Continuous glucose monitoring and metrics for clinical trials: an international consensus statement.

Randomised controlled trials and other prospective clinical studies for novel medical interventions in people with diabetes have traditionally reported HbA1c as the measure of average blood glucose levels for the 3 months preceding the HbA1c test date. The use of this measure highlights the long-established correlation between HbA1c and relative risk of diabetes complications; the change in the measure, before and after the therapeutic intervention, is used by regulators for the approval of medications for diabetes. However, with the increasing use of continuous glucose monitoring (CGM) in clinical practice, prospective clinical studies are also increasingly using CGM devices to collect data and evaluate glucose profiles among study participants, complementing HbA1c findings, and further assess the effects of therapeutic interventions on HbA1c. Data is collected by CGM devices at 1-5 min intervals, which obtains data on glycaemic excursions and periods of asymptomatic hypoglycaemia or hyperglycaemia (ie, details of glycaemic control that are not provided by HbA1c concentrations alone that are measured continuously and can be analysed in daily, weekly, or monthly timeframes). These CGM-derived metrics are the subject of standardised, internationally agreed reporting formats and should, therefore, be considered for use in all clinical studies in diabetes. The purpose of this consensus statement is to recommend the ways CGM data might be used in prospective clinical studies, either as a specified study endpoint or as supportive complementary glucose metrics, to provide clinical information that can be considered by investigators, regulators, companies, clinicians, and individuals with diabetes who are stakeholders in trial outcomes. In this consensus statement, we provide recommendations on how to optimise CGM-derived glucose data collection in clinical studies, including the specific glucose metrics and specific glucose metrics that should be evaluated. These recommendations have been endorsed by the American Association of Clinical Endocrinologists, the American Diabetes Association, the Association of Diabetes Care and Education Specialists, DiabetesIndia, the European Association for the Study of Diabetes, the International Society for Pediatric and Adolescent Diabetes, the Japanese Diabetes Society, and the Juvenile Diabetes Research Foundation. A standardised approach to CGM data collection and reporting in clinical trials will encourage the use of these metrics and enhance the interpretability of CGM data, which could provide useful information other than HbA1c for informing therapeutic and treatment decisions, particularly related to hypoglycaemia, postprandial hyperglycaemia, and glucose variability.

Improved glycaemic variability and time in range with dapagliflozin versus gliclazide modified release among adults with type 2 diabetes, evaluated by continuous glucose monitoring: A 12-week randomized controlled trial.

AIMS: To evaluate whether there is a difference between the effects of dapagliflozin and gliclazide modified release (MR) on glycaemic variability (GV) and glycaemic control, as assessed by continuous glucose monitoring (CGM), in individuals with uncontrolled type 2 diabetes. MATERIALS AND METHODS: This randomized, open-label, active-controlled study was conducted in individuals with uncontrolled type 2 diabetes who were drug-naïve or on steady-dose metformin monotherapy. Participants were treated once daily with 10 mg dapagliflozin or 120 mg gliclazide MR. CGM and GV index calculations were performed at baseline and after 12 weeks. RESULTS: In total, 97 participants (age 57.9 ± 8.7 years, 50.5% men, baseline glycated haemoglobin 63 ± 9.8 mmol/mol [7.9 ± 0.9%]) were randomized, and 94 completed the 12-week protocol. Intention-to-treat (ITT) and per-protocol (PP) analyses showed that the reduction in GV, as measured by the mean amplitude of glycaemic excursions, was superior in the dapagliflozin group versus the gliclazide MR group (-0.9 mmol/L [95% CI -1.5, -0.4] vs -0.2 mmol/L [95% CI -0.6, 0.3]; P = 0.030 [ITT]). The reductions in GV estimated by the coefficient of variation and SD were greater in the dapagliflozin group. Moreover, dapagliflozin increased the glucose time in range (TIR; 3.9-10 mmol/L) by 24.9% (95% CI 18.6, 31.2) vs. 17.4% (95% CI 11.6, 23.3) in the gliclazide MR group (P = 0.089 [ITT]; P = 0.041 [PP]). CONCLUSIONS: Dapagliflozin improved GV and increased TIR more efficiently than gliclazide MR in individuals with type 2 diabetes over 12 weeks, as demonstrated by CGM.

International Consensus on Use of Continuous Glucose Monitoring.

Measurement of glycated hemoglobin (HbA1c) has been the traditional method for assessing glycemic control. However, it does not reflect intra- and interday glycemic excursions that may lead to acute events (such as hypoglycemia) or postprandial hyperglycemia, which have been linked to both microvascular and macrovascular complications. Continuous glucose monitoring (CGM), either from real-time use (rtCGM) or intermittently viewed (iCGM), addresses many of the limitations inherent in HbA1c testing and self-monitoring of blood glucose. Although both provide the means to move beyond the HbA1c measurement as the sole marker of glycemic control, standardized metrics for analyzing CGM data are lacking. Moreover, clear criteria for matching people with diabetes to the most appropriate glucose monitoring methodologies, as well as standardized advice about how best to use the new information they provide, have yet to be established. In February 2017, the Advanced Technologies & Treatments for Diabetes (ATTD) Congress convened an international panel of physicians, researchers, and individuals with diabetes who are expert in CGM technologies to address these issues. This article summarizes the ATTD consensus recommendations and represents the current understanding of how CGM results can affect outcomes.

Striving for control: lessons learned from a successful international Type 1 Diabetes Youth Challenge.

AIMS: To demonstrate whether young people with T1D using modern insulin treatment and CGM could successfully participate in extreme sport activity while maintaining good glycemic control. METHODS: The challenge took place in Crete/Greece over 4 days combining a long-distance trek of different levels of severity with final destination the summit of the White Mountains at 2080 m. Eleven participants (5/6 female/male, age 18.2 ± 1.3 years, T1D duration 7.9 ± 3.5 years, HbA1c 7.3 ± .7% (56 ± 16 mmol/mol); mean ± SD) from 11 SWEET centers in Belgium, Brazil, Canada, Germany, Greece, France, India, Italy, Portugal, Slovenia and Sweden participated to the challenge. Five participants were on CSII, six on MDI; all were wearing a continuous glucose monitoring system. The glycemic targets during trekking were defined as 80-180 mg/dl (4.4-10 mmol/l). RESULTS: All participants completed the challenge. In total, the group walked 54.5 km under varying climate conditions (temperature 14-35 °C). During the challenge, insulin requirements decreased significantly compared to baseline: total daily insulin by 31.1 ± 16.7% (p < .001), basal by 30.8 ± 14.9% (p < .001), and prandial by 32.5 ± 28.0% (p = .023), with no differences between participants with CSII or MDI. No episode of severe hypoglycemia or DKA occurred. Mean glucose levels were 170.7 ± 60.1 mg/dl with 61.5 ± 18.7% of CGM values in the target range, 5.4 ± 5.4% under 80 mg/dl and 32.8 ± 16.6% above 180 mg/dl. CONCLUSIONS: The results of this SWEET Initiative activity demonstrated that well-educated adolescents and young adults with T1D using modern insulin treatments are able to perform successfully even extraordinary physical challenges while maintaining good glycemic control without diabetes-related acute complications.

Insulin pump therapy in children with type 1 diabetes: analysis of data from the SWEET registry.

BACKGROUND: Intensified insulin delivery using multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) is recommended in children with type 1 diabetes (T1D) to achieve good metabolic control. OBJECTIVE: To examine the frequency of pump usage in T1D children treated in SWEET (Better control in Paediatric and Adolescent diabeteS: Working to crEate CEnTers of Reference) centers and to compare metabolic control between patients treated with CSII vs MDI. METHODS: This study included 16 570 T1D children participating in the SWEET prospective, multicenter, standardized diabetes patient registry. Datasets were aggregated over the most recent year of treatment for each patient. Data were collected until March 2016. To assess the organization of pump therapy a survey was carried out. RESULTS: Overall, 44.4% of T1D children were treated with CSII. The proportion of patients with pump usage varied between centers and decreased with increasing age compared with children treated with MDI. In a logistic regression analysis adjusting for age, gender and diabetes duration, the use of pump was associated with both: center size [odd ratio 1.51 (1.47-1.55), P < .0001) and the diabetes-related expenditure per capita [odd ratio 1.55 (1.49-1.61), P < .0001]. Linear regression analysis, adjusted for age, gender, and diabetes duration showed that both HbA1c and daily insulin dose (U/kg/d) remained decreased in children treated with CSII compared to MDI (P < .0001). CONCLUSIONS: Insulin pump therapy is offered by most Sweet centers. The differences between centers affect the frequency of use of modern technology. Despite the heterogeneity of centers, T1D children achieve relatively good metabolic control, especially those treated with insulin pumps and those of younger age.

Twenty-one additional cases of familial renal glucosuria: absence of genetic heterogeneity, high prevalence of private mutations and further evidence of volume depletion.

INTRODUCTION: Familial renal glucosuria (FRG) is a rare renal tubular disorder caused by mutations within the SLC5A2 gene. It is characterized by persistent glucosuria in the absence of hyperglycaemia and any other signs of generalized tubular dysfunction. In small series of patients previously reported, the molecular and phenotypic findings in FRG families, including first hints of extracellular volume depletion and activation of the renin-angiotensin-aldosterone system induced by natriuresis, have been described. We have now extended this analysis to another 21 consecutive cases from 17 pedigrees, including 11 cases with severe glucose excretion. METHODS: Mutation analysis was performed by direct sequencing of the genomic coding segments of the SLC5A2 gene. In two cases with severe glucosuria, basal plasma renin activity and serum aldosterone concentrations were determined. RESULTS: Within the 17 pedigrees, we have identified a total of 20 different SLC5A2 mutations. Fifteen have not been previously reported. In all glucosuric individuals tested, at least one SLC5A2 mutation could be identified. Heterozygous individuals were found to have only mild glucose excretion whereas homozygous or compound heterozygous patients had severe glucosuria, ranging from 10 to 86.5 g/1.73 m(2)/24 h. In two patients of the latter group, basal plasma renin activity and serum aldosterone concentration were determined and found to be raised to an average of 4.6-fold and 3.1-fold of the upper limit of the normal range, respectively. Discussion. The identification of at least one mutated allele in every affected individual in this cohort of 17 consecutively investigated families strongly suggests that genetic heterogeneity is not prevalent in FRG. Although 5 of the detected alleles have been described previously, 15 are novel, confirming that most mutations in FRG are private. Our finding of an activation of compensatory mechanisms for salt loss may warrant more detailed studies of long-term hormonal and metabolic imbalances in patients with FRG.

The application of catalase for the elimination of hydrogen peroxide residues after bleaching of cotton fabrics.

Results of dyeing of cotton fabrics with a bifunctional reactive dye were significantly improved when the fabric after bleaching with hydrogen peroxide was treated with catalase for the elimination of hydrogen peroxide residues from the fabrics. Compared to processes with a varying number of washing steps, with and without commercial reducing agents, the consumption of water could be significantly reduced, without altering the final color shade.

The application of catalase for the elimination of hydrogen peroxide residues after bleaching of cotton fabrics

Results of dyeing of cotton fabrics with a bifunctional reactive dye were significantly improved when the fabric after bleaching with hydrogen peroxide was treated with catalase for the elimination of hydrogen peroxide residues from the fabrics. Compared to processes with a varying number of washing steps, with and without commercial reducing agents, the consumption of water could be significantly reduced, without altering the final color shade

A new method of microvolume back-extraction procedure for enrichment of Pb and Cd and determination by flame atomic absorption spectrometry.

The need for highly reliable methods for the determination of trace elements has been recognised in analytical chemistry and environmental science. A method for the trace analysis of Pb and Cd in natural waters is described. In a preconcentration step, 500 ml of an aqueous sample containing lead and cadmium were extracted into 3.5 ml of a solution containing a complexing agent (dithizone) in xylene. Subsequently, the dithizonate complexes were back-extracted into 600 mul of nitric acid solution for direct determination by flame atomic absorption spectrometry. Important microextraction parameters were optimised using spiked deionised water. The 3sigma detection limits, relative standard deviations and linear calibration graphs were, respectively, 0.39 mugl(-1), 6.3% and 1.0-20.0 mugl(-1) for lead and 8.2 ngl(-1), 4.0% and 0.05-1.0 mugl(-1) for cadmium for solvent microextraction times of 4 min and microvolume back-extraction times of 1 min. The preconcentration factors were 543- and 331-fold for lead and cadmium, respectively.