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 HbA1c
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
]. 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 HbA1c
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
], with a mean reduction in HbA1c
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 HbA1c
levels and HbA1c
Studies consistently show that sufficient sensor use is crucial to the success of CGM [6
]. 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 A1c
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 HbA1c
-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 HbA1c
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.
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 HbA1c
has been previously reported [10
]; however, this is the first report of a concomitant decrease in HbA1c
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 HbA1c
levels and reducing the time spent in hypoglycaemia. Indeed, in a large observational study with 1,041 patients on insulin pumps, lower HbA1c
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
], 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 HbA1c
in the Sensor On arm did not plateau after 6 months, as observed in other trials [7
]. Therefore, HbA1c
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.