SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial

Didde Kidmose Kristensen; Frank Holden Mose; Niels Henrik Buus; Camilla Lundgreen Duus; Frederik Husum Mårup; Jesper Nørgaard Bech; Steffen Flindt Nielsen

doi:10.1111/dom.16097

SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial

Didde Kidmose Kristensen, Frank Holden Mose, Niels Henrik Buus, Camilla Lundgreen Duus, Frederik Husum Mårup, Jesper Nørgaard Bech, Steffen Flindt Nielsen

Department of Clinical Medicine - University Clinic in Nephrology and Hypertension, Holstebro Hospital
Department of Clinical Medicine - Department of Medicine and Nephrology

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

Abstract

AIMS: The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM).

MATERIALS AND METHODS: In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well.

RESULTS: Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.

CONCLUSIONS: Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed.

TRIAL REGISTRATION: EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).

Original language	English
Journal	Diabetes, Obesity and Metabolism
Volume	27
Issue	3
Pages (from-to)	1123-1131
Number of pages	9
ISSN	1462-8902
DOIs	https://doi.org/10.1111/dom.16097
Publication status	Published - Mar 2025

Keywords

SGLT2 inhibitor
cardiovascular disease
drug mechanism
empagliflozin
randomized trial
type 2 diabetes

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10.1111/dom.16097

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@article{1ff82986e28e4ede98aebe7d50eae77a,

title = "SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial",

abstract = "AIMS: The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM).MATERIALS AND METHODS: In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well.RESULTS: Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.CONCLUSIONS: Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed.TRIAL REGISTRATION: EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).",

keywords = "SGLT2 inhibitor, cardiovascular disease, drug mechanism, empagliflozin, randomized trial, type 2 diabetes",

author = "Kristensen, {Didde Kidmose} and Mose, {Frank Holden} and Buus, {Niels Henrik} and Duus, {Camilla Lundgreen} and M{\aa}rup, {Frederik Husum} and Bech, {Jesper N{\o}rgaard} and Nielsen, {Steffen Flindt}",

note = "{\textcopyright} 2024 John Wiley & Sons Ltd.",

year = "2025",

month = mar,

doi = "10.1111/dom.16097",

language = "English",

volume = "27",

pages = "1123--1131",

journal = "Diabetes, Obesity and Metabolism",

issn = "1462-8902",

publisher = "John Wiley & Sons Inc.",

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SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial. / Kristensen, Didde Kidmose; Mose, Frank Holden ; Buus, Niels Henrik et al.
In: Diabetes, Obesity and Metabolism, Vol. 27, No. 3, 03.2025, p. 1123-1131.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes

T2 - A double-blind, randomized, placebo-controlled crossover trial

AU - Kristensen, Didde Kidmose

AU - Mose, Frank Holden

AU - Buus, Niels Henrik

AU - Duus, Camilla Lundgreen

AU - Mårup, Frederik Husum

AU - Bech, Jesper Nørgaard

AU - Nielsen, Steffen Flindt

PY - 2025/3

Y1 - 2025/3

N2 - AIMS: The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM).MATERIALS AND METHODS: In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well.RESULTS: Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.CONCLUSIONS: Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed.TRIAL REGISTRATION: EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).

AB - AIMS: The objective of this study was to examine the effects of empagliflozin on endothelium-dependent and endothelium-independent vasodilatation and systemic hemodynamic parameters and to assess the role of the nitric oxide (NO) system in patients with type 2 diabetes (T2DM).MATERIALS AND METHODS: In this double-blind, placebo-controlled cross over trial, patients with T2DM were treated with either empagliflozin 10 mg or matching placebo for 4 weeks. Following a 2-week washout, participants were crossed over to 4 weeks of the opposite treatment. Forearm blood flow (FBF) was measured after each treatment period using venous occlusion plethysmography. Acetylcholine and sodium nitroprusside (SNP) were infused into the brachial artery to assess endothelium-dependent and endothelium-independent vasodilatory function, respectively. Total peripheral resistance, 24-h blood pressure (BP) and biochemical markers of NO activity were measured as well.RESULTS: Sixteen participants completed the trial. The mean age was 68 ± 8 years, and 69% were male. The SNP response increased by 21% (geometric mean ratio 1.21, 95% CI: 1.09; 1.33) during treatment with empagliflozin compared to placebo (p ≤ 0.001), but not during acetylcholine infusion (p = 0.290). Empagliflozin decreased 24-h systolic BP by 5 mmHg (95% CI: -9; -1 mmHg) (p = 0.015), diastolic BP by 2 mmHg (95% CI: -5; 0 mmHg) (p = 0.029) and systemic vascular resistance by 48 dyn×s/m5 (95% CI: -94; -1 dyn×s/m5) (p = 0.044). Furthermore, empagliflozin reduced plasma levels of nitrite and urinary levels of NOx.CONCLUSIONS: Empagliflozin improves endothelium-independent vasodilation, reduces vascular resistance and lowers 24-h BP in patients with T2DM, whereas no change in endothelial-dependent vasodilation was observed.TRIAL REGISTRATION: EU Clinical Trials Register number: 2019-004303-12 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004303-12/DK).

KW - SGLT2 inhibitor

KW - cardiovascular disease

KW - drug mechanism

KW - empagliflozin

KW - randomized trial

KW - type 2 diabetes

UR - http://www.scopus.com/inward/record.url?scp=85210499312&partnerID=8YFLogxK

U2 - 10.1111/dom.16097

DO - 10.1111/dom.16097

M3 - Journal article

C2 - 39610328

SN - 1462-8902

VL - 27

SP - 1123

EP - 1131

JO - Diabetes, Obesity and Metabolism

JF - Diabetes, Obesity and Metabolism

IS - 3

ER -

SGLT2 inhibition improves endothelium-independent vasodilatory function in type 2 diabetes: A double-blind, randomized, placebo-controlled crossover trial

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