The hope for a cure fails: Two years after receiving transplants of insulin-producing beta islet cells, only five of 36 patients with type 1 diabetes remained free of the need for insulin injections. Although most patients in this small multinational trial sooner or later reverted to exogenous insulin, the transplanted cells continued to protect the majority from severe hypoglycemia and helped them maintain lower levels of glycosylated hemoglobin (HbA1c), reported A.M. James Shapiro, M.D., Ph.D., of the University of Alberta here, and colleagues.
The patients were treated under the Edmonton protocol, in which islet cells harvested from the pancreases of brain-dead donors are infused into the portal vein of the liver. The investigators reported two-year follow-up results on the 36 patients in the Sept. 27 issue of the New England Journal of Medicine.
In an accompanying editorial, Jonathan S. Bromberg, M.D., Ph.D., and Derek LeRoith, M.D., Ph.D., of Mount Sinai in New York lauded the work of the Edmonton protocol researchers, but noted that the technique is fraught with challenges and may address the needs of only a fraction of patients with type 1 diabetes.
"It is noteworthy that in order to recruit 36 patients, the investigators screened more than 2,000 subjects for eligibility," they wrote. "Only 7% fulfilled the initial screening criteria, which included severe recurrent hypoglycemia, severe glycemic lability, progressive secondary complications, and the failure of conventional therapy."
In addition, they noted that only 45% of islet isolations resulted in transplants, there was a high rate of serious adverse events, and the clinical results were mixed.
The study was designed to test whether the protocol, developed here, could be reproduced successfully elsewhere. To this end, investigators in nine centers in Canada, the United States, Germany, and Switzerland treated four patients each. The patients were all adults from the ages of 18 to 65 with type 1 diabetes who could not achieve good glucose control despite best efforts.
Each patient received infusions into the hepatic portal vein of prepared donor islets from brain-dead multi-organ donors. Post-transplant immunosuppression consisted of five doses of Zenapax (daclizumab) at 1 mg/kg administered intravenously over eight weeks following each transplantation. Rapamune (sirolimus) was administered once daily to achieve a target trough therapeutic range of 12 to 15 ng/ml for three months after transplantation, after which the target trough range was lowered to 7 to 12 ng per ml. Prograf (tacrolimus) was administered twice daily and adjusted to achieve a target trough level of 3 to 6 ng/ml.
The primary study endpoint was insulin independence, which the authors defined as freedom from the need to take exogenous insulin, with adequate glycemic control, as defined by an HbA1c level of less than 6.5%, and a fasting overnight glucose level not exceeding 140 mg/dL (7.8 mmol/L) more than three times in any week (based on the morning fasting glucose level) and not exceeding two-hour postprandial levels of 180 mg/dL(10 mmol/L) more than four times per week.
"We recognize that applying more stringent measures for glycemic control might have altered the outcome," the investigators wrote.
Secondary endpoints included insulin independence with adequate glycemic control throughout follow-up; improved values for levels of HbA1c, the mean amplitude of glycemic excursions, and of basal and stimulated blood C-peptide levels in response to arginine challenge; and a reduction over baseline in the need for insulin.
They found that at one year, 16 of the 36 participants (44%) were insulin independent and had good glycemic control, 10 (28%) had partial function, and 10 (28%) had experienced complete graft loss.
In all, 21 of the 36 patients had achieved the primary study endpoint at some time during the study, but 16 of the 21 (76%) required exogenous insulin again by two years. The remaining five participants remained insulin independent at two years.
There were 38 total serious adverse events, 23 of which were considered to be related to the study therapy; 18 of these events were associated with hospitalization.
Serious adverse events included neutropenia, pneumonia, mouth ulcers, gastrointestinal conditions, fever, chest pain, pericardial effusion, pyelonephritis, worsening genital herpes, and appendiceal abscess
The results suggest that "islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable," the investigators wrote.
Nonetheless, there was evidence that residual, persistent islet function even in the absence of insulin independence provides protection from severe hypoglycemia and improved HbA1c levels, the authors wrote.
Both the authors and the editorialists pointed out that pancreatic transplantation was the better option for the general population of patients with type 1 diabetes.
"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," worte Drs. Bomberg and LeRoith.
Shapiro AMJ et al. "International Trial of the Edmonton Protocol for Islet Transplantation." N Engl J Med 2006;355:1318-30
Bromberg JS and LeRoith D. "Diabetes Cure — Is the Glass Half Full?" N Engl J Med 2006;355:1372-74
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