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Clinical Trial
. 2025 Apr 25;24(1):182.
doi: 10.1186/s12933-025-02679-8.

The effect of empagliflozin on peripheral microvascular dysfunction in patients with heart failure with preserved ejection fraction

Sanne G J Mourmans  1 , Anouk Achten  1 , Raquel Hermans  1 , Marijne J E Scheepers  1 , Elisa D'Alessandro  2 , Geertje Swennen  2 , Janneke Woudstra  3 , Yolande Appelman  3 , Harry van Goor  4 , Casper Schalkwijk  5 , Christian Knackstedt  1 , Jerremy Weerts  1 , Etto C Eringa #  2   6 , Vanessa P M van Empel #  7
Affiliations
Clinical Trial

The effect of empagliflozin on peripheral microvascular dysfunction in patients with heart failure with preserved ejection fraction

Sanne G J Mourmans et al. Cardiovasc Diabetol. .

Abstract

Background: Empagliflozin is an effective treatment for heart failure with preserved ejection fraction (HFpEF), but its definite mechanism of action is unclear. Systemic microvascular dysfunction strongly relates to HFpEF aetiology, and we hypothesised that empagliflozin improves microvascular function in HFpEF.

Objective: To investigate the effect of the sodium-glucose cotransporter-2 inhibitor empagliflozin on peripheral microvascular function in HFpEF.

Methods: This is a pre-post intervention study in patients diagnosed with HFpEF who are eligible for treatment with empagliflozin. Microvascular function assessment using laser speckle contrast analysis of the dorsal forearm during iontophoresis of vasoactive stimuli (acetylcholine, insulin sodium nitroprusside) was performed at baseline and after 3 months of empagliflozin treatment (10 mg daily). The primary outcome was the difference in blood flow measured in the forearm microvasculature between baseline and at follow-up (cutaneous vascular conductance, CVC). Secondarily we investigated quality-of-life based on the EQ-5D-5 L questionnaire at baseline and follow-up.

Results: Twenty six patients finished the study according to protocol (mean age of 74 ± 7 years, 62% female). We observed a decreased blood flow response to acetylcholine after 3 months of empagliflozin (CVC: 0.77 ± 0.24 vs. 0.64 ± 0.20, p < 0.001). In contrast, the response to insulin improved (CVC: 0.61 ± 0.43 vs. 0.81 ± 0.32, p = 0.03), and the response to sodium nitroprusside remained stable after 3 months. No significant correlations were found between the changes in blood flow and quality of life.

Conclusion: This study shows that three months treatment with empagliflozin changed peripheral microvascular function in patients with HFpEF. Empagliflozin may enhance microvascular blood flow specifically via vascular actions of insulin, rather than a general effect on endothelial vasoregulation or smooth muscle cell function. As such, systemic microvascular dysfunction can be a modifiable factor in patients with HFpEF, while the clinical implications thereof warrant further investigations.

Trial registration: The trial was preregistered at clinicaltrials.gov (NCT06046612).

Keywords: Acetylcholine; Endothelial function; Heart failure; Insulin; Laser speckle contrast analysis; Microcirculation; Nitroprusside; SGLT-2 inhibitor.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study complies with the declaration of Helsinki and was approved by the Medical Ethics Committee University Hospital Maastricht/ Maastricht University as a low-intervention clinical trial according to the Clinical Trial Regulation (EU CT 2022-501682-45). All patients provided written informed consent before enrolment. Consent for publication: Not applicable. Competing interests: V.P.M.v.E received sponsoring/grants from Roche, Vifor Pharma, Boehringer Ingelheim, Astra Zeneca and Pfizer (paid to institute), and received consultancy fees from Novartis, Janssen, Boehringer Ingelheim, Novonordisk (paid to institute).Pfizer and Astra Zeneca provided an unrestricted research grant to Maastricht University Medical Centre.C.K. received consulting fees from Pfizer, Novartis, BMS, and Alnylam (paid to institute).J.W. received grants from Corvia Medical, CSL Vifor, and Boehringer Ingelheim and is a member of the scientific committee on Atrial Disorders of the Heart Failure Association of the European society of cardiology.

Figures

Fig. 1
Fig. 1
Example measurement for laser speckle contrast analysis during iontophoresis of insulin
Fig. 2
Fig. 2
Study flow diagram. *Applicable to acetylcholine and sodium nitroprusside analyses. N = 25 for insulin per protocol analysis, due to 1 non-valid measurement. ** Applicable to acetylcholine and sodium nitroprusside analyses. N = 35 for insulin intention to treat analysis, due to 2 non-valid measurements
Fig. 3
Fig. 3
Changes in cutaneous vascular conductance at baseline and after 3 months of empagliflozin treatment. The results are shown during iontophoresis of acetylcholine (A), insulin (B) and sodium nitroprusside (SNP; C)
Fig. 4
Fig. 4
Endothelin levels before and after empagliflozin treatment in HFpEF patients. A Endothelin levels in plasma before (baseline) and after 3 months of empagliflozin treatment. B–D Correlations between changes in plasma ET-1 during empagliflozin treatment and skin blood flow stimulated by insulin (B), acetylcholine (C) and sodium nitroprusside (D). CVC Cutaneous vascular conductance
Fig. 5
Fig. 5
Adiponectin levels before and after empagliflozin treatment in HFpEF patients. A Adiponectin levels in plasma before (baseline) and after 3 months of empagliflozin treatment. B–D Correlations between changes in plasma ET-1 during empagliflozin treatment and skin blood flow stimulated by insulin (B), acetylcholine (C) and sodium nitroprusside (D). CVC Cutaneous vascular conductance
Fig. 6
Fig. 6
Patients reporting moderate or severe problems of EQ-5D-5 L dimensions at baseline and 3 months follow-up
See this image and copyright information in PMC

References

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