Tonya D. Riddlesworth

Effect of Continuous Glucose Monitoring on Glycemic Control in Adults With Type 1 Diabetes Using Insulin Injections: The DIAMOND Randomized Clinical Trial.

Importance Previous clinical trials showing the benefit of continuous glucose monitoring (CGM) in the management of type 1 diabetes predominantly have included adults using insulin pumps, even though the majority of adults with type 1 diabetes administer insulin by injection. Objective To determine the effectiveness of CGM in adults with type 1 diabetes treated with insulin injections. Design, Setting, and Participants Randomized clinical trial conducted between October 2014 and May 2016 at 24 endocrinology practices in the United States that included 158 adults with type 1 diabetes who were using multiple daily insulin injections and had hemoglobin A1c (HbA1c) levels of 7.5% to 9.9%. Interventions Random assignment 2:1 to CGM (n = 105) or usual care (control group; n = 53). Main Outcomes and Measures Primary outcome measure was the difference in change in central-laboratory–measured HbA1c level from baseline to 24 weeks. There were 18 secondary or exploratory end points, of which 15 are reported in this article, including duration of hypoglycemia at less than 70 mg/dL, measured with CGM for 7 days at 12 and 24 weeks. Results Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women; mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years [interquartile range, 10-31 years]), 155 (98%) completed the study. In the CGM group, 93% used CGM 6 d/wk or more in month 6. Mean HbA1c reduction from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the adjusted treatment-group difference in mean change in HbA1c level from baseline was –0.6% (95% CI, –0.8% to –0.3%; P < .001). Median duration of hypoglycemia at less than <70 mg/dL was 43 min/d (IQR, 27-69) in the CGM group vs 80 min/d (IQR, 36-111) in the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in each group. Conclusions and Relevance Among adults with type 1 diabetes who used multiple daily insulin injections, the use of CGM compared with usual care resulted in a greater decrease in HbA1c level during 24 weeks. Further research is needed to assess longer-term effectiveness, as well as clinical outcomes and adverse effects. Trial Registration clinicaltrials.gov Identifier: NCT02282397

REPLACE-BG: A Randomized Trial Comparing Continuous Glucose Monitoring With and Without Routine Blood Glucose Monitoring in Adults With Well-Controlled Type 1 Diabetes

OBJECTIVE To determine whether the use of continuous glucose monitoring (CGM) without confirmatory blood glucose monitoring (BGM) measurements is as safe and effective as using CGM adjunctive to BGM in adults with well-controlled type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS A randomized noninferiority clinical trial was conducted at 14 sites in the T1D Exchange Clinic Network. Participants were ≥18 years of age (mean 44 ± 14 years), had T1D for ≥1 year (mean duration 24 ± 12 years), used an insulin pump, and had an HbA1c ≤9.0% (≤75 mmol/mL) (mean 7.0 ± 0.7% [53 ± 7.7 mmol/mol]); prestudy, 47% were CGM users. Participants were randomly assigned 2:1 to the CGM-only (n = 149) or CGM+BGM (n = 77) group. The primary outcome was time in range (70–180 mg/dL) over the 26-week trial, with a prespecified noninferiority limit of 7.5%. RESULTS CGM use averaged 6.7 ± 0.5 and 6.8 ± 0.4 days/week in the CGM-only and CGM+BGM groups, respectively, over the 26-week trial. BGM tests per day (including the two required daily for CGM calibration) averaged 2.8 ± 0.9 and 5.4 ± 1.4 in the two groups, respectively (P < 0.001). Mean time in 70–180 mg/dL was 63 ± 13% at both baseline and 26 weeks in the CGM-only group and 65 ± 13% and 65 ± 11% in the CGM+BGM group (adjusted difference 0%; one-sided 95% CI −2%). No severe hypoglycemic events occurred in the CGM-only group, and one occurred in the CGM+BGM group. CONCLUSIONS Use of CGM without regular use of confirmatory BGM is as safe and effective as using CGM with BGM in adults with well-controlled T1D at low risk for severe hypoglycemia.

Effect of initiating use of an insulin pump in adults with type 1 diabetes using multiple daily insulin injections and continuous glucose monitoring (DIAMOND): a multicentre, randomised controlled trial

BACKGROUND The benefit of initiation of insulin pump therapy (continuous subcutaneous insulin infusion; CSII) in patients with type 1 diabetes using continuous glucose monitoring (CGM) has not been studied. We aimed to assess glycaemic outcomes when switching from multiple daily injections (MDI) to CSII in adults with type 1 diabetes using CGM. METHODS In this multicentre, randomised controlled trial, 75 adults with type 1 diabetes in the CGM group of the DIAMOND trial were randomly assigned via the study website using a computer-generated sequence to continue MDI or switch to CSII, with continuation of CGM, for 28 weeks. The primary outcome was CGM-measured time in the glucose concentration range of 70-180 mg/dL (3·9-10·0 mmol/L). This study is registered with ClinicalTrials.gov, number NCT02282397. FINDINGS Between April 14, 2015, and May 5, 2016, 37 participants were randomly assigned to the CGM plus CSII group and 38 participants were randomly assigned to the CGM plus MDI group. The study was completed by 36 (97%) of 37 participants in the CGM plus CSII group and 35 (92%) of 38 participants in the CGM plus MDI group. Mean CGM use was 6·7 days per week (SD 0·8) in the CGM plus CSII group and 6·9 days per week (0·3) in the CGM plus MDI group (p=0·86). No participants in the CGM plus CSII group who completed the trial discontinued CSII. Over the follow-up period, mean time in the glucose concentration range of 70-180 mg/dL (3·9-10·0 mmol/L) was 791 min per day (SD 157) in the CGM plus CSII group and 741 min per day (225) in the CGM plus MDI group (adjusted mean treatment group difference: 83 min, 95% CI 17-149; p=0·01). Participants in the CGM plus CSII group had a greater reduction in CGM-measured mean glucose (p=0·005) and hyperglycaemia (on four metrics: p=0·007 for >180 mg/dL [>10·0 mmol/L], p=0·02 for >250 mg/dL [>13·9 mmol/L], p=0·04 for >300 mg/dL [>16·6 mmol/L], and p=0·02 for the area under the curve for 180 mg/dL [10·0 mmol/L]), but also an increase in CGM-measured hypoglycaemia (p=0·0001 for <70 mg/dL [<3·9 mmol/L], p=0·0002 for <60 mg/dL [<3·3 mmol/L], p=0·0009 for <50 mg/dL [<2·8 mmol/L], p=0·0002 for the area over the curve for 70 mg/dL [3·9 mmol/L]). Mean HbA1c change from baseline to 28 weeks was 0·3% (SD 0·9; 3·3 mmol/mol [SD 9·8]) in the CGM plus CSII group and 0·1% (0·4; 1·1 mmol/mol [4·4]) in the CGM plus MDI group (p=0·32). Severe hypoglycaemia occurred in one participant in the CGM plus MDI group, and diabetic ketoacidosis and severe hyperglycaemia occurred in one participant each in the CGM plus CSII group. INTERPRETATION Our findings show that glycaemic control measured by time in the glucose range of 70-180 mg/dL (3·9-10·0 mmol/L) is improved by initiation of CSII in adults with type 1 diabetes. However, biochemical hypoglycaemia also was increased in the study, which will be important to consider when incorporating these results into clinical practice. FUNDING Dexcom.

Continuous Glucose Monitoring in Older Adults With Type 1 and Type 2 Diabetes Using Multiple Daily Injections of Insulin: Results From the DIAMOND Trial

Objective: The objective was to determine the effectiveness of real-time continuous glucose monitoring (CGM) in adults ≥ 60 years of age with type 1 (T1D) or type 2 (T2D) diabetes using multiple daily insulin injections (MDI). Methods: A multicenter, randomized trial was conducted in the United States and Canada in which 116 individuals ≥60 years (mean 67 ± 5 years) with T1D (n = 34) or T2D (n = 82) using MDI therapy were randomly assigned to either CGM (Dexcom™ G4 Platinum CGM System® with software 505; n = 63) or continued management with self-monitoring blood glucose (SMBG; n = 53). Median diabetes duration was 21 (14, 30) years and mean baseline HbA1c was 8.5 ± 0.6%. The primary outcome, HbA1c at 24 weeks, was obtained for 114 (98%) participants. Results: HbA1c reduction from baseline to 24 weeks was greater in the CGM group than Control group (−0.9 ± 0.7% versus −0.5 ± 0.7%, adjusted difference in mean change was −0.4 ± 0.1%, P < .001). CGM-measured time >250 mg/dL (P = .006) and glycemic variability (P = .02) were lower in the CGM group. Among the 61 in the CGM group completing the trial, 97% used CGM ≥ 6 days/week in month 6. There were no severe hypoglycemic or diabetic ketoacidosis events in either group. Conclusion: In adults ≥ 60 years of age with T1D and T2D using MDI, CGM use was high and associated with improved HbA1c and reduced glycemic variability. Therefore, CGM should be considered for older adults with diabetes using MDI.

The relationship between neuropsychological assessment, numeracy, and functional status in older adults with type 1 diabetes

ABSTRACT While data are accumulating on the association between neuropsychological performance and real-world endpoints, less is known about the association with medical self-management skills. The self-management of type 1 diabetes (T1D) is often complex, and mismanagement can result in hypoglycaemia and hyperglycaemia and associated morbidity and mortality. The T1D Exchange conducted a case-control study evaluating factors associated with severe hypoglycaemia in older adults (≥ 60 years old) with longstanding T1D (≥ 20 years). A battery of neuropsychological and functional assessments was administered, including measures of diabetes-specific self-management skill (diabetes numeracy) and instrumental activities of daily living (IADL). After adjusting for confounding variables, diabetes numeracy was related to memory and complex speeded attention; while IADL were associated with simple processing speed, executive functioning, complex speeded attention and dominant hand dexterity. The severity of overall cognitive deficit was uniquely associated with both diabetes numeracy and IADL, when controlling for age, education, frailty and depression. This study demonstrates that the cognitive deficits in older adults with T1D have functional implications for both diabetes management and IADL. Further research is needed to determine specific interventions to maximise diabetes self-management in older adults with declining cognition.

Continuous glucose monitoring versus usual care in patients with type 2 diabetes receiving multiple daily insulin injections

IN RESPONSE: The treatment group difference used to calculate a sample size is the postulated estimate of the true population value and is not intended to indicate what would be considered clinically significant, which is a common misconception. The upper limit of the 95% CI for the observed treatment group difference in HbA1c levels was 0.6%, extending beyond the projected true population value of 0.4%. We believe that a treatment group difference of 0.3% represents a meaningful shift in the HbA1c distributions, as evidenced by our finding that 73% of the CGM group achieved an HbA1c reduction of 0.5% or greater at 24 weeks compared with only 49% of the control group. Our conjecture that the alerts offered by the Dexcom G4 Platinum CGM System (Dexcom) but not the FreeStyle Libre may be an important factor in achieving lower HbA1c levels seems reasonable in the absence of an alternative explanation. Dr. Haak postulates that slight increases in insulin dose (0.1 U/kg of body weight daily) and weight (1.3 kg) in the CGM group may explain why we found a significant effect on HbA1c whereas REPLACE (1) found no effect. However, the small insulin increase in our studyeven if meaningfulwould still be a consequence of CGM use, and understanding how weight gain would reduce HbA1c levels is difficult. The central question is not why our study showed a reduction in HbA1c levels but why REPLACE did not, considering that CGM has consistently been shown to do so in other populations. We believe that medians and interquartile ranges are generally more appropriate for hypoglycemia metrics than means and SDs because the data are almost always skewed, as was the case in both our study and REPLACE. In our study, the mean time that the glucose level was below 3.89 mmol/L (<70 mg/dL) at baseline and 24 weeks in the CGM group was 30 minutes per day (SD, 50) and 16 minutes per day (SD, 31), respectively, compared with 31 minutes per day (SD, 43) and 27 minutes per day (SD, 40), respectively, in the control group. The participants in REPLACE had substantially more baseline hypoglycemia (approximately 74 minutes per day) than the participants in our study (approximately 30 minutes per day), possibly because of the low bias of the FreeStyle Libre in hypoglycemia (2). The limited amount of baseline hypoglycemia decreased our ability to show a statistically significant reduction in this variable. However, the relative reduction in hypoglycemia in our study was of similar magnitude to that found in REPLACE.

Sex- and age-dependent effects of celiac disease on growth and weight gain in children with type 1 diabetes: Analysis of the type 1 diabetes Exchange Clinic Registry

Celiac disease (CD) is common in patients with type 1 diabetes (T1D) and effects of CD on growth in children with T1D remain unclear.

Glucose Management Indicator (GMI): A New Term for Estimating A1C From Continuous Glucose Monitoring

While A1C is well established as an important risk marker for diabetes complications, with the increasing use of continuous glucose monitoring (CGM) to help facilitate safe and effective diabetes management, it is important to understand how CGM metrics, such as mean glucose, and A1C correlate. Estimated A1C (eA1C) is a measure converting the mean glucose from CGM or self-monitored blood glucose readings, using a formula derived from glucose readings from a population of individuals, into an estimate of a simultaneously measured laboratory A1C. Many patients and clinicians find the eA1C to be a helpful educational tool, but others are often confused or even frustrated if the eA1C and laboratory-measured A1C do not agree. In the U.S., the Food and Drug Administration determined that the nomenclature of eA1C needed to change. This led the authors to work toward a multipart solution to facilitate the retention of such a metric, which includes renaming the eA1C the glucose management indicator (GMI) and generating a new formula for converting CGM-derived mean glucose to GMI based on recent clinical trials using the most accurate CGM systems available. The final aspect of ensuring a smooth transition from the old eA1C to the new GMI is providing new CGM analyses and explanations to further understand how to interpret GMI and use it most effectively in clinical practice. This Perspective will address why a new name for eA1C was needed, why GMI was selected as the new name, how GMI is calculated, and how to understand and explain GMI if one chooses to use GMI as a tool in diabetes education or management.

Validation of Time in Range as an Outcome Measure for Diabetes Clinical Trials

OBJECTIVE This study evaluated the association of time in range (TIR) of 70–180 mg/dL (3.9–10 mmol/L) with the development or progression of retinopathy and development of microalbuminuria using the Diabetes Control and Complications Trial (DCCT) data set in order to validate the use of TIR as an outcome measure for clinical trials. RESEARCH DESIGN AND METHODS In the DCCT, blood glucose concentrations were measured at a central laboratory from seven fingerstick samples (seven-point testing: pre- and 90-min postmeals and at bedtime) collected during 1 day every 3 months. Retinopathy progression was assessed every 6 months and urinary microalbuminuria development every 12 months. Proportional hazards models were used to assess the association of TIR and other glycemic metrics, computed from the seven-point fingerstick data, with the rate of development of microvascular complications. RESULTS Mean TIR of seven-point profiles for the 1,440 participants was 41 ± 16%. The hazard rate of development of retinopathy progression was increased by 64% (95% CI 51–78), and development of the microalbuminuria outcome was increased by 40% (95% CI 25–56), for each 10 percentage points lower TIR (P < 0.001 for each). Results were similar for mean glucose and hyperglycemia metrics. CONCLUSIONS Based on these results, a compelling case can be made that TIR is strongly associated with the risk of microvascular complications and should be an acceptable end point for clinical trials. Although hemoglobin A1c remains a valuable outcome metric in clinical trials, TIR and other glycemic metrics—especially when measured with continuous glucose monitoring—add value as outcome measures in many studies.