Full Title:

Efficacy of REAL-Time continuous glucose monitoring on glycaemic control and

glucose variability in Type 1 diabetic patients treated with either insulin pumps or

multiple insulin injection therapy: a randomised controlled cross-over trial

Short Title:

Efficacy of REAL-Time continuous glucose monitoring in Type 1 diabetic patients

Andrea Tumminia, MD,1 Salvatore Crimi, MD,1 Laura Sciacca, MD, PhD,1 Massimo

Buscema, MD,1 Lucia Frittitta, MD, PhD,1 Sebastiano Squatrito, MD,1 Riccardo Vigneri,

MD,2, 3 Letizia Tomaselli, MD.2

1
Endocrinology, Department of Clinical and Molecular Biomedicine, University of Catania,

Garibaldi-Nesima Hospital, Via Palermo 636, 95122 Catania, Italy.

2
Endocrinology, Garibaldi-Nesima Hospital, Via Palermo 636, 95122 Catania, Italy.
3
Humanitas, Catania Oncology Center, Catania, Italy.

Corresponding author: Andrea Tumminia

Via Palermo n 636, 95122, Catania, Italy

e-mail: andreatumminia@libero.it

tel: +393384755108 +39095361732 +390957598702

fax: +39095472988

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article
as doi: 10.1002/dmrr.2557

This article is protected by copyright. All rights reserved.

Abstract

Background The aim of this study was to determine the efficacy of REAL-Time continuous

glucose monitoring (CGM) in Type 1 diabetic (T1D) patients treated with insulin pumps

(CSII) or multiple daily insulin injection (MDI) therapy.

Methods Twenty adult patients (10 CSII and 10 MDI) with poor glycaemic control (HbA1c

> 8.0%) were randomised into two groups for 6 months: the CGM arm (using REAL-Time

CGM) and the blood glucose self-monitoring (SMBG) arm. After 2 months of wash-out, the

participants crossed over. The primary outcome was HbA1c reduction. The secondary

outcomes were hypo- and hyper-glycaemia risk assessment (AUC < 70 mg/dl/day and AUC

> 200 mg/dl/day, respectively) and glucose variability.

Results Fourteen patients (8 MDI, 6 CSII) used CGM appropriately (at least 40% of the time).

In these patients, the improvement in glycaemic control was more evident during the REAL-

Time CGM period (7.76% 0.4 vs. 8.54% 0.4, p < 0.05) than during the SMBG period

(8.42% 0.4 vs. 8.56% 0.5, p = 0.2). Better results with CGM were observed in patients

using MDI with greater improvement in both glycaemic control (7.71% 0.2 vs. 8.58% 0.2,

p < 0.05) and glucose variability and with a marked reduction in the risk of both hypo- and

hyper-glycaemia.

Conclusions Appropriate use of REAL-Time CGM improved glyco-metabolic control in

T1D patients. The effects of CGM were more evident in patients under MDI treatment,

compared to CSII. Glucose variability, in addition to glycaemic control, was improved in

compliant diabetic patients.

Keywords

Blood glucose self-monitoring; Type 1 diabetes; glucose variability; REAL-Time continuous

glucose monitoring; insulin pump therapy.

This article is protected by copyright. All rights reserved.

Abbreviations

T1D Type 1 diabetes

CGM Continuous glucose monitoring

SMBG Self-monitoring of blood glucose

CSII Insulin pump therapy

MDI Multiple daily insulin

SAP Sensor-augmented insulin pump therapy

Introduction

Good metabolic control has been associated with a reduced risk of micro- and macro-vascular

complications in Type 1 diabetic (T1D) patients 1 . Despite considerable efforts by both

patients and healthcare providers, however, only a minority of patients achieves an HbA1c

level within the target range 1-3 . The use of insulin pump therapy (CSII) reduces HbA1c

levels more than multiple daily insulin injections (MDI) 4,5 , and therefore, next to other

indications 6 , this treatment is recommended for improving metabolic control when the

glycaemic target values have not been obtained 3 . Additionally, continuous glucose

monitoring (CGM) ameliorates metabolic control in terms of both HbA1c reduction 7-9 and

time spent in hypoglycaemia 10,11 . By combining CSII and CGM (sensor-augmented

insulin pump therapy, or SAP), additional advantages have been obtained in both adult and

paediatric patients 12-14 ; therefore, SAP is considered the most efficacious treatment for

T1D patients.

This article is protected by copyright. All rights reserved.

Glucose variability, in addition to glycaemic level, is another factor that increases metabolic

stress and mortality in acute states 15-19 . Therefore, using only HbA1c measurements does

not adequately define the metabolic status and risk level in patients with diabetes. Diabetes-

related complications, in fact, depend not only on long-term abnormal glucose level

abnormality, but they also depend on short-term glucose variability in terms of both peaks

and nadirs. Fluctuating glucose concentrations can be more deleterious than sustained chronic

hyperglycaemia for both endothelial function and oxidative stress, which are two key players

in the development and progression of diabetic cardiovascular complications. Short-term

fluctuations, however, are difficult to quantify in terms of both entity and duration, except

when using CGM, which continuously measures glucose over a period of several days.

The purpose of this study was to evaluate the effectiveness of REAL-Time (RT) CGM in

improving glycaemic control and reducing glucose fluctuations in T1D patients treated with

either MDI or CSII. CGM efficacy has usually been evaluated in CSII-treated patients

9,12,13,20 . In contrast, our crossover study compared the effectiveness of CGM in CSII- vs.

MDI-treated patients because MDI is still and will certainly remain, in the near future, a very

diffuse treatment for diabetic patients. We evaluated CGM effectiveness not only in terms of

glycaemia decrease but also in terms of changes in glucose variability and the risk of hyper-

and hypo-glycaemia.

This article is protected by copyright. All rights reserved.

Materials and methods

In this controlled, randomised, cross-over intervention study, we evaluated the effects of

CGM on the amelioration of metabolic control, in terms of both glycaemic values and

fluctuations.

Twenty T1D patients, aged 18 - 60 years old, with similar school education (secondary

school) and middle class socio-economic status, were studied. All had diabetes durations

longer than 1 year and HbA1c levels greater than 8.0% (64 mmol/mol). Before entering the

study, ten patients were under MDI treatment, and ten were under CSII treatment for at least

one year (average 4.8 1.3 years). The study was performed at the Diabetes Center at the

Garibaldi-Nesima Hospital, Catania (Italy), in accordance with the principles of the

Declaration of Helsinki.

Exclusion criteria Pregnant women and women planning pregnancy were excluded, as well

as patients with concomitant chronic illness and/or poor compliance to diet, insulin therapy

and/or glucose monitoring (plasma glucose had to be measured at least 4-5 times/day,

correcting the insulin dose when required).

Randomisation was electronically generated, according to a predefined randomisation

sequence. Neither the participants nor the investigators were blinded to the HbA1c data.

Interventions The twenty patients were randomised into two groups: the CGM arm, using

RT-CGM (Guardian REAL-Time Clinical; Medtronic, Tolochenaz, Switzerland) and the

blood glucose self-monitoring (SMBG) arm. After 6 months, they had two-month wash-out

period and then crossed over to the other arm (Figure 1). During the wash-out period the

patients continued the same treatment and monitored diabetes by using only SMBG; no

This article is protected by copyright. All rights reserved.

control visit was performed. When using RT-CGM, the patients were advised to use the

device at least 2-3 weeks per month 13,21 .

All of the patients underwent a structured educational program by attending 2 initial meetings

one month before starting the study. Each meeting dealt with self-management of blood

glucose monitoring, dietary education, carbohydrate counting and training for the electronic

devices (glucometers, CGM system). Patients were also given the basic rules to prevent and

correct the hypo- and hyper-glycaemia episodes (by using carbohydrates and insulin,

respectively) and to intervene in case of CGM alerts (set at threshold levels for blood glucose

at 70 and 200 mg/dl, respectively). Moreover, all of the participants had their knowledge and

capacity assessed monthly 22 with the support of a dietician and a nurse.

HbA1c was measured at the beginning of each study period and after three and six months by

the chromatographic method (high pressure liquid chromatography - HPLC).

Continuous glucose monitoring was performed for one week at the beginning and at the end

of each study period, using a system in which the patients were blinded to glycaemic values

(iPro2 CGM; Medtronic, Tolochenaz, Switzerland). During each visit, data from the devices

were uploaded to a computer using diabetes management software (CareLink Therapy

Management System for Diabetes-Clinical; Medtronic, Tolochenaz, Switzerland).

Outcomes The primary outcome end-point was HbA1c decrease during the two study

periods.

We also evaluated two secondary outcomes. One was the risk of either hyper- or hypo-

glycaemia, measured on the basis of the area under the curve (AUC) calculated from

continuous glucose monitoring for glucose > 200 mg/dl/day or < 70 mg/dl/day, respectively,

which are measurements of the frequency, severity and duration of time spent in hyper- or

hypo-glycaemia. We chose to evaluate AUC > 200 mg/dl/day (that is, nearly the average of

This article is protected by copyright. All rights reserved.

the values considered by the STAR 3 Study Group: 180 and 250 mg/dl/day) 12 , to detect,

using a single parameter, the risk of moderate to severe hyperglycemic episodes.

The other secondary outcome was the evaluation of changes in the glucose fluctuation, both

inter- and intra-day, measured at the end of each monitoring period, in comparison to the

beginning. Day-to-day variation was calculated using the mean of the daily serum glucose

differences (MODDs), defined as the mean of the absolute differences between glucose

values on day 2 and the corresponding values on day 1, at the same time of day 23 . Intra-

day glucose variability was measured according to the standard deviation (SD) of daily

glucose values, the coefficient of variation (CV) (calculated as the SD divided by the mean of

all of the glucose values) and the MAGE procedure, designed by Service et al. in 1970 24

as a marker of the amplitude of glycaemic excursions. Finally, we used a recently proposed

indicator: continuous overlapping net glycaemic action (CONGA-n) at different (n) time

intervals, to gain insight into rapid glucose variability 23,25 . We used CONGA-1,

indicating intra-day variability based on 1 h time intervals, and using the same procedure,

CONGA-2, CONGA-4, CONGA-6 and CONGA-24 values were also calculated.

From the CGM data, the mean and median values of interstitial glucose concentrations were

also assessed.

Finally, we evaluated the changes in insulin requirement (insulin dose/kg) and in body mass

index (BMI) during the study period.

Statistical analysis The comparison between HbA1c levels during the two study periods and

the analysis of the data obtained from the iPRO2 system were evaluated. Continuous

variables are presented as average standard deviation (SDs) and were compared using

Students t-test for paired data. Moreover, the relationship between the RT-CGM utilisation

This article is protected by copyright. All rights reserved.

rate and the decrease in HbA1c levels was assessed by using Pearsons correlation coefficient

(r).

All the indices of glucose variability were calculated using a Web-based application for the

rapid computation of numerous glucose variability parameters based on CGM data:

(GlyCulator) 26 .

Results

From January to March 2012, twenty poorly controlled T1D patients (14 women and 6 men)

treated with MDI (n=10) or CSII (n=10) were recruited for the study. Patients treated with the

two methods were comparable in terms of age, baseline HbA1c values, body mass index

(BMI), years of diabetes duration and insulin dosage (Table 1). During each study period, the

patients underwent the same number of blood glucose measurements (4.5 1.2 per day

during RT CGM period vs. 4.6 1.0 during the SMBG period, p = 0.7) and a similar number

of correcting insulin doses (2.9 1.2 vs. 2.7 1.4 per day during the two study periods,

respectively, p = 0.5).

Primary outcome

Because it has been reported that metabolic control is improved only when RT-CGM is used

at least 60-70% of the time 13,20,27 , we first evaluated this limiting factor for CGM

effectiveness.

Our data indicate that CGM use greater than 40% is sufficient to obtain a benefit from the

device. This cut-off was generated considering the regression curve of the HbA1c decrease

on the basis of the CGM utilisation rate (Figure 2). This curve confirmed that the HbA1c

This article is protected by copyright. All rights reserved.

decrease was strongly influenced by appropriate utilisation of the device (correlation nearly

significant, r = 0.41, p = 0.06), but it also indicated that patients who used CGM at least 40%

of the planned time had a clear benefit in terms of HbA1c reduction (Figure 2).

In our series, the average sensor use was 44% (range 1380%). Fourteen patients (70%, 8

MDI and 6 CSII) used the RT-CGM at least 40% of the total time. As expected, in these 14

patients, improvement in glycaemic control was more marked during the RT-CGM period

(7.76% 0.4 [61.3 mmol/mol] vs. 8.54% 0.4 [69.8 mmol/mol], p < 0.05) than during the

SMBG period (8.42% 0.4 [68.5 mmol/mol] vs. 8.56% 0.5 [70.1 mmol/mol], p = 0.2). The

decrease was significant both in the 8 MDI patients (7.71% 0.2 [60.8 mmol/mol] vs. 8.58%

0.2 [70.3 mmol/mol], p < 0.05) and in the 6 CSII patients (7.82% 0.2 [62.0

mmol/mol] vs. 8.50% 0.3 [69.4 mmol/mol], p < 0.05) (Table 2, Figure 3).

In contrast, in the 6 patients with CGM utilisation rates < 40%, HbA1c did not decrease but

rather increased during the RT-CGM period (8.53% 0.5 [69.7 mmol/mol] vs. 8.22% 0.6

[66.3 mmol/mol], p < 0.05).

Secondary outcomes

Risk of hypo- and hyper-glycaemia In the fourteen patients using CGM properly, the risk of

hyperglycaemia (AUC > 200 mg/dl/day) decreased considerably during the RT-CGM period

(17.3 vs. 23.2 mg/dl/day, p < 0.05). The decrease was more marked in the MDI group (14.4

vs. 21.3 mg/dl/day, p < 0.05), while it was non-significant in the CSII patients (Table 2).

Additionally, the risk of hypoglycaemia (AUC < 70 mg/dl/day) significantly decreased in the

MDI-treated patients (0.49 vs. 1.50 mg/dl/day, p < 0.05) (Table 2).

Glucose fluctuations During the RT-CGM period, improvements in intra-day and inter-day

glucose variability were more marked in MDI-using patients in whom a significant decrease

was observed for both SD (62.3 7.8 vs. 75.5 11.5, p < 0.05) and MAGE (132.3 20.2 vs.

This article is protected by copyright. All rights reserved.

175.3 39.2, p < 0.05). Conversely, the decrease was not present in the CSII patients (Fig. 4,

Table 2).

In the MDI patients, all of the CONGA-n indices decreased during the RT-CGM period but

not significantly (Table 2). When the CONGA-n data were analysed together, however, the

reduction was significant in these patients (64.2 24.0 vs. 73.0 25.9, p < 0.01) (Fig. 4). In

contrast, both SD (71.8 7.7 vs. 63.7 4.8) and CV (41.2 6.7 vs. 35.4 4.4) did not

decrease but rather increased during the SMBG period.

In the six CSII patients, the benefit of RT-CGM was less evident. Both the mean (167 19

mg/dl vs. 190 39 mg/dl, p < 0.05) and the median interstitial glucose values (152 19

mg/dl vs. 186 41 mg/dl, p < 0.05) significantly decreased, but there was no significant

improvement in glucose variability (Table 2).

Additional end-points The fourteen patients who appropriately used RT-CGM had

significant BMI decreases during the study (22.6 3 kg/m2 vs. 23.2 3 kg/m2 p < 0.05), with

no difference in the insulin dose required (units/kg/day).

During the study, no patient experienced severe hypoglycaemia (plasma glucose < 50 mg/dl

requiring the support of another person). One CSII patient required 1 hospitalisation for

ketoacidosis during the SMBG period.

This article is protected by copyright. All rights reserved.

Discussion

Increasing evidence has indicated that the CGM, when correctly used, reduces HbA1c levels

and increases the number of diabetic patients obtaining their therapeutic goals, without

increasing the risk of hypoglycaemia 6-10 . At variance with previous studies that compared

the combined use of semi-automated electronic devices (CSII and CGM) with the combined

use of manual procedures (MDI and SMBG) 12,13,20 , we investigated in a crossover study

the two main glucose monitoring systems (SMBG and CGM) and the two main insulin

delivery procedures (CSII and MDI) to evaluate the benefits of RT-CGM use in T1D patients

treated with either insulin pumps or multiple insulin injection therapy, a therapeutic

procedure that is still diffusely used and that will be used for the foreseeable future.

Our data confirmed that the RT-CGM device, when properly used, was significantly more

efficacious than SMBG. We found, however, different cut-off levels for defining the proper

use of CGM, which were much lower (>40%) than those usually reported in previous studies

(>60-70% of total time) 13,20,27 . The benefits observed at this lower time of use cut-off

were similar to those with more prolonged use of RT-CGM. This observation is novel and

important for CGM use in real-life settings in which patients generally use the device less

than 60-70% of the time because of flexibility/lifestyle concerns and the lack of

reimbursement for continuous use in most countries 28 . Further studies, with larger cohorts

of patients, are needed to confirm our findings.

Although all of the patients using CGM for more than 40% of the time had significant

improvements in glycaemic control, HbA1c decreases were more rapid in CSII patients than

in MDI patients (Figure 3), a possible consequence of the less extensive experience of the

This article is protected by copyright. All rights reserved.

MDI patients using electronic devices (such as the CGM system). These patients, therefore,

might need longer training to obtain the full benefits of the RT-CGM approach.

The use of RT-CGM significantly reduced the risks of hypo- and hyper-glycaemia, especially

in MDI patients.

During the RT-CGM period, the decrease in both the intra-day and inter-day indices of

glucose fluctuations were significantly greater than during SMBG use. As for glycaemic

levels, the decrease in glucose variability was also more marked in MDI patients than in CSII

patients. Considering the relationships among glucose fluctuations, endothelium oxidative

stress and the development of chronic complications of diabetes, particularly cardiovascular

complications 23-25,29,30 , the reduction in glycaemic fluctuations represents an additional

target in the treatment of diabetic patients, and the use of the CGM was effective for

obtaining this result.

Therefore, CGM use provides an effective technology in the management of diabetes. Both

CSII- and MDI-treated T1D patients can take advantage from the use of CGM. Moreover,

health care providers can easily measure from CGM numerous indices of glucose variability

favouring better glycaemic control.

An unexpected advantage of the appropriate use of the RT-CGM was a positive indirect

effect on BMI, which significantly decreased in patients using CGM for at least 40% of the

time and which was a possible consequence of behaviour modification derived from CGM

use, including a modified diet, changed exercise habits and optimisation of insulin therapy.

In conclusion, our study indicated that, even if extensive use of RT-CGM is not currently

possible because of its high cost, RT-CGM is an effective approach for improving overall

glycaemic control in diabetic patients, in terms of both average values and fluctuations. Its

This article is protected by copyright. All rights reserved.

appropriate use (>40%) should be suggested, therefore, in a selected subgroup of T1D

patients who are not on target for metabolic control and who have been provided intensive

therapeutic education. MDI-treated patients, in particular, could greatly benefit from the use

of the RT-CGM device.

Acknowledgments

Medtronic (Tolochenaz, Switzerland) for providing insulin pumps, CGM systems (Mini-Med

Paradigm REAL-Time and iPro2 CGM systems) and the diabetes management software

(CareLink Therapy Management System for Diabetes-Clinical).

Conflict of interest

No authors have anything to disclose related to the content of this article.

This article is protected by copyright. All rights reserved.

References

1. Nathan DM, Cleary PA, Backlund JY et al. Intensive diabetes treatment and cardiovascular

disease in patients with type 1 diabetes. N Engl J Med 2005; 353:26432653.

2. Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and

Complications (DCCT/EDIC) Research Group, Nathan DM, Zinman B et al. Modern-day

clinical course of type 1 diabetes mellitus after 30 years duration: the diabetes control and

complications trial/epidemiology of diabetes interventions and complications and Pittsburgh

epidemiology of diabetes complications experience (1983-2005). Arch Intern Med 2000;

169:13071316.

3. American Diabetes Association: Standards of medical care in diabetes 2011. Diabetes

Care 2011; 34 (Suppl 1):S11S61.

4. Misso ML, Egberts KJ, Page M, OConnor D, Shaw J. Continuous subcutaneous insulin

infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane

Database Syst Rev 2010; Issue 1, Art. No.: doi:10.1002/14651858.CD005103. pub2.

5. Pickup JC, Sutton AJ. Severe hypoglycaemia and glycaemic control in type 1 diabetes:

meta-analysis of multiple daily insulin injections compared with continuous subcutaneous

insulin infusion. Diabet Med 2008; 25:765774.

6. Cummins E, Royle P, Snaith A, Greene A, Robertson L, McIntyre L, Waugh N. Clinical

effectiveness and cost-effectiveness of continuous subcutaneous insulin infusion for diabetes:

systematic review and economic evaluation. Health Technol Assess 2010; 14(11):1181.

7. Deiss D, Bolinder J, Riveline JP et al. Improved glycemic control in poorly controlled

patients with type 1 diabetes using real-time continuous glucose monitoring. Diabetes Care

2006; 29:27302732.

This article is protected by copyright. All rights reserved.

8. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group,

Tamborlane WV, Beck RW et al. Continuous glucose monitoring and intensive treatment of

type 1 diabetes. N Engl J Med 2008; 359:14641476.

9. O'Connell MA, Donath S, ONeal DN et al. Glycaemic impact of patient-led use of sensor-

guided pump therapy in type 1 diabetes: a randomised controlled trial. Diabetologia 2009;

52:12501257.

10. Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group,

Beck RW, Hirsch IB, et al. The effect of continuous glucose monitoring in well-controlled

type 1 diabetes. Diabetes Care 2009; 32:13781383.

11. Battelino T, Phillip M, Bratina N et al. Effect of continuous glucose monitoring on

hypoglycemia in type 1 diabetes. Diabetes Care 2011; 34:795800.

12. Bergenstal RM, Tamborlane WV, Ahmann A et al. Effectiveness of sensor-augmented

insulin-pump therapy in type 1 diabetes. N Engl J Med 2010; 363:311320.

13. Hermanides J, Nrgaard K, Bruttomesso D et al. Sensor augmented pump therapy lowers

HbA1c in suboptimally controlled type 1 diabetes: a randomized controlled trial. Diabet Med

2011; 28:11581167.

14. Yeh HC, Brown TT, Maruthur N et al. Comparative effectiveness and safety of methods

of insulin delivery and glucose monitoring for diabetes mellitus: a systematic review and

meta-analysis. Ann Intern Med 2012; 157(5):336-47.

15. Sun J, Xu Y, Sun S, Sun Y, Wang X. Intermittent high glucose enhances cell proliferation

and VEGF expression in retinal endothelial cells: the role of mitochondrial reactive oxygen

species. Mol Cell Biochem 2010; 343(1-2):2735.

16. Sun J, Xu Y, Deng H, et al. Intermittent high glucose exacerbates the aberrant production

of adiponectin and resistin through mitochondrial superoxide overproduction in adipocytes. J

Mol Endocrinol 2010; 44(3):17985.

This article is protected by copyright. All rights reserved.

17. Krinsley JS. Glycemic variability in critical illness and the end of Chapter 1. Crit Care

Med 2010; 38(4):12068.

18. Monnier L, Mas E, Ginet C et al. Activation of oxidative stress by acute glucose

fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes.

JAMA 2006; 295(14):16817.

19. Hermanides J, Vriesendorp TM, Bosman RJ et al. Glucose variability is associated with

intensive care unit mortality. Crit Care Med 2010; 38(3):83842.

20. Hirsch IB, Abelseth J, Bode BW et al. Sensor-augmented insulin pump therapy: results of

the first randomized treat-to-target study. Diabetes Technol Ther 2008; 10:377383.

21. Raccah D, Sulmont V, Reznik Y, et al. Incremental value of continuous glucose

monitoring when starting pump therapy in patients with poorly controlled type 1 diabetes:

The Real Trend study. Diabetes Care 2009; 32:22452250.

22. Conget I, Battelino T, GimenezM, Gough H, Castaneda J, Bolinder J. The SWITCH

study (sensing with insulin pump therapy to control HbA1c): design and methods of a

randomized controlled crossover trial on sensor-augmented insulin pump efficacy in type 1

diabetes suboptimally controlled with pump therapy. Diabetes Technol Ther 2011;13:4954.

23. McDonnell CM, Donath SM, Vidmar SI, Werther GA, Cameron FJ. A novel approach to

continuous glucose analysis utilizing glycemic variation. Diabetes Technol Ther 2005;

7:253263.

24. Service FJ, Molnar GD, Rosevear JW et al. Mean amplitude of glycemic excursions, a

measure of diabetic instability. Diabetes 1970; 19:644655.

25. Wentholt IME, Kulik W, Michels RPJ, Hoekstra JBL, DeVries JH. Glucose fluctuations

and activation of oxidative stress in patients with type 1 diabetes. Diabetologia 2008;

51:183190.

This article is protected by copyright. All rights reserved.

26. Czerwoniuk D, Fendler W, Walenciak L, Mlynarski W. GlyCulator: a Glycemic

Variability Calculation Tool for Continuous Glucose Monitoring Data. J Diabetes Sci

Technol 2011; 5(2):447-451.

27. Nrgaard K, Scaramuzza A, Bratina N et al. Routine Sensor-Augmented Pump Therapy

in Type 1 Diabetes: The INTERPRET Study. Diabetes Technol Ther 2013; 15:27380.

28. Peyrot M, Rubin RR. Patient-reported outcomes for an integrated real-time continuous

glucose monitoring/insulin pump system. Diabetes Technol Ther 2009; 11:5762.

29. Kilpatrick ES, Rigby AS, Atkin SL. A1C variability and the risk of microvascular

complications in type 1 diabetes: data from the Diabetes Control and Complications Trial.

Diabetes Care 2008; 31(11):2198202.

30. Monnier L, Colette C, Owens DR. Glycemic variability: the third component of the

dysglycemia in diabetes. Is it important? How to measure it? J Diabetes Sci Technol 2008;

2(6):1094100.

This article is protected by copyright. All rights reserved.

 Table 1. Baseline characteristics in the two groups of T1D patients treated with either MDI or CSII.

FEATURES MDI (n=10) CSII (n=10) p

Age (years) 36.6 14.4 31.3 7.9 0.34

Years of Diabetes 19.4 11.0 15.1 7.8 0.38
Baseline BMI (kg/m2) 22.9 3.1 25.0 3.6 0.25
Insulin Dose (units/kg/day) 0.7 0.1 0.6 0.2 0.43
HbA1c (%) 8.7 0.6 8.6 1.0 0.82
Data reported as mean SD.

This article is protected by copyright. All rights reserved.

Table 2. Glycaemic control and glucose variability in the 14 patients (8 MDI and 6 CSII) who used

REAL-Time CGM at least 40% of the total time, compared to the same patients during the SMBG period.

MDI PATIENTS (n=8)

SMBG period p REAL-Time CGM period p
BASELINE END BASELINE END
HbA1c (%) 8.83 0.5 8.63 0.4 0.04 8.58 0.2 7.71 0.2 0.04
AUC >200 (mg/dl/day) 19.03 13.4 20.85 9.2 0.67 21.34 7.2 14.45 9.7 0.04
AUC <70 (mg/dl/day) 1.54 0.5 1.81 1.0 0.54 1.50 2.4 0.49 0.5 0.03
Average glucose
(mg/dl) 182 27 176 25 0.60 176 22 165 21 0.19
Median glucose (mg/dl) 179 30 171 32 0.55 167 29 159 24 0.41
MODD 71.13 22.2 67.00 23.3 0.79 75.88 30.6 59.00 21.5 0.11
SD 63.75 4.8 71.88 7.7 0.02 75.50 11.5 62.38 7.8 0.04
CV 35.38 4.4 41.25 6.7 0.04 43.00 11.5 37.63 4.9 0.26
MAGE 132.25 22.5 160.75 27.6 0.08 175.38 39.2 132.38 20.2 0.03
CONGA 1 h 40.38 5.9 45.25 8.3 0.13 44.25 11.8 40.75 11.9 0.57
CONGA 2 h 59.63 8.2 66.25 16.6 0.25 63.88 11.4 57.25 14.9 0.30
CONGA 4 h 77.38 15.3 83.50 27.4 0.55 86.75 15.7 74.13 20.5 0.15
CONGA 6 h 84.50 15.9 88.38 30.2 0.71 95.38 20.1 80.88 24.2 0.12
CONGA 24 h 74.38 17.4 79.88 28.5 0.72 74.75 31.2 68.00 26.6 0.49
CSII PATIENTS (n=6)
SMBG period p REAL-Time CGM period p
BASELINE END BASELINE END
HbA1c (%) 8.22 0.3 8.15 0.7 0.07 8.50 0.3 7.82 0.2 0.04
AUC >200 (mg/dl/day) 19.8 12.9 21.3 7.5 0.75 25.60 19.4 21.05 14.1 0.12
AUC <70 (mg/dl/day) 1.7 1.0 3 1.3 0.56 1.7 0.3 1.5 0.3 0.24
Average glucose
164 16 167 17 0.75 190 39 167 19 0.04
(mg/dl)
Median glucose (mg/dl) 147 16 157 22 0.48 186 41 152 19 0.04
MODD 73.3 14.2 67.3 23.5 0.46 69.50 16.9 53.83 18.3 0.23
SD 78.8 15.5 78.2 13.8 0.90 66.83 9.2 71.83 14.8 0.20
CV 47.5 4.6 47.0 9.5 0.90 35.67 5.3 44.17 8.4 0.08
MAGE 173.5 40.7 175.8 44.8 0.87 153.50 29.5 162.17 38.7 0.23
CONGA 1 h 47.8 10.2 42.5 11.8 0.32 45.33 11.6 44.33 12.6 0.88
CONGA 2 h 70.5 17.6 66.2 18.8 0.46 61.83 14.3 66.33 20.3 0.61
CONGA 4 h 90.5 32.3 89.8 32.8 0.94 78.17 19.9 80.83 33.0 0.84
CONGA 6 h 97 35.5 98.5 39.4 0.87 80.17 20.3 85.67 35.6 0.70
CONGA 24 h 77.3 20.0 71.2 29.5 0.56 71.33 17.3 57.83 21.4 0.21
Data reported as mean SD.

This article is protected by copyright. All rights reserved.

 Figure 1. Study design.

This article is protected by copyright. All rights reserved.

Figure 2. Relationship between RT-CGM utilization rate (expressed in % of the total time) and HbA1c reduction

(expressed in %).

This article is protected by copyright. All rights reserved.

Figure 3. HbA1c changes (%) during the RT-CGM period in the 14 patients (8 MDI and 6 CSII) with

appropriate use of the device (>40% of the total time).

This article is protected by copyright. All rights reserved.

Figure 4. Inter- and intra-day glucose variability indices evaluated at baseline and at the end of the RT-CGM

period in the two groups of patients (MDI- and CSII-treated patients) using CGM appropriately (>40% of the

total time).

This article is protected by copyright. All rights reserved.