Combination Therapy May Help in Islet Transplant Failure

JDRF-funded scientists provided new evidence that a two-drug combination can extend the function of pancreatic islet transplants that have begun to fail and restore insulin independence in some transplant recipients with type 1 diabetes (T1D). This research finding was presented at the American Diabetes Association’s 72nd Scientific Sessions in Philadelphia in June 2012 by Peter Senior, M.D., Ph.D., medical director of the Clinical Islet Transplant Program at the University of Alberta, Canada.

Islet transplantation is a life-changing treatment for some individuals with T1D. In this procedure, clusters of hormone-producing cells, including insulin-producing beta cells, are transplanted from a donor pancreas into the liver of an individual with T1D. When the procedure is successful, the transplanted islets engraft or embed themselves into the recipient’s liver, produce insulin, and restore physiological regulation of glucose to the patient. Some transplant recipients become fully insulin-independent, meaning they are no longer reliant on insulin injections or a pump for survival. Other recipients are able to drastically reduce their insulin needs. However, maintaining insulin independence in the long term is a challenge. For a variety of reasons, transplanted islets often fail over time, so that recipients must resume or increase their insulin therapy.

Dr. Senior and his colleagues had two goals in mind when they tested the combination therapy of sitagliptin and pantoprazole. They asked whether these drugs could improve how well transplanted beta cells release insulin in response to blood glucose and whether the drugs could prevent beta cell death and stimulate the growth of new beta
cells in transplant recipients.

Sitagliptin is an FDA-approved drug for the treatment of type 2 diabetes that promotes beta cell survival and function. Pantoprazole, also FDA-approved, is used to treat gastroesophageal reflux disease, or GERD. Researchers have previously shown that a combination of sitagliptin and high doses of a drug similar in action to pantoprazole trigger new beta cell formation in animal models of T1D.

The study team recruited eight individuals who had received islet transplants from two months to 12 years prior to the start of the study and were showing signs of early transplant failure. These subjects were treated with 100 mg sitagliptin per day and 40 mg pantoprazole twice daily for six months. By the end of the treatment period, five of the eight subjects had regained insulin independence. The study participants tolerated the drugs well, and none of them experienced an increase in episodes of hypoglycemia.

While these findings are encouraging, it is important to note that only four of the five patients maintained their insulin independence at six months after the drug treatment period ended. Furthermore, the insulin dosage increased after the treatment was stopped for six months in the other patients. This outcome suggests that the drug combination
of sitagliptin and pantoprazole may improve metabolic control and the function of transplanted islets during the treatment, but there is a lack of evidence for a sustained increase in functional beta cell mass or regeneration of beta cells in the failing islet transplant setting.

“The drugs’ effect on islet transplants is important as we continue to look for ways to maintain long-term islet graft function,” explains Albert Hwa, Ph.D., JDRF senior scientific program manager of cure therapies. “In addition, without a means to directly measure functional beta cell mass, islet transplant recipients provide a unique opportunity to test these drugs’ effect on beta cell mass.”

This study sheds light on a key JDRF research area—improving beta cell survival and function in islet transplant recipients, as well as in newly diagnosed individuals with T1D who might have some remaining beta cells in their pancreases. JDRF is supporting a clinical research study with a similar combination of drugs—sitagliptin and lansoprazole—with the goal to restore beta cell function in people with new-onset T1D. This multicenter study, known as the REPAIR-T1D trial, is led by Alex Rabinovitch, M.D., of the Sanford Research Center in Sioux Falls, ND. The trial is in progress with 54 enrolled subjects.