Objective and Key Questions

The overall objective of this report is to systematically review and synthesize available evidence on the outcomes of islet transplantation in patients with type 1 diabetes who lack functioning islets. The report's scope is limited to transplantation of unaltered human allogeneic islets harvested from donor organs. Thus, cultured islets are included, but the following are excluded: autologous islets, porcine islets, genetically altered islets, and islets prepared from stem cells.

Relevant evidence for this review only includes studies that used the Edmonton protocol or subsequently developed protocols. Outcomes of islet transplants using earlier procedures than the Edmonton protocol were summarized briefly in the Introduction chapter of this review. They are considered relevant evidence only insofar as they may contribute to a causal chain that can be linked to outcomes of islet transplants using the Edmonton or subsequently developed transplant protocols.

To achieve these objectives, the report addresses the following key questions:

1. What are the outcomes of managing selected diabetes patients with islet transplantation compared with similar patients receiving whole-organ pancreas transplant or medical management? Are similar outcomes achievable outside of the investigational setting?
2. What criteria should be used to select patients for islet transplantation and what are the outcomes for relevant patient subgroups? Relevant subgroups include:
   • patients with severe or uncontrolled diabetes symptoms such as hypoglycemia unawareness despite (or due to) intensive medical management;
   • patients with prior, failed, whole-organ pancreas transplant (i.e., have alreadymet eligibility criteria for pancreas transplant alone [PTA]);
   • patients with existing, functioning kidney transplants or who are candidates for kidney transplant and will thus be on immunosuppressive therapy;
   • special patient populations, including women, racial and ethnic minorities, pediatric and elderly populations, and those of low socioeconomic status.
3. What are the incidence and severity of adverse effects associated with the islet transplantation procedure and with the immunosuppressive regimens? How do these compare with the adverse effects associated with whole-organ pancreas transplantation or medical management?
4. What is the evidence that insulin independence or significantly reduced insulin dependence achieved with islet transplantation can be maintained long-term after the initial transplant or with additional transplants in the event of failure? How often must successive transplants be performed?

An initial review of the islet transplant literature revealed the following limitations: small patient sample sizes from a small number of islet transplant centers; relatively short followup times; and, variably reported outcomes. These limitations precluded a comparison of islet transplant outcomes with those for whole organ pancreas transplantation. Thus, a formal literature search and data abstraction on the clinical outcomes of whole-organ transplantation was not attempted and whole-organ transplantation was instead summarized in the Introduction chapter.

Search Strategy

Available registry data, recent meeting abstracts and presentations by investigators from key research centers are the primary sources of evidence for Key Questions 1–4. The MEDLINE database was searched for recently published research articles and for relevant background information. The database was searched initially from 1966 through October, 2002; subsequent search updates were performed through October, 2003. Additionally, bibliographies of relevant articles were also searched and the project's Technical Expert Panel was queried for any relevant articles omitted from the search results. During the peer review process, reviewers informed the Evidence-based Practice Center (EPC) staff of articles recently published or accepted for publication and in the case of certain imminent publications, provided prepublication manuscripts.

The search strategy selected for review all citations that included any of the following terms:

“Islets of Langerhans Transplantation”[Medical Subject Heading^® (MeSH^®)];

“Islets of Langerhans”[MeSH^®] AND “transplantation”[MeSH^®];

islet*[tw] AND transplant*[tw]; or

beta cell*[tw] AND transplant*[tw]

The search was limited to studies on human subjects with English-language abstracts. Papers published in foreign languages were reviewed if the English abstract appeared to meet inclusion criteria. No studies relevant to the evidence review were published in a language other than English.

Study Selection Criteria

For all key questions in this report, studies were included if they:

1. reported prospective series of islet transplantation; AND
2. reported on outcomes of interest with at least 3 months of followup (1 year preferred); AND
3. used a transplant protocol based on the Edmonton protocol or a subsequently developed protocol; AND
4. provided sufficient details on study design, methods, and outcomes to assess study quality (see below); AND
5. were available as a full-length publication, abstract, or poster/slide presentation provided by the original presenter.

Patients

Patients of interest for this review were those with long-standing type 1 diabetes mellitus based on a stimulated serum C-peptide concentration of less than 0.48 ng per milliliter; whose glucose concentration remained uncontrolled despite exogenous insulin therapy; who had episodes of severe hypoglycemia requiring assistance or labile diabetes with evidence of daily lifestyle disruption; and had no comorbidities precluding transplantation or immunosuppression therapy. In general, eligible patients were judged by the treating centers to be at greater risk from uncontrolled diabetes than they would be from the global risk of transplantation and immunosuppression.

Outcomes of Interest

The outcomes of interest are grouped into near-term and long-term efficacy outcomes and adverse events. Near-term efficacy outcomes include clinical outcomes:

• proportion of patients remaining insulin independent at yearly intervals after transplantation;
• percentage of baseline insulin use at yearly intervals after transplantation; and
• severe episodes of hypoglycemia.

Biological outcomes include:

• C-peptide levels;
• hemoglobin A1c.

Long-term efficacy outcomes include effects on complications of diabetes, such as:

• nephropathy;
• retinopathy;
• atherosclerosis, etc.

Adverse outcomes include those related to the islet infusion procedure, such as:

• mortality;
• bleeding;
• thrombosis;
• pain;

and those related to the immunosuppressive regimen:

• mortality;
• nephrotoxicity;
• hypertension;
• hypercholesterolemia;
• thrombocytopenia;
• leukopenia;
• infection;
• post-transplant lymphoproliferative disease.

Additional adverse outcomes of interest are:

• possible long-term effects of islets; and
• need for additional transplants.

Methods of the Review