乌鸦传媒

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BERLIN -- The novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide (GLP)-1 receptor agonist LY3298176 helped improve glucose control in patients with type 2 diabetes, according to a phase IIb clinical trial presented here.

Once-weekly injectable treatment of the dual agonist significantly improved glycated hemoglobin (HbA1c) after 26 weeks compared with placebo, Juan Pablo Frias, MD, of the National Research Institute in Los Angeles, reported here.

As shown in the findings reported at the annual meeting of the and published simultaneously online in , this effect size was largely dose-dependent, with the greatest benefit seen at the 15 mg dose, which yielded a nearly 2% reduction in HbA1c from baseline:

• 1 mg LY3298176: posterior mean differences versus placebo -1.00% (-1.22% to -0.79%)
• 5 mg: -1.67% (-1.88% to -1.46%)
• 10 mg: -1.83% (-2.04% to -1.61%)
• 15 mg: -1.89% (-2.11% to -1.67%)
• Placebo: mean change from baseline -0.06%

In the active comparator arm of the trial, the dual agonist also achieved significantly greater HbA1c reductions with doses 5 mg and above compared with the GLP-1 receptor agonist dulaglutide (Trulicity):

• 1 mg LY3298176: posterior mean difference versus dulaglutide 0.15% (-0.08% to 0.38%)
• 5 mg: -0.52% (-0.72% to -0.31%)
• 10 mg: -0.67% (-0.89% to -0.46%)
• 15 mg: -0.73% (-0.95% to -0.52%)
• Dulaglutide: mean change from baseline -1.21%

More people were able to achieve lower target glucose goals with the dual agonist as well: At the end of the trial, 33%-90% of those treated with the dual agonist at any dose were able to achieve a target under 7%, compared with 52% of those on dulaglutide and 12% of those on placebo. A total of 15%-82% of those on the dual agonist were even able to achieve an A1c target of 6.5% compared with 39% of those on dulaglutide and 2% of those on placebo.

The participants included 316 individuals with poorly controlled type 2 diabetes at an average HbA1c of 8.1%. Those on the novel treatment also had a benefit in regards to body weight, as those on the dual agonist lost 19.8 to 24.9 lbs (9.0-11.3 kg) compared with 6.0 lbs (2.7 kg) for the dulaglutide-treated patients and 0.9 lb (0.4 kg) for those on placebo.

More patients on the 5 mg, 10 mg, and 15 mg doses of the dual agonist were also able to achieve a body weight reduction of at least 10%, as well.

However, a larger portion of patients on the dual agonist had gastrointestinal events, which was the most commonly reported adverse effect with this treatment. This incidence was also dose related, although most of the events were generally mild to moderate in severity, as follows:

• 1 mg LY3298176: 23.1% had a GI event
• 5 mg: 32.7%
• 10 mg: 51.0%
• 15 mg: 66.0%
• Dulaglutide: 42.6%
• Placebo: 9.8%

"As an investigator and a clinician, I have actually never seen this magnitude of A1c reduction in this percentage of patients normalizing their glucose, and also with this level of weight loss," said Frias during a press conference.

"One point I think is important to make and really highlights the effect that we have here -- more likely from the GIP component -- is that at the 5 and 10 mg doses of the dual agonist, there was superior efficacy compared to dulaglutide with respect to A1c and weight reduction," Frias continued, adding that there was also very similar incidence and event rates for GI side effects, which suggests that the addition of GIP activity may complement the pharmacology of selective GLP-1 receptor agonists.

"We're really getting something from both binding and activating the GLP-1, as well as the GIP," he said.

Writing in an , Michael Stumvoll, MD, of the Universitätsklinikum Leipzig, and Matthias Tschöp, MD, of the Helmholtz Zentrum München, both in Germany, praised the study and said the findings "re-emphasize that the strategy of dual and triple coagonism (based on combinatorial integration of multiple gut hormones into one molecule) is promising, with potential to reverse the obesity and type 2 diabetes pandemic."

Stumvoll and Tschöp continued: "With all due caution that is appropriate when analyzing a study of only 26 weeks' duration, this trial is the next logical step towards replacing GLP-1 mono-agonists with dual or, perhaps eventually, triple agonists. However, despite the small but significant competitive edge of this twincretin over a classic GLP-1 mono-agonist, it is too early for any far-reaching clinical conclusion or recommendation."