Dual GIP, GLP-1 Receptor Agonist Effective for Weight Loss, Glucose Control in T2D
To enhance the metabolic effects of GLP-1 receptor agonists, researchers used the complementary actions of another enteropancreatic hormone, glucose dependent insulinotropic polypeptide (GIP).
LY3298176, a dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptor agonist, showed significantly better efficacy than dulaglutide with regard to glucose control and weight loss in type 2 diabetes, according a study published in The Lancet.
A team of researchers sought to examine the costimulation of the GLP-1 and GIP receptors with LY3298176 compared with either placebo treatment or dulaglutide for selective GLP-1 receptor stimulation. In a double-blind randomized phase 2 study, 316 patients (53% men) with type 2 diabetes were randomly assigned once-weekly treatment with subcutaneous LY3298176 (in 1-mg, 5-mg, 10-mg, or 15-mg doses), dulaglutide (1.5 mg), or a placebo for 26 weeks. Eligible patients were age 18 to 75 years with type 2 diabetes for ≥6 months that was not adequately controlled with diet and exercise alone or metformin therapy.
The primary efficacy end point was measured by change in hemoglobin (Hb) A1c level from baseline to 26 weeks in the modified intention-to-treat population. Additional end points measured several other clinical factors, including change in fasting plasma glucose, proportion of patients reaching HbA1c target range, and waist circumference. Safety and tolerability were measured by overall adverse events.
At baseline, mean age was 57 years, average body mass index was 32.4 kg/m2, and average duration of diabetes was 9 years. At 26 weeks, the effect of LY3298176 on change in HbA1c was dose dependent and did not plateau. Mean changes from baseline in HbA1c with LY3298176 were -1.06% for 1 mg, -1.73% for 5 mg, -1.89% for 10 mg, and -1.94% for 15 mg, compared with -0.06% for placebo. Compared with dulaglutide (-1.21%), the posterior mean differences for change in HbA1c from baseline to 26 weeks with the LY3298176 doses were 0.15% for 1 mg, -0.52% for 5 mg, -0.67% for 10 mg, and -0.73% for 15 mg.
At 26 weeks, 33% to 90% of patients treated with LY3298176 achieved the HbA1c target of less than 7.0% (vs 52% with dulaglutide, 12% with placebo) and 15% to 82% achieved the HbA1c target of at least 6.5% (vs 39% with dulaglutide, 2% with placebo). Changes in fasting plasma glucose ranged from -0.4 mmol/L to -3.4 mmol/L for LY3298176 (vs 0.9 mmol/L for placebo, -1.2 mmol/L for dulaglutide). Changes in mean body weight ranged from -0.9 kg to -11.3 kg for LY3298176 (vs -0.4 kg for placebo, -2.7 kg for dulaglutide). Changes in waist circumference ranged from -2.1 cm to -10.2 cm for LY3298176 (vs -1.3 cm for placebo, -2.5 cm for dulaglutide). Safety findings for LY3298176 were similar to safety profiles of other GLP-1 receptor agonists.
Limitations to the study included the small homogenous study population and short duration, which may have restricted evaluation of long-term glycemic and weight loss effects.
The researchers concluded that “combined GIP and GLP-1 receptor stimulation might offer a new therapeutic option in the treatment of type 2 diabetes.”
Frias JP, Nauck MA, Van J, et al. Efficacy and safety of LY3298176, a novel dual GIP and GLP-1 receptor agonist, in patients with type 2 diabetes: a randomized, placebo-controlled and active comparator-controlled phase 2 trial [published online October 4, 2018]. Lancet. doi:10.1016/S0140-6736(18)32260-8