The findings of two studies appearing in The New England Journal of Medicine (NEJM) on May 30 bring researchers a step closer to the goals of preventing type 1 diabetes and of preserving insulin production in people newly diagnosed with the disease. The studies, though different in size, goals, design, and outcomes, illustrate the therapeutic potential of an improved understanding of the autoimmune process that leads to type 1 diabetes.
One study--a large, multicenter, controlled clinical trial in 339 people at high risk (50 percent or greater chance) of developing type 1 diabetes in 5 years--found that low-dose insulin injections do not delay or prevent type 1 diabetes. The finding clearly negated earlier animal studies and a small pilot study in people, both of which suggested that insulin injections could prevent type 1 diabetes. Some physicians, relying on these preliminary studies, had begun using insulin injections to prevent diabetes in their at-risk patients.
"This trial showed the importance of conducting well-designed, carefully controlled clinical trials to definitively answer questions about the value of specific prevention approaches," said study chair Dr. Jay S. Skyler of the University of Miami. "We've learned that insulin injections, given in the way tested in this trial and in people at high risk of developing type 1 diabetes, do not delay or prevent type 1 diabetes. But from this study we've also learned a great deal about how type 1 diabetes develops and proven that immune and metabolic markers can be used to quantify the risk of diabetes. This knowledge is already proving extremely valuable for prevention efforts that will be tested in upcoming clinical trials."
The findings of the low-dose insulin injection trial, one of two trials that make up the Diabetes Prevention Trials-Type 1 (DPT-1), have laid the groundwork for other prevention studies by yielding a great deal of useful information about the antibody markers for type 1 diabetes risk, how the level of risk can be assessed for individual patients, and the immune events that lead to diabetes.
The trial compared insulin injections and close observation in high-risk people whose ability to make insulin was below normal, though they did not yet have diabetes. Half the participants were randomized to receive low-dose insulin injections twice a day under the skin. Once a year, they also received a 4-day course of low-dose, continuous intravenous insulin. The other half received no treatment but were closely observed throughout the trial, which began in 1995. Participants' ages ranged from 4 to 45 years old, with a median age of 11 years. After 5 years of observation, nearly 60 percent of participants developed type 1 diabetes, a rate of diabetes onset that was virtually identical in both groups.
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A separate trial is currently testing whether insulin taken by mouth can prevent or delay type 1 diabetes in people at an earlier stage in the development of diabetes. The ongoing trial targets people who have evidence of autoimmunity but no significant loss in their ability to produce insulin. These individuals have a lower (25 to 50 percent) risk of developing diabetes in 5 years. The oral insulin trial is based on a different immune mechanism, so the results of the injection trial do not predict the outcome of the oral trial. In contrast to insulin injections, insulin taken by mouth does not affect blood glucose. Rather, it targets the immune response to down regulate the immune cells that attack the insulin-producing beta cells of the pancreas. Patient recruitment for the oral trial is nearly complete, and enrollment is scheduled to end in August.
The other study published in the NEJM was an early-phase clinical trial that tested an experimental drug with selective immunosuppressive effects in patients with newly diagnosed type 1 diabetes. The drug, a modified form of anti-CD3 antibody that minimizes first-dose side effects, was studied by comparing 12 people aged 7 to 30 who were treated with the antibody to an equal number of patients in a control group who did not receive the drug. The researchers report that a 14-day course of the drug delayed the progressive decline in insulin production typically seen in type 1 diabetes.
One year after treatment with anti-CD3 mAb, the treated patients produced more insulin and needed less insulin therapy than the untreated patients. Retention of even some insulin production is an important clinical goal in the treatment of patients with type 1 diabetes since, in general, most patients with the disease eventually lose the ability to make insulin entirely and need to rely completely on injected insulin to maintain metabolic control. Those who received the antibody treatment also had better hemoglobin A1c (HbA1c) levels, a reflection of average blood glucose over a 2- to 3-month period. "The goal of this trial was to induce tolerance to the beta cell, which is the target of autoimmune destruction in type 1 diabetes. This was in effect achieved, because the clinical effect we saw persisted long after patients had finished treatment with the anti-CD3 antibody," said the lead author, Columbia University's Dr. Kevan Herold.
The anti-CD3 mAb was designed to act on the immune system's T cells in a more specific manner than previous attempts at immune intervention in early diabetes. "Our animal research suggests that it reorients the immune response, suppressing destructive T cells and stimulating production of protective immune-signaling molecules. In fact, the antibody may selectively inhibit previously activated immune cells that are involved in the development of diabetes," said senior author, University of California at San Francisco's Dr. Jeffrey Bluestone. Dr. Bluestone developed the monoclonal antibody in the 1980s in collaboration with Johnson & Johnson.
Side effects of anti-CD3 mAb included fever, rash, anemia, nausea, vomiting, and joint pain but were mild and transient, according to the authors. The study's encouraging results have led to new trials involving additional patients.
"The results of both these studies underscore the complexity of the events leading up to the onset of diabetes. The immune system's response to antigens at various stages in the development of diabetes depends on many factors. While the insulin injection trial did not prevent diabetes, the information gathered provides a platform for other prevention studies. Clinical trials are a critical step in the quest for answers, and we appreciate the participation of the patients who have helped us reach this far in our search for a cure," said Dr. Robert Goldstein, chief scientific officer at the Juvenile Diabetes Research Foundation International (JDRF).
"We're looking forward to the results of the oral insulin trial, the expanded trials of the anti-CD3 mAb, and other trials soon to be testing a number of promising agents for type 1 diabetes," said Dr. Judith Fradkin, director of the Division of Diabetes, Endocrinology, and Metabolic Diseases in the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which funded both studies reported in the NEJM. "The NIH has in place an infrastructure to build on the exciting early results of the anti-CD3 mAb and to explore the potential of other new drugs. Two complementary clinical trial networks will be testing these agents in type 1 diabetes."
The Type 1 Diabetes TrialNet, led by Dr. Skyler, is a collaborative network of researchers, clinical centers, and laboratories solely dedicated to testing new approaches to understanding, preventing, and treating type 1 diabetes. TrialNet will complete the important oral insulin trial and will have the capacity to mount large-scale type 1 diabetes prevention studies as well as smaller studies in new onset diabetes. The Immune Tolerance Network (ITN), directed by Dr. Bluestone, is a consortium of basic and clinical researchers focused on evaluating promising treatments that modulate the immune system to improve outcomes in islet and kidney transplantation, autoimmune diseases (such as type 1 diabetes), and asthma and allergic diseases. The ITN plans to test anti-CD3 mAb in a larger group of patients with new onset type 1 diabetes and in people with other autoimmune diseases. If the results of the diabetes trial are positive, TrialNet will expand studies to include people at risk for type 1 diabetes.
TrialNet is funded by the NIDDK, the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute of Child Health and Human Development (NICHD), and the JDRF. The ITN is funded by NIAID, NIDDK, and the JDRF.
The low-dose insulin injection trial was sponsored by the NIDDK and also received support from the NIAID, NICHD, and the National Center for Research Resources (NCRR) within the NIH as well as the American Diabetes Association and the JDRF. The anti-CD3 mAb trial received support from the NIDDK, NIAID, NCRR, and the JDRF.
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About 17 million Americans have diabetes. Of these, 5 to 10 percent have type 1 diabetes, an autoimmune disease that destroys the insulin-producing cells of the pancreas. Formerly known as juvenile onset or insulin-dependent diabetes, type 1 diabetes develops when the body's immune system destroys pancreatic beta cells, the only cells in the body that make the hormone insulin, which regulates blood glucose. This form of diabetes usually strikes children and young adults, who need several insulin injections a day or an insulin pump to survive.