Cyclical Variation in HbA1c Values During the Year: Clinical and Research Implications

T he association between glycated he-moglobin (HbA 1c) and long-term diabetes complications is well established (1). Although HbA 1c is a key process and outcome measure in clinical and research settings, reporting varies from single annual measurements to an average of interval measurements per year. Seasonal HbA 1c variability within an individual may impact on audit and intervention studies in clinical trials (2). Previous seasonal variability studies have used small datasets and short time intervals. Six equidistant samples are required to describe a cycle of seasonal variation , which means that a minimum dataset of 3 years is required. We examined seasonal variation using HbA 1c measurements collected quarterly from children aged 2–21 years (mean 12.9 years) attending a single clinic between 1999 and 2012. HbA 1c was measured using the Diabetes Control and Complications Trial–aligned DCA1000 (Siemens IL). Bias was determined over the HbA 1c range 5.0–10.9% (31–96 mmol/mol) using the U.K. External Quality Assessment. The scheme over the time period was 20.08%. A total of 5,140 measurements (average 3.6 measurements/patient/year) were collected and coded for the months January– March, April–June, July–September, and October–December. The data were then subjected to time series analysis. The clinic size increased from 22 to 356 between 1999 and 2012, with a decline in the median HbA 1c from 10.2 to 7.7% (88–61 mmol/mol). The percentage of the clinic with HbA 1c , 7.5% (58 mmol/mol) increased from 9.7 to 40.8%. Insulin pump therapy increased from 0 to 77% of the clinic and was associated with a lower median HbA 1c level (7.5%; 58 mmol/mol) than that with the multiple daily injection regimen (8.8%; 73 mmol/mol) (P , 0.001), and a lower SD (1.2%; 13.1 mmol/mol) than the multiple daily injection regimen (2.0%; 21.9 mmol/mol). The data were stationarized (i.e., the difference plus the mean) prior to analysis to remove the trend of continuous decline in HbA 1c , which interferes with the precise identification of oscillations. Fourier transformation was then used to determine oscillations within the time series (Fig. 1) (3). The decimal precision was confirmed using autocorrelation analysis. Figure 1 shows a dominant (highest power) periodicity (the frequency is the reciprocal) at 6.3 months, indicating a greater than random tendency for the cycle in the time series to recur at this pe-riodicity. The power spectrum translates into a seasonal variation in HbA 1c of 0.3% (3.3 mmol/mol), with values lower in the …