Effect of Dipeptidyl Peptidase-4 (DPP-4) Inhibition on Biomarkers of Kidney Injury and Vascular Calcification in Diabetic Kidney Disease: A Randomized Controlled Trial

Thananda Trakarnvanich, Bancha Satirapoj, Swangjit Suraamornkul, Thanit Chirananthavat, Anoma Sanpatchayapong, Torpong Claimon, Thananda Trakarnvanich, Bancha Satirapoj, Swangjit Suraamornkul, Thanit Chirananthavat, Anoma Sanpatchayapong, Torpong Claimon

Abstract

Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors improve glycemic control and have pleiotropic effects on kidney injury, albuminuria, and vascular inflammation, especially in animal models. We evaluated the effects of a potent DPP4 inhibitor (gemigliptin) on these processes among patients with diabetic kidney disease (DKD).

Methods: This study employed a multicenter, prospective, randomized, placebo-controlled design. A total of 201 participants were enrolled and randomly assigned to one of two groups, one received treatment with 50 mg gemigliptin daily along with standard care for diabetes mellitus for 6 months. The changes in the coronary calcium score (CAC score), cardio-ankle vascular index (CAVI), estimated glomerular filtration rate (eGFR), vascular calcification level, and tubular renal injury marker expression were evaluated at baseline and 6 months.

Results: In total, 182 patients completed the study. Significant reductions in hemoglobin A1C levels were observed in both groups. The changes in the CAC score, CAVI, eGFR, and level of proteinuria over the 6 months of the study did not significantly differ between the gemigliptin and control groups. However, biomarkers of vascular calcification, including serum bone alkaline phosphatase and kidney injury, including urine neutrophil gelatinase-associated lipocalin (NGAL)/Cr and urine liver fatty acid-binding protein (L-FABP)/Cr, were improved significantly in the gemigliptin treatment group compared with the control group. No serious adverse events were observed during the study.

Conclusion: Our study showed that gemigliptin significantly improved the expression of renal tubular injury biomarkers and vascular calcification levels among patients with DKD; however, gemigliptin did not affect renal function or coronary calcification compared with those observed in the control. A larger study with a longer follow-up is essential to verify these beneficial effects. Clinical Trials. This trial is registered with ClinicalTrials.Gov Identifier NCT04705506.

Conflict of interest statement

The authors declare that they have no competing interests.

Copyright © 2021 Thananda Trakarnvanich et al.

Figures

Figure 1
Figure 1
Enrollment, follow-up, and vital status.
Figure 2
Figure 2
Box plot indicating changes in fasting blood sugar (a) and glycated hemoglobin (b) during the trial period. Data were set on the basis of scheduled visits.
Figure 3
Figure 3
Changes in bone alkaline phosphatase in both groups at baseline and at the end of the study.
Figure 4
Figure 4
Comparisons between urine NGAL and urine NGAL factors for urine creatinine in both groups at baseline and at the end of the study.
Figure 5
Figure 5
Comparisons between urine LFABP and urine LFABP factors for urine creatinine in both groups at baseline and at the end of the study.

References

    1. Panchapakesan U., Pollock C. The role of dipeptidyl peptidase -4 inhibitors in diabetic kidney disease. Frontiers in Immunology . 2015;6:p. 443. doi: 10.3389/fimmu.2015.00443.
    1. Hwang H. J., Chung H. S., Jung T. W., et al. The dipeptidyl peptidase-IV inhibitor inhibits the expression of vascular adhesion molecules and inflammatory cytokines in HUVECs via Akt- and AMPK- dependent mechanisms. Molecular and Cellular Endocrinology . 2015;405:25–34. doi: 10.1016/j.mce.2015.01.025.
    1. Gutch M., Joshi A., Kumar S., Agarwal A., Pahan R. K., Razi S. M. Gemigliptin: newer promising gliptin for type 2 diabetes mellitus. Indian J Endocrinol Metab . 2017;21(6):898–902. doi: 10.4103/ijem.IJEM_20_17.
    1. Choi S. Y., Ryu H. M., Oh E. J., et al. Dipeptidyl peptidase-4 inhibitor gemigliptin protects against vascular calcification in an experimental chronic kidney disease and vascular smooth muscle cells. PLoS One . 2017;12(7, article e0180393) doi: 10.1371/journal.pone.0180393.
    1. Min H. S., Kim J. E., Lee M. H., et al. Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction. Laboratory Investigation . 2014;94(6):598–607. doi: 10.1038/labinvest.2014.50.
    1. Jung E., Kim J., Ho Kim S., Kim S., Cho M. H. Gemigliptin improves renal function and attenuates podocyte injury in mice with diabetic nephropathy. European Journal of Pharmacology . 2015;761:116–124. doi: 10.1016/j.ejphar.2015.04.055.
    1. Joo K. W., Kim S., Ahn S. Y., et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. BMC Nephrology . 2013;14(1) doi: 10.1186/1471-2369-14-98.
    1. Agatston A. S., Janowitz W. R., Hildner F. J., Zusmer N. R., Viamonte M., Jr., Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. Journal of the American College of Cardiology . 1990;15(4):827–832. doi: 10.1016/0735-1097(90)90282-T.
    1. Kim S. H., Yoo J. H., Lee W. J., Park C. Y. Gemigliptin: an update of its clinical use in the management of type 2 diabetes mellitus. Diabetes and Metabolism Journal . 2016;40(5):339–353. doi: 10.4093/dmj.2016.40.5.339.
    1. Solerte S. B., Di Sabatino A., Galli M., Fiorina P. Dipeptidyl peptidase-4 (DPP4) inhibition in COVID-19. Acta Diabetologica . 2020;57(7):779–783. doi: 10.1007/s00592-020-01539-z.
    1. Xu J., Wang J., He M., et al. Dipeptidyl peptidase IV (DPP-4) inhibition alleviates pulmonary arterial remodeling in experimental pulmonary hypertension. Laboratory Investigation . 2018;98(10):1333–1346. doi: 10.1038/s41374-018-0080-1.
    1. Solerte S. B., D’Addio F., Trevisan R., et al. Sitagliptin treatment at the time of hospitalization was associated with reduced mortality in patients with type 2 diabetes and COVID-19: a multicenter, case-control, retrospective, observational study. Diabetes Care . 2020;43(12):2999–3006. doi: 10.2337/dc20-1521.
    1. Malvandi A. M., Loretelli C., Ben Nasr M., Zuccotti G. V., Fiorina P. Sitagliptin favorably modulates immune-relevant pathways in human beta cells. Pharmacological Research . 2019;148:p. 104405. doi: 10.1016/j.phrs.2019.104405.
    1. Yamamoto A., Katayama Y., Tomiyama K., Hosoai H., Hirata F., Yasuda H. A short-term admission improved brachial-ankle pulse wave velocity in type 2 diabetic patients. Diabetes Research and Clinical Practice . 2005;70(3):248–252. doi: 10.1016/j.diabres.2005.04.009.
    1. Yan J., Li L., Zhang M., Cai H., Ni Z. Circulating bone-specific alkaline phosphatase and abdominal aortic calcification in maintenance hemodialysis patients. Biomarkers in Medicine . 2018;12(11):1231–1239. doi: 10.2217/bmm-2018-0089.
    1. Shantouf R., Kovesdy C. P., Kim Y., et al. Association of serum alkaline phosphatase with coronary artery calcification in maintenance hemodialysis patients. Clinical Journal of the American Society of Nephrology . 2009;4(6):1106–1114. doi: 10.2215/CJN.06091108.
    1. Tiruppathi C., Miyamoto Y., Ganapathy V., Roesel R. A., Whitford G. M., Leibach F. H. Hydrolysis and transport of proline-containing peptides in renal brush-border membrane vesicles from dipeptidyl peptidase IV-positive and dipeptidyl peptidase IV-negative rat strains. The Journal of Biological Chemistry . 1990;265(3):1476–1483. doi: 10.1016/S0021-9258(19)40041-0.
    1. Kim D. R., Lee S. Y., Kim J. S., et al. Ameliorating Effect of Gemigliptin on Renal Injury in Murine Adriamycin- Induced Nephropathy. BioMed Research International . 2017;2017 doi: 10.1155/2017/7275109.7275109
    1. Choi S. H., Leem J., Lee I. K. Protective effects of gemigliptin, a dipeptidyl peptidase-4 inhibitor, against cisplatin-induced nephrotoxicity in mice. Mediators of Inflammation . 2017;2017 doi: 10.1155/2017/4139439.4139439
    1. Satirapoj B. Tubulointerstitial biomarkers for diabetic nephropathy. Journal Diabetes Research . 2018;2018, article 2852398:p. 6. doi: 10.1155/2018/2852398.
    1. Wu J., Shao X., Lu K., et al. Urinary RBP and NGAL levels are associated with nephropathy in patients with type 2 diabetes. Cellular Physiology and Biochemistry . 2017;42(2):594–602. doi: 10.1159/000477860.
    1. Wu C., Wang Q., Lv C., et al. The changes of serum sKlotho and NGAL levels and their correlation in type 2 diabetes mellitus patients with different stages of urinary albumin. Diabetes Research and Clinical Practice . 2014;106(2):343–350. doi: 10.1016/j.diabres.2014.08.026.
    1. Kamijo A., Sugaya T., Hikawa A., et al. Urinary excretion of fatty acid-binding protein reflects stress overload on the proximal tubules. The American Journal of Pathology . 2004;165(4):1243–1255. doi: 10.1016/S0002-9440(10)63384-6.
    1. Suzuki K., Babazono T., Murata H., Iwamoto Y. Clinical significance of urinary liver-type fatty acid-binding protein in patients with diabetic nephropathy. Diabetes Care . 2005;28(8):2038–2039. doi: 10.2337/diacare.28.8.2038.
    1. Nielsen S. E., Sugaya T., Hovind P., Baba T., Parving H. H., Rossing P. Urinary liver-type fatty acid-binding protein predicts progression to nephropathy in type 1 diabetic patients. Diabetes Care . 2010;33(6):1320–1324. doi: 10.2337/dc09-2242.
    1. Han W. K., Bailly V., Abichandani R., Thadhani R., Bonventre J. V. Kidney injury molecule-1 (KIM-1): a novel biomarker for human renal proximal tubule injury. Kidney International . 2002;62(1):237–244. doi: 10.1046/j.1523-1755.2002.00433.x.
    1. Satirapoj B., Pooluea P., Nata N., Supasyndh O. Urinary biomarkers of tubular injury to predict renal progression and end stage renal disease in type 2 diabetes mellitus with advanced nephropathy: a prospective cohort study. Journal of Diabetes and its Complications . 2019;33(9):675–681. doi: 10.1016/j.jdiacomp.2019.05.013.
    1. Ichimura T., Bonventre J. V., Bailly V., et al. Kidney injury molecule-1 (KIM-1), a putative epithelial cell adhesion molecule containing a novel immunoglobulin domain, is up-regulated in renal cells after injury∗. The Journal of Biological Chemistry . 1998;273(7):4135–4142. doi: 10.1074/jbc.273.7.4135.
    1. Yoon S. A., Han B. G., Kim S. G., et al. Efficacy, safety and albuminuria-reducing effect of gemigliptin in Korean type 2 diabetes patients with moderate to severe renal impairment: a 12-week, double-blind randomized study (the GUARD Study) Diabetes, Obesity & Metabolism . 2017;19(4):590–598. doi: 10.1111/dom.12863.
    1. .

Source: PubMed

Sponsorit ja yhteistyökumppanit

Sairaudet

Huumeiden interventiot

3
Tilaa