A once-daily oral agent that preserves the action of the glucagon like peptide GLP-1, improves glycemic control in patients who are inadequately controlled with metformin. The positive effects on glycemia were durable for up to one year, according to Bo Ahrén, MD, from the University of Lund in Sweden. The drug, LAF237, is the first in a new class of agents known as dipeptidyl peptidase IV (DPP-4) inhibitors. Unlike exenatide (Exendin-4), a synthetic version of GLP-1, LAF237 inhibits the action of DPP-4, which rapidly degrades GLP-1. Dr. Ahren said that the serum half-life of GLP-1 is about 1.0 to 1.5 minutes, making naturally occurring GLP-1 impractical as a diabetes therapeutic agent. LAF237 in contrast allows for larger plasma concentrations of GLP-1 by interfering with its degradation. (The exenatide molecule is altered to cancel out the effects of DPP-4).
GLP-1 is secreted from the intestine in response to food. It stimulates beta-cell secretion, suppresses glucagon secretion, and contributes to satiety, making it an attractive target for drug therapy to treat type 2 diabetes. In addition, GLP-1 appears to preserve beta-cell function, suggesting that it could be used in conjunction with islet cell transplantation.
The LAF237 study involved 107 patients who were inadequately controlled on metformin at doses ranging from 1,500 to 3,000 mg per day. Patients were randomly assigned to receive 50 mg orally of LAF237 once daily or placebo plus metformin. They were evaluated at baseline and at various time points up to one year for A1c, fasting plasma glucose, insulin levels, lipid levels, and adverse effects. The adjusted mean A1c was 7.7% at baseline, with no significant difference between the treatment or placebo groups.
The authors found that patients in the LAF237 group had a mean A1c that was 1.1% lower than those receiving placebo. The rate of increase in A1c was 0.013% per month in patients receiving LAF237 compared with 0.0655% per month in the placebo group, which is not statistically different from zero, Dr. Ahren said. The between-group difference in adjusted mean A1c at study end point was -1.1 ± 0.2% (P = .0001).
In contrast to exenatide, however, patients receiving LAF237 did not lose a significant amount of weight compared with those receiving placebo. In both groups, there was a slight decrease of 0.2 kg.
Ralph DeFronzo, MD, professor of medicine and chief of the diabetes division at the University of Texas Health Science Center in San Antonio stated that, "I think it’s too early to tell how they’re going to compare, and there are remaining questions about efficacy and safety." "Obviously, the oral preparation has the advantage of being oral. This was a study of only about 70 patients, and in a completely different population in Europe than in the United States, where we have a much heavier population. I suspect with time we’ll see weight loss with DPP-4 inhibitors."
Martin Abrahamson, MD, acting chief medical officer of the Joslin Diabetes Center in Boston, Massachusetts, commented "These are all drugs that have additive effects, which is interesting because we know that treatment of diabetes is really polypharmacy: we have to target insulin resistance, we have to target beta-cell secretory dysfunction, and now we have got potentially two different mechanisms to target the beta-cell secretory dysfunction." PowerPoint Presentation Available
ADA 64th Annual Scientific Sessions: Abstract 7-LB. Presented June 6, 2004.