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10-04-2018 | GLP-1 agonists | EASD 2018 | News

Promising phase II data for dual GIP and GLP-1 receptor agonist

medwireNews: A compound that stimulates the receptors for both glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 has dose-dependent effects on glucose levels and bodyweight in people with type 2 diabetes.

For the study, presented at the 54th EASD Annual Meeting in Berlin, Germany, and published in The Lancet, the researchers recruited 318 patients and randomly assigned them to receive 26 weekly doses of the dual agonist LY3298176 at doses of 1, 5, 10, or 15 mg, or the comparator treatments of dulaglutide 1.5 mg or placebo.

All doses of LY3298176 outperformed placebo, and the higher doses outperformed dulaglutide, reported study author Juan Frias (National Research Institute, Los Angeles, California, USA).

For the primary efficacy endpoint of change in glycated hemoglobin (HbA1c), there were reductions of 0.7%, 1.6%, 2.0%, and 2.4% for the 1, 5, 10, and 15 mg doses, respectively. All of these reductions were significant versus placebo, for which there was a 0.1% rise, and the two highest doses achieved significantly greater reductions than dulaglutide, which produced a 1.1% reduction.

There was likewise a dose-response relationship for the proportion of patients achieving various HbA1c targets, with the highest LY3298176 doses again offering significantly better outcomes  versus dulaglutide.

“And I think perhaps most impressive of all was the percent of patients who actually achieved normoglycemia,” said Frias. He highlighted that 30.2% of patients taking the highest LY3298176 dose achieved an HbA1c below 5.7%, compared with 1.9% of those taking dulaglutide.

The patients had average starting HbA1c levels of around 8.1% and a diabetes duration of about 8–9 years. Their starting BMI was about 32–33 kg/m2, and the researchers saw a similar dose effect of LY3298176 on bodyweight. The average bodyweight reductions were 0.4, 2.7, and 0.9–11.3 kg with placebo, dulaglutide, and LY3298176, respectively.

Frias noted that more than one in five patients taking the higher doses of the dual agonist lost at least 15% of their bodyweight, “which is consistent with some bariatric procedures.”

Safety monitoring included an additional 4 weeks after the conclusion of the randomized phase. Side effects were mostly mild to moderate and consistent with those reported for GLP-1 receptor agonists, said Frias.

Hypoglycemia occurred in 1.9–9.8% of patients taking LY3298176 and in 3.9% and 3.7% in the placebo and dulaglutide groups, respectively, and there were no severe episodes.

Nausea and diarrhea were both frequent in the active treatment groups, particularly in patients taking the 15 mg dose of LY3298176, at 39.6% and 32.1%, respectively, compared with 29.6% and 16.7% in the dulaglutide group. But Frias noted that the investigators are now titrating up to the highest doses more slowly than they did in this trial, which is helping to reduce the frequency of these side effects.

In a linked commentary, Michael Stumvoll (Universitätsklinikum Leipzig, Germany) and Matthias Tschöp (Helmholtz Zentrum München, Germany) observe that LY3298176 treatment did not affect pulse rate, giving it “an important edge over a GLP-1 and glucagon coagonist (MEDI0382), with which increases of 6–8 beats per min in heart rate were reported.”

They say that despite the promising results with this “twincretin,” the small size of the trial makes it “too early for any far-reaching clinical conclusion or recommendation.”

The commentators stress that further studies are also necessary to monitor for the theoretical increase in risk for acute pancreatitis, and in lipase or amylase, and add that “it remains to be shown in direct comparison whether an optimised twincretin will also outperform semaglutide, which is the most potent GLP-1 monoagonist to date.”

By Eleanor McDermid

medwireNews is an independent medical news service provided by Springer Healthcare. © 2018 Springer Healthcare part of the Springer Nature group

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