Glucagon-like peptide-1 (GLP-1) potentiates the release of insulin from pancreatic beta cells in a glucose-dependent manner. While pharmacologic studies have shown that GLP-1 delays gastric emptying, reduces appetite, decreases food intake, and therefore, contributes to improved glucose homeostasis and bodyweight, some patients fail to achieve glycemic and bodyweight targets. LY3298176 is a novel dual glucose-dependent insulinotropic polypeptide (GIP) and GLP-1 receptor agonist. Similar to GLP-1, GIP is a potent stimulator of glucose-dependent insulin secretion. In this double-blind randomized phase 2 study, 318 patients with inadequately controlled type 2 diabetes were randomly assigned (1:1:1:1:1:1) to receive either once-weekly subcutaneous LY3298176 (1 mg, 5 mg, 10 mg, or 15 mg), dulaglutide (1.5 mg), or placebo for 26 weeks to assess the efficacy and safety of co-stimulation of the GLP-1 and GIP receptor compared to placebo or selective stimulation of GLP-1 receptors with dulaglutide in patients with poorly controlled type 2 diabetes. Researchers found that at 26 weeks, the effect of LY3298176 on change in HbA1c was dose-dependent and did not plateau; the mean change from baseline in HbA1c with LY3298176 was -1.06% in the 1 mg group, -1.73% for the 5 mg group, -1.89% for the 10 mg group, and -1.94% for 15 mg group, as compared to -0.06% in the placebo group. This corresponded to mean differences of -1.00% (-1.22% to -0.79%) for 1 mg,
-1.67% (-1.88% to -1.46%) for 5 mg, -1.83% (-2.04% to -1.61%) for 10 mg, and -1.89% (-2.11% to -1.67%) for 15 mg. Posterior mean differences for change in HbA1c were also significantly different in the 5 mg (-0.52%), 10 mg (-0.67%) and 15 mg (-0.73%) intervention groups when compared to patients that received dulaglutide. At 26 weeks of follow-up, 33-90% of patients treated with LY3298176 achieved a HbA1c target <7.0% compared to 52% of patients in the dulaglutide group and 12% of patients from the placebo group. In addition, 14-71% of those treated with LY3298176 achieved the weight loss target of at least 5% as compared to 22% of patients in the dulaglutide group and 0% of patients in the placebo group. The 12-week outcomes were like those at 26 weeks for all secondary outcomes. Gastrointestinal events (nausea, diarrhea, and vomiting) were the most common treatment-emergent adverse events in the intervention groups. This study therefore indicates that this dual GIP and GLP-1 receptor agonist shows better efficacy with regard to glucose control and weight loss than dulaglutide and may thus represent a new treatment option in the management of type 2 diabetes.
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