Combined Amylin/GLP-1 pharmacotherapy to promote and sustain long-lasting weight loss

Abstract

A growing appreciation of the overlapping neuroendocrine mechanisms controlling energy balance has highlighted combination therapies as a promising strategy to enhance sustained weight loss. Here, we investigated whether amylin- and glucagon-like-peptide-1 (GLP-1)-based combination therapies produce greater food intake- and body weight-suppressive effects compared to monotherapies in both lean and diet-induced obese (DIO) rats. In chow-maintained rats, systemic amylin and GLP-1 combine to reduce meal size. Furthermore, the amylin and GLP-1 analogs salmon calcitonin (sCT) and liraglutide produce synergistic-like reductions in 24 hours energy intake and body weight. The administration of sCT with liraglutide also led to a significant enhancement in cFos-activation in the dorsal-vagal-complex (DVC) compared to mono-therapy, suggesting an activation of distinct, yet overlapping neural substrates in this critical energy balance hub. In DIO animals, long-term daily administration of this combination therapy, specifically in a stepwise manner, results in reduced energy intake and greater body weight loss over time when compared to chronic mono- and combined-treated groups, without affecting GLP-1 receptor, preproglucagon or amylin-receptor gene expression in the DVC.

The Dual Amylin and Calcitonin Receptor Agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile 

“…During OGTT, both short and longterm treatment with KBP-089 improved glucose tolerance in accordance with previous studies performed with KBP-089 (Gydesen, Andreassen, 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, consistent with the study by Liberini et al (2019). Importantly, along with improved glucose clearance, signi cantly lower insulin levels during OGTT were observed in KBP-089 (1.25 and 2.5 µg/kg) and combination therapy groups, indicating improved insulin sensitivity.…”

“…the dorsal-vagal-complex (DVC), which contains the area postrema and the nucleus tractus solitarius (Liberini et al, 2019). These studies showed a combined effect of SCT and liraglutide on c-fos activation in the DVC, consistent with a combined suppression of food intake and gastric emptying (Liberini et al, 2019;. Furthermore, earlier work indicated that this effect may entail a local upregulation of brain IL-6 in the hypothalamus, by both amylin and GLP-1 (Jansson and Palsdottir, 2015).…”

“…These studies have highlighted that both amylin and GLP-1 activate receptors in the same areas of the hind brain, i.e. the dorsal-vagal-complex (DVC), which contains the area postrema and the nucleus tractus solitarius (Liberini et al, 2019). These studies showed a combined effect of SCT and liraglutide on c-fos activation in the DVC, consistent with a combined suppression of food intake and gastric emptying (Liberini et al, 2019;.…”

“…The inhibited gastric emptying can positively affect postprandial blood glucose levels by delaying entry of glucose into circulation, a central factor in diabetes treatment. From a mechanistic point-of-view, a series of studies have looked into co-administration of either amylin or the DACRA salmon calcitonin (SCT) in combination with incretin-based therapies (Liberini et al, 2019;Bello et al, 2010;. These studies have highlighted that both amylin and GLP-1 activate receptors in the same areas of the hind brain, i.e.…”

The dual amylin and calcitonin receptor agonist KBP-089 and the GLP-1 receptor agonist liraglutide act complimentarily on body weight reduction and metabolic profile

“…The inhibited gastric emptying can positively affect postprandial blood glucose levels by delaying entry of glucose into circulation, a central factor in diabetes treatment. From a mechanistic point-of-view, a series of studies have looked into co-administration of either amylin or the DACRA salmon calcitonin (SCT) in combination with incretin-based therapies [ 4 , 12 , 28 ]. These studies have highlighted that both amylin and GLP-1 activate receptors in the same areas of the hind brain, i.e.…”