Dipeptidyl Peptidase-4: A Potential Therapeutic Target in Diabetic Kidney Disease with SARS-CoV-2 Infection

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.

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DIPEPTIDYL-PEPTIDASE 4 INHIBITORS DID NOT IMPROVE RENAL ENDPOINTS IN ADVANCED DIABETIC KIDNEY DISEASE

Endocrine Practice ◽

10.4158/ep-2020-0143 ◽

2020 ◽

Vol 26 (12) ◽

pp. 1486-1496

Author(s):

Edy Kornelius ◽

Chien-Ning Huang ◽

Shih-Chang Lo ◽

Yu-Hsun Wang ◽

Yi-Sun Yang

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Dipeptidyl Peptidase ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4 ◽

Urine Albumin ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Stage Renal Disease ◽

End Stage

Objective: The efficacy of dipeptidyl-peptidase 4 inhibitors (DPP4is) in advanced diabetic kidney disease (DKD) is unknown. We investigated whether DPP4is confer renal protective benefits in DKD patients. Methods: We conducted a retrospective cohort study between 2012 and 2018 in Taiwan. We only included type 2 diabetes patients with estimated glomerular filtration rate (eGFR) between 30 and 90 mL/min/1.73 m2 and urine albumin to creatinine ratio between 300 and 5,000 mg/g. Patients with DPP4i prescriptions were selected as cases, while non-DPP4i users served as controls. We followed these patients until the presence of composite primary renal endpoints, which was defined by the earliest occur-rence of clinical renal outcomes. Results: A total of 522 patients were included in the analysis, comprising 273 patients with a DPP4i prescription who were selected as cases and 249 patients without DPP4i prescription who were assigned as controls. Median follow-up duration for DPP4i users and nonusers was 2.2 years and 3.4 years, respectively. At baseline, the mean glycated hemoglobin levels for DPP4i users and nonusers were 8.1% and 8.3%, respectively. Among patients with DPP4i prescriptions, there was no reduction in composite primary renal outcome, with a crude hazard ratio (HR) of 1.50 (95% confidence interval [CI], 0.95 to 2.36). Similar results were observed for the risk of persistent eGFR <15 mL/min/1.73 m2, with a HR of 1.68 (95% CI, 0.90 to 3.13), doubling of serum creatinine level, with a HR of 1.05 (95% CI, 0.15 to 7.45), and end-stage renal disease, with a HR of 0.87 (95% CI, 0.14 to 5.19). Conclusion: DPP4i prescription did not reduce the risk of composite renal endpoints in DKD patients. Abbreviations: BMI = body mass index; CI = confidence interval; CVOT = cardiovascular outcomes trial; DPP4i = dipeptidyl-peptidase 4 inhibitor; DKD = diabetic kidney disease; eGFR = estimated glomerular filtration rate; ESRD = end-stage renal disease; HbA1c = glycated hemoglobin; HR = hazard ratio; SGLT2i = sodium-glucose cotransporter 2 inhibitor; T2D = type 2 diabetes; UACR = urine albumin to creatinine ratio

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Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon-like peptide 1 and dipeptidyl peptidase 4

Experimental Physiology ◽

10.1113/expphysiol.2014.078766 ◽

2014 ◽

Vol 99 (9) ◽

pp. 1140-1145 ◽

Cited By ~ 15

Author(s):

Volker Vallon ◽

Neil G. Docherty

Keyword(s):

Kidney Disease ◽

Sodium Excretion ◽

Diabetic Kidney Disease ◽

Urinary Sodium Excretion ◽

Dipeptidyl Peptidase ◽

Urinary Sodium ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4 ◽

Glucagon Like Peptide ◽

Glucagon Like Peptide 1

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Serotonin and Its Receptor as a New Antioxidant Therapeutic Target for Diabetic Kidney Disease

Journal of Diabetes Research ◽

10.1155/2017/7680576 ◽

2017 ◽

Vol 2017 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

Yu Yang ◽

Hui Huang ◽

Zheng Xu ◽

Jun-kai Duan

Keyword(s):

Oxidative Stress ◽

Kidney Disease ◽

Therapeutic Target ◽

Diabetic Kidney Disease ◽

Vascular Complications ◽

Controlled Clinical Trials ◽

Potential Therapeutic Target ◽

Diabetic Kidney ◽

Diabetic Vascular Complications ◽

Physiological Pathways

Diabetic kidney disease (DKD) is a widespread chronic microvascular complication of diabetes mellitus (DM), affects almost 30–50% of patients, and represents a leading cause of death of DM. Serotonin or 5-hydroxytryptamine (5-HT) is a multifunctional bioamine that has crucial roles in many physiological pathways. Recently, emerging evidence from experimental and clinical studies has demonstrated that 5-HT is involved in the pathogenesis of diabetic vascular complications. The 5-HT receptor (5-HTR) antagonists exert renoprotective effects by suppressing oxidative stress, suggesting that 5-HTR can be used as a potential target for treating DKD. In this review, therefore, we summarize the published information available for the involvement of 5-HT and 5-HTR antagonists in the pathogenesis of various diabetic complications with a particular focus of DKD. We conclude that 5-HTR is a potential therapeutic target for treating DKD, as it has been successfully applied in animal models and has currently being investigated in randomized and controlled clinical trials.

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