Outcomes of Clinical Islet Transplantation: 1999-2010
Outcomes of Clinical Islet Transplantation: 1999-2010
OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.
RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years.
RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).
CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.
Allogeneic islet transplantation offers a minimally invasive option for β-cell replacement in people with type 1 diabetes complicated by recurrent severe hypoglycemia and/or marked glycemic lability. Before 1999, less than 10% of islet transplant recipients achieved insulin independence. In 2000, the Edmonton Protocol for islet transplantation achieved insulin independence in seven consecutive participants who received islets from more than one donor under a steroid-free immunosuppression regimen. After this proof-of-concept success, islet transplant programs expanded in North America and elsewhere. These centers have offered evolving strategies of islet preparation and immunosuppression, although the limited resources available have prevented anything but independent Phase I/II attempts to standardize processes, achieve success, and stabilize outcomes.
Even in the absence of insulin independence, an islet transplant can protect type 1 diabetic recipients from severe hypoglycemic episodes as long as residual islet graft function is maintained, as proven by restoration of C-peptide production. Despite this compelling rationale, islet transplantation for type 1 diabetes has produced variable success and elusive durability, has frequently required multiple donor organs, and has balanced one disease load—severe hypoglycemia—with another—long-term immunosuppression. In some countries outside the U.S., islet transplantation has been designated and funded as nonexperimental over the last decade, where the trade-off between severe hypoglycemia and the risks of immunosuppression was felt to be justifiable in carefully selected patients. Islet transplantation remains an experimental procedure in the U.S. and awaits formal results of ongoing Phase III trials to justify biologic licensure and transition to standard of care.
The Collaborative Islet Transplant Registry (CITR) has been established to monitor progress and safety of islet transplantation by using data from the U.S., Canada, and several centers in Europe and Australia supported by the Juvenile Diabetes Research Foundation (JDRF). The CITR represents the most complete collection of information on islet transplantation in the last decade. The purpose of the present inquiry is to describe trends of primary outcomes and safety profiles of islet transplantation according to cohorts defined by the year of first islet infusion (early: 1999–2002; mid: 2003–2006; or recent: 2007–2010). The analysis comprises allogeneic islet-alone and islet-after-kidney (IAK) transplants performed through 31 December 2010 with data updated through 4 January 2012.
Abstract and Introduction
Abstract
OBJECTIVE To describe trends of primary efficacy and safety outcomes of islet transplantation in type 1 diabetes recipients with severe hypoglycemia from the Collaborative Islet Transplant Registry (CITR) from 1999 to 2010.
RESEARCH DESIGN AND METHODS A total of 677 islet transplant-alone or islet-after-kidney recipients with type 1 diabetes in the CITR were analyzed for five primary efficacy outcomes and overall safety to identify any differences by early (1999–2002), mid (2003–2006), or recent (2007–2010) transplant era based on annual follow-up to 5 years.
RESULTS Insulin independence at 3 years after transplant improved from 27% in the early era (1999–2002, n = 214) to 37% in the mid (2003–2006, n = 255) and to 44% in the most recent era (2007–2010, n = 208; P = 0.006 for years-by-era; P = 0.01 for era alone). C-peptide ≥0.3 ng/mL, indicative of islet graft function, was retained longer in the most recent era (P < 0.001). Reduction of HbA1c and resolution of severe hypoglycemia exhibited enduring long-term effects. Fasting blood glucose stabilization also showed improvements in the most recent era. There were also modest reductions in the occurrence of adverse events. The islet reinfusion rate was lower: 48% by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01). Recipients that ever achieved insulin-independence experienced longer duration of islet graft function (P < 0.001).
CONCLUSIONS The CITR shows improvement in primary efficacy and safety outcomes of islet transplantation in recipients who received transplants in 2007–2010 compared with those in 1999–2006, with fewer islet infusions and adverse events per recipient.
Introduction
Allogeneic islet transplantation offers a minimally invasive option for β-cell replacement in people with type 1 diabetes complicated by recurrent severe hypoglycemia and/or marked glycemic lability. Before 1999, less than 10% of islet transplant recipients achieved insulin independence. In 2000, the Edmonton Protocol for islet transplantation achieved insulin independence in seven consecutive participants who received islets from more than one donor under a steroid-free immunosuppression regimen. After this proof-of-concept success, islet transplant programs expanded in North America and elsewhere. These centers have offered evolving strategies of islet preparation and immunosuppression, although the limited resources available have prevented anything but independent Phase I/II attempts to standardize processes, achieve success, and stabilize outcomes.
Even in the absence of insulin independence, an islet transplant can protect type 1 diabetic recipients from severe hypoglycemic episodes as long as residual islet graft function is maintained, as proven by restoration of C-peptide production. Despite this compelling rationale, islet transplantation for type 1 diabetes has produced variable success and elusive durability, has frequently required multiple donor organs, and has balanced one disease load—severe hypoglycemia—with another—long-term immunosuppression. In some countries outside the U.S., islet transplantation has been designated and funded as nonexperimental over the last decade, where the trade-off between severe hypoglycemia and the risks of immunosuppression was felt to be justifiable in carefully selected patients. Islet transplantation remains an experimental procedure in the U.S. and awaits formal results of ongoing Phase III trials to justify biologic licensure and transition to standard of care.
The Collaborative Islet Transplant Registry (CITR) has been established to monitor progress and safety of islet transplantation by using data from the U.S., Canada, and several centers in Europe and Australia supported by the Juvenile Diabetes Research Foundation (JDRF). The CITR represents the most complete collection of information on islet transplantation in the last decade. The purpose of the present inquiry is to describe trends of primary outcomes and safety profiles of islet transplantation according to cohorts defined by the year of first islet infusion (early: 1999–2002; mid: 2003–2006; or recent: 2007–2010). The analysis comprises allogeneic islet-alone and islet-after-kidney (IAK) transplants performed through 31 December 2010 with data updated through 4 January 2012.