The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy
Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled...
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MDPI AG
2022-09-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/10/2365 |
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| author | Nina Sonne Anna Thorsø Larsen Morten Asser Karsdal Kim Henriksen |
| author_facet | Nina Sonne Anna Thorsø Larsen Morten Asser Karsdal Kim Henriksen |
| author_sort | Nina Sonne |
| collection | DOAJ |
| description | Background: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles. Methods: To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague–Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats. Results: KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control. Conclusion: different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar. |
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| id | doaj.art-6425aa391afa4888abc1d5be6ca5c1f1 |
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| language | English |
| last_indexed | 2024-03-09T20:39:50Z |
| publishDate | 2022-09-01 |
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| series | Biomedicines |
| spelling | doaj.art-6425aa391afa4888abc1d5be6ca5c1f12023-11-23T23:01:53ZengMDPI AGBiomedicines2227-90592022-09-011010236510.3390/biomedicines10102365The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist TherapyNina Sonne0Anna Thorsø Larsen1Morten Asser Karsdal2Kim Henriksen3Nordic BioscienceA/S, Department of Endocrinology, Herlev Hovedgade 205-207, 2730 Herlev, DenmarkNordic BioscienceA/S, Department of Endocrinology, Herlev Hovedgade 205-207, 2730 Herlev, DenmarkNordic BioscienceA/S, Department of Endocrinology, Herlev Hovedgade 205-207, 2730 Herlev, DenmarkNordic BioscienceA/S, Department of Endocrinology, Herlev Hovedgade 205-207, 2730 Herlev, DenmarkBackground: Dual Amylin and Calcitonin Receptor Agonists (DACRAs) are treatment candidates for obesity and type 2 diabetes. Recently, a once-weekly DACRA (KBP-A) showed promise, potentially due to its different exposure profile compared to daily DACRA (KBP). Parathyroid hormone, a G-protein-coupled receptor (GPCR) class B agonist, is an example of the exposure profile being critical to the effect. Since KBP and KBP-A also activate GPCR class B, we compared the effects of injection to continuous infusion of short-acting KBP and long-acting KBP-A in obese and diabetic rats to shed light on the role of exposure profiles. Methods: To explore the metabolic benefits of dose optimization, the following dosing profiles were compared in High Fat Diet (HFD)-fed Sprague–Dawley rats and diabetic Zucker Diabetic Fatty (ZDF) rats: (1) KBP dosed once-daily by injection or by continuous infusion in HFD and ZDF rats; (2) KBP injected once-daily and KBP-A injected once every 3rd day (Q3D) in HFD rats; (3) KBP-A injected Q3D or by infusion in ZDF rats. Results: KBP and KBP-A, delivered by either injection or infusion, resulted in similar weight and food intake reductions in HFD rats. In ZDF rats, injection of KBP improved glucose control significantly compared to infusion, while delivery of KBP-A by injection and continuous infusion was comparable in terms of glucose control. Conclusion: different dosing profiles of KBP and KBP-A had no impact on metabolic benefits in HFD rats. In diabetic ZDF rats, KBP by injection instead of infusion was superior, while for KBP-A the effects were similar.https://www.mdpi.com/2227-9059/10/10/2365DACRAGPCRobesitytype 2 diabetespreclinical |
| spellingShingle | Nina Sonne Anna Thorsø Larsen Morten Asser Karsdal Kim Henriksen The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy Biomedicines DACRA GPCR obesity type 2 diabetes preclinical |
| title | The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy |
| title_full | The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy |
| title_fullStr | The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy |
| title_full_unstemmed | The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy |
| title_short | The Impact of Exposure Profile on the Efficacy of Dual Amylin and Calcitonin Receptor Agonist Therapy |
| title_sort | impact of exposure profile on the efficacy of dual amylin and calcitonin receptor agonist therapy |
| topic | DACRA GPCR obesity type 2 diabetes preclinical |
| url | https://www.mdpi.com/2227-9059/10/10/2365 |
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