Reply to Letter by Alexander Seibold on “Impact of Switching from Intermittently Scanned to Real-Time Continuous Glucose Monitoring Systems in a Type 1 Diabetes Patient French Cohort: An Observational Study of Clinical Practices” by Yannis Préau, et al.

Yannis Préau, Martine Armand, Sébastien Galie, Pauline Schaepelynck, Denis
Raccah

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Yannis Préau, Martine Armand, Sébastien Galie, Pauline Schaepelynck, Denis Raccah. Reply to Letter by Alexander Seibold on “Impact of Switching from Intermittently Scanned to Real-Time Continuous Glucose Monitoring Systems in a Type 1 Diabetes Patient French Cohort: An Observational Study of Clinical Practices” by Yannis Préau, et al.. Diabetes Technology and Therapeutics, 2021, 23 (8), pp.595 - 597. 10.1089/dia.2021.0087. hal-03590210

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# Reply to Letter by Alexander Seibold on "Impact of Switching from Intermittently Scanned to Real-Time Continuous Glucose Monitoring Systems in a Type 1 Diabetes Patient French Cohort: An Observational Study of Clinical Practices" by Yannis Préau, et al. (doi: 10.1089/dia.2020.0674)

Yannis Préau, MSc, MD,<fnref n="1" />,<fnref n="2" /> Martine Armand, PhD,<fnref n="2" /> Sébastien Galie, MD,<fnref n="1" /> Pauline Schaepelynck, MD,<fnref n="1" /> and Denis Raccah, MD, PhD<fnref n="1" />,<fnref n="2" />

Dear Editor,

WE THANK ALEXANDER SEIBOLD for his comments<fnref n="1" /> on our observational study evaluating, retrospectively and in a real-world setting, the benefits in glucose management of a switch from an intermittently scanned continuous glucose monitoring (isCGM) to a real time CGM (rtCGM) systems in type 1 diabetes (T1D) patients with persistent glycemic disorders (hypoglycemia issue and/or high level of hemoglobin A1c [HbA1c]) despite an intensified insulin regimen and use of a FreeStyle Libre 1 (FSL1) device for at least 1 year.<fnref n="2" />

First, our monocentric study was not designed as a study comparing the efficiency of two different devices and was not funded by any company; it is an observational study of clinical practice. Thus, the notion of superiority of one device to another is never mentioned, as the design and the context of the study did not aim supporting this. As explained in our article, in our department of diabetology, we propose, as one “therapeutical option,” a switch to rtCGM (Dexcom G4 platinum [DG4] because it is a system reimbursed by the French Health Insurance) when patients with poor glycemic control on FSL1 want to keep their usual insulin pump (for continuous subcutaneous insulin infusion) or to continue using multiple daily insulin injection. Only a moderate fraction of our followed up T1D population is concerned, explaining the limited number of patients whose data are reportable. In addition, out of 25 concerned medical folders, 7 were not usable to respect the availability of the needed data (i.e., due to missing data when DG4 use was stopped) or the adherence to the Therapeutic Patient Educational Program (rejected when missing planned visits) that is essential in our clinical practice on CGM. The withdrawal of such folders did

not constitute a study bias for us but rather a logical way to do. As already mentioned in our article, we agree that the small number of patients is a limitation, and those results have to be considered with caution and in the narrow conditions of the specific profile of our observed patients, that is, patients encountering difficulties in making optimal use of the FSL system in everyday life for different reasons (decline in adherence, lack of educational reminders on the behaviors to adopt according to displayed values and trends arrows, and repeated skin reactions to the sensor)³,⁴ explaining the moderate number of daily scans (average of 6 scans/day), whereas an almost linear relationship exists between scans frequency and the improvement of CGM metrics (even beyond 14 scans/day).⁵,⁶ Also, even though averages are needed in scientific publications, we think that considering the benefits for each patient individually is more pertinent to a physician's point of view rather than considering a global impact on a group of population, which cannot be generalizable, especially when patients can be responders or nonresponders. In the light of this opinion, it was satisfactory that 50% of the followed up patients underwent improvement from switching FSL1 to DG4 for a 6-month period in our study. The reasons why only half of the studied patients underwent benefits deserve further interest.

Second, as mentioned in our article as a limitation,<fnref n="2" /> we agree that all sensor systems exhibit different accuracy (in euglycemic and even more in hypoglycemic range), sensitivity, and specificity in functioning (e.g., glycemia calibration, presence of alarms or not, need of scanning or not, implantation site, bleeding on insertion site, and sensor lifetime)⁷ in line with the commentary on the data reported by A. Seibold<fnref n="1" /> as well as by M. Reddy and colleagues in a response to a

<footnote n="1">¹AP-HM, University Hospital Sainte Marguerite, Department of Nutrition and Diabetes, Marseille, France.</footnote>

<footnote n="2">²Aix Marseille Univ, CNRS, CRMBM, Marseille, France.</footnote>
previous letter for the I HART CGM study.⁸ Such points are of high importance in the efficiency of sensors to inform on the achievability of ambulatory glucose profile targets as defined by the Advanced Technologies and Treatments for Diabetes (ATTD) consensus for a good glycemia management.⁹ Indeed, as raised by A. Seibold¹ the hypoglycemia level is underestimation by +19% for DG4 and by +4.9% for FSL1 when reading interstitial glucose in the range 61–80 mg/dL. If transposing this limitation by applying such respective “correcting factor” to our previous data for time below range <70 mg/dL, it emerges a still significant difference on its decrease with a mean (standard deviation [SD]) change of –5.03 (6.13) percentage points (P=0.0029) at 3 months of DG4 use, and a mean (SD) change of –4.13 (6.66) percentage points (P=0.0176) at 6 months of DG4 use. We do not mean this corrective simulation has to be done, but if done the results are still optimistic. Nevertheless, whatever the device used, we have noticed in our article that few of these patients at high risk of hypoglycemia or/and high level of HbA1c were reaching the targets defined by the ATTD.

Third, the relationship between changes in biological HbA1c and average glucose or with the glucose management indicator (GMI) or with improvement in time in range (TIR) 70–180 mg/dL is not so clear. Indeed, in the I HART CGM study extension phase investigating a switch from FSL1 to Dexcom G5, a significant change in TIR was not accompanied by changes in HbA1c in the T1D patients studied that exhibited all a baseline level <8%.¹⁰ In our study,² in a statistical point of view, HbA1c and GMI mean values with FSL1 or with DG4 (at 3 or 6 months of use) were not significantly different (P > 0.5 or P > 0.14, respectively), so there was no trend to consider. However, HbA1c levels were more heterogeneous in our study,² with 50% of patients (n=9) having an elevated HbA1c (≥8%) at baseline (i.e., at the stop of FSL1), and 6 out of 9 underwent, at 3 or 6 months of DG4 use, respectively, a decrease in HbA1c (–0.67 ± 0.33 or –0.43 ± 0.46 percentage points), in GMI (–0.44 ± 1.33 or –0.53 ± 1.13 percentage points), in time above range >180 mg/dL (–3.3 ± 16.7 or –10.2 ± 15.7 percentage points), in average glucose (–11.2 ± 41.7 mg/dL or –21.7 ± 28.9 mg/dL), and an increase in TIR (+10.4 ± 8.4 or +11.9 ± 10.9 percentage points). These data, obtained for patients with elevated HbA1c, are in agreement with the article of Beck et al. showing an increase of 10 percentage points in TIR being predictive of a reduction of HbA1c of –0.6 points on average in 545 T1D patients.¹¹ The nondecrease in HbA1c for the other patients despite an increase in TIR could be due to red blood cell lifespan or other factors influencing HbA1c levels unrelated to the degree of glycemia (chronic renal disease, hemoglobinopathies or hemoglobin variants, hypertriglyceridemia, and hyperbilirubinemia),¹² and was observed by Beck et al. since a 10 percentage points of increase in TIR can correspond to a wide variation in HbA1c (from –1.74 to +0.60 points).

Finally, our study showed benefits on glucose management in a specific group of T1D patients (high risk of hypoglycemia and/or elevated HbA1c) after switching from FSL1 (not optimally used) to DG4 during 3 months of use, benefits that plateaued at 6 months (metrics values not significantly different), and it will be of high interest to observe the evolution on a longer period of follow-up that is, at 12 months (ongoing analyses). We believe in the absolute need for data implying the switch from different combinations of systems (isCGM to

isCGM, rtCGM to isCGM, rtCGM to rtCGM, and isCGM to rtCGM) over long monitoring periods and concerning large number of patients, whereas considering analytical limits in the comparison of CGM data from different devices but having to be part of a search for overall glycemic benefit (including biological HbA1c) and also quality of life and satisfaction for each patient. The principal goal is the setting of personalized medicine counseling the glucose monitoring device best suited to each patient.

## Author Disclosure Statement and Funding Information

Y.P., M.A., and D.R. have no conflict of interest. S.G. discloses congress invitations from Abbott and Medtronic. P.S. discloses congress invitations, honoraria, and consultancies from Abbott. No funding was received for this study.

## References

1. Seibold A: Incongruent changes in lab HbA1c and average glucose underscore significant differences in calibration between continuous glucose monitoring systems during the conduct of a study on glycemic control in type 1 diabetes. Comment on Préau et al. Diabetes Technol Ther 2021; DOI: 10.1089/dia.2020.0674.

2. Préau Y, Armand M, Galie S, et al.: Impact of switching from intermittently scanned to real-time continuous glucose monitoring systems in a type 1 diabetes patient French cohort: an observational study of clinical practices. Diabetes Technol Ther 2021;23: DOI: 10.1089/dia.2020.0515.

3. Reach G: Decisions in the psychology of glucose monitoring. J Diabetes Sci Technol 2019;13:1169–1174.

4. Mine Y, Urakami T, Matsuura D: Allergic contact dermatitis caused by isobornyl acrylate when using the Freestyle Libre. J Diabetes Investig 2019;10:1382–1384.

5. Dunn TC, Xu Y, Hayter G, et al.: Real-world flash glucose monitoring patterns and associations between self-monitoring frequency and glycemic measures: a European analysis of over 60 million glucose tests. Diabetes Res Clin Pract 2018;137:37–46.

6. Riveline JP, Guerci B, Wojtusciszyn, et al.: The frequency of FreeStyle Libre glucose sensor scans performed by the diabetic patient on a daily basis is associated with better parameters form monitoring his glucose profile: analysis of 312 million hours of monitoring in real life in France. Med Mal Metab 2020;14:585–593.

7. Kirchsteiger H, Heinemann L, Freckmann G, et al.: Performance comparison of CGM systems: MARD values are not always a reliable indicator of CGM system accuracy. J Diabetes Sci Technol 2015;9:1030–1040.

8. Reddy M, Oliver N: Reply to Letter by Seibold regarding Monika Reddy, Narvada Jugnee, Sinthuka Anantharaja, and Nick Oliver, Switching from Flash Glucose Monitoring to Continuous Glucose Monitoring on Hypoglycemia in Adults with Type 1 Diabetes at High Hypoglycemia Risk: the Extension Phase of the I HART CGM Study. Diabetes Technol Ther 2019;21:99–100.

9. Battelino T, Danne T, Bergenstal RM, et al.: Clinical targets for continuous glucose monitoring data interpretation: recommendations from the international consensus on time in range. Diabetes Care 2019;42:1593–1603.

10. Reddy M, Jugnee N, Anantharaja S, Oliver N: Switching from flash glucose monitoring to continuous glucose
monitoring on hypoglycemia in adults with type 1 diabetes at high hypoglycemia risk: the extension phase of the I HART CGM study. Diabetes Technol Ther 2018;20:751–757.

11. Beck RW, Bergenstal RM, Cheng P, et al.: The relationships between time in range, hyperglycemia metrics, and HbA1c. J Diabetes Sci Technol 2019;13:614–626.

12. Gallagher EJ, Le Roith D, Bloomgarden Z: Review of haemoglobin A1c in the management of diabetes. J Diabetes 2009;1:9–17.

Address correspondence to:

Yannis Préau, MSc, MD

Department of Nutrition and Diabetes

AP-HM, University Hospital Sainte Marguerite
Pavillon 6, 270 Bd Sainte Marguerite

Marseille 13009

France

E-mail: yannis.preau@ap-hm.fr