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Highlights of the American Diabetes Association annual meeting are presented here.
There was good news and bad news coming from the American Diabetes Association (ADA) annual meeting, held last month in New Orleans. The bad news is that oral insulin does not prevent or delay Type 1 diabetes. The good news is that the first of a diverse new therapeutic class of drugs, derived from gut hormones, is nearing the marketplace as therapy for Type 2 diabetes.
To start with the good news, more than 40 years of extensive research is nearing clinical application. Results of an open-label trial of exenatide, a synthetic form of exendin-4, were presented by Alain Baron, M.D., senior VP of clinical research at Amylin Pharmaceuticals.
The 155 male and female participants had Type 2 diabetes and were already being treated unsuccessfully with oral agents (metformin, a sulfonylurea, or both). Daily subcutaneous injections of exenatide (5 mcg before the morning and evening meal for the first four weeks and 10 mcg b.i.d. thereafter) improved glycemic control: hemoglobin A1c levels fell from 8.6% to 7.2% over the 20 weeks of the study, and 54% of the participants achieved an A1c level of 7% or lower. (The normal level for A1c is 6%, and the ADA sets 7% as the target goal for diabetics; a level of 8% or higher is associated with long-term complications including retinopathy, neuropathy, and nephropathy.) Baseline fasting glucose (218 mg/dl) was decreased by 30 mg/dl at week four, and the effect was sustained at week 20.
Exenatide was not associated with weight gain, a paradoxical effect of most oral antidiabetic agents and insulin injections. Most participants lost weighton average, 2.4 kg. Mild to moderate nausea was the most common toxicity, with six participants withdrawing from the study.
Exendin-4 was originally isolated from the salivary gland secretions of the Gila monster, an American lizard of the Southwest that was studied because of its strange eating patternit dines only four times a year, with much of its gastrointestinal tract involuting during the long periods of abstinence. Exendin-4 has many of the same actions as human glucagon-like peptide (GLP-1), one of a class of gut hormones known as incretins. GLP-1 is produced in the small intestine in response to food intake; it can stimulate insulin production without causing the hypoglycemia associated with therapeutic use of insulin injections or oral antidiabetic agents.
Unfortunately, GLP-1 cannot be used therapeutically because it is enzymatically degraded and rapidly. Efforts to develop stable analogs of GLP-1 failed for many years; stable compounds were synthesized, but none had adequate biological activity. With the isolation of exendin-4, which has a long half-life, a new era of research began. Many pharmaceutical companies are now involved in the development of GLP-1 analogs or compounds that block the degradation of GLP-1, as well as a host of other gut hormones that play a role in the development of obesity and diabetes. But Amylin's product is the closest to a viable one. Three ongoing phase III trials of exenatide will be reporting by November of this year, and the data may be filed with the Food & Drug Administration as early as January of 2004.
On the downside, DPT-1, the Diabetes Prevention Trial-Type 1, joins two other large-scale studies with negative results. Neither the European Nicotinamide Diabetes Intervention Trial (ENDIT) nor the first DPT-1 trial delayed or prevented the onset of Type 1 diabetes. ENDIT utilized nicotinamide, a vitamin present at low concentrations in the normal diet, and the first DPT-1 trial utilized low-dose insulin injections in people with a 50% or higher risk of developing diabetes over five years.
Ongoing research indicates that Type 1 diabetes is an autoimmune disease in which the body destroys insulin-producing pancreatic beta cells. Animal studies had suggested that oral insulin given before development of diabetes could reduce or delay disease onset. And so the second DPT-1 trial was undertaken.
The 711 participants, with a family history of diabetes and a 25%-50% risk of developing the disease within five years, were randomized to a daily capsule of insulin crystals (7.5 mg) or a placebo. The trial began in 1996. Most of the participants were children (median age 10 years, range three-45 years). At mean follow-up of 4.3 years, about 35% of each group developed Type 1 diabetes, with a similar yearly rate of onset: 7.2%. Most cases of diabetes were detected before symptoms developed, enabling prompt, early treatment, and no side effects were linked to oral insulin.
"The study was well designed and rigorously conducted," said Jay Skyler, M.D., of the University of Miami, who chaired the study. "We asked the question carefully, and we now know the answer. We don't like the answer, but we do know that oral insulin does not prevent or delay Type 1 diabetes."
KT Porter. Here's good news for Type 2 diabetes, bad news for Type 1.
Jul. 21, 2003;147:HSE26.