Although evidence and experience show that A1C is commonly used to assess diabetes control over time, A1C may not appropriately measure glycemic burden in patients with chronic kidney disease (CKD), with both bias and more variability around the mean possible, according to Leila R. Zelnick, PhD. With red blood cell (RBC) turnover increased in patients with CKD, less opportunity is provided for hemoglobin glycation for a given level of glycemia, such that even small changes in RBC life span can affect A1C; consequently, A1C has been shown to underestimate glycemia in those with estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 and those on dialysis. Also, anemia—common in CKD—and its treatment can affect A1C.

Comparing Biomarkers
With glycated albumin and fructosamine postulated to be better biomarkers of glycemic control than A1C in patients with CKD, Dr. Zelnick and colleagues conducted a study—published in Diabetes Care—to evaluate the accuracy, variability, and covariate bias of all three when compared with those of continuous glucose monitoring (CGM)–derived measurement of glycemia across eGFR in patients with type 2 diabetes. “A total of 104 participants with type 2 diabetes (80 with eGFR <60 mL/min/1.73m2 and not treated with dialysis, and 24 frequency-matched controls subjects with eGFR ≥60 mL/min/1.73m2) wore a blinded CGM for two 6-day periods separated by 2 weeks,” explains Dr. Zelnick. “We collected blood and urine at the end of each CGM period.” A1C, glycated albumin, and fructosamine were measured by high-performance liquid chromatographic, enzymatic, and colorimetric nitroblue tetrozolium methods, respectively.

“Our study found that glycated albumin and fructosamine were not less variable than A1C at a given mean CGM glucose level, with several additional sources of bias,” notes Dr. Zelnick. “Compared with mean CGM glucose, glycated albumin and fructosamine were significantly biased by age, BMI, serum iron concentration, transferrin saturation, and albuminuria; A1C was underestimated in those with albuminuria. These results support measuring A1C to monitor long-term trends in glycemia among patients with eGFR <60 mL/min/1.73m2 not treated with dialysis.”

When assessing within-person repeatability of glycemia markers and mean CGM glucose over about 3 weeks, the study team found all three biomarkers tended to be highly consistent, “which makes sense since these are measures of long-term glycemic exposure,” Dr. Zelnick says (Table I). “CGM mean glucose changed more over this period, which could reflect variability as a result of lifestyle, medication use, or in some cases, physician intervention. Knowing about short-term changes in blood glucose can be important clinically; the biomarkers we studied are for long-term glycemic management and cannot capture short-term variability and hypoglycemia in the same way that CGM-derived measurements can.” Despite similar correlation with CGM mean glucose for each of the three biomarkers studied, observed values fell within 10% of that predicted by CGM mean glucose more often for A1C than for glycated albumin or fructosamine (Table II). All biomarkers were significantly more variable as a marker of CGM mean glucose for participants with lower eGFR.

A1C No More Variable & Less Biased

“Our results suggest that A1C is no more variable and is less biased than other biomarkers in patients with type 2 diabetes and eGFR <60 mL/min/1.73m2 not treated with dialysis, and they support guideline recommendations—including the most recently published—to measure A1C to monitor long-term trends in glycemia in this patient population,” says Dr. Zelnick. “Where shorter-term variability is important, these biomarkers are not a substitute for direct measurements of blood glucose, such as those obtained using CGM.”