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DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment

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Abstract

The continuously increasing incidence of diabetes worldwide has attracted the attention of the scientific community and driven the development of a novel class of antidiabetic drugs that can be safely and effectively used in diabetic patients. Of particular interest in this context are complications associated with diabetes, such as renal impairment, which is the main cause of high cardiovascular morbidity and mortality in diabetic patients. Intensive control of glucose levels and other risk factors associated with diabetes and metabolic syndrome provides the foundations for both preventing and treating diabetic nephropathy. Dipeptidyl peptidase-4 (DPP-4) inhibitors represent a highly promising novel class of oral agents used in the treatment of type 2 diabetes mellitus that may be successfully combined with currently available antidiabetic therapeutics in order to achieve blood glucose goals. Beyond glycemic control, emerging evidence suggests that DPP-4 inhibitors may have desirable off-target effects, including renoprotection. All type 2 diabetes mellitus patients with impaired renal function require dose adjustment of any DPP-4 inhibitor administered except for linagliptin, for which renal excretion is a minor elimination pathway. Thus, linagliptin is the drug most frequently chosen to treat type 2 diabetes mellitus patients with renal failure.

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References

  1. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2014;37(Suppl 1):S81–90.

  2. Animaw W, Seyoum Y. Increasing prevalence of diabetes mellitus in a developing country and its related factors. PLoS One. 2017;12(11):e0187670-e. https://doi.org/10.1371/journal.pone.0187670.

    Article  CAS  Google Scholar 

  3. Chawla A, Chawla R, Jaggi S. Microvasular and macrovascular complications in diabetes mellitus: distinct or continuum? Indian J Endocrinol Metab. 2016;20(4):546–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Fowler MJ. Microvascular and macrovascular complications of diabetes. Clin Diabetes. 2011;29(3):116–22.

    Article  Google Scholar 

  5. Cade WT. Diabetes-related microvascular and macrovascular diseases in the physical therapy setting. Phys Ther. 2008;88(11):1322–35.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Koye DN, Shaw JE, Reid CM, Atkins RC, Reutens AT, Magliano DJ. Incidence of chronic kidney disease among people with diabetes: a systematic review of observational studies. Diabet Med. 2017;34(7):887–901.

    Article  CAS  PubMed  Google Scholar 

  7. Ashby K, Navarro Almario EE, Tong W, Borlak J, Mehta R, Chen M. Review article: therapeutic bile acids and the risks for hepatotoxicity. Aliment Pharmacol Ther. 2018;47(12):1623–38.

    Article  CAS  PubMed  Google Scholar 

  8. Ritz E, Rychlik I, Locatelli F, Halimi S. End-stage renal failure in type 2 diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis. 1999;34(5):795–808.

    Article  CAS  PubMed  Google Scholar 

  9. Patel A, MacMahon S, Chalmers J, Neal B, Billot L, Woodward M, et al. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med. 2008;358(24):2560–72.

    Article  CAS  PubMed  Google Scholar 

  10. Dreisbach AW, Lertora JJL. The effect of chronic renal failure on drug metabolism and transport. Expert Opin Drug Metab Toxicol. 2008;4(8):1065–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ibrahim S, Honig P, Huang SM, Gillespie W, Lesko LJ, Williams RL. Clinical pharmacology studies in patients with renal impairment: past experience and regulatory perspectives. J Clin Pharmacol. 2000;40(1):31–8.

    Article  CAS  PubMed  Google Scholar 

  12. Nolin T. Drug metabolism in kidney disease. In: Xie W, editor. Drug metabolism in diseases. Amsterdam: Elsevier; 2017. p. 91–113.

  13. Munar MY, Singh H. Drug dosing adjustments in patients with chronic kidney disease. Am Fam Physician. 2007;75(10):1487–96.

    PubMed  Google Scholar 

  14. Lam YW, Banerji S, Hatfield C, Talbert RL. Principles of drug administration in renal insufficiency. Clin Pharmacokinet. 1997;32(1):30–57.

    Article  CAS  PubMed  Google Scholar 

  15. Elrick H, Stimmler L, Hlad CJ Jr, Arai Y. Plasma insulin response to oral and intravenous glucose administration. J Clin Endocrinol Metab. 1964;24:1076–82.

    Article  CAS  PubMed  Google Scholar 

  16. Perley MJ, Kipnis DM. Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic sujbjects. J Clin Invest. 1967;46(12):1954–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Nauck MA, Homberger E, Siegel EG, Allen RC, Eaton RP, Ebert R, et al. Incretin effects of increasing glucose loads in man calculated from venous insulin and C-peptide responses. J Clin Endocrinol Metab. 1986;63(2):492–8.

    Article  CAS  PubMed  Google Scholar 

  18. Williams JA. GLP-1 mimetic drugs and the risk of exocrine pancreatic disease: cell and animal studies. Pancreatology. 2016;16(1):2–7.

    Article  CAS  PubMed  Google Scholar 

  19. Holst JJ. Glucagon and glucagon-like peptides 1 and 2. Results Probl Cell Differ. 2010;50:121–35.

    CAS  PubMed  Google Scholar 

  20. Brubaker PL. Glucagon-like peptide-2 and the regulation of intestinal growth and function. Compr Physiol. 2018;8(3):1185–210.

    Article  PubMed  Google Scholar 

  21. Paternoster S, Falasca M. Dissecting the physiology and pathophysiology of glucagon-like peptide-1. Front Endocrinol (Lausanne). 2018;9:584. https://doi.org/10.3389/fendo.2018.00584.

    Article  Google Scholar 

  22. Karhus ML, Bronden A, Sonne DP, Vilsboll T, Knop FK. Evidence connecting old, new and neglected glucose-lowering drugs to bile acid-induced GLP-1 secretion: a review. Diabetes Obes Metab. 2017;19(9):1214–22.

    Article  CAS  PubMed  Google Scholar 

  23. Đanić M, Stanimirov B, Pavlovic N, Golocorbin-Kon S, Al-Salami H, Stankov K, et al. Pharmacological applications of bile acids and their derivatives in the treatment of metabolic syndrome. Front Pharmacol. 2018;9:1382. https://doi.org/10.3389/fphar.2018.01382.

    Article  CAS  Google Scholar 

  24. Orskov C, Wettergren A, Holst JJ. Secretion of the incretin hormones glucagon-like peptide-1 and gastric inhibitory polypeptide correlates with insulin secretion in normal man throughout the day. Scand J Gastroenterol. 1996;31(7):665–70.

    Article  CAS  PubMed  Google Scholar 

  25. Meier JJ, Nauck MA, Kranz D, Holst JJ, Deacon CF, Gaeckler D, et al. Secretion, degradation, and elimination of glucagon-like peptide 1 and gastric inhibitory polypeptide in patients with chronic renal insufficiency and healthy control subjects. Diabetes. 2004;53(3):654–62.

    Article  CAS  PubMed  Google Scholar 

  26. Deacon CF. Peptide degradation and the role of DPP-4 inhibitors in the treatment of type 2 diabetes. Peptides. 2018;100:150–7.

    Article  CAS  PubMed  Google Scholar 

  27. Tuch BE. Clinical use of GLP-1 agonists and DPP4 inhibitors. Pancreatology. 2016;16(1):8–9.

    Article  CAS  PubMed  Google Scholar 

  28. Farilla L, Hui H, Bertolotto C, Kang E, Bulotta A, Di Mario U, et al. Glucagon-like peptide-1 promotes islet cell growth and inhibits apoptosis in Zucker diabetic rats. Endocrinology. 2002;143(11):4397–408.

    Article  CAS  PubMed  Google Scholar 

  29. Tortosa F, Dotta F. Incretin hormones and beta-cell mass expansion: what we know and what is missing? Arch Physiol Biochem. 2013;119(4):161–9.

    Article  CAS  PubMed  Google Scholar 

  30. Dalsgaard NB, Vilsboll T, Knop FK. Effects of glucagon-like peptide-1 receptor agonists on cardiovascular risk factors: a narrative review of head-to-head comparisons. Diabetes Obes Metab. 2018;20(3):508–19.

    Article  CAS  PubMed  Google Scholar 

  31. Liu L, Shao Z, Xia Y, Qin J, Xiao Y, Zhou Z, et al. Incretin-based therapies for patients with type 1 diabetes: a meta-analysis. Endocr Connect. 2019;8(3):277–88. https://doi.org/10.1530/ec-18-0546.

  32. Doupis J, Veves A. DPP4 inhibitors: a new approach in diabetes treatment. Adv Ther. 2008;25(7):627–43.

    Article  CAS  PubMed  Google Scholar 

  33. Deacon CF. Physiology and pharmacology of DPP-4 in glucose homeostasis and the treatment of type 2 diabetes. Front Endocrinol (Lausanne). 2019;10:80. https://doi.org/10.3389/fendo.2019.00080.

    Article  Google Scholar 

  34. Panchapakesan U, Pollock C. The role of dipeptidyl peptidase-4 inhibitors in diabetic kidney disease. Front Immunol. 2015;6:443. https://doi.org/10.3389/fimmu.2015.00443.

  35. Mulvihill EE, Drucker DJ. Pharmacology, physiology, and mechanisms of action of dipeptidyl peptidase-4 inhibitors. Endocr Rev. 2014;35(6):992–1019.

    Article  CAS  PubMed  Google Scholar 

  36. Mentlein R. Dipeptidyl-peptidase IV (CD26)—role in the inactivation of regulatory peptides. Regul Pept. 1999;85(1):9–24.

  37. Ryan GJ, Moniri NH, Smiley DD. Clinical effects of once-weekly exenatide for the treatment of type 2 diabetes mellitus. Am J Health Syst Pharm. 2013;70(13):1123–31.

    Article  CAS  PubMed  Google Scholar 

  38. Sisson EM. Liraglutide: clinical pharmacology and considerations for therapy. Pharmacotherapy. 2011;31(9):896–911.

    Article  CAS  PubMed  Google Scholar 

  39. Romera I, Cebrian-Cuenca A, Alvarez-Guisasola F, Gomez-Peralta F, Reviriego J. A review of practical issues on the use of glucagon-like peptide-1 receptor agonists for the management of type 2 diabetes. Diabetes Ther. 2019;10(1):5–19.

    Article  PubMed  Google Scholar 

  40. Meier JJ. GLP-1 receptor agonists for individualized treatment of type 2 diabetes mellitus. Nat Rev Endocrinol. 2012;8(12):728–42.

    Article  CAS  PubMed  Google Scholar 

  41. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev. 2008;60(4):470–512.

    Article  CAS  PubMed  Google Scholar 

  42. Scheen AJ. DPP-4 inhibitors in the management of type 2 diabetes: a critical review of head-to-head trials. Diabetes Metab. 2012;38(2):89–101.

    Article  CAS  PubMed  Google Scholar 

  43. Rohrborn D, Wronkowitz N, Eckel J. DPP4 in diabetes. Front Immunol. 2015;6:386. https://doi.org/10.3389/fimmu.2015.00386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Gallwitz B. Sitagliptin: profile of a novel DPP-4 inhibitor for the treatment of type 2 diabetes. D Drugs Today (Barc). 2007;43(1):13–25.

    Article  CAS  Google Scholar 

  45. Nabeno M, Akahoshi F, Kishida H, Miyaguchi I, Tanaka Y, Ishii S, et al. A comparative study of the binding modes of recently launched dipeptidyl peptidase IV inhibitors in the active site. Biochem Biophys Res Commun. 2013;434(2):191–6.

    Article  CAS  PubMed  Google Scholar 

  46. Berger JP, SinhaRoy R, Pocai A, Kelly TM, Scapin G, Gao YD, et al. A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice. Endocrinol Diabetes Metab. 2018;1(1):e00002. https://doi.org/10.1002/edm2.2.

    Article  CAS  PubMed  Google Scholar 

  47. Makdissi A, Ghanim H, Vora M, Green K, Abuaysheh S, Chaudhuri A, et al. Sitagliptin exerts an antinflammatory action. J Clin Endocrinol Metab. 2012;97(9):3333–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ommen ES, Xu L, O’Neill EA, Goldstein BJ, Kaufman KD, Engel SS. Comparison of treatment with sitagliptin or sulfonylurea in patients with type 2 diabetes mellitus and mild renal impairment: a post hoc analysis of clinical trials. Diabetes Ther. 2015;6(1):29–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Ueda S, Shimabukuro M, Arasaki O, Node K, Nomiyama T, Morimoto T. Effect of anagliptin and sitagliptin on low-density lipoprotein cholesterol in type 2 diabetic patients with dyslipidemia and cardiovascular risk: rationale and study design of the REASON trial. Cardiovasc Drugs Ther. 2018;32(1):73–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kitada M, Tsuda SI, Konishi K, Takeda-Watanabe A, Fujii M, Kanasaki K, et al. Anagliptin ameliorates albuminuria and urinary liver-type fatty acid-binding protein excretion in patients with type 2 diabetes with nephropathy in a glucose-lowering-independent manner. BMJ Open Diabetes Res Care. 2017;5(1):e000391. https://doi.org/10.1136/bmjdrc-2017-000391.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Shinjo T, Nakatsu Y, Iwashita M, Sano T, Sakoda H, Ishihara H, et al. DPP-IV inhibitor anagliptin exerts anti-inflammatory effects on macrophages, adipocytes, and mouse livers by suppressing NF-kappaB activation. Am J Physiol Endocrinol Metab. 2015;309(3):E214–23.

    Article  CAS  PubMed  Google Scholar 

  52. McHugh KR, DeVore AD, Mentz RJ, Edmonston D, Green JB, Hernandez AF. The emerging role of novel antihyperglycemic agents in the treatment of heart failure and diabetes: a focus on cardiorenal outcomes. Clin Cardiol. 2018;41(9):1259–67.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Muskiet MHA, Tonneijck L, Smits MM, van Baar MJB, Kramer MHH, Hoorn EJ, et al. GLP-1 and the kidney: from physiology to pharmacology and outcomes in diabetes. Nat Rev Nephrol. 2017;13(10):605–28.

    Article  CAS  PubMed  Google Scholar 

  54. Tsimihodimos V, Karanatsis N, Tzavela E, Elisaf M. Antidiabetic drugs and the kidney. Curr Pharm Des. 2017;23(41):6310–20.

  55. Muskiet MH, Smits MM, Morsink LM, Diamant M. The gut-renal axis: do incretin-based agents confer renoprotection in diabetes? Nat Rev Nephrol. 2014;10(2):88–103.

    Article  CAS  PubMed  Google Scholar 

  56. Hoorn EJ, Zietse R. Gut-kidney kaliuretic signaling: looking forward to feeding. Kidney Int. 2015;88(6):1230–2.

    Article  CAS  PubMed  Google Scholar 

  57. Michell AR, Debnam ES, Unwin RJ. Regulation of renal function by the gastrointestinal tract: potential role of gut-derived peptides and hormones. Annu Rev Physiol. 2008;70:379–403.

    Article  CAS  PubMed  Google Scholar 

  58. Yang J, Jose PA, Zeng C. Gastrointestinal-renal axis: role in the regulation of blood pressure. J Am Heart Assoc. 2017;6(3):e005536. https://doi.org/10.1161/JAHA.117.005536.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Jensen EP, Poulsen SS, Kissow H, Holstein-Rathlou NH, Deacon CF, Jensen BL, et al. Activation of GLP-1 receptors on vascular smooth muscle cells reduces the autoregulatory response in afferent arterioles and increases renal blood flow. Am J Physiol Renal Physiol. 2015;308(8):F867–77.

    Article  CAS  PubMed  Google Scholar 

  60. Schlatter P, Beglinger C, Drewe J, Gutmann H. Glucagon-like peptide 1 receptor expression in primary porcine proximal tubular cells. Regul Pept. 2007;141(1–3):120–8.

    Article  CAS  PubMed  Google Scholar 

  61. Gutzwiller JP, Tschopp S, Bock A, Zehnder CE, Huber AR, Kreyenbuehl M, et al. Glucagon-like peptide 1 induces natriuresis in healthy subjects and in insulin-resistant obese men. J Clin Endocrinol Metab. 2004;89(6):3055–61.

    Article  CAS  PubMed  Google Scholar 

  62. Tonneijck L, Smits MM, Muskiet MHA, Hoekstra T, Kramer MHH, Danser AHJ, et al. Acute renal effects of the GLP-1 receptor agonist exenatide in overweight type 2 diabetes patients: a randomised, double-blind, placebo-controlled trial. Diabetologia. 2016;59(7):1412–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Nistala R, Savin V. Diabetes, hypertension, and chronic kidney disease progression: role of DPP4. Am J Physiol Renal Physiol. 2017;312(4):F661–70.

    Article  CAS  PubMed  Google Scholar 

  64. Girardi AC, Knauf F, Demuth HU, Aronson PS. Role of dipeptidyl peptidase IV in regulating activity of Na+/H+ exchanger isoform. N Am J Physiol Cell Physiol. 2004;287(5):C1238–45.

    Article  CAS  Google Scholar 

  65. Marina AS, Kutina AV, Shakhmatoba EI, Natochin YV. Involvement of glucagon-like peptide-1 in the regulation of selective excretion of sodium or chloride ions by the kidneys. Bull Exp Biol Med. 2017;162(4):436–40.

    Article  CAS  PubMed  Google Scholar 

  66. Marina AS, Kutina AV, Shakhmatova EI, Balbotkina EV, Natochin YV. Stimulation of glucagon-like peptide-1 secretion by water loading in human. Dokl Biol Sci. 2014;459:323–5.

    Article  CAS  PubMed  Google Scholar 

  67. McKay NJ, Galante DL, Daniels D. Endogenous glucagon-like peptide-1 reduces drinking behavior and is differentially engaged by water and food intakes in rats. J Neurosci. 2014;34(49):16417–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Gutzwiller JP, Hruz P, Huber AR, Hamel C, Zehnder C, Drewe J, et al. Glucagon-like peptide-1 is involved in sodium and water homeostasis in humans. Digestion. 2006;73(2–3):142–50.

    Article  CAS  PubMed  Google Scholar 

  69. McKay NJ, Daniels D. Glucagon-like peptide-1 receptor agonist administration suppresses both water and saline intake in rats. J Neuroendocrinol. 2013;25(10):929–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Bankir L, Roussel R, Bouby N. Protein- and diabetes-induced glomerular hyperfiltration: role of glucagon, vasopressin, and urea. Am J Physiol Renal Physiol. 2015;309(1):F2–23.

    Article  CAS  PubMed  Google Scholar 

  71. Makino Y, Fujita Y, Haneda M. Dipeptidyl peptidase-4 inhibitors in progressive kidney disease. Curr Opin Nephrol Hypertens. 2015;24(1):67–73.

    Article  CAS  PubMed  Google Scholar 

  72. Tang-Christensen M, Larsen PJ, Göke R, Fink-Jensen A, Jessop DS, Møller M, et al. Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats. Am J Physiol. 1996;271(440–4):R848–56.

    CAS  PubMed  Google Scholar 

  73. Moreno C, Mistry M, Roman RJ. Renal effects of glucagon-like peptide in rats. Eur J Pharmacol. 2002;434(3):163–7.

    Article  CAS  PubMed  Google Scholar 

  74. du Cheyron D, Chalumeau C, Defontaine N, Klein C, Kellermann O, Paillard M, et al. Angiotensin II stimulates NHE3 activity by exocytic insertion of the transporter: role of PI 3-kinase. Kidney Int. 2003;64(3):939–49.

    Article  PubMed  Google Scholar 

  75. Riquier-Brison AD, Leong PK, Pihakaski-Maunsbach K, McDonough AA. Angiotensin II stimulates trafficking of NHE3, NaPi2, and associated proteins into the proximal tubule microvilli. Am J Physiol Cell Physiol. 2010;298(1):F177–86.

    Article  CAS  Google Scholar 

  76. Girardi AC, Fukuda LE, Rossoni LV, Malnic G, Reboucas NA. Dipeptidyl peptidase IV inhibition downregulates Na+–H+ exchanger NHE3 in rat renal proximal tubule. Am J Physiol Cell Physiol. 2008;294(2):F414–22.

    Article  CAS  Google Scholar 

  77. Alter ML, Ott IM, von Websky K, Tsuprykov O, Sharkovska Y, Krause-Relle K, et al. DPP-4 inhibition on top of angiotensin receptor blockade offers a new therapeutic approach for diabetic nephropathy. Kidney Blood Press Res. 2012;36(1):119–30.

    Article  CAS  PubMed  Google Scholar 

  78. Crajoinas RO, Polidoro JZ, Carneiro de Morais CP, Castelo-Branco RC, Girardi AC. Angiotensin II counteracts the effects of cAMP/PKA on NHE3 activity and phosphorylation in proximal tubule cells. Am J Physiol Cell Physiol. 2016;311(5):C768–76.

    Article  PubMed  Google Scholar 

  79. Crajoinas RO, Oricchio FT, Pessoa TD, Pacheco BPM, Lessa LMA, Malnic G, et al. Mechanisms mediating the diuretic and natriuretic actions of the incretin hormone glucagon-like peptide-1. Am J Physiol Renal Physiol. 2011;301(2):F355–63.

    Article  CAS  PubMed  Google Scholar 

  80. Farah LXS, Valentini V, Pessoa TD, Malnic G, McDonough AA, Girardi ACC. The physiological role of glucagon-like peptide-1 in the regulation of renal function. Am J Physiol Renal Physiol. 2015;310(2):F123F7.

    Google Scholar 

  81. Mima A, Hiraoka-Yamomoto J, Li Q, Kitada M, Li C, Geraldes P, et al. Protective effects of GLP-1 on glomerular endothelium and its inhibition by PKCβ activation in diabetes. Diabetes. 2012;61(11):2967–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Rieg T, Gerasimova M, Murray F, Masuda T, Tang T, Rose M, et al. Natriuretic effect by exendin-4, but not the DPP-4 inhibitor alogliptin, is mediated via the GLP-1 receptor and preserved in obese type 2 diabetic mice. Am J Physiol Renal Physiol. 2012;303(7):F963–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Takashima S, Fujita H, Fujishima H, Shimizu T, Sato T, Morii T, et al. Stromal cell–derived factor-1 is upregulated by dipeptidyl peptidase-4 inhibition and has protective roles in progressive diabetic nephropathy. Kidney Int. 2016;90(4):783–96.

    Article  CAS  PubMed  Google Scholar 

  84. Yang J, Campitelli J, Hu G, Lin Y, Luo J, Xue C. Increase in DPP-IV in the intestine, liver and kidney of the rat treated with high fat diet and streptozotocin. Life Sci. 2007;81(4):272–9.

    Article  CAS  PubMed  Google Scholar 

  85. Skovso S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J Diabetes Investig. 2014;5(4):349–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Kanasaki K. The role of renal dipeptidyl peptidase-4 in kidney disease: renal effects of dipeptidyl peptidase-4 inhibitors with a focus on linagliptin. Clin Sci. 2018;132(4):489–507.

    Article  CAS  Google Scholar 

  87. Fuchs H, Binder R, Greischel A. Tissue distribution of the novel DPP-4 inhibitor BI 1356 is dominated by saturable binding to its target in rats. Biopharm Drug Dispos. 2009;30(5):229–40.

    Article  CAS  PubMed  Google Scholar 

  88. Gill A, Gray SP, Watson AMD, Cooper ME, Jandeleit-Dahm KAM. Renoprotective effects of linagliptin and empagliflozin in a rat model of early diabetic nephropathy. Diabetes. 2017;66:A130(492–P).

    Google Scholar 

  89. Kanasaki K, Shi S, Kanasaki M, He J, Nagai T, Nakamura Y, et al. Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen. Diabetes. 2014;63(6):2120–31.

    Article  CAS  PubMed  Google Scholar 

  90. Mega C, Vala H, Rodrigues-Santos P, Oliveira J, Teixeira F, Fernandes R, et al. Sitagliptin prevents aggravation of endocrine and exocrine pancreatic damage in the Zucker Diabetic Fatty rat—focus on amelioration of metabolic profile and tissue cytoprotective properties. Diabetol Metab Syndr. 2014;6(1):42. https://doi.org/10.1186/1758-5996-6-42.

  91. Liu WJ, Xie SH, Liu YN, Kim W, Jin HY, Park SK, et al. Dipeptidyl peptidase IV inhibitor attenuates kidney injury in streptozotocin-induced diabetic rats. J Pharmacol Exp Ther. 2012;340(2):248–55.

    Article  CAS  PubMed  Google Scholar 

  92. Zhang J, Chen Q, Zhong J, Liu C, Zheng B, Gong Q. DPP-4 inhibitors as potential candidates for antihypertensive therapy: improving vascular inflammation and assisting the action of traditional antihypertensive drugs. Front Immunol. 2019;10:1050. https://doi.org/10.3389/fimmu.2019.01050.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tomovic K, Lazarevic J, Kocic G, Deljanin-Ilic M, Anderluh M, Smelcerovic A. Mechanisms and pathways of anti-inflammatory activity of DPP-4 inhibitors in cardiovascular and renal protection. Med Res Rev. 2019;39(1):404–22.

    Article  CAS  PubMed  Google Scholar 

  94. Sun F, Wu S, Wang J, Guo S, Chai S, Yang Z, et al. Effect of glucagon-like peptide-1 receptor agonists on lipid profiles among type 2 diabetes: a systematic review and network meta-analysis. Clin Ther. 2015;37(1):225–41.

    Article  CAS  PubMed  Google Scholar 

  95. Monami M, Lamanna C, Desideri CM, Mannucci E. DPP-4 inhibitors and lipids: systematic review and meta-analysis. Adv Ther. 2012;29(1):14–25.

    Article  CAS  PubMed  Google Scholar 

  96. Liu SC, Tu YK, Chien MN, Chien KL. Effect of antidiabetic agents added to metformin on glycaemic control, hypoglycaemia and weight change in patients with type 2 diabetes: a network meta-analysis. Diabetes Obes Metab. 2012;14(9):810–20.

    Article  CAS  PubMed  Google Scholar 

  97. Aaboe K, Knop FK, Vilsbøll T, Deacon CF, Holst JJ, Madsbad S, et al. Twelve weeks treatment with the DPP-4 inhibitor, sitagliptin, prevents degradation of peptide YY and improves glucose and non-glucose induced insulin secretion in patients with type 2 diabetes mellitus. Diabetes Obes Metab. 2010;12(4):323–33.

    Article  CAS  PubMed  Google Scholar 

  98. Zhang X, Zhao Q. Effects of dipeptidyl peptidase-4 inhibitors on blood pressure in patients with type 2 diabetes: a systematic review and meta-analysis. J Hypertens. 2016;34(2):167–75.

    Article  CAS  PubMed  Google Scholar 

  99. McGuire DK, Alexander JH, Johansen OE, Perkovic V, Rosenstock J, Cooper ME, et al. Linagliptin effects on heart failure and related outcomes in individuals with type 2 diabetes mellitus at high cardiovascular and renal risk in CARMELINA. Circulation. 2019;139(3):351–61.

    Article  CAS  PubMed  Google Scholar 

  100. Rosenstock J, Perkovic V, Johansen OE, Cooper ME, Kahn SE, Marx N, et al. Effect of linagliptin vs placebo on major cardiovascular events in adults with type 2 diabetes and high cardiovascular and renal risk: the CARMELINA randomized clinical trial. JAMA. 2019;321(1):69–79.

    Article  CAS  PubMed  Google Scholar 

  101. Scirica BM, Braunwald E, Raz I, Cavender MA, Morrow DA, Jarolim P, et al. Heart failure, saxagliptin, and diabetes mellitus: observations from the SAVOR-TIMI 53 randomized trial. Circulation. 2014;130(18):1579–88.

    Article  CAS  PubMed  Google Scholar 

  102. Zannad F, Cannon CP, Cushman WC, Bakris GL, Menon V, Perez AT, et al. Heart failure and mortality outcomes in patients with type 2 diabetes taking alogliptin versus placebo in EXAMINE: a multicentre, randomised, double-blind trial. Lancet. 2015;385(9982):2067–76.

    Article  CAS  PubMed  Google Scholar 

  103. McGuire DK, Van De Werf F, Armstrong PW, Standl E, Koglin J, Green JB, et al. Association between sitagliptin use and heart failure hospitalization and related outcomes in type 2 diabetes mellitus: secondary analysis of a randomized clinical trial. JAMA Cardiol. 2016;1(2):126–35.

    Article  PubMed  Google Scholar 

  104. Bergman A, Ebel D, Liu F, Stone J, Wang A, Zeng W, et al. Absolute bioavailability of sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers. Biopharm Drug Dispos. 2007;28(6):315–22.

    Article  CAS  PubMed  Google Scholar 

  105. Pathak R, Bridgeman MB. Dipeptidyl peptidase-4 (DPP-4) inhibitors in the management of diabetes. P T. 2010;35(9):509–13.

    PubMed  PubMed Central  Google Scholar 

  106. Karasik A, Aschner P, Katzeff H, Davies MJ, Stein PP. Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials. Curr Med Res Opin. 2008;24(2):489–96.

    Article  CAS  PubMed  Google Scholar 

  107. Herman GA, Stevens C, Van Dyck K, Bergman A, Yi B, De Smet M, et al. Pharmacokinetics and pharmacodynamics of sitagliptin, an inhibitor of dipeptidyl peptidase IV, in healthy subjects: results from two randomized, double-blind, placebo-controlled studies with single oral doses. Clin Pharmacol Ther. 2005;78(6):675–88.

    Article  CAS  PubMed  Google Scholar 

  108. Bergman AJ, Cote J, Yi B, Marbury T, Swan SK, Smith W, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care. 2007;30(7):1862–4.

    Article  CAS  PubMed  Google Scholar 

  109. Chan JCN, Scott R, Arjona Ferreira JC, Sheng D, Gonzalez E, Davies MJ, et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes Metab. 2008;10(7):545–55.

    Article  CAS  PubMed  Google Scholar 

  110. Gupta V, Kalra S. Choosing a gliptin. Indian J Endocrinol Metab. 2011;15(4):298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Boulton DW. Clinical pharmacokinetics and pharmacodynamics of saxagliptin, a dipeptidyl peptidase-4 inhibitor. Clin Pharmacokinet. 2017;56(1):11–24.

    Article  CAS  PubMed  Google Scholar 

  112. Boulton B, Li L, Frevert EU, Tang A, Castaneda L, Vachharajani NN, et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin Pharmacokinet. 2011;50(4):253–65.

    Article  CAS  PubMed  Google Scholar 

  113. He YL. Clinical pharmacokinetics and pharmacodynamics of vildagliptin. Clin Pharmacokinet. 2012;51(3):147–62.

    Article  CAS  PubMed  Google Scholar 

  114. He H, Tran P, Yin H, Smith H, Batard Y, Wang L, et al. Absorption, metabolism, and excretion of [14C]vildagliptin, a novel dipeptidyl peptidase 4 inhibitor, in humans. Drug Metab Dispos. 2009;37(3):536–44.

    Article  CAS  PubMed  Google Scholar 

  115. Russo E, Penno G, Del Prato S. Managing diabetic patients with moderate or severe renal impairment using DPP-4 inhibitors: focus on vildagliptin. Diabetes Metab Syndr Obes. 2013;6:161–70.

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Dineen L, Law C, Scher R, Pyon E. Alogliptin (nesina) for adults with type-2 diabetes. P T. 2014;39(3):186–202.

    PubMed  PubMed Central  Google Scholar 

  117. Sakai Y, Suzuki A, Mugishima K, Sumi Y, Otsuka Y, Otsuka T, et al. Effects of alogliptin in chronic kidney disease patients with type 2 diabetes. Intern Med. 2014;53(3):195–203.

    Article  CAS  PubMed  Google Scholar 

  118. Barnett AH. Linagliptin: a novel dipeptidyl peptidase 4 inhibitor with a unique place in therapy. Adv Ther. 2011;28(6):447–59.

    Article  CAS  PubMed  Google Scholar 

  119. Blech S, Ludwig-Schwellinger E, Grafe-Mody EU, Withopf B, Wagner K. The metabolism and disposition of the oral dipeptidyl peptidase-4 inhibitor, linagliptin, in humans. Drug Metab Dispos. 2010;38(4):667–78.

    Article  CAS  PubMed  Google Scholar 

  120. He YL, Kulmatycki K, Zhang Y, Zhou W, Reynolds C, Ligueros-Saylan M, et al. Pharmacokinetics of vildagliptin in patients with varying degrees of renal impairment. Int J Clin Pharmacol Ther. 2013;51(9):693–703.

    Article  CAS  PubMed  Google Scholar 

  121. Naik H, Czerniak R, Vakilynejad M. Application of pharmacometric approaches to evaluate effect of weight and renal function on pharmacokinetics of alogliptin. Br J Clin Pharmacol. 2016;81(4):700–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. 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(10):939–46.

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia

    Momir Mikov & Maja Đanić

  2. Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia

    Nebojša Pavlović & Svetlana Goločorbin-Kon

  3. Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Vojvodina, Serbia

    Bojan Stanimirov & Karmen Stankov

  4. Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia

    Hani Al-Salami

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  1. Momir Mikov
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  2. Nebojša Pavlović
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Correspondence to Momir Mikov.

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Funding

This research was supported by HORIZON 2020 MEDLEM project no. 690876, Project for Scientific and Technological Development of Vojvodina no. 114-451-2072-/2016-02, and Project of Ministry of Education, Science and Technological Development of the Republic of Serbia, Grant no. III41012.

Conflict of Interest

The authors of the manuscript (MM, NP, BS, MĐ, SGK, KS, and HAS) have no commercial associations or other arrangements that may pose a conflict of interest in connection with the article.

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Mikov, M., Pavlović, N., Stanimirov, B. et al. DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment. Eur J Drug Metab Pharmacokinet 45, 1–14 (2020). https://doi.org/10.1007/s13318-019-00570-y

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