1011-P: Therapeutic Potential of Novel Combination of a Long-Acting Glucagon Analog (HM15136) and Antidiabetic Drugs for the Treatment of Obesity

The obesity epidemic represents a major challenge for public health. However, existing anti-obesity drugs have limited efficacy because they only suppress appetite, emphasizing the development of next generation therapeutic option. Recently, we showed that prolonged glucagon (GCG) receptor activation with HM15136, a long-acting GCG analog, could provide potent body weight loss (BWL) in obese animal models. Considering the stimulatory effect of GCG on glucose production, transient blood glucose (BG) elevation might be important when utilizing HM15136 as a novel anti-obesity drug. Antidiabetic drugs such as metformin, and DPP-4 inhibitor have been widely used for T2DM patients. Considering their safety profile and treatment adherence in addition to BG lowering nature, we hypothesized that combination of antidiabetic drugs might minimize the transient BG elevation by HM15136 and confer additional BWL. To investigate this hypothesis, the present study evaluated the combination effect of HM15136 and antidiabetic medication on BG and BW in vivo. In normal mice, HM15136-induced BG increase was effectively reversed by concomitant treatment of metformin, sitagliptin, or empagliflozin. To further confirm, DIO mice were chronically administered with HM15136 and/or antidiabetic drugs, and normal BG control was continuously maintained in COMBO groups. These results indicate that when combined, antidiabetic drugs could effectively counteract the transient BG elevation by HM15136. As to the BWL efficacy, combination of HM15136 either with metformin, sitagliptin, or empagliflozin provided additional BWL (-18% to -31% by metformin COMBO; -35% to -47% by sitagliptin COMBO; -35% to -40% by empagliflozin COMBO), highlighting the therapeutic benefit of this novel combination.

In conclusion, our results demonstrate the prolonged GCG receptor stimulation with antidiabetic medication as a novel therapeutic option for obesity treatment.