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MEETING SUMMARIES
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Diabetes Mellitus Interagency Coordinating Committee Meeting on Islet Transplantation
Democracy 2, Room 701
6707 Democracy Boulevard
Bethesda, Maryland
November 23, 2004
Judith Fradkin, Director of the Division of Diabetes, Endocrinology, and Metabolic Diseases, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), welcomed the Committee members and guests. She stressed the importance of this meeting on islet transplantation because of recent legislation that will impact National Institutes of Health (NIH) initiatives and programs. The Pancreatic Islet Cell Transplantation Act of 2004 was passed by the U.S. Congress in November and included two key provisions; one making pancreata procured by an organ procurement organization (OPO) and used for islet cell transplantation count for purposes of certification by the Center for Medicare and Medicaid Services (CMS), and the second giving new responsibilities to the Diabetes Mellitus Interagency Coordinating Committee (DMICC) regarding islet transplantation. The DMICC is mandated to report annually on progress in implementing the Act. One purpose of this meeting is to begin discussing approaches being initiated by DMICC member agencies, either independently or through cooperative arrangements with other agencies, that can be included in the mandated report.
Dr. Fradkin reviewed additional legislation related to islet transplantation, including section 733 of the Medicare Modernization Act (MMA), which provided for a demonstration project to be initiated between the CMS and NIH. This legislation may allow for licensure and for CMS subsequently to make funding decisions about islet transplantation under federal programs. In addition, this legislation allows CMS to cover medical care costs associated with islet transplantation for Medicare beneficiaries; for patients with type 1 diabetes, coverage will include patients with renal failure undergoing renal transplantation or previously having received a renal transplant.
In response to the MMA, NIH, NIDDK, and the National Institute of Allergy and Infectious Diseases (NIAID) issued a request for applications to create a clinical islet transplantation consortium. Those awards were made this past September, and the consortium had its first steering committee meeting in October. Materials related to the consortium are included in the meeting packet and will be reviewed by subsequent presenters.
Islet Transplantation Over view and PerpectivesTom L. Eggerman, M.D., Ph.D., Director, Islet Transplantation Program, Division of Diabetes, Endocrinology, and Metabolism, NIDDK
Dr. Eggerman provided an update on efforts by the U.S. Department of Health and Human Services (DHHS) on islet transplantation and facilitated a discussion of current issues facing researchers and clinicians. In brief, islet transplantation is a treatment for patients with type 1 diabetes who receive injections of islet cells procured from donors. Islet cells are injected through the portal vein; the cells implant in the liver and produce insulin in response to glucose levels. Immunosuppression is needed to prevent rejection for as long as the implanted islet cells are functional.
Four DHHS agencies–NIH, CMS, the U.S. Food and Drug Administration (FDA), and the Health Resources and Services Administration (HRSA)¾interact and provide oversight for different aspects of basic preclinical and clinical research on islet transplantation.
The NIH supports basic research efforts in both academic and small-business settings. This includes a multitude of human and nonhuman studies (especially rodent studies) involving stem cells, embryology, physiology, imaging, encapsulation and transplantation, and the Beta Cell Biology Consortium, which was established to better understand the development of the islet, including identification of potential stem cell precursors. A preclinical effort at the NIH headed by the NIAID and cosponsored by the NIDDK is the Non-Human Primate Immune Tolerance Cooperative Study Group. This effort has resulted in the finding that there can be tolerance development with islet transplantation that obviates the use of long-term immunosuppression. Another NIAID-NIDDK preclinical collaboration that will be funded in 2005 is the Immunobiology of Xenotransplantation Consortium, which will focus on porcine transplantation and rodent-porcine islet transplantation into nonhuman primates.
Clinical efforts on islet research and transplantation include the Immune Tolerance Network, which sponsored the multicenter Edmonton trial and other clinical islet transplantation studies. It is cosponsored by the NIDDK and the NIAID. The NIDDK also is sponsoring individual investigator clinical studies.
The Islet Cell Resource Centers, cosponsored by the NIDDK and the Juvenile Diabetes Research Foundation (JDRF), provide human islets for clinical and basic research. The lead institute/center is the National Center for Research Resources (NCRR). The program includes 10 centers in the United States whose analyses include product quality and clinical outcomes and who collaborate with the UNOS to improve coordination of donor data. In addition, the Clinical Islet Transplantation Consortium (CITC), cosponsored by the NIDDK and the NIAID, was established to facilitate cooperative clinical trials using new approaches in islet transplantation. The CITC had its first meeting in October 2004 and will focus on clinical and mechanistic studies, with five funded clinical sites and a coordinating center. As part of the mandate issued by the MMA, the NIDDK is implementing an investigation of islet transplantation in Medicare beneficiaries for whom the cost of pancreas islet isolation and usual medical care costs will be covered by Medicare. This investigation is being implemented through the CITC and will include Medicare patients with renal failure or those who have received a renal transplant. The need for additional centers for the CITC beyond the five that currently are part of the consortium is anticipated to accrue a sufficient number of patients. Workshops are planned to identify the major questions and approaches for this clinical investigation, and the outcome will be the safety and efficacy of islet transplantation in Medicare beneficiaries and the consideration of Medicare reimbursement and FDA licensure.
To collect, analyze, and communicate data on all islet and beta cell transplants performed in North America, the NIDDK initiated and funded the Collaborative Islet Transplantation Registry (CITR) in 2001. Currently, there are 17 North American centers providing data, and five European sites are being added through the JDRF. The first CITR annual report was produced in September 2004 and contained data from 158 islet infusions.
FDA Oversight: Pancreatic Islet Cells
Joyce Frey-Vasconcells, Ph.D., Acting Deputy Office Director, Office of Cells, Tissue and Gene Therapies, Center for Biologics Evaluation and Research, FDA
Dr. Frey-Vasconcells provided an overview of FDA responsibilities and authority regarding pancreatic islet cell regulation and licensure. In September 2000, the FDA notified transplant centers that the agency has regulatory authority over islet cell therapy and that the centers are subject to licensure under section 351 of the Public Health Service (PHS) Act. In addition, products for islet transplantation meet the definition of a drug and, therefore, are subject to compliance with the Food, Drug and Cosmetic (FDC) Act. A new regulatory approach for cells and tissues has been established that
New tissue regulatory rules¾the Donor Eligibility and the Good Tissue Practices (GTP) rules¾have been issued and will take effect on May 25, 2005. The following rules define what the FDA considers a cell therapy, a tissue, and cellular and tissue-based products (HCT/Ps):
To determine the criteria for distinguishing between a tissue and a regulated article, the FDA determined that a product is a tissue if it is minimally manipulated; for homologous use only, based on advertising, labeling, or the intent of the investigator; not combined with a drug or a device; and its activity is not systemic or metabolic, unless it is for autologous or reproductive use.
Pancreatic islet cells fall within the FDA criteria for cell therapies because they fit the definition of HCT/Ps and therefore are regulated under section 351 of the PHS Act, are more than minimally manipulated, their activity is systemic and metabolic and most islet transplantation is allogeneic, and they are not a vascularized organ. There currently are 39 active IND applications for pancreatic islet cell therapy products that will require FDA licensure through the biologics license application (BLA) process.
DiscussionDr. Frey-Vasconcells noted that additional slides on the regulatory process were included in participant packets but were not presented at this time. These have been placed on the NIDDK DMICC meeting website at www.niddk.nih.gov/federal/dmicc/meetings.htm. A participant asked if the studies discussed by Dr. Eggerman include products that adhere to the new regulations regarding packaging and other requirements. Dr. Frey-Vasconcells responded that the cell therapies in research trials of INDs are required only to state that the agent is only for investigational use. After the trials, if the agent is to be licensed, it will need to meet the new labeling requirements.
CMS Perspective
Paul Olenick, Director, Division of Technical Payment Policy, Center for Medicare and Medicaid Services
Paul Olenick provided information on the MMA, which directed the Secretary of DHHS to have Medicare pay for the costs of the experimental pancreatic cell transplant program. This was unusual for CMS because it normally does not pay for experimental procedures. CMS fit reimbursement for pancreatic transplants into the normal payment system, which involves the Hospital Prospective Payment System. CMS determined which diagnosis-related group (DRG) these procedures would apply to and determined a reimbursement amount per procedure to isolate pancreatic islet cells for transplantation based on data from the isolation centers. In addition, CMS will pay a reasonable cost for acquisition, although no set amount is specified in CMS policies.
Last spring, CMS published proposed changes in acquisition costs, with final provisions published in August that took effect on October 1, 2004. This process will occur yearly so that proposed acquisition costs can be updated based on data for the past year. There remains the restriction that CMS cannot reimburse for patients in a trial unless they are Medicare patients. Among Medicare patients who receive kidney transplants, CMS will reimburse expenses only for 3 years following transplantation. Among comments received during the comment period for proposed reimbursement changes, CMS had many questions about the possibility of extending the 3-year reimbursement period. Changes of this nature must evolve from the legislative process rather than through internal CMS rule changes.
DiscussionDr. Fradkin commented that the Modification of Diet in Renal Disease (MDRD) clinical trial was conducted jointly between NIH and CMS, and there may have been relaxation of requirements regarding Medicare eligibility. She asked for comments on this trial. Dr. Allen Spiegel, Director of NIDDK, added that the MDRD was a protein-restricted trial to see if protein restriction could delay end-stage renal disease (ESRD) and was completed in the early to mid-1990s. Mr. Olenick said he was not familiar with details of the trial, but it might be advantageous to determine if individuals at CMS or the Healthcare Financing Administration (HCFA) who participated in the MDRD could provide information on its relevance to Medicare eligibility. Dr. Spiegel added that Medicare eligibility is critical to designing trials in this population, in which there are limitations on the number of islets that are available and the accrual rate is limited, especially in a longer-term trial with the usual kinds of endpoints and a 3-year time limit for patient coverage through Medicare. Mr. Olenick reiterated that this has been discussed in his agency, but the conclusion has been that coverage beyond the 3-year requirement is against the statute as currently written.
Update on HRSA/Organ Procurement and Transplantation Network (OPTN) Activities in Pancreas and Islet Transplantation
Laura M. Saint Martin, M.D., M.P.H., Chief Medical Officer, Health Resources and Services Administration, Division of Transplantation
Dr. Saint Martin provided an update of the HRSA oversight of the national OPTN. At present, there are 45 pancreatic islet programs. Earlier in 2004, the OPTN Board of Directors approved criteria developed by the OPTN Kidney and Pancreas Committee for islet program membership and also for requirements for physician and surgeon experience and training. These significant decisions were made, although islet transplantation still is a relatively experimental procedure, to give patients as much information as possible on the options of whole-organ transplantation and islet transplantation.
Reporting requirements for islet programs are being developed; in the interim, islet programs are required to report every 6 months on patients transplanted, including information on whether the islets received are disposed through transplantation, whether they were transplanted into the patients to whom they were allocated, or whether they were discarded or used for another purpose. The islet programs also must have adequate clinical and laboratory facilities as defined by the FDA and must document that they have a required IND application in effect. Other requirements include the existence of a collaborative relationship with a physician qualified to cannulate the portal system, and the isolation of the islets must occur in a facility with an FDA IND application in effect. Additional criteria exist for programs in centers without a whole-pancreas transplant program. A few islet programs exist where there is not a whole-pancreas transplant program within the same center; such programs may be allowed to qualify if they have a demonstrated affiliation with a qualified whole-pancreas transplant program.
Currently, all patients who are potential recipients of organ transplants must be listed on the computer waiting list, including islet transplant recipients. As of November 5, 2004, the waiting list contains 1,648 pancreas candidates, 2,461 pancreas and kidney combined candidates, and 324 islet candidates. In 2003, only 502 whole-pancreas transplants were performed and 870 combined kidney-pancreas transplants were performed. Data on islet transplantation were not collected in 2003.
Dr. Saint Martin presented information on the OPTN allocation algorithm that gives local priority for whole-organ transplantation but has approved variances for granting higher priority for local allocation of pancreata for use in islet transplantation. Under the new pancreas allocation algorithm, priority is given based on length of time on the waiting list, with the highest priority given to zero-mismatched and highly sensitized candidates (i.e., Panel Reactive Antibody [PRA] < 20). If there are no zero-mismatch candidates, the local isolated pancreas or combined kidney-pancreas or combined cell-organ-islet candidates receive the next highest priority; if the pancreas is still not accepted by a program, it is allocated based on donor age and body mass index (BMI). The algorithm for age and BMI is as follows:
There still are ongoing issues and concerns, despite the new policies. The allocation priority for whole-organ transplants may mean that there are fewer ideal pancreata available for islet transplants when other factors are considered, such as the time it takes to offer the organ and local need. In addition, cost and reimbursement issues are involved in all procurements by OPOs of pancreata and in patient transplants. Although whole-pancreas transplantation is an accepted therapy, no substantial comparisons have been done between islet transplantation and whole-pancreas transplantation. Another issue is developing a system to inform patients and families about the benefits and barriers to whole-pancreas versus islet transplantation.
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Dr. Eggerman began the discussion by noting that the FDA considers pancreatic islet cells a cell therapy; HRSA designates them as an organ. These disparate definitions have implications for use, collection, procurement, allocation, and cost. In particular, a designation of “tissue” instead of “organ” by the FDA and HRSA would be most beneficial for most considerations regarding islet transplantation. Dr. Frey-Vasconcells reiterated that pancreatic islets are viewed as neither tissues nor organs, and there is no way under current regulations to designate them as such. As a cell therapy, islet cells are regulated; this does not appear to have impeded progress in the field. Dr. Eggerman noted that islet cells are highly vascularized in vivo but lose this characteristic during processing; after transplantation, they become vascularized again. Dr. Frey-Vasconcells again stated that the FDA regulates products given to patients and designates them only at that point; at the point of transplantation, islet cells are not vascularized.
Dr. Jim Bowman, CMS, emphasized that it is important to maintain the allocation process under the jurisdiction of HRSA and OPTN, and that nothing recommended in these meetings should interfere with or impede progress of planned studies on pancreatic islet transplantation. It is important to keep in mind safety versus access issues. Registration as a tissue bank is not characteristic of all OPOs, and there are consequences if OPOs must contain a tissue bank. This issue will come to the forefront if islet research results in treatment success and islets become viewed by the medical and consumer communities as a commodity. Dr. Bowman’s opinion is that this issue should be addressed as early as possible so that planned studies can proceed without impediments caused by allocation problems.
Dr. Eggerman summarized that, from these discussions, it appears that the manner in which the FDA and HRSA view the process is appropriate, that no changes are needed at this time, and that progress will not be impeded. Participants added that, at this point, accruing patients to trials is not a problem and shortages do not exist. Once licensure is given, however, there will be the potential for product shortages. The HRSA has experience with organ shortages and can use that experience to address islet shortages if they emerge as an issue.
There were differing opinions among participants on whether it is advisable to classify islets as tissues. Some participants felt there would be no benefit in classifying islets as tissues; others felt that islets should be classified as tissues because the FDA would regulate them and there is a strong safety component in the FDA’s regulatory process. A participant asked if someone could address how the May 2005 regulations will affect the IND process, particularly whether an OPO that has not been registered under the first of the three regulations¾Rule 21CFR 1271.3(d)(1)¾as a tissue bank can provide islets for the study. A participant stated that, if the FDA designates islets as tissues, its only control would be over safety regarding transmission of communicable diseases; the FDA will not have control over the quality of islets, the data, or other parameters. Dr. Frey-Vasconcells responded that the OPOs would have to meet the tissue rules that apply to them for the processes they do at the time islets are licensed. Tissue rules do not apply to investigational products. For the OPOs, if they are procuring a cell therapy, they must register unless the procurement is related to products under investigation. This would not impede the conduct of studies on islet transplantation, although there would be more regulation once the investigational product is licensed. OPOs can register with the FDA online. Preventing the transmission of communicable disease is the only safety control under section 361, and any additional safety controls or safety issues fall under section 351. In summary, OPOs that retrieve tissue must register and only must adhere to the parts of the GTPs that apply to their processes.
One issue that needs clarification is the impact of designating islet cells on the cost of procurement and reimbursement by Medicare. Depending on whether islets are called cells, tissues, or organs, the cost reimbursed by Medicare can range from $5,000 for cells to as much as $25,000 for organs. Dr. Fradkin questioned whether organs that are part of the Medicare Demonstration Project would be reimbursed at the higher rate even though only the islets or whole pancreas are being used for the project. This was affirmed in discussions among CMS attendees but still leaves open the question of how to determine reimbursement for less-than-ideal organs. In addition, CMS often pays a reduced price, not because of a tissue designation, but because the organs would not otherwise be used by the OPO. Dr. Fradkin pointed out that one way islets get used is from organs that have vasculature that make them unusable for whole-organ transplantation. A participant added that many of these questions should be addressed at the upcoming OPTN/UNOS meeting in January.
Issue #2: The development of the special organ product (cells or tissue derived from organs) category for transplantation
Dr. Jim Burdick, Director of the Division of Transplantation, DHHS, provided information on a proposal for joint interagency regulation of living organ products. This will address many of the issues regarding islet transplantation and the problems of classifying islets within existing federal regulations and oversight. Removal of the pancreas for islets utilizes a considerable portion of the OPO’s resources. It is not just the operation, it is all of the steps that lead up to the operation and the expense of distribution for transplantation. Understanding who will pay for these procedures is critical to the process, and ensuring that everyone involved defines the materials in a consistent manner is important for both patients and OPOs. A participant noted that these also are important for research on islets; it is important to have some means of support to help with the costs of research. A CMS participant stated that CMS will pay for the cost of the whole organ even if only a portion is used. There may be differences among OPOs, but the amount paid generally is about $25,000 per organ. CMS agrees that there are additional costs for the OPOs other than procuring and distributing organs.
Dr. Gilman Grave asked if there were patient data on the number of pancreata needed for the number of islet transplants performed. Does it generally take more than one pancreas to collect enough cells for one patient? A participant responded that the majority have been two or more, with a minority of patients needing only one pancreas. The problem is the imperfect process for extracting the million or so islets that exist in a normal pancreas. The issue of collection is being investigated by the NCRR to improve yields without compromising cell efficacy. Also, there are problems regarding the transplantation procedure itself. Many of the islets that are infused do not implant and subsequently are inactive and then are lost. By improving the process of collection and storage, the number of pancreata needed to complete transplantation can be reduced.
Dr. Burdick commented that there are two key issues to address. The first is cost, which can be settled by establishing agreements among the agencies involved in organ procurement and distribution. There may be an alternate way to address islet transplantation. The second issue is that of safety versus access, as stated before. This is a fundamental issue, but it is important to focus first on the availability of organs. Dr. Fradkin recommended that Dr. Burdick’s draft be circulated to the participants for discussion at future meetings.
Issue #3: Resolution of issues related to credit for OPOs when pancreata are used for islets (with passage of the Pancreatic Islet Cell Transplantation Act of 2004)
In Section 2 of the Pancreatic Islet Cell Transplantation Act of 2004, pancreata procured by an OPO and used for islet cell transplantation or research are counted for purposes of certification or recertification. The DMICC will report on progress in this area for the 2005 DMICC Annual Report. Issues related to islet cells for transplantation or research have been discussed in the context of issues 1 and 2, above. At a minimum, the adequacy of federal funding for taking advantage of scientific opportunities related to pancreatic cell transplantation can be enhanced by crediting OPOs for the use of islet cells in research. Other issues include adequacy of supply of pancreata. Crediting OPOs for using islet cells for research should serve as an incentive to these groups to make an effort to distribute as many of the procured pancreata as possible.
Issue # 4: Update on the Islet Transplantation ConsortiumNancy Bridges, M.D., Chief, Clinical Transplantation Section, NIAID, provided an update on the islet transplant consortium, which has granted five awards to investigators to create a 5-year agenda and to develop strategies for moving the islet field forward. The five investigators are Drs. Bernard Hering at the University of Minnesota; Olle Korsgren at Uppsala University in Sweden; Ali Naji at the University of Pennsylvania; Camillo Ricordi at the University of Miami; and James Shapiro at the University of Alberta, Edmonton. In addition, Bill Clark at the University of Iowa will head a consortium coordinating center. The first steering committee meeting was held recently to develop scientific goals for the consortium, including
The proof-of-concept has successfully been demonstrated by the Edmonton protocol, which indicates it is possible to transplant islets into human beings and have them become functional, although the approach is not yet perfected. The Edmonton protocol was innovative in how it treated the immunosuppression issue by developing a steroid-free immunosuppression regimen that included an investigational (at the time) agent, Sirolimus, to try to protect the islet graft from rejection.
Evidence suggests it is not just alloimmunity that results in the loss of islets and that the innate immune system also is a significant problem. Three consortium investigators have identified approaches to target innate immunity after islet transplantation. Dr. Hering has a protocol that uses an investigational agent, deoxyspergualin, along with a tumor necrosis factor (TNF) blocker, Etanercept; Dr. Korsgren and his group in Sweden have very good preliminary data using low molecular weight dextran as an anti-inflammatory agent along with melagatran, an anticoagulant agent; and Dr. Ricordi is investigating two anti-inflammatory/anti-apototic investigational agents, lisofylline and exenatide. These studies exemplify the significant focus on the innate immune and coagulation systems in trying to improve both islet engraftment and islet survival. Targets of innate immunity aside from TNF include a cascade of cytokines that results in a nonalloimmune response. Other studies, including one by Dr. Naji, have produced data in a nonhuman primate model that show that simultaneously attacking both the T-cells and B-cells with Rituximab can result in tolerance or near-tolerance after islet transplantation; human trials are needed to confirm this approach. The fifth grantee, Dr. James Shapiro, is investigating a costimulatory blockade with the use of LEA29Y, an investigational agent that blocks some poststimulatory interactions. This, too has been shown to be promising in animal studies.
DiscussionA participant asked what outcome measures are being designated for islet therapy. Dr. Bridges responded that insulin dependence will be monitored as a primary outcome in all trials, and microvascular complications will be monitored as a secondary outcome in some trials. Dr. Fradkin added that Dr. Eggerman is planning a meeting of investigators who have been involved with some major diabetes clinical trials and epidemiological studies to examine the kind of power that might be expected for certain outcomes. After determining issues of power and outcomes, input will be sought from the FDA and CMS. Based on the results of these trials, it is anticipated that product licensing will occur. This will have implications for standard treatments and public awareness.
Issue # 5: Update on the Medicare Islet Transplantation Clinical Investigation
A workshop is planned to better define the type of clinical trial approach that might be implemented to provide more information on Medicare islet transplantation. Input will be sought from experts in diabetes and transplantation and from colleagues in Europe who have been heavily involved in islet-renal transplantation. This will not be a typical study with thousands of patients; at most, hundreds of patients will be involved.
A subcommittee will determine potential approaches and address such details as the means for adding additional trial sites. The task is complicated by the facts that the harvesting and processing of islets are involved, and the postoperative care of patients is crucial to ensuring successful transplants. Thus, patients must be located at other sites; then costly, complicated details of their travel, transplant, and postoperative and ambulatory care must be arranged and managed. Limiting the number of sites that produce the islets and transplanting the islets to patients at multiple clinical sites may minimize variables. The Edmonton trial, in which good results were achieved in some cases and bad results were achieved in others, exemplifies the complicated nature of this type of trial.
Processes to be determined include
The structuring of these processes over the next 5 years will determine whether the desired results are achieved from the trial.
The pancreas transplantation legislation mandates that the DMICC report regularly on progress related to this effort. A subgroup of the DMICC will be created specifically to address the new tasks given to the DMICC under the pancreas transplantation legislation. Dr. Eggerman will lead this group, and relevant/interested member agencies and institutes (including the FDA, HRSA, NIAID, NCRR, and the Centers for Disease Control and Prevention [CDC]) should be represented. The group will meet regularly and report to the DMICC on progress in islet transplantation.
Items to be addressed in these reports include
The group can determine the timing of the report to maximize its effectiveness.
Future updates of the patient registry will be standardized and enabled by the use of software packages. This will be accomplished particularly at the major centers and will facilitate the entry of additional patients into the registry.
Issue #6: The upcoming consensus conference on pancreas allocation for whole-organ and islet transplantation sponsored by the Kidney and Pancreas Transplantation Committee of the OPTN/UNOS on January 23-24, 2005
Dr. Saint Martin commented that one of the concerns that the OPTN/UNOS Kidney-Pancreas Committee has expressed is the ongoing representation of some of the islet concerns on the committee. The committee is considering having a representative with specific interest in islet transplantation join the committee to raise concerns and discuss issues brought forward at this meeting. A Consensus Conference on Pancreas Allocation for Whole Organ and Islet Transplantation will be held as a separate meeting, with recommendations to address allocation, procurement, data reporting, regulatory, and reimbursement issues.
Dr. Fradkin asked Dr. Saint Martin to review the consensus process and how OPTN/UNOS will handle recommendations from the meeting. Dr. Saint Martin responded that the process is not like the NIH consensus process, and the recommendations will have to be presented to the full OPTN Kidney and Pancreas Transplantation Committee to determine which recommendations should become OPTN policy and which need further study. Recommendations will proceed through the regular committee deliberative process before being considered for implementation. Dr. Fradkin asked if the consensus conference would examine changes to the new pancreas allocation algorithm. Dr. Saint Martin indicated that the committee will review the algorithm and give it special attention. Input will be garnered from a wide spectrum of opinion leaders. The OPTN Kidney and Pancreas Transplantation Committee intends to designate one kidney-pancreas committee meeting per year specifically for examining pancreas and islet issues, which is a major step forward.
A participant asked if the issue of acquired pancreata that subsequently are discarded because of various matching problems and other issues will be discussed. Dr. Spiegel added that he has heard that there is more concentration on kidney transplantation than on pancreas transplantation, and this may be reflected in the makeup of the committees that are discussing these issues. He said he would like to see a group address these issues from an independent viewpoint by looking at the evidence that exists for pancreas-only versus pancreas-kidney or kidney-only transplantation to make scientifically sound decisions. Having the consensus conference is a good idea and will add to the knowledge base regarding pancreas or islet transplantation, but the decision to treat an individual patient must be based on the best available evidence.
Dr. Spiegel interjected that there must be a way to increase the number of people who receive transplants because many organs never make it into the transplant pipeline. A participant responded that geographical problems in the transplant milieu may be overcome if new ways to transport organs or extend their useable life are discovered.
Dr. Spiegel asked whether the current policy as outlined at this meeting would impede and retard the planned demonstration project or trials on islet transplantation. A participant affirmed this contention. Dr. Spiegel indicated that this, then, becomes the main barrier to be overcome in designing and conducting the trial. Dr. Fradkin responded that two significant barriers appear to have been overcome. The first is the issue of reimbursement; the second is the issue of allocation, although issues of timeliness and geographic distribution still must be addressed. Dr. Spiegel added that placement of trial centers could address the geographical issue, and developing some variance mechanism that gives consideration in terms of islets could address the allocation issue. A participant said that variances have been implemented in some locations, and it seems that data from those locations would help address the potential benefits of using variances. Dr. Spiegel added that variances are issued by the OPTN. Dr. Saint Martin noted that the current policy for facilitated placement is 5 hours. After 5 hours of attempted placement without being placed for whole-organ transplant, the organ then may be allocated locally, regionally, or nationally, before being allocated for islet use and then finally for research.
A participant introduced the issue of the lack of data on the optimal time needed to procure and transplant an organ or islets. These data may be available from the OPOs, and some effort might be expended to see what can be gathered from these organizations. r. Fradkin mentioned that this data might be useful in developing policies on variances. For example, presentations by sources such as the demonstration project in Miami may answer some of the questions about collection and allocation. Dr. John Ridge of NIAID added that one of the largest pancreas transplant centers in the United States, in Minnesota, has a variance and may have some data regarding this issue, although the center completes only one-on-one studies and does not conduct controlled trials. A participant commented that there may be a benefit in looking outside the funded network to find groups with experience and data on variance.
Next StepsDr. Fradkin summarized the mandate of the DMICC required by the pancreas transplantation legislation and stated that the DMICC will report on progress related to this effort. She proposed that Dr. Eggerman create a DMICC subcommittee to address the responsibilities related to promoting islet transplantation under the legislation with each of the member agencies and institutes that are relevant or interested in islet transplantation taking part and that this subcommittee should meet regularly and report back to the DMICC on progress. A participant commented that the FDA, HRSA, CDC, NIAID, and NCRR should be involved because the legislative mandate includes requirements that can best be answered by these agencies. Dr. Eggerman will take the lead in developing the concept of a subcommittee and will contact DMICC members for input. Dr. Spiegel thanked those in attendance, and the meeting was adjourned.
Diabetes Mellitus Interagency Coordinating Committee Update on Current and Planned Initiatives
Building 31C, Conference Room 6C10
9000 Rockville Pike
Bethesda, Maryland
March 21, 2005
SUMMARY MINUTES
Welcome and Introductions
Allen Spiegel, M.D., Director, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland
Dr. Spiegel welcomed members of the Diabetes Mellitus Interagency Coordinating Committee (DMICC) and guests. Dr. Spiegel said this was an opportunity to exchange views on joint activities of DMICC member organizations. He pointed out that the U.S. Department of Health and Human Services (DHHS) recently released Diabetes: A National Action Plan, to focus the attention of health professionals, businesses, schools, and researchers on steps necessary to reduce the impact of diabetes on society. This initiative will be of interest to DMICC members.
Type 1 Diabetes Initiative and the Special Funding Program
Judith E. Fradkin, M.D., Director, Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK, NIH, Bethesda, Maryland
Dr. Fradkin reviewed the implementation status of recommendations from the January expert panel planning and evaluation meeting on the Special Statutory Funding Program for Type 1 Diabetes Research. She noted that the panel focused on ongoing projects being supported with the special funds. One recommendation of the expert panel was to initiate a broader review of the entire state-of-the-science regarding type 1 diabetes with an emphasis on new and emerging opportunities that could be pursued with the special funding. To implement this recommendation, the NIDDK is spearheading a new strategic planning effort in type 1 diabetes research. Dr. Fradkin suggested that this strategic plan framed around the six goals that have guided the use of the special funds: (1) Identify genetic and environmental causes of type 1 diabetes. (2) Prevent or reverse type 1 diabetes. (3) Develop cell replacement therapies. (4) Prevent or reduce hypoglycemia. (5) Prevent or reduce complications from type 1 diabetes. (6) Attract new talent and apply new technologies.
The DMICC will be the entity responsible for coordinating the strategic plan with the help of working groups that are being established for five of the six goal areas. The working groups will identify major research advances in type 1 diabetes research that have occurred since 1998 and identify emerging opportunities in these areas of research that can be pursued by the NIH or other DHHS agencies in the next 10 years. Dr. Fradkin presented the preliminary timetable for the initiative and asked for cooperation from each of the DMICC organizations in making this a priority initiative. Dr. Spiegel stressed the importance of DMICC member organizations’ commitment to supporting the development of the strategic plan in the areas that are key to the missions of their specific organizations. It is not expected that all organizations will want to be involved in all areas of the research. This strategic plan will contribute to the development of the final report on the use of the special funds that will be submitted in January 2007 to the U.S. Congress.
A second recommendation from the expert panel included support for “self-assembled” teams of scientists to tackle specific barriers in type 1 diabetes research. Dr. Fradkin suggested that challenges to be pursued by these teams include: (1) the development of assays and biomarkers useful for assessing the response to immunomodulatory interventions in type 1 diabetes; (2) development of methods to image beta-cell mass and immune infiltration of the pancreas; (3) development of biomarkers for complications; and (4) development of outcome measures that could enable complications trials to be conducted with shorter durations and/or fewer patients. Funding will be available for this research using the P20 grant mechanism, and successful projects will receive 3 years of funding beginning in fiscal year (FY) 2006.
Other recommendations of the expert panel included the establishment of External Advisory Committees for existing consortia and resources and a plan to enhance coordination among existing consortia and resources. As a first step for enhancing consortia coordination, a meeting will take place in May 2005 in Boston in conjunction with the Federation of Clinical Immunology Societies (FOCIS) meeting. There also will be more focused coordination meetings involving subsets of related consortia and networks. One of these will involve TrialNet, Immune Tolerance Network (ITN), and Clinical Islet Transplantation (CIT) consortium investigators. The Type 1 Diabetes Genetics Consortium (T1DGC), Genetics of Kidneys in Diabetes Study (GoKinD), Family Investigation of Nephropathy and Diabetes (FIND) study, and the Epidemiology of Diabetes Interventions and Complications (EDIC) Genetics Study consortia will hold a joint meeting in July. At the next meeting of The Environmental Determinants of Diabetes in the Young (TEDDY) consortium, representatives from the Trial to Reduce the Incidence of Type 1 Diabetes in the Genetically At Risk (TRIGR) and National Immunization Program (NIP) will meet to discuss standardization across studies. Dr. Fradkin asked each of the DMICC organizations that have consortia or resources participating in the type 1 diabetes funding effort to identify scientists from the consortia to participate in these meetings.
Dr. Spiegel thanked Dr. Fradkin for the presentation and added that there are many exciting collaborative investigations taking place around the country for both type 1 and type 2 diabetes.
Updates by DMICC Members
Health Resources and Services Administration (HRSA)
Suzanne Feetham, Ph.D., R.N., F.A.A.N, Senior Advisor, Office of Director, Bureau of Primary Health Care (BPHC), Acting Director Division of Clinical Quality, BPHC, HRSA, Bethesda, Maryland
Dr. Feetham provided background information on the HRSA and collaborations currently being implemented in the HRSA that include diabetes components. The Diabetes Detection Initiative (DDI) operates in 10 regions around the country within primary health care clinics, most of which are HRSA federally qualified health centers. The DDIs have distributed more than 600,000 diabetes risk tests resulting in a 40 percent increase in the screening of blood glucose tests; results of these tests identified approximately 5,000 new cases of diabetes. Approximately 90 percent of patients served in HRSA clinics have incomes more than 200 percent below the poverty level.
The HRSA Health Disparities Collaboratives, a national effort to improve health outcomes among medically underserved people, have been successful in focusing collaborative efforts in this population. Outcomes of the collaboratives, which focus on patient/health center goals, are increasing community partnerships. An important lesson learned in the development of these collaborations is that there must be system change when creating prevention collaboratives because the health centers have to intervene in the health of every patient who enters the center rather than just those with a disease. The Diabetes Prevention Program (DPP) is a model of a prevention collaborative that is investigating system change. Dr. Feetham presented data on patients participating in the DPP that showed baseline data and results, which indicated that it is possible to identify patients at high risk for diabetes who then can be managed in a primary care center.
The Sentinel Center Network (SCN) is a collaboration among the HRSA, the Johns Hopkins University, and the Morehouse School of Medicine. The primary goal of the SCN is to provide information to the HRSA and centers to assess health center practice patterns and outcomes on patients who use the centers. Over one million patients are participating in the 52 SCN health centers; 6.2 percent of total participants have diabetes.
During the discussion period, Dr. Feetham said that intervention through training and information distribution within the health centers has been one of the most significant reasons for system change. It was noted that all six goals should be addressed at the same time for maximum effectiveness. An assessment of the outcome of the DPP is incomplete and may take a number of years before enough data are available to make an accurate evaluation. Dr. Feetham also explained that the reason for the small differences in diabetes prevalence by race and ethnicity in this study may result from the disproportionately high number of low-income patients in the centers.
Veterans Health Administration (VHA)
Leonard M. Pogach, M.D., M.B.A., Veterans Administration National Program Director for Diabetes, East Orange Veterans Affairs Medical Center, East Orange, New Jersey
Dr. Pogach presented information from the VHA perspective on systematizing quality improvement and quality innovation for persons with diabetes. Diabetes is just one part of the VHA’s efforts to improve health care among American veterans. More than 1 million of the estimated 5 million veterans who use the VHA have diabetes. Dr. Pogach presented data showing that the VHA population has high levels of risk factors for chronic diseases such as cardiovascular disease, chronic kidney disease, stroke, and mental health disorders.
Since 1997, the VHA has instituted patient care principles that are some of the most forward looking in the nation. These include: (1) assignment of patients to an identified primary care provider; (2) development of evidence of explicit clinical care guidelines for common conditions, including diabetes; (3) development of performance measures and contracts for directors in the system; (4) development of a national electronic medical records database with local customization capabilities; (5) initiation of a translational research initiative, the Quality Enhancement Research Initiative; (6) the adoption of telemedicine, including home-based telemedicine and teleretinal imaging
Examples of clinical reminders were given to show the types of systems the VHA has implemented to encourage veterans to keep appointments. A sample of the electronic medical record used to allow physicians to get real-time data also was presented.
The VHA’s diabetes performance measures for FY 2004 indicate that the VHA is doing very well in improving screening and interventions compared to indemnity plans. Long-term outcomes are being tracked for some conditions, and it appears that complications from diabetes have remained constant from FY 1999 to 2003, except for a decrease in amputations. It is expected that innovations will continue to be implemented within the VHA.
National Institute of Child Health and Human Development (NICHD)
Gilman D. Grave, M.D.; Chief, Endocrinology, Nutrition, and Growth Branch, Center for Research for Mothers and Children, NICHD, NIH, Bethesda, Maryland
Dr. Grave provided information on ongoing initiatives of the NICHD for diabetes research. The Trial to Reduce the Incidence of Type 1 Diabetes in the Genetically at Risk (TRIGR) has 73 sites in 15 countries that will test the hypothesis that infants, who are genetically at risk according to human leukocyte antigen (HLA)-type, can be prevented from getting diabetes in the next 10 years if they are weaned to a hydrolyzed cow milk formula (Nutramigen) instead of a non-hydrolyzed formula (Similac). So far nearly 1,300 of the targeted enrollment of 2,032 infants have been enrolled and randomized.
Another initiative is DirecNet, which has five centers in the United States and a centrally located glucose-monitoring laboratory in Minnesota. DirecNet is investigating glucose monitors to determine if improvements can be achieved in monitoring high and low glucose levels with the Glucowatch or with the Continuous Glucose Monitoring System. A new subcutaneously implanted monitor called the Navigator is being investigated in a study of 30 children. This monitor uses the glucose oxidase method to assay glucose levels in interstitial fluid 1,40 times per day. Another investigation will use glucose monitors to document the effect of exercise on the basal insulin requirements of children on insulin pumps and the best strategies to avoid late night hypoglycemia.
Dr. Grave reported that he has become interested in helminth infections (e.g., hookworm and filarial worm) and their possible role in preventing type 1 diabetes and other autoimmune diseases. A recent open label study by Robert Summers et al [Gut 2005; 54:87-90] reported that 80 percent of 29 patients with regional enteritis who ingested sanitized ova of pig whipworm went into remission. It has been shown that helminth infections are anti-inflammatory and that a pentasaccaride found on the surface of the ova triggers an increase in interleukin-10 and other anti-inflammatory cytokines. Interestingly, similar oligosaccharides are found in breast milk and may account for antidiarrheal effects in breast-fed infants. How surface oligosaccharides on microbes, parasites and their ova interact with the immune system of the intestine is an emerging field of study that may have application in diabetes research.
Dr. Spiegel suggested that Dr. Grave contact Dr. Steve James at NIDDK to discuss the helminth findings because Dr. James is studying parasitic interactions in Crohn’s disease. There is a “hygiene hypothesis” that suggests autoimmune diseases such as asthma and possibly type 1 diabetes are increasing in incidence as a more clean and sanitized environment is achieved. Much of this is speculative but may be worth pursuing.
National Center for Research Resources (NCRR)
Richard Knazek, M.D., Contractor for the Division of Clinical Research Resources, NCRR, NIH, Bethesda, Maryland
Dr. Knazek provided an update on the Islet Cell Resource (ICR) Center Consortium; the consortium partners include NIDDK, NCRR, and the Juvenile Diabetes Research Foundation. The mission of the ICR is to generate and distribute Good Manufacturing Practices (GMP)-grade human pancreatic islets to clinical investigators for transplantation into patients who have severe type 1 diabetes mellitus. Additional goals of the ICR are optimizing the methodologies and technologies for generating the islets and determining the characteristics of the cells that will allow successful transplantation. In the past few years, the ICR has expanded its mission to include distribution of islet cells for basic research. The islets are available to investigators at no charge, which is very advantageous for increasing islet research. Dr. Knazek explained the ease with which investigators may apply to take part in this research, which begins with an application at http://icr.coh.org/.
National Heart, Lung, and Blood Institute (NHLBI)
Cristina Rabadan-Diehl, Ph.D., Program Official, Vascular Biology Research Program, Division of Heart and Vascular Diseases, NHLBI, NIH, Bethesda, Maryland
Dr. Rabadan-Diehl described a program that was funded fully by the type 1 diabetes fund and involves investigation of the cardiovascular (CV) complications of diabetes. She reported on a joint meeting between NIDDK and NHLBI in 2003 that recommended support for mechanistic studies of the vascular wall and endothelial dysfunction and the onset and progression of CV complications and type 1 diabetes. As a result, NHLBI and NIDDK issued an initiative, Progression of CV Disease in Type 1 Diabetes that invited applications for investigations in this area. Of 49 applications, eight projects were found to be highly meritorious and currently are being funded. Among these eight projects are investigations of vascular disease and cardioneuropathy.
In addition, two clinical studies also are being supported by the initiative. One is using an existing cohort of the Coronary Artery Calcification in Type 1 (CACTI) Diabetes Study, which investigates the role of inflammation and immune responses in the progression of coronary artery calcification, as well as the role of insulin resistance and the metabolic syndrome in accelerated atherosclerosis among patients with type 1 diabetes. This cohort also will be used to characterize the morphology of coronary plaque and the arterial wall remodeling processes. The investigators also will reanalyze past studies such as the Epidemiology of Diabetes Complications Study to determine if there are data that can be utilized for understanding the relationship of diabetes and clinical arteriosclerosis and the incidence of clinical coronary artery disease.
The second study, Coronary Artery Disease and Renal Disease in Type 1 Diabetes, will investigate the role of insulin resistance. This study will investigate whether individuals with both coronary artery disease (CAD) and overt nephropathy have greater insulin resistance than those with CAD or nephropathy alone, or with neither of these conditions.
Dr. Spiegel concluded by commenting that one of the NIH Roadmap P20s is investigating the relationship between diabetes and the heart and stressed that it is important that NHLBI be aware of this ongoing study.
NIDDK Office of Minority Health Research Coordination (OMHRC)
Lawrence Agodoa, M.D., Director, OMHRC, NIDDK, NIH, Bethesda, Maryland
Dr. Agodoa provided background information on the Diabetes Based Science Education in Tribal Schools (DETS) initiative, which originally was discussed at the DMICC in 2000. At the time, there was concern about the high incidence and prevalence of diabetes in American Indian and Alaska Native communities, especially in light of data showing that diabetes was rare in these communities until approximately 50 years ago. The DETS program grew out of these discussions to target diabetes education toward children in these communities. Goals of the initiative include educating children on healthy lifestyles and risk factors for diabetes, with an emphasis on maintaining balance among families and their communities; increasing understanding of the process of developing scientific and community knowledge in relationship to health, diabetes, and maintaining balance; and encouraging interest in health science professions among American Indian and Alaska Native children.
A pilot study was conducted for 1 year in science classes for grades K-12. The science curriculum being developed is being aligned with national and state teaching standards and benchmarks, is culturally sensitive, and includes hands-on science-based materials that reflect traditional learning styles emphasizing visual, spatial, and perceptual modes of learning.
In discussions, it was pointed out that obesity also is a severe problem in tribal communities and this is being addressed in DETS as part of diabetes education. It was suggested that DETS investigators should consider contacting investigators from the Diabetes Prevention Program (DPP) because they may be able to add their perspectives on working with these communities.
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)Dr. Fradkin commented that many of the diabetes initiatives at NIDDK have been discussed at previous DMICC meetings, and she would focus on only a few activities related to the priority area of obesity and type 2 diabetes in children.
On September 26-27, 2005, a meeting will be held on the effects of the intrauterine environment and specifically maternal diabetes, obesity, and associated metabolic changes on the future risk of offspring developing diabetes and obesity.
The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, which compares three approaches to treating type 2 diabetes in children, began recruitment 1 year ago. A school-based prevention study to address risk factors for diabetes in middle school aged children has conducted pilot and feasibility studies and has developed important information on the prevalence of risk factors in this population. A full trial is under development for possible implementation in September 2006.
In addition, the National Diabetes Education Program, a joint effort of the NIDDK with the Centers for Disease Control and Prevention, is creating a new campaign that focuses on women with gestational diabetes and their offspring. The purpose of the program is to encourage obstetricians and gynecologists who are caring for women, and family physicians and pediatricians who are caring for children, to ascertain a history of gestational diabetes and implement the kinds of interventions that were successful in the DPP.
Dr. Fradkin asked Dr. Thomas Eggerman, Director of the Islet Transplantation Program, NIDDK, to comment on a recent meeting in Chicago on islet transplantation that involved staff from NIDDK, NIAID, and NCRR. A significant outcome of the meeting was the decision to coordinate the efforts of several groups and standardize data fields. This will minimize the amount of time investigators spend on data submission to multiple groups involved in collection of islet transplantation data.
Closing RemarksDr. Fradkin thanked Dr. Saul Malozowski for his service to the DMICC and welcomed Dr. Sanford Garfield, who will be replacing Dr. Malozowski as DMICC Executive Secretary.
Dr. Fradkin asked DMICC members for suggestions for topics for future DMICC meetings. It was suggested that a future meeting focus on recent data on young adults related to changing risk factors for diabetes and cardiovascular disease, particularly increases in the prevalence and incidence of obesity in this group. Novel approaches such as the “polypill”¾combining in a single pill multiple agents (e.g., high blood pressure, high cholesterol, and diabetes)¾should be considered, including what this may mean for diabetes prevention.
Dr. Fradkin thanked participants for their presentations and comments. The meeting adjourned at 3:35 p.m., E.S.T.
Diabetes Mellitus Interagency Coordinating
Committee:
Risk Factors Related To Development of Pre-Diabetes and Diabetes:
Deterioration and Opportunities for
Prevention in Young and Middle-Aged Adults
Natcher Conference Center, Conference Room A
National Institutes of Health
Bethesda, Maryland
September 12, 2005
Dr. Spiegel welcomed members of the Diabetes Mellitus Interagency Coordinating Committee (DMICC), guest speakers, and guest attendees. He introduced Dr. Judith Fradkin to give a progress report on the Type 1 Diabetes Initiative and the Special Funding Program.
Judith E. Fradkin, M.D., Director, Division of Diabetes, Endocrinology, and Metabolic Diseases, NIDDK, NIH, Bethesda, Maryland
Dr. Fradkin provided an update on the implementation of recommendations from the January expert panel planning and evaluation meeting, for the Special Statutory Funding Program for Type 1 Diabetes Research. One recommendation of the expert panel was that the NIH develop a Strategic Plan to identify future opportunities for type 1 diabetes research. This Strategic Plan is being developed under the auspices of the DMICC. Major input for the plan has come from working groups that were established for five of the six overarching goals that have informed the use of the Special Funds. Because the sixth goal is cross-cutting, each of the five working groups will contribute to development of the strategic plan related to this goal. An executive committee comprised of NIH representatives and the chairs of the five working groups was established to guide the development of the Strategic Plan. Draft chapters for these five goals are being compiled and will be distributed to the executive committee in anticipation of the executive committee meeting scheduled for September 28.
Dr. Fradkin also noted that the Congressional appropriations report called for a report on progress toward meeting HbA1c guidelines and how best to close the disparities that exist between treatment guidelines and the care that people with diabetes receive in the first year after diagnosis. The strategies to be used in preparing the report include defining the problem and identifying factors that contribute to the disparity between HbA1c guidelines and actual treatment; identifying barriers and challenges to implementation, adoption, and dissemination; and suggesting possible courses of action to promote greater diffusion and adoption of the guidelines.
Dr. Fradkin explained the role of the DMICC members in providing input for the report. DMICC representatives will be asked to prepare material that can be incorporated into the report and to submit this by November 15, 2005. This material should include: (1) two to three sentences on the barriers and challenges to implementation, adoption, and dissemination of the guidelines, and (2) one-half page on suggested ways in which each Institute, Center or Agency can promote greater implementation, adoption, and dissemination of the HbA1c guidelines. At the next DMICC meeting on December 12, 2005, DMICC representatives will be asked to give a brief presentation on his or her agency’s plans. Not every member agency of the DMICC may be involved directly in this report, if its mission does not focus on glycemic control. The December 12 meeting also will include an external speaker to help provide perspectives on opportunities to improve implementation of HbA1c guidelines within health care systems. Dr. Fradkin is contacting New York City health officials regarding a potential initiative there that would involve collecting information on HbA1c values in New York City residents and providing feedback to the patients and their health care providers regarding HbA1c targets Dr. Spiegel commented on the rationale for the New York City program and potential involvement of DMICC member agencies. He noted that this initiative would be relevant to many of the agencies represented on the DMICC, such as the Center for Medicare and Medicaid Services, the Centers for Disease Control and Prevention (CDC), and the Agency for Healthcare Research and Quality (AHRQ), among others.
Turning to the topic of today’s DMICC meeting, Dr. Fradkin commented that there is considerable interest in risk factors for diabetes, and that there is commonability among risk factors for diabetes and cardiovascular disease (CVD). Identification of risk factors is a pre-requisite for prevention. This meeting will include presentations by researchers who have collected important prospective data on the development of diabetes and CVD. A list of questions to be addressed during the meeting was presented, including the types of outcome measures that would be useful in planning for meaningful initiatives.
Peter J. Savage, M.D., Director, Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute (NHLBI)
Dr. Savage noted that there is much to be gained from delaying the onset of diabetes, including beneficial effects for CVD. He introduced Dr. Kiang Liu, who is a Principal Investigator at Northwestern University for the Coronary Artery Risk Development in Young Adults (CARDIA) study, funded by NHLBI. Dr. Savage, as NHLBI Project Officer for the CARDIA study, has seen data on the links between several risk factors, premature disease, and public health.
Risk Factor Change in Young Adults: The CARDIA StudyDr. Liu focused his presentation on data from the CARDIA study on risk factors in relation to diabetes and prediabetes. He addressed three issues:
With regard to the first issue, comparisons were made in normal, IGT, and T2D groups (classified according to the oral glucose tolerance test results at year 10) of baseline data for CVD risk factors. Risk factors assessed included systolic blood pressure (SBP), high-density lipoprotein-C (HDL-C), low-density lipoprotein-C (LDL-C), triglycerides, uric acid, fasting glucose, fasting insulin, BMI, and waist circumference. In each case, the baseline CVD risk factors were graded with the highest level (lowest for HDL-C) in the diabetes group and lowest level (highest for HDL-C) in the normal group. The differences between the diabetes group or IGT group and the normal group were significant statistically. When analyses of the data were controlled for waist circumference and BMI, only triglycerides, uric acid, and fasting insulin factors appeared to be significant. For those who developed diabetes or IGT, increases in risk factors appeared to change more over time than for those in the normal group.
For the second issue, data were analyzed to determine the impact of clusters of risk factors (i.e., the Metabolic Syndrome) on coronary atherosclerosis as determined by surrogate marker CAC. The Metabolic Syndrome is defined as those with a waist circumference of greater than 102 cm (40 in) in men and greater than 88 cm (35 in) in women; triglycerides greater than 150 mg/dl; HDL cholesterol greater than 40 mg/dl in men and 50 mg/dl in women; blood pressure greater than or equal to 130/85 mmHg or on treatment; and a fasting glucose greater than or equal to 100 mg/dl. For each race and gender group, there is a clustering of risk factors in those with CAC evidence of early atherosclerosis, even when adjusted for age, LDL-C, and cigarette smoking.
Regarding the third issue, Dr. Liu presented data on the potential impact of BMI change and CVD risk factors. BMI was stratified according to those who increased BMI, had stable or decreased BMI, or had fluctuating BMI at year 15. Few individuals who were obese at baseline remained stable or were included in the fluctuating group; the vast majority continued to gain weight. For every risk factor over time, there was an increase in risk among those who gained weight. The increase, however, was small for those who had stable or decreased BMI. In addition, increasing weight over 15 years increased the risk for Metabolic Syndrome by as much as 6 to 9 times compared to the stable weight group; those who gained weight and then lost weight (fluctuating) were able to reduce their risk as compared to those who gained but did not lose weight. For impaired fasting glucose (IFG) and diabetes, those who were overweight at baseline had a higher risk of developing IFG or diabetes over 15 years.
Dr. Liu summarized his findings by noting the following:
The implications of these findings are that greater public health efforts should be aimed at weight stabilization over the long term for young and middle-aged adults.
A participant asked why there appears to be no disparity between white and African-American men regarding CAC. Dr. Liu responded that the lower calcium levels seen in African-American men and women do not necessarily indicate a lower risk of CVD. Another participant asked whether individuals with high BMI (overweight or obese) could be physically fit. Dr. Liu described investigations of people regarded as “fit and fat,” who appear to do better healthwise than “low-fit and fat” individuals; however, their risk factor levels are not as low as “fit and not fat” individuals. Another participant wondered if women in the fluctuating group appeared to be at higher risk of CVD than women in the other groups. Dr. Liu replied that this was not so and did not address whether women whose weight fluctuates because of dieting cycles are at higher risk than those whose weight remains stable.
Risk Factor Change in Middle Ages: The ARIC Study
Frederick Brancati, M.D., M.H.S., Professor of Medicine and Epidemiology, Director, Division of General Internal Medicine, Johns Hopkins University, Baltimore, Maryland
Dr. Brancati provided an historical perspective on the causes of T2D and results from the Nurses’ Health Study (NHS) and Physicians’ Health Study (PHS) that indicated that BMI and physical activity are associated strongly with T2D. His presentation focused on emerging risk factors and the Atherosclerosis Risk in Communities Study (ARIC). Dr. Brancati noted that BMI or adiposity are key risk factors for T2D, although other risk factors also are important.
Data on food constituents and lifestyle choices indicate that some may modify T2D risk. For example, high intake of cereal fiber and coffee, high levels of serum magnesium, alcohol use among women, and low caloric intake in general may lower the risk of T2D; high intake of saturated fat, monounsaturated fat, alcohol use in men, smoking tobacco, high C-reactive protein (CRP) levels, and a high inflammation score may increase the risk of T2D. In the NHS, the odds ratio (OR) of incident diabetes among women with high CRP levels and aspirin use was lower than among women with high CRP levels and nonaspirin use. Lower risk also is indicated by higher adiponectin levels, as seen in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.
Dr. Brancati commented that, in the Diabetes Prevention Program, the screening eligibility committee eliminated participants who were taking medications that might lead to a T2D phenotype. This included those on HIV retroviral therapy, oral or inhaled steroids, and certain antipsychotic medications. In addition, possible participants on antihypertension medication (i.e., beta-blockers) also were eliminated. Another lesser known risk factor for T2D may be unexplained aminotransferase elevation, which has been shown in National Health and Nutrition Examination Survey (NHANES) data to be a strong predictor of risk of T2D.
Intriguing associations between anthropomorphic measures and diabetes have been reported. To illustrate, although the lung generally is not considered an organ that is involved in diabetes complications, a study of fasting and 2-hour insulin levels and an Apnea-Hypopnea Index (AHI) in overweight adults found that insulin levels increased with elevated AHI. In addition, a recent analysis of ARIC data found that middle-aged women in the lowest quartile of forced vital capacity had double the risk of incident diabetes compared to those in the highest quartile. An analysis of NHANES III data also found a possible association between IGT and T2D and upper leg length. Finally, the Barker hypothesis, which asserts an association between various medical conditions and birth weight, appears to suggest that low birth weight is associated with incident diabetes in middle age, even in leaner Chinese adults.
Dr. Brancati completed his presentation by showing retinal photographs in ARIC in year 6 that indicated that, the smaller the artery diameter compared to the vein in the retina, the higher the risk of diabetes and coronary heart disease and stroke. In addition, analysis of ARIC data on whole blood viscosity (WBV) indicated that higher viscosity is associated with the risk of diabetes.
In conclusion, Dr. Brancati cautioned that the data presented came primarily from prospective studies and would need to be tested in intervention studies to determine if they are associated with diabetes or the risk of diabetes.
A participant commented that, when he speaks to the media after a study shows a new association of dietary or anthropomorphic measures and diabetes, he likes to emphasize that there are long-known risks for diabetes that are more powerful than what is being reported in the media. Dr. Brancati responded that it is important to keep to the public health message of risks that are well known, but we should not disregard strategies that may work for some individuals. Another participant asked Dr. Brancati to comment on the impact of weight change on diabetes. Dr. Brancati responded that weight loss, on the order of 5 to 7 percent of body weight, is achievable and has been proven to have a significant impact on diabetes prevention. There are, however, bariatric surgery studies in which some individuals lost 30 to 40 kilograms and glucose normalized or dropped precipitously.
Risk Factors in Pima Indians: Lessons From the Pima IndiansDr. Krakoff described the Pima Indian population in the Gila River Indian Community and diabetes risk factors in those under 20 years of age. Diabetes in Pima Indians exclusively is T2D, and all data shown reflected this status. The prevalence of diabetes in Pima youth increased dramatically in all age groups from 1965 until 2002. In those exposed to diabetes in utero, the prevalence of diabetes among 15- to 19-year-olds was extremely high, approaching one in four, with an OR of approximately 3.5 calculated for offspring exposed to diabetes in utero compared to their siblings born prior to the mother having developed diabetes.
Dr. Krakoff presented unpublished data on risk factors for developing T2D in more recent cohorts of children in a longitudinal study. The cohorts were first examined at ages 5 to 9, 10 to 14, and 15 to 19 years. In the younger cohort (age 5-9 years), waist circumference was the most powerful predictor of T2D; in the 10 to 14 and 15 to 19 year age groups, 2-hour glucose and fasting insulin appeared to be the most powerful predictors. It is interesting that fasting glucose did not appear to be a powerful predictor in any group. Receiver Operating Characteristic (ROC) curves of this data confirmed these findings.
Studies of IGT and conversion to diabetes suggest that age is the predominant indicator of risk; populations with a high diabetes prevalence risk tend to form a “U” shaped curve, whereas populations with a lower diabetes prevalence risk tend to undergo conversion to IGT at a steady increased rate with age. Comparing the progression from IGT to diabetes between adults and youth (age less than 20 years) showed that progression in youth is approximately one-half that of young adults. This remained valid in the data for 2-hour glucose and BMI, even when adjusted for multiple variables. The one variable that equalized the risk of progression from IGT to diabetes among adults and youth was accounting for their in utero exposure to diabetes.
Dr. Krakoff presented data on risk factors for diabetes in young adults with normal glucose regulation, defined as individuals with both a 2-hour glucose measure of less than 140 mg/dl and a fasting glucose of less than 100 mg/dl. Analysis in this cohort of Pima Indians who were euglycemic at baseline and underwent extensive physiologic testing indicated that the most important diabetes risk factor predictors were insulin resistance and acute insulin response.
A possibly important surrogate for assessing the risk of diabetes is adiponectin. Adiponectin is secreted by adipocytes, but lower levels are seen in obese individuals and in those with insulin resistance. In a cohort of individuals from the longitudinal study with normal glucose regulation and matched for BMI, age and sex, adiponectin was a better predictor of the development of diabetes than traditional risk factors or other inflammatory markers.
Dr. Krakoff summarized the results of the investigations presented on youth and diabetes risk factors. The best early predictor of T2D is waist circumference among youth age 5 to 9 years and the 2-hour glucose test for those age 10 to 19 years. Among euglycemic young adults, insulin resistance and acute insulin response are key predictors, and hyperinsulinemia and adiponectin also are important. For targeting prevention efforts among youth, these early risk factors are important for reducing the burden of disease among Pima youth and young adults.
Dr. Spiegel asked if there is a mechanistic basis for the impact of in utero exposure and diabetes risk. Dr. Krakoff said it is a complicated issue that is in the early stages of investigation, and no clear etiology has been determined. He added that the data on acute insulin response indicate that an early beta-cell defect may influence this process. He also clarified that the definition of diabetes in these studies did not include gestational diabetes.
The Indian Health Service: Perspective on Risk ManagementDr. Wilson presented information on diabetes risk management from the perspective of American Indian and Alaska Native (AI/AN) populations. The AI/AN population is very young; approximately 11 percent of the AI population is older than 55 years of age, which is one-half of the proportion of the general U.S. population that is age 55 years or older. Between 1990 and 2001, the prevalence of T2D increased 106 percent in those 15 to 19 years of age and 79 percent among those 25 to 34 years of age. During this time period, data from ARIC and the Strong Heart Study (SHS) indicated that the incidence of heart disease increased in the AI/AN populations to become more common than the incidence of heart disease in the general U.S. population. This is a troubling statistic given that, in the past, heart disease was not found in the AI population. Much of the increase in CVD seems to have come from the increase in diabetes. SHS data indicate that coronary heart disease is attributable to diabetes in approximately 76 percent of women and 61 percent of men. Thus, managing risk factors for diabetes and cardiovascular disease (CVD) is of great importance to the U.S. Indian Health Service (IHS).
For many years, the HIS has defined Standards of Care for people with diabetes and has conducted Diabetes Care and Outcome Audits to evaluate the care provided and outcomes attained in IHS programs. In April 2005, a panel of experts was convened to gather the best available evidence on standards of care (IHS Guidelines for Care of Adults with Prediabetes and/or Metabolic Syndrome in Clinical Settings) that can be used to address the issues of prediabetes and management of people at risk for diabetes. A full PDF version of the report is available at: http://www.ihs.gov/medicalPrograms/diabetes/resources/2005NDPPreDMMetsynGuidelines042605.pdf#search='IHS%20Guidelines%20for%20Care%20of%20Adults%20with%20Prediabetes%20and%2For%20Metabolic%20Syndrome%20in%20Clinical%20Settings'. One of the main controversies in establishing Standards of Care involved how to address people who had the Metabolic Syndrome. Data from the SHS indicated that insulin resistance and the Metabolic Syndrome are comparable risk factors for the development of diabetes. The data also indicated that these risk factors are poor predictors of CVD independently of diabetes. Combined with the strong attributable risk conveyed by diabetes on the development of CVD, this suggests that prediabetes and the Metabolic Syndrome are strong predictors of diabetes and that, in turn, diabetes predicts the development of CVD. Thus, a major focus of the Prediabetes and/or Metabolic Syndrome standards of care is the prevention of diabetes.
Dr. Wilson presented a list of factors included in the IHS guidelines for testing for prediabetes. In the absence of risk factors in the AI population, the guidelines also suggest testing every 3 years in those over age 45 years. A Letter to the Editor will appear in an upcoming issue of Diabetes Research and Clinical Practice and will outline the approach for developing these guidelines.
The IHS has assessed the use of screening programs to identify those with diabetes. Dr. Wilson presented data from a survey that asked clinical programs if they screen for diabetes and prediabetes and if they keep a registry of individuals in each category. In 2004, much of the screening occurred in community programs and involved glucose meter tests. Paper and pencil checklists of risk factors were used less frequently. Data also show that children and youth are being screened, but not at the same rate as older adults. The IHS Competitive Grant Program is applying a model of the Diabetes Prevention Program in 33 AI/AN communities and is applying a model of case management in addressing the goal of lowering blood pressure and lipid values in people with known diabetes. An evaluation will be conducted to ascertain how well research findings are being translated into clinical practice.
As in many communities, important unanswered questions about diabetes exist in the AI/AN community. These include:
Via teleconference, Dr. Valdez presented information on the study design and data management of the Collaborative Study of Obesity and Diabetes in Adults (CODA). Study selection was made by CODA investigators for meta-analyses of relevant studies; 34 studies were identified for CODA-1, a meta-analysis of studies containing data on obesity and diabetes. The CODA data management team at the University of Minnesota received original data sets from investigators for the 34 relevant studies. Dr. Valdez provided a list of population-based cross-sectional studies and cohort studies that comprised the CODA-1 meta-analyses. A total population of approximately 270,000 study participants was available for these analyses.
Dr. Valdez presented results of the CODA-1 meta-analysis for the OR of patients with newly diagnosed diabetes using American Diabetes Association (ADA) criteria by risk factor. For BMI and waist circumference, all but one of 31 studies reported an OR greater than 1.0. There was significant heterogeneity among the studies. For incident cases of diabetes among individuals who attended a screening, did not report that they had been diagnosed with diabetes, but were assessed as meeting the ADA criteria for diabetes, the relative risk (RR) with BMI and waist circumference was approximately 2.0. A pooled estimate of incident cases of diabetes for BMI (RR = 1.8) and waist circumference (RR = 2.1) indicates that both are strong predictors of diabetes. Over a 10-year period, there was a continuous increase in risk among both men and women by BMI and waist circumference at baseline.
ROC curves for BMI and waist circumference also indicate that diabetes can be predicted by BMI and waist circumference. The area under the ROC curve for BMI is larger for men (0.73) than for women (0.64); for waist circumference, it is 0.72 for men and 0.65 for women. This indicates that both anthropomorphic measures are good predictors of diabetes in both men and women. In the pooled analyses of incident diabetes relative to BMI and waist circumference independently by sex, the RR for both measures for men and women was similar. The same data assessed for age group indicated a small increase in risk with age, with the increase in men being slightly higher than in women.
Dr. Valdez summarized these finding by stating that waist circumference is a somewhat better predictor of incident diabetes than BMI, but both appear to offer substantial predictive value. The CODA data will continue to be analyzed, and it is expected that additional findings will be published during the next few years.
American Diabetes Association: ADA and Risk Factor Management
Nathaniel Clark, M.D., M.S., R.D., National Vice President for Clinical Affairs, American Diabetes Association, Alexandria, Virginia
Dr. Clark presented an update on ADA activities that have occurred or are ongoing regarding risk factor management and prevention of T2D. The ADA has published a list of T2D risk factors that has been used by clinicians, and included in the ADA Standards of Care. The purpose of the list is to make patients and professionals aware of the risk factors so that they can focus on prevention and treatment among high-risk individuals. Dr. Clark reviewed results of the Diabetes Prevention Program (DPP), a randomized diabetes prevention clinical trial that indicated a 58 percent reduction in diabetes through lifestyle changes and a 31 percent reduction in diabetes with the use of metformin. These findings led to a series of meetings to develop recommendations to delay or prevent diabetes. The recommendations included the following:
Dr. Clark described the FPG criteria as Normal (less than 100 mg/dl), Impaired (IFG = 100-125 mg/dl), and Diabetes (> 126 mg/dl) (slide 9). ADA categories for 2-hour oral glucose tolerance test (OGTT) plasma glucose levels include Normal (less than 140 mg/dl), Impaired (IGT – 140-199 mg/dl), and Diabetes (> 200 mg/dl). Pre-diabetes affects approximately 41 million Americans and significantly increases the risk of developing overt diabetes as well as the risk of CVD, and diagnosis can be made either by IFG or IGT.
Dr. Clark summarized the impact of changing the definition of diabetes from 110 mg/dl to 100 mg/dl, which took place a few years ago. Under the old definition, the greatest number of individuals diagnosed had elevated IFT, with smaller numbers having IFG or IFG and IFT. Using the old definition, the number of people with pre-diabetes was approximately 20 million. Under the new definition, most people have IFG, with smaller numbers having IFT or IFG and IFT. This has practical consequences for prevention and treatment.
The prevalence of diabetes in the United States is increasing as the prevalence of obesity increases. This has led to a new organization established by the ADA, “Shaping America’s Health: Association for Weight Management and Obesity Prevention,” a collaboration between the ADA, North American Association for the Study of Obesity (NAASO), and Shaping America’s Youth (SAY). The collaboration will address scientific issues by the developing clinical guidelines and holding conferences on the science and medicine of overweight and obesity. Medical education issues will include community action activities coordinated by the ADA with SAY, and town meetings to discuss community mobilization and to share “best practices.”
Dr. Clark presented information on the progression to T2D. The question of measuring insulin levels comes about as the diagnosis of T2D does not often occur until 9 to 12 years after diabetes actually begins. In theory, tracking insulin levels over time may allow interventions early in the process to prevent T2D. A significant concern exists that clinicians are now ordering insulin levels and making clinical decisions based on these results despite the fact that the assay is not now standardized and there are no guidelines available regarding how to interpret the insulin level result. The Insulin Assay Standardization Work Group of the ADA is exploring the first part of this issue. The purpose of this work group is to devise protocols to determine the reproducibility and specificity of each assay. Most manufacture’s of insulin assays have participated and provided assayed samples. Recommendations will be published that describe criteria that assays must meet to be “insulin specific,” and a clinical advisory group will be formed to recommend how insulin assays should be used in clinical practice.
Discussion: Where Do We Go From Here?
Dr. Fradkin asked if participants would comment on the issue of measuring glucose. A participant asked if any test is better than another in this regard. Dr. Clark responded that this has not been determined. Having a test or series of tests that could lead to the development of a risk equation such as Framingham would be helpful, but no such protocol exists at this time. A series of participants spoke about the need to develop a clear direction on this issue.
Dr. Savage mentioned that while DMI is clearly useful, adding insulin to this mix may cause confusion rather than create benefit. Another participant added that what is known does not apply to all populations.
Dr. Fradkin asked if there is a consensus that BMI and waist circumference are strong enough predictors that there is no need for a risk equation such as that used with Framingham data for heart disease. Dr. Brancati responded that, in the past, when the population has a healthier BMI, there was little T2D. As obesity becomes more prevalent, it may be important to find a way to better identify those at higher risk. Dr. Liu added that we do not know how to shift the entire population to a lower risk level, such as through weight control or reduction. Education is important, but there may be a need to lower the cutpoints for intervention if insulin resistance is present. Dr. Leonard Pogach said that current guidelines allow for lower cutpoints for the use of pharmacological interventions. Another participant outlined the manner in which intervention is recommended in the NHLBI obesity guidelines. If a person has a certain BMI without comorbidities, the clinician is requested to treat him or her differently than a person with the same BMI who has comorbidities. These guidelines recognize that treatment should be started earlier for the latter group.
Dr. Fradkin asked participants to comment on the Diabetes Prevention Program (DPP) trial and the endpoints that should be developed for diabetes prevention. Dr. Brancati commented that DPP was very expensive and was designed to create a proof-of-principle on weight loss and diabetes prevention. It was a highly select group of people and was not designed to reveal everything about preventing diabetes in all people. Dr. Pogach said that DPP was successful in showing some things, but it did not show how to change society using social factors. Several participants commented that, when you have a common problem that affects multiple risk factors that in the aggregate are responsible for a large percentage of the chronic diseases in this country, several models that address all interventions are needed.
Dr. Fradkin asked for input on the prevention of diabetes risk factors in children. Participants commented on the importance of addressing risk factors in children, and weight maintenance appeared to be the initial area of concentration. Dietary advice and intervention can have a positive impact in children and adolescents, although it is likely that one set of dietary guidelines will not be appropriate for all children in all settings.
Adjournment
Dr. Fradkin thanked the speakers, DMICC members, and guests for attending the meeting and participating in the discussions. She adjourned the meeting at 3:40 p.m.
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