Islet Cell Transplantation for Patients with Unstable or Uncontrollable Diabetes Mellitus: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines

Christopher Freige; Suzanne McCormack; Caitlyn Ford

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Islet Cell Transplantation for Patients with Unstable or Uncontrollable Diabetes Mellitus: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines

CADTH Rapid Response Report: Summary with Critical Appraisal

Christopher Freige, Suzanne McCormack, and Caitlyn Ford.

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Apr 29.

Abbreviations

AMSTAR 2: A Measurement Tool to Assess Systematic Reviews 2
CSII: continuous subcutaneous insulin infusion
GRADE: Grading of Recommendations Assessment, Development and Evaluation
HbA1c: glycated hemoglobin A1c
ICER: incremental cost-effectiveness ratio
NRS: non-randomized study
QALY: quality-adjusted life year
RCT: randomized controlled trial
SR: systematic review

Context and Policy Issues

Type 1 diabetes is a chronic autoimmune disease characterized by the destruction of pancreatic beta cells which leads to an insulin deficiency.¹ The onset of type 1 diabetes mostly occurs before 25 years of age, but can also occur later in life.¹ In 2015, 3.4 million Canadians were living with diabetes, of which an estimated 9% of adult patients and most pediatric patients are classified as type 1. Of this cohort, 0.3% of patients suffer from labile diabetes (also referred to as brittle or unstable diabetes and meaning hard to control) and may experience frequent episodes of hyperglycemia and hypoglycemia, diabetic ketoacidosis, and hypoglycemic unawareness.² The lability of these patients’ blood glucose levels leads to a decreased quality of life and may reduce life expectancy.²

Type 1 diabetes is generally treated with insulin replacement therapy in the form of multiple daily injections.¹ However, one alternative to insulin therapy, which may be beneficial to patients with labile diabetes, involves restoring endogenous insulin production via islet cell transplantation.³ Islet cell transplantation involves the infusion of purified islet cells from a deceased donor pancreas into the liver through the portal vein.³ As such, islet cell transplantation recipients require life-long treatment with immunosuppressive agents.³ With the introduction of ever improving, steroid free immunosuppression regimens (the first of which was the Edmonton Protocol in the year 2000), islet cell transplantation has become an increasingly feasible treatment option for patients with labile diabetes.²

In patients with type 1 diabetes, islet cell transplantation may result in glucose stability (i.e., a reduction or elimination of hypoglycemia), improvement in glycated hemoglobin A1c (HbA1c), insulin independence, and may stabilize or improve microvascular complications (retinopathy and neuropathy) of diabetes.³ However, as a result of the small number of specialized transplantation centers and donor pancreases, the availability of treatment with islet cell transplantations for patients with type 1 diabetes has been limited.³

A CADTH report⁴ published in 2014 reviewed the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding islet cell transplantation in patients with unstable diabetes. The report concluded that there was limited evidence to suggest that islet transplantation was effective in improving clinical outcomes in patients with unstable type 1 diabetes.⁴ Another CADTH report,⁵ which examined islet cell transplantation relative to different interventions, was published in March 2020 and provided a reference list of studies and evidence-based guidelines published since the end of the aforementioned report’s literature search. This report aims to provide a summary and critical appraisal of the evidence regarding the clinical effectiveness, cost-effectiveness, and evidence-based guidelines regarding the use of islet cell transplantation in patients with unstable type I diabetes mellitus which was identified in the previous CADTH Reference List report.⁵

Research Questions

What is the clinical effectiveness of islet cell transplantation in patients with unstable type I diabetes mellitus?
What is the cost-effectiveness of islet cell transplantation in patients with unstable type I diabetes mellitus?
What are the evidence-based guidelines regarding the use of islet cell transplantation in patients with unstable type I diabetes mellitus?

Key Findings

One systematic review, one randomized controlled trial, and five non-randomized studies were identified regarding the clinical effectiveness of islet cell transplantation compared to insulin therapy in patients with unstable type 1 diabetes. Overall, compared to insulin therapy, islet cell transplantation was associated with better glycemic control, quality of life, and some secondary complications of diabetes including macrovascular and microvascular complications. However, the results of these studies should be interpreted with caution as numerous methodological limitations were identified. One relevant economic evaluation was identified which compared the cost-effectiveness of islet cell transplantation to intensive insulin therapy in a theoretical cohort of patients with unstable type 1 diabetes. Islet cell transplantation was not cost-effective. One evidence-based guideline developed by Diabetes Canada was identified that states that patients with unstable type 1 diabetes who have preserved renal function or who have had a successful kidney transplant may be considered for islet cell transplantation (low quality evidence; weak recommendation).

Methods

Literature Search Methods

This report makes use of a literature search conducted for a previous CADTH report.⁵ The limited literature search was conducted by an information specialist on key resources including PubMed, the Cochrane Library, the University of York Centre for Reviews and Dissemination (CRD) databases, the websites of Canadian and major international health technology agencies, as well as a focused internet search. The search strategy was comprised of both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concepts were islet cell transplantation and type 1 diabetes. No filters were applied to limit the retrieval by study type. Where possible, retrieval was limited to the human population. The search was also limited to English language documents published between January 1, 2014 and February 25, 2020. Internet links were provided, where available.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles and abstracts were reviewed and potentially relevant articles were retrieved and assessed for inclusion. The final selection of full-text articles was based on the inclusion criteria presented in Table 1.

Table 1

Selection Criteria.

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they were duplicate publications, or were published prior to 2014. Guidelines with unclear methodology were also excluded.

Critical Appraisal of Individual Studies

The included systematic review (SR) was critically appraised by one reviewer using A Measurement Tool to Assess Systematic Reviews 2⁶ (AMSTAR 2), primary clinical studies were critically appraised using the Downs and Black Checklist,⁷ the economic evaluation was assessed using the Drummond Checklist,⁸ and the evidence-based guideline was assessed with the Appraisal of Guidelines for Research and Evaluation II⁹ (AGREE II) instrument. Summary scores were not calculated for the included studies; rather, the strengths and limitations of each included study were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 359 citations were identified in the literature search. Following screening of titles and abstracts, 351 citations were excluded and eight potentially relevant reports from the electronic search were retrieved for full-text review. Five potentially relevant publications were retrieved from the grey literature search for full-text review. Of these potentially relevant articles, four publications were excluded for various reasons, and nine publications met the inclusion criteria and were included in this report. These comprised one SR,² one randomized controlled trial (RCT),¹⁰ five non-randomized studies (NRSs),¹¹^–¹⁵ one economic evaluation,¹⁶ and one evidence-based guideline.³ Appendix 1 presents the PRISMA¹⁷ flowchart of the study selection. Additional references of potential interest are provided in Appendix 5.

Summary of Study Characteristics

Additional details regarding the characteristics of the included publications are provided in Appendix 2.

Study Design

One SR,² published in 2015, searched two databases for studies published from January 1, 2003 to November 27, 2014. The SR used a two-step process to identify relevant literature.² First, a search for systematic reviews and health technology assessments was conducted, and a recent and methodologically sound health technology assessment was identified.² Second, a search for primary studies (from December 2010 to November 27, 2014 with alerts until March 23, 2014) was conducted to update the chosen health technology assessment.² The SR assessed the quality of evidence for each outcome according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group.² The quality of the evidence for each outcome was assigned a GRADE: High (the true effect lies close to the estimate of the effect), Moderate (the true effect is most likely close, but may also be substantially different than the estimate of the effect), Low (the true effect may be substantially different than the estimate of the effect), or Very Low (the true effect is likely to be substantially different than the estimate of the effect).² The GRADE assignment first considered study design (randomized controlled trials were high quality; observational studies were low quality).² Limitations that lowered the quality of evidence (i.e., risk of bias, inconsistency, indirectness, imprecision, and publication bias) and strengths that raised the quality of evidence (e.g., a large magnitude of effect) were also considered for the final GRADE assignment.² The SR had inclusion criteria that were broader in scope than the criteria for this report as different comparators (e.g., pancreas transplantation) were also included.² Thus, the SR contained seven observational comparative studies and 25 case series relevant to this report.² Only the characteristics and results of the subset of relevant studies will be described in this report.

Six primary clinical studies relevant to this report were identified, including one RCT and five NRSs. The RCT¹⁰ was a phase 3, open-label, multicenter, two-arm trial published in 2018. The five NRSs were a prospective, parallel-arm, cohort study (with the two arms combined for a comparison against baseline) published in 2019;¹¹ a before-and-after study published in 2018;¹² a study published in 2017 which used data from two previous single arm studies;¹³ a phase 3 prospective, open-label, single arm study published in 2016;¹⁴ and a study published in 2015 which used data from two single arm trials.¹⁵

The economic evaluation,¹⁶ published in 2016, was a Markov model based, cost-utility analysis from the perspective of a provincial health care payer (Alberta Health Services). The evaluation used a lifetime time horizon (62.5 years) and obtained their clinical and cost inputs from four clinical studies, the University of Alberta Hospital, and expert opinion.¹⁶ The main assumptions made in the analysis included the proportion of patients with partial and full graft function per transplant cycle, the reduction in diabetes-related complications over the model time horizon, the reduction of life expectancy in patients treated with intensive insulin therapy, and the proportion of patients experiencing complications secondary to the immunosuppressive regimen.¹⁶

One evidence-based guideline,³ published in 2018, was developed by Diabetes Canada and was informed by a SR of the literature. The Diabetes Canada guideline assigned a level of evidence (highest being 1a and lowest being 4) and a grade (highest being A and lowest being D) a to each recommendation.³ Diabetes Canada utilizes a standardized methodology for each of their guidelines; as such, specific details regarding the methodology used to develop the guideline were not provided.³ Additional details regarding the level of evidence and grade of recommendation ratings are provided in Appendix 2.

Country of Origin

The authors of the SR² were based in Canada. The relevant primary studies included in the SR were conducted in Canada, the United States, Italy, France, Switzerland, Belgium, Sweden and Australia.² The RCT¹⁰ was conducted in France and Switzerland whereas the five NRSs were conducted in France,¹¹^,¹⁵ the United States¹²^,¹⁴, Switzerland,¹⁵ and Australia.¹³ The economic evaluation¹⁶ was conducted in Canada. The Diabetes Canada guideline³ was developed for Canada.

Patient Population

The SR included adult (aged 18 years or older) patients with type 1 diabetes mellitus with or without kidney disease.² The sample size in the relevant primary studies ranged from 20 to 75 patients for comparative observational studies and from 10 to 99 patients for case series studies.²

The RCT¹⁰ was conducted at 15 university hospitals and included 50 patients living with type 1 diabetes for a minimum of 5 years. These patients had a history of severe glycemic lability associated with at least two severe hypoglycemia events per year, had a severe impairment in quality of life due to the hypoglycemic events, and had hypoglycemia unawareness.¹⁰

The five NRSs included adult patients with type 1 diabetes and a history of hypoglycemic events.¹¹^–¹⁵ The sample size in the five NRSs ranged from 10¹³ to 48¹²^,¹⁴ patients. They were conducted at hospitals or used data from studies conducted at hospitals.¹¹^–¹⁵ The median baseline number of severe hypoglycemia events varied by study and ranged from 2¹¹ to 8¹³ per year.¹¹^–¹⁵

The patient population in the economic evaluation was a hypothetical cohort of patients with unstable type 1 diabetes that met the transplantation inclusion criteria of the University of Alberta Hospital.¹⁶ The transplantation criteria used were unclear.

The target population for the Diabetes Canada guideline is Canadians living with diabetes.³ Its intended users are healthcare professionals involved in the management of patients with diabetes and Canadians living with diabetes.³

Interventions and Comparators

The relevant primary studies in the SR compared all types of islet transplantation (i.e., islet transplantation alone, islet-after-kidney transplantation and simultaneous islet-kidney transplantation) to intensive insulin therapy, a waiting list or to baseline (i.e., before-and-after studies).² The types of insulin or the regimens used by patients were not provided.²

The RCT¹⁰ first compared islet cell transplantation to a flexible insulin therapy regimen (types of insulin and regimens not provided, but insulin doses were adjusted every 3 months to achieve an HbA1c <7% without severe hypoglycemia). At 6 months post-randomization, the insulin therapy group was registered on the transplantation list and received an islet cell transplantation as soon as a compatible preparation was available.¹⁰ At 12 months after the first islet cell infusion (in both trial arms), the full cohort was compared to baseline.¹⁰ Again, the types of insulin and regimens used by the patients at baseline were not provided.

Four of the NRSs¹¹^,¹²^,¹⁴^,¹⁵ compared islet cell transplantation to baseline (types of insulin and regimens patients used at baseline were not provided). A fifth NRS¹³ compared islet cell transplantation to continuous subcutaneous insulin infusion (CSII). Patients used multiple daily injections at baseline and were switched to CSII for at least 3 months prior to undergoing islet cell transplantation.¹³

The economic evaluation¹⁶ compared islet cell transplantation to intensive insulin therapy (manual or device-based injections).

The Diabetes Canada guideline³ considered the interventions of islet cell allotransplantation, islet cell autotransplantation after pancreatectomy and pancreas transplantation. The intervention of interest for this report was islet cell allotransplantation.

Outcomes

The outcomes considered in the SR² were glycemic control (i.e., HbA1c, hypoglycemia events/unawareness, graft loss/insulin independence, and reduction in insulin dose requirements), secondary complications of diabetes (i.e., cardiovascular disease and risk factors, nephropathy, retinopathy and neuropathy), health-related quality of life (both generic and diabetes specific questionnaires), and adverse events of the procedure and maintenance of islet cell transplantation.

In the RCT,¹⁰ outcomes were measured 6 months after the first infusion in the immediate transplantation group and compared to a group who continued 6 months of insulin therapy. The primary outcome was the proportion of participants with a modified β-score of 6 or higher. The modified β-score is based on the following variables: fasting glucose, fasting or stimulated C-peptide, HbA1c, and absence of insulin or oral hypoglycemic drug use.¹⁰ Up to two points are rewarded for each variable; the score can range from 0 (no graft function) to 8 (optimal graft function).¹⁰ Secondary outcomes, were glycemic control (i.e., HbA1c, fasting blood glucose level, proportion of participants with an HbA1c <7% without severe hypoglycemia, number of severe hypoglycemia events per year, proportion of participants free from severe hypoglycemia, number of non-severe hypoglycemia events per year, and insulin requirements), and quality of life (Short Form 36 Health Survey and the Diabetes Quality of Life questionnaire).¹⁰ Outcomes assessed at 12 months after the first islet cell infusion in the full cohort were the previously listed glycemic control outcomes and the proportion of participants achieving insulin independence and the median Clarke Score.¹⁰ Insulin independence was defined as the ability to maintain an HbA1c <7% and 2-hour post-prandial blood glucose levels <10 mmol/L without exogenous insulin while maintaining a stimulated or fasting plasma C-peptide level of ≥17 nmol/L.¹⁰ The Clarke score consists of questions on hypoglycemia awareness and the presence or absence of symptoms accompanying low blood glucose.¹⁰ The score can range from 0 to 8 where a score of 5 or higher indicates the presence of hypoglycemia unawareness.¹⁰

Four NRSs reported the effects of islet cell transplantation on various outcomes of glycemic control (i.e., HbA1c,¹¹^,¹³^–¹⁵ hypoglycemia events,¹¹^,¹³^–¹⁵ insulin requirements,¹¹^,¹³^–¹⁵ insulin independence,¹¹^,¹⁴^,¹⁵ various blood glucose measurements via continuous glucose monitoring,¹¹^,¹³ and fasting blood glucose levels¹⁵). A fifth NRS¹² reported condition-specific health-related quality of life via the Diabetes Distress Scale and the Hypoglycemic Fear Survey and functional health status and health utility via the Short Form 36 Health Survey and EuroQoL 5 Dimensions.

The economic evaluation¹⁶ estimated the incremental cost-effectiveness ratios (ICERs) for islet cell transplantation compared to intensive insulin therapy.

The Diabetes Canada guideline³ included one recommendation relevant to this report. The guideline development group considered the outcomes of reduction or elimination of hypoglycemia, improvements in HbA1c, and the proportion of patients attaining insulin independence, when formulating the recommendation.

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of included publications are provided in Appendix 3.

Systematic Reviews

The included SR had several strengths including a clearly defined objective and clearly described eligibility criteria for the included population, interventions, and outcomes.² A comprehensive literature search was performed and the search strategies for the databases were reported and appropriate.² A list of included studies was provided and the studies characteristics were well described.² The authors appraised the studies for quality and assigned a GRADE quality score to each outcome of interest.² The authors also described the heterogeneity across included studies and the decision not to conduct a meta-analysis was justified.²

However, the SR was appraised to be of critically low quality using the AMSTAR 2⁶ tool because of the numerous weaknesses identified. An a priori protocol was not reported, the eligible comparators were unclear and, although reasons for the exclusion of studies were provided, a list of the excluded studies was not provided (so it was unclear which publications may have been omitted). Furthermore, study screening and selection were done by a single reviewer and it was unclear how data extraction was completed.² Although the authors appraised the studies for quality, they did not consider the risk of bias for individual studies when interpreting and discussing results. Lastly, the authors disclosed that they had no conflicts of interest related to this review, however, the funding sources of the primary studies were not reported.² Thus, the potential impact of funding organizations was unclear.

Randomized Controlled Trial

The RCT¹⁰ had several strengths including a clear research question, relevant population eligibility criteria, and a well-defined intervention which included a description of the immunosuppression regimens. Participants were appropriately randomized and the time period of patient recruitment was provided.¹⁰ The measured outcomes were clearly described and the statistical tests used to assess the main outcomes were described and appropriate.¹⁰ Furthermore, estimates of random variability in the main outcomes were provided.¹⁰ The prespecified sample size was met as 50 patients were included in the trial compared to the calculated 32 participants needed to yield a 95% power to detect a difference between groups in the primary outcome.¹⁰ Drop-out rates were low (one patient in the intervention group and two in the control group) and only one patient in the control group was lost to follow-up.¹⁰ The trial had an a priori protocol and was also registered (NCT01148680).¹⁰ Finally, the authors declared the sources of funding for the trial and reported that they had no conflicts of interest.¹⁰

The RCT¹⁰ also had numerous limitations. The trial was open label for all participants and investigators.¹⁰ Although the majority of the outcomes were objective in nature, some outcomes, such as quality of life, were subjective and there was the possibility that being aware of the treatment assignment may have influenced the results.¹⁰ Differences in baseline characteristics of the groups were also present (e.g., fasting blood glucose, units of insulin administered per day) and no statistical testing or descriptions of what would represent clinically meaningful differences were provided.¹⁰ Participants in the comparator group were asked to do at least four capillary glucose tests per day, to practice carbohydrate counting and their insulin doses were adjusted every 3 months by the investigator.¹⁰ However, the intervention in the insulin group was poorly described (i.e., may not have constituted intensive insulin therapy) and compliance with insulin regimens was not provided.¹⁰ Thus, there was the possibility that participant glycemic control and adherence may have been negatively influenced by the fact that they would eventually receive islet cell transplantations. Lastly, although the trial was multicenter, it was conducted in France;¹⁰ the results may not be generalizable to the Canadian setting.

Non-Randomized Studies

The five NRSs¹¹^–¹⁵ all had clearly described objectives, patient populations which seemed to be representative of the population of interest, and provided the time periods of patient recruitment. Four NRSs¹¹^,¹²^,¹⁴^,¹⁵ had well defined population eligibility criteria, whereas the NRS by Holmes-Walker et al.¹³ had unclear inclusion and exclusion criteria. Specifically, the study included 10 participants whereas the two referenced studies from which patient data were retrieved had a total of 23 participants.¹³ Furthermore, four NRSs¹¹^,¹²^,¹⁴^,¹⁵ had well defined interventions and included descriptions of the immunosuppression regimens while the intervention and immunosuppression regimens of one NRS¹³ were not specifically detailed, but were reported in referenced studies. The five NRSs¹¹^–¹⁵ also had clearly described outcomes and provided estimates of random variability in the main outcomes. Whereas four of the NRSs¹¹^–¹⁴ described the statistical tests used to assess the main outcomes, one NRS¹⁵ did not provide the details of the statistical analysis. The two prospective NRSs¹¹^,¹⁴ used intention-to-treat analyses and provided characteristics of patients lost to follow-up. However, only one prospective NRS¹⁴ conducted a sample size calculation. Finally, the five NRSs¹¹^–¹⁵ all reported their funding sources and declared conflicts of interest.

Various limitations were also uniformly present across the five NRSs. Although the five NRSs¹¹^–¹⁵ provided baseline characteristics, including exogenous insulin requirements, it was unclear what types of insulin, insulin regimens, or regimens of blood glucose monitoring were used or how insulin requirements were calculated; therefore, the “insulin therapy” comparison was unclear. Furthermore, patient recruitment in the five NRSs began between 2003 and 2008.¹¹^–¹⁵ It is unclear if newer technologies (e.g., hybrid closed loop insulin delivery systems) would have provided the patients better glycemic control. Lastly, the five NRSs were conducted in various countries other than Canada;¹¹^–¹⁵ the results may not be generalizable to the Canadian setting.

Economic Evaluation

The economic evaluation¹⁶ included numerous strengths such as a clearly stated research question and justification of the economic importance of the research question. The perspective of the analysis, the form of economic evaluation used, the treatment alternatives being compared, the sources of effectiveness estimates and the primary outcome measures were clearly described.¹⁶ Details of the model used were provided and the choice of model used and the key parameters on which it was based were justified.¹⁶ Furthermore, the time horizon of costs and benefits, the discount rate, the choice of discount rate and the currency and price data were provided.¹⁶ The approach to the sensitivity analysis was provided and the choice of variables for the sensitivity analysis was justified.¹⁶ Major outcomes were presented in a disaggregated as well as an aggregated form, the answer to the study question was provided and conclusions followed from the data reported and were accompanied by the appropriate caveats.¹⁶ Lastly, funding sources of the evaluation were provided and the authors declared that they had no conflicts of interest.¹⁶

However, the economic evaluation also had limitations. Although the form of economic evaluation was stated, there was no justification for the use of a clinical-utility analysis to address the research question.¹⁶ Furthermore, details of the designs and results of the effectiveness studies (i.e., clinical inputs) were not provided.¹⁶ Quantities of resource use were not reported separately from their unit costs, methods for the estimation of quantities and unit costs were not described, and details of currency price adjustments for inflation were not provided.¹⁶ Furthermore, the majority of the cost information in the economic evaluation was provided by the University of Alberta Hospital.¹⁶ As such, there is uncertainty whether the calculated costs would apply throughout Canada.

Evidence-Based Guideline

The Diabetes Canada guideline³ was appraised to be of high quality as only minor limitations were identified. The objective of the guideline and the population to whom the guideline is meant to apply were clearly described.³ Although there was no health question specifically described, the intent of the authors was easily perceived.³ The guideline development group included relevant healthcare professionals and patient representatives and clearly defined the target users.³ The development of the guideline included a systematic search for evidence and clear criteria for selecting the evidence.³ Furthermore, the strengths and limitations of the evidence were clearly described, there was an explicit link between the supporting evidence and the recommendations, and the risks and benefits of islet cell transplantation were considered in the formulation of recommendations.³ In terms of editorial independence, the guideline development group declared competing interests transparently and the views of funding bodies do not seem to have influenced the content of the guideline.³ However, the Diabetes Canada guideline did not describe facilitators and barriers to its application, potential resource implications of implementing recommendations, or monitoring criteria.

Summary of Findings

The overall findings of the included studies are highlighted below and Appendix 4 presents tables with summaries of findings and recommendations.

Clinical Effectiveness of Islet Cell Transplantation

Glycemic Control

The identified SR,² RCT,¹⁰ and four NRSs¹¹^,¹³^–¹⁵ reported glycemic control outcomes.

The SR² reported that in non-uremic patients, islet cell transplantation was associated with better glycemic control compared to patients’ baseline prior to transplantation in case series or intensive insulin therapy in observational comparative studies. This was based on 15 studies that reported improved graft loss or insulin independence (high quality evidence), 15 studies that reported improved HbA1c (low quality evidence), 11 studies that reported reductions in insulin dose requirements (low quality evidence), and 9 studies that reported improved hypoglycemia events or unawareness (low quality evidence), from before to after islet cell transplantation.² Furthermore, in uremic patients, islet cell transplantation was also associated with better glycemic control compared to patients’ baseline prior to transplantation in case series or intensive insulin therapy in observational comparative studies.² This was based on 7 studies that reported improved graft loss or insulin independence (high quality evidence), 8 studies that reported improved HbA1c (very low quality evidence), 8 studies that reported reductions in insulin dose requirements (low quality evidence) and 2 studies that reported improved hypoglycemia events or unawareness (low quality evidence), from before to after islet cell transplantation.²

The RCT reported there was a significantly greater proportion of patients with a modified β-score of 6 or higher in those who received islet cell transplantation compared to insulin therapy.¹⁰ Furthermore, compared to insulin therapy, islet cell transplantation significantly improved median HbA1c, the median number of severe hypoglycemia events per year, the median number of non-severe hypoglycemia events per year, and the median insulin dose requirements.¹⁰ However, there was no statistically significant difference in median fasting blood glucose levels.¹⁰ In the full cohort, compared to baseline, islet cell transplantation was associated with a significant increase in the proportion of patients with a modified β-score of 6 or higher and was associated with significant reductions in median HbA1c, the median fasting blood glucose level, the median number of severe hypoglycemia events per year, the median number of non-severe hypoglycemia events per year and the median insulin dose requirements.¹⁰ Of the full cohort, 59% of patients achieved insulin independence.¹⁰

The NRS by Vantyghem et al.¹¹ reported that following islet cell transplantation there were significant reductions in median HbA1c, median number of severe hypoglycemia events in the previous year, median insulin dose requirements and outcomes measured via continuous glucose monitoring (e.g., median mean glucose, median percentage of time spent below <70 mg/dL) at 1, 5, and 10 years. The NRS by Hering et al.¹⁴ reported that following islet cell transplantation there was a significant increase in the proportion of patients with an HbA1c <7.0% and eradicated severe hypoglycemic events, and significant reductions in median HbA1c, the proportion of participants experiencing at least one severe hypoglycemic event, and median insulin dose requirements at 1 year. The NRS by Lablanche et al.¹⁵ reported that following islet cell transplantation there was a significant increase in the proportion of patients with an HbA1c ≤7% or experiencing a drop in HbA1c of ≥2%, and significant reductions in median HbA1c, mean number of severe hypoglycemic events, and median insulin dose requirements at 5 years follow-up. Similarly, the NRS by Holmes-Walker et al.¹³ reported that following islet cell transplantation there were significant reductions in average HbA1c and median hypoglycemic events per person year, and a numerical reduction in the average insulin requirements (statistical analysis not provided). Three of the NRSs¹¹^,¹⁴^,¹⁵ also reported proportions of patients who achieved insulin independence which varied considerably by study and based on the follow-up periods (39% at 5 years and 28% at 10 years¹¹ 52.1% at 1 year and 42% at 2 years;¹⁴ 45% at 1 year and 31.5% at 5 years in islet after kidney transplant recipients, 37.5% at 1 year and 14% at 5 years in islet cell transplantation alone recipients¹⁵). Generally, there was a trend in which the proportion of patients with insulin independence decreased over time.

Secondary Complications of Diabetes

The identified SR² included evidence on the effect of islet cell transplantation on secondary complications of diabetes. Compared to patients’ baseline prior to transplantation in case series or to intensive insulin therapy in observational comparative studies, islet cell transplantation was associated with improvements in secondary complications of diabetes. This was based on 4 studies that reported improved cardiovascular disease (very low quality evidence), 5 studies that reported improved retinopathy (low quality evidence), 6 studies that reported improved nephropathy (very low quality evidence), and 5 studies that reported improved neuropathy (very low quality evidence) in non-uremic patients and 6 studies that reported improved cardiovascular risk (low quality evidence) and 6 studies that reported improved nephropathy (low quality evidence) in uremic patients.²

Quality of Life

The identified SR,² RCT,¹⁰ and one NRS¹² reported evidence on the effect of islet cell transplantation on the quality of life of patients with labile type 1 diabetes.

The SR contained 12 relevant studies (very low quality evidence) in non-uremic patients and 2 relevant studies (very low quality evidence) in uremic patients which showed health-related quality of life was significantly greater following islet cell transplantation compared to baseline prior to transplantation in case series studies, or compared to continued intensive insulin therapy in observational comparative studies.²

The identified RCT found that islet cell transplantation, compared to insulin therapy, significantly improved the median gain in “Satisfaction”, “Impact of Diabetes”, “Diabetes-Related Worry” and the “Global Score” quality of life dimensions assessed with the Diabetes Quality of Life questionnaire, whereas no statistically significant difference was found in the “Wellbeing” quality of life dimension.¹⁰ The RCT also found that islet cell transplantation, compared to insulin therapy, significantly improved the median gain in “General Health” and “Health Transition” quality of life dimensions assessed with the Short Form 36 Health Survey.¹⁰ However, no statistically significant differences were found in the “Physical Functioning”, “Physical Role Limitations”, “Bodily Pain”, “Vitality”, “Social Functioning”, “Emotional Role Limitations”, “Mental Health”, “Physical Component Score” or “Mental Component Score” quality of life dimensions.¹⁰

The NRS by Foster et al.¹² used four unique questionnaires to determine the effect of islet cell transplantation on quality of life at day 75, 365 and 730 post-transplantation compared to patients’ pre-transplantation baseline. Islet cell transplantation was associated with significant improvements in all dimensions of the Diabetes Distress Scale and Hypoglycemia Fear Survey at day 75, 365 and 730 post-transplantation.¹² In terms of the Short Form 36 Health Survey, islet cell transplantation was associated with significant improvements in the “Role Physical Scale”, “General Health Scale” and “Vitality Scale” dimensions at day 75, 365 and 730 post-transplantation whereas there were either no significant differences at day 75, 365 or 730 or a significant difference at only one or two of the assessed time periods for the “Physical Component Summary”, “Mental Component Summary”, “Physical Functioning Scale”, “Bodily Pain Scale”, “Social Functioning Scale”, “Role Emotional Scale”, and “Mental Health Scale” dimensions.”¹² Finally, in terms of the EuroQoL 5 Dimensions questionnaire, islet cell transplantation was associated with significant improvements in the “Visual Analogue Scale” dimension at day 360 and 730 post-transplantation, but there was no significant difference at any time period for the remaining dimensions (“Health Preference Weight”, “Usual Activities”, “Anxiety/Depression”, “Mobility”, “Pain/Discomfort”, and “Self-Care”).¹²

Adverse Events

The identified SR,² RCT,¹⁰ and four NRSs¹¹^,¹³^–¹⁵ reported adverse events. The SR contained 21 relevant studies (low quality evidence) in non-uremic patients and 5 relevant studies (low quality evidence) in uremic patients which showed islet cell transplantation was associated with procedure-related and immunosuppression-related adverse events.² The RCT reported adverse events in the full cohort of islet cell transplantation recipients as follows: infections and infestation (43%), gastrointestinal disorders (39%), blood and lymphatic system disorders (35%), procedural complications (20%), and other less prevalent serious adverse events.¹⁰ Of these adverse events, three (15%) infections and infestations and one (4%) blood and lymphatic system disorder occurred during the pre-infusion period while the rest occurred post-transplantation.¹⁰ The NRSs¹¹^,¹³^–¹⁵ reported various adverse events related to the transplant procedure, such as bleeding events,¹⁴^,¹⁵ and adverse events related to immunosuppression such as hematological disorders,¹¹^,¹³^,¹⁴ infections,¹¹^,¹⁴ and renal dysfunction.¹³^,¹⁴ None of the identified studies reported the statistical significance of these findings.

Cost-Effectiveness of Islet Cell Transplantation

For islet cell transplantation compared to intensive insulin therapy, the ICER was $150,006 per QALY gained which had a 95% probability of being cost-effective at a willingness-to-pay threshold of $196,000, a 13% probability of being cost-effective at a willingness-to-pay threshold of $125,000, and a 0.5% probability of being cost-effective at a willingness-to-pay threshold of $100,000.¹⁶

Guidelines

The Diabetes Canada guideline³ states patients with labile type 1 diabetes who have preserved renal function or have had a successful kidney transplant may be considered for islet cell transplantation (Level of Evidence: 3 [evidence from a NRS or SR/MA of NRS]; Grade of Recommendation: C [Best evidence was at Level 3]).

Limitations

There were several limitations to this report, one of which was the quality of evidence identified. Owing to the nature of the intervention, randomizing patients with labile type 1 diabetes to their current therapy (i.e., insulin therapy) may be unethical. As such, most included studies (including those in the SR) were non-randomized and single-arm studies which provided low-quality evidence and had a high risk of bias.

Most studies identified in this report compared islet cell transplantation to intensive insulin therapy or to baseline (which represents some sort of insulin therapy as the population of interest was patients with type 1 diabetes who do not have an alternative to insulin therapy). The identified studies either had unclear descriptions or did not describe the baseline insulin therapy regimens. As such, the effect of islet cell transplantation was compared to unknown types or regimens of insulin. Furthermore, the care of complex patients, such as the population of interest of this report, often involves multidisciplinary and interprofessional teams who provide education or resources regarding nutrition, exercise, and insulin dosing amongst other aspects of treatment.

The identified studies that measured quality of life as an outcome utilized generic or diabetes specific questionnaires. However, these questionnaires may not adequately consider the effect of immunosuppression regimens on quality of life. The medications used for the maintenance of immunosuppression can cause numerous serious side effects³ Although islet cell transplantation may decrease the consequences of labile diabetes, these effects must be weighed against the need for life-long immunosuppression.

Lastly, the identified studies are at risk of history bias. None of the identified studies took newer diabetes technologies, such as hybrid closed loop insulin delivery systems, into consideration for the treatment of type 1 diabetes. These new and continuously improving technologies may significantly reduce the burden of labile diabetes making islet cell transplantation an unattractive option.

Conclusions and Implications for Decision or Policy Making

One SR,² one RCT,¹⁰ five NRSs,¹¹^–¹⁵ and one economic evaluation¹⁶ were identified regarding the clinical effectiveness and cost-effectiveness of islet cell transplantation in patients with unstable diabetes mellitus. Furthermore, one evidence-based guideline³ was identified regarding the use of islet cell transplantation in patients with unstable diabetes mellitus.

The identified literature reported positive results regarding the clinical effectiveness of islet cell transplantations compared to insulin therapy in patients with labile type 1 diabetes. Overall, the literature suggests that islet cell transplantation may lead to improved glycemic control and quality of life, and reduced secondary complications of diabetes.²^,¹¹^–¹⁵ However, there were numerous limitations present across the studies, the foremost of which was the poor descriptions of the comparators (i.e., insulin therapy). Furthermore, a trend of decreased insulin independence over time was observed in three NRSs¹¹^,¹⁴^,¹⁵ (statistical analyses not reported) which had long term follow-ups of 2,¹⁴ 5,¹⁵ and 10¹¹ years, which suggests that the effectiveness of islet cell transplantation may decrease over time. As the patients in the identified studies were often middle-aged (median age 43,¹¹ 46¹⁵ and 48¹⁴ years) and type 1 diabetes is a life-long, chronic disease, there is also uncertainty regarding the lifetime clinical effectiveness of islet cell transplantations.

Cost-effectiveness was reported in one identified economic evaluation¹⁶ which reported the ICER of islet cell transplantation compared to intensive insulin therapy in a hypothetical cohort of patients with unstable type 1 diabetes. Overall, islet cell transplantation was reported to be not cost-effective.¹⁶

The Diabetes Canada guideline³ included one recommendation relevant to this report which was informed by evidence from an NRS or an SR of NRSs. The guideline states that patients with unstable type 1 diabetes who have preserved renal function or who have had a successful kidney transplant may be considered for islet cell transplantation (Level of Evidence: 3; Grade of Recommendation: C).³

These findings are largely in agreement with those of the 2014 CADTH report⁴ on this topic. In the previous report, there was low quality evidence regarding the clinical effectiveness of islet cell transplantation for patients with unstable type 1 diabetes, in which islet cell transplantation was similarly associated with improved glycemic control, quality of life, and secondary complications.⁴ In contrast to the current report, the cost-effectiveness of islet cell transplantation was reported to be undetermined based on the limited evidence identified.⁴

The studies identified in this report suggest islet cell transplantation may be effective in improving the treatment of patients with labile type 2 diabetes. However, the lack of high-quality evidence with long term follow-up suggests the need for well-designed clinical studies to investigate the clinical effectiveness of islet cell transplantation compared to insulin therapy over the lifetime of patients with unstable type 1 diabetes.

References

1.: Punthakee Z. 2018: clinical practice guidelines: Definition, classification and diagnosis of diabetes, prediabetes and metabolic syndome. Can J Diabetes. 2018;42:S10–S15. [PubMed: 29650080]
2.: Pancreas islet transplantation for patients with Type1 Diabetes Mellitus: A clinical evidence review. Ont Health Technol Assess Ser. 2015;15(16):1–84. [PMC free article: PMC4664938] [PubMed: 26644812]
3.: Senior P, AlMehthel M, Miller A, Paty BW. 2018 clinical practice guidelines: Diabetes and transplatation. Can J Diabetes. 2018;42:S145–S149. [PubMed: 29650087]
4.: Islet cell transplantation in patients with unstable diabetes: A review of clinical and cost-Effectiveness and Guidelines. (Rapid response report: Summary with critical appraisal). Ottawa (ON): CADTH; 2014: https://cadth.ca/sites/default/files/pdf/htis/dec-2014/RC0614_Islet%20Cell%20Transplantation_Final.pdf. Accessed 2020 Apr 9.
5.: Freige C, McCormack S, Ford C. Islet cell transplantation for patients with unstable or uncontrollable diabetes mllitus: Clinical efectiveness, cost-effectiveness and guidelines. (Rapid response report: reference list). Ottawa (ON): CADTH; 2020: https://cadth.ca/islet-cell-transplantation-patients-unstable-or-uncontrollable-diabetes-mellitus-clinical. Accessed 2020 Mar 20.
6.: Shea BJ, Reeves BC, Wells G, Thuku M, Hamel C, Moran J, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ. 2017;358:j4008. http://www.bmj.com/content/bmj/358/bmj.j4008.full.pdf. Accessed 2020 Apr 9. [PMC free article: PMC5833365] [PubMed: 28935701]
7.: Downs SH, Black N. The feasibility of creating a checklist for the assessment of the methodological quality both of randomised and non-randomised studies of health care interventions. J Epidemiol Community Health. 1998;52(6):377–384. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdf. Accessed 2020 Apr 9. [PMC free article: PMC1756728] [PubMed: 9764259]
8.: Higgins JPT, Green S, editors. Figure 15.5.a: Drummond checklist (Drummond 1996). Cochrane handbook for systematic reviews of interventions. London (GB): The Cochrane Collaboration; 2011: http://handbook-5-1.cochrane.org/chapter_15/figure_15_5_a_drummond_checklist_drummond_1996.htm. Accessed 2020 Apr 9.
9.: Agree Next Steps Consortium. The AGREE II Instrument. [Hamilton, ON]: AGREE Enterprise; 2017: https://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf. Accessed 2020 Apr 9.
10.: Lablanche S, Vantyghem MC, Kessler L, Wojtusciszyn A, Borot S, Thivolet C, et al. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018;6(7):527–537. [PubMed: 29776895]
11.: Vantyghem MC, Chetboun M, Gmyr V, Jannin A, Espiard S, Le Mapihan K, et al. Ten-Year Outcome of Islet Alone or Islet After Kidney Transplantation in Type 1 Diabetes: A Prospective Parallel-Arm Cohort Study. Diabetes Care. 2019;42(11):2042–2049. [PubMed: 31615852]
12.: Foster ED, Bridges ND, Feurer ID, Eggerman TL, Hunsicker LG, Alejandro R. Improved Health-Related Quality of Life in a Phase 3 Islet Transplantation Trial in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. 2018;41(5):1001–1008. [PMC free article: PMC5911786] [PubMed: 29563196]
13.: Holmes-Walker DJ, Gunton JE, Hawthorne W, Payk M, Anderson P, Donath S, et al. Islet Transplantation Provides Superior Glycemic Control With Less Hypoglycemia Compared With Continuous Subcutaneous Insulin Infusion or Multiple Daily Insulin Injections. Transplantation. 2017;101(6):1268–1275. [PubMed: 27490410]
14.: Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, et al. Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia. Diabetes Care. 2016;39(7):1230–1240. [PMC free article: PMC5317236] [PubMed: 27208344]
15.: Lablanche S, Borot S, Wojtusciszyn A, Bayle F, Tetaz R, Badet L, et al. Five-Year Metabolic, Functional, and Safety Results of Patients With Type 1 Diabetes Transplanted With Allogenic Islets Within the Swiss-French GRAGIL Network. Diabetes Care. 2015;38(9):1714–1722. [PubMed: 26068866]
16.: Wallner K, Shapiro AM, Senior PA, McCabe C. Cost effectiveness and value of information analyses of islet cell transplantation in the management of ‘unstable’ type 1 diabetes mellitus. BMC Endocr Disord. 2016;16:17. [PMC free article: PMC4826503] [PubMed: 27061400]
17.: Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol. 2009;62(10):e1–e34. [PubMed: 19631507]

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 2Characteristics of Included Systematic Review

First Author, Publication Year, Country, Funding

Study Design, Search Strategy, Number of Studies Included, Quality Assessment Tool, and Objective

Population Characteristics

Intervention and Comparators

Clinical Outcomes, Length of Follow-Up

Health Quality Ontario, 2015²

Canada

Funding: Not disclosed

Study design: Systematic review

Literature search: Two-step literature search in MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations and EBM Reviews from January 1, 2003 to November 27, 2014. The first step was a search for health technology assessments in which the most recent one with the best methodology was chosen (according to AMSTAR scores) while the second step was a search for primary studies to update the chosen health technology assessment. Reference lists of selected studies were also searched.

Number of studies included: 17 studies including one health technology assessment representing 2 systematic reviews, 6 observational studies (with 8 publications) and 13 case series (with 20 publications).

Number of studies relevant to this report: 7 observational comparative studies and 25 case series studies

Quality assessment tool: AMSTAR tool for health technology assessments and systematic reviews. Assessment of primary studies was conducted using an unnamed tool

Objective: To determine the clinical effectiveness of islet cell transplantation in patients with type 1 diabetes mellitus (with or without kidney disease)

Patients with type 1 diabetes aged 18 years or older with or without kidney disease

Intervention: All types of islet transplantations (islet transplantation alone, islet-after-kidney transplantation, or simultaneous islet-kidney transplantation)

Comparators: Unclear, however the included studies compared islet transplantation to intensive insulin therapy, a waiting list, baseline (before-and-after studies), or controls such as pancreas transplantation or another islet cell transplantation

Glycemic control (HbA1c, hypoglycemia events/unawareness, graft loss/insulin independence, reduction in insulin dose requirements)
Secondary complications of diabetes (cardiovascular disease and risk factors, nephropathy, retinopathy, neuropathy)
Adverse events
Health-related quality of life (generic and diabetes specific questionnaires)

Follow-up: Variable with a minimum of 1 year and the longest being 8 years

: AMSTAR = A Measurement Tool to Assess Systematic Reviews; EBM Reviews = Evidence-Based Medicine Reviews; HbA1c = glycated hemoglobin A1c; MEDLINE = Medical Literature Analysis and Retrieval System Online.

Table 3Characteristics of Included Primary Clinical Studies

First Author, Publication Year, Country, Funding

Study Design, Setting, Purpose

Population Characteristics

Intervention and Comparator(s)

Relevant Clinical Outcomes, Length of Follow-Up

Randomized Controlled Trial

Lablanche, 2018¹⁰

France

Funding: Programme Hospitalier de Recherche Clinique grant from the French Government

Study design: Phase 3, open-label, two-arm, multicenter, randomized control trial (N= 50).

Setting: 15 university hospitals in France and three islet preparation units in France (2) and Switzerland (1)

Purpose: To compare the efficacy of allogenic islet transplantation with insulin therapy for improving metabolic outcomes in patients with type 1 diabetes

Patients with type 1 diabetes diagnosed at least 5 years beforehand and a basal and stimulated C-peptide concentration of <0.1 nmol/mL

Inclusion criteria:

Presence of severe glycemic lability associated with at least two severe hypoglycemia events per year (defined as one in which the patient required third-party assistance for its correction)
Severe impairment of quality of life related to hypoglycemia
Hypoglycemia unawareness (patient unaware of blood glucose concentrations <3 mmol/L)
Functional kidney graft (GFR >50 mL/min per 1.73m², proteinuria <0.5 g per day), poor glycemic control or substantial deterioration in quality of life related to diabetes specifically for patients with type 1 diabetes who received a kidney graft

Exclusion criteria:

Insulin requirement >0.85 UI/kg/day
BMI >30 kg/m²
Pregnancy and women with an intention to conceive or breastfeed
Several diseases: hemostatic disorders, anemia, pre-existing liver disease, gallbladder lithiasis, proliferative retinopathy, nephropathy, macroangiopathy, hypertension, systemic infections including hepatitis B, hepatitis C, and/or HIV
Immunosuppressive treatment with methylprednisolone dose >0.1 mg/kg/day for patients who had received a kidney graft

Number of participants in trial arms (intervention vs. control):

25 vs. 22

Participant age (intervention vs. control):

52 vs. 51

Duration of diabetes (intervention vs. control):

34 years vs. 30 years

Participant average baseline HbA1c (intervention vs. control):

8.1% vs. 8.1%

Participant average baseline fasting blood glucose (intervention vs. control):

8.1 mmol/L vs. 9.8 mmol/L

Participant average baseline insulin requirement (intervention vs. control):

36 units/day vs. 30 units/day

Baseline modified β-score^a (intervention vs. control):

0: 52% vs. 59%

1: 20% vs. 32%

2: 24% vs. 9%

3: 4% vs. 0%

Intervention: Immediate islet transplantation. Patients were immediately registered on the transplant list and transplanted as soon as a compatible preparation was available.

Comparator: Insulin therapy for 6 months followed by registration on the islet transplantation list. Patients were asked to conduct at least 4 capillary glucose tests per day, practice carbohydrate counting and use a flexible insulin therapy regimen. Insulin doses were adjusted every 3 months to achieve an HbA1c <7% without severe hypoglycemia.

Pancreases were obtained from brain-dead, multi-organ donors. Patients were scheduled to receive 11,000 islet equivalents/kg in one to three infusions.

At 12 months post islet cell infusion in the full cohort (i.e. the immediate transplantation group and the transplantation group post 6 month insulin regimen) was compared to baseline

Primary outcome (measured 6 months after the first infusion in the immediate transplantation group and 6 months after randomization in the insulin group):

Proportion of participants with a modified β-score^a of 6 or higher

Secondary outcomes (measured 6 months after the first infusion in the immediate transplantation group and 6 months after randomization in the insulin group):

Median HbA1c
Median fasting blood glucose level
Proportion of participants with an HbA1c <7% without severe hypoglycemia
Median number of severe hypoglycemia events per year
Proportion of participants free from severe hypoglycemia
Median number of non-severe hypoglycemia events per year
Median insulin requirements
Quality of life (Short Form 36 Health Survey and Diabetes Quality of Life questionnaire)

Outcomes assessed at 12 months in the full cohort:

Proportion of participants with a modified β-score^a of 6 or higher
Median HbA1c
Median fasting blood glucose level
Proportion of participants with an HbA1c <7% without severe hypoglycemia
Median number of severe hypoglycemia events per year
Proportion of participants free from severe hypoglycemia
Median number of non-severe hypoglycemia events per year
Median insulin requirements
Median Clarke Score^b
Proportion of participants achieving insulin independence

Follow-up: At 6 months and 12 months after first islet cell infusion

Non-Randomized Studies

Vantyghem, 2019¹¹

France

Funding: French Ministry of Health, Programme Hospitalier de Recherche Clinique 2001, the European Community (Fond Européen de Développement Régional), Conseil Régional du Nord-Pas-de-Calais, Programme d’Investissements D’Avenir Labex European Genomic Institute for Diabetes, Société Francophone du Diabète, Santelys, and Agence de la Biomédecine

Study design: Observational, prospective, parallel-arm, cohort study. The two arms were also combined for a comparison against baseline (N= 28)

Setting: Participants from two single-arm phase 2 studies conducted at the Lille University Hospital

Purpose: To evaluate the 10-year outcome of islet transplantation in patients with type 1 diabetes

Patients with type 1 diabetes for at least 5 years and a stimulated C-peptide <0.3 ng/mL

Inclusion criteria:

Patients with hypoglycemia unawareness and/or documented metabolic lability and an eGFR >60mL/min/1.73m² (for non-uremic patients)
Patients with a functioning kidney graft and blood pressure in the normal range (for uremic patients)

Exclusion criteria:

Aged <18 or >65 years
BMI ≥28 kg/m²
Albuminuria >300 mg/24 hours
Unstable arteritis or heart disease
Insulin requirements >1.2 units/kg/day
History of malignancy
Smokers
Desire for pregnancy
Psychiatric disorders
Lack of compliance

Median patient age: 43 years

Median diabetes duration: 28 years

Median baseline exogenous insulin requirements: 0.57 units/kg/day

Median baseline number of severe hypoglycemia events in the previous year: 2

Median baseline HbA1c: 8.15%

Intervention: Islet cell transplantation consisting of up to three islet infusions within 3 months

Comparator: Baseline

Islets were isolated from pancreases from deceased donors of ABO blood type. Patients received a median of 13,450 islet equivalents/kg.

Median number of severe hypoglycemia events in the previous year
Median HbA1c
Median exogenous insulin requirements
Median mean glucose (via continuous glucose monitor)
Median standard deviation of mean glucose (via continuous glucose monitor)
Median time below range (<70 mg/dL)

Follow-up: 10 years

Foster, 2018¹²

United States

Funding: National Institute of Allergy and Infectious Disease, National Institute of Diabetes and Digestive and Kidney Diseases

Study design: Before-and-after study using data from a phase 3, prospective, open-label single arm study¹⁴ (N= 48)

Setting: 8 hospitals in North America

Purpose: To report the impact of islet transplantation on health-related quality of life

Patients with type 1 diabetes and a history of severe hypoglycemic events in the previous year

Inclusion and exclusion criteria were not reported, but a reference to the original study was provided in the study (see details of Hering et al., 2016¹⁴)

Intervention: Islet cell transplantation

Comparator: Baseline

See details of Hering et al., 2016¹⁴

Condition specific health-related quality of life via the Diabetes Distress Scale and the Hypoglycemic Fear Survey
Functional health status and health utility via the Short Form 36 Health Survey and EuroQoL 5 Dimensions

Follow-up: 75, 365 and 730 days post transplantation

Holmes-Walker, 2017¹³

Australia

Funding: Juvenile Diabetes Research Foundation, National Health and Research Council Australia

Study design: Before-and-after study using data from two previous single arm studies (N=10)

Setting: Two hospitals in Australia

Purpose: To assess the impact of CSII compared to MDI in patients with severe hypoglycemia suitable for islet transplantation and to compare glycemic control with CSII and MDI with that of islet transplantation at 12 months.

Patients with type 1 diabetes mellitus with recurrent severe hypoglycemia (defined as hypoglycemia requiring assistance from a third party to recognize and/or treat) and assessed as suitable for islet transplantation

Average age: 50.6 years

Average duration of diabetes: 40.1 years

Average daily insulin requirements: 0.4 units/kg/day

Median severe hypoglycemia events per person year: 8

Average HbA1c: 8.1%

Intervention: Within subject, paired comparison of MDI to CSII and of CSII to 12 months post-islet transplantation

Average insulin requirements
Average HbA1c
Median HYPOscore^c
Median hypoglycemic events per person year
Median percentage of time with glucose <4 mmol/L
Median percentage of time with glucose between 4 to 8 mmol/L
Average blood glucose level
Average standard deviation of blood glucose level
Continuous overlapping net glycemic action 4-hour interval

Follow-up: 12 months post-transplantation

Hering, 2016¹⁴

United States

Funding: National Institute of Allergy and Infectious Diseases, National Institute for Diabetes and Digestive and Kidney Diseases

Study design: Phase 3, prospective, open-label, single arm study (N= 48)

Setting: 8 hospitals in North America

Purpose: To evaluate the effectiveness and safety of islet transplantations in patients with impaired awareness of hypoglycemia and severe hypoglycemia events

Patients aged 18 to 65 years with type 1 diabetes for at least 5 years

Inclusion criteria:

Absent stimulated C-peptide
Impaired awareness of hypoglycemia and/or marked glycemic lability and a history of severe hypoglycemic events in the prior 12 months despite medical care provided by an endocrinologist who asserted that the patient has been compliant with their treatment plan

Exclusion criteria:

BMI >30kg/m²
Weight ≤50 kg
Insulin requirement >1.0 units/kg/day or <15 units/day
HbA1c >10%
Measured GFR <80 mL/min/1.73m²
History of reactive anti-HLA antibodies by flow cytometry
Significant comorbid conditions

Median age: 48 years

Median duration of diabetes: 28.5 years

Median insulin requirement: 32.6 units/day

Median serious hypoglycemic events in the past year: 6.5

Median HbA1c: 7.2%

Intervention: Islet cell transplantation consisting of up to three islet infusions

Comparator: Baseline

Pancreases were obtained from deceased donors 15 to 65 years of age. The median total dose/kg was 11,972 islet equivalents.

Primary outcome:

Proportion of participants with an HbA1c <7.0% with eradication of severe hypoglycemic events

Secondary outcomes:

Proportion of participants with an HbA1c <6.5% with eradication of severe hypoglycemic events
Proportion of participants with an HbA1c <7.0%
Median HbA1c
Proportion of participants experiencing at least one severe hypoglycemic event
Proportion of participants achieving insulin independence
Median insulin requirements

Follow-up: 2 years

Lablanche, 2015¹⁵

France and Switzerland

Funding: The included studies received funding from ALFEDIAM, Association Française des Diabétigues, Aide aux Jeunes Diabétigues, Agir pour les Maladies chroniques, the PHRC from the French Ministry of Health and the Swiss National Foundation for Scientific Research

Study design: Before and after study using data from the GRAGIL-1c and GRAGIL-2 trials (N= 44)

Setting: Multiple university hospitals within the GRAGIL network

Purpose: To describe the 5-year outcome of islet transplantation in patients with type 1 diabetes from the GRAGIL-1c and GRAGIL-2 trials

The GRAGIL-1c trial included patients with type 1 diabetes with a functional kidney graft.

Inclusion criteria:

Creatinine clearance >50 mL/min
Proteinuria <0.5 g/day
Daily insulin requirement <0.7 units/kg/day
BMI <26 kg/m²
Body weight <75 kg (male) or <70 kg (female)

Exclusion criteria:

Liver and coagulation abnormalities
Unstable diabetic retinopathy
Poor cardiovascular prognosis

The GRAGIL-2 trial included patients aged 18 to 65 years with type 1 diabetes for at least 5 years

Inclusion criteria:

Negative C-peptide
Frequent episodes of severe hypoglycemia despite intensive insulin therapy

Exclusion criteria:

Kidney disease
Liver and coagulation abnormalities
Unstable ischemic diabetic retinopathy
Poor cardiovascular prognosis
BMI ≥26 kg/m²
Insulin requirement >0.7 units/kg/day

Median age: 46 years

Median duration of diabetes: 33 years

Median daily insulin requirements: 0.5 units/kg

Median number of severe hypoglycemic events in the past year: 5.5

Median HbA1c: 8.1%

Intervention: Islet cell transplantation consisting of up to three islet infusions

Comparator: Baseline

Pancreases were obtained from brain dead multiorgan donors. The mean total dose/kg was 9715.75 islet equivalents.

Median HbA1c
Proportion of patients with an HbA1c ≤7% or experiencing a drop in HbA1c of ≥2%
Median fasting blood glucose
Mean number of severe hypoglycemic events/patient/year
Median insulin requirements
Proportion of patients attaining insulin independence

Follow-up: 5 years

: BMI = body mass index; CSII = continuous subcutaneous insulin infusion; GFR = glomerular filtration rate; HbA1c = glycated hemoglobin A1c; HIV = human immunodeficiency virus; MDI = multiple daily injections.
a: = The modified β-score is based on the following variables: fasting glucose, fasting or stimulated C-peptide, HbA1c, and absence of insulin or oral hypoglycemic drug use. Up to two points are rewarded for each variable. As such, the score can range from 0 (no graft function) to 8 (optimal graft function). Contrary to the original β-score, the modified β-score does not assign an overall score of zero when stimulated C-peptide is negative.
b: = The Clarke Score consists of questions on hypoglycemia awareness and the presence or absence on symptoms accompanying low blood glucose. The score can range from 0 to 8 where a score of 5 or higher indicates the presence of hypoglycemia unawareness.
c: = The HYPOscore is a composite hypoglycemia score based on the frequency, severity and degree of unawareness of hypoglycemia. A HYPOscore of ≥1047 indicates serious problems with hypoglycemia.

Table 4Characteristics of Included Economic Evaluation

First Author, Publication Year, Country

Type of Analysis, Time Horizon, Perspective

Decision Problem

Population Characteristics

Intervention and Comparator

Clinical and Cost Data Used in Analysis

Main Assumptions

Wallner 2016¹⁶

Canada

Funding: Stem Cell Network grant and a Collaborative Research and Innovation Opportunities grant by Alberta Innovates Health Solutions

Analysis: Cost-utility analysis

Approach: Model-based analysis (Markov Model)

Time Horizon: Life-time horizon (62.5 years)

Cycle Length: 1/16^th of a year (~23 days)

Perspective: Provincial health care payer (Alberta Health Services)

Discount Rate: 5% per year

Cost Expression: 2012 Canadian dollars

Analytic Approach: Probabilistic analysis and structural sensitivity analysis

To evaluate the cost-effectiveness of allogenic islet cell transplantation compared to intensive insulin therapy.

A hypothetical cohort of patients with unstable type 1 diabetes that met the transplantation inclusion criteria of the University of Alberta Hospital (criteria not described).

Gender: 55% female

Average age: 47 years

Diabetes duration: 29.4 years

Weight: 71.1 kg

BMI: 24.8 kg/m²

HbA1c: 8.2%

Insulin requirements: 0.6 units/kg/day

Intervention: Islet cell transplantation

Comparator: Intensive insulin therapy

Clinical Inputs:

Probability of patients experiencing initial complications
Probability of achieving insulin independence after the 1^st, 2^nd, 3^rd, and 4^th transplantation
Probabilities of patients getting diabetes-related complications with partial graft function and with full graft function
Probability of becoming partially insulin dependent with full graft function
Probability of graft failure after previous full graft function
Probability of graft failure within the first 6 months and after the first 6 for patients with partial graft function
Probability of major immunosuppressive related complications and the probability of ending immunosuppression because of the complications
Probability of additional diabetes related complications
Probability of background all-cause mortality
Probability of mortality due to hypoglycemia and mortality due to diabetes-related complications

Cost Inputs:

Cost savings from reduced diabetes related complications
Costs savings from reduced insulin therapy
Short term increased cost from procedure itself including organ procurement, islet cell processing, transplantation procedure, follow-up visits, immunosuppression, and possible treatment of complications
Increased costs from resource use for graft survival including immunosuppression, clinical follow-up, insulin therapy and other medications

Utility Inputs:

Full graft function with no complications
Partial graft function with no complications
Hypoglycemia unawareness
Diabetes-related complications (other than hypoglycemia unawareness)

All patients without diabetes-related complications will have some graft survival in the cycle after transplantation
The proportion of patients with full graft function increased from the first to the third and fourth transplantation
Patients had a 55% risk of diabetes-related complications over the model horizon and these complications are reduced by 75% with full or partial graft function
Patients treated with intensive insulin therapy had a 12 years shorter life expectancy compared to the general, non-diabetic population
65% of patients experienced minor and 1.5% of patients experienced major immunosuppressive complications
10% of patients will stop immunosuppressive therapy because of complications
The price of generic immunosuppressant drugs was 1/3^rd the cost of the brand name

: BMI = body mass index; HbA1c = glycated hemoglobin A1c.

Table 5Characteristics of Included Guideline

Intended Users, Target Population, Interventions

Relevant Major Outcomes Considered

Evidence Collection, Selection, and Synthesis

Evidence Quality Assessment

Recommendations Development and Evaluation

Guideline Validation

Diabetes Canada, 2018³

Intended Users: Healthcare professionals involved in the management of patients with diabetes or prediabetes with a focus on primary care providers as well as Canadians living with diabetes

Target Population: Canadians living with diabetes

Interventions: Islet cell allotransplantation, islet cell autotransplantation after pancreatectomy, pancreas transplantation

Reduction or elimination of hypoglycemia, improvements in HbA1c, proportion of insulin independence

Systematic literature search by two health science librarians of relevant English-language, published, peer reviewed literature. Electronic databases were searched from September 2013 or later for previously included topics and since 1990 for new topics in the guideline and included searches of MEDLINE, EMBASE, CINAHL, the Cochrane Register of Trials and PsycINFO [where appropriate]. Screening was done in duplicate whereas full-text review was completed by a diabetes clinician and a methodologist.

Level of Evidence:

1a: SR or MA of high-quality RCTs
1B: Non-randomized clinical trial or cohort study with indisputable results
2: RCT or SR that does not meet Level 1 criteria
3: Non-randomized clinical trial or cohort study; SR or MA of Level 3 studies
4: Other

Grade of Recommendations:

A: The best evidence was at Level 1
B: The best evidence was at Level 2
C: The best evidence was at Level 3
D: The best evidence was at Level 4 or consensus

The relevant literature was evaluated by members of the Expert Committee who developed the guidelines and recommendations. If no new evidence was identified since the publication of the 2013 guidelines, recommendations from the 2013 document were not changed.

A draft document was externally peer reviewed by experts in relevant fields including specialists, community primary care providers, academic department of family medicine across Canada, and specialty and disease support organizations.

: CINAHL = Cumulative Index to Nursing and Allied Health Literature; EMBASE = Excerpta Medica database; MA = meta-analysis; MEDLINE = Medical Literature Analysis and Retrieval System Online; PsycINFO = Psychological Information database; RCT = randomized controlled trial; SR = systematic review.

Appendix 3. Critical Appraisal of Included Publications

Table 6Strengths and Limitations of the Systematic Review using AMSTAR 2⁶

Strengths

Limitations

Health Quality Ontario, 2015²

The objective of the review was clearly stated
The eligible population, interventions and outcomes of the review were well defined
The inclusion and exclusion criteria were clearly described
Two databases (MEDLINE and EBM Reviews) were searched and reference lists from selected studies were also reviewed
Search strategies of the databases were provided and appropriate
A list of included studies was provided and the studies’ characteristics were well described
The authors provided a GRADE quality score to each outcome of interest
Authors described heterogeneity across studies and the reason for not conducting a meta-analysis of the results
Authors disclosed that they had no conflicts of interest related to this review

An a priori protocol was not reported for the review
The eligible comparators of the review were unclear
It was unclear if a search of the grey literature was performed
Study screening and selection were done by a single reviewer
It was unclear how data extraction was completed
Although reasons for the exclusion of studies were provided, a list of the excluded studies was not
Although the authors appraised the studies for quality, they did not consider the risk of bias for individual studies when interpreting and discussing results
Funding sources of included studies were not provided

: EBM Reviews = Evidence-Based Medicine Reviews; GRADE = Grading of Recommendations Assessment, Development and Evaluation; MEDLINE = Medical Literature Analysis and Retrieval System Online.

Table 7Strengths and Limitations of Clinical Studies using the Downs and Black Checklist⁷

Strengths	Limitations
Randomized Controlled Trial
Lablanche, 2018¹⁰
The study addressed an appropriate and clearly focused research question The inclusion and exclusion criteria were well defined and appropriate considering the study population and the research question Patients recruited to the study appeared to be representative of the population of interest The time period of patient recruitment was provided (June 2010 to July 2013) The assignment of patients to the intervention and control arms was randomized (one to one ratio using a computer-generated randomization) The intervention was well defined and included a description of the immunosuppression regimens Estimates of random variability in the main outcomes were provided The measured outcomes were clearly described The statistical tests used to assess the main outcomes were described and appropriate A power calculation was included in which enrolling 32 participants yielded a 95% power to detect a difference between groups in the primary outcome (50 patients included in the trial) Drop-out rates were low as only one participant in the intervention group and two in the control group did not receive their assigned interventions Follow-up was well conducted as only one patient in the control group was lost to follow-up (died before receiving islet transplantation) A list of adverse events was included The trial had an a priori protocol and was registered (NCT01148680) The funding source was declared (Programme Hospitalier de Recherche Clinique grant from the French Government), and they had no input in the design or conduct of the study Authors declared conflicts of interest (none reported)	The trial was open label for all participants, investigators and the statistician Differences in baseline characteristics of the groups were present (i.e., fasting blood glucose, units of insulin administered per day) and no statistical testing or description of what would represent clinically meaningful differences was provided The intervention of the insulin group was poorly described and may not have constituted intensive insulin therapy (i.e., the participants were asked to do at least four capillary glucose tests per day and to practice carbohydrate counting, insulin doses were adjusted every 3 months by the investigator) Compliance with insulin regimens was not provided and the patients in the insulin group knew they would receive islet cell transplantations eventually, which may have influenced adherence Although the trial was conducted in multiple hospitals, these French findings may not be generalizable to the Canadian setting
Non-Randomized Studies
Vantyghem et al., 2019¹¹
The aim of the study was clearly described The inclusion and exclusion criteria were well defined Patient data were retrieved from 2 single-arm trials which were representative of the population of interest The time period of patient recruitment was provided (March 2003 to December 2012) The intervention was well defined and included a description of the immunosuppression regimens Estimates of random variability in the main outcomes were provided The measured outcomes were clearly described The statistical tests used to assess the main outcomes were described and appropriate The authors used an intention-to-treat analysis to report results Characteristics of patients lost to follow-up were provided A list of adverse events was included Authors conflicts of interest were provided (none reported) Funding sources were provided	It was unclear how the included trials calculated the sample sizes which were small (N=14 each) Although baseline characteristics were provided, including exogenous insulin requirements, it was unclear what types of insulins, insulin regimens, or regimens of blood glucose level monitoring were used and how patients calculated insulin requirements (therefore the “insulin therapy” comparison was unclear) As patients were first recruited in 2003, it was unclear if newer technologies (e.g., hybrid closed loop insulin delivery systems) would have provided the patients better glycemic control At 10 years, 8 patients (29%) were not followed-up The studies were conducted at a single center in France and may not be generalizable to the Canadian context
Foster et al., 2018¹²
The aim of the study was clearly described Estimates of random variability in the main outcomes were provided The measured outcomes were clearly described The statistical tests used to assess the main outcomes were described and appropriate P-values were adjusted for multiple comparisons using the false discovery rate approach Authors conflicts of interest were provided Funding sources were provided Note: This study utilized the data from Hering et al., 2016¹⁴ and referenced it for key information. For additional strengths and limitations (i.e., pertaining to population inclusion and exclusion criteria, population baseline characteristics, time period of patient recruitment, details of the intervention, sample size calculation) see Hering et al., 2016¹⁴	Although four unique questionnaires were utilized, certain issues that can affect patients’ quality of life (e.g., the need for lifelong immunosuppression) may not have been properly captured Although baseline characteristics were provided, including exogenous insulin requirements, it was unclear what types of insulins, insulin regimens, or regimens of blood glucose level monitoring were used and how patients calculated insulin requirements (therefore the “insulin therapy” comparison was unclear) As patients were first recruited in 2008, it was unclear if newer technologies (e.g., hybrid closed loop insulin delivery systems) would have provided the patients better glycemic control At 2 years, up to 15 patients (34%) were lost to follow-up in some outcomes Characteristics of patients lost to follow-up were not provided The study was conducted at multiple centers in the United States and may not be generalizable to the Canadian context
Holmes-Walker et al., 2017¹³
The aim of the study was clearly described Patient data were retrieved from 2 single-arm trials which appear to be representative of the population of interest The time period of patient recruitment was provided (January 2006 to December 2010) The intervention and immunosuppression regimens were not specifically detailed, but were reported in the referenced studies Although only briefly described, there was an attempt to optimize insulin therapy and provide dietician and regular endocrinologist review prior to transplantation Estimates of random variability in the main outcomes were provided The measured outcomes were clearly described The statistical tests used to assess the main outcomes were described and appropriate A list of adverse events was included Authors conflicts of interest were provided (none reported) Funding sources were provided	Although the study referenced the two studies from which participants’ data was pulled, the inclusion and exclusion criteria were not specifically clear: the study included 10 participants whereas the two referenced studies had N=23 Although baseline characteristics were provided, including exogenous insulin requirements, it was unclear what types of insulins, insulin regimens, or regimens of blood glucose level monitoring were used and how patients calculated insulin requirements (therefore the “insulin therapy” comparison was unclear) As patients were first recruited in 2006, it was unclear if newer technologies (e.g., hybrid closed loop insulin delivery systems) would have provided the patients better glycemic control The studies were conducted at two centers in Australia and may not be generalizable to the Canadian context
Hering et al., 2016¹⁴
The aim of the study was clearly described The inclusion and exclusion criteria were well defined Patients recruited to the study appeared to be representative of the population of interest The time period of patient recruitment was provided (the first patient consented in October 2008) The intervention was well defined and included a description of the immunosuppression regimens Estimates of random variability in the main outcomes were provided The measured outcomes were clearly described The statistical tests used to assess the main outcomes were described and appropriate A sample size calculation was provided (assuming a true rate of success for the primary endpoint of at least 70%, 48 participants allow for an at least 84% power to declare islet transplantation effective) P-values were adjusted for multiple comparisons using the Bonferroni method The authors used an intention-to-treat analysis to report results Characteristics of patients lost to follow-up were provided A list of adverse events was included The trial had an a priori protocol and was registered (NCT00434811) Authors conflicts of interest were provided Funding sources were provided	Although baseline characteristics were provided, including exogenous insulin requirements, it was unclear what types of insulins, insulin regimens, or regimens of blood glucose level monitoring were used and how patients calculated insulin requirements (therefore the “insulin therapy” comparison was unclear) As patients were first recruited in 2008, it was unclear if newer technologies (e.g., hybrid closed loop insulin delivery systems) would have provided the patients better glycemic control At 2 years, 8 patients (17%) were lost to follow-up The study was conducted at multiple centers in the United States and may not be generalizable to the Canadian context
Lablanche et al., 2015¹⁵
The aim of the study was clearly described The inclusion and exclusion criteria were well defined Patient data were retrieved from 2 single-arm trials which appear to be representative of the population of interest The time period of patient recruitment was provided (September 2003 to April 2010) The intervention was well defined and included a description of the immunosuppression regimens Estimates of random variability in the main outcomes were provided The measured outcomes were clearly described A list of adverse events was included Authors conflicts of interest were provided (none reported) Funding sources were provided	The statistical tests used to assess the main outcomes were not described P-values were provided; however, it was unclear which data they were attributed with as a single p-value was provided after sets of multiple outcome measurements Although baseline characteristics were provided including exogenous insulin requirements, it was unclear what types of insulins, insulin regimens, or regimens of blood glucose level monitoring were used and how patients calculated insulin requirements (therefore the “insulin therapy” comparison was unclear) As patients were first recruited in 2003, it was unclear if newer technologies (e.g., hybrid closed loop insulin delivery systems) would have provided the patients better glycemic control The studies were conducted at multiple centers in France and Switzerland. They may not be generalizable to the Canadian context

Table 8Strengths and Limitations of Economic Studies using the Drummond Checklist⁸

Strengths

Limitations

Wallner et al., 2016¹⁶

The research question was clearly stated
The economic importance of the research question was stated
The perspective of the analysis was clearly stated and justified
The treatment alternatives being compared were clearly described
The form of economic evaluation used was stated
The sources of effectiveness estimates used were stated
The primary outcome measures for the economic evaluation were clearly stated
Currency and price data were recorded
Details of the model used were provided and the choice of model used and the key parameters on which it was based were justified
The time horizon of costs and benefits was stated
The discount rate was stated and the choice of discount rate was justified
The approach to the sensitivity analysis was provided
The choice of variables for the sensitivity analysis was justified
Major outcomes were presented in a disaggregated as well as an aggregated form
The answer to the study question was provided
Conclusions followed from the data reported and conclusions were accompanied by appropriate caveats
Funding sources of the evaluation were provided and conflicts of interest declared (none)

The choice of form of economic evaluation was not justified in relation to the question addressed
Details of the design and results of effectiveness studies were not provided
Quantities of resource use were not reported separately from their unit costs
Methods for the estimation of quantities and unit costs were not described
Details of currency of price adjustments for inflation were not provided

Table 9Strengths and Limitations of Guidelines using AGREE II⁹

Item	Guideline
Item	Diabetes Canada, 2018³
Domain 1: Scope and Purpose
1. The overall objective(s) of the guideline is (are) specifically described.	Yes
2. The health question(s) covered by the guideline is (are) specifically described.	No - but the intent was easily perceived
3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.	Yes
Domain 2: Stakeholder Involvement
4. The guideline development group includes individuals from all relevant professional groups.	Yes
5. The views and preferences of the target population (patients, public, etc.) have been sought.	Yes
6. The target users of the guideline are clearly defined.	Yes
Domain 3: Rigour of Development
7. Systematic methods were used to search for evidence.	Yes
8. The criteria for selecting the evidence are clearly described.	Yes
9. The strengths and limitations of the body of evidence are clearly described.	Yes
10. The methods for formulating the recommendations are clearly described.	Yes
11. The health benefits, side effects, and risks have been considered in formulating the recommendations.	Yes
12. There is an explicit link between the recommendations and the supporting evidence.	Yes
13. The guideline has been externally reviewed by experts prior to its publication.	Yes
14. A procedure for updating the guideline is provided.	Yes
Domain 4: Clarity of Presentation
15. The recommendations are specific and unambiguous.	Yes
16. The different options for management of the condition or health issue are clearly presented.	Yes
17. Key recommendations are easily identifiable.	Yes
Domain 5: Applicability
18. The guideline describes facilitators and barriers to its application.	No
19. The guideline provides advice and/or tools on how the recommendations can be put into practice.	Yes
20. The potential resource implications of applying the recommendations have been considered.	No
21. The guideline presents monitoring and/or auditing criteria.	No
Domain 6: Editorial Independence
22. The views of the funding body have not influenced the content of the guideline.	Yes
23. Competing interests of guideline development group members have been recorded and addressed.	Yes

: AGREE II = Appraisal of Guidelines for Research and Evaluation II.

Appendix 4. Main Study Findings and Authors’ Conclusions

Table 10Summary of Findings Included Systematic Review

Main Study Findings

Authors’ Conclusion

Health Quality Ontario, 2015²

Note: The SR summarized the body of evidence for each outcome, and assigned quality scores according to the GRADE Working Group criteria as High, Moderate, Low or Very Low^a. Findings from case series and observational comparative studies were pooled for each outcome.

Non-Uremic Patients

Islet transplantation alone compared to baseline prior to transplantation in case series or intensive insulin therapy in observational comparative studies:

Improved glycemic control (GRADE: Low to High)

Improved graft loss/insulin independence (15 studies; GRADE: High)
Improved HbA1c (15 studies; GRADE: Low)
Reduction in insulin requirements (11 studies; GRADE: Low)
Improved hypoglycemia events/unawareness (9 studies; GRADE: Low)

Improved secondary complications of diabetes (GRADE: Very Low to Low)

Improved cardiovascular disease (4 studies; GRADE: Very Low)
Improved retinopathy (5 studies; GRADE: Low)
Improved nephropathy (6 studies; GRADE: Very Low)
Improved neuropathy (5 studies; GRADE: Very Low)

Increased procedure-related and immunosuppression-related adverse events (21 studies; GRADE: Low)

Improved health-related quality of life (12 studies; GRADE: Very Low)

Uremic Patients

Islet after kidney transplantation and simultaneous islet-kidney transplantation compared to baseline prior to transplantation in case series or intensive insulin therapy in observational comparative studies:

Improved glycemic control (GRADE: Low to High)

Improved graft loss/insulin independence (7 studies; GRADE: High)
Improved HbA1c (8 studies; GRADE: Very Low)
Reduction in insulin requirements (8 studies; GRADE: Low)
Improved hypoglycemia events/unawareness (2 studies; GRADE: Low)

Improved secondary complications of diabetes (GRADE: Low)

Improved cardiovascular risk factors (6 studies; GRADE: Low)
Improved nephropathy (6 studies; GRADE: Low)

Increased procedure-related and immunosuppression-related adverse events (5 studies; GRADE: Low)

Improved health-related quality of life (2 studies; GRADE: Very Low)

“Islet transplantation offers an alternative for patients with type 1 diabetes who have brittle diabetes with difficult-to-control blood glucose levels or hypoglycemic unawareness despite optimal insulin therapy.” (p. 67)

: HbA1c = glycated hemoglobin A1c; GRADE = Grading of Recommendations Assessment, Development and Evaluation; SR = systematic review.
a: = High: the true effect lies close to the estimate of the effect; Moderate: the true effect is most likely close, but may also be substantially different than the estimate of the effect; Low: the true effect may be substantially different than the estimate of the effect; Very Low: the true effect is likely to be substantially different than the estimate of the effect.

Table 11Summary of Findings of Included Primary Clinical Studies

Main Study Findings	Authors’ Conclusion
Randomized Controlled Trial
Lablanche, 2018¹⁰
Primary outcome: Proportion of participants with a modified β-score^a of 6 or higher (islet transplantation group vs. insulin therapy group): 64% (95% CI, 43 to 82) vs. 0% (95% CI, 0 to 15), P < 0.0001 Secondary outcomes: Median HbA1c (islet transplantation group vs. insulin therapy group): 5.6% vs. 8.2%, P < 0.0001 (IQRs not provided) Median fasting blood glucose level (islet transplantation group vs. insulin therapy group): 5.9 mmol/L (IQR, 5.2 to 6.7) vs. 5.7 mmol/L (IQR, 4.9 to 10.9), P = 0.92 Proportion of participants with an HbA1c <7% without severe hypoglycemia (islet transplantation group vs. insulin therapy group): 84% (95% CI, 64 to 96) vs. 0% (95% CI, 0 to 15), P < 0.0001 Median number of severe hypoglycemia events per year (islet transplantation group vs. insulin therapy group): 0 (IQR, 0 to 0) vs. 2 (IQR, 0 to 4), P < 0.0001 Proportion of participants free from severe hypoglycemia (islet transplantation group vs. insulin therapy group): 92% (95% CI, 74 to 99) vs. 36% (95% CI, 17 to 59), P < 0.0001 Median number of non-severe hypoglycemia events per year (islet transplantation group vs. insulin therapy group): 0 (IQR, 0 to 0) vs. 5 (IQR, 0 to 17), P < 0.0003 Median insulin requirements (numerical data not provided): Statistically significant improvement with immediate islet transplantation compared to insulin group, P < 0.0001 Median gain in quality of life dimensions assessed with the Diabetes Quality of Life questionnaire (numerical data not provided): Statistically significant improvement with immediate islet transplantation compared to insulin group in Satisfaction (P < 0.0001), Impact of Diabetes (P < 0.0001), Diabetes-Related Worry (P = 0.005) and Global Score (P < 0.0001) No statistically significant difference with immediate islet transplantation compared to insulin group in Wellbeing (P = 0.21) No statistical analysis conducted in Social Worry category because of the low number of respondents for this item Median gain in quality of life dimensions assessed with the Short Form 36 Health Survey (numerical data not provided): Statistically significant improvement with immediate islet transplantation compared to insulin group in General Health (P = 0.008) and Health Transition (P = 0.0006) No statistically significant difference with immediate islet transplantation compared to insulin group in Physical Functioning (P = 0.20), Physical Role Limitations (P = 0.91), Bodily Pain (P = 0.82), Vitality (P = 0.08), Social Functioning (P = 0.58), Emotional Role Limitations (P = 0.70), Mental Health (P = 0.14), Physical Component Score (P = 0.08), Mental Component Score (P = 0.67) Outcomes assessed at 12 months after the first infusion in the full cohort (islet transplantation group compared to baseline): Modified β-score^a of 6 or higher: 63% (95% CI, 48 to 77) vs. 0%, P < 0.0001 Median HbA1c: 5.8% (IQR, 5.5 to 6.7) vs. 8.1% (IQR, 7.4 to 8.9), P < 0.0001 Median fasting blood glucose level: 5.7 mmol/L (IQR, 5.2 to 7.3) vs. 9.1 mmol/L (IQR, 5.9 to 13.0), P = 0.0002 Proportion of participants with an HbA1c <7% without severe hypoglycemia: 70% (95% CI, 54 to 82) vs. 2% (95% CI, 0 to 11), P < 0.0001 Median number of severe hypoglycemia events per year: 0 (IQR, 0 to 0) vs. 2 (IQR, 0 to 4), P < 0.0001 Proportion of participants free from severe hypoglycemia: 85% (95% CI, 71 to 94) vs. 34% (95% CI, 21 to 49), P < 0.0001 Median number of non-severe hypoglycemia events per patient year: 0 (IQR, 0 to 0) vs. 10 (IQR, 4 to 17), P < 0.0001 Median Clarke Score^b: 0 (IQR, 0 to 2) vs. 5 (IQR, 3 to 6), P < 0.0001 Proportion of participants achieving insulin independence: 59% (95% CI, 43 to 73, P < 0.0001 vs. baseline) Median insulin requirements (numerical data not provided): Statistically significant improvement with islet cell transplantation compared to baseline, P < 0.0001 Adverse events: Infections and infestations (43%), gastrointestinal disorders (39%), blood and lymphatic system disorders (35%), procedural complications (20%), nervous system disorders (17%), renal and urinary disorders (13%), cardiac disorders (11%), metabolism and nutrition disorders (13%)	“Although studies with longer-term follow-up are needed, our findings suggest that islet transplantation is a valid option for patients with severe, unstable type 1 diabetes who are not responding to intensive medical treatments.” (p. 535) “In conclusion, the results of the TRIMECO trial suggest that, compared with insulin therapy, islet transplantation is an effective intervention in patients with severe forms of type 1 diabetes. We suggest that islet transplantation should be integrated into the stepped-care approach for the treatment of such patients.” (p. 536)
Non-Randomized Studies
Vantyghem, 2019¹¹
Primary Outcome Proportion of patients achieving insulin independence following islet transplantation: 5 years: 39% (95% CI, 22 to 57) 10 years: 28% (95% CI, 13 to 45) Secondary Outcomes Median number of severe hypoglycemia events in previous year (following islet transplantation vs. baseline): 1 year: 0 (IQR, 0 to 0) vs. 2 (IQR, 1 to 5), P < 0.0001 5 years: 0 (IQR, 0 to 0) vs. 2 (IQR, 1 to 5), P < 0.0001 10 years: 0 (IQR, 0 to 0) vs. 2 (IQR, 1 to 5), P < 0.0001 Median HbA1c (following islet transplantation vs. baseline): 1 year: 5.9% (IQR, 5.5 to 6.7) vs. 8.15% (IQR, 7.3 to 8.95), P < 0.0001 5 years: 6.9% (IQR, 6.1 to 7.5) vs. 8.15% (IQR, 7.3 to 8.95), P < 0.0001 10 years: 6.7% (IQR, 6.1 to 8.0) vs. 8.15% (IQR, 7.3 to 8.95), P = 0.0009 Median exogenous insulin requirements (following islet transplantation vs. baseline): 1 year: 0 units/kg/day (IQR, 0 to 0.04) vs. 0.57 units/kg/day (IQR, 0.41 to 0.74), P < 0.0001 5 years: 0 units/kg/day (IQR, 0 to 0.36) vs. 0.57 units/kg/day (IQR, 0.41 to 0.74), P < 0.0001 10 years: 0.28 units/kg/day (IQR, 0 to 0.43) vs. 0.57 units/kg/day (IQR, 0.41 to 0.74), P < 0.0001 Median mean glucose via continuous glucose monitoring (following islet transplantation vs. baseline): 1 year: 112 mg/dL (IQR, 102 to 133) vs. 146 mg/dL (IQR, 131 to 208), P < 0.0001 5 years: 126 mg/dL (IQR, 110 to 144) vs. 146 mg/dL (IQR, 131 to 208), P < 0.0001 10 years: 118 mg/dL (IQR, 113 to 154) vs. 146 mg/dL (IQR, 131 to 208), P = 0.0007 Median standard deviation of mean glucose via continuous glucose monitoring (following islet transplantation vs. baseline): 1 year: 22 mg/dL (IQR, 15 to 41) vs. 63 mg/dL (IQR, 45 to 77), P < 0.0001 5 years: 29 mg/dL (IQR, 17 to 52) vs. 63 mg/dL (IQR, 45 to 77), P < 0.0001 10 years: 40 mg/dL (IQR, 18 to 54) vs. 63 mg/dL (IQR, 45 to 77), P < 0.0001 Median percentage of time spent below range (<70 mg/dL) (following islet transplantation vs. baseline): 1 year: 0% (IQR, 0 to 5) vs. 9% (IQR, 3 to 16), P < 0.0001 5 years: 1% (IQR, 0 to 3) vs. 9% (IQR, 3 to 16), P < 0.0001 10 years: 3% (IQR, 0 to 9) vs. 9% (IQR, 3 to 16), P = 0.0012 Adverse events: During the first year post-transplantation: 11 adverse events related to the infusion procedure, 5 adverse events related to immunosuppression (hematological disorders, infections, diarrhea) From 1 year to 10 years post-transplantation: 8 adverse events related to immunosuppression (infections, skin carcinomas)	“To conclude, the current study provides direct evidence that islet transplantation performed alone or after a kidney graft in patients with type 1 diabetes can markedly improve metabolic control and suppress SHEs during 10 years.” (p. 2048)
Foster, 2018¹²
Note: The effect size was calculated as the mean change from baseline divided by the baseline standard deviation. Condition Specific Health Related Quality of Life: Diabetes Distress Scale Total score: Baseline (Mean, Standard deviation): 2.62, 0.98 Day 75 (Mean, Effect size, P-value): 1.83, −0.80, < 0.0001 Day 365 (Mean, Effect size, P-value): 1.50, −1.22, < 0.0001 Day 730 (Mean, Effect size, P-value): 1.32, −1.33, < 0.0001 Emotional Burden: Baseline (Mean, Standard deviation): 3.75, 1.31 Day 75 (Mean, Effect size, P-value): 2.59, −0.83, < 0.0001 Day 365 (Mean, Effect size, P-value): 1.85, −1.48, < 0.0001 Day 730 (Mean, Effect size, P-value): 1.43, −1.79, < 0.0001 Physician-Related Distress: Baseline (Mean, Standard deviation): 1.67, 1.02 Day 75 (Mean, Effect size, P-value): 1.19, −0.47, < 0.0001 Day 365 (Mean, Effect size, P-value): 1.06, −0.58, < 0.0001 Day 730 (Mean, Effect size, P-value): 1.10, −0.51, = 0.0013 Regimen-Related Distress: Baseline (Mean, Standard deviation): 2.66, 1.20 Day 75 (Mean, Effect size, P-value): 1.77, −0.78, < 0.0001 Day 365 (Mean, Effect size, P-value): 1.61, −0.94, < 0.0001 Day 730 (Mean, Effect size, P-value): 1.42, −1.05, < 0.0001 Interpersonal Distress: Baseline (Mean, Standard deviation): 2.19, 1.38 Day 75 (Mean, Effect size, P-value): 1.59, −0.42, = 0.0002 Day 365 (Mean, Effect size, P-value): 1.47, −0.55, < 0.0001 Day 730 (Mean, Effect size, P-value): 1.35, −0.70, < 0.0001 Hypoglycemic Fear Survey Total score: Baseline (Mean, Standard deviation): 2.36, 0.66 Day 75 (Mean, Effect size, P-value): 1.33, −1.51, < 0.0001 Day 365 (Mean, Effect size, P-value): 0.54, −2.59, < 0.0001 Day 730 (Mean, Effect size, P-value): 0.41, −2.85, < 0.0001 Hypoglycemic Avoidance Behavior: Baseline (Mean, Standard deviation): 2.52, 0.54 Day 75 (Mean, Effect size, P-value): 1.47, −1.86, < 0.0001 Day 365 (Mean, Effect size, P-value): 0.64, −3.34, < 0.0001 Day 730 (Mean, Effect size, P-value): 0.67, −3.31, < 0.0001 Worry About Hypoglycemia: Baseline (Mean, Standard deviation): 2.20, 0.90 Day 75 (Mean, Effect size, P-value): 1.27, −1.13, < 0.0001 Day 365 (Mean, Effect size, P-value): 0.53, −1.79, < 0.0001 Day 730 (Mean, Effect size, P-value): 0.47, −1.88, < 0.0001 Functional Health Status and Health Utility: Short Form 36 Health Survey Physical Component Summary: Baseline (Mean, Standard deviation): 47.52, 8.77 Day 75 (Mean, Effect size, P-value): 49.97, 0.31, NS Day 365 (Mean, Effect size, P-value): 52.52, 0.54, < 0.0001 Day 730 (Mean, Effect size, P-value): 52.44, 0.39, = 0.0004 Mental Component Summary: Baseline (Mean, Standard deviation): 49.23, 10.48 Day 75 (Mean, Effect size, P-value): 53.03, 0.28, = 0.0081 Day 365 (Mean, Effect size, P-value): 51.86, 0.28, NS Day 730 (Mean, Effect size, P-value): 54.40, 0.30, NS Physical Functioning Scale: Baseline (Mean, Standard deviation): 50.62, 8.04 Day 75 (Mean, Effect size, P-value): 53.30, 0.29, = 0.0034 Day 365 (Mean, Effect size, P-value): 53.67, 0.35, = 0.0005 Day 730 (Mean, Effect size, P-value): 52.29, 0.19, NS Role Physical Scale: Baseline (Mean, Standard deviation): 45.69, 10.57 Day 75 (Mean, Effect size, P-value): 49.17, 0.31, = 0.0008 Day 365 (Mean, Effect size, P-value): 51.70, 0.57, < 0.0001 Day 730 (Mean, Effect size, P-value): 52.67, 0.48, < 0.0001 Bodily Pain Scale: Baseline (Mean, Standard deviation): 50.52, 10.04 Day 75 (Mean, Effect size, P-value): 49.96, −0.05, NS Day 365 (Mean, Effect size, P-value): 52.72, 0.22, NS Day 730 (Mean, Effect size, P-value): 53.22, 0.08, NS General Health Scale: Baseline (Mean, Standard deviation): 44.31, 12.42 Day 75 (Mean, Effect size, P-value): 50.19, 0.49, < 0.0001 Day 365 (Mean, Effect size, P-value): 51.57, 0.57, < 0.0001 Day 730 (Mean, Effect size, P-value): 51.60, 0.39, = 0.0064 Vitality Scale: Baseline (Mean, Standard deviation): 48.81, 10.94 Day 75 (Mean, Effect size, P-value): 54.67, 0.51, = 0.0001 Day 365 (Mean, Effect size, P-value): 53.38, 0.40, = 0.0029 Day 730 (Mean, Effect size, P-value): 55.38, 0.44, = 0.0015 Social Functioning Scale: Baseline (Mean, Standard deviation): 46.99, 10.78 Day 75 (Mean, Effect size, P-value): 49.38, 0.19, NS Day 365 (Mean, Effect size, P-value): 50.98, 0.30, NS Day 730 (Mean, Effect size, P-value): 51.70, 0.28, NS Role Emotional Scale: Baseline (Mean, Standard deviation): 48.02, 10.25 Day 75 (Mean, Effect size, P-value): 51.58, 0.20, NS Day 365 (Mean, Effect size, P-value): 50.82, 0.31, = 0.0090 Day 730 (Mean, Effect size, P-value): 52.11, 0.25, NS Mental Health Scale: Baseline (Mean, Standard deviation): 53.48, 15.70 Day 75 (Mean, Effect size, P-value): 56.10, 0.21, NS Day 365 (Mean, Effect size, P-value): 55.12, 0.28, NS Day 730 (Mean, Effect size, P-value): 57.41, 0.22, NS EuroQoL 5 Dimensions Visual Analogue Scale: Baseline (Mean, Standard deviation): 74.13, 14.66 Day 75 (Mean, Effect size, P-value): 79.06, 0.29, NS Day 365 (Mean, Effect size, P-value): 82.86, 0.71, < 0.0001 Day 730 (Mean, Effect size, P-value): 85.74, 0.73, < 0.0001 Health Preference Weight: Baseline (Mean, Standard deviation): 0.87, 0.12 Day 75 (Mean, Effect size, P-value): 0.86, −0.06, NS Day 365 (Mean, Effect size, P-value): 0.86, −0.04, NS Day 730 (Mean, Effect size, P-value): 0.88, 0.009, NS Usual Activities: Baseline (Percent “No Problems” responses): 68.09% Day 75 (Percent “No Problems” responses, P-value): 74.47%, NS Day 365 (Percent “No Problems” responses, P-value): 78.57%, NS Day 730 (Percent “No Problems” responses, P-value): 84.38%, NS Anxiety/Depression: Baseline (Percent “No Problems” responses): 68.09% Day 75 (Percent “No Problems” responses, P-value): 72.34%, NS Day 365 (Percent “No Problems” responses, P-value): 69.05%, NS Day 730 (Percent “No Problems” responses, P-value): 71.88%, NS Mobility: Baseline (Percent “No Problems” responses): 80.85% Day 75 (Percent “No Problems” responses, P-value): 85.11%, NS Day 365 (Percent “No Problems” responses, P-value): 82.93%, NS Day 730 (Percent “No Problems” responses, P-value): 81.25%, NS Pain/Discomfort: Baseline (Percent “No Problems” responses): 53.19% Day 75 (Percent “No Problems” responses, P-value): 57.45%, NS Day 365 (Percent “No Problems” responses, P-value): 57.14%, NS Day 730 (Percent “No Problems” responses, P-value): 68.75%, NS Self-Care: Baseline (Percent “No Problems” responses): 95.74% Day 75 (Percent “No Problems” responses, P-value): 97.87%, NS Day 365 (Percent “No Problems” responses, P-value): 92.86%, NS Day 730 (Percent “No Problems” responses, P-value): 90.63%, NS	“These patient-reported outcomes corroborate the clinical importance of the objective benefits of islet transplantation already documented in the CIT-07.” (p. 1007)
Holmes-Walker, 2017¹³
Average insulin requirements (12-months post-islet transplantation vs. CSII) (no statistical comparison provided): 0.2 ±0.2 IU/kg vs. 0.4 ±0.2 IU/kg Average HbA1c (12-months post-islet transplantation vs. CSII): 6.4 ±1.3% vs. 8.2 ±1.8%, P = 0.01 Median HYPOscore^c (12-months post-islet transplantation vs. CSII): 0 (IQR, 0 to 1) vs. 1085 (IQR, 622 to 1400), P < 0.01 Median hypoglycemic events per person year (12-months post-islet transplantation vs. CSII): 0 (IQR, 0 to 1) vs. 8 (IQR, 0 to 18), P < 0.05 Median percentage of time with glucose less than 4 mmol/L (12-months post-islet transplantation vs. CSII): 0% (IQR, 0 to 1) vs. 1% (IQR, 1 to 8) (no P-value provided, but authors stated no statistically significant difference) Median percentage of time with glucose between 4 to 8 mmol/L (12-months post-islet transplantation vs. CSII): 81% (IQR, 71 to 95) vs. 48.5% (IQR, 44 to 66), P < 0.01 Average blood glucose level via continuous glucose monitoring (12-months post-islet transplantation vs. CSII): 7.1 ±1.9 mmol/L vs. 8.8 ±1.9 mmol/L (no P-value provided, but authors stated no statistically significant difference) Average standard deviation of blood glucose level (12-months post-islet transplantation vs. CSII): 1.7 ±0.8 mmol/L vs. 3.2 ±1.1 mmol/L, P = 0.01 Continuous overlapping net glycemic action 4-hour interval (no numerical data provided): Significantly reduced in 12 months post-islet transplantation vs CSII, P = 0.04 Adverse events: Transient lymphopenia in 4 patients, >20% reduction in glomerular filtration rate in 2 patients	“In our study, islet transplantation was the only treatment which reduced severe hypoglycemia to near-normal and improved HbA1c. The present study is further evidence that in appropriately selected patients with severe hypoglycemia with large glycemic variability, islet transplantation provides superior control and reduction in hypoglycemia over and above that achieved with CSII and therefore has the potential to have a greater impact on survival and long-term complications.” (p. 1273–1274)
Hering, 2016¹⁴
Primary outcome Proportion of participants with an HbA1c <7.0% with eradication of severe hypoglycemic events following islet transplant: Day 365: 87.5%, lower boundary of CI 76.8%, P < 0.001 Day 730: 71%, P< 0.01 (confidence interval not provided) Note: For the primary endpoint, a one-sided 95% lower confidence bound was calculated and the prespecified criterion for efficacy was that the lower bound be >50%. Secondary outcomes Proportion of participants with an HbA1c <6.5% with eradication of severe hypoglycemic events following islet transplant: Day 365: 79.1%, P < 0.001 (confidence interval not provided) Day 730: 68.8%, P = 0.02 (confidence interval not provided) Proportion of participants with an HbA1c <7.0% (islet cell transplantation vs. baseline): Day 75: 87.5% vs. 40%, P < 0.0003 Day 365: 87.5% vs. 40%, P < 0.0003 Median HbA1c (islet cell transplantation vs. baseline): Day 75: 5.9% vs. 7.2%, P < 0.0003 Day 365: 5.2% vs. 7.2%, P < 0.0003 Proportion of participants experiencing at least one severe hypoglycemic event: 2 of 45 in post islet transplantation vs 48 of 48 baseline, P < 0.0003 Proportion of participants achieving insulin Independence following islet transplant: Day 75: 23% Day 365: 52.1% Day 730: 42% Median insulin requirements (islet cell transplantation vs. baseline): Day 75: 0.13 units/kg vs. 0.49 units/kg, P < 0.0003 Day 365: 0.00 units/kg vs. 0.49 units/kg, P < 0.0003 Other outcomes Measures of hypoglycemia awareness, hypoglycemic events and glycemic lability/variability using the Clarke score^b, HYPOscore^c and mean amplitude of glycemic excursions: All improved significantly compared to baseline, P < 0.0002 (numerical data not provided) Adverse events: 30 serious adverse events occurred in year 1, 22 of which were procedure related bleeding events or immunosuppression related events including cytopenia, abdominal pain, toxic drug levels, infections and renal dysfunction 8 serious adverse events occurred in year 2, 2 of which were immunosuppression related events (infections)	“In conclusion, this trial demonstrates that transplantation of human islets is an effective treatment for T1D complicated by IAH and SHEs, resulting in the restoration of hypoglycemia awareness, elimination of SHEs, and normal or near-normal glycemic control in 87.5% of participants. Islet transplantation should be considered for patients with T1D and IAH in whom a stepped-care approach, including current educational, pharmacological, and technological interventions, has failed to prevent life-threatening SHEs.” (p. 1238)
Lablanche, 2015¹⁵
Median HbA1c: 6.20% (IQR, 4.60 to 9.60), 6.60% (IQR, 5.50 to 9.40), and 6.70% (IQR, 5.40 to 9.60) at 12, 48, and 60 months respectively post islet transplantation vs. 8.1% (IQR, 7.60 to 9.00) at baseline, P < 0.05 Proportion of patients with an HbA1c ≤7% or experiencing a drop in HbA1c of ≥2%: 84%, 70%, and 59% at 12, 48 and 60 months respectively post islet transplantation vs. 9% before islet infusion, P < 0.005 Median fasting blood glucose: 6.44 mmol/L (IQR, 4.11 to 11.3), 6.57 mmol/L (IQR, 3.4 to 11.8), and 7.28 mmol/l (IQR, 4.1 to 15.1) at 12, 48, and 60 months respectively post islet transplantation vs. 8.19 mmol/L (IQR, 1.56 to 22.4) at baseline, P < 0.05 Mean number of severe hypoglycemia (throughout 5-year follow up): 0 events/patient/year in the islet transplantation alone recipients and 0.01 events/patient/year in the islet after kidney transplant recipients, P < 0.005 (vs. baseline [not reported]) Median insulin requirements: 0.15 units/kg/day (IQR, 0 to 0.47), 0.17 units/kg/day (IQR, 0 to 0.7) and 0.18 units/kg/day (IQR, 0 to 0.57) at 12, 48, and 60 months respectively post islet transplantation vs. 0.50 units/kg/day (IQR, 0.42 to 0.58) at baseline, P < 0.05 Proportion of patients attaining insulin independence: 45%, 40%, 40%, 35%, and 31.5% at 12, 24, 36, 48, and 60 months in islet after kidney transplant recipients 37.5%, 45.8%, 37.5%, 25%, and 14% at 12, 24, 36, 48, and 60 months respectively in islet transplantation alone recipients Adverse events: Related to the infusion procedure (1 cytolysis, 1 abdominal pain, 1 segmental portal vein thrombosis, 7 hemorrhages) or to immunosuppression (18 adverse events)	“In conclusion, islet transplantation within the multicenter GRAGIL Network provided important and lasting clinical benefits to patients with type 1 diabetes, permitting improvement of glucose variability and preventing the occurrence of severe hypoglycemia.” (p. 1721)

: CI = confidence interval; CSII = continuous subcutaneous insulin infusion; HbA1c = glycated hemoglobin A1c; IAH = impaired awareness hypoglycemia; IQR = interquartile range; NS = not statistically significant; SHEs = severe hypoglycemia events; T1D = type 1 diabetes.
a: = The modified β-score is based on the following variables: fasting glucose, fasting or stimulated C-peptide, HbA1c, and absence of insulin or oral hypoglycemic drug use. Up to two points are rewarded for each variable. As such, the score can range from 0 (no graft function) to 8 (optimal graft function). Contrary to the original β-score, the modified β-score does not assign an overall score of zero when stimulated C-peptide is negative.
b: = The Clarke Score consists of questions on hypoglycemia awareness and the presence or absence on symptoms accompanying low blood glucose. The score can range from 0 to 8 where a score of 5 or higher indicates the presence of hypoglycemia unawareness.
c: = The HYPOscore is a composite hypoglycemia score based on the frequency, severity and degree of unawareness of hypoglycemia. A HYPOscore of ≥1047 indicates serious problems with hypoglycemia.

Table 12Summary of Findings of Included Economic Evaluation

Main Study Findings

Authors’ Conclusion

Wallner et al., 2016¹⁶

Base-case probabilistic analysis (assuming a 12 year difference in life expectancy caused by hypoglycemia):

Costs:

Standard care: $56,560

Islet cell transplantation: $347,377

Cost difference: $290,816

QALYs:

Standard care: 9.59

Islet cell transplantation: 11.52

Benefit difference: 1.94

ICER:

$150,006 per QALY gained

Analysis:

95% probability of being cost-effective at a willingness-to-pay threshold of $196,000

13% probability of being cost-effective at a willingness-to-pay threshold of $125,000

0.5% probability of being cost-effective at a willingness-to-pay threshold of $100,000

Scenario Analysis:

Model most sensitive to decreased discount rates and the use of immunosuppression regimens made of generic (rather than brand name) drugs

“We found that islet cell transplantation is not cost-effective when compared to standard therapy for unstable T1DM. Although it shows large improvements in health outcomes over standard therapy, as anticipated it is also much more costly. These extra costs are not offset by more than proportionate improvements in health outcomes.” (p. 13)

: ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year; T1DM = type 1 diabetes mellitus.

Table 13. Summary of Recommendations in Included Guideline (PDF, 209K)

Appendix 5. Additional References of Potential Interest

Health Technology Assessment Included in Previous CADTH Report

Xie X, Rich B, Dendukuri N. Islet transplantation in patients with Type 1 Diabetes Mellitus. (Report No. 66). Montreal (QC): Technology Assessment Unit (TAU) of the McGill University Health Centre (MUHC); 2014 https://muhc.ca/sites/default/files/micro/m-TAU/muhc_tau_2014_66_islet_transplantation.pdf Accessed 2020 Apr 28

Non-Randomized Study – No Comparator

Anazawa T, Saito T, Goto M, et al. Long-term outcomes of clinical transplantation of pancreatic islets with uncontrolled donors after cardiac death: a multicenter experience in Japan. Transplant Proc. 2014 Jul-Aug;46(6):1980–1984. PubMed: PM25131088 [PubMed: 25131088]

Clinical Practice Guideline

Clinical guidelines for pancreatic islet transplantation. Vancouver (BC): BC Transplant; 2014. http://www.transplant.bc.ca/Documents/Health%20Professionals/Clinical%20guidelines/Clinical%20Guidelines%20for%20Pancreatic%20Islet%20Transplantation_01Sept2014_0.pdf Accessed 2020 Apr 28

New Health Technologies Report

Health Policy Advisory Committee on Technology. New and emerging health technologies for diabetes. Herston (AU): HealthPACT Secretariat; 2015. https://www.coaghealthcouncil.gov.au/Portals/0/December%202015_New%20and%20Emerging%20Health%20Technologies%20for%20Diabetes.pdf Accessed 2020 Apr 28

About the Series

CADTH Rapid Response Report: Summary with Critical Appraisal

ISSN: 1922-8147

Version: 1.0

Funding: CADTH receives funding from Canada’s federal, provincial, and territorial governments, with the exception of Quebec.

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Islet Cell Transplantation for Patients with Unstable or Uncontrollable Diabetes Mellitus: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines. Ottawa: CADTH; 2020 Apr. (CADTH rapid response report: summary with critical appraisal).

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Freige C, McCormack S, Ford C. Islet Cell Transplantation for Patients with Unstable or Uncontrollable Diabetes Mellitus: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines [Internet]. Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2020 Apr 29.
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Context and Policy Issues
Research Questions
Key Findings
Methods
Summary of Evidence
Conclusions and Implications for Decision or Policy Making
References
Selection of Included Studies
Characteristics of Included Publications
Critical Appraisal of Included Publications
Main Study Findings and Authors’ Conclusions
Additional References of Potential Interest

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Islet Cell Transplantation for Patients with Unstable or Uncontrollable Diabetes Mellitus: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines

Abbreviations

Context and Policy Issues

Research Questions

Key Findings

Methods

Literature Search Methods

Selection Criteria and Methods

Table 1

Exclusion Criteria

Critical Appraisal of Individual Studies

Summary of Evidence

Quantity of Research Available

Summary of Study Characteristics

Study Design

Country of Origin

Patient Population

Interventions and Comparators

Outcomes

Summary of Critical Appraisal

Systematic Reviews

Randomized Controlled Trial

Non-Randomized Studies

Economic Evaluation

Evidence-Based Guideline

Summary of Findings

Clinical Effectiveness of Islet Cell Transplantation

Glycemic Control

Secondary Complications of Diabetes

Quality of Life

Adverse Events

Cost-Effectiveness of Islet Cell Transplantation

Guidelines

Limitations

Conclusions and Implications for Decision or Policy Making

References

Appendix 1. Selection of Included Studies

Appendix 2. Characteristics of Included Publications

Table 2Characteristics of Included Systematic Review

Table 3Characteristics of Included Primary Clinical Studies

Table 4Characteristics of Included Economic Evaluation

Table 5Characteristics of Included Guideline

Appendix 3. Critical Appraisal of Included Publications

Table 6Strengths and Limitations of the Systematic Review using AMSTAR 26

Table 7Strengths and Limitations of Clinical Studies using the Downs and Black Checklist7

Table 8Strengths and Limitations of Economic Studies using the Drummond Checklist8

Table 9Strengths and Limitations of Guidelines using AGREE II9

Appendix 4. Main Study Findings and Authors’ Conclusions

Table 10Summary of Findings Included Systematic Review

Table 11Summary of Findings of Included Primary Clinical Studies

Table 12Summary of Findings of Included Economic Evaluation

Appendix 5. Additional References of Potential Interest

Health Technology Assessment Included in Previous CADTH Report

Non-Randomized Study – No Comparator

Clinical Practice Guideline

New Health Technologies Report

About the Series

Suggested citation:

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In this Page

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Related information

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Recent Activity

Table 6Strengths and Limitations of the Systematic Review using AMSTAR 2⁶

Table 7Strengths and Limitations of Clinical Studies using the Downs and Black Checklist⁷

Table 8Strengths and Limitations of Economic Studies using the Drummond Checklist⁸

Table 9Strengths and Limitations of Guidelines using AGREE II⁹