Conclusions
The HypoDE study investigated the benefits of rtCGM in people with type 1 diabetes using MDI and having an increased risk for hypoglycemic events. The present analysis provides clinically relevant insights into possible mechanistic associations between the use of rtCGM and the observed reduction of hypoglycemic events, namely adjustments in diabetes therapy.
The following mechanistic associations were identified in participants with impaired hypoglycemia awareness:
Based on patient-reported details of carbohydrate consumption and insulin therapy, common therapy factors of participants using rtCGM in this study were not systematically changed. In this sense, no relevant modifications regarding insulin dosing were made by participants using rtCGM or treating physicians; participants used the same factors they did when using only SMBG and showed in general the same nutritional behavior.
Participants rather made situational behavioral adaptations in their hypoglycemia management; therefore, a behavioral shift from reacting to present hypoglycemia to prophylactically preventing impending hypoglycemia was reached. A better timing of fast-acting carbohydrate intake, that is, an earlier intervention already at higher glucose levels, was identified as being a main predictor for the occurrence of hypoglycemic events.
An rtCGM system, along with adequate training, supports an optimized placing of rescue carbohydrates on the one hand by providing current glucose values continuously and on the other hand through alarms that inform the users even in situations when they are not concerned about their glucose level. With regard to the specific participant population in this study who suffered from impaired hypoglycemia awareness this feature is extremely valuable for the prevention of (severe) hypoglycemic events. The pronounced effectiveness of this rather small action might be a reason why no further systematic adjustments were made; however, the exact reasons were not identified.
Given the lack of systematic therapy adjustments due to the retrospective CGM data analysis, the full potential of rtCGM might still not be exhaustively unfolded. There is, thus, still the potential of enhancing the beneficial effects of CGM if more systematic therapy adjustments were made. Referring to this, advanced training might have supported further options. Results from this study may be used to direct further educational measures for users but also for healthcare professionals, as it provides insight into which adjustments users perceived necessary and which they dared to make. Participants in this study did not receive structured training or education, but were still able to reduce the occurrence of hypoglycemia. Whether structured training in the avoidance of hypoglycemia could lead to additional benefit, and whether such training is cost-efficient, should be assessed in further studies.
Nevertheless, in some aspects or at least in some participants, retrospective analyses were likely used. The intake of smaller portion sizes of rescue carbohydrates, for example, might have been initiated by direct feedback regarding the postprandial glucose curve provided by the CGM system. Similarly, the modifications regarding IMI were most likely made after review of postprandial curves, if deemed necessary. This could explain the decreased glycemic variability reported for rtCGM group participants in HypoDE,6 but did not show an effect on the occurrence of low glucose events.
Regression analysis confirmed that the only therapy-related variables that are independently and significantly associated with the frequency of low glucose events are those related to behavioral changes in spontaneous hypoglycemia management, that is, raising the rescue threshold. While the number of rescue carbohydrate intakes was also affected by the number of low glucose events, the rescue threshold seems independent of that. Due to the observed reduction of low glucose events one might expect that rescue carbohydrate intake is also reduced. The observed increased intake, however, supports the importance of rescue carbohydrates and especially distribution and timing as a preventive action. The reduction in rescue carbohydrate portion size might also be a result of the raised threshold. In general, results from the multivariate analysis indicate the importance of human factors in the beneficial effects of rtCGM.
Recommendations on how to use rtCGM data for therapy adjustments mainly describe adjustment of insulin doses based on glucose trends.13–15 From the data presented here, it cannot be concluded on whether these recommendations were followed, as trend arrows were not recorded. In addition, the recommendations rather affect individual real-time decisions that depend on current situations. These would unlikely have become visible in this analysis where only mean values of several days and participants were evaluated. Other recommendations focus on the retrospective analysis of ambulatory glucose profiles and subsequent therapy adjustments; however, these focus on when to act rather than how to act in particular.16 Therapy adjustments are thus made on an individual case-by-case basis at the discretion of the healthcare professional.
In a survey of 222 well-controlled people with type 1 diabetes, it became obvious that most participants only use glucose information for current treatment decisions instead of analyzing retrospective data to detect patterns and make general adjustments.17 The cross-over design of the IN CONTROL study revealed that positive effects of CGM on glycemic control arise rapidly, but are transient and washed out after 12 weeks when CGM use is terminated.18 Although therapy adjustments were not systematically assessed in this study, the results do not suggest any systematic modifications but also hint at behavioral changes that are present as long as rtCGM can be used. Participants reported diverging reactions to rtCGM: while some reported becoming more active in adjusting their therapy, others became rather passive relying on alarms. Taken together with the results of the present mechanistic analyses, it is likely that there will be no significant long-term effects once rtCGM use is discontinued, as the identified adjusting screws rely on real-time availability of the system.
It has to be noted that participants of the HypoDE study all had hypoglycemia issues, but apart from that had a good glycemic control.6 It can therefore not be excluded that participants with a poor glycemic control would make more extensive self-managed therapy adjustments. In addition, all participants in this study were on MDI therapy which is less flexible than insulin pump therapy. The possibility to adapt insulin delivery in the short term using temporary basal rates, for instance, might have been an alternative to taking rescue carbohydrates likely leading to the same results. For instance, an increased use of temporary basal rates, low glucose suspension and bolus calculator features was reported in continuous subcutaneous insulin infusion (CSII) patients when using rtCGM.7
Besides the specific participant group that limits generalization of the presented results to all rtCGM users, this analysis has some further limitations. All information drawn from the logbooks was self-reported. An automated data capture, for example, through smart insulin pens, might have improved data quality. In addition, the level of detail strongly varied between participants and all analyses comprising quantities of carbohydrates rely on participants’ estimations if available. Furthermore, variables that required exact time specification like IMI had to be analyzed from descriptions in the questionnaire, because documentation of times of meal intake in the logbooks was not precise enough. A more robust recording would allow a detailed evaluation of the timing aspects. Nevertheless, the findings of this evaluation allow conclusive statements that might be verified in further particular evaluations.
Detailed training about CGM and respective therapy guidance was an indispensable part of the intervention in this study; on the one hand for safety reasons, and on the other hand because it has been shown that without structured training CGM does not achieve the desired effects.19 Therefore, it cannot be clearly differentiated whether rtCGM use, training or both caused the behavioral changes. However, in clinical practice, CGM should always be initiated with extensive and appropriate training.
In conclusion, in a population of people with type 1 diabetes with an increased risk for hypoglycemia using MDI, implementation of rtCGM reduced the occurrence of hypoglycemic events without any major therapy adjustments, but by actively preventing the impending hypoglycemia with carbohydrate intake at higher glucose levels.