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

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.

Overall and inter‐individual effect of four different drug classes on soluble urokinase plasminogen activator receptor in type 1 and type 2 diabetes

“…One previous study has investigated the effect of the sodiumglucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, on suPAR levels in an acute setting and after 12 weeks of treatment. 8 In that study, no overall effect of the treatment was found, despite the reports of possible anti-inflammatory effects of SGLT2 inhibitors seen in other studies. 9,10 The effects of kidney protective medications on urinary albumin excretion, the "gold standard" marker of early kidney damage in diabetes, have been shown to be highly variable.…”

“…We have previously published a study in which the effect of dapagliflozin, an SGLT2 inhibitor, on plasma suPAR levels 12 hours after intake, and after 12 weeks of treatment, was investigated, but no overall effect on suPAR was demonstrated. 8 Another previous study investigating the effect of 8 weeks of treatment with renin-angiotensin system blockade on urinary suPAR levels, however, showed a significant decrease compared to placebo in people with type 2 diabetes. 24 The drug classes investigated in this trial have large differences in their mode of action and in the tissues in which they are activealthough complete characterizations of their effects are still lacking.…”

“…While similar studies are warranted before causality can be determined in other diseases and complications, these results reveal the need to further explore the role of suPAR as not only a risk marker, but a treatment target as well. We have previously published a study in which the effect of dapagliflozin, an SGLT2 inhibitor, on plasma suPAR levels 12 hours after intake, and after 12 weeks of treatment, was investigated, but no overall effect on suPAR was demonstrated 8 . Another previous study investigating the effect of 8 weeks of treatment with renin‐angiotensin system blockade on urinary suPAR levels, however, showed a significant decrease compared to placebo in people with type 2 diabetes 24 …”

“…One previous study has investigated the effect of the sodium‐glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, on suPAR levels in an acute setting and after 12 weeks of treatment 8 . In that study, no overall effect of the treatment was found, despite the reports of possible anti‐inflammatory effects of SGLT2 inhibitors seen in other studies 9,10 …”