Response to the Letter by Pfützner and Forst

Pfützner and Forst (1) report that they found no significant blood glucose (BG) differences between the arm and finger during 1) BG decrease induced by intravenous insulin injection, and 2) BG increase and decrease induced by a standardized meal in combination with subcutaneous insulin injection.

As previously suggested by Pfützner and Forst, the observed differences between our data and their observations are caused by differences in experimental design. Our study protocol aimed at rapid BG decreases and achieved a mean BG change at the finger (averaged over total decline) of 3 mg · dl⁻¹ · min⁻¹. Hypoglycemic values at the finger were reached faster after insulin injection. This velocity has not been repeated by Pfützner and Forst, as their mean rate of BG decline did not exceed 2 mg · dl⁻ · min⁻¹ during the first hour after insulin injection and fell below 1 mg · dl⁻¹ · min⁻¹ during the second hour after insulin injection. Hypoglycemic values <60 mg/dl were not reached at all (Fig. 1 of Pfützner and Forst).

The same applies to the BG data in Pfützner and Forst’s Fig. 2, as these BG values declined at a mean rate <0.5 mg · dl⁻¹ · min⁻¹ from the second until the eighth hour after subcutaneous insulin injection. These results are well in agreement with our own observations that the chance of observing clinically relevant BG differences are very low if mean BG change rates (averaged over at least 45–60 min) are <2 mg · dl⁻¹ · min⁻¹ (2). Applying our original study protocol, we have provided evidence that the described BG differences between the arm and finger can be observed with the Soft-Sense device (Fig. 1) (used by Pfützner and Forst), as well as with other BG devices approved for alternative-site testing. We conclude that the data provided by Pfützner and Forst do not sufficiently address the question of the effects of rapid BG changes on BG differences between the finger and alternate skin sites such as the arm. Therefore, their data do not support their unrestricted statement that Soft-Sense would be a suitable alternative option, as far as rapid BG changes are concerned, for glucose monitoring in daily practice.

Concerning the likelihood of rapid BG changes >2 mg · dl⁻¹ · min⁻¹ in daily life, it is well known from continuous glucose monitoring studies, particularly in insulin-treated patients with type 1 diabetes, that such rapid BG changes can occur and often go unrecognized by patients (3,4). Based on our studies with 17 diabetic patients on subcutaneous continuous glucose monitoring up to 72 h/patient (4), an average 7% of all BG changes have been >2 mg · dl⁻¹ · min⁻¹ (maximum 5.7). Therefore, our study design does match daily treatment situations and is so far realistic, not artificial.

Our study was designed to examine whether potential clinical risks can be associated with alternative-site monitoring at the forearm and, if such risks exist, to estimate the potential severity of the risks. A standardized experimental protocol was therefore used. Exact determination of the probability and severity of the described potential hazard is an important task originating from our findings. Keeping the probability of rapid BG changes in mind, we feel that experimental studies per se, even if they are designed to mimic daily life (as done by Pfützner and Forst), are an inadequate tool to exclude the relevance of our findings in daily life. We would suggest proving clinical significance under real daily life conditions in population-based field studies that include samples taken at times of presumed rapid BG change. Such a study has been performed and presented to the U.S. Federal Drug Administration (5). The results of this study support our concern that clinically relevant BG differences occur under daily life conditions, as BG differences between fingertip and forearm exceeding even 100 mg/dl were observed. Therefore, our preliminary clinical recommendations remain unchanged. This is supported by essentially identical recommendations of the Clinical Chemistry and Clinical Toxicology Devices Panel of the Medical Devices Advisory Committee Panel to the U.S. Food and Drug Administration (6).