Impact of blood glucose self-monitoring errors on glucose variability, risk for hypoglycemia, and average glucose control in type 1 diabetes: an in silico study

Abstract

Background: Clinical trials assessing the impact of errors in self-monitoring of blood glucose (SMBG) on the quality of glycemic control in diabetes are inherently difficult to execute. Consequently, the objectives of this study were to employ realistic computer simulation based on a validated model of the human metabolic system and to provide potentially valuable information about the relationships among SMBG errors, risk for hypoglycemia, glucose variability, and long-term glycemic control.

Methods: Sixteen thousand computer simulation trials were conducted using 100 simulated adults with type 1 diabetes. Each simulated subject was used in four simulation experiments aiming to assess the impact of SMBG errors on detection of hypoglycemia (experiment 1), risk for hypoglycemia (experiment 2), glucose variability (experiment 3), and long-term average glucose control, i.e., estimated hemoglobin A1c (HbA1c)(experiment 4). Each experiment was repeated 10 times at each of four increasing levels of SMBG errors: 5, 10, 15, and 20% deviation from the true blood glucose value.

Results: When the permitted SMBG error increased from 0 to 5-10% to 15-20%-the current level allowed by International Organization for Standardization 15197-(1) the probability for missing blood glucose readings of 60 mg/dl increased from 0 to 0-1% to 3.5-10%; (2) the incidence of hypoglycemia, defined as reference blood glucose <or=70 mg/dl, changed from 0 to 0-0% to 0.1-5.5%; (3) glucose variability increased as well, as indicated by control variability grid analysis; and (4) the incidence of hypoglycemia increased from 15.0 to 15.2-18.8% to 22-25.6%. When compensating for this increase, glycemic control deteriorated with HbA1c increasing gradually from 7.00 to 7.01-7.12% to 7.26-7.40%.

Conclusions: A number of parameters of glycemic control deteriorated substantially with the increase of permitted SMBG errors, as revealed by a series of computer simulations (e.g., in silico) experiments. A threshold effect apparent between 10 and 15% permitted SMBG error for most parameters, except for HbA1c, which appeared to be increasing relatively linearly with increasing SMBG error above 10%.

Figure 1.

Distribution of simulated SMBG errors at the maximum error level of 20% permitted for BG >75 mg/dl by the ISO standard. The error for BG ≤75 mg/dl is kept within ±15 mg/dl from reference. To simulate a lower degree of error, e.g., 15, 10, or 5%, this distribution is scaled by appropriate reduction in its standard deviation.

Figure 2.

(A) Probability of SMBG missing hypoglycemia as a function of BG level and permitted SMBG error. It is evident that even significant hypoglycemic episodes of 60 mg/dl or lower can be missed by SMBG with errors within 20% as allowed by ISO 15197. (B) Reference BG is fixed at 60 mg/dl. The probability for missing that hypoglycemic event increases, initially slowly, until the permitted SMBG error reaches a level between 10 and 15%. After that error threshold, the increase accelerates substantially.

Figure 3.

Distribution of BG levels achieved when a correction bolus was calculated precisely to bring each of the simulated subjects from 200 to 100 mg/dl. It is evident that the chances for not achieving the target increase substantially with the increase in meter error.

Figure 4.

A CVGA plot comparing 5% permitted meter error (white dots) to 20% permitted meter error (black dots) in terms of glucose variability caused by SMBG inaccuracy. It is evident that the amplitude of BG fluctuations increases with increased SMBG error.

Figure 5.

Relationship between the degree of permitted SMBG error and percent days with hypoglycemia during experiment 4 (A). Deterioration in HbA1c as mediated by risk for hypoglycemia (B).