Comparing the performance of different Continuous Glucose Monitoring (CGM) systems is challenging due to the lack of comprehensive guidelines for clinical study design. In particular, the absence of broadly accepted requirements for the distribution of comparator blood glucose (BG) concentrations and their rate of change (RoC) impairs comparability.
In 2024, a group of experts proposed requirements for an adequate distribution of comparator glucose measurements and a testing procedure for the manipulation of glucose levels. The proposed testing procedure consists of a meal to raise BG concentrations and a delayed individualized insulin bolus to reach the normo-/hypoglycemic range without any control of the RoC between both ranges [1].
However, especially rapidly falling BG concentrations deserve special interest because of the risk for serious hypoglycemia and, due to the well-known time lag of the CGMs, there is a potential for large differences between measured CGM values and the actual BG concentration.
Therefore, we modified the operation mode of our Glucose Clamp device ClampArt® (see figure below) from using a predefined fixed target level for the entire duration of the clamp experiment to a predefined target level for each minute of the experiment. We defined the minute-by-minute target levels to follow the glucose profile proposed by the experts, as shown in the left panel of the figure above [1].
Methods
The ClampArt® device measures BG values every minute, calculates, and applies the glucose infusion rate, needed to keep the BG concentration at the predefined target level.
For this in-vitro study, we refined the software of ClampArt® and implemented the option of clamps with precise RoC-settings by introducing a glucose target profile rather than a fixed target level.
For the evaluation the ClampArt® device was used in an in-vitro setting to determine the glucose concentration in a 5 L container filled with a glucose solution, using a setup as realistically as possible (same pumps, same tubing, same catheter,…).
The blood glucose lowering effect of an insulin was simulated by infusing water into the container (i.e. diluting the glucose solution in the container) using an external programmable precision pump.
With this setup we are able to reach the proposed hyper-, normo- and hypoglycemic targets and to create reproducible RoCs for a reliable comparison of CGMs.
The glucose clamp device was used to calculate and administer the appropriate amount of glucose solution to keep the glucose concentration within the container at the fixed target levels and the predefined rising and falling target levels as close as possible.
Figure 1: Definition of the glucose profile used in the study.
We decided to use a RoC of 2.0 mg/dl/min for positive slopes und a smaller RoC of -1.5 mg/dl/min for negative slopes above a glucose concentration of 150 mg/dl and -1.0 mg/dl/min below 150 mg/dl, respectively.
At any point in time we had a pre-defined BG target level and assessed how the ClampArt® device was able to keep the BG values close to the target.
Results
Figure 2: BG and GIR course of in-vitro glucose clamp with a predefined target profile.
The rise in glucose values up to 250 mg/dl was caused by ClampArt® appropriately infusing glucose into the 5 L container (glucose infusion rate in green). At 250 mg/dl a water infusion into the container was started to simulate the BG lowering effect of insulin. The insulin effect i.e. the dilution of the glucose concentration within the container via water infusion was maintained throughout the remaining time of the experiment.
In all in-vitro experiments, we achieved excellent agreement between the BG values and the target levels and time in normo-, hyper- and hypoglycemia with a precision between 1.5% - 5.5% as well as highly reproducible positive and negative RoCs resulting in a control deviation (mean sum of target BG – actual BG) of 1.1 mg/dl and an absolute control deviation (mean sum of abs(target BG – actual BG)) of 4.7 mg/dl.
The modified software of ClampArt® establishes precise and automatically controlled BG target levels with predefined change rates for rising and declining BG values.
Figure 3: Dynamic glucose region plot of the in-vitro glucose clamp.
Figure 3 shows the so-called dynamic glucose region plot, a graphical representation for the combination of BG concentrations and RoC, developed by [1]. This plot is divided into five regions comprising four critical regions (red and orange) an one neutral region (green). The critical regions were chosen to reflect situations in which adequate CGM accuracy is of particular importance and are based on commonly used BG concentration thresholds.
In contrast to the meal-and-late-insulin-bolus approach by the experts in [1], the measured BG-values can be clearly assigned to different pre-defined and therefore reproducible RoCs.
Reproducible RoCs are key for the comparison of different CGM devices in that particular situation.
Conclusion
The modified software of ClampArt® automatically establishes BG at target levels with predefined rates of change for rising and declining BG values.
This work is a step towards establishing a future standard for the performance evaluation of CGM devices, ensuring that desired periods are spent in the hypo-, normo- and hyperglycemic ranges, with desired RoCs in a safe and reproducible way.
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[1] Eichenlaub M., Pleus S., Rothenbühler M., et al. Comparator Data Characteristics and Testing Procedures for the Clinical Performance Evaluation of Continuous Glucose Monitoring Systems, Diabetes Technology & Therapeutics 2024; 26(4): 263-275