Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry

Bernhard J. Hering; Cassandra M. Ballou; Melena D. Bellin; Elizabeth H. Payne; Fouad Kandeel; Piotr Witkowski; Rodolfo Alejandro; Michael R. Rickels; Franca B. Barton

doi:10.1007/s00125-022-05804-4

Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry

Bernhard J. Hering, Cassandra M. Ballou, Melena D. Bellin, Elizabeth H. Payne, Fouad Kandeel, Piotr Witkowski, Rodolfo Alejandro, Michael R. Rickels, Franca B. Barton

Research output: Contribution to journal › Article › peer-review

24 Scopus citations

Abstract

AIMS/HYPOTHESIS: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR).

METHODS: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs).

RESULTS: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA 1c <53 mmol/mol (7.0%), 73% had HbA 1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups.

CONCLUSIONS/INTERPRETATION: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes.

Original language	English (US)
Pages (from-to)	163-173
Number of pages	11
Journal	Diabetologia
Volume	66
Issue number	1
DOIs	https://doi.org/10.1007/s00125-022-05804-4
State	Published - Jan 2023

Bibliographical note

Funding Information:
The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UC4DK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The JDRF provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006 to 2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-10. PW is supported in part by the US Public Health Service Grant P30DK020595. The funding agencies of the study had no role in study design, data collection, data analysis, data interpretation or writing of this report.

Funding Information:
We thank all the study participants and staff at the centres who contributed study data: CBCT, Peter MacCallum Cancer Institute; University of Minnesota; University of Miami; University of Tennessee, Memphis; Baylor College of Medicine/The Methodist Hospital; University of Alberta; City of Hope; University of Virginia; Emory Transplant Center; UMass Memorial Health Care; Washington University, St Louis; University of Pennsylvania; Northwestern University; University of Chicago; University of Illinois, Chicago; San Raffaele Hospital; University of Colorado Health Sciences Center; Geneva University Hospitals; Benaroya Research Institute; Mayo Clinic; University of California, San Francisco; Weill Cornell Medical College; University of Wisconsin; Baylor Regional Transplant Institute; Lille University Hospital; St Vincent’s Institute; Westmead Hospital; and Grenoble University Hospital. This publication has been approved by the CITR Publications and Presentations Committee. BJH has an equity interest in and serves as a paid executive officer of Diabetes-Free, an organisation that may commercially benefit from the results of this research. This interest has been reviewed and managed by the University of Minnesota in accordance with its Conflict of Interest policies. MDB receives research support from ViaCyte and Dexcom and serves in an advisory capacity (DSMB) for Insulet. PW provide consulting service for Dompe Pharmaceutical and Sernova Corp, for which he received honoraria. PW currently provides consulting services to Vertex Pharmaceuticals, Eledon and Humancyte, for which he receives honoraria. RA provides consulting service for Lilly USA LLC, Vertex Pharmaceuticals and eGenesis Inc. MRR reports serving in an advisory capacity (DSMB) for Sernova Corp., and providing consulting services to Vertex Pharmaceuticals, for which he received honoraria. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. BJH designed the study, was involved in the analysis of data, co-wrote the first draft of the manuscript, and was the co-principal investigator of the study. CB compiled and analysed the data. MDB, FK, PW, RA, and MRR contributed to study design, critical review and editing of the manuscript. FBB designed the study, specified the analyses, coordinated and supervised the analysis of data, co-wrote the first draft of the manuscript, and was the co-principal investigator of the study. All authors contributed to revision of the report and agreed to its publication. The corresponding authors had full access to the data in the study and had final responsibility for the decision to submit for publication. EHP contributed to analysis and interpretation, critical review and editing of the manuscript and is the guarantor of this work.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Keywords

Clinical islet transplantation
Favourable factors
Severe hypoglycaemia
Type 1 diabetes

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1007/s00125-022-05804-4

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Cite this

Hering, B. J., Ballou, C. M., Bellin, M. D., Payne, E. H., Kandeel, F., Witkowski, P., Alejandro, R., Rickels, M. R., & Barton, F. B. (2023). Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry. Diabetologia, 66(1), 163-173. https://doi.org/10.1007/s00125-022-05804-4

Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry. / Hering, Bernhard J.; Ballou, Cassandra M.; Bellin, Melena D. et al.
In: Diabetologia, Vol. 66, No. 1, 01.2023, p. 163-173.

Research output: Contribution to journal › Article › peer-review

Hering, BJ, Ballou, CM, Bellin, MD, Payne, EH, Kandeel, F, Witkowski, P, Alejandro, R, Rickels, MR & Barton, FB 2023, 'Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry', Diabetologia, vol. 66, no. 1, pp. 163-173. https://doi.org/10.1007/s00125-022-05804-4

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abstract = "AIMS/HYPOTHESIS: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR).METHODS: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs).RESULTS: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA 1c <53 mmol/mol (7.0%), 73% had HbA 1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups. CONCLUSIONS/INTERPRETATION: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes.",

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note = "Funding Information: The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UC4DK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The JDRF provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006 to 2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-10. PW is supported in part by the US Public Health Service Grant P30DK020595. The funding agencies of the study had no role in study design, data collection, data analysis, data interpretation or writing of this report. Funding Information: We thank all the study participants and staff at the centres who contributed study data: CBCT, Peter MacCallum Cancer Institute; University of Minnesota; University of Miami; University of Tennessee, Memphis; Baylor College of Medicine/The Methodist Hospital; University of Alberta; City of Hope; University of Virginia; Emory Transplant Center; UMass Memorial Health Care; Washington University, St Louis; University of Pennsylvania; Northwestern University; University of Chicago; University of Illinois, Chicago; San Raffaele Hospital; University of Colorado Health Sciences Center; Geneva University Hospitals; Benaroya Research Institute; Mayo Clinic; University of California, San Francisco; Weill Cornell Medical College; University of Wisconsin; Baylor Regional Transplant Institute; Lille University Hospital; St Vincent{\textquoteright}s Institute; Westmead Hospital; and Grenoble University Hospital. This publication has been approved by the CITR Publications and Presentations Committee. BJH has an equity interest in and serves as a paid executive officer of Diabetes-Free, an organisation that may commercially benefit from the results of this research. This interest has been reviewed and managed by the University of Minnesota in accordance with its Conflict of Interest policies. MDB receives research support from ViaCyte and Dexcom and serves in an advisory capacity (DSMB) for Insulet. PW provide consulting service for Dompe Pharmaceutical and Sernova Corp, for which he received honoraria. PW currently provides consulting services to Vertex Pharmaceuticals, Eledon and Humancyte, for which he receives honoraria. RA provides consulting service for Lilly USA LLC, Vertex Pharmaceuticals and eGenesis Inc. MRR reports serving in an advisory capacity (DSMB) for Sernova Corp., and providing consulting services to Vertex Pharmaceuticals, for which he received honoraria. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. BJH designed the study, was involved in the analysis of data, co-wrote the first draft of the manuscript, and was the co-principal investigator of the study. CB compiled and analysed the data. MDB, FK, PW, RA, and MRR contributed to study design, critical review and editing of the manuscript. FBB designed the study, specified the analyses, coordinated and supervised the analysis of data, co-wrote the first draft of the manuscript, and was the co-principal investigator of the study. All authors contributed to revision of the report and agreed to its publication. The corresponding authors had full access to the data in the study and had final responsibility for the decision to submit for publication. EHP contributed to analysis and interpretation, critical review and editing of the manuscript and is the guarantor of this work. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.",

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T1 - Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry

AU - Hering, Bernhard J.

AU - Ballou, Cassandra M.

AU - Bellin, Melena D.

AU - Payne, Elizabeth H.

AU - Kandeel, Fouad

AU - Witkowski, Piotr

AU - Alejandro, Rodolfo

AU - Rickels, Michael R.

AU - Barton, Franca B.

N1 - Funding Information: The CITR has been funded continuously by grants from the National Institute of Diabetes and Digestive and Kidney Diseases since 2001 (Grants 1UC4DK098086-01, 1UC4DK114839-01) to collect data on the efficacy and safety of clinical islet transplantation from US and collaborating international institutions. The JDRF provided supplemental funding for reimbursement of efforts to report data from the European and Australian sites from 2006 to 2015. No other sponsors have provided support to the CITR. MRR is supported in part by Public Health Service Research Grant R01 DK 091331-10. PW is supported in part by the US Public Health Service Grant P30DK020595. The funding agencies of the study had no role in study design, data collection, data analysis, data interpretation or writing of this report. Funding Information: We thank all the study participants and staff at the centres who contributed study data: CBCT, Peter MacCallum Cancer Institute; University of Minnesota; University of Miami; University of Tennessee, Memphis; Baylor College of Medicine/The Methodist Hospital; University of Alberta; City of Hope; University of Virginia; Emory Transplant Center; UMass Memorial Health Care; Washington University, St Louis; University of Pennsylvania; Northwestern University; University of Chicago; University of Illinois, Chicago; San Raffaele Hospital; University of Colorado Health Sciences Center; Geneva University Hospitals; Benaroya Research Institute; Mayo Clinic; University of California, San Francisco; Weill Cornell Medical College; University of Wisconsin; Baylor Regional Transplant Institute; Lille University Hospital; St Vincent’s Institute; Westmead Hospital; and Grenoble University Hospital. This publication has been approved by the CITR Publications and Presentations Committee. BJH has an equity interest in and serves as a paid executive officer of Diabetes-Free, an organisation that may commercially benefit from the results of this research. This interest has been reviewed and managed by the University of Minnesota in accordance with its Conflict of Interest policies. MDB receives research support from ViaCyte and Dexcom and serves in an advisory capacity (DSMB) for Insulet. PW provide consulting service for Dompe Pharmaceutical and Sernova Corp, for which he received honoraria. PW currently provides consulting services to Vertex Pharmaceuticals, Eledon and Humancyte, for which he receives honoraria. RA provides consulting service for Lilly USA LLC, Vertex Pharmaceuticals and eGenesis Inc. MRR reports serving in an advisory capacity (DSMB) for Sernova Corp., and providing consulting services to Vertex Pharmaceuticals, for which he received honoraria. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work. BJH designed the study, was involved in the analysis of data, co-wrote the first draft of the manuscript, and was the co-principal investigator of the study. CB compiled and analysed the data. MDB, FK, PW, RA, and MRR contributed to study design, critical review and editing of the manuscript. FBB designed the study, specified the analyses, coordinated and supervised the analysis of data, co-wrote the first draft of the manuscript, and was the co-principal investigator of the study. All authors contributed to revision of the report and agreed to its publication. The corresponding authors had full access to the data in the study and had final responsibility for the decision to submit for publication. EHP contributed to analysis and interpretation, critical review and editing of the manuscript and is the guarantor of this work. Publisher Copyright: © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

PY - 2023/1

Y1 - 2023/1

N2 - AIMS/HYPOTHESIS: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR).METHODS: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs).RESULTS: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA 1c <53 mmol/mol (7.0%), 73% had HbA 1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups. CONCLUSIONS/INTERPRETATION: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes.

AB - AIMS/HYPOTHESIS: Islet transplantation has been studied in small cohorts of recipients with type 1 diabetes complicated by severe hypoglycaemic events (SHEs). We determined factors associated with favourable outcomes in a large cohort of recipients reported to the Collaborative Islet Transplant Registry (CITR).METHODS: In 398 non-uraemic islet transplant alone (ITA) recipients with type 1 diabetes and SHEs, transplanted between 1999 and 2015 and with at least 1 year follow-up, we analysed specified favourable outcomes against each of all available characteristics of pancreas donors, islet grafts, recipients and immunosuppressive regimens, as well as immunosuppression and procedure-related serious adverse events (SAEs).RESULTS: Four factors were associated with the highest rates of favourable outcomes: recipient age ≥35 years; total infused islets ≥325,000 islet equivalents; induction immunosuppression with T cell depletion and/or TNF-α inhibition; and maintenance with both mechanistic target of rapamycin (mTOR) and calcineurin inhibitors. At 5 years after the last islet infusion, of the recipients meeting these four common favourable factors (4CFF; N=126), 95% were free of SHEs, 76% had HbA 1c <53 mmol/mol (7.0%), 73% had HbA 1c <53 mmol/mol (7.0%) and absence of SHEs, and 53% were insulin independent, significantly higher rates than in the remaining recipients (<4CFF; N=272). The incidence of procedural and immunosuppression-related SAEs per recipient that resulted in sequelae, disability or death was low in both the 4CFF (0.056 per person) and <4CFF (0.074 per person) groups. CONCLUSIONS/INTERPRETATION: In recipients with type 1 diabetes complicated by SHEs, islet transplantation meeting 4CFF protected 95% from SHEs at 5 years after the last islet infusion and exerted a large and significant benefit on glycaemic control, with an acceptable safety profile for this subgroup of type 1 diabetes.

KW - Clinical islet transplantation

KW - Favourable factors

KW - Severe hypoglycaemia

KW - Type 1 diabetes

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Factors associated with favourable 5 year outcomes in islet transplant alone recipients with type 1 diabetes complicated by severe hypoglycaemia in the Collaborative Islet Transplant Registry

Abstract

Bibliographical note

Keywords

PubMed: MeSH publication types

UN SDGs

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