Experimental Dulaglutide Is Superior to Sitagliptin in One-Year Trial

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A year-long phase 3 trial comparing the experimental GLP-1 receptor agonist dulaglutide to sitagliptin and placebo in metformin-treated patients with type 2 diabetes found that it had superior efficacy to sitagliptin in treating diabetes, although with more side effects. The primary endpoint of the study was non-inferiority of dulagutide to sitagliptin in reducing HbA1C a marker for a patient’s blood glucose level but two separate doses of the experimental drug were found superior to sitagliptin at 52 weeks.

“Rates of hypoglycemia were the same in the different arms of the study, because we compared only drugs that don’t cause hypoglycemia,” said Michael Nauck, MD, the head physician at the Diabetes Center of Bad Lauterberg in Germany.

Dulaglutide is a GLP1 receptor agonist, a class of drugs which operate by stimulating insulin secretion in the pancreas, but they don’t cause hypoglycemia because they only cause the secretion to occur when a potassium channel is closed in the cell membrane, explained Nauck, who gave an oral presentation entitled “Efficacy and Safety of Dulaglutide vs. Sitagliptin after 52 Weeks in Type 2 diabetes (AWARD-5)” at the annual scientific sessions of the American Diabetes Association in Chicago.

In the study, 1,098 patients were randomized to receive either sitagliptin, placebo, or dulaglutide. For ethical reasons, the placebo arm was stopped at 26 weeks, and placebo patients were shifted to the sitagliptin arm, according to the abstract. A number of other arms using various doses of dulaglutide (0.25, 0.50, 1, 2, and 3 milligrams) were also stopped. “The three milligram arm was discontinued because there was too much of an increase in the pulse rate,” Nauck said.

Three arms continued for another 26 weeks: 315 patients who received 100 milligrams of sitagliptin; 302 patients who received 0.75 milligrams of dulaglutide; and 304 patients who received 1.5 milligrams of dulaglutide. Of the patients in the 1.5 milligram dulaglutide arm, 66 patients, or about 20 percent, discontinued the trial, while the rate was slightly less in the other arms, Nauck said.

To be included, patients had to have an HbA1c level between 7.7 percent and 9.5 percent. At baseline, the patients had a mean age of 54, mean HbA1c level of 8.1 percent, weight of 86.4 kilograms, and had had diabetes for approximately seven years, according to the abstract.

Both doses of the experimental agent were superior to sitagliptin with regard to glycemic control, body weight, and fasting glucose, Nauck said.

At one year, the mean HbA1c level of patients in the sitagliptin arm was 7.57 percent, compared to 7.08 percent in the 0.75 milligram arm of dulaglutide, and 6.83 percent in the 1.5 milligram arm, according to the slide. Patients on the high dose of dulaglutide saw HbA1c decrease by 1.1 percent, compared to 0.87 percent in the 0.75 milligram arm, and 0.39 percent in the sitagliptin arm, with a p value of less than 0.01, according to Nauck.

Patients on dulaglutide also lost more weight, with those on the large dose losing 3.22 kilograms, compared to 2.7 kilograms on the 0.75 milligram dose, and 1.63 kilograms for those on sitagliptin, also with a p value below 0.01.

However, side effects were higher for those on dulaglutide. with about 76 percent of patients in both of the dulaglutide arms experiencing adverse events, compared to 69.5 percent in the sitagliptin arm. Of those on the large dose of dulaglutide, 17.4 percent experienced nausea, compared to 13.9 percent of those in the 0.75 milligram arm, and 5.1 percent of those on sitagliptin. Although hypoglycemia rates were low, 2.6 percent of patients on the large dose of the experimental agent had nausea, compared to 1.1 percent of those on sitagliptin.

Vomiting occurred in 13 percent of the patients on the large dose of dulaglutide, and 8 percent of those on the smaller dose; diarrhea occurred in 15% percent of those on the larger 1.5 milligram dose, and 10 percent of those on the smaller 0.75 milligram dose, the abstract said

There were also about two cases of pancreatitis in the sitagliptin arm, according to Nauck. Sometimes, commentators express the theory that GLP-1 receptor agonists may be associated with increased rates of carcinoma and pancreatic disease.

The study was part of a series called the AWARD-5 trial, which tested dulaglutide in anticipation of marketing applications which the manufacturer hopes to submit in Europe and the US this autumn, Nauck added.

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“In the whole AWARD program, we experienced two carcinomas one of which was diagnosed right after recruiting the patient, while the other case was discovered several months into treatment,” Nauck said.