Discussion
This systematic review and meta-analysis found that in non-pregnant patients with T1DM, CLS application increased TIR and decreased TBR, TAR, and HbA1c, as compared with controls, validating previous findings that glucose control improves and the risk of hypoglycemia is reduced with CLS even in longer applications.
In this study, TIR was used as the primary outcome indicator. The results revealed that the use of CLS resulted in an additional 10.32% increase in TIR when compared with controls. This TIR difference was achieved by reductions in time above and below target range, respectively. The closed-loop system allows for responsive, progressive regulation of insulin delivery, either below or above a predetermined glucose threshold range. This improves the proportion of time spent in the target glucose range and reduces average blood glucose levels without increasing the risk of hypoglycemia. TIR was described as the percentage of time for glucose levels to fall in the target range according to the recommendations of the guidelines for T1DM, starting from 70 mg/dL to 180 mg/dL.22 23 Besides being reflective of the day-to-day experience of individuals with diabetes,24 TIR can be used to predict the risk of future diabetic complications, mainly microvascular complications.25 Beck et al26 reported the relationship between TIR and the development of DR and microalbuminuria using a 7-point glucose curve from the DCCT data set to validate TIR as a clinical trial outcome measure. With each 10% decrease in TIR, there was 64% and 40% increase in the risk of DR and microalbuminuria, respectively. In contrast, it is reasonable to assume that increased TIR could retard the progression of DR and microalbuminuria. Generally, the 2021 American Diabetes Association guidelines have recommended TIR for assessment of glucose control and indicated that the target value for TIR was greater than 70%. Each 5% increase in TIR resulted in clinically significant benefits for patients with either T1DM or type 2 diabetes mellitus (T2DM).22 The significant improvement in TIR associated with CLS suggested its importance in improving glucose control and reducing the risk of future complications in patients with T1DM. Most of the previous studies covered a study period of 2 weeks or less.27–30 Studies included in this meta-analysis, however, had an observation period of 8–26 weeks. More importantly, the results obtained from the meta-analysis are consistent with previous studies.7 8 31 The longer periodicity of the studies included in this meta-analysis means that there are more variables and confounding factors and the results of these longer period studies are more convincing. Long-term use of the CLS system allows for good glycemia control over time, rather than short-term effects.
HbA1c level was used as an acceptable standard for glucose control since its recommendation by DCCT. In DCCT, an inverse relationship was found between the HbA1c value and the incidence of DR in patients with T1DM. With each 1% increase in HbA1c, the risk of DR and nephropathy increased by 54% and 42%, respectively. Moreover, other studies have confirmed higher HbA1c level as an independent risk factor for diabetic complications.32 33 This study showed that CLS has better HbA1c levels, suggesting that the use of CLS in T1DM was more likely to reduce diabetes-related complications. The control group for most of the studies included in this meta-analysis was SAP. It has been demonstrated that the use of SAP significantly improves glycemia control and reduces HbA1c levels compared with regular insulin therapy.34 Patients with CLS in this study bear a better HbA1c level even compared with those with SAP, suggesting that the use of CLS in T1DM could further reduce the risk of diabetes-related complications.
In the Beck et al26 study, it was shown that TIR was negatively correlated with HbA1c (r=−0.67) and a 10-percentile decrease in TIR should result in a decrease in HbA1c of around 0.6 percentile.35 However, a decrease of only 0.3 percentile was shown in this meta-analysis. The consistency between TIR and HbA1c could be influenced by other factors, such as glycemic variability.36 CV and SD are the metrics for GV, which reflects blood glucose fluctuations. Analysis of the DCCT data set did not show any relationship between microvascular complications and above-average GV.31 32 A larger study found no relationship between GV and composite score of cardiovascular risk.33 In the study, CV and SD were lower in CLS when compared with controls. GV was shown to be predictive of severe hypoglycemia in type 1 diabetes.37 38 This suggests that the use of CLS could reduce the risk of hypoglycemia without increasing the risk of microvascular and cardiovascular complications.
Undoubtedly, hypoglycemia acts as a barrier to improving glycemic control and compliance in clinical practice. In the Action to Control Cardiovascular Risk in Diabetes trial, it was shown that patients with T2DM in the intensive treatment group with more than one event of severe hypoglycemia had significantly higher annual mortality than those without severe hypoglycemia, suggesting that severe hypoglycemia is an important cause of increased mortality.39 It is reasonable to speculate that this also applies to patients with T1DM. Acute hypoglycemia could exacerbate chronic inflammation, endothelial dysfunction, and arteriosclerosis by its proinflammatory effects.40 This meta-analysis used TBR, time below 3 mmol/L and 3.3 mmol/L (50 mg/dL and 54 mg/dL), and LBGI to assess the risk of hypoglycemia and showed that these measurements improved compared with controls. This suggests that the use of CLS may reduce the risk of hypoglycemia and thus reduce mortality in patients with type 1 diabetes.
Some of the adverse events observed in the CLS group occurred as a result of operator error, device disconnection, and low battery levels. This requires clinicians to train patients more carefully and correctly in the use of CLS, such as with device disconnections or battery replacements, and demand professionals to check the device regularly. Although their quality of life did not improve significantly compared with the control group, subjects in the CLS group felt more positive about their diabetes status and gained greater satisfaction from managing their condition compared with the control group. The absence of an increase in diabetes treatment satisfaction or a reduction in diabetes distress in our trial could partly be explained by the counterbalancing of potential benefits with the burden of adding new technology to diabetes self-management or trial protocol requirements.
The strengths of this meta-analysis are the high-quality studies included, which are multicenter and multicountry studies, the long follow-up period of not less than 8 weeks, and the wide age range of participants from children to seniors, supporting the generalizability of the findings. Limitations of the analysis included statistical assumptions, such as deriving the mean and SD from the median and IQR, respectively. Specific definitions of night-time varied among the studies included, but was taken as 12 hours when calculating the specific time, which might overstate the effect of nocturnal glucose control. The most important limitation is the heterogeneity of the control groups. It is indeed very different to have an insulin pump or an MDI treatment, for example.