SAN FRANCISCO — The physiological lag between glucose levels in the blood and in interstitial fluid can wreak havoc in continuous glucose monitoring if the lag isn't considered when calibrating the monitors, according to Dr. Howard A. Wolpert.

Patients with diabetes who want to use continuous glucose monitors need to be instructed to calibrate the devices when their glucose levels are in a steady state rather than during a period of changing glucose levels, Dr. Wolpert said at a meeting sponsored by the American Diabetes Association.

Finger-stick monitors and the electrochemical sensors in continuous glucose monitors (CGMs) work on the same principle, based on glucose oxidase breaking down glucose and generating electrons, which are measured by the monitor's sensors. Finger-stick monitors measure serum glucose, and continuous monitors measure glucose in the interstitial fluid. When glucose levels are changing—such as rising glucose levels seen particularly after meals—there can be as much as a 30-minute delay before a changed glucose level in blood is reflected in interstitial fluid.

“If patients calibrate the continuous glucose monitoring devices when their glucose is changing and they're not in steady state, their sensor is going to be calibrated inaccurately and not give them reliable readings,” said Dr. Wolpert of the Joslin Diabetes Center, Boston.

This has implications not only for accuracy but also for the patient's confidence in the device and willingness to monitor glucose levels. It also can affect the choices the patient makes when recovering from a hypoglycemic episode, and when setting the monitor's alarms at optimal levels, he said.

Dr. Wolpert gave the example of a person's blood glucose increasing 3 mg/dL per minute, which is not uncommon after a meal. If that patient has a 10-minute physiological lag, there's a 30-mg/dL discrepancy between the blood glucose and interstitial fluid glucose. By calibrating a continuous glucose monitor at that time, the patient might tell the monitor that the 140 mg/dL that it's measuring in the interstitial fluid should be 170 mg/dL instead, which would be inaccurate. That throws off future readings.

“It's something that patients need to be aware of—otherwise, they'll lose confidence in the technology. They'll think it's an inaccurate device rather than just a biologic lag,” he said.

Data from a study of one model of continuous glucose monitor show that when it was calibrated as glucose levels were rapidly changing—either increasing or decreasing by more than 2 mg/dL per minute—only 50%-60% of its readings were in the clinically accurate Clarke error grid A zone, with a mean absolute relative difference of around 17%, Dr. Wolpert said. When the monitor was calibrated while glucose was relatively stable, accuracy improved, with up to 85% of readings in the A zone and a mean absolute relative difference of 9%.

In addition, when glucose is changing rapidly, the physiological lag results in the monitor not fully registering the rate of change, which can mislead the patient. Patients recovering from hypoglycemia may think they need more carbohydrates because the monitor reading is 55 mg/dL although the plasma glucose has come up to normal, above 70 mg/dL. These patients should do a finger-stick measurement before deciding whether to take any more carbohydrates, Dr. Wolpert said.

The lag also has implications for sensor alarm settings. One patient who had set his continuous glucose monitor alarms to alert him when glucose levels hit a high of 200 mg/dL or a low of 60 mg/dL was awakened by a high alarm at night. A finger-stick test showed a glucose level of 238 mg/dL. He gave himself a bolus of insulin and went back to sleep. In the morning, his finger-stick glucose measurement was 52 mg/dL, but the continuous glucose monitor hadn't warned him with a low alarm because it still read a level of 70 mg/dL. “This is a reflection of the lag,” Dr. Wolpert said.

He recommended that the patient increase the low alarm to a higher level of 70–75 mg/dL. The patient tried that but complained of too many false alarms, and reverted to the former settings. Dr. Wolpert noted that wider settings for alarm levels will reduce the number of irritating and intrusive false alarms, but patients won't know of all their high and low glucose levels.

The narrower alarm settings may be best for patients with severe hypoglycemia or frequent hypoglycemic reactions, to be sure they're alerted of those situations, he suggested. Wider alarm settings may be best for patients new to continuous glucose monitors, “until they really get a handle on their glucose fluctuations,” he said. “As they improve their control, tighten up those thresholds.”

Dr. Wolpert has relationships with several companies that make continuous glucose monitors and other monitoring equipment, including Medtronic Inc., Lifescan Inc., Roche Diagnostics, and Novo Nordisk.

Timing an Issue When Calibrating CGMs : Lag time between serum glucose and interstitial fluid can cause chaos with sensor readings.