The Dual Amylin and Calcitonin Receptor Agonist, KBP-066, Induces an Equally Potent Weight Loss Across a Broad Dose Range While Higher Doses May Further Improve Insulin Action

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 a novel, highly potent dual amylin and calcitonin receptor agonist (DACRA), KBP-089. Furthermore, we tested the GLP-1 add-on potential of KBP-089 in high-fat diet (HFD)-fed rats. KBP-089 potently activated both the amylin and calcitonin receptors in vitro and demonstrated a prolonged receptor activation as well as a potent reduction of acute food intake. HFD rats dosed every day or every second day obtained equal weight loss at study end, albeit with an uneven reduction in both food intake and body weight in rats dosed every second day. In a 4-fold dose escalation, KBP-089 induced a transient reduction in 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 an ~15% vehicle-corrected weight loss, a corresponding reduction in adipose tissue (AT), and, in all treatment groups, improved oral glucose tolerance ( P < 0.01). Twofold and linear escalations suppressed body weight evenly with no significant reduction in food intake at either escalation step. KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) reduced 24-h food intake by 29% and 37% compared with vehicle, respectively; however, when they were combined, 24-h food intake was reduced by 87%. Chronically, KBP-089 (1.25 µg/kg) and liraglutide (50 µg/kg) lowered body weight 8% and 2% in HFD rats, respectively, whereas the combination resulted in a 12% body weight reduction. Moreover, the combination improved glucose tolerance ( P < 0.05). In conclusion, DACRAs act complementarily with GLP-1 on food intake and body weight. Furthermore, on escalation, KBP-089 was well tolerated and 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.

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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

BMC Endocrine Disorders ◽

10.1186/s12902-020-00678-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Anna Thorsø Larsen ◽

Sofie Gydesen ◽

Nina Sonne ◽

Morten Asser Karsdal ◽

Kim Henriksen

Keyword(s):

Weight Loss ◽

Body Weight ◽

Gastric Emptying ◽

Food Intake ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Weight Reduction ◽

Receptor Agonist ◽

Calcitonin Receptor ◽

Body Weight Reduction

Abstract Background 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. 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. Methods In 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. Results Increasing 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. Conclusion DACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.

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A novel dual amylin and calcitonin receptor agonist, KBP-089, induces weight loss through a reduction in fat, but not lean mass, while improving food preference

British Journal of Pharmacology ◽

10.1111/bph.13723 ◽

2017 ◽

Vol 174 (7) ◽

pp. 591-602 ◽

Cited By ~ 22

Author(s):

Sofie Gydesen ◽

Sara Toftegaard Hjuler ◽

Zenia Freving ◽

Kim Vietz Andreassen ◽

Nina Sonne ◽

...

Keyword(s):

Weight Loss ◽

Lean Mass ◽

Receptor Agonist ◽

Food Preference ◽

Calcitonin Receptor

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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

10.21203/rs.3.rs-39438/v2 ◽

2020 ◽

Author(s):

Anna Thorsø Larsen ◽

Sofie Gydesen ◽

Nina Sonne ◽

Morten Asser Karsdal ◽

Kim Henriksen

Keyword(s):

Weight Loss ◽

Body Weight ◽

Gastric Emptying ◽

Food Intake ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Weight Reduction ◽

Receptor Agonist ◽

Calcitonin Receptor ◽

Body Weight Reduction

Abstract Background: 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. 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. Methods: In 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. Results: Increasing 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. Conclusion: DACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.

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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

10.21203/rs.3.rs-39438/v3 ◽

2021 ◽

Author(s):

Anna Thorsø Larsen ◽

Sofie Gydesen ◽

Nina Sonne ◽

Morten Asser Karsdal ◽

Kim Henriksen

Keyword(s):

Weight Loss ◽

Body Weight ◽

Gastric Emptying ◽

Food Intake ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Weight Reduction ◽

Receptor Agonist ◽

Calcitonin Receptor ◽

Body Weight Reduction

Abstract Background: 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. 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. Methods: In 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. Results: Increasing 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. Conclusion: DACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.

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KBP-066A, a Long-Acting Dual Amylin and Calcitonin Receptor Agonist, Induces Weight Loss and Improves Glycemic Control in Obese and Diabetic Rats

Molecular Metabolism ◽

10.1016/j.molmet.2021.101282 ◽

2021 ◽

pp. 101282

Author(s):

K.V. Andreassen ◽

A.T. Larsen ◽

N. Sonne ◽

K.E. Mohamed ◽

M.A. Karsdal ◽

...

Keyword(s):

Weight Loss ◽

Glycemic Control ◽

Receptor Agonist ◽

Diabetic Rats ◽

Calcitonin Receptor ◽

Long Acting

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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

10.21203/rs.3.rs-39438/v1 ◽

2020 ◽

Author(s):

Anna Thorsø Larsen ◽

Sofie Gydesen ◽

Nina Sonne ◽

Morten Asser Karsdal ◽

Kim Henriksen

Keyword(s):

Weight Loss ◽

Body Weight ◽

Gastric Emptying ◽

Food Intake ◽

Glucose Metabolism ◽

Glucose Tolerance ◽

Weight Reduction ◽

Receptor Agonist ◽

Calcitonin Receptor ◽

Body Weight Reduction

Abstract Background 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. 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. Methods In 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. Results Increasing 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. Conclusion DACRAs complement GLP-1 on food intake, body weight, and glucose tolerance indicating the potential for an add-on therapy.

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