Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Noninsulin glucose-lowering agents for the treatment of patients on dialysis

Nature Reviews Nephrology volume 9, pages 147–153 (2013)Cite this article

Subjects

Abstract

Chronic kidney disease (CKD) is a common complication of diabetes mellitus and the most common cause of end-stage renal disease (ESRD). As the worldwide prevalence of diabetes continues to increase, the number of patients with CKD will also increase. Therefore, it is essential that physicians know how to safely and effectively manage diabetes in the setting of CKD. Adequate glycaemic control in patients with diabetes is important to prevent ESRD and other complications and to decrease mortality. However, many glucose-lowering agents need to be dose-adjusted or should not be used in the setting of stage 3 CKD or higher (defined as an estimated glomerular filtration rate [eGFR] <60 ml/min/1.73 m2), particularly in patients with stage 5 CKD (eGFR <15 ml/min/1.73 m2) and in those receiving dialysis. Insulin therapy is appropriate for patients undergoing dialysis; however, several orally administered glucose-lowering agents can also be used safely in these patients. In this Review, we provide an overview of the use of noninsulin glucose-lowering agents in the dialysis population.

Key Points

  • Adequate glycaemic control in patients with diabetes who are receiving dialysis reduces the risk of diabetic complications such as neuropathy and blindness

  • Most oral hypoglycaemic agents have pharmacokinetic and elimination profiles that preclude their use in patients with stage 5 chronic kidney disease (CKD), including those receiving dialysis

  • Adjusted doses of repaglinide, pioglitazone, short-acting sulfonylureas, linagliptin and liraglutide should be considered for patients with type 2 diabetes and stage 5 CKD as well as for patients on dialysis

  • In patients on dialysis with anaemia and haemoglobin levels <10 g/l, glycated albumin and daily fasting blood glucose levels more accurately reflect glycaemic control than haemoglobin A1c levels

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Sites of action of noninsulin glucose lowering agents that can be used in patients with type 2 diabetes and stage 3 or higher CKD.

Similar content being viewed by others

References

  1. Slinin, Y. et al. Management of hyperglycemia, dyslipidemia, and albuminuria in patients with diabetes and CKD: a systematic review for a KDOQI Clinical Practice Guideline. Am. J. Kidney Dis. 60, 747–769 (2012).

    Article  Google Scholar 

  2. Kidney Disease Outcomes Quality Initiative. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for diabetes and chronic kidney disease. Am. J. Kidney Dis. 49, S12–S154 (2007).

  3. Shinohara, K. et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J. Am. Soc. Nephrol. 13, 1894–1900 (2002).

    Article  Google Scholar 

  4. Weiss, E. P. & Fontana, L. Caloric restriction: powerful protection for the aging heart and vasculature. Am. J Physiol. Heart Circ. Physiol. 301, H1205–H1219 (2011).

    Article  CAS  Google Scholar 

  5. Aparicio, M. et al. Protein-restricted diets plus keto/amino acids—a valid therapeutic approach for chronic kidney disease patients. J. Ren. Nutr. 22, S1–S21 (2012).

    Article  CAS  Google Scholar 

  6. Morioka, T. et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care 24, 909–913 (2001).

    Article  CAS  Google Scholar 

  7. Yu, C. C. et al. Predialysis glycemic control is an independent predictor of clinical outcome in type II diabetics on continuous ambulatory peritoneal dialysis. Perit. Dial. Int. 17, 262–268 (1997).

    CAS  PubMed  Google Scholar 

  8. Fu, A. Z., Qiu, Y. & Radican, L. Impact of fear of insulin or fear of injection on treatment outcomes of patients with diabetes. Curr. Med. Res. Opin. 25, 1413–1420 (2009).

    Article  CAS  Google Scholar 

  9. Kovesdy, C. P., Park, J. C. & Kalantar-Zadeh, K. Glycemic control and burnt-out diabetes in ESRD. Semin. Dial. 23, 148–156 (2010).

    Article  Google Scholar 

  10. Rocha, A., Almeida, M., Santos, J. & Carvalho, A. Metformin in patients with chronic kidney disease: strengths and weaknesses. J. Nephrol. (2012).

  11. Vasisht, K. P., Chen, S. C., Peng, Y. & Bakris, G. L. Limitations of metformin use in patients with kidney disease: are they warranted? Diabetes Obes. Metab. 12, 1079–1083 (2010).

    Article  CAS  Google Scholar 

  12. Sun, C. Y., Lee, C. C. & Wu, M. S. Hypoglycemia in diabetic patients undergoing chronic hemodialysis. Ther. Apher. Dial. 13, 95–102 (2009).

    Article  CAS  Google Scholar 

  13. Bailey, C. J. Biguanides and NIDDM. Diabetes Care 15, 755–772 (1992).

    Article  CAS  Google Scholar 

  14. Ball, A. J., McCluskey, J. T., Flatt, P. R. & McClenaghan, N. H. Drug-induced desensitization of insulinotropic actions of sulfonylureas. Biochem. Biophys. Res. Commun. 271, 234–239 (2000).

    Article  CAS  Google Scholar 

  15. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001).

    Article  CAS  Google Scholar 

  16. Reitman, M. L. & Schadt, E. E. Pharmacogenetics of metformin response: a step in the path toward personalized medicine. J. Clin. Invest. 117, 1226–1229 (2007).

    Article  CAS  Google Scholar 

  17. Kirpichnikov, D., McFarlane, S. I. & Sowers, J. R. Metformin: an update. Ann. Intern. Med. 137, 25–33 (2002).

    Article  CAS  Google Scholar 

  18. Bailey, C. J. & Turner, R. C. Metformin. N. Engl. J. Med. 334, 574–579 (1996).

    Article  CAS  Google Scholar 

  19. Abe, M., Okada, K. & Soma, M. Antidiabetic agents in patients with chronic kidney disease and end-stage renal disease on dialysis: metabolism and clinical practice. Curr. Drug Metab. 12, 57–69 (2011).

    Article  CAS  Google Scholar 

  20. DeFronzo, R. A. Pharmacologic therapy for type 2 diabetes mellitus. Ann. Intern. Med. 131, 281–303 (1999).

    Article  CAS  Google Scholar 

  21. Holman, R. R. Long-term efficacy of sulfonylureas: a United Kingdom Prospective Diabetes Study perspective. Metabolism 55 (Suppl. 1), S2–S5 (2006).

    Article  CAS  Google Scholar 

  22. United Kingdom Prospective Diabetes Study Group. United Kingdom Prospective Diabetes Study 24: a 6-year, randomized, controlled trial comparing sulfonylurea, insulin, and metformin therapy in patients with newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann. Intern. Med. 128, 165–175 (1998).

  23. Koski, R. R. Practical review of oral antihyperglycemic agents for type 2 diabetes mellitus. Diabetes Educ. 32, 869–876 (2006).

    Article  Google Scholar 

  24. Zoungas, S. et al. Combined effects of routine blood pressure lowering and intensive glucose control on macrovascular and microvascular outcomes in patients with type 2 diabetes: new results from the ADVANCE trial. Diabetes Care 32, 2068–2074 (2009).

    Article  CAS  Google Scholar 

  25. Paul, S., Best, J., Klein, K., Han, J. & Maggs, D. Effects of HbA1c and weight reduction on blood pressure in patients with type 2 diabetes mellitus treated with exenatide. Diabetes Obes. Metab. 14, 826–834 (2012).

    Article  CAS  Google Scholar 

  26. Demuth, H. U., McIntosh, C. H. & Pederson, R. A. Type 2 diabetes—therapy with dipeptidyl peptidase IV inhibitors. Biochim. Biophys. Acta 1751, 33–44 (2005).

    Article  CAS  Google Scholar 

  27. Herman, G. A. et al. Effect of single oral doses of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on incretin and plasma glucose levels after an oral glucose tolerance test in patients with type 2 diabetes. J. Clin. Endocrinol. Metab. 91, 4612–4619 (2006).

    Article  CAS  Google Scholar 

  28. American Diabetes Association. Standards of medical care in diabetes—2012. Diabetes Care 35 (Suppl. 1), S11–S63 (2012).

  29. Chan, J. C. et al. Safety and efficacy of sitagliptin in patients with type 2 diabetes and chronic renal insufficiency. Diabetes Obes. Metab. 10, 545–555 (2008).

    Article  CAS  Google Scholar 

  30. Boulton, D. W. et al. Influence of renal or hepatic impairment on the pharmacokinetics of saxagliptin. Clin. Pharmacokinet. 50, 253–265 (2011).

    Article  CAS  Google Scholar 

  31. Fura, A. et al. Pharmacokinetics of the dipeptidyl peptidase 4 inhibitor saxagliptin in rats, dogs, and monkeys and clinical projections. Drug Metab. Dispos. 37, 1164–1171 (2009).

    Article  CAS  Google Scholar 

  32. Scheen, A. J. Pharmacokinetics of dipeptidylpeptidase-4 inhibitors. Diabetes Obes. Metab. 12, 648–658 (2010).

    Article  CAS  Google Scholar 

  33. Kothny, W., Shao, Q., Groop, P. H. & 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. 14, 1032–1039 (2012).

    Article  CAS  Google Scholar 

  34. Brown, D. X., Choudhury, M. & Evans, M. Linagliptin as add-on therapy for type 2 diabetes—an overview. Drugs Today (Barc.) 48, 645–654 (2012).

    Article  CAS  Google Scholar 

  35. Huttner, S., Graefe-Mody, E. U., Withopf, B., Ring, A. & Dugi, K. A. Safety, tolerability, pharmacokinetics, and pharmacodynamics of single oral doses of BI 1356, an inhibitor of dipeptidyl peptidase 4, in healthy male volunteers. J. Clin. Pharmacol. 48, 1171–1178 (2008).

    Article  CAS  Google Scholar 

  36. Yki-Jarvinen, H. Thiazolidinediones. N. Engl. J. Med. 351, 1106–1118 (2004).

    Article  Google Scholar 

  37. Inzucchi, S. E. Oral antihyperglycemic therapy for type 2 diabetes: scientific review. JAMA 287, 360–372 (2002).

    Article  CAS  Google Scholar 

  38. Shimabukuro, M., Zhou, Y. T., Lee, Y. & Unger, R. H. Troglitazone lowers islet fat and restores β cell function of Zucker diabetic fatty rats. J. Biol. Chem. 273, 3547–3550 (1998).

    Article  CAS  Google Scholar 

  39. Iglesias, P. & Diez, J. J. Peroxisome proliferator-activated receptor γ agonists in renal disease. Eur. J. Endocrinol. 154, 613–621 (2006).

    Article  CAS  Google Scholar 

  40. Kahn, S. E. et al. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N. Engl. J. Med. 355, 2427–2443 (2006).

    Article  CAS  Google Scholar 

  41. Bilik, D. et al. Thiazolidinediones, cardiovascular disease and cardiovascular mortality: translating research into action for diabetes (TRIAD). Pharmacoepidemiol. Drug Saf. 19, 715–721 (2010).

    Article  CAS  Google Scholar 

  42. Loke, Y. K., Kwok, C. S. & Singh, S. Comparative cardiovascular effects of thiazolidinediones: systematic review and meta-analysis of observational studies. BMJ 342, d1309 (2011).

    Article  Google Scholar 

  43. Ramirez, S. P. et al. Rosiglitazone is associated with mortality in chronic hemodialysis patients. J. Am. Soc. Nephrol. 20, 1094–1101 (2009).

    Article  CAS  Google Scholar 

  44. Budde, K. et al. The pharmacokinetics of pioglitazone in patients with impaired renal function. Br. J. Clin. Pharmacol. 55, 368–374 (2003).

    Article  CAS  Google Scholar 

  45. Abe, M. et al. Clinical effectiveness and safety evaluation of long-term pioglitazone treatment for erythropoietin responsiveness and insulin resistance in type 2 diabetic patients on hemodialysis. Expert Opin. Pharmacother. 11, 1611–1620 (2010).

    Article  CAS  Google Scholar 

  46. Wong, T. Y. et al. Rosiglitazone reduces insulin requirement and C-reactive protein levels in type 2 diabetic patients receiving peritoneal dialysis. Am. J. Kidney Dis. 46, 713–719 (2005).

    Article  CAS  Google Scholar 

  47. Borsting, E., Cheng, V. P., Glass, C. K., Vallon, V. & Cunard, R. Peroxisome proliferator-activated receptor-γ agonists repress epithelial sodium channel expression in the kidney. Am. J. Physiol. Renal Physiol. 302, F540–F551 (2012).

    Article  CAS  Google Scholar 

  48. Nesto, R. W. et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. October 7, 2003. Circulation 108, 2941–2948 (2003).

    Article  Google Scholar 

  49. Yew, T., Toh, S. A. & Millar, J. S. Selective peroxisome proliferator-activated receptor-γ modulation to reduce cardiovascular risk in patients with insulin resistance. Recent Pat. Cardiovasc. Drug Discov. 7, 33–41 (2012).

    Article  CAS  Google Scholar 

  50. Fuhlendorff, J. et al. Stimulation of insulin release by repaglinide and glibenclamide involves both common and distinct processes. Diabetes 47, 345–351 (1998).

    Article  CAS  Google Scholar 

  51. Scott, L. J. Repaglinide: a review of its use in type 2 diabetes mellitus. Drugs 72, 249–272 (2012).

    Article  CAS  Google Scholar 

  52. Niemi, M., Backman, J. T., Juntti-Patinen, L., Neuvonen, M. & Neuvonen, P. J. Coadministration of gemfibrozil and itraconazole has only a minor effect on the pharmacokinetics of the CYP2C9 and CYP3A4 substrate nateglinide. Br. J. Clin. Pharmacol. 60, 208–217 (2005).

    Article  CAS  Google Scholar 

  53. Meneilly, G. S. et al. Effect of acarbose on insulin sensitivity in elderly patients with diabetes. Diabetes Care 23, 1162–1167 (2000).

    Article  CAS  Google Scholar 

  54. Abe, M., Kikuchi, F., Kaizu, K. & Matsumoto, K. Combination therapy of pioglitazone with voglibose improves glycemic control safely and rapidly in Japanese type 2-diabetic patients on hemodialysis. Clin. Nephrol. 68, 287–294 (2007).

    Article  CAS  Google Scholar 

  55. Fehse, F. et al. Exenatide augments first- and second-phase insulin secretion in response to intravenous glucose in subjects with type 2 diabetes. J. Clin. Endocrinol. Metab. 90, 5991–5997 (2005).

    Article  CAS  Google Scholar 

  56. Koliaki, C. & Doupis, J. Incretin-based therapy: a powerful and promising weapon in the treatment of type 2 diabetes mellitus. Diabetes Ther. 2, 101–121 (2011).

    Article  CAS  Google Scholar 

  57. Nauck, M. A. et al. Normalization of fasting hyperglycaemia by exogenous glucagon-like peptide 1 (7–36 amide) in type 2 (non-insulin-dependent) diabetic patients. Diabetologia 36, 741–744 (1993).

    Article  CAS  Google Scholar 

  58. Nauck, M. A. et al. Glucagon-like peptide 1 inhibition of gastric emptying outweighs its insulinotropic effects in healthy humans. Am. J. Physiol. 273, E981–E988 (1997).

    CAS  PubMed  Google Scholar 

  59. Baggio, L. L. & Drucker, D. J. Biology of incretins: GLP-1 and GIP. Gastroenterology 132, 2131–2157 (2007).

    Article  CAS  Google Scholar 

  60. Linnebjerg, H. et al. Effect of renal impairment on the pharmacokinetics of exenatide. Br. J. Clin. Pharmacol. 64, 317–327 (2007).

    Article  CAS  Google Scholar 

  61. Copley, K. et al. Investigation of exenatide elimination and its in vivo and in vitro degradation. Curr. Drug Metab. 7, 367–374 (2006).

    Article  CAS  Google Scholar 

  62. Jacobsen, L. V., Hindsberger, C., Robson, R. & Zdravkovic, M. Effect of renal impairment on the pharmacokinetics of the GLP-1 analogue liraglutide. Br. J. Clin. Pharmacol. 68, 898–905 (2009).

    Article  CAS  Google Scholar 

  63. Johnson, K. H. et al. Immunolocalization of islet amyloid polypeptide (IAPP) in pancreatic β cells by means of peroxidase-antiperoxidase (PAP) and protein A-gold techniques. Am. J. Pathol. 130, 1–8 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Gedulin, B. R., Rink, T. J. & Young, A. A. Dose-response for glucagonostatic effect of amylin in rats. Metabolism 46, 67–70 (1997).

    Article  CAS  Google Scholar 

  65. Lutz, T. A., Mollet, A., Rushing, P. A., Riediger, T. & Scharrer, E. The anorectic effect of a chronic peripheral infusion of amylin is abolished in area postrema/nucleus of the solitary tract (AP/NTS) lesioned rats. Int. J. Obes. Relat. Metab. Disord. 25, 1005–1011 (2001).

    Article  CAS  Google Scholar 

  66. Young, A. A., Gedulin, B., Vine, W., Percy, A. & Rink, T. J. Gastric emptying is accelerated in diabetic BB rats and is slowed by subcutaneous injections of amylin. Diabetologia 38, 642–648 (1995).

    Article  CAS  Google Scholar 

  67. Younk, L. M., Mikeladze, M. & Davis, S. N. Pramlintide and the treatment of diabetes: a review of the data since its introduction. Expert Opin. Pharmacother. 12, 1439–1451 (2011).

    Article  CAS  Google Scholar 

  68. Amylin Pharmaceuticals, Inc. Symlin® (pramlintide acetate) injection prescribing information. Symlin.com[online], (2008).

  69. Inaba, M. et al. Glycated albumin is a better glycemic indicator than glycated hemoglobin values in hemodialysis patients with diabetes: effect of anemia and erythropoietin injection. J. Am. Soc. Nephrol. 18, 896–903 (2007).

    Article  CAS  Google Scholar 

  70. Bisse, E. & Wieland, H. High-performance liquid chromatographic separation of human haemoglobins. Simultaneous quantitation of foetal and glycated haemoglobins. J. Chromatogr. 434, 95–110 (1988).

    Article  CAS  Google Scholar 

  71. Drechsler, C., Krane, V., Ritz, E., Marz, W. & Wanner, C. Glycemic control and cardiovascular events in diabetic hemodialysis patients. Circulation 120, 2421–2428 (2009).

    Article  CAS  Google Scholar 

  72. Mittman, N. et al. Serum fructosamine versus glycosylated hemoglobin as an index of glycemic control, hospitalization, and infection in diabetic hemodialysis patients. Kidney Int. Suppl. 117, S41–S45 (2010).

    Article  CAS  Google Scholar 

  73. Shafi, T. et al. Serum fructosamine and glycated albumin and risk of mortality and clinical outcomes in hemodialysis patients. Diabetes Care http://dx.doi.org/10.2337/dc12-1896.

Download references

Author information

Authors and Affiliations

  1. American Society of Hypertension Comprehensive Hypertension Center, Section of Endocrinology, Diabetes and Metabolism, The University of Chicago Medicine, 5841 South Maryland Avenue, MC 6092, Chicago, 60637, IL, USA

    Colleen Flynn & George L. Bakris

Authors
  1. Colleen Flynn
    View author publications

    Search author on:PubMed Google Scholar

  2. George L. Bakris
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Both authors contributed to discussion of content for the article, researching data for the article, writing the article and reviewing and editing of the manuscript before submission.

Corresponding author

Correspondence to George L. Bakris.

Ethics declarations

Competing interests

C. Flynn declares no competing interests. G.L. Bakris has acted as a consultant for Abbott, Eli Lilly, Johnson and Johnson, and Takeda.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Flynn, C., Bakris, G. Noninsulin glucose-lowering agents for the treatment of patients on dialysis. Nat Rev Nephrol 9, 147–153 (2013). https://doi.org/10.1038/nrneph.2013.12

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/nrneph.2013.12

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing