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.

van Ruiten CC, Smits MM, Kok MD, Serné EH, van Raalte DH, Kramer MHH, Nieuwdorp M, IJzerman RG

Cardiovascular diabetology28 Apr 2022Cited by 36 (Europe PMC)

PMID35484607PMCIDPMC9052512DOI10.1186/s12933-022-01492-xPepBankPUB-35484607

Summary

BackgroundSodium-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.MethodsSixty-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.ResultsAfter 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.ConclusionsThe 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.

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study7

2 results from studies that gave the peptide. 2 results from people.

01HumanRandomized controlled trialMechanism
In people with diabetes, exenatide did not affect systolic blood pressure versus placebo.
In plain wordsIn people with diabetes, exenatide did not affect systolic blood pressure versus placebo.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeSystolic blood pressure
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Blood pressure · Cardiovascular
Studied dose
10 µg twice daily · 10 days and 16 weeksAs given in this study (human).
Source sentences
Summary
Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
Show in the study text Report a problemFND-3548460701
02HumanRandomized controlled trialMechanism
In people with diabetes, exenatide reduced parasympathetic activity versus placebo after 10 days and 16 weeks.
In plain wordsIn people with diabetes, exenatide reduced parasympathetic activity versus placebo after 10 days and 16 weeks.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseParasympathetic nervous system activity
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Receptor activity and mechanism · Cardiovascular
Studied dose
10 µg twice daily · 10 days and 16 weeksAs given in this study (human).
Source sentences
Summary
Exenatide had no effect on SBP, but reduced parasympathetic nervous system activity after 10 days and 16 weeks.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
Show in the study text Report a problemFND-3548460702

Studies that did not test the peptide alone5

In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Exenatide (exendin-4).

03HumanNot a test of Exenatide (exendin-4) aloneRandomized controlled trialMechanism
In people with diabetes, dapagliflozin-exenatide reduced systolic blood pressure versus placebo after 10 days.
In plain wordsIn people with diabetes, dapagliflozin-exenatide reduced systolic blood pressure versus placebo after 10 days.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseSystolic blood pressure at 10 days
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Blood pressure · Cardiovascular
Measurements
Systolic blood pressure change
−4.2 mmHg
combination at 10 days
Source sentences
Summary
After 10 days, dapagliflozin-exenatide reduced SBP by - 4.2 mmHg, and reduced plasma volume.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-3548460703
04HumanNot a test of Exenatide (exendin-4) aloneRandomized controlled trialMechanism
In people with diabetes, dapagliflozin-exenatide reduced plasma volume versus placebo after 10 days.
In plain wordsIn people with diabetes, dapagliflozin-exenatide reduced plasma volume versus placebo after 10 days.
Peptide
Exenatide (exendin-4)
Outcome
DecreasePlasma volume at 10 days
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
After 10 days, dapagliflozin-exenatide reduced SBP by - 4.2 mmHg, and reduced plasma volume.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-3548460704
05HumanNot a test of Exenatide (exendin-4) aloneRandomized controlled trialMechanism
In people with diabetes, dapagliflozin-exenatide reduced systolic blood pressure versus placebo after 16 weeks.
In plain wordsIn people with diabetes, dapagliflozin-exenatide reduced systolic blood pressure versus placebo after 16 weeks.
Peptide
Exenatide (exendin-4)
Outcome
DecreaseSystolic blood pressure at 16 weeks
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Blood pressure · Cardiovascular
Measurements
Systolic blood pressure change
−6.8 mmHg
combination at 16 weeks
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-3548460705
06HumanNot a test of Exenatide (exendin-4) aloneRandomized controlled trialMechanism
In people with diabetes, dapagliflozin-exenatide reduced plasma volume versus placebo after 16 weeks.
In plain wordsIn people with diabetes, dapagliflozin-exenatide reduced plasma volume versus placebo after 16 weeks.
Peptide
Exenatide (exendin-4)
Outcome
DecreasePlasma volume at 16 weeks
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-3548460706
07HumanNot a test of Exenatide (exendin-4) aloneRandomized controlled trialMechanism
In people with diabetes, dapagliflozin-exenatide did not affect sympathetic activity versus placebo after 16 weeks.
In plain wordsIn people with diabetes, dapagliflozin-exenatide did not affect sympathetic activity versus placebo after 16 weeks.
Peptide
Exenatide (exendin-4)
Outcome
No significant changeSympathetic nervous system activity at 16 weeks
Study
n: not reported in source
Comparator
Placebo
Analysis
Secondary
Outcome group
Receptor activity and mechanism · Cardiovascular
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
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.
Summary · context
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.
In this study, Exenatide (exendin-4) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Exenatide (exendin-4).
Show in the study text Report a problemFND-3548460707

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials1

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

1 trial · 1 completed · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 4NCT03361098

DECREASE: Dapagliflozin Plus Exenatide on Central REgulation of Appetite in diabeteS typE 2

Amsterdam UMC, location VUmcn = 6518 Sept 2017 to 25 Mar 2020

Type 2 Diabetes Mellitus · Obesity

Trial page ClinicalTrials.govUpdated 11 Jun 2021

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
22 Oct 2026, 02:26 UTC
Study results updated
Version 1
21 Oct 2026, 18:59 UTC
First added · source update from Europe PMC

Subjects

Terms as the source lists them.

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