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Much investigation has been directed at interdicting the type 1 diabetes disease process, both during the stage of evolution of the disease and at the time of disease onset. The goal of intervention before disease onset is to arrest the immune destruction and thus prevent or delay clinical disease. The goal of intervention at disease onset is to halt the destruction of remaining β-cells, perhaps allowing these residual β-cells to recover function, hopefully lessening the severity of clinical manifestations and disease progression. This paper will review the worldwide efforts to prevent type 1 diabetes(T1D).
Studies aimed at prevention or delay of clinical T1D are critically dependent on the ability to identify individuals at risk of the disease. The potential timing of interventions to interdict the disease process is illustrated in Figure 1. The more an individual has progressed down the pathway towards clinical disease, the higher the risk. The challenge has been to accurately articulate the risk of any given individual. Thus, there is a 78% five-year risk of T1D amongst individuals who have dysglycemia (impaired glucose tolerance, impaired fasting glucose, or an OGTT-stimulated glucose value greater than 200 mg/dl at 30, 60, or 90 minutes). If there is impairment of first phase insulin response (FPIR) to intravenous (IV) glucose, in the presence of diabetes-related autoantibodies, the projected five-year risk of T1D is greater than 50%. For those with intact FPIR to IV glucose, and the presence of two or more diabetes-related autoantibodies, the projected five-year risk of T1D is greater than 25%.
Studies have been conducted to try to prevent or delay the clinical onset of T1D, mostly amongst relatives at risk. Although a number of immunosuppressive drugs (e.g. azathioprine or cyclosporine) have been considered and some even given to a few individuals, these were not really evaluated in a disciplined way. In recent years, there have been large scale multicenter randomized controlled clinical trials designed to prevent T1D. These have used nicotinamide, parenteral insulin, oral insulin, nasal insulin, and the elimination of cow’s milk from infant feeding.
The European Nicotinamide Diabetes Intervention Trial (ENDIT) was a prospective, placebo-controlled, double-blind international trial (1). ENDIT recruited ICA-positive, first-degree relatives of individuals with T1D that had onset at less than 20 years of age, and who were 5–40 years old (2). The projected five year risk of T1D was 40%. The ENDIT Study Group randomized 552 subjects either to nicotinamide (1.2 g/m2/day) or matching placebo. The study had a target of35% reduction in incidence of T1Dover5 years. They screened35,000 first-degree relatives to identify eligible subjects. By the end of four years of follow-up, 159 subjects developed T1D - 82 in the nicotinamide group and 77 in the placebo group (Figure 2) (3). Unfortunately, this meant that nicotinamide did not prevent or delay development of T1D. The unadjusted hazard ratio for the development of diabetes was 1.07 (95% CI 0.78–1.45; p=0.69), and the hazard ratio adjusted for age-at entry, baseline glucose tolerance, and number of islet autoantibodies detected was 1.01 (0.73–1.38; p=0.97)(3).
The Diabetes Prevention Trial of Type 1 Diabetes (DPT-1), conducted throughout the United States and Canada, was designed to assess the effects of antigen-based therapy with insulin in relatives at risk of T1D. DPT-1 sought to determine whether intervention with insulin can delay the appearance of injected parenteral insulin in relatives with a five year projected risk of T1D of greater than 50%, and the other of which evaluated oral insulin in relatives with a five year projected risk of T1D of 26–50%. The injected insulin study was a randomized, controlled, multicenter clinical trial (4). The experimental intervention group received parenteral insulin – both annual intravenous insulin infusions and twice daily low dose subcutaneous insulin injections (0.25 units per kg per day of human ultralente insulin); the control group received close observation. The oral insulin study was a randomized, placebo-controlled, double-masked, multicenter clinical trial (5). The experimental intervention group received oral insulin(7.5 mg/day) or matched placebo. In both cohorts, to determine whether T1D developed, an oral glucose tolerance test was performed every six months; the diagnosis of diabetes was confirmed by a second test.
DPT-1 screened 103,391 relatives of patients with T1Dand 97,273 samples were analyzed for islet cell antibodies (ICA), with 3483 (3.58%) ICA positive on initial testing. (The insulin injection study completed enrollment after only 84,228 samples had been analyzed). Of 2523 who underwent staging to quantify risk of T1D, 372 relatives progressed in their staging evaluations to be classified as having a risk projection for T1Dof greater than 50%, and 339 were randomized in the injected insulin study. Another 388 relatives were classified as having a risk projection for T1Dof 26–50% over 5 years, and 372 were randomized in the oral insulin study.
In the injected insulin study, the median duration of follow-up was 3.7 years; 139subjectsdeveloped T1D – 69 in the intervention group and 70 in the close observation group. The average proportion of subjects who progressed to diabetes was 15.1% per year in the intervention group and 14.6% per year in the close observation group(Figure 3) (4). Unfortunately, this meant that insulin in the dose and regimen used did not prevent or delay development of T1D. The hazard ratio for development of T1D was 0.96(95% CI 0.69–1.34; p=0.80). However, most participants diagnosed with diabetes were asymptomatic at the time of diagnosis. Of note, there was a higher rate of progression to T1D among those with abnormal base-line glucose tolerance(22%per year) than among those with normal baseline glucose tolerance (10%peryear, p<0.001)(4).
In the oral insulin study, the median duration of follow-up was 4.3 years; 97 subjects developed T1D – 44 in the oral insulin group and 53 in the placebo group. The average proportion of subjects who progressed to diabetes was 6.4% per year in the oral insulin group and 8.2% per year in the placebo group(Figure 4) (5). Unfortunately, this meant that oral insulin did not prevent or delay development of T1D. The hazard ratio for development of T1Dwas 0.764(95% CI 0.511–1.142; p=0.189).
However, among participants in the oral insulin study with confirmed insulin autoantibodies (IAA) >80 nU/ml (n=263), the proportion who developed diabetes was 6.2%per year in the oral insulin group and 10.4% per year in the placebo group(Figure 5) (5). In this subgroup, the hazard ratio for development of T1Dwas0.566, 95% CI 0.361–0.888; p=0.015. Unfortunately, this subgroup was not pre-specified; however, the delay in T1D, calculated from median survival times, was projected as 4.5 years (5). If one confined the analysis to those with baseline IAA >300 nU/ml (n=132), the benefit was even more dramatic, with a projected delay in T1D of nearly 10 years (Figure 6). These subgroup analyses have led to the development of another large oral insulin prevention study, conducted by Type 1 Diabetes TrialNet in relatives with characteristics similar to that of the DPT-1 subgroup with apparent benefit (6).
Type 1 Diabetes Prediction and Prevention Study (DIPP) was conducted in Finland amongst newborns from the general population (i.e., without relatives) with high risk genotypes for T1D, and a parallel study amongst siblings of infants identified as high risk. In the birth cohort, the DIPP Study screened 116,720 consecutively born Finnish infants and identified 17,397 (~15%) with high or moderate genetic risk, of whom 10,577 participated in a prospective study in which there was serial analysis for diabetes autoantibodies. Of these, 328 met the enrollment criteria of ≥2 antibodies in at least 2 consecutive samples, and 224 were randomized to receive intranasal insulin (1 unit/kg body weight daily) or placebo. The median duration of follow-up was 2 years, with some followed up to 10 years; 80 subjects developed T1D – 42 in the nasal insulin group and 38 in the placebo group (7). The hazard ratio for development of T1Dwas 1.14, 95% CI 0.73–1.77;p=0.55). In the sibling cohort, DIPP screened 3430 siblings and identified 1613 (~47%) with high or moderate risk genes, of whom 1423 participated in prospective follow-up. Of these, 52 met the enrollment criteria, and 40 were randomized to receive nasal insulin or placebo. T1Ddeveloped in 11 subjects – 7 in the nasal insulin group and 4 in the placebo group (7). The hazard ratio for development of T1Dwas 1.93, 95% CI 0.56–2.68; p=0.30. Unfortunately, this meant that nasal insulin did not prevent or delay development of T1D. However, again, most participants diagnosed with diabetes were asymptomatic at the time of diagnosis.
The Trial to Reduce Incidence of Diabetes in Genetically at Risk (TRIGR) is a multi-national, randomized prospective trial, has been initiated to determine whether the frequency of T1D can be reduced by preventing exposure to cow milk proteins (CMP) early in life (8). TRIGR involves 77 centers in 15 countries, and registered approximately 5,000 newborns and randomized a total of2160 newborns over a 4.7 year period, completing enrollment at the end of 2006. Subjects with the risk HLA genotypes (approximately 45%) were included in the prevention trial, which involves randomization to either a a casein hydrolysate formula or a conventional cow’s milk-based formula, with breast feeding permitted ad lib. Planned follow up is for 10 years for the development of T1D. Thus, TRIGR is a “true” primary prevention study.
Type 1 Diabetes TrialNet is conducting four prevention studies. The TrialNet Oral Insulin Study has as its primary objective to determine if oral insulin (7.5 mg per day) will prevent or delay the development of clinical T1D in non-diabetic relatives of patients with T1D, age 3–45, who are positive for insulin autoantibodies but who do not have a metabolic defect. The study is a two-arm, multicenter, randomized, double-masked, placebo-controlled clinical trial.
TrialNet is planning a GAD-Alum Prevention Study, with a primary objective to determine GAD-Alum vaccine will prevent or delay the development of clinical T1D in non-diabetic relatives of patients with T1D, age 3–45, who are positive for GAD autoantibodies but not insulin autoantibodies. The planned study, still in development, is a multicenter, randomized, double-masked, placebo-controlled clinical trial.
TrialNet also is embarking on a study of anti-CD3 for prevention of diabetes in relatives at very high risk for T1D, age 8–45. A subset of individuals in DPT-1 had impaired fasting glucose, impaired glucose tolerance, or a plasma glucose greater than 200 mg/dL (11.1 mmol/L) at 30, 60, or 90 minutes of an oral glucose tolerance test. Collectively, these “dysglycemic” subjects in DPT-1 had a 5 year risk for T1D of 78%. Previous experience from a European trial with anti-CD3 in subjects with new onset T1D suggest that the high risk subjects are more likely to respond to drug treatment compared even to individuals with disease, because subjects who had greater β-cell function as measured by the upper ½ of C-peptide responses at time of diagnosis showed better responses to treatment with anti-CD3(9). The planned study is a 2-arm, multicenter, randomized, partially masked, controlled clinical trial. Subjects <18 years of age will receive double-masked infusions. Subjects <18 years of age will receive infusions only if assigned to active therapy. All subjects will receive close monitoring for development of T1D.
The Nutritional Intervention to Prevent (NIP) Type 1 Diabetes Pilot Trial is assessing the feasibility of implementing a full-scale study to determine if nutritional supplements with an omega 3 fatty acid, docosahexaenoic acid(DHA), during the last trimester of pregnancy and the first few years of life, will prevent the development of islet cell autoimmunity in children at high risk for T1D. The hypothesis is that supplementation with DHA will prevent autoantibody development in children at genetic risk for T1D. The NIP Diabetes Pilot is a multicenter, two-arm, randomized, double-masked, placebo-controlled clinical trial. There are two entry pathways for study participants:  pregnant mothers are randomized after the 24th week of pregnancy to take either DHA or placebo study capsules. At birth, or soon after, their babies are tested for HLA type. If the HLA typing shows the baby is at risk for T1D, they will then continue in the study on either DHA or placebo;  babies who are deemed eligible upon HLA testing are entered directly up until 6 months of age.
Recent T1D prevention studies are well designed, adequately powered, and carefully conducted. Sample sizes require a collaborative, cooperative, multi-center approach. The diabetes community is prepared to continue the effort to interdict the T1Ddisease process, with the ultimate goal of preventing T1D. Successful modulation of immune mechanisms also will be required for cellular replacement therapies. Results in studies in progress in new-onset T1D will lead to the nomination of other interventions that might be useful in prevention of T1D. There has been a tremendous amount of progress in recent years. The field has progressed to a stage now where we can predict that T1D will be prevented.