Desmond A. Schatz, MD; William E. Winter, MD

Disclosures

June 17, 2002

Question

What have been the outcomes from type 1 diabetes prevention trials?

Response from Desmond A. Schatz, MD and William E. Winter, MD

Because a combination of genetic, immunologic, and metabolic markers can be used to predict type 1 diabetes, multicenter prevention studies were initiated worldwide in nondiabetic relatives in the mid 1990s. The objective of the American Diabetes Prevention Trial[1] (DPT-1) is to determine whether antigen-based (insulin) therapy of nondiabetic relatives prevents or delays the onset of clinical disease. High-risk subjects (> 50% 5-year risk) were randomized either to receive an annual 4-day intravenous insulin infusion followed by twice-daily low doses of subcutaneous injections of ultralente insulin, or to a closely observed group. Intermediate-risk subjects (25%-50% 5-year risk) were randomized to receive either oral insulin or placebo.

In this mammoth undertaking, over 100,000 relatives of type 1 diabetes probands have been screened for islet cell autoantibodies as an initial assessment of risk, and 339 high-risk subjects were randomized. In high-risk relatives at the dose and regimen used in DPT-1, insulin therapy did not delay or prevent the development of type 1 diabetes. Long-term follow-up of this group is ongoing to determine any effects on the progression to and course of diabetes. It may, however, be too late in the disease process to slow the course of the disease.

Studies conducted earlier in the disease process, such as the oral insulin trial in relatives with a 26% to 50% projected 5-year risk, may be more successful. Over 350 subjects have (to date) been enrolled, and enrollment is scheduled to be complete by late 2002. Results can be expected 1-2 years later.

The European Nicotinamide Diabetes Intervention Trial [2] (ENDIT) will prospectively address whether nicotinamide will reduce the rate of progression to diabetes in relatives. Over 40,000 first-degree relatives (5-40 years) have been screened, and enrollment is complete. Five hundred fifty-two subjects (ICA titers 20 JDF units) have been randomized to receive either nicotinamide or placebo. (These subjects have an approximately 40% risk of developing diabetes over 5 years.) No major side effects have been reported. Analysis of data is expected in 2002 or 2003.

The Trial to Reduce Diabetes in the Genetically At-Risk (TRIGR) was initially piloted in Finland, and now has collaborative sites in Europe and North America. This trial is based on epidemiologic studies in humans[3] suggesting that prolonged breastfeeding of infants and the delayed introduction of cow's milk into their diets led to decreased frequency of the disease. The TRIGR seeks to determine whether genetically at-risk infants who are not exposed to cow's milk for the first 6 months of life will be protected from the development of diabetes. Preliminary data in this randomized study reveal that there may be a decrease in autoimmunity as evidenced by lower frequencies of islet autoantibodies in the experimental group compared with the control group. The most recent report is that 3/84 in the experimental arm have evidence of autoimmunity compared with 10/89 of controls (P = .06).

Trials using inhaled insulin to prevent diabetes are currently being conducted in Finland and Australia (Harrison LC, personal communication, 2001).[4] In the Australian crossover study, 38 young islet antibody-positive individuals at risk for type 1 diabetes were randomized to treatment with intranasal insulin or carrier solution and followed for a median of about 3 years. Intranasal insulin was associated with enhanced antibody and suppressed T-cell responses to insulin, mirroring those changes seen in NOD mice protected from diabetes by similar treatment. Subjects with a normal first-phase insulin response (FPIR) had no deterioration over time, whereas those with an already significantly impaired FPIR progressed to diabetes, suggesting that intranasal insulin may be immunoprotective and retard the loss of beta-cell function in at least a subgroup of people at risk for the disease. No adverse effects were noted. Clearly a larger study needs to be conducted in the future.

In the Finnish Type 1 Diabetes Prediction and Prevention Study (DIPP), newborns from the general population are screened for genetic risk and then followed for the appearance of islet-related antibodies. More than 90 infants have been randomized to nasal insulin or placebo, and results are expected in 2-3 years.

The DPT-1 and ENDIT trials have shown that extensive collaboration is not only necessary but also essential for implementing prevention studies. TrialNet, a cooperative type 1 diabetes intervention group in the United States, is now operative and will soon begin to test the safety and efficacy of several potential therapeutic interventions.

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