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. 2022 Apr 27:13:799915.
doi: 10.3389/fphar.2022.799915. eCollection 2022.

Acute and Long-Term Treatment With Dapagliflozin and Association With Serum Soluble Urokinase Plasminogen Activator Receptor

Viktor Rotbain Curovic  1 , Morten B Houlind  2 , Tine W Hansen  1 , Jesper Eugen-Olsen  2 , Jens Christian Laursen  1 , Mie K Eickhoff  1 , Frederik Persson  1 , Peter Rossing  1   3
Affiliations

Acute and Long-Term Treatment With Dapagliflozin and Association With Serum Soluble Urokinase Plasminogen Activator Receptor

Viktor Rotbain Curovic et al. Front Pharmacol. .

Abstract

Background: Elevated soluble urokinase plasminogen activator receptor (suPAR) is highly associated with increased risk of diabetic complications. Dapagliflozin is a drug inhibiting the sodium-glucose co-transporter 2 in the kidney to decrease blood glucose, while also decreasing risk of kidney disease, heart failure, and death. Therefore, we have investigated suPAR as a monitor for treatment effect with dapagliflozin in diabetes. Methods: suPAR was measured in two double-blinded randomized clinical cross-over trials. The first trial investigated the effect of a single dose dapagliflozin 50 mg or placebo 12 h after intake, in individuals with type 1 diabetes and albuminuria. The second trial investigated the effect of a daily dose dapagliflozin 10 mg or placebo for 12 weeks, in individuals with type 2 diabetes and albuminuria. suPAR was measured in serum samples taken, in the acute trial, after treatment with dapagliflozin and placebo, and in the long-term trial, before and after treatment with dapagliflozin and placebo. Effect of dapagliflozin on suPAR levels were assessed using paired t-test. Results: 15 participants completed the acute trial and 35 completed the long-term trial. Mean difference in suPAR between dapagliflozin and placebo in the acute trial after 12 h was 0.70 ng/ml (95% CI: 0.66; 1.33, p = 0.49). In the long-term trial the mean difference was 0.06 ng/ml (95% CI -0.15; 0.27, p = 0.57). Conclusion: Based on our findings we conclude that suPAR is not a feasible marker to monitor the effect of treatment with dapagliflozin. Thus, a further search of suitable markers must continue.

Keywords: biomarker; clinical trial; inflammation; randomized controlled trial; soluble urokinase receptor; suPAR; type 1 diabetes; type 2 diabetes.

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Conflict of interest statement

T.W.H. reports having equity interest in Novo Nordisk. J.E.O is CSO, cofounder and shareholder in ViroGates, and is named inventor on patents on suPAR, owned by Copenhagen University Hospital Hvidovre, Denmark. F.P. reports having received research grants from AstraZeneca, Novo Nordisk and Novartis and lecture fees from Novartis, Eli Lilly, MSD, AstraZeneca, Sanofi, Novo Nordiskand Boehringer Ingelheim and having served as a consultant for Astra Zeneca, Bayer, Amgen, Novo Nordisk and MSD. P.R. reports giving lectures for AstraZeneca, Bayer, Novo Nordisk, Merck, and Boehringer Ingelheim; serving as a consultant for AbbVie, AstraZeneca, Bayer, Eli Lilly, Boehringer Ingelheim, Astellas, Gilead, Mundipharma, and Novo Nordisk, with all fees given to Steno Diabetes Center Copenhagen; and having equity interest in Novo Nordisk. All other authors report no competing interests. There is no external funding to declare. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Violin plots visualizing the distribution of soluble urokinase plasminogen activator receptor (suPAR) in the acute and long-term trials. In the acute trial suPAR levels 12 h after treatment with a single dose of 50 mg dapagliflozin are shown. In the long-term trial suPAR level is shown at baseline, after 12 weeks treatment with dapagliflozin 10 mg daily, and after 12 weeks treatment with placebo. Baseline data of suPAR level was not available in the acute trial. All comparisons are performed using paired t-tests.
FIGURE 2
FIGURE 2
Correlation matrices showing Pearson’s R for all associations between soluble urokinase plasminogen activator receptor (suPAR), interleukin 6 (IL6), tumor necrosis factor alpha (TNF-a), and the primary outcomes for each trial (cortical renal oxygenation (R2-Cortex) and medullary renal oxygenation (R2-Medulla), and the CKD273 classifier, respectively), after treatment with placebo and dapagliflozin. Non-significant correlations are crossed over. Positive correlations are colored red, and negative colored blue.
See this image and copyright information in PMC

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