Abstract
BackgroundWeight loss therapy is becoming more and more important, and two classes of molecules, namely amylin receptor and GLP-1 receptor agonists, have shown promise in this regard. Interestingly, these molecules have several overlapping pharmacological effects, such as suppression of gastric emptying, reduction of glucagon secretion and weight loss in common; however, they also have distinct effects on prandial insulin secretion. Hence, a combination of these two mechanisms is of significant interest.MethodsIn this study, we investigated the add-on potential of the dual amylin and calcitonin receptor agonist (DACRA) KBP-089 in combination with the GLP-1 receptor agonist liraglutide as obesity treatment in high-fat diet (HFD) fed rats.ResultsIncreasing doses of KBP-089 and liraglutide alone and in combination were studied with respect to their effects on body weight, food intake and glucose metabolism during a 9-week intervention study conducted in HFD rats. Further, the gastric emptying rate during an oral glucose tolerance was assessed. Treatment with KBP-089 and liraglutide dose-dependently lowered body weight 15% (at 2.5 μg/kg/day) and 7% (at 400 μg/kg/day) in HFD rats, respectively, while the combination resulted in a 21% body weight reduction, which was mirrored by reduction in fat depot sizes. Gastric emptying and glucose metabolism were improved, primarily by KBP-089, although liraglutide led to a reduction in fasting plasma glucagon.ConclusionDACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.
Highlights
Weight loss therapy is becoming more and more important, and two classes of molecules, namely amylin receptor and Glucagon-like peptide 1 (GLP-1) receptor agonists, have shown promise in this regard
Multiple GLP-1 agonists are approved for treatment of type 2 diabetes and recently high dose liraglutide was approved for treatment of obesity, as it promotes sustained weight loss via effects on satiety and appetite [5, 39]
GLP-1 and amylin analogues have several overlapping pharmacological effects including marked reductions in food intake, delay of gastric emptying and inhibition of glucagon secretion, they act through different sites and mechanisms of action [36]
Summary
Weight loss therapy is becoming more and more important, and two classes of molecules, namely amylin receptor and GLP-1 receptor agonists, have shown promise in this regard. These molecules have several overlapping pharmacological effects, such as suppression of gastric emptying, reduction of glucagon secretion and weight loss in common; they have distinct effects on prandial insulin secretion. Obesity is an increasing health problem due to modern lifestyle and excessive caloric intake Multiple complications such as insulin resistance, type 2 diabetes, cardiovascular disease, cancer and non-alcoholic fatty liver disease, among others, are frequently associated with obesity [11, 15, 22]. GLP-1 and amylin analogues have several overlapping pharmacological effects including marked reductions in food intake, delay of gastric emptying and inhibition of glucagon secretion, they act through different sites and mechanisms of action [36]
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