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Tight control of blood glucose in type 1 diabetes delays onset of macrovascular and microvascular diabetic complications; however, glucose levels need to be closely monitored to prevent hypoglycaemia. We aimed to assess whether a factory-calibrated, sensor-based, flash glucose-monitoring system compared with self-monitored glucose testing reduced exposure to hypoglycaemia in patients with type 1 diabetes. In this multicentre, prospective, non-masked, randomised controlled trial, we enrolled adult patients with well controlled type 1 diabetes (HbA1c ≤58 mmol/mol [7·5%]) from 23 European diabetes centres. After 2 weeks of all participants wearing the blinded sensor, those with readings for at least 50% of the period were randomly assigned (1:1) to flash sensor-based glucose monitoring (intervention group) or to self-monitoring of blood glucose with capillary strips (control group). Randomisation was done centrally using the biased-coin minimisation method dependent on study centre and type of insulin administration. Participants, investigators, and study staff were not masked to group allocation. The primary outcome was change in time in hypoglycaemia (<3·9 mmol/L [70 mg/dL]) between baseline and 6 months in the full analysis set (all participants randomised; excluding those who had a positive pregnancy test during the study). This trial was registered with ClinicalTrials.gov, number NCT02232698. Between Sept 4, 2014, and Feb 12, 2015, we enrolled 328 participants. After the screening and baseline phase, 120 participants were randomly assigned to the intervention group and 121 to the control group, with outcomes being evaluated in 119 and 120, respectively. Mean time in hypoglycaemia changed from 3·38 h/day at baseline to 2·03 h/day at 6 months (baseline adjusted mean change −1·39) in the intervention group, and from 3·44 h/day to 3·27 h/day in the control group (−0·14); with the between-group difference of −1·24 (SE 0·239; p<0·0001), equating to a 38% reduction in time in hypoglycaemia in the intervention group. No device-related hypoglycaemia or safety issues were reported. 13 adverse events were reported by ten participants related to the sensor—four of allergy events (one severe, three moderate); one itching (mild); one rash (mild); four insertion-site symptom (severe); two erythema (one severe, one mild); and one oedema (moderate). There were ten serious adverse events (five in each group) reported by nine participants; none were related to the device. Novel flash glucose testing reduced the time adults with well controlled type 1 diabetes spent in hypoglycaemia. Future studies are needed to assess the effectiveness of this technology in patients with less well controlled diabetes and in younger age groups. Abbott Diabetes Care.

Aims/hypothesisThe aim of this work was to evaluate changes in glycaemic control (HbA1c) and rates of severe hypoglycaemia over a 2 year period after initiation of flash glucose monitoring (FM) in type 1 diabetes.MethodsUsing data from the Swedish National Diabetes Registry, 14,372 adults with type 1 diabetes with a new registration of FM during 2016–2017 and with continued FM for two consecutive years thereafter, and 7691 control individuals using conventional self-monitoring of blood glucose (SMBG) during the same observation period, were included in a cohort study. Propensity sores and inverse probability of treatment weighting (IPTW) were used to balance FM users with SMBG users. Changes in HbA1c and events of severe hypoglycaemia were compared.ResultsAfter the start of FM, the difference in IPTW change in HbA1c was slightly greater in FM users compared with the control group during the follow-up period, with an estimated mean absolute difference of −1.2 mmol/mol (−0.11%) (95% CI −1.64 [−0.15], −0.75 [−0.07]; p < 0.0001) after 15–24 months. The change in HbA1c was greatest in those with baseline HbA1c ≥70 mmol/mol (8.5%), with the estimated mean absolute difference being −2.5 mmol/mol (−0.23%) (95% CI −3.84 [−0.35], −1.18 [−0.11]; p = 0.0002) 15–24 months post index. The change was also significant in the subgroups with initial HbA1c ≤52 mmol/mol (6.9%) and 53–69 mmol/mol (7.0–8.5%). Risk of severe hypoglycaemic episodes was reduced by 21% for FM users compared with control individuals using SMBG (OR 0.79 [95% CI 0.69, 0.91]; p = 0.0014)].Conclusions/interpretationIn this large cohort, the use of FM was associated with a small and sustained improvement in HbA1c, most evident in those with higher baseline HbA1c levels. In addition, FM users experienced lower rates of severe hypoglycaemic events compared with control individuals using SMBG for self-management of glucose control.

OBJECTIVE: To assess the impact of continuous glucose monitoring on hypoglycemia in people with type 1 diabetes. RESEARCH DESIGN AND METHODS: In this randomized, controlled, multicenter study, 120 children and adults on intensive therapy for type 1 diabetes and a screening level of glycated hemoglobin A₁c (HbA₁c) <7.5% were randomly assigned to a control group performing conventional home monitoring with a blood glucose meter and wearing a masked continuous glucose monitor every second week for five days or to a group with real-time continuous glucose monitoring. The primary outcome was the time spent in hypoglycemia (interstitial glucose concentration <63 mg/dL) over a period of 26 weeks. Analysis was by intention to treat for all randomized patients. RESULTS: The time per day spent in hypoglycemia was significantly shorter in the continuous monitoring group than in the control group (mean ± SD 0.48 ± 0.57 and 0.97 ± 1.55 h/day, respectively; ratio of means 0.49; 95% CI 0.26-0.76; P = 0.03). HbA₁c at 26 weeks was lower in the continuous monitoring group than in the control group (difference -0.27%; 95% CI -0.47 to -0.07; P = 0.008). Time spent in 70 to 180 mg/dL normoglycemia was significantly longer in the continuous glucose monitoring group compared with the control group (mean hours per day, 17.6 vs. 16.0, P = 0.009). CONCLUSIONS: Continuous glucose monitoring was associated with reduced time spent in hypoglycemia and a concomitant decrease in HbA₁c in children and adults with type 1 diabetes.

Type 1 diabetes results from autoimmune destruction of insulin-producing beta cells, yet many patients retain endogenous beta-cell function several years after clinical onset — some for decades, as evidenced by persistent C-peptide secretion. 1 Residual C-peptide secretion has been associated with substantial clinical benefits. For example, data from the Diabetes Control and Complications Trial (DCCT) and the Epidemiology of Diabetes Interventions and Complications follow-up study showed that among DCCT participants who entered the trial within 1 to 5 years after diabetes onset and had a C-peptide response (defined as a mixed meal–stimulated C-peptide peak response of ≥0.2 pmol per milliliter) at . . .

OBJECTIVE:--C-peptide replacement in animals results in amelioration of diabetes-induced functional and structural abnormalities in peripheral nerves. The present study was undertaken to examine whether C-peptide administration to patients with type 1 diabetes and peripheral neuropathy improves sensory nerve function. RESEARCH DESIGN AND METHODS--This was an exploratory, double-blinded, randomized, and placebo-controlled study with three study groups that was carried out at five centers in Sweden. C-peptide was given as a replacement dose (1.5 mg/day, divided into four subcutaneous doses) or a dose three times higher (4.5 mg/day) during 6 months. Neurological examination and neurophysiological measurements were performed before and after 6 months of treatment with C-peptide or placebo. RESULTS:--The age of the 139 patients who completed the protocol was 44.2 ± 0.6 (mean ± SE) years and their duration of diabetes was 30.6 ± 0.8 years. Clinical neurological impairment (NIA) (score >7 points) of the lower extremities was present in 86% of the patients at baseline. Sensory nerve conduction velocity (SCV) was 2.6 ± 0.08 SD below body height-corrected normal values at baseline and improved similarly within the two C-peptide groups (P < 0.007). The number of patients responding with a SCV peak potential improvement >1.0 m/s was greater in C-peptide-treated patients than in those receiving placebo (P < 0.03). In the least severely affected patients (SCV < 2.5 SD below normal at baseline, n = 70) SCV improved by 1.0 m/s (P < 0.014 vs. placebo). NIA score and vibration perception both improved within the C-peptide-treated groups (P < 0.011 and P < 0.002). A1C levels (7.6 ± 0.1% at baseline) decreased slightly but similarly in C-peptide-and placebo-treated patients during the study. CONCLUSIONS:--C-peptide treatment for 6 months improves sensory nerve function in early-stage type 1 diabetic neuropathy.

Many decisions in drug development and medical practice are based on measuring blood concentrations of endogenous and exogenous molecules. Yet most biochemical and pharmacological events take place in the tissues. Also, most drugs with few notable exceptions exert their effects not within the bloodstream, but in defined target tissues into which drugs have to distribute from the central compartment. Assessing tissue drug chemistry has, thus, for long been viewed as a more rational way to provide clinically meaningful data rather than gaining information from blood samples. More specifically, it is often the extracellular (interstitial) tissue space that is most closely related to the site of action (biophase) of the drug. Currently microdialysis (microD) is the only tool available that explicitly provides data on the extracellular space. Although microD as a preclinical and clinical tool has been available for two decades, there is still uncertainty about the use of microD in drug research and development, both from a methodological and a regulatory point of view. In an attempt to reduce this uncertainty and to provide an overview of the principles and applications of microD in preclinical and clinical settings, an AAPS-FDA workshop took place in November 2005 in Nashville, TN, USA. Stakeholders from academia, industry and regulatory agencies presented their views on microD as a tool in drug research and development.

Aims/hypothesisEvidence for the effectiveness of interstitial glucose monitoring in individuals with type 1 diabetes using multiple daily injection (MDI) therapy is limited. In this pre-specified subgroup analysis of the Novel Glucose-Sensing Technology and Hypoglycemia in Type 1 Diabetes: a Multicentre, Non-masked, Randomised Controlled Trial’ (IMPACT), we assessed the impact of flash glucose technology on hypoglycaemia compared with capillary glucose monitoring.MethodsThis multicentre, prospective, non-masked, RCT enrolled adults from 23 European diabetes centres. Individuals were eligible to participate if they had well-controlled type 1 diabetes (diagnosed for ≥5 years), HbA1c ≤ 58 mmol/mol [7.5%], were using MDI therapy and on their current insulin regimen for ≥3 months, reported self-monitoring of blood glucose on a regular basis (equivalent to ≥3 times/day) for ≥2 months and were deemed technically capable of using flash glucose technology. Individuals were excluded if they were diagnosed with hypoglycaemia unawareness, had diabetic ketoacidosis or myocardial infarction in the preceding 6 months, had a known allergy to medical-grade adhesives, used continuous glucose monitoring (CGM) within the previous 4 months or were currently using CGM or sensor-augmented pump therapy, were pregnant or planning pregnancy or were receiving steroid therapy for any disorders. Following 2 weeks of blinded (to participants and investigator) sensor wear by all participants, participants with sensor data for more than 50% of the blinded wear period (or ≥650 individual sensor results) were randomly assigned, in a 1:1 ratio by a central interactive web response system (IWRS) using the biased-coin minimisation method, to flash sensor-based glucose monitoring (intervention group) or self-monitoring of capillary blood glucose (control group). The control group had two further 14 day blinded sensor-wear periods at the 3 and 6 month time points. Participants, investigators and staff were not masked to group allocation. The primary outcome was the change in time in hypoglycaemia (<3.9 mmol/l) between baseline and 6 months in the full analysis set.ResultsBetween 4 September 2014 and 12 February 2015, 167 participants using MDI were enrolled. After screening and the baseline phase, participants were randomised to intervention (n = 82) and control groups (n = 81). One woman from each group was excluded owing to pregnancy; the full analysis set included 161 randomised participants. At 6 months, mean time in hypoglycaemia was reduced by 46.0%, from 3.44 h/day to 1.86 h/day in the intervention group (baseline adjusted mean change, −1.65 h/day), and from 3.73 h/day to 3.66 h/day in the control group (baseline adjusted mean change, 0.00 h/day), with a between-group difference of −1.65 (95% CI −2.21, −1.09; p < 0.0001). For participants in the intervention group, the mean ± SD daily sensor scanning frequency was 14.7 ± 10.7 (median 12.3) and the mean number of self-monitored blood glucose tests performed per day reduced from 5.5 ± 2.0 (median 5.4) at baseline to 0.5 ± 1.0 (median 0.1). The baseline frequency of self-monitored blood glucose tests by control participants was maintained (from 5.6 ± 1.9 [median 5.2] to 5.5 ± 2.6 [median 5.1] per day). Treatment satisfaction and perception of hypo/hyperglycaemia were improved compared with control. No device-related hypoglycaemia or safety-related issues were reported. Nine serious adverse events were reported for eight participants (four in each group), none related to the device. Eight adverse events for six of the participants in the intervention group were also reported, which were related to sensor insertion/wear; four of these participants withdrew because of the adverse event.Conclusions/interpretationUse of flash glucose technology in type 1 diabetes controlled with MDI therapy significantly reduced time in hypoglycaemia without deterioration of HbA1c, and improved treatment satisfaction.Trial registration:ClinicalTrials.gov NCT02232698Funding:Abbott Diabetes Care, Witney, UK

Aims/hypothesis We assessed the impact of initiating intermittently scanned continuous glucose monitoring (isCGM) compared with capillary blood glucose monitoring (BGM) on HbA 1c levels and hospitalisations for diabetes-related complications in adults with insulin-treated type 2 diabetes in Sweden. Methods This retrospective comparative cohort study included adults with type 2 diabetes who had a National Diabetes Register initiation date for isCGM after 1 June 2017. Prescribed Drug Register records identified subgroups treated with multiple daily insulin injections (T2D-MDI) or basal insulin (T2D-B), with or without other glucose-lowering drugs. The National Patient Register provided data on hospitalisation rates. Results We identified 2876 adults in the T2D-MDI group and 2292 in the T2D-B group with an isCGM index date after 1 June 2017, matched with 33,584 and 43,424 BGM control participants, respectively. The baseline-adjusted difference in the change in mean HbA 1c for isCGM users vs BGM control participants in the T2D-MDI cohort was −3.7 mmol/mol (−0.34%) at 6 months, and this was maintained at 24 months. The baseline-adjusted difference in the change in HbA 1c for isCGM users vs BGM control participants in the T2D-B cohort was −3.5 mmol/mol (−0.32%) at 6 months, and this was also maintained at 24 months. Compared with BGM control participants, isCGM users in the T2D-MDI cohort had a significantly lower RR of admission for severe hypoglycaemia (0.51; 95% CI 0.27, 0.95), stroke (0.54; 95% CI 0.39, 0.73), acute non-fatal myocardial infarction (0.75; 95% CI 0.57, 0.99) or hospitalisation for any reason (0.84; 95% CI 0.77, 0.90). isCGM users in the T2D-B cohort had a lower RR of admission for heart failure (0.63; 95% CI 0.46, 0.87) or hospitalisation for any reason (0.76; 95% CI 0.69, 0.84). Conclusions/interpretation This study shows that Swedish adults with type 2 diabetes on insulin who are using isCGM have a significantly reduced HbA 1c and fewer hospital admissions for diabetes-related complications compared with BGM control participants. Graphical Abstract

We assessed the impact of initiating intermittently scanned continuous glucose monitoring (isCGM) compared with capillary blood glucose monitoring (BGM) on HbA levels and hospitalisations for diabetes-related complications in adults with insulin-treated type 2 diabetes in Sweden. This retrospective comparative cohort study included adults with type 2 diabetes who had a National Diabetes Register initiation date for isCGM after 1 June 2017. Prescribed Drug Register records identified subgroups treated with multiple daily insulin injections (T2D-MDI) or basal insulin (T2D-B), with or without other glucose-lowering drugs. The National Patient Register provided data on hospitalisation rates. We identified 2876 adults in the T2D-MDI group and 2292 in the T2D-B group with an isCGM index date after 1 June 2017, matched with 33,584 and 43,424 BGM control participants, respectively. The baseline-adjusted difference in the change in mean HbA for isCGM users vs BGM control participants in the T2D-MDI cohort was -3.7 mmol/mol (-0.34%) at 6 months, and this was maintained at 24 months. The baseline-adjusted difference in the change in HbA for isCGM users vs BGM control participants in the T2D-B cohort was -3.5 mmol/mol (-0.32%) at 6 months, and this was also maintained at 24 months. Compared with BGM control participants, isCGM users in the T2D-MDI cohort had a significantly lower RR of admission for severe hypoglycaemia (0.51; 95% CI 0.27, 0.95), stroke (0.54; 95% CI 0.39, 0.73), acute non-fatal myocardial infarction (0.75; 95% CI 0.57, 0.99) or hospitalisation for any reason (0.84; 95% CI 0.77, 0.90). isCGM users in the T2D-B cohort had a lower RR of admission for heart failure (0.63; 95% CI 0.46, 0.87) or hospitalisation for any reason (0.76; 95% CI 0.69, 0.84). This study shows that Swedish adults with type 2 diabetes on insulin who are using isCGM have a significantly reduced HbA and fewer hospital admissions for diabetes-related complications compared with BGM control participants.

Aims/hypothesis Previous studies have shown that individuals with similar mean glucose levels (MG) or percentage of time in range (TIR) may have different HbA 1c values. The aim of this study was to further elucidate how MG and TIR are associated with HbA 1c . Methods Data from the randomised clinical GOLD trial ( n =144) and the follow-up SILVER trial ( n =98) of adults with type 1 diabetes followed for 2.5 years were analysed. A total of 596 paired HbA 1c /continuous glucose monitoring measurements were included. Linear mixed-effects models were used to account for intra-individual correlations in repeated-measures data. Results In the GOLD trial, the mean age of the participants (± SD) was 44±13 years, 63 (44%) were female, and the mean HbA 1c (± SD) was 72±9.8 mmol/mol (8.7±0.9%). When correlating MG with HbA 1c , MG explained 63% of the variation in HbA 1c ( r =0.79, p <0.001). The variation in HbA 1c explained by MG increased to 88% ( r =0.94, p value for improvement of fit <0.001) when accounting for person-to-person variation in the MG–HbA 1c relationship. Time below range (TBR; <3.9 mmol/l), time above range (TAR) level 2 (>13.9 mmol/l) and glycaemic variability had little or no effect on the association. For a given MG and TIR, the HbA 1c of 10% of individuals deviated by >8 mmol/mol (0.8%) from their estimated HbA 1c based on the overall association between MG and TIR with HbA 1c . TBR and TAR level 2 significantly influenced the association between TIR and HbA 1c . At a given TIR, each 1% increase in TBR was related to a 0.6 mmol/mol lower HbA 1c (95% CI 0.4, 0.9; p <0.001), and each 2% increase in TAR level 2 was related to a 0.4 mmol/mol higher HbA 1c (95% CI 0.1, 0.6; p =0.003). However, neither TIR, TBR nor TAR level 2 were significantly associated with HbA 1c when accounting for MG. Conclusions/interpretation Inter-individual variations exist between MG and HbA 1c , as well as between TIR and HbA 1c , with clinically important deviations in relatively large groups of individuals with type 1 diabetes. These results may provide important information to both healthcare providers and individuals with diabetes in terms of prognosis and when making diabetes management decisions. Graphical Abstract