Renal safety profile of di-peptidyl-peptidase inhibitors: a review of available literature

Arindam Dey, Unnikrishanan A.G., Gaurav Saxena, Rishi Jain


Diabetic Nephropathy has become the single most import cause of End Stage Renal Disease (ESRD). Various strategies to limit or slow the progress the Diabetic nephropathy are suggested by the guidelines and evidences. By maintaining strict glycemic control the progression of diabetic nephropathy can be altered. Glycemic control in diabetic patients with nephropathy is complex as falling eGFR renders many ant diabetic medications contraindicated while others are needed to be done in low dose. The intent of this review article is to collate the available evidences for renal safety with one such anti diabetic class of medication, dipeptidyl peptidase 4 inhibitor and evaluate the guideline based antidiabetic treatment in Type 2 Diabetes Mellitus patients with renal insufficiency. 


DPP4 inhibitor, Diabetic Kidney Disease, Linagliptin, Saxagliptin, Sitagliptin, Vildagliptin

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International diabetes federation; diabetes Atlas 2015 seventh edition; 2015:11.

ADA. Microvascular complications and foot care. Sec. 9. In standards of medical care in diabetes - 2015. Diabetes Care. 2015;38:S58-66.

Gerich JE. Physiology of glucose homeostasis. Diabetes Obes Metab. 2000;2(6):345-50.

Zanchia A. Antidiabetic drugs and kidney disease Recommendations of the Swiss Society for Endocrinology and Diabetology Swiss Med Wkly. 2012;142:w13629.

KDOQI (Kidney Disease Outcomes Quality Initiative). Clinical Practice Guideline for Diabetes and CKD: Am J Kidney Dis. 2012;60:850-86.

EDIC. Sustained effect of intensive treatment of type 1 diabetes mellitus on development and progression of diabetic nephropathy: the Epidemiology of Diabetes Interventions and Complications (EDIC) study. JAMA. 2003;290:2159-67.

Rabkin R, Ryan MP, Duckworth WC. The renal metabolism of insulin. Diabetologia. 1984;27:351-7.

Hecking M, Werzowa J, Haidinger M. Novel views on newonset diabetes after transplantation: Development, prevention and treatment. Nephrol Dial Transplant. 2013;28:550-66.

Sharif A. Metformin for patients with diabetes and concomitant renal restrictions-is there an evidence base? QJM. 2013;106:291-94.

Sambol NC, Chiang J, Lin ET, Goodman AM, Liu CY, Benet LZ, et al. Kidney function and age are both predictors of pharmacokinetics of metformin. J Clin Pharmacol. 1995;35:1094-102.

Holstein A, Plaschke A, Hammer C, Ptak M, Kuhn J, Kratzsch C, et al. Hormonal counterregulation and consecutive glimepiride serum concentrations during severe hypoglycaemia associated with glimepiride therapy. Eur J Clin Pharmacol. 2003;59:747-54.

Tjeerd Van S, Abenhaim L, Monette J. Rates of hypoglycemia in users of sulfonylureas, Journal of Clinical Epidemiology. 1997;50(6):735-41.

Inoue T, Shibahara N, Miyagawa K, Itahana R, Izumi M, Nakanishi T, et al. Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. Clin Nephrol. 2003;60:90-5.

Hasslacher C. Safety and efficacy of repaglinide in type 2 diabetic patients with and without impaired renal function. Diabetes Care. 2003;26:886-91.

Kalra S. Sodium Glucose Co-Transporter-2 (SGLT2) Inhibitors: A Review of Their Basic and Clinical Pharmacology. Diabetes Ther. 2014;5:355-66.

Efficacy and safety of dipeptidyl peptidase-4 inhibitors in type 2 diabetes mellitus patients with moderate to severe renal impairment: a systematic review and meta-analysis PLoS One. 2014 Oct;9(10):e111543.

Glorie LL, Verhulst A, Matheeussen V, Baerts L, Magielse J, et al. DPP4 inhibition improves functional outcome after renal ischemia-reperfusion injury, associated with antiapoptotic, immunological, and antioxidative changes. Am J Physiol Renal Physiol. 2012;303:F681-8.

Joo KW, Kim S, Ahn SY, Chin HJ, Chae DW. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in rat remnant kidney. BMC Nephrol. 2013;14:98.

Herman GA, Stevens C, Van Dyck K. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, doubleblind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78:675-88.

Bergman AJ, Stevens C, Zhou Y. Pharmacokinetic and pharmacodynamic properties of multiple oral doses of sitagliptin, a dipeptidyl peptidase-IV inhibitor: a double-blind, randomized, placebocontrolled study in healthy male volunteers. Clin Ther. 2006;28:55-72.

Bergman AJ, Cote J, Bingming Yi. Effect of Renal Insufficiency on the Pharmacokinetics of Sitagliptin, a Dipeptidyl Peptidase-4 Inhibitor Diabetes Care 2007 Jul;30(7):1862-4.

Eligar VS, Bain SC. A review of sitagliptin with special emphasis on its use in moderate to severe renal impairment. Drug design, development and therapy. 2013;7:893.

Jacob A. Udell, Deepak L. Bhatt, Eugene Braunwald, Matthew A. Cavende Saxagliptin and Cardiovascular Outcomes in Patients With Type 2 Diabetes and Moderate or Severe Renal Impairment: Observations From the SAVOR-TIMI 53 Trial Diabetes Care 2015 Apr;38(4):696-705.

Boulton D, Li L, Frevert EU. Influence of Renal or Hepatic Impairment on the Pharmacokinetics of Saxagliptin Clin Pharmacokinet. 2011;50:253.

Pi-Sunyer FX, Schweizer A, Mills D, Dejager S. Efficacy and tolerability of vildagliptin monotherapy in drug naïve patients with type 2 diabetes. Diabetes Res Clin Pract. 2007;76:132-8.

Bosi E, Camisasca RP, Collober C, Rochotte E, Garber AJ. Effects of vildagliptin on glucose control over 24 weeks in patients with type 2 diabetes inadequately controlled with metformin. Diabetes Care. 2007;30:890-5.

Pratley RE, Jauffret-Kamel S, Galbreath E, Holmes D. Twelve-week monotherapy with the DPP-4 inhibitor vildagliptin improves glycemic control in subjects with type 2 diabetes. Horm Metab Res. 2006;38:423-8.

Pratley RE, Rosenstock J, Pi-Sunyer FX, Banerji MA, Schweizer A, Couturier A et al. Management of type 2 diabetes in treatment-naive elderly patients: benefits and risks of vildagliptin monotherapy Diabetes Care. 2007;30:3017-22.

Villhauer EB, Brinkman JA, Naderi GB, Burkey BF, Dunning BE, Prasad K, et al. 1-[(3-hydroxy-1-adamantyl)amino]acetyl]-2-cyano-(S)-pyrrolidine: a potent, selective, and orally bioavailable dipeptidyl peptidase IV inhibitor with antihyperglycemic properties. J Med Chem. 2003;46:2774-89.

He YL, Sabo R, Campestrini J, Wang Y, Ligueros-Saylan M, Lasseter KC, et al. The influence of hepatic impairment on the pharmacokinetics of the dipeptidyl peptidase IV (DPP-4) inhibiton vildagliptin. Eur J Clin Pharmacol. 2007;63:677-86.

Hocher, Berthold, Reichetzeder C, Markus L. Alter. Renal and cardiac effects of DPP4 inhibitors-from preclinical development to clinical research. Kidney and Blood Pressure Research. 2012;36(1):65-84.

Kothny W, Shao Q, Groop PH, Lukashevich V. One-year safety, tolerability and efficacy of vildagliptin in patients with type 2 diabetes and moderate or severe renal impairment. Diabetes Obes Metab. 2012;14:1032-9.

Banerji MA, Purkayastha D, Francis BH. Safety and tolerability of vildagliptin vs. thiazolidinedione as add-on to metformin in type 2 diabetic patients with and without mild renal impairment: a retrospective analysis of the GALIANT study. Diabetes research and clinical practice. 2010;90(2):182-90.

Lukashevich V, Schweizer A, Shao Q, Groop PH, Kothny W. Safety and efficacy of vildagliptin versus placebo in patients with type 2 diabetes and moderate or severe renal impairment: a prospective 24-week randomized placebo-controlled trial. Diabetes Obes Metab. 2011;13:947-54.

Christensen M, Vedtofte L, Holst JJ, Vilsbøll T, Knop FK. Glucose-dependent insulinotropic polypeptide: a bifunctional glucose-dependent regulator of glucagon and insulin secretion in humans. Diabetes. 2011;60:3103-9.

Boehringer Ingelheim Pharmaceuticals Inc. Tradjenta. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc, 2013. Available from: Accessed 9 November 2013Servlet.ser?docBase=renetnt&folderPath=/Prescribing+Information/PIs/Tradjenta/Tradjenta.pdf.

Groop PH, Del Prato S, Taskinen MR, Owens DR, Gong Y, Crowe S, et al. Linagliptin treatment in subjects with type 2 diabetes with and without mild-to-moderate renal impairment. Diabetes Obes Metab. 2014;16:560-8.

Janet B. McGill, Lance Sloan, Jennifer Newman, Sanjay Patel Long-Term Efficacy and Safety of Linagliptin in Patients With Type 2 Diabetes and Severe Renal Impairment Diabetes Care 2013 Feb;36(2):237-44.

Graefe-Mody U, Friedrich C, Port A, Ring A, Retlich S, Heise T, et al. Effect of renal impairment on the pharmacokinetics of the dipeptidyl peptidase-4 inhibitor linagliptin(*). Diabetes Obes Metab. 2011;13:939-46.

Chang YT, Wu JL, Hsu CC, Wang JD, Sung JM. Diabetes and end-stage renal disease synergistically contribute to increased incidence of cardiovascular events: a nationwide follow-up study during 1998-2009. Diabetes Care. 2014;37:277-85.

Matsui T, Nishino Y, Takeuchi M, Yamagishi S. Vildagliptin blocks vascular injury in thoracic aorta of diabetic rats by suppressin advanced glycation end product-receptor axis. Pharmacol Res. 2011;63:383-8.

Schweizer A, Dejager S, Foley JE, Couturier A, Ligueros-Saylan M, Kothny W. Assessing the cardiocerebrovascular safety of vildagliptin: meta-analysis of adjudicated events from a large Phase III type 2 diabetes population. Diabetes Obes Metab. 2010;12:485-94.