The Role of Dipeptidyl Peptidase – 4 Inhibitors in Diabetic Kidney Disease

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

ACS Pharmacology & Translational Science ◽

10.1021/acsptsci.0c00097 ◽

2020 ◽

Vol 3 (5) ◽

pp. 1020-1022

Author(s):

Chhanda Charan Danta

Keyword(s):

Kidney Disease ◽

Therapeutic Target ◽

Diabetic Kidney Disease ◽

Dipeptidyl Peptidase ◽

Potential Therapeutic Target ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4

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Correction: The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin

Clinical Science ◽

10.1042/cs20180031_cor ◽

2019 ◽

Vol 133 (1) ◽

pp. 151-151

Author(s):

Keizo Kanasaki

Keyword(s):

Kidney Disease ◽

Dipeptidyl Peptidase ◽

Renal Effects ◽

Dipeptidyl Peptidase 4 ◽

Dipeptidyl Peptidase 4 Inhibitors

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Sitagliptin ameliorates ER stress in diabetic kidney disease through upregulation of SIRT1

Diabetic Nephropathy ◽

10.2478/dine-2021-0007 ◽

2021 ◽

Vol 1 (1) ◽

pp. 33-41

Author(s):

Qunzi Zhang ◽

Junjie Jia ◽

Li He ◽

Ying Fan ◽

Niansong Wang

Keyword(s):

Kidney Disease ◽

Er Stress ◽

Diabetic Kidney Disease ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4 ◽

Beneficial Effects ◽

Er Homeostasis

Abstract Objectives Endoplasmic reticulum (ER) stress plays a significant role in the progression of diabetic kidney disease (DKD), and dipeptidyl peptidase-4 (DPP4) inhibitors are widely used antihyperglycemic agents, exerting renal beneficial effects in DKD. Here, we investigated the role of DPP4 inhibitor Sitagliptin (Sita) in ER homeostasis in the kidneys of diabetic DBA2/J (D2) mice and in albumin-stimulated HK-2 cells. Methods and Results ER stress was observed both in vivo and in vitro, as reflected by notably increased glucose-regulated protein of 78 kDa (GRP78), CHOP, high phosphorylation of PERK (p-PERK), and cleaved caspase3 (c-CASP3), whereas Sita effectively attenuated these disorders. Meanwhile, Sita increased the expression of SIRT1 both in vivo and in vitro. To further validate the potential effects of SIRT1 in regulating ER stress, we regulated SIRT1 by siRNA and overexpressed plasmids in albumin-overloaded HK-2 cells. Elevated SIRT1 alleviated albumin-induced ER stress, while decreased SIRT1 further aggravated ER stress in albumin-treated HK-2 cells. Conclusion The results suggest that a novel mechanism links the DPP4 enzyme to ER stress during tubular injury in DKD and highlight that SIRT1 may be a potential target for managing DKD.

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

Journal of Diabetes Research ◽

10.1155/2021/7382620 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Thananda Trakarnvanich ◽

Bancha Satirapoj ◽

Swangjit Suraamornkul ◽

Thanit Chirananthavat ◽

Anoma Sanpatchayapong ◽

...

Keyword(s):

Kidney Disease ◽

Vascular Calcification ◽

Diabetic Kidney Disease ◽

Controlled Trial ◽

Kidney Injury ◽

Dipeptidyl Peptidase ◽

Control Group ◽

Fatty Acid Binding ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4

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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Incretins in the Therapy of Diabetic Kidney Disease

International Journal of Molecular Sciences ◽

10.3390/ijms222212312 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12312

Author(s):

Agnieszka Przezak ◽

Weronika Bielka ◽

Andrzej Pawlik

Keyword(s):

Kidney Disease ◽

Diabetic Kidney Disease ◽

Oral Glucose ◽

Antidiabetic Drug ◽

Diabetic Kidney ◽

Dipeptidyl Peptidase 4 ◽

Drug Classes ◽

Increased Risk ◽

Dipeptidyl Peptidase 4 Inhibitors ◽

Patients With Diabetes

Diabetic kidney disease is a microvascular complication that occurs in patients with diabetes. It is strongly associated with increased risk of kidney replacement therapy and all-cause mortality. Incretins are peptide hormones derived from the gastrointestinal tract, that besides causing enhancement of insulin secretion after oral glucose intake, participate in many other metabolic processes. Antidiabetic drug classes, such as dipeptidyl peptidase 4 inhibitors and glucagon-like peptide receptor agonists, which way of action is based on incretins facility, not only show glucose-lowering properties but also have nephroprotective functions. The aim of this article is to present the latest information about incretin-based therapy and its influence on diabetic kidney disease appearance and progression, point its potential mechanisms of kidney protection and focus on future therapeutic possibilities bound with these two antidiabetic drug classes.

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