Daniel M. Keller, PhD

October 08, 2012

October 8, 2012 (Berlin, Germany) — A ghrelin receptor agonist (GRA) in clinical development improved the symptoms of gastroparesis in both type 1 and type 2 diabetes, according to a study reported here at the European Association for the Study of Diabetes 48th Annual Meeting.

Previous studies have shown that ghrelin itself enhances gastric emptying and that, in an animal model of gastric emptying, the receptor agonist has prokinetic activity. However, Niels Ejskjaer, MD, from the Department of Endocrinology at Aarhus University Hospital in Denmark, and colleagues found no correlation between symptoms and the rate of gastric emptying.

Their phase 2 double-blind randomized controlled trial was designed to assess the effect of oral GRA on gastroparesis symptoms in diabetic patients. For inclusion, patients with type 1 or type 2 diabetes had to have a score of 2.66 or greater on the 5-point Gastroparesis Cardinal Symptom Index (GCSI). They also had to have delayed gastric emptying, measured with a 13C-octanoate breath test.

The trial ran for 28 days, with a 30-day follow-up. The researchers randomly assigned participants to receive GRA 10 mg, 20 mg, or 40 mg, or placebo orally once daily. Participants completed the GCSI at baseline, during treatment, and at follow-up, and underwent a 13C-octanoate breath test at baseline, after the first dose on day 1, and after the last dose on day 28.

The mean age of the 55 patients with type 1 diabetes was 46.4 years and of the 37 patients with type 2 diabetes was 55.2 years. There were about twice as many women as men in each group. The duration of diabetes was about 25 years in the type 1 group and about 10 years in the type 2 group. At baseline, glycated hemoglobin was higher in the type 1 group than in the type 2 group (8.9% vs 7.4%).

At baseline, GCSI scores were 3.2 in the type 1 group and 3.4 in the type 2 group. Gastric emptying times were equivalent in the 2 groups (191 to 194 minutes).

The improvement in symptoms was similar for all doses of GRA, but the greatest improvement was with the 20 mg dose (n = 21). On day 28, the GSCI score in the 20 mg group had decreased by 1.4 points from baseline (P = .02), representing an improvement in symptoms from moderate to mild, whereas in the placebo group, it had decreased by only 0.6 points.

With the 20 mg dose, symptoms of nausea, early satiety, bloating, and upper abdominal pain began to improve by day 8. By day 28, all of the symptom scores were significantly different from baseline (≤ .04 for all). At 42-day follow-up, all symptom scores had rebounded somewhat. In the placebo group, symptom scores showed some mild improvement both during and after the treatment period.

"We wanted to find out whether there was a difference in symptoms in type 1 and type 2 diabetes," Dr. Ejskjaer explained. "Certainly, there must be different pathological forces for these symptoms in type 1 and type 2 diabetes...but really we found no difference," he reported.

In the 20 mg group, symptom scores had improved on day 28 to a similar degree in the type 1 and type 2 groups (about –0.75 to –1.00 point). The only exception was for early satiety, where the outcome was better in the type 2 group than in the type 1 group (–1.20 vs –0.95 points).

Gastroparesis symptoms on the GCSI were unrelated to gastric emptying at baseline or at day 21 (gastric half-emptying times ranged from 150 to 350 minutes).

Session cochair Rayaz Malik, MD, PhD, professor of medicine at the University of Manchester, United Kingdom, said that "this is common. You always find a major disconnect between symptoms and deficits. That's always been the case for diabetic gastroparesis."

He sees GRA as a welcome development. "We really have had no new therapies for 30-plus years; we're still stuck with metoclopramide or domperidone," he told Medscape Medical News. "From a mechanistic point of view, from a clinical point of view, the effect of the new agent, which potentially has something to do with the actual functioning of the stomach in terms of ghrelin, is really very positive," he explained.

He cautioned, however, that the study only ran for 28 days and that longer studies are needed.

The study was supported by Tranzyme Ltd. Dr. Ejskjaer reports being on advisory panels or being a board member for Novo Nordisk, Eli Lilly, Pfizer, and Tranzyme; and receiving research support from Maersk Research Foundation, Novo Nordisk, Eli Lilly, and Tranzyme. Dr. Malik has disclosed no relevant financial relationships.

European Association for the Study of Diabetes (EASD) 48th Annual Meeting: Abstract 47. Presented October 2, 2012.