Reviews

Managing diabetes in hemodialysis patients: Observations and recommendations

Cleveland Clinic Journal of Medicine. 2009 November;76(11):649-655 | 10.3949/ccjm.76a.09054

References

National Institute of Diabetes and Digestive and Kidney Diseases: United States Renal Data System: USRDS 2005 Annual Data Report. Bethesda, MD: National Institutes of Health, 2005.
Wu MS, Yu CC, Yang CW, et al. Poor pre-dialysis glycaemic control is a predictor of mortality in type II diabetic patients on maintenance haemodialysis. Nephrol Dial Transplant 1997; 12:2105–2110.
Morioka T, Emoto M, Tabata T, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care 2001; 24:909–913.
McMurray SD, Johnson G, Davis S, McDougall K. Diabetes education and care management significantly improve patient outcomes in the dialysis unit. Am J Kidney Dis 2002; 40:566–575.
Oomichi T, Emoto M, Tabata T, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study. Diabetes Care 2006; 29:1496–1500.
Williams ME, Lacson E, Teng M, Ofsthun N, Lazarus JM. Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival. Kidney Int 2006; 70:1503–1509.
Tzamaloukas AH, Yuan ZY, Murata GH, Avasthi PS, Oreopoulos DG. Clinical associations of glycemic control in diabetics on CAPD. Adv Perit Dial 1993; 9:291–294.
Tzamaloukas AH, Murata GH, Zager PG, Eisenberg B, Avasthi PS. The relationship between glycemic control and morbidity and mortality for diabetics on dialysis. ASAIO J 1993; 39:880–885.
Kalantar-Zadeh K, Kopple JD, Regidor DL, et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007; 30:1049–1055.
Kovesdy C, Sharma K, Kalantar-Zadeh. Glycemic control in diabetic CKD patients: where do we stand? Am J Kidney Dis 2008; 52:766–777.
Mak RH. Intravenous 1,25-dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney Int 1992; 41:1049–1054.
Hajjar SM, Fadda GZ, Thanakitcharu P, Smogorzewski M, Massry SG. Reduced activity of Na(+)-K+ ATPase of pancreatic islet cells in chronic renal failure: role of secondary hyperparathyroidism. J Am Soc Nephrol 1992; 2:1355–1359.
Grodstein GP, Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW. Glucose absorption during continuous ambulatory peritoneal dialysis. Kidney Int 1981; 19:564–567.
Joy MS, Cefali WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002; 39:297–307.
Lamb E, Venton TR, Cattell WR, Dawnay A. Serum glycated albumin and fructosamine in renal dialysis patients. Nephron 1993; 64:82–88.
Inaba M, Okuno S, Kumeda Y, et al; Osaka CKD Expert Research Group. 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 2007; 18:896–903.
Constanti C, Simo JM, Joven J, Camps J. Serum fructosamine concentration in patients with nephrotic syndrome and with cirrhosis of the liver: the influence of hypoalbuminaemia and hypergammaglobulinaemia. Ann Clin Biochem 1992; 29:437–442.
Ford HC, Lim WC, Crooke MJ. Hemoglobin A1 and serum fructosamine levels in hyperthyroidism. Clin Chim Acta 1987; 166:317–321.
Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial 2000; 13:4–8.
Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med 1981; 70:361–372.
Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease. Am J Kidney Dis 2000; 35:500–505.
Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial 2004; 17:365–370.
United Kingdom Prospective Diabetes Study (UKPDS) 13. Relative efficacy of randomly allocated diet, sulphonylureas, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310:83–88.
Inoue T, Shibahara N, Miyagawa K, et al. Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. Clin Nephrol 2003; 60:90–95.
Nagai T, Imamura M, Iizuka K, Mori M. Hypoglycemia due to nateglinide administration in diabetic patient with chronic renal failure. Diabetes Res Clin Pract 2003; 59:191–194.
Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res 2002; 30:391–399.
Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27:256–263.
Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007; 9:733–745.
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, et al; Sitagliptin Study 020 Group Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29:2638–2643.
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007; 30:1979–1987.
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9:194–205.
Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006; 28:1556–1568.
Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007; 30:1862–1864.
Carone FA, Peterson DR. Hydrolysis and transport of small peptides by the proximal tubule. Am J Physiol 1980; 238:F151–F158.
Rabkin R, Simon NM, Steiner S, Colwell JA. Effects of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 1970; 282:182–187.
Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron 1992; 61:377–382.
Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabet Med 2003; 20:642–645.
Aisenpreis U, Pfützner A, Giehl M, Keller F, Jehle PM. Pharmacokinetics and pharmacodynamics of insulin Lispro compared with regular insulin in hemodialysis patients with diabetes mellitus. Nephrol Dial Transplant 1999; 14( suppl 4):5–6.
Tunbridge FK, Newens A, Home PD, et al. A comparison of human ultralente- and lente-based twice-daily injection regimens. Diabet Med 1989; 6:496–501.
Freeman SL, O’Brien PC, Rizza RA. Use of human ultralente as the basal insulin component in treatment of patients with IDDM. Diabetes Res Clin Pract 1991; 12:187–192.
Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000; 26( suppl 4):73–85.
Aronoff GR, Berns JS, Brier ME, et al, eds. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th ed. Philadelphia, PA: American College of Physicians, 1999.

ESRD REDUCES INSULIN CLEARANCE

In healthy nondiabetic people, the pancreatic beta cells secrete half of the daily insulin requirement (about 0.5 units/kg/day) at a steady basal rate independent of glucose levels. The other half is secreted in response to prandial glucose stimulation.

Secreted into the portal system, insulin passes through the liver, where about 75% is metabolized, with the remaining 25% metabolized by the kidneys. About 60% of the insulin in the arterial bed is filtered by the glomerulus, and 40% is actively secreted into the nephric tubules.³⁴ Most of the insulin in the tubules is metabolized into amino acids, and only 1% of insulin is secreted intact.

For diabetic patients receiving exogenous insulin, renal metabolism plays a more significant role since there is no first-pass metabolism in the liver. As renal function starts to decline, insulin clearance does not change appreciably, due to compensatory peritubular insulin uptake.³⁵ But once the GFR drops below 20 mL/min, the kidneys clear markedly less insulin, an effect compounded by a decrease in the hepatic metabolism of insulin that occurs in uremia.³⁶ Thus, despite the increase in insulin resistance caused by renal failure, the net effect is a reduced requirement for exogenous insulin in ESRD.³⁷

A variety of insulin preparations are available, including rapid-acting, intermediate-acting, and long-acting forms and premixed combinations, each with its specific onset, peak, and duration of action (Table 2). To our knowledge, no study of neutral protamine Hagedorn (NPH) insulin or other long-acting insulins has been done in patients with ESRD, and very few studies have described the use of insulin analogues in ESRD.

Aisenpreis et al³⁸ showed that the pharmacokinetic profile of insulin lispro (Humalog), which has a short onset of action and a short duration of action, may not only facilitate the correction of hyperglycemia but may also decrease the risk of late hypoglycemic episodes, which is of increased relevance in hemodialysis patients.

On the basis of the available evidence,^39,40 we recommend a long-acting insulin such as insulin glargine (Lantus) or NPH insulin for basal requirements, along with a rapid-acting insulin analogue such as lispro or insulin aspart (NovoLog) before meals two or three times daily.

When the GFR drops to between 10 and 50 mL/min, the total insulin dose should be reduced by 25%; once the filtration rate is below 10 mL/min, as in ESRD, the insulin dose should be decreased by 50% from the previous amount.^41,42

The newer insulins such as glargine and lispro are more favorable than NPH and regular insulin, but they cost more, which can be an obstacle for some patients.

OBSERVATIONS AND RECOMMENDATIONS

After reviewing the available evidence for the use of diabetic therapy in ESRD, we offer the following observations and recommendations:

Glycemic control and monitoring in ESRD are complex.
Patients with ESRD are especially susceptible to hypoglycemia, so diabetic drug therapy requires special caution.
ESRD patients need ongoing diabetes education, with an emphasis on how to recognize and treat hypoglycemia.
Diabetic pharmacotherapy in ESRD should be individualized. The targets of therapy are a hemoglobin A_1c value between 6% and 7%, a fasting blood glucose level less than 140 mg/dL, and a postprandial glucose level less than 200 mg/dL.
Of the oral antidiabetic drugs available, glipizide, sitagliptin, and saxagliptin may be used in ESRD. Glipizide, starting with 2.5 mg daily, should be reserved for ESRD patients with a hemoglobin A_1c value less than 8.5%.
Thiazolidinediones may cause fluid overload and thus should be avoided in ESRD.
We recommend a long-acting insulin (glargine or NPH) for basal requirements, along with rapid-acting insulin before meals two or three times daily.
The newer basal insulin (glargine) and rapid-acting insulin analogues (lispro or aspart insulin) are more favorable than NPH and regular insulin, but their higher cost could be an issue.
Some patients may prefer a premixed insulin combination for convenience of dosing. In that case, NPH plus lispro insulin may be better than NPH plus regular insulin.
For ESRD patients with type 1 diabetes, insulin therapy should be started at 0.5 IU/kg, which is half the calculated dose in patients without renal failure.
For ESRD patients with type 2 diabetes, insulin therapy should be started at a total daily dose of 0.25 IU/kg.
Further adjustments to the regimen should be individualized based on self-monitored blood glucose patterns.
We recommend consulting an endocrinologist with expertise in managing diabetes in ESRD.

References

National Institute of Diabetes and Digestive and Kidney Diseases: United States Renal Data System: USRDS 2005 Annual Data Report. Bethesda, MD: National Institutes of Health, 2005.
Wu MS, Yu CC, Yang CW, et al. Poor pre-dialysis glycaemic control is a predictor of mortality in type II diabetic patients on maintenance haemodialysis. Nephrol Dial Transplant 1997; 12:2105–2110.
Morioka T, Emoto M, Tabata T, et al. Glycemic control is a predictor of survival for diabetic patients on hemodialysis. Diabetes Care 2001; 24:909–913.
McMurray SD, Johnson G, Davis S, McDougall K. Diabetes education and care management significantly improve patient outcomes in the dialysis unit. Am J Kidney Dis 2002; 40:566–575.
Oomichi T, Emoto M, Tabata T, et al. Impact of glycemic control on survival of diabetic patients on chronic regular hemodialysis: a 7-year observational study. Diabetes Care 2006; 29:1496–1500.
Williams ME, Lacson E, Teng M, Ofsthun N, Lazarus JM. Hemodialyzed type I and type II diabetic patients in the US: characteristics, glycemic control, and survival. Kidney Int 2006; 70:1503–1509.
Tzamaloukas AH, Yuan ZY, Murata GH, Avasthi PS, Oreopoulos DG. Clinical associations of glycemic control in diabetics on CAPD. Adv Perit Dial 1993; 9:291–294.
Tzamaloukas AH, Murata GH, Zager PG, Eisenberg B, Avasthi PS. The relationship between glycemic control and morbidity and mortality for diabetics on dialysis. ASAIO J 1993; 39:880–885.
Kalantar-Zadeh K, Kopple JD, Regidor DL, et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care 2007; 30:1049–1055.
Kovesdy C, Sharma K, Kalantar-Zadeh. Glycemic control in diabetic CKD patients: where do we stand? Am J Kidney Dis 2008; 52:766–777.
Mak RH. Intravenous 1,25-dihydroxycholecalciferol corrects glucose intolerance in hemodialysis patients. Kidney Int 1992; 41:1049–1054.
Hajjar SM, Fadda GZ, Thanakitcharu P, Smogorzewski M, Massry SG. Reduced activity of Na(+)-K+ ATPase of pancreatic islet cells in chronic renal failure: role of secondary hyperparathyroidism. J Am Soc Nephrol 1992; 2:1355–1359.
Grodstein GP, Blumenkrantz MJ, Kopple JD, Moran JK, Coburn JW. Glucose absorption during continuous ambulatory peritoneal dialysis. Kidney Int 1981; 19:564–567.
Joy MS, Cefali WT, Hogan SL, Nachman PH. Long-term glycemic control measurements in diabetic patients receiving hemodialysis. Am J Kidney Dis 2002; 39:297–307.
Lamb E, Venton TR, Cattell WR, Dawnay A. Serum glycated albumin and fructosamine in renal dialysis patients. Nephron 1993; 64:82–88.
Inaba M, Okuno S, Kumeda Y, et al; Osaka CKD Expert Research Group. 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 2007; 18:896–903.
Constanti C, Simo JM, Joven J, Camps J. Serum fructosamine concentration in patients with nephrotic syndrome and with cirrhosis of the liver: the influence of hypoalbuminaemia and hypergammaglobulinaemia. Ann Clin Biochem 1992; 29:437–442.
Ford HC, Lim WC, Crooke MJ. Hemoglobin A1 and serum fructosamine levels in hyperthyroidism. Clin Chim Acta 1987; 166:317–321.
Mak RH. Impact of end-stage renal disease and dialysis on glycemic control. Semin Dial 2000; 13:4–8.
Skillman TG, Feldman JM. The pharmacology of sulfonylureas. Am J Med 1981; 70:361–372.
Krepinsky J, Ingram AJ, Clase CM. Prolonged sulfonylurea-induced hypoglycemia in diabetic patients with end-stage renal disease. Am J Kidney Dis 2000; 35:500–505.
Snyder RW, Berns JS. Use of insulin and oral hypoglycemic medications in patients with diabetes mellitus and advanced kidney disease. Semin Dial 2004; 17:365–370.
United Kingdom Prospective Diabetes Study (UKPDS) 13. Relative efficacy of randomly allocated diet, sulphonylureas, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995; 310:83–88.
Inoue T, Shibahara N, Miyagawa K, et al. Pharmacokinetics of nateglinide and its metabolites in subjects with type 2 diabetes mellitus and renal failure. Clin Nephrol 2003; 60:90–95.
Nagai T, Imamura M, Iizuka K, Mori M. Hypoglycemia due to nateglinide administration in diabetic patient with chronic renal failure. Diabetes Res Clin Pract 2003; 59:191–194.
Thompson-Culkin K, Zussman B, Miller AK, Freed MI. Pharmacokinetics of rosiglitazone in patients with end-stage renal disease. J Int Med Res 2002; 30:391–399.
Nesto RW, Bell D, Bonow RO, et al. Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association. Diabetes Care 2004; 27:256–263.
Hermansen K, Kipnes M, Luo E, Fanurik D, Khatami H, Stein P; Sitagliptin Study 035 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, in patients with type 2 diabetes mellitus inadequately controlled on glimepiride alone or on glimepiride and metformin. Diabetes Obes Metab 2007; 9:733–745.
Charbonnel B, Karasik A, Liu J, Wu M, Meininger G, et al; Sitagliptin Study 020 Group Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled with metformin alone. Diabetes Care 2006; 29:2638–2643.
Goldstein BJ, Feinglos MN, Lunceford JK, Johnson J, Williams-Herman DE; Sitagliptin 036 Study Group. Effect of initial combination therapy with sitagliptin, a dipeptidyl peptidase-4 inhibitor, and metformin on glycemic control in patients with type 2 diabetes. Diabetes Care 2007; 30:1979–1987.
Nauck MA, Meininger G, Sheng D, Terranella L, Stein PP; Sitagliptin Study 024 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor, sitagliptin, compared with the sulfonylurea, glipizide, in patients with type 2 diabetes inadequately controlled on metformin alone: a randomized, double-blind, non-inferiority trial. Diabetes Obes Metab 2007; 9:194–205.
Rosenstock J, Brazg R, Andryuk PJ, Lu K, Stein P; Sitagliptin Study 019 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing pioglitazone therapy in patients with type 2 diabetes: a 24-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther 2006; 28:1556–1568.
Bergman AJ, Cote J, Yi B, et al. Effect of renal insufficiency on the pharmacokinetics of sitagliptin, a dipeptidyl peptidase-4 inhibitor. Diabetes Care 2007; 30:1862–1864.
Carone FA, Peterson DR. Hydrolysis and transport of small peptides by the proximal tubule. Am J Physiol 1980; 238:F151–F158.
Rabkin R, Simon NM, Steiner S, Colwell JA. Effects of renal disease on renal uptake and excretion of insulin in man. N Engl J Med 1970; 282:182–187.
Mak RH, DeFronzo RA. Glucose and insulin metabolism in uremia. Nephron 1992; 61:377–382.
Biesenbach G, Raml A, Schmekal B, Eichbauer-Sturm G. Decreased insulin requirement in relation to GFR in nephropathic type 1 and insulin-treated type 2 diabetic patients. Diabet Med 2003; 20:642–645.
Aisenpreis U, Pfützner A, Giehl M, Keller F, Jehle PM. Pharmacokinetics and pharmacodynamics of insulin Lispro compared with regular insulin in hemodialysis patients with diabetes mellitus. Nephrol Dial Transplant 1999; 14( suppl 4):5–6.
Tunbridge FK, Newens A, Home PD, et al. A comparison of human ultralente- and lente-based twice-daily injection regimens. Diabet Med 1989; 6:496–501.
Freeman SL, O’Brien PC, Rizza RA. Use of human ultralente as the basal insulin component in treatment of patients with IDDM. Diabetes Res Clin Pract 1991; 12:187–192.
Charpentier G, Riveline JP, Varroud-Vial M. Management of drugs affecting blood glucose in diabetic patients with renal failure. Diabetes Metab 2000; 26( suppl 4):73–85.
Aronoff GR, Berns JS, Brier ME, et al, eds. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults, 4th ed. Philadelphia, PA: American College of Physicians, 1999.

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Managing diabetes in hemodialysis patients: Observations and recommendations

References

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Managing diabetes in hemodialysis patients: Observations and recommendations

References

ESRD REDUCES INSULIN CLEARANCE

OBSERVATIONS AND RECOMMENDATIONS

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