NEW YORK — A new generation of clinical trials is evaluating various ways of interrupting autoimmune β-cell destruction in type 1 diabetes, thereby preventing development of the disease, Dr. Carla J. Greenbaum said at a meeting sponsored by the American Diabetes Association.
Two studies begun in the early 1990s, the Diabetes Prevention Trial-Type 1 (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT), showed the feasibility of conducting large, well-designed, rigorously controlled clinical trials in patients at risk for diabetes. But the therapies tested—low-dose insulin injections, oral insulin, and nicotinamide—failed to delay or prevent the onset of type 1 diabetes, said Dr. Greenbaum, director of the diabetes research program at Benaroya Research Institute at Virginia Mason, Seattle.
Today, with significant advances in understanding of immune regulation and β-cell growth and development, multiple primary, secondary, and tertiary prevention trials are being conducted. These studies are needed because of the tremendous recent increase in the incidence of type 1 diabetes worldwide, including a 300% increase in type 1 incidence among children younger than 4 years, she said.
▸ Primary prevention. The goals of primary prevention studies are to identify patients who are genetically at risk because they have certain genetic mutations or because a close relative has the disease, to monitor those patients for the development of autoantibodies, and to intervene when antibodies appear.
In the randomized Trial to Reduce Insulin-Dependent Diabetes in the Genetically at Risk (TRIGR), the effects of cow's milk or soy-based formula in addition to breast-feeding is being evaluated in at-risk babies. A previous pilot study suggested that cow's milk was associated with a higher incidence of antibody development.
In the Nutritional Intervention to Prevent Diabetes (NIP) trial, anti-inflammatory omega-3 fatty acids are being given to mothers and infants to determine if this beneficial fatty acid can inhibit the initial autoimmune process.
▸ Secondary prevention. The goal in patients who already are antibody positive and in whom the autoimmune process is underway is to prevent the development of clinical disease, Dr. Greenbaum said.
ENDIT and DPT-1 were secondary prevention studies, and although unsuccessful, they provided data that have proved useful in the newer generation of prevention trials. In DPT-1, for example, although oral insulin was not effective overall, it was beneficial in a subset of patients who had very high levels of autoantibodies. This is now being tested again in patients considered most likely to benefit, she said.
▸ Tertiary prevention. For patients who already have clinical disease, the goal is to preserve β-cell function and thereby prevent both short- and long-term complications; of particular concern in the short term is severe hypoglycemia. Patients in the Diabetes Control and Complications Trial who had some residual β-cell function and who received intensive therapy had a 60% reduction in risk of hypoglycemia, Dr. Greenbaum said.
To prevent long-term complications and to stabilize pancreatic function, the concept of using immunotherapy is being explored. This premise was first tested in the 1980s with cyclosporine, and although the trial showed some benefit to patients, toxicity was a problem. The intention now is to find a tolerable drug or drugs that can be used for a short course that will “reset” the immune system so it stops attacking the pancreas, she said. Among the agents being evaluated are the newer immunosuppressants mycophenolate mofetil, thymoglobulin, daclizumab, and rituximab.
“We can cure diabetes in mice, but we can't yet cure it in people,” Dr. Greenbaum said. “When I think about what cure is going to look like, multiple avenues are going to be needed.” For patients who are genetically at risk, there may be dietary interventions, and for those who go on to develop autoimmunity, antigen-specific therapies may block β-cell destruction. In those who lose β-cell function, achieving a cure may involve tolerance induction, intermittent immunotherapy, and the use of β-cell growth factors and insulin sensitizers, she predicted.
Dr. Greenbaum concluded with a plea for clinicians to refer patients and relatives willing to participate in these trials. Information is available at www.diabetestrialnet.org