Effect of dapagliflozin on collectins and complement activation in plasma from patients with type 2 diabetes and albuminuria: Data from the DapKid cohort

Mia Jensen, Mie K. Eickhoff, Frederik Persson, Peter Rossing, Steffen Thiel, Søren Hansen, Yaseelan Palarasah, Per Svenningsen, Boye Lagerbon Jensen

Research output: Contribution to journalJournal articleResearchpeer-review

Abstract

Background: Sodium-glucose cotransporter 2 (SGLT- 2) inhibitors exert cardiovascular and kidney-protective effects in people with diabetes. Attenuation of inflammation could be important for systemic protection. The lectin pathway of complement system activation is linked to diabetic nephropathy. We hypothesized that SGLT-2 inhibitors lower the circulating level of pattern-recognition molecules of the lectin cascade and attenuate systemic complement activation. Methods: Analysis of paired plasma samples from the DapKid crossover intervention study where patients with type 2 diabetes mellitus (T2DM) and albuminuria were treated with dapagliflozin and placebo for 12 weeks (10 mg/day, n=36). ELISA was used to determine concentrations of collectin kidney 1 (CL-K1), collectin liver 1 (CL-L1), mannose-binding lectin (MBL), MBL-associated serine protease 2 (MASP-2), the anaphylatoxin complement factor 3a (C3a), the stable C3 split product C3dg and the membrane attack complex (sC5b-9). Results: As published before, dapagliflozin treatment lowered Hba 1C from 74 (14.9) mmol/mol to 66 (13.9) mmol/mol (p<0.0001), and the urine albumin/creatinine ratio from 167.8 mg/g to 122.5 mg/g (p<0.0001). Plasma concentrations of CL-K1, CL-L1, MBL, and MASP-2 did not change significantly after dapagliflozin treatment (P>0.05) compared to placebo treatment. The plasma levels of C3a (P<0.05) and C3dg (P<0.01) increased slightly but significantly, 0.6 [0.2] units/mL and 76 [52] units/mL respectively, after dapagliflozin treatment. The C9-associated neoepitope in C5b-9 did not change in plasma concentration by dapagliflozin (P>0.05). Conclusion: In patients with type 2 diabetes and albuminuria, SGLT-2 inhibition resulted in modest C3 activation in plasma, likely not driven by primary changes in circulating collectins and not resulting in changes in membrane attack complex. Based on systemic analyses, organ-specific local protective effects of gliflozins against complement activation cannot be excluded.

Original languageEnglish
Article number152797
JournalImmunobiology
Volume229
Issue number3
Number of pages6
ISSN0171-2985
DOIs
Publication statusPublished - 15. Mar 2024

Keywords

  • Albuminuria
  • Complement system
  • Lectin cascade
  • SGLT-2 inhibitor
  • Type 2 diabetes mellitus

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