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Effect of dipeptidyl peptidase‐4 inhibitors on complement activation
Author(s) -
HoffmannPetersen Ingeborg T.,
Holt Charlotte B.,
Jensen Lisbeth,
Hage Camilla,
Mellbin Linda G.,
Thiel Steffen,
Hansen Troels K.,
Østergaard Jakob A.
Publication year - 2021
Publication title -
diabetes/metabolism research and reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.307
H-Index - 110
eISSN - 1520-7560
pISSN - 1520-7552
DOI - 10.1002/dmrr.3385
Subject(s) - lectin pathway , complement system , dipeptidyl peptidase 4 , dipeptidyl peptidase , sitagliptin , chemistry , pharmacology , in vivo , mannan binding lectin , serine protease , lectin , biochemistry , classical complement pathway , immune system , diabetes mellitus , immunology , protease , biology , enzyme , endocrinology , type 2 diabetes , microbiology and biotechnology
Background Adverse activation of the complement cascade in the innate immune system appears to be involved in development of vascular complications in diabetes. Dipeptidyl peptidase‐4 (DPP‐4) is a cell surface serine protease expressed in a variety of tissues. DPP‐4 inhibitors are widely used in treatment of type 2 diabetes and appear to yield beneficial pleiotropic effects beyond their glucose‐lowering action, for example, renoprotective and anti‐inflammatory properties, but the exact mechanisms remain unknown. We hypothesised that DPP‐4 inhibitors block adverse complement activation by inhibiting complement‐activating serine proteases. Materials and methods We analysed the effects of 7 different DPP‐4 inhibitors on the lectin and classical pathway of the complement system in vitro by quantifying complement factor C4b deposition onto mannan or IgG coated surfaces, respectively. Furthermore, plasma concentrations of mannan‐binding lectin (MBL), soluble membrane attack complex (sMAC), and C4b deposition were quantified in 71 patients with a recent acute coronary syndrome and glucose disturbances, randomly assigned to sitagliptin 100 mg ( n = 34) or placebo ( n = 37) for 12 weeks. Results All the 7 DPP‐4 inhibitors tested in the study directly inhibited functional activity of the lectin pathway in a dose‐dependent manner with varying potency in vitro. In vivo, MBL, sMAC, and C4b declined significantly during follow‐up in both groups without significant effect of sitagliptin. Conclusions We demonstrated an inhibitory effect of DPP‐4 inhibitors on the lectin pathway in vitro. The clinical relevance of this effect of DPP‐4 inhibitors remains to be fully elucidated.