Anne Peters, MD, and Lori Laffel, MD, MPH, Editors
Jane Lee Chiang, MD, Managing Editor
Prevention of Beta-cell Destruction and Preservation for Those with Existing Type 1 Diabetes
Jane Lee Chiang, MD, and Stephen E. Gitelman, MD
- Prevention, before the development of diabetes
- Preservation, after the diagnosis, while functional beta-cells remain
- Beta-Cell replacement, for those with preexisting diabetes for an extended period of time and who have no endogenous beta-cell function…
There are important philosophical issues to consider for intervention at each of these stages. In designing such studies, investigators are mindful that T1D is very different from a life-threatening condition such as cancer and therefore must carefully balance the potential risks of the proposed therapy vs. possible benefits. Promising efforts are now underway at all three of these stages.
T1D may occur at any age, but children are at highest risk and may have a more rapid process of beta-cell destruction than found in adults. However, due to potential safety concerns, the Food and Drug Administration (FDA) often mandates that clinical studies start in adults or older youth, unless there is past experience with the proposed therapeutic in a younger age-group. Clinical studies may proceed in progressively younger age-groups upon an acceptable safety review and approval from regulatory authorities. However, the studies often require long recruitment times, and ultimately many trials may not be conducted in the youngest age-groups due to lack of efficacy in the older cohorts, presence of safety signals, or feasibility. A lack of efficacy in adults could lead to dismissal of possible therapies that could benefit children, the highest-risk population.
One limitation has been defining early surrogate markers that predict long-term, clinically meaningful end points. The pancreas is inaccessible to routine biopsy, and thus there is no direct means to visualize islets. Currently, there is no imaging modality for routine clinical use nor surrogate immunological measures that correlate with preservation of beta-cell mass. Most new-onset trials rely on a stimulated measure of endogenous insulin production as the primary measure, such as response to a mixed-meal tolerance test with C-peptide area under the curve (AUC) at 2 or 4 h.1 This outcome reflects beta-cell function, and may not necessarily correlate with beta-cell mass. Others have adopted a composite end point that may have more robust clinical significance, such as A1C <6.5% coupled with <0.5 units/kg/day of exogenous insulin.2 For prevention trials, the primary outcome may be development of auto-antibodies, or change in metabolism, from euglycemia to impaired glucose tolerance or progression to frank diabetes.
Preclinical models of T1D are very limited, with greatest reliance on the non-obese diabetic (NOD) mouse.3 Agents that have demonstrated efficacy in preclinical models of T1D, such as the NOD mouse, have often been considered for clinical trials. Over 300 agents have been shown to prevent T1D in the NOD mouse, but such results have generally not translated to man. Thus, there has been widespread criticism of this model as a means of informing investigators about potential therapies in humans. Further thought may need to be given for the particular agent under consideration, such as dose, the timing, and protocols used in humans. Of note, a handful of agents have even more robust effects and can actually reverse T1D in the NOD mouse. These very drugs are, in general, the ones that have shown greatest promise in humans, but durable clinical remissions have remained elusive. In addition, certain drugs, such as monoclonal anti-bodies, cannot be evaluated in animal models. Thus, investigators must also draw on clinical experiences in other settings, such as transplantation or other autoimmune conditions, to find other potential agents that could be applied to T1D.
Since T1D results from T-cell–mediated destruction of beta-cells, the goal has been to identify therapies that target T-cells (see Figure 3.1). Therapeutics may be subdivided into several broad categories based on their intended targets, including: 1) antigen-based therapies, such as insulin or glutamate decarboxylase (GAD); 2) anti-inflammatory agents, including docosahexaenoic acid (DHA), nicotinamide, α-1-anti-trypsin, and interleukin 1-blockade; and 3) immunosuppressants or immunomodulators, such as anti-CD3 monoclonal antibody (mAb) and CTLA4 Ig. Preferably, the therapy would be tolerizing, meaning that it could be given for a brief period of time and withdrawn and have fundamentally changed the immune system so that continuous therapy is not needed. In addition to blocking the immune destruction, one would ideally 4) enhance beta-cell repair and regeneration. Specific growth factors for beta-cells have proven elusive, although there have been suggestions that islet neogenesis-associated peptide and GLP-1 agonists and DPP-IV inhibitors may have salutary effects.
Figure 3.1 Overview of the current understanding of pathogenesis of T1D pathogenesis, highlighting a number of key pathways that are being targeted by current therapeutics. Source: Matthews JB, Staeva TP, Bernstein PL, Peakman M, Von Herrath M: ITN-JDRF Type 1 Diabetes Combination Therapy Assessment Group: Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN–JDRF Type 1 Diabetes Combination Therapy Assessment Group. Clin Exp Immunol 160:176–184, 2010. Reprinted with permission from the publisher.
In order to prevent disease, one must have an effective means to determine risk for T1D. A combination of immunologic, genetic, and metabolic indices can be used to assess risk. Prevention efforts can be broadly divided into those that serve as a means for primary prevention (those with underlying genetic risk but before the onset of autoimmunity) and secondary prevention (after autoimmunity has been detected but before the onset of clinical disease).
The goal at this stage is to distinguish higher-risk subjects from the general population, and offer a therapy that will prevent progression to autoimmune destruction, and frank T1D. The challenge posed by studies at this level is that one has less predictive power in identifying individuals who will eventually develop diabetes, and thus one must conduct larger trials. Further, if diabetes occurs, the progression often happens over a long time period, sometimes 5–10 years or more, thereby necessitating longer trials. Individuals recruited for primary prevention trials are now targeted early in life, in some cases during pregnancy or in the newborn period, and are from families with an index case of T1D or with high-risk HLA haplotypes associated with T1D, or both. Because of the protracted timeline needed to follow such individuals to T1D onset, investigators may utilize a surrogate end point, such as the development of one or more beta-cell autoantibodies, rather than T1D development. Nonetheless, the benefit of early intervention is that a less intense approach may prevent disease, as opposed to more aggressive interventions undoubtedly necessary to interdict autoimmune destruction later in the disease process. Given the nature of primary prevention studies, with large subject numbers, requisite long-term follow-up, and attendant expense, such studies are rarely undertaken. Fully powered studies are usually not initiated until a pilot study demonstrates safety and tolerability, feasibility and perhaps a hint of efficacy.
Trial to Reduce IDDM in the Genetically at Risk (TRIGR)
Animal studies and epidemiological evidence suggests that lack of breast-feeding, shorter breast-feeding duration, or early exposure to cow’s milk may increase risk for beta-cell autoimmunity. Postulated mechanisms include reduced gut inflammation, enhanced permeability to autoantigens, changes in regulatory T-cells (Tregs) in the lymphoid tissue lining the gut, modified gut microflora, or some combination thereof. A Finnish pilot study of infants with a high-risk HLA haplotype and a first-degree relative with T1D showed that weaning to a highly hydrolyzed formula was associated with ~50% risk reduction in development of 1 or more beta-cell autoantibodies, as compared to those randomized to conventional cow’s milk formula.4
TRIGR is a fully powered study that will definitively address this question.5 This trial is an ongoing primary intervention study that is now fully enrolled. It is designed to determine if supplementation of breast-feeding with a highly hydrolyzed milk formula (Nutramigen) and, in the first 6–8 months of life, avoidance of foods containing bovine protein will decrease the cumulative incidence of islet-related autoantibodies, as opposed to those who are supplemented with usual cow’s milk formula. The targeted population is newborns with a first-degree relative with T1D and a high-risk HLA haplotype. They will be followed until 10 years of age. The primary end point is T1D development. Secondary end points are diabetes associated islet antibodies (NCT00179777). If effective, this approach could then be tested in the general population, and could be adapted on a wider scale as a public health measure to lower T1D risk. The beauty of such an approach is that, if effective, it confers absolutely no risk, would be easy to implement, and a simple intervention early in life could have a huge impact on the general population.
TrialNet conducted the Nutritional Intervention Program (NIP), evaluating if docosahexaenoic acid (DHA) (NCT00333554) in genetically at-risk newborns could prevent islet autoimmunity. The study was based on epidemiological evidence that a diet rich in omega-3 fatty acid and vitamin D lowers autoimmunity risk. Secular trends indicate that, over time, less DHA is being consumed. This randomized, placebo-controlled pilot study enrolled pregnant mothers and infants. The eligible subjects were required to have a first-degree relative with T1D and a high-risk HLA haplotype. Infants were supplemented with DHA until 36 months of age. Analysis of results and long-term follow-up are ongoing.
The BABYDIET group conducted a pilot study to determine the effects of gluten avoidance on autoimmunity in infants of first-degree relatives with T1D (NCT01115621).6 This study was based on both encouraging data from mouse models as well as human epidemiological studies linking age of gluten exposure with islet autoimmunity development. Delaying gluten exposure to 12 months of age did not reduce islet autoimmunity, but the study was not powered for efficacy, and compliance was problematic with this open-label study design.
Interest also lies in vitamin D supplementation as a primary intervention. Aside from its effects on calcium and bone metabolism, vitamin D mediates many aspects of the immune response. Animal studies and epidemiological findings, particularly in pregnant women and infants deficient in vitamin D, support its role in ameliorating autoimmunity.7 A case-controlled study aimed at early intervention found that in pregnant women the odds of T1D were more than twofold higher for the offspring of women with the lowest levels of 25-hydroxy-vitamin D versus those with levels above the upper quartile.8 Clinical trials with vitamin D supplementation in recent onset T1D have not demonstrated efficacy. However, vitamin D may need to be administered earlier in the disease process, or the therapeutic dose for inducing a change in the immune response may need to be significantly higher than that for calcium and bone effects, or both. Further studies are underway in animal models with novel analogs that may have immunomodulatory effects without the effects on calcium and bone. While a randomized intervention trial is needed, these data suggest that enhancing maternal 25-hydroxy-vitamin D during pregnancy may be beneficial.
Secondary prevention trials attempt to prevent progression to diabetes in those with evidence of autoimmunity, but without T1D. Those with a single autoantibody are very unlikely to progress to T1D, whereas those with a greater number of autoantibodies, and higher titers, have progressively increased risk, starting from a 25–50% risk of developing T1D in the next 5 years.9,10 Those who also exhibit altered glucose metabolism (e.g., low first-phase insulin secretion on an intravenous glucose tolerance test [IVGTT] or abnormalities on an oral glucose tolerance test [OGTT]) are at highest risk, >50%, for developing T1D in the ensuing 5 years. From the OGTT results, the DPT-1 study group and Trial-Net have defined an at-risk population with dysglycemia, referring to any one of the following: impaired fasting glucose or impaired 120-min glucose, as defined by American Diabetes Association criteria, or an intervening glucose on a 2-h OGTT >200 mg/dl. In general, secondary prevention trials are not as long or as large as primary prevention studies. However, they still require a significant effort by a well-funded network to screen, enroll, and follow enough subjects over a sufficient time period to evaluate the agent.
Given that these are prevention trials, investigators search for therapies that offer promise but do not pose significant risk for subjects. Such risks could include adverse side effects or toxicities, or possibly accelerating disease progression. The trials to date have primarily utilized antigen based or anti-inflammatory approaches, rather than immunosuppressive therapies. The Diabetes Prevention Trial-1, European Nicotinamide Diabetes Intervention Trial, and Finnish intra-nasal insulin prevention trial discussed in detail below represent signature efforts for T1D secondary prevention.9,11-13
Diabetes prevention trial–type 1 (DPT-1). Insulin is one of the primary antigens initially recognized by the immune system in T1D. NOD mice and early human pilot studies have suggested that exogenous insulin may alter disease course. DPT-1 was a randomized, controlled, non-blinded North American effort to determine if insulin exposure could prevent or delay T1D onset.9,11 The study was notable for establishing a collaborative network throughout North America to efficiently screen a large number of subjects and for identifying an algorithm that identified an intermediate and high-risk cohort.
The DPT-1 study group screened ~100,000 first-degree relatives for the presence of beta-cell autoantibodies. The antibody-positive subjects were subdivided into two arms: a high-risk group (>50% chance of developing T1D in the next 5 years), who were islet cell autoantibody (ICA) positive with abnormal beta-cell function (e.g., low first-phase insulin secretion on IVGTT or dysglycemia on an OGTT); and an intermediate-risk group (25–50% risk of developing T1D in 5 years), with ICA and insulin autoantibodies present.
In a randomized, controlled, non-blinded trial, subjects in the high-risk group received parenteral insulin, with low-dose daily subcutaneous ultralente insulin and 4 days of intravenous insulin annually.9 The therapy was safe but not effective in preventing progression to T1D. Possible reasons for study failure include the late stage at which the therapy was offered, and the dosing scheme (limited by hypoglycemia risk at higher insulin doses).
Subjects in the intermediate-risk group participated in a randomized, double-blinded, placebo-controlled trial with oral insulin.11 The primary analysis showed that oral insulin did not delay progression to T1D. However, in a secondary post-hoc analysis, subjects with higher baseline insulin autoantibody titers appeared to have a statistically significant delay in the onset of T1D, by ~4.5 years with an IAA titer ≥80 nU/ml, and a 10-year delay with an IAA titer >300 nU/ml. Furthermore, the hazard rate for diabetes progression increased after cessation of therapy and approximated the rate in the placebo group, further suggesting that therapy was efficacious but that ongoing therapy may be needed.14 A follow-up confirmatory study with oral insulin is ongoing in Trial-Net (NCT00419562). As a further extension of these efforts, the JDRF-funded POINT trial (Primary Oral/Intranasal INsulin Trial) is a randomized, placebo- controlled, multi-centered, dose-finding study that will evaluate the optimal oral insulin dose in a primary intervention study, rather than as a secondary effort as described within TrialNet.15 The hypothesis is that an even earlier exposure to antigen, prior to the initiation of autoimmunity, will have even greater efficacy in T1D prevention.
Type 1 Diabetes Prediction and Prevention Study (DIPP). DIPP was a randomized, double-blinded, placebo-controlled study evaluating the efficacy of intra-nasal insulin in children from the general population with high-risk genotypes and 2 autoantibodies (NCT00223613).13 As in DPT-1, 100,000 children were screened, eventually identifying 264 at-risk individuals. In those with HLA susceptibility to T1D, intranasal insulin administered soon after detection of autoantibodies did not prevent or delay T1D.13 The findings may be due to inadequate antigen dose, the method for antigen presentation, or the stage at which it was introduced.
Australian investigators have also evaluated intranasal insulin effects, initially in new-onset T1D adults. They found that it did not retard loss of residual beta-cell function but noted that the treatment may induce tolerance, at least to exogenous insulin.16 They have since launched a phase II prevention trial in first- degree relatives with 2 autoantibodies, Intranasal Insulin Trial II (INIT II) (NCT00336674).
- Palmer JP, Fleming GA, Greenbaum CJ, Herold KC, Jansa LD, Kolb H, Lachin JM, Polonsky KS, Pozzilli P, Skyler JS, Steffes MW: C-peptide is the appropriate outcome measure for type 1 diabetes clinical trials to preserve beta-cell function: report of an ADA workshop, 21–22 October 2001. Diabetes 53:250–264, 2004 [Erratum in: Diabetes 53:1934, 2004]
- Sherry N, Hagopian W, Ludvigsson J, Jain SM, Wahlen J, Ferry RJ, Bode B, Aronoff S, Holland C, Carlin D, King KL, Wilder RL, Pillemer S, Bonvini E, Johnson S, Stein KE, Koenig S, Herold KC:, Daifotis AG for the Protégé Trial Investigators: Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trial. Lancet 378:487–497, 2011
- Shoda LK, Young DL, Ramanujan S, Whiting CC, Atkinson MA, Bluestone JA, Eisenbarth GS, Mathis D, Rossini AA, Campbell SE, Kahn R, Kreuwel HT: A comprehensive review of interventions in the NOD mouse and implications for translation. Immunity 23:115–126, 2005
- Knip M, Virtanen SM, Seppä K, Ilonen J, Savilahti E, Vaarala O, Reunanen A, Teramo K, Hämäläinen AM, Paronen J, Dosch HM, Hakulienen T, Åkerblom HK: for the Finnish TRIGR Study Group: Dietary intervention in infancy and later signs of beta-cell autoimmunity. N Engl J Med 363:1900–1908, 2010
- TRIGR Study Group: Study design of the Trial to Reduce IDDM in the Genetically at Risk (TRIGR). Pediatr Diabetes 8:117–137, 2007
- Hummel S, Plfuger M, Hummel M, Bonifacio E, Ziegler AG: Primary dietary intervention study to reduce the risk of islet autoimmunity in children at increased risk for type 1 diabetes: the BABYDIET study. Diabetes Care 34:1301–1305, 2011
- Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM: Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358:1500– 1503, 2001
- Sorensen IM, Joner G, Jenum PA, Eskild A, Torjesen PA, Stene LC: Maternal serum levels of 25-Hydroxy-vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes 61:175 –178, 2012
- Diabetes Prevention Trial (DPT)—Type 1 Diabetes Study Group: Effects of insulin in relatives of patients with type 1 diabetes mellitus. N Engl J Med 346:1685–1691, 2002
- Sosenko JM, Palmer JP, Greenbaum CJ, Mahon J, Cowie C, Krischer JP, Chase HP, White NH, Buckingham B, Herold KC, Cuthbertson D, Skyler JS, and the Diabetes Prevention Trial—Type 1 Study Group (DPT-1): Patterns of metabolic progression to type 1 diabetes in the Diabetes Prevention Trial—Type 1. Diabetes Care 29:643–649, 2006
- Skyler JS, Krischer JP, Wolfsdorf J, Cowie C, Palmer JP, Greenbaum C, Cuthbertson D, Rafkin-Mervis LE, Chase HP, Leschek E: Effects of oral insulin in relatives of patients with type 1 diabetes: the Diabetes Prevention Trial—Type 1. Diabetes Care 28:1068–1076, 2005
- Gale EA, Bingley PJ, Emmett CL, Collier T: European Nicotinamide Dia-betes Intervention Trial (ENDIT): European Nicotinamide Diabetes Intervention Trial (ENDIT): a randomized controlled trial of intervention before the onset of type 1 diabetes. Lancet 363:925–931, 2004
- Näntö-Salonen K, Kupila A, Simell S, Siljander H, Salonsaari T, Hekkala A, Korhonen S, Erkkola R, Sipilä JI, Haavisto L, Siltala M, Tuominen J, Hakalax J, Hyöty H, Ilonen J, Veijola R, Simell T, Knip M, Simell O: Nasal insulin to prevent type 1 diabetes in children with HLA genotypes and auto-antibodies conferring increased risk of disease: a double-blind, randomized controlled trial. Lancet 372:1746–1755, 2008. Epub 22 September 2008
Used with permission by the American Diabetes Association. Copyright © 2013 American Diabetes Association.
Please note: We are proud to have Dr. Anne Peters as a member of our Advisory Board member for Diabetes In Control, Inc.