with residual islet function were completely protected from severe hypoglycemic episodes, as reported from days 28 to 365 after transplantation,” the researchers wrote.

A total of 21 (58%) patients reached insulin independence, but 16 (76%) of these were insulin dependent again by the second year.

Eleven patients had at least partial graft function after three years, and six patients remained insulin independent. A correlation was found between attainment of insulin independence and autoantibody status (P=.03), and C-peptide secretion was detectable (>0.3 ng/mL) in 70% of patients at two years.

Replication at multiple centers

Shapiro told Endocrine Today that this study also indicates that the Edmonton Protocol can be successfully replicated at a large number of centers.

“The level of success in replication varies, depending on the center’s experience. If they have experience in making islets and giving the anti-rejection drugs, the results were unquestionably better,” he said.

The study’s primary endpoint was achieved by 12 (67%) of 18 patients at centers where at least four islet transplantations had been performed in the preceding two years; this is contrast to only four of 18 (22%) patients at sites where fewer than four had been performed (P=.007).

Patients experienced a total of 38 serious adverse events during the study, 23 of which were considered to be related to study therapy. These events included neutropenia (five cases), pneumonia, mouth ulcers, gastrointestinal conditions (two cases), fever, chest pain, pericardial effusion, pyelonephritis, worsening genital herpes and appendiceal abscess. There were also seven cases of acute intraperitoneal bleeding (9% of transfusions) related to the procedure itself.

Shapiro said that this trial indicates that this procedure is extremely effective in providing stable glycemic control and insulin independence. The latter, however, “is not permanent,” he said. “We lose insulin independence over time.”

The presence of relatively high levels of C-peptide indicates that patients still maintained some islet function that was “more than sufficient to provide stable glycemic control,” Shapiro said. “Islet transplantation is therefore still beneficial, even when patients are not completely insulin-free.”

Questions remain

Jonathan S. Bromberg, MD, PhD, and Derek LeRoith, MD, PhD, of the Mount Sinai School of Medicine in New York, wrote an accompanying editorial discussing the potential of islet transplantation. LeRoith is a member of the Endocrine Today Editorial Board.

“The study by Shapiro et al. shows that institutions all over the world can successfully perform the protocol with at least short-term results that are promising,” they wrote. “The problem remains that the medium- to long-term results are not durable, so much more work is needed.”

The question now is whether this procedure should be aimed at a much larger portion of the population. Other currently developing technologies, such as continuous glucose monitoring devices, have the potential to change diabetes care for every patient, not just a select few.

“Islet transplantation is at a crossroads,” Bromberg and LeRoith wrote. “It is clear that poor long-term results, high costs, and the relatively high incidence of major and minor serious adverse events make it difficult to argue for expansion of islet transplantation to the general population. Nonetheless, the dramatic discoveries and successful dissemination of information in a relatively short period encourage us to believe that these advances will continue apace. Additional research investments are likely to be high yield and to have a positive effect on many patients in the not-too-distant future.” – by Dave Levitan

For more information:

Shapiro AMJ, Ricordi C, Hering BJ, et al. International trial of the Edmonton Protocol for islet transplantation. N Engl J Med. 2006;355:1318-1330.

Bromberg JS, LeRoith D. Diabetes cure: is the glass half full? N Engl J Med. 2006;355:1372-1374.