Introduction
Near normoglycaemia is associated with a reduced risk of microvascular and macrovascular complications in type 1 diabetes but is difficult to achieve despite considerable effort from patients and healthcare providers; only a minority of patients achieve a HbA
1c level within the target range [
1‐
3]. The use of insulin pump therapy (CSII) reduces the HbA
1c level without an increase in hypoglycaemia, compared with multiple daily insulin injections in meta-analyses [
4,
5], and is recommended for the improvement of metabolic control [
3]. Continuous glucose monitoring (CGM) has also been associated, in various randomised controlled trials, with reductions in HbA
1c [
6‐
8] and time spent in hypoglycaemia [
9,
10]. Sensor-augmented insulin pump therapy (SAP), combining CSII and CGM, was recently shown to significantly decrease HbA
1c without an increase in hypoglycaemia in adults and children, compared with multiple daily injections, in two large multicentre trials [
11,
12]. However, studies investigating whether SAP can further improve glycaemic control in patients with type 1 diabetes using CSII alone have yielded conflicting results [
13,
14]. The present randomised, controlled, crossover study was therefore designed to determine whether patients with poorly controlled type 1 diabetes who are already using insulin pump therapy can achieve improved metabolic control with the addition of personal CGM, and to evaluate associated changes in insulin treatment patterns while using SAP.
Discussion
This multicentre, randomised, controlled crossover study demonstrated a decrease in HbA1c and a concurrent reduction in time spent in hypoglycaemia, through the addition of CGM to existing CSII for 6 months in participants with type 1 diabetes. Crossover studies of longer duration are seldom used in trials evaluating diabetes-related technology. However, bias resulting from differences in education and patient–healthcare provider interactions is largely prevented by this study design. Moreover, in the present study the number of participants lost to follow-up was lower than expected and the washout period prevented any appreciable treatment carry-over.
Although the studies cannot be directly compared, the significant decreases in HbA
1c in both age groups in our study are not consistent with the results of the Juvenile Diabetes Research Foundation (JDRF) trial, where no change in metabolic control was demonstrated in children or adolescents using CGM [
7]. Two other randomised controlled trials directly comparing SAP to CSII alone demonstrated a significant improvement in glycaemic control in both the treatment and control groups, and the observed difference between the study groups did not attain statistical significance in the ITT analyses [
13,
14]. These substantial study effects, together with dissimilarities in dropout rates, may account for the differences between the present study and those in which no significant improvement in HbA
1c was demonstrated. Two recent meta-analyses of all randomised controlled trials comparing CSII with or without CGM also demonstrated a significant, albeit modest, benefit of CGM [
16,
17], with a mean reduction in HbA
1c that was comparable to that found in the present study. However, unlike the findings in the meta-analyses, we did not observe any relationship between baseline HbA
1c levels and HbA
1c reduction.
Studies consistently show that sufficient sensor use is crucial to the success of CGM [
6,
7,
11,
14]. In the present study, 72% of participants wore a sensor for more than 70% of the required time, which is similar to that observed in the adult cohort, but greater than that in the paediatric cohort, in the JDRF study [
7], and similar to that observed in Sensor-augmented pump Therapy for A
1c Reduction (STAR)3 [
11]. The latter study demonstrated that an increase in the frequency of sensor use from 41% to 80% was associated with a doubling of the HbA
1c-lowering effect. Moreover, in the On/Off sequence there was a loss of effect following the removal of CGM during the washout period and Sensor Off arm, whereas no change in the HbA
1c was observed during the washout period in the Off/On sequence. Taken together, these findings demonstrate that the efficacy of CGM depends upon its continuous use.
The HbA
1c decrease in this study was accompanied by improvements in several secondary endpoints, including increased time spent in normoglycaemia, decreased time in hyperglycaemia and reduced time in hypoglycaemia. A decrease in time spent in hypoglycaemia in patients with well-controlled diabetes with substantially lower mean HbA
1c has been previously reported [
10]; however, this is the first report of a concomitant decrease in HbA
1c and time spent in hypoglycaemia in participants with less well controlled diabetes using CGM.
As participants did not receive specific written instructions on how to use the data from CGM, it was of interest to investigate modifications of treatment patterns during the Sensor On period. More frequent insulin bolus administration along with more frequent use of temporary basal rates and manual basal suspend function could contribute to lowering HbA
1c levels and reducing the time spent in hypoglycaemia. Indeed, in a large observational study with 1,041 patients on insulin pumps, lower HbA
1c was associated with more frequent insulin bolus administration [
18]. With CGM, the participants also used the bolus wizard calculator feature more often. Hence, considered together, our data indicate that SAP is associated with more active self-adjustments of the insulin therapy.
The frequency of SMBG values <3.9 mmol/l was not statistically different between the Sensor On and Sensor Off arms; however, significantly fewer SMBGs were performed during the Sensor On arm. The rate of severe hypoglycaemia was very low and did not significantly differ between the Sensor On and Sensor Off arms, however, this study excluded participants with a known history of severe hypoglycaemia. Similarly, the rates of severe hypoglycaemia were low in the JDRF and STAR3 trials [
10,
11], and did not differ between study groups. None of these trials was powered to detect differences in severe hypoglycaemia.
Potential limitations apply to this study, which may affect the generalisability of our findings. The small study effect observed during the run-in period could have persisted into the treatment periods. No common protocol was used for adjusting the therapy based on CGM or SMBG during the study, which could have lessened the effect of sensor use. However, a recent study did not show a metabolic benefit of a physician-led structured use of CGM over patient-led use [
19]. In addition, all participants had pre-existing knowledge of diabetes management. The definition of hypoglycaemia as <3.9 mmol/l was conservative. Finally, the decrease in HbA
1c in the Sensor On arm did not plateau after 6 months, as observed in other trials [
7,
11]. Therefore, HbA
1c levels may have continued to decrease following longer treatment. By its nature, the study precluded blinding. The addition of CGM to established CSII has cost implications, and analyses are being conducted to assess the health economic impact on medical resource utilisation and direct costs.
In conclusion, in both paediatric and adult participants with type 1 diabetes using CSII therapy alone, the addition of CGM resulted in an improvement in HbA1c with a concomitant decrease in time spent in hypoglycaemia. More frequent self-adjustments of insulin therapy with SAP may have contributed to these effects. The removal of CGM resulted in a loss of metabolic benefit.
Acknowledgements
The SWITCH Study Group includes T. Battelino, I. Conget, B. Olsen, I. Schütz-Fuhrmann, E. Hommel, R. Hoogma, U. Schierloh, N Sulli, J. Bolinder, N. Bratina (University Children’s Hospital, Ljubljana, Slovenia), M. Gimenez (ICMDM Hospital Clínici Universitari, Barcelona, Spain), C. de Beaufort (Centre Hospitalier de Luxembourg, Luxembourg), S. Cvach (Hospital Hietzing, Vienna, Austria), L. Tarnow (Steno Diabetes Center,Gentofte, Denmark), F. Tillemans (Groene Hart Ziekenhuis, Gouda,the Netherlands) and B. Shashaj (Servizio Diabetologia, Policlinico Umberto I, Rome, Italy).
The SWITCH Study Group would like to acknowledge M. Vidal (ICMDM Hospital Clínici Universitari, Barcelona, Spain), A. M. Hertz (Glostrup Hospital, Glostrup, Denmark), Y. Rayane (Centre Hospitalier de Luxembourg, Luxembourg) and I. Zupančič (University Children’s Hospital, Ljubljana, Slovenia) for clinical assistance in the conduct of the study, C. Kollman (Jaeb Center for Health Research, Tampa, FL, USA), for his review and comment on the statistical analysis plan, and H. Gough and J. Castañeda (Medtronic International Trading Sarl, Tolochenaz, Switzerland) for their support throughout the study. Writing and editorial assistance was given by N. Fisher and Springer Healthcare Ltd (London, UK), for which financial remuneration was given. T. Battelino was supported in part by the Slovenian National Research Agency Grant no. P3-0343.