Association between hypoglycaemic glucose variability and autonomic function in type1 diabetes with impaired hypoglycaemia awareness.

Cardiovascular autonomic neuropathy (CAN) is suggested to underlie hypoglycaemic risk in impaired awareness of hypoglycaemia (IAH). We assessed the prevalence of CAN and the association between glucose variability (GV) and cardiovascular autonomic function in patients with type 1 diabetes (T1DM) and IAH. This study is a post-hoc-analysis of results obtained with the IN-CONTROL-trial, designed to assess the effects of continuous glucose monitoring (CGM) on glycaemia. Forty participants (aged 46.4 ± 11.4 years, diabetes duration 29.1 ± 13.5 years, HbA1c 7.5 ± 0.8%(58.2 ± 8.8 mmol/mol)) underwent 2-week blinded CGM measurements to obtain GV indices. Standardized cardiovascular reflex tests were used to determine the presence of CAN. Cardiovascular autonomic function was assessed with heart rate variability (HRV) measures. 14(35%) participants were classified as having CAN. Participants with CAN had lower percentage time spent in hypoglycaemic range and low blood glucose index(LBGI). After correction for confounders, a significant positive association was found between the coefficient of variation (CV) or time spent in hypoglycaemic range and HRV measures SDRR or RMSSD, and between LBGI and RMSSD. In patients with T1DM and IAH, hypoglycaemic parameters were associated with better cardiovascular autonomic function and lower prevalence of CAN. This suggests that autonomic neuropathy does not seem to further deteriorate hypoglycaemic risk in patients with IAH.

The relation between HbA1c and hypoglycemia revisited; a secondary analysis from an intervention trial in patients with type 1 diabetes and impaired awareness of hypoglycemia.

AIMS: We aimed to re-assess the previously shown but recently disputed association between HbA1c and severe hypoglycemia. METHODS: 52 Patients with T1D and IAH participated in an earlier reported randomized, crossover trial with two 16-week intervention periods comparing continuous glucose monitoring (CGM) with self-monitoring of blood glucose (SMBG). In this previous study, time spent in normoglycemia (the primary outcome), was improved by 9.6% (p<0.0001). We performed post-hoc analyses using a zero-inflated Poisson regression model to assess the relationship between severe hypoglycemia and HbA1c, glucose variability and duration of diabetes. RESULTS: During SMBG use, HbA1c and the number of severe hypoglycemic events were negatively associated (OR 0.20 [95% CI 0.09 to 0.44]). During CGM use, this relationship showed an odds ratio of 0.65 (95% CI 0.42 to 1.01). There was no significant relationship between glucose variability or duration of diabetes and severe hypoglycemia. CONCLUSIONS: In patients with T1D and IAH, treated with standard SMBG, a negative association exists between HbA1c and the number of severe hypoglycemic events. Thus, reaching target HbA1c values still comes with a higher risk of severe hypoglycemia. CGM weakens this association, suggesting CGM enables patients to reach their target HbA1c more safely.

Continuous Glucose Monitoring in Patients with Type 1 Diabetes and Impaired Awareness of Hypoglycemia: Also Effective in Patients with Psychological Distress?

The aim of this study was to evaluate whether psychological distress modifies the effect of continuous glucose monitoring (CGM) in patients with type 1 diabetes (T1D) and impaired awareness of hypoglycemia. Fifty-two patients with T1D and impaired awareness of hypoglycemia participated in an earlier reported randomized crossover trial with two 16-week intervention periods comparing CGM with self-monitoring of blood glucose (SMBG). During the CGM phase, time spent in euglycemia (4-10 mmol/L), the primary outcome, was 9.6% higher compared with the SMBG phase (P < 0.0001). Psychological distress was operationalized as low emotional well-being (World Health Organization Well-being Index 5 [WHO-5] < 50), high diabetes-related distress (Problem Areas in Diabetes 5 [PAID-5] ≥ 8), and/or high fear of hypoglycemia (Hypoglycemia Fear Survey [HFS] Worry > mean HFS Worry score +1 standard deviation). Modifying effects were assessed by analyzing psychological distress score × intervention-interaction effects. Results showed that both the low emotional well-being group and normal emotional well-being group had equal glycemic outcomes during the CGM phase. High diabetes distress and elevated fear of hypoglycemia did not result in significant interaction effects for glycemic outcomes. This study demonstrated that CGM is equally effective in terms of glycemic improvements in high versus low distressed patients with T1D and impaired awareness of hypoglycemia.

Continuous glucose monitoring for patients with type 1 diabetes and impaired awareness of hypoglycaemia (IN CONTROL): a randomised, open-label, crossover trial.

BACKGROUND: Patients with type 1 diabetes who have impaired awareness of hypoglycaemia have a three to six times increased risk of severe hypoglycaemia. We aimed to assess whether continuous glucose monitoring (CGM) improves glycaemia and prevents severe hypoglycaemia compared with self-monitoring of blood glucose (SMBG) in this high-risk population. METHODS: We did a randomised, open-label, crossover trial (IN CONTROL) at two medical centres in the Netherlands. Eligible participants were patients diagnosed with type 1 diabetes according to American Diabetes Association criteria, aged 18-75 years, with impaired awareness of hypoglycaemia as confirmed by a Gold score of at least 4, and treated with either continuous subcutaneous insulin infusion or multiple daily insulin injections and doing at least three SMBG measurements per day. After screening, re-education about diabetes management, and a 6-week run-in phase (to obtain baseline CGM data), we randomly assigned patients (1:1) with a computer-generated allocation sequence (block size of four) to either 16 weeks of CGM followed by 12 weeks of washout and 16 weeks of SMBG, or 16 weeks of SMBG followed by 12 weeks of washout and 16 weeks of CGM (where the SMBG phase was the control). During the CGM phase, patients used a real-time CGM system consisting of a Paradigm Veo system with a MiniLink transmitter and an Enlite glucose sensor (Medtronic, CA, USA). During the SMBG phase, patients were equipped with a masked CGM device, consisting of an iPro 2 continuous glucose monitor and an Enlite glucose sensor, which does not display real-time glucose values. The number of SMBG measurements per day and SMBG systems were not standardised between patients, to mimic real-life conditions. During both intervention periods, patients attended follow-up visits at the centres each month and had telephone consultations 2 weeks after each visit inquiring about adverse events, episodes of hypoglycaemia, etc. The primary endpoint was the mean difference in percentage of time spent in normoglycaemia (4-10 mmol/L) over the total intervention periods, analysed on an intention-to-treat basis. Severe hypoglycaemia (requiring third party assistance) was a secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01787903. FINDINGS: Between March 4, 2013, and Feb 9, 2015, we recruited and randomly assigned 52 patients to either the CGM-SMBG sequence (n=26) or the SMBG-CGM sequence (n=26). The last patient visit was on March 21, 2016. Time spent in normoglycaemia was higher during CGM than during SMBG: 65·0% (95% CI 62·8-67·3) versus 55·4% (53·1-57·7; mean difference 9·6%, 95% CI 8·0-11·2; p<0·0001), with reductions in both time spent in hypoglycaemia (ie, blood glucose ≤3·9 mmol/L [6·8% vs 11·4%, mean difference 4·7%, 3·4-5·9; p<0·0001]) and time spent in hyperglycaemia (ie, blood glucose >10 mmol/L [28·2% vs 33·2%, mean difference 5·0%, 3·1-6·9; p<0·0001]). During CGM, the number of severe hypoglycaemic events was lower (14 events vs 34 events, p=0·033). Five serious adverse events other than severe hypoglycaemia occurred during the trial, but all were deemed unrelated to the trial intervention. Additionally, no mild to moderate adverse events were related to the trial intervention. INTERPRETATION: CGM increased time spent in normoglycaemia and reduced severe hypoglycaemia in patients with type 1 diabetes and impaired awareness of hypoglycaemia, compared with SMBG. Our results support the concept of using CGM in this high-risk population. FUNDING: Eli Lilly and Sanofi.

Continuous Glucose Monitoring: Impact on Hypoglycemia.

The necessity of strict glycemic control is unquestionable. However, hypoglycemia remains a major limiting factor in achieving satisfactory glucose control, and evidence is mounting to show that hypoglycemia is not benign. Over the past decade, evidence has consistently shown that real-time continuous glucose monitoring improves glycemic control in terms of lowering glycated hemoglobin levels. However, real-time continuous glucose monitoring has not met the expectations of the diabetes community with regard to hypoglycemia prevention. The earlier trials did not demonstrate any effect on either mild or severe hypoglycemia and the effect of real-time continuous glucose monitoring on nocturnal hypoglycemia was often not reported. However, trials specifically designed to reduce hypoglycemia in patients with a high hypoglycemia risk have demonstrated a reduction in hypoglycemia, suggesting that real-time continuous glucose monitoring can prevent hypoglycemia when it is specifically used for that purpose. Moreover, the newest generation of diabetes technology currently available commercially, namely sensor-augmented pump therapy with a (predictive) low glucose suspend feature, has provided more convincing evidence for hypoglycemia prevention. This article provides an overview of the hypoglycemia outcomes of randomized controlled trials that investigate the effect of real-time continuous glucose monitoring alone or sensor-augmented pump therapy with a (predictive) low glucose suspend feature. Furthermore, several possible explanations are provided why trials have not shown a reduction in severe hypoglycemia. In addition, existing evidence is presented of real-time continuous glucose monitoring in patients with impaired awareness of hypoglycemia who have the highest risk of severe hypoglycemia.

Design and rationale of the IN CONTROL trial: the effects of real-time continuous glucose monitoring on glycemia and quality of life in patients with type 1 diabetes mellitus and impaired awareness of hypoglycemia.

BACKGROUND: Hypoglycemia is the main side effect of intensified insulin therapy in type 1 diabetes and recognized as a limitation in achieving glycemic targets. Patients with impaired awareness of hypoglycemia have a threefold to sixfold increased risk of severe hypoglycemia. Real-time continuous glucose monitoring may help patients with type 1 diabetes to achieve better glycemic control with less hypoglycemic episodes. Accordingly, one may hypothesize that particularly type 1 diabetes mellitus patients with impaired awareness of hypoglycemia will profit most from this technology with improvements in their quality of life. However, this has not yet been established. This trial aims to study the effect of real-time continuous glucose monitoring on glycemia and quality of life specifically in type 1 diabetes mellitus patients with established impaired awareness of hypoglycemia. METHODS/DESIGN: This is a two-center, randomized, cross-over trial with a 12-week wash-out period in between intervention periods. A total of 52 type 1 diabetes mellitus patients with impaired awareness of hypoglycemia according to Gold et al. criteria will be randomized to receive real-time continuous glucose monitoring or blinded continuous glucose monitoring for 16 weeks. After a wash-out period, patients will cross over to the other intervention. The primary outcome measure is time spent in euglycemia. Secondary outcomes include (diabetes-specific) markers of quality of life and other glycemic variables. DISCUSSION: It remains unclear whether patients with type 1 diabetes and impaired awareness of hypoglycemia benefit from real-time continuous glucose monitoring in real-life. This study will provide insight into the potential benefits of real-time continuous glucose monitoring in this patient population. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01787903.

Analysis: The Accuracy and Efficacy of the Dexcom G4 Platinum Continuous Glucose Monitoring System.

In this issue of Journal of Diabetes Science and Technology, Nakamura and Balo report on accuracy and efficacy of the Dexcom G4 Platinum Continuous Glucose Monitoring System. The authors demonstrate good overall performance of this real-time continuous glucose monitoring (RT-CGM) system, although accuracy data of the next generation RT-CGM system, the G4AP, is already available. Also, now that MARDs seem to move to single-digit numbers, the question comes up how low we need to go with accuracy. Results of the study also showed a reduction in time spent in hypoglycemia, although the clinical relevance should be questioned. To date, few trials have demonstrated a reduction of severe hypoglycemia. Conventional RT-CGM, without threshold suspension or closing the loop, might be insufficient in preventing severe hypoglycemia.