In this article we present data underlining the potential of combination therapy for obesity with the DACRA KBP-089 and the GLP-1 analog.
In general, combination therapies are showing promise in the treatment of metabolic disorders, such as obesity, NASH and T2DM, including the combination of GLP-1 and amylin therapy (Roth et al., 2012). These agonists have several overlapping effects, although the mechanisms of action might differ (Roth et al., 2012; Jansson and Palsdottir, 2015). A previous study in non-human primates suggested a synergistic reduction in food intake when combining GLP-1 and amylin agonism (Bello et al., 2010). In addition, the combination of sub-optimal doses of the DACRA, KBP-089, and the GLP-1 agonist liraglutide was recently shown to act complementarily (Gydesen, Andreassen, et al., 2017). Therefore, we studied the combination of KBP-089 with liraglutide at their individual maximum efficacious doses.
In this study, we found a significant effect on appetite suppression and body weight loss when combining the two peptides over a period of nine weeks, an effect superior to either monotherapy alone. Importantly, this also manifested in reduction in food efficiency and overall adiposity. Generally, KBP-089 was superior to liraglutide therapy, and the effects on body weight and food intake dose dependently followed KBP-089 concentrations when combing the two therapies. This suggests that KBP-089 is responsible for the majority of the efficacy of the combination therapy. These findings correspond well with earlier observations using lower doses of the two peptides (Gydesen, Andreassen, et al., 2017), and demonstrate an additive effect.
In terms of glucoregulatory actions both amylin receptor agonism (Ratner et al., 2004; Ryan et al., 2009; Mack et al., 2011) and GLP-1R agonism (Vilsbøll et al., 2007; Klein et al., 2014; Van Can et al., 2014) have shown potential. However, the glucose-lowering effect of GLP-1 receptor agonists involves increased post-prandial insulin secretion (Vilsbøll et al., 2008; Ladenheim, 2015). During OGTT, both short and long-term treatment with KBP-089 improved glucose tolerance in accordance with previous studies performed with KBP-089 (Gydesen, Andreassen, et al., 2017; Gydesen, Hjuler, et al., 2017). Interestingly, the effect on blood glucose during OGTT was especially pronounced in combination therapy groups, particularly after eight weeks of treatment, supporting that the peptides act though complimentary pathways, and possibly that the combination leads to increased durability of the glucoregulatory effects compared to stand-alone treatment. Importantly, along with improved glucose clearance, significantly lower plasma insulin levels were observed in KBP-089 (1.25 and 2.5 µg/kg) and combination therapy groups, indicating improved insulin sensitivity. This together with the significant weight loss suggest potential not only as anti-obesity therapy, but also in treatment of obesity related co-morbidities such as type 2 diabetes and NASH (Kahn et al., 2006; Guh et al., 2009; Milić et al., 2014). Surprisingly, liraglutide did not increase plasma insulin as expected for a GLP-1 receptor agonist. Other studies in obese rats found similar lack of liraglutide induced increase in plasma insulin during OGTT (Raun et al., 2007; Gydesen, Andreassen, et al., 2017), suggesting that the lack of effect observed here might be explained by the animal model that is non-diabetic. Plasma glucagon levels were assessed after 8 weeks of treatment. All treatments, except liraglutide (200 µg/kg), tended towards a lowering of fasting plasma glucagon levels compared to vehicle. Though, all treatment groups had nearly constant glucagon levels during OGTT and no significant differences between groups were observed. This suggests that the HFD rat model does not show inappropriate elevated glucagon levels as seen in diabetic conditions and might explain why there is no clear effect of the therapies post glucose challenge.
GLP-1 and amylin analogues are both known to delay gastric emptying (Roth et al., 2012), hence gastric emptying rates were assessed. In accordance with earlier studies using DACRAs (Hjuler et al., 2015, 2016), KBP-089 (2.5 µg/kg) markedly reduced gastric emptying after both short- and long-term treatment. A similar effect was observed in the group receiving high-dose combination therapy. Perhaps surprisingly, liraglutide alone only had minor effect on gastric emptying, even trending towards increasing vehicle-corrected gastric emptying after 8 weeks of treatment. Several clinical studies have shown that chronic treatment with liraglutide delays gastric emptying (Flint et al., 2011; Horowitz et al., 2012; Van Can et al., 2014). However, in a pre-clinical setting the ability of liraglutide to reduce gastric emptying markedly diminished within 14 days of treatment, explaining the lack of effect observed here (Jelsing et al., 2012). The inhibited gastric emptying can positively affect postprandial blood glucose levels by delaying entry of glucose into circulation, a central factor in diabetes treatment. Overall, the weight lowering and glucoregulatory actions of both the mono- and the combination therapies might be limited by the fact that the HFD rat model does not have indications of insulin resistance and seems to have reached their maximal weight loss. Therefore, further studies in a diabetic model would be of importance.
In conclusion, KBP-089 acts complementary with the GLP-1 analogue, liraglutide, on food consumption, weight loss and glucose tolerance, indicating the potential for an add-on therapy causing additional improvement in metabolic profile.