First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 6: patient selection for pilot clinical trials of islet xenotransplantation.

Pancreas and Islet Transplantation

Problematic hypoglycemia is defined as a condition in which episodes of severe hypoglycemia are unpredictable and/or cannot be easily explained or prevented, typically associated with impaired awareness of hypoglycemia. The treatment algorithm for patients with type 1 diabetes and problematic hypoglycemia emphasizes the stepwise approach including structured education regarding multiple daily injections of insulin, use of technology such as sensor-augmented pump with low glucose suspension, and islet or pancreas transplantation. Although the prevalence of insulin independence at 5 years is 25~50% in most recent clinical trials of islet transplantation, both islet and pancreas transplantation are equally efficient to cure severe hypoglycemia for more than 5 years in about 70% of the recipients. To date, international cohorts of clinical islet transplantation such as the French-Swiss GRAGIL Network have successfully reproduced the long-term C-peptide positivity initially achieved with the Edmonton protocol, with long-term insulin independence demonstrated in selected cases. Several cases with partial islet graft function have been reported in Korea, with the first case of long-term insulin independence being reported in late 2015. Therefore, islet transplantation can offer freedom from life-threatening severe hypoglycemia for type 1 diabetes patients with problematic hypoglycemia, even in non-responders to the latest technology-based treatment.

The discovery of insulin in 1922 changed the treatment of type 1 diabetes mellitus (DM) forever. Insulin was the first effective therapy for type 1 DM; however, its success engendered a terrible paradox for patients with this disease. The use of insulin transformed type 1 DM from a rapidly fatal

Chapter 35 - Simultaneous islet-kidney and islet-after-kidney transplantation

The International Xenotransplantation Association has updated its original "Consensus Statement on Conditions for Undertaking Clinical Trials of Porcine Islet Products in Type 1 Diabetes," which was published in Xenotransplantation in 2009. This update is timely and important in light of scientific progress and changes in the regulatory framework pertinent to islet xenotransplantation. Except for the chapter on "informed consent," which has remained relevant in its 2009 version, all other chapters included in the initial consensus statement have been revised for inclusion in this update. These chapters will not provide complete revisions of the original chapters; rather, they restate the key points made in 2009, emphasize new and under-appreciated topics not fully addressed in 2009, suggest relevant revisions, and communicate opinions that complement the consensus opinion. Chapter 1 provides an update on national regulatory frameworks addressing xenotransplantation. Chapter 2 a, previously Chapter 2, suggests several important revisions regarding the generation of suitable source pigs from the perspective of the prevention of xenozoonoses. The newly added Chapter 2b discusses conditions for the use of genetically modified source pigs in clinical islet xenotransplantation. Chapter 3 reviews porcine islet product manufacturing and release testing. Chapter 4 revisits the critically important topic of preclinical efficacy and safety data required to justify a clinical trial. The main achievements in the field of transmission of all porcine microorganisms, the rationale for more proportionate recipient monitoring, and response plans are reviewed in Chapter 5. Patient selection criteria and circumstances where trials of islet xenotransplantation would be both medically and ethically justified are examined in Chapter 6 in the context of recent advances in available and emerging alternative therapies for serious and potentially life-threatening complications of diabetes. It is hoped that this first update of the International Xenotransplantation Association porcine islet transplant consensus statement will assist the islet xenotransplant scientific community, sponsors, regulators, and other stakeholders actively involved in the clinical translation of islet xenotransplantation.

Pancreatic transplantation for patients with Type I diabetes

Impaired awareness of hypoglycemia has been found to be prevalent in 20% to 40% of people with type 1 diabetes. If a similar prevalence exists in Koreans with type 1 diabetes, at a minimum, thousands of people with type 1 diabetes suffer at least one unpredicted episode of severe hypoglycemia per year in Korea. For patients with problematic hypoglycemia, an evidence-based stepwise approach was suggested in 2015. The first step is structured education regarding multiple daily injections of an insulin analog, and the second step is adding a technological intervention, such as continuous subcutaneous insulin infusion or real-time continuous glucose monitoring. The next step is a sensor-augmented pump, preferably with a low glucose suspension feature or very frequent contact, and the final step is islet or pancreas transplantation. In Korea, however, none of these treatments are reimbursed by the National Health Insurance, and thus have not been widely implemented. The low prevalence of type 1 diabetes means that Korean physicians are relatively unfamiliar with the new technologies in this field. Therefore, the roles of new technologies and pancreas or islet transplantation in the treatment of problematic hypoglycemia need to be defined in the current clinical setting of Korea.

Impaired awareness of hypoglycemia (IAH) has been linked to an increased rate of severe hypoglycemia (SH) in T1DM. Yet, few investigations have focused on quantifying this relationship in the context of T2DM, particularly from a pragmatic epidemiological lens. This study leverages the value of self-reported SH data to explore the real-world, population-based effect of IAH severity on SH rates in T2DM. A validated questionnaire (InHypo-DMPQ) was administered online to a nationally representative panel comprising Canadians (≥18 years) with T2DM using insulin and/or secretagogues. Data were collected on respondents’ socio-demographic/clinical traits; self-reported incidence of SH (in the past year); and IAH severity, trisected by no, moderate, and severe impairment. Multivariable negative binomial regression (NBR) analysis was used to isolate the effect of IAH on SH. A directed acyclic graph was devised to identify the minimally sufficient adjustment set. Of the 452 complete respondents (mean age: 53.2 (SD: 14.7) years; male: 56%), 6% were classified with severe IAH, 67% with moderate IAH, and 27% with no IAH. Those with severe IAH had the highest crude annual SH rate (5.89 events/person-year, 95% CI: 5.01-6.88), which over doubled and tripled the SH rate in people with moderate IAH (p<0.001) and no IAH (p<0.001), respectively. The adjusted NBR analysis revealed a statistically significant association between IAH and SH (p=0.039). Individuals with severe IAH reported an adjusted annual SH rate that was 3.23 (95% CI: 1.13-9.27, p=0.029) times greater than those with no IAH. A similar trend was observed for moderate IAH versus no IAH (p=0.038). This real-world, population-based study provides timely insight into the high prevalence of moderate and severe IAH in people with T2DM using insulin and/or secretagogues. The marked impact of IAH on increased SH rates underscores a pressing need for the clinical prioritization of IAH assessment and management in T2DM. Disclosure A. Ratzki-Leewing: None. S.B. Harris: Advisory Panel; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Lilly/Boehringer Ingelheim, Merck & Co., Inc., Novo Nordisk Inc., Sanofi. Research Support; Self; Abbott, AstraZeneca, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Sanofi. Other Relationship; Self; Canadian Diabetes Association, Canadian Institutes of Health Research, The Lawson Foundation. N.H. Au: None. S. Webster-Bogaert: None. J.B. Brown: None. S.M. Reichert: Advisory Panel; Self; Abbott, AstraZeneca, Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Canadian Institutes of Health Research. Speaker's Bureau; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi. B.L. Ryan: None. Funding Sanofi Canada

IAH occurs in up to 1/3 of adults with T1D and it increases the risk of severe hypoglycemia (SH).Studies demonstrate that using CGM reduces the time spent in hypoglycemia (HG), but the effect of CGM on reversing IAH is not clear. We have enrolled many study subjects with T1D and IAH over the years and recently contacted them to determine how many continue to have IAH, how many have used CGM, and if there is a correlation between CGM use and restoration of HG awareness. Thirty six with T1D and IAH according to the Clarke/Cox questionnaire (CC) administered 2009-2015 were contacted to complete an online survey that included the CC, the Gold questionnaire, and questions about their diabetes. 12 M, 11 F responded. One had an islet cell transplant and was excluded. Median duration was 36 ± 12 years, mean age was 50 ± 12 years and the median HgB A1C was 6.8 ± 1%. Persistent IAH defined by both questionnaires was typical. Nineteen of 22 classified as IAH on the current survey reported severe HG over the last 6 mo. While there was a trend that showed consistent use of CGM was higher among people with no episodes of severe HG over the last 6 months this was not statistically significant. These observations show that persistent IAH is common in T1D. While the consistent use of CGM among our participants was high it did not translate into restoration of HG awareness in this population. Consistent use of CGM defined as more than 75% of the time over the last six monthsNo consistent use of CGMParticipants with persistent IAH (n = 18/22 using Gold)126Participants with persistent IAH (n = 19/22 using Cox)137Participants without persistent IAH (n= 4/22 using Gold)22Participants without persistent IAH (n= 3/22 using Cox)12Participants with severe HG in 6 months before survey (n = 19/22)118Participants without severe HG in 6 months before survey (n = 3/22)21 Disclosure K. Zekarias: None. A. Moheet: None. A. Kumar: None. E.R. Seaquist: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company, Sanofi, Zucera, InfoMed, 360 consulting. Other Relationship; Self; Novo Nordisk Inc..

Pancreas.

It's education, Jim, but not as we know it

Due to the recent changes in reimbursement politics in islet and pancreas transplantation in Switzerland, the question, which patients with type 1-diabetes mellitus get which form of beta-cell replacement, is of utmost importance for referring physicians. As of July 1, 2010 all forms of islet- or pancreas-transplantations are reimbursed by the Swiss health care system. The limited availability of donor organs and the necessity of transplantation of the islets of several pancreata in order to achieve insulin independence has led to a change in paradigms in Switzerland, where insulin independence by multiple islet transplantations is not the key goal in islet transplantation any longer. The primary goal is achieving a good blood glucose control and avoidance of severe hypoglycaemic episodes. This goal can be achieved in 80 - 90 % of all patients. Only if this goal cannot be achieved by a single islet transplantation, a second or third islet transplantation is performed. By adapting this strategy more patients can benefit from this new therapy. Unlike the North American centers, the Swiss centers in Zurich and Geneva concentrated their efforts on islet after kidney and simultaneous islet kidney transplantation. Due to the organ donor shortage in Switzerland, 50 % of kidney transplants are nowadays living-organ donations, therefore this option has to be included in the decision tree of a beta cell replacement. The choice between islet and pancreas transplantation depends on the existence of diabetes complications (because the perioperative risk is considerably higher in pancreas transplantation) and the potential benefit of a pancreas- or islet transplantation. The first question in the decision tree is, therefore, whether the patient with type 1-diabetes and severe renal failure is a potential candidate for simultaneous pancreas-islet transplantation. If the perioperative risk is considered to be too high, or if revascularisation procedures cannot be done before transplantation, the patient qualifies only for islet transplantation. If a living organ donation for the kidney is possible and the patient not yet on dialysis then the patient can be listed for simultaneous islet-kidney or pancreas-kidney-transplantation. If dialysis is imminent or already performed, a living-donor kidney should be transplanted with the option of a later islet- or pancreas after kidney transplantation. If the patient with type 1-diabetes mellitus is able to maintain a reasonable glycemic level, he would be a good candidate for islet transplantation. If the patient is willing to take the additional risk of complications associated with a pancreas transplant, was never able to maintain a good glycated haemoglobin, has an acceptable perioperative risk, and wishes to become insulin-independent, a simultaneous pancreas-kidney transplant would be recommended. If the kidney has already been transplanted previously, a pancreas- after kidney transplantation would be the procedure of choice. An islet or pancreas transplantation alone is reserved for the patient with type 1-diabetes with a good renal function and frequent life-threatening hypoglycemias, which have to be balanced against the risks of a life-long immunosuppression. In this review article the advantages, disadvantages, and current indications for both beta-cell replacement options in Switzerland are discussed in the light of the available evidence with the help of a new flow chart.

β-Cell replacement therapy, including allogeneic pancreas and islet transplantation, can normalize HbA1c levels in unstable type 1 diabetic (T1D) patients, but a donor shortage is a serious issue. To overcome this problem, xenotransplantation is an attractive option. In fact, islet transplantation from porcine pancreata was performed in the 1990s, which opened the door for islet xenotransplantation, but the possibility of porcine endogenous retrovirus (PERV) infection was raised, which has restricted progress in this field. The International Xenotransplantation Association published a consensus statement on conditions for undertaking clinical trials of porcine islet products in T1D to restart islet xenotransplantation safely. Clinical porcine islet xenotransplantation was restarted under comprehensive regulations in New Zealand. In addition, newly emerged gene-editing technologies have activated the xenotransplantation field. Islet xenotransplantation is becoming a clinical reality, with the results of recent studies showing promise to advance this field.

Pancreas transplantation is a crucial surgical intervention for managing diabetes, but it faces challenges such as its invasive nature, stringent patient selection criteria, organ scarcity, and centralized expertise. Despite the steadily increasing number of pancreas transplants in the United States, there is a need to understand global trends in interest to increase awareness of and participation in pancreas and islet cell transplantation. We analyzed Google Search trends for "Pancreas Transplantation" and "Islet Cell Transplantation" from 2004 to 14 November 2023, assessing variations in search interest over time and across geographical locations. The Augmented Dickey-Fuller (ADF) test was used to determine the stationarity of the trends (p < 0.05). Search interest for "Pancreas Transplantation" varied from its 2004 baseline, with a general decline in peak interest over time. The lowest interest was in December 2010, with a slight increase by November 2023. Ecuador, Kuwait, and Saudi Arabia showed the highest search interest. "Islet Cell Transplantation" had its lowest interest in December 2016 and a more pronounced decline over time, with Poland, China, and South Korea having the highest search volumes. In the U.S., "Pancreas Transplantation" ranked 4th in interest, while "Islet Cell Transplantation" ranked 11th. The ADF test confirmed the stationarity of the search trends for both procedures. "Pancreas Transplantation" and "Islet Cell Transplantation" showed initial peaks in search interest followed by a general downtrend. The stationary search trends suggest a lack of significant fluctuations or cyclical variations. These findings highlight the need for enhanced educational initiatives to increase the understanding and awareness of these critical transplant procedures among the public and professionals.

Attaining glycemic targets without severe hypoglycemic events (SHEs) is a challenging treatment goal for patients with type 1 diabetes complicated by impaired awareness of hypoglycemia (IAH). The CIT Consortium Protocol 07 (CIT-07) trial showed islet transplantation to be an effective treatment for subjects with IAH and intractable SHEs. We evaluated health-related quality of life (HRQOL), functional health status, and health utility before and after pancreatic islet transplantation in CIT-07 trial participants. Four surveys, the Diabetes Distress Scale (DDS), the Hypoglycemic Fear Survey (HFS), the Short Form 36 Health Survey (SF-36), and the EuroQoL 5 Dimensions (EQ-5D), were administered repeatedly before and after islet transplantation. Summary statistics and longitudinal modeling were used to describe changes in survey scores from baseline and to characterize change in relation to a minimally important difference (MID) threshold of half an SD. Improvements in condition-specific HRQOL met the MID threshold. Reductions from baseline in the DDS total score and its four DDS subscales (all P ≤ 0.0013) and in the HFS total score and its two subscales (all P < 0.0001) were observed across all time points. Improvements were observed after both 1 and 2 years for the EQ-5D visual analog scale (both P < 0.0001). In CIT-07, 87.5% of the subjects achieved the primary end point of freedom from SHE along with glycemic control (HbA1c <7% [<53 mmol/mol]) at 1 year post-initial islet transplantation. The same subjects reported consistent, statistically significant, and clinically meaningful improvements in condition-specific HRQOL as well as self-assessments of overall health.