Amylin and GLP-1 agonism induce a well-known anorexic effect at dose initiation, which is managed by dose escalation. In this study, we investigated how to optimize tolerability, while maintaining efficacy of KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in HFD rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro, demonstrated a prolonged receptor activation, and potently reduced acute food intake. HFD rats dosed every or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and bodyweight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 transiently reduced food intake at every escalation step - with reducing magnitude over time - and the following treatment with 2.5, 10 and 40 µg/kg resulted in a ~15% vehicle corrected weight loss, a corresponding reduction in adipose tissue (AT), and all treatment groups improved oral glucose tolerance (p<0.01). Two-fold and linear escalations suppressed bodyweight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered bodyweight 8% and 2% in HFD rats, respectively, while the combination resulted in a 12% bodyweight reduction. Moreover, the combination improved glucose tolerance (p<0.05) In conclusion, DACRAs act complementary with GLP-1 on food intake and bodyweight. Furthermore, upon escalation KBP-089 was well tolerated, induced and sustained a significant weight loss and a reduction in AT in lean and HFD rats, underscoring the potential of KBP-089 as an anti-obesity agent.