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Journal of the American Academy of Physician Assistants:
Commentary

Glycemic control in patients with diabetes and nephropathy

Freedman, Barry I. MD, FACP; Tuttle, Audrey B. PA‐C

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practice in the Department of Internal Medicine, Section on Nephrology, Wake Forest School of Medicine, Winston‐Salem, North Carolina.

Disclosure: Dr. Freedman previously received research support from Asahi Kasei Pharma Corporation (Tokyo), which makes an assay that measures GA.

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To view the references, please see the online version of this article at www.jaapa.com.

How aggressively to control blood sugars in patients with diabetes mellitus continues to be debated.1

Despite this uncertainty, the hemoglobin A1C assay remains useful for monitoring recent serum glucose control in patients without advanced kidney disease. The A1C reflects glycemic control during the preceding 120 days, particularly within the past 30 days. Improved glycemic control based on A1C reduces the development and progression of diabetic microvascular complications, including nephropathy and retinopathy.2

A1C levels are impacted not only by ambient blood sugar concentrations but also by the half‐life of circulating RBCs. Hemoglobin resides in RBCs and chemically interacts with glucose to yield glycated hemoglobin. As such, A1C concentrations are significantly reduced in hemolysis and after large volume blood transfusion, so A1C should not be relied on in such scenarios. Instead, frequent blood sugar testing, assays that do not depend on normal RBC survival—such as fructosamine or glycated albumin (GA)—or continuous glucose monitoring may be more useful. A1C is also significantly impacted by severe nephropathy, particularly stage 5 chronic kidney disease (CKD) and end‐stage renal disease (ESRD) in patients undergoing hemodialysis or peritoneal dialysis.3,4 Given equal degrees of glycemic control, A1C values are markedly lower in diabetic patients with advanced nephropathy than in diabetic patients with normal kidney function; and the situation is exacerbated by more severe anemia and/ or receipt of high dose erythropoietin.3‐6 Reduced A1C levels tend to give these patients and their caregivers a false sense of security, suggesting that blood sugars are lower than they really are. This effect may contribute to the dismal mortality rates seen in diabetic patients receiving dialysis.

An important question thus arises: Should clinicians rely on A1C values in patients with ESRD and subsequently adjust for the factors that appear to alter its concentration, or should alternative assays be employed? Several recent studies weigh in on this question. Ricks and colleagues demonstrated that an adjusted A1C has validity in determining outcomes in patients on dialysis.7 Reports by Inaba and colleagues3 and our group4‐6 reveal that the GA assay, measuring glycation of albumin (not hemoglobin), is more accurate in patients with advanced nephropathy and better predicts survival and hospitalizations. The GA assay reflects blood sugar concentrations over the preceding 60 days, particularly during the past 17 days. Armed with an improved understanding of how kidney disease impacts assays of glycemic control, clinicians will be better able to decide which approach to use.

Two large reports evaluating hemodialysis patient survival based on A1C reached opposing conclusions;8,9 another demonstrated that only extreme A1C values—those less than 5.01% or greater than 11%—predicted hospitalization rates.10 A recent analysis involving nearly 55,000 prevalent patients on hemodialysis revealed a U‐shaped survival curve; poorer survival was seen in those with the lowest and the highest A1Cs.7 Lower values likely reflect malnutrition, whereas the adverse effects of high A1C on patient survival were detectable only after adjustment for a large number of demographic and clinical variables. In unadjusted analyses, higher A1C levels were paradoxically associated with improved survival, likely reflecting better nutritional status. Therefore, clinicians employing the A1C assay to predict patient survival on dialysis must consider performing intensive statistical adjustment as raw scores do not predict outcomes. The assay fared better among the subset of dialysis patients who lack severe anemia.11 Unfortunately, this includes a minority of the ESRD population.

Several reports demonstrate that the GA assay more accurately reflects recent glycemic control in patients on dialysis relative to A1C. Although loss of urinary albumin (nephrotic syndrome secondary to diabetes) or via peritoneal dialysate can interfere with GA results, in practice this does not appear to be an issue. A longitudinal study following 444 patients treated in one outpatient dialysis program for 2.3 years revealed that GA predicted patient survival and hospitalizations in those on dialysis,12 an effect seen with minimal statistical adjustment. Hence, GA results may be easier to apply and interpret in patients on dialysis. Although the GA assay is widely utilized in Asia, it has not yet been FDA approved for use in the United States.

At present, clinicians who treat patients with diabetes on dialysis or with advanced CKD must choose how best to perform glucose monitoring. Options include frequently measuring blood sugars (by patients or by way of continuous glucose monitoring) as serum glucose readings are accurate in patients with ESRD; using assays that do not reflect RBC survival (eg, fructosamine); or relying on adjusted A1C. GA will provide another useful option once it becomes available.

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REFERENCES

1. Hemmingsen B, Lund SS, Gluud C, et al. Intensive glycaemic control for patients with type 2 diabetes: systematic review with meta-analysis and trial sequential analysis of randomised clinical trials. BMJ. 2011;343:d6898.

2. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012;35(suppl 1):S64-S71.

3. Inaba M, Okuno S, Kumeda Y, 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. 2007;18(3):896-903.

4. Peacock TP, Shihabi ZK, Bleyer AJ, et al. Comparison of glycated albumin and hemoglobin A(1c) levels in diabetic subjects on hemodialysis. Kidney Int. 2008;73(9):1062-1068.

5. Freedman BI, Shenoy RN, Planer JA, et al. Comparison of glycated albumin and hemoglobin A1c concentrations in diabetic subjects on peritoneal and hemodialysis. Perit Dial Int. 2010;30(1):72-79.

6. Freedman BI, Shihabi ZK, Andries L, et al. Relationship between assays of glycemia in diabetic subjects with advanced chronic kidney disease. Am J Nephrol. 2010;31(5):375-379.

7. Ricks J, Molnar MZ, Kovesdy CP, et al. Glycemic control and cardiovascular mortality in hemodialysis patients with diabetes: a 6-year cohort study. Diabetes. 2012;61(3):708-715.

8. Kalantar-Zadeh K, Kopple JD, Regidor DL, et al. A1C and survival in maintenance hemodialysis patients. Diabetes Care. 2007;30(5):1049-1055.

9. Williams ME, Lacson E Jr, Teng M, et al. Hemodialyzed type I and type II diabetic patients in the US: Characteristics, glycemic control, and survival. Kidney Int. 2006;70(8):1503-1509.

10. Williams ME, Lacson E Jr, Teng M, et al. Extremes of glycemic control (HbA1c) increase hospitalization risk in diabetic hemodialysis patients in the USA. Am J Nephrol. 2009;29(1):54-61.

11. Duong U, Mehrotra R, Molnar MZ et al. Glycemic control and survival in peritoneal dialysis patients with diabetes mellitus. Clin J Am Soc Nephrol. 2011;6(5):1041-1048.

12. Freedman BI, Andries L, Shihabi ZK, et al. Glycated albumin and risk of death and hospitalizations in diabetic dialysis patients. Clin J Am Soc Nephrol. 2011;6(7):1635-1643.

© 2012 Lippincott Williams & Wilkins, Inc.

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