Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial
Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely...
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| Format: | Article |
| Language: | English |
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BMC
2022-04-01
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| Series: | Cardiovascular Diabetology |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12933-022-01492-x |
| _version_ | 1828336515293380608 |
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| author | Charlotte C. van Ruiten Mark M. Smits Megan D. Kok Erik H. Serné Daniël H. van Raalte Mark H. H. Kramer Max Nieuwdorp Richard G. IJzerman |
| author_facet | Charlotte C. van Ruiten Mark M. Smits Megan D. Kok Erik H. Serné Daniël H. van Raalte Mark H. H. Kramer Max Nieuwdorp Richard G. IJzerman |
| author_sort | Charlotte C. van Ruiten |
| collection | DOAJ |
| description | Abstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely understood. The aim of this study was to assess the mechanisms underlying the BP reduction with the SGLT2i dapagliflozin, GLP-1RA exenatide, and dapagliflozin-exenatide compared with placebo in people with obesity and type 2 diabetes. Methods Sixty-six people with type 2 diabetes were randomized to 16 weeks of dapagliflozin 10 mg/day, exenatide 10 µg twice daily, dapagliflozin-exenatide, or placebo treatment. The effect of treatments on estimates of: (1) plasma volume (calculated by Strauss formula, bioimpedance spectroscopy, hematocrit, (2) autonomic nervous system activity (heart rate variability), (3) arterial stiffness (pulse wave applanometry), (4) systemic hemodynamic parameters including peripheral vascular resistance, cardiac output and stroke volume (all derived from non-invasively systemic hemodynamic monitoring), and (5) natriuresis (24-hour urine collection) were assessed after 10 days and 16 weeks of treatment. Results After 10 days, dapagliflozin reduced systolic BP (SBP) by − 4.7 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin reduced SBP by − 4.4 mmHg, and reduced sympathetic nervous system (SNS) activity. Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks. After 10 days, dapagliflozin-exenatide reduced SBP by − 4.2 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin-exenatide reduced SBP by − 6.8 mmHg, and the reduction in plasma volume was still observed, but SNS activity was unaffected. Conclusions The dapagliflozin-induced plasma volume contraction may contribute to the initial SBP reduction, while a reduction in SNS activity may contribute to the persistent SBP reduction. Dapagliflozin-exenatide resulted in the largest decrease in SBP. The effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, therefore other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, which need further investigation. Trial registration Clinicaltrials.gov, NCT03361098. |
| first_indexed | 2024-04-13T22:01:50Z |
| format | Article |
| id | doaj.art-2f213ea61ef843a7a51f21a2f65b1f70 |
| institution | Directory Open Access Journal |
| issn | 1475-2840 |
| language | English |
| last_indexed | 2024-04-13T22:01:50Z |
| publishDate | 2022-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Cardiovascular Diabetology |
| spelling | doaj.art-2f213ea61ef843a7a51f21a2f65b1f702022-12-22T02:28:04ZengBMCCardiovascular Diabetology1475-28402022-04-0121111210.1186/s12933-022-01492-xMechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trialCharlotte C. van Ruiten0Mark M. Smits1Megan D. Kok2Erik H. Serné3Daniël H. van Raalte4Mark H. H. Kramer5Max Nieuwdorp6Richard G. IJzerman7Department of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterDepartment of Internal Medicine, Diabetes Center, Amsterdam University Medical Center, Location VU University Medical CenterAbstract Background Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) lower blood pressure (BP). When SGLT2i and GLP-1RA are combined, synergistic effects on BP have been observed. The mechanisms underlying these BP reductions are incompletely understood. The aim of this study was to assess the mechanisms underlying the BP reduction with the SGLT2i dapagliflozin, GLP-1RA exenatide, and dapagliflozin-exenatide compared with placebo in people with obesity and type 2 diabetes. Methods Sixty-six people with type 2 diabetes were randomized to 16 weeks of dapagliflozin 10 mg/day, exenatide 10 µg twice daily, dapagliflozin-exenatide, or placebo treatment. The effect of treatments on estimates of: (1) plasma volume (calculated by Strauss formula, bioimpedance spectroscopy, hematocrit, (2) autonomic nervous system activity (heart rate variability), (3) arterial stiffness (pulse wave applanometry), (4) systemic hemodynamic parameters including peripheral vascular resistance, cardiac output and stroke volume (all derived from non-invasively systemic hemodynamic monitoring), and (5) natriuresis (24-hour urine collection) were assessed after 10 days and 16 weeks of treatment. Results After 10 days, dapagliflozin reduced systolic BP (SBP) by − 4.7 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin reduced SBP by − 4.4 mmHg, and reduced sympathetic nervous system (SNS) activity. Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks. After 10 days, dapagliflozin-exenatide reduced SBP by − 4.2 mmHg, and reduced plasma volume. After 16 weeks, dapagliflozin-exenatide reduced SBP by − 6.8 mmHg, and the reduction in plasma volume was still observed, but SNS activity was unaffected. Conclusions The dapagliflozin-induced plasma volume contraction may contribute to the initial SBP reduction, while a reduction in SNS activity may contribute to the persistent SBP reduction. Dapagliflozin-exenatide resulted in the largest decrease in SBP. The effect on plasma volume was comparable to dapagliflozin monotherapy, and SNS activity was not reduced, therefore other mechanisms are likely to contribute to the blood pressure lowering effect of this combination, which need further investigation. Trial registration Clinicaltrials.gov, NCT03361098.https://doi.org/10.1186/s12933-022-01492-xSGLT2 inhibitorDapagliflozinGLP-1 receptor agonistExenatideType 2 diabetesBlood pressure |
| spellingShingle | Charlotte C. van Ruiten Mark M. Smits Megan D. Kok Erik H. Serné Daniël H. van Raalte Mark H. H. Kramer Max Nieuwdorp Richard G. IJzerman Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial Cardiovascular Diabetology SGLT2 inhibitor Dapagliflozin GLP-1 receptor agonist Exenatide Type 2 diabetes Blood pressure |
| title | Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial |
| title_full | Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial |
| title_fullStr | Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial |
| title_full_unstemmed | Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial |
| title_short | Mechanisms underlying the blood pressure lowering effects of dapagliflozin, exenatide, and their combination in people with type 2 diabetes: a secondary analysis of a randomized trial |
| title_sort | mechanisms underlying the blood pressure lowering effects of dapagliflozin exenatide and their combination in people with type 2 diabetes a secondary analysis of a randomized trial |
| topic | SGLT2 inhibitor Dapagliflozin GLP-1 receptor agonist Exenatide Type 2 diabetes Blood pressure |
| url | https://doi.org/10.1186/s12933-022-01492-x |
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