Population-Level Impact and Cost-effectiveness of Continuous Glucose Monitoring and Intermittently Scanned Continuous Glucose Monitoring Technologies for Adults With Type 1 Diabetes in Canada: A Modeling Study

OBJECTIVEMaintaining healthy glucose levels is critical for the management of type 1 diabetes (T1D), but the most efficacious and cost-effective approach (capillary self-monitoring of blood glucose [SMBG] or continuous [CGM] or intermittently scanned [isCGM] glucose monitoring) is not clear. We modeled the population-level impact of these three glucose monitoring systems on diabetes-related complications, mortality, and cost-effectiveness in adults with T1D in Canada.RESEARCH DESIGN AND METHODSWe used a Markov cost-effectiveness model based on nine complication states for adults aged 18–64 years with T1D. We performed the cost-effectiveness analysis from a single-payer health care system perspective over a 20-year horizon, assuming a willingness-to-pay threshold of CAD 50,000 per quality-adjusted life-year (QALY). Primary outcomes were the number of complications and deaths and the incremental cost-effectiveness ratio (ICER) of CGM and isCGM relative to SMBG.RESULTSAn initial cohort of 180,000 with baseline HbA_1c of 8.1% was used to represent all Canadians aged 18–64 years with T1D. Universal SMBG use was associated with ∼11,200 people (6.2%) living without complications and ∼89,400 (49.7%) deaths after 20 years. Universal CGM use was associated with an additional ∼7,400 (4.1%) people living complications free and ∼11,500 (6.4%) fewer deaths compared with SMBG, while universal isCGM use was associated with ∼3,400 (1.9%) more people living complications free and ∼4,600 (2.6%) fewer deaths. Relative to SMBG, CGM and isCGM had ICERs of CAD 35,017/QALY and 17,488/QALY, respectively.CONCLUSIONSUniversal use of CGM or isCGM in the Canadian T1D population is anticipated to reduce diabetes-related complications and mortality at an acceptable cost-effectiveness threshold.     

Glycemic Control and Blood Glucose Monitoring Over Time in a Sample of Young Australians With Type 1 Diabetes: The role of personality

OBJECTIVE

To determine whether personality traits (conscientiousness, agreeableness, emotional regulation, extraversion, and openness to experience) are associated with glycemic control and blood glucose monitoring behavior, and change or stability of these outcomes over time, in young people with type 1 diabetes.

RESEARCH DESIGN AND METHODS

A 3-year longitudinal study was conducted using data from 142 individuals with type 1 diabetes, 8–19 years of age. Personality was assessed at baseline using the Five-Factor Personality Inventory for Children. Data relating to glycemic control (HbA_1c) and frequency of blood glucose monitoring (based on meter memory) were collected annually. Relationships between personality traits and HbA_1c and monitoring frequency were examined using regression models and mixed-design ANOVA.

RESULTS

Three of the Five-Factor domains were independently associated with glycemic control. Individuals high in conscientiousness and agreeableness had a lower and more stable HbA_1c across the 3-year study period. In contrast, the HbA_1c of individuals scoring low on these traits was either consistently worse or deteriorated over time. Low or high emotional regulation scores were also associated with worse glycemic control. By the third year, these domains, together with initial HbA_1c, accounted for 39% of HbA_1c variance. Conscientiousness was the only personality factor associated with blood glucose monitoring behavior.

CONCLUSIONS

Results of this study underline the importance of personality in contributing to diabetes outcomes. Attention to a young person’s personality, and appropriate tailoring of diabetes management to ensure an individualized approach, may help to optimize diabetes outcomes.In Australia, and many other countries, a large proportion of young people with diabetes are not reaching glycemic targets (1–6). This is likely to have life-long consequences. Indeed, those subjects who were randomized to the conventional treatment arm of the Diabetes Control and Complications Trial (7) and who had an average HbA_1c of 9.1% during the course of the study continued to develop significantly more micro- and macrovascular complications compared with the intensive group when followed up in the Epidemiology of Diabetes Interventions and Complications study. This occurred despite the rapid convergence of mean HbA_1c between the groups at the end of the active study phase (8).While there are many factors that contribute to suboptimal control, there is mounting evidence that an individual’s personality may play an important role. Several studies in the late 1980s showed that personality traits could account for substantial variability in glycemic control in school-aged children (9,10). However, there has been increasing complexity in treatment regimens since that time. For example, current treatment now involves multiple daily injections or insulin pump therapy. Today, therefore, young people and their families are required to make more complex medical decisions on a daily basis.The role of personality in these new treatment contexts is not well-understood. Personality can be understood in terms of the Five-Factor model. The Five-Factor model states that there are five broad, independent, and stable dimensions that make up an individual’s personality (11). These factors are termed conscientiousness, agreeableness, emotional regulation, extraversion, and openness to experience. Conscientiousness refers to an individual’s tendency to be reliable, perseverant, and self-disciplined. Agreeableness refers to one’s tendency to be empathetic, considerate, friendly, and helpful. Emotional regulation refers to a person’s capability to regulate their emotional responses to their environment and others. Extraversion refers to an individual’s tendency to be gregarious, assertive, and seek out social situations. Openness refers to one’s tendency to be imaginative, sensitive, and have intellectual curiosity.Recent work by Vollrath et al. (12) suggests that personality, as measured using the Five-Factor model, influences glycemic control in the first 2 years following diagnosis of type 1 diabetes. In particular, higher levels of conscientiousness and agreeableness appear to have a positive influence on management of blood glucose values, while moderate levels of emotional regulation also appear to be protective (12). Further studies are needed to confirm these relationships between personality and glycemic control and to determine whether this is ameliorated by duration of diabetes. Studies are also needed to examine the role of personality in terms of self-care behavior.Accordingly, this study was designed to answer two research questions. 1) Are Five-Factor model personality traits associated with a young person’s glycemic control, as measured by HbA_1c, and their frequency of self-monitoring of blood glucose (SMBG)? 2) Are these traits associated with change or stability in HbA_1c and SMBG over time?     

Sustained Benefit of Continuous Glucose Monitoring on A1C, Glucose Profiles, and Hypoglycemia in Adults With Type 1 Diabetes

OBJECTIVE

To evaluate long-term effects of continuous glucose monitoring (CGM) in intensively treated adults with type 1 diabetes.

RESEARCH DESIGN AND METHODS

We studied 83 of 86 individuals ≥25 years of age with type 1 diabetes who used CGM as part of a 6-month randomized clinical trial in a subsequent 6-month extension study.

RESULTS

After 12 months, median CGM use was 6.8 days per week. Mean change in A1C level from baseline to 12 months was −0.4 ± 0.6% (P < 0.001) in subjects with baseline A1C ≥7.0%. A1C remained stable at 6.4% in those with baseline A1C <7.0%. The incidence rate of severe hypoglycemia was 21.8 and 7.1 events per 100 person-years in the first and last 6 months, respectively. Time per day with glucose levels in the range of 71–180 mg/dl increased significantly (P = 0.02) from baseline to 12 months.

CONCLUSIONS

In intensively treated adults with type 1 diabetes, CGM use and benefit can be sustained for 12 months.In a 6-month randomized trial of intensively treated individuals with type 1 diabetes and baseline A1C ≥7.0%, adults ≥25 years of age benefited from use of continuous glucose monitoring (CGM) compared with adults using conventional blood glucose monitoring (1). In a contemporaneous parallel study of individuals with type 1 diabetes who had A1C levels <7.0%, those in the CGM group had a reduction in biochemical hypoglycemia compared with those in the control group while maintaining A1C levels in the target range (2). This report describes the 12-month follow-up of adult subjects in the two randomized trials'' CGM groups.     

Real-Time Continuous Glucose Monitoring Significantly Reduces Severe Hypoglycemia in Hypoglycemia-Unaware Patients With Type 1 Diabetes

OBJECTIVE

To evaluate the effect of continuous glucose monitoring (CGM) on the frequency of severe hypoglycemia (SH) in patients with established hypoglycemia unawareness.

RESEARCH DESIGN AND METHODS

We conducted a retrospective audit of 35 patients with type 1 diabetes and problematic hypoglycemia unawareness, despite optimized medical therapy (continuous subcutaneous insulin infusion/multiple daily insulin injections), who used CGM for >1 year.

RESULTS

Over a 1-year follow-up period, the median rates of SH were reduced from 4.0 (interquartile range [IQR] 0.75–7.25) episodes/patient-year to 0.0 (0.0–1.25) episodes/patient-year (P < 0.001), and the mean (±SD) rates were reduced from 8.1 ± 13 to 0.6 ± 1.2 episodes/year (P = 0.005). HbA_1c was reduced from 8.1 ± 1.2% to 7.6 ± 1.0% over the year (P = 0.005). The mean Gold score, measured in 19 patients, did not change: 5.1 ± 1.5 vs. 5.2 ± 1.9 (P = 0.67).

CONCLUSIONS

In a specialist experienced insulin pump center, in carefully selected patients, CGM reduced SH while improving HbA_1c but failed to restore hypoglycemia awareness.Although real-time continuous glucose monitoring (CGM) has been shown in randomized controlled trials to improve glycemic control and mild-to-moderate hypoglycemia, studies to date have not shown convincing reductions in severe hypoglycemia (SH) (1,2). Clinically, CGM may benefit patients with impaired awareness of hypoglycemia (IAH), who have an increased risk of SH (3), by alerting them to impending hypoglycemia, and thus providing them with “technological” awareness to replace the loss of their “physiological” awareness. In our clinical service, across two associated tertiary hospitals, we have obtained case-specific funding for CGM for 35 patients with type 1 diabetes, IAH, and problematic hypoglycemia limiting daily activities during intensified insulin therapy. This audit evaluates outcomes at 1 year to see whether the use of CGM can reduce SH or improve awareness.     

Quality-of-Life Measures in Children and Adults With Type 1 Diabetes: Juvenile Diabetes Research Foundation Continuous Glucose Monitoring randomized trial

OBJECTIVE

To evaluate the impact of continuous glucose monitoring (CGM) on quality of life (QOL) among individuals with type 1 diabetes.

RESEARCH DESIGN AND METHODS

In a multicenter trial, 451 children and adults with type 1 diabetes were randomly assigned to CGM treatment or the control group. Generic and diabetes-specific QOL questionnaires were completed at baseline and 26 weeks by all participants and parents of participants <18 years old, and the CGM satisfaction scale was completed by the CGM group (participants and parents) at 26 weeks.

RESULTS

After 26 weeks, QOL scores remained largely unchanged for both the treatment and the control group, although there was a slight difference favoring the adult CGM group on several subscales (P < 0.05). There was substantial satisfaction with CGM technology after 26 weeks among participants and parents.

CONCLUSIONS

Baseline QOL was high, and the measures showed little change with CGM use, although a high level of CGM satisfaction was reported.In the Juvenile Diabetes Research Foundation (JDRF) Continuous Glucose Monitoring (CGM) trial, real-time CGM improved glycemia for adults with type 1 diabetes with entry A1C ≥7.0% (1–3), and more frequent CGM use was associated with a greater reduction in A1C in all age-groups (2). Participants with A1C <7.0% at enrollment who used CGM maintained low A1C levels more often than those who used standard blood glucose monitoring (BGM) and also had reduced biochemical hypoglycemia (3). This analysis assesses change in quality of life (QOL) among adults and children with type 1 diabetes and parent-proxy reports of youth QOL for participants in the trial.     

The Effect of Discontinuing Continuous Glucose Monitoring in Adults With Type 2 Diabetes Treated With Basal Insulin

OBJECTIVETo explore the effect of discontinuing continuous glucose monitoring (CGM) after 8 months of CGM use in adults with type 2 diabetes treated with basal without bolus insulin.RESEARCH DESIGN AND METHODSThis multicenter trial had an initial randomization to either real-time CGM or blood glucose monitoring (BGM) for 8 months followed by 6 months in which the BGM group continued to use BGM (n = 57) and the CGM group was randomly reassigned either to continue CGM (n = 53) or discontinue CGM with resumption of BGM for glucose monitoring (n = 53).RESULTSIn the group that discontinued CGM, mean time in range (TIR) 70–180 mg/dL, which improved from 38% before initiating CGM to 62% after 8 months of CGM, decreased after discontinuing CGM to 50% at 14 months (mean change from 8 to 14 months −12% [95% CI −21% to −3%], P = 0.01). In the group that continued CGM use, little change was found in TIR from 8 to 14 months (baseline 44%, 8 months 56%, 14 months 57%, mean change from 8 to 14 months 1% [95% CI −11% to 12%], P = 0.89). Comparing the two groups at 14 months, the adjusted treatment group difference in mean TIR was −6% (95% CI −16% to 4%, P = 0.20).CONCLUSIONSIn adults with type 2 diabetes treated with basal insulin who had been using real-time CGM for 8 months, discontinuing CGM resulted in a loss of about one-half of the initial gain in TIR that had been achieved during CGM use.     

A Randomized Clinical Trial Assessing Continuous Glucose Monitoring (CGM) Use With Standardized Education With or Without a Family Behavioral Intervention Compared With Fingerstick Blood Glucose Monitoring in Very Young Children With Type 1 Diabetes

OBJECTIVEThis study evaluated the effects of continuous glucose monitoring (CGM) combined with family behavioral intervention (CGM+FBI) and CGM alone (Standard-CGM) on glycemic outcomes and parental quality of life compared with blood glucose monitoring (BGM) in children ages 2 to <8 years with type 1 diabetes.RESEARCH DESIGN AND METHODSThis was a multicenter (N = 14), 6-month, randomized controlled trial including 143 youth 2 to <8 years of age with type 1 diabetes. Primary analysis included treatment group comparisons of percent time in range (TIR) (70–180 mg/dL) across follow-up visits.RESULTSApproximately 90% of participants in the CGM groups used CGM ≥6 days/week at 6 months. Between-group TIR comparisons showed no significant changes: CGM+FBI vs. BGM 3.2% (95% CI −0.5, 7.0), Standard-CGM vs. BGM 0.5% (−2.6 to 3.6), CGM+FBI vs. Standard-CGM 2.7% (−0.6, 6.1). Mean time with glucose level <70 mg/dL was reduced from baseline to follow-up in the CGM+FBI (from 5.2% to 2.6%) and Standard-CGM (5.8% to 2.5%) groups, compared with 5.4% to 5.8% with BGM (CGM+FBI vs. BGM, P < 0.001, and Standard-CGM vs. BGM, P < 0.001). No severe hypoglycemic events occurred in the CGM+FBI group, one occurred in the Standard-CGM group, and five occurred in the BGM group. CGM+FBI parents reported greater reductions in diabetes burden and fear of hypoglycemia compared with Standard-CGM (P = 0.008 and 0.04) and BGM (P = 0.02 and 0.002).CONCLUSIONSCGM used consistently over a 6-month period in young children with type 1 diabetes did not improve TIR but did significantly reduce time in hypoglycemia. The FBI benefited parental well-being.     

Thresholds of Glycemia and the Outcomes of COVID-19 Complicated With Diabetes: A Retrospective Exploratory Study Using Continuous Glucose Monitoring

OBJECTIVEAlthough elevated glucose levels are reported to be associated with adverse outcomes of coronavirus disease 2019 (COVID-19), the optimal range of glucose in patients with COVID-19 and diabetes remains unknown. This study aimed to investigate the threshold of glycemia and its association with the outcomes of COVID-19.RESEARCH DESIGN AND METHODSGlucose levels were assessed through intermittently scanned continuous glucose monitoring in 35 patients for an average period of 10.2 days. The percentages of time above range (TAR), time below range (TBR), time in range (TIR), and coefficient of variation (CV) were calculated. Composite adverse outcomes were defined as either the need for admission to the intensive care unit, need for mechanical ventilation, or morbidity with critical illness.RESULTSTARs using thresholds from 160 to 200 mg/dL were significantly associated with composite adverse outcomes after adjustment of covariates. Both TBR (<70 mg/dL) and TIR (70–160 mg/dL), but not mean sensor glucose level, were significantly associated with composite adverse outcomes and prolonged hospitalization. The multivariate-adjusted odds ratios of the CV of sensor glucose across tertiles for composite adverse outcomes of COVID-19 were 1.00, 1.18, and 25.2, respectively.CONCLUSIONSPatients with diabetes and COVID-19 have an increased risk of adverse outcomes with glucose levels >160 mg/dL and <70 mg/dL and a high CV. Therapies that improve these metrics of glycemic control may result in better prognoses for these patients.     

Early Hyperglycemia Detected by Continuous Glucose Monitoring in Children at Risk for Type 1 Diabetes

OBJECTIVE

We explore continuous glucose monitoring (CGM) as a new approach to defining early hyperglycemia and diagnosing type 1 diabetes in children with positive islet autoantibodies (Ab+).

RESEARCH DESIGN AND METHODS

Fourteen Ab+ children, free of signs or symptoms of diabetes, and nine antibody-negative (Ab−) subjects, followed by the Diabetes Autoimmunity Study in the Young, were asked to wear a Dexcom SEVEN CGM.

RESULTS

The Ab+ subjects showed more hyperglycemia, with 18% time spent above 140 mg/dL, compared with 9% in Ab− subjects (P = 0.04). Their average maximum daytime glucose value was higher, and they had increased glycemic variability. The mean HbA_1c in the Ab+ subjects was 5.5% (37 mmol/mol). Among Ab+ subjects, ≥18–20% CGM time spent above 140 mg/dL seems to predict progression to diabetes.

CONCLUSIONS

CGM can detect early hyperglycemia in Ab+ children who are at high risk for progression to diabetes. Proposed CGM predictors of progression to diabetes require further validation.     

Morning Cortisol Levels and Cognitive Abilities in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

People with type 2 diabetes are at increased risk of cognitive impairment but the mechanism is uncertain. Elevated glucocorticoid levels in rodents and humans are associated with cognitive impairment. We aimed to determine whether fasting cortisol levels are associated with cognitive ability and estimated lifetime cognitive change in an elderly population with type 2 diabetes.

RESEARCH DESIGN AND METHODS

This was a cross-sectional study of 1,066 men and women aged 60–75 years with type 2 diabetes, living in Lothian, Scotland (the Edinburgh Type 2 Diabetes Study). Cognitive abilities in memory, nonverbal reasoning, information processing speed, executive function, and mental flexibility were tested, and a general cognitive ability factor, g, was derived. Prior intelligence was estimated from vocabulary testing, and adjustment for scores on this test was used to estimate lifetime cognitive change. Relationships between fasting morning plasma cortisol levels and cognitive ability and estimated cognitive change were tested. Models were adjusted for potential confounding and/or mediating variables including metabolic and cardiovascular variables.

RESULTS

In age-adjusted analyses, higher fasting cortisol levels were not associated with current g or with performance in individual cognitive domains. However, higher fasting cortisol levels were associated with greater estimated cognitive decline in g and in tests of working memory and processing speed, independent of mood, education, metabolic variables, and cardiovascular disease (P < 0.05).

CONCLUSIONS

High morning cortisol levels in elderly people with type 2 diabetes are associated with estimated age-related cognitive change. Strategies targeted at lowering cortisol action may be useful in ameliorating cognitive decline in individuals with type 2 diabetes.Type 2 diabetes is associated with cognitive impairments, including deficits in processing speed, executive function and declarative memory, and with structural changes in the brain including reductions in hippocampal and amygdalar volumes, which are key areas influencing learning and long-term memory (1,2). Hyperglycemia, cerebral microvascular disease, and recurrent severe hypoglycemic episodes have all been implicated as potential causative factors of cognitive decline (3) but are unlikely to explain the entire effect of diabetes on cognition.Increasing evidence supports a link between elevated plasma glucocorticoids and cognitive dysfunction. Exogenous glucocorticoid administration and elevated endogenous glucocorticoids (as occurs in Cushing''s syndrome) are associated with cognitive impairment in animals and humans. More subtle alterations in hypothalamic-pituitary-adrenal (HPA) axis function have also been linked with cognitive function, with higher plasma cortisol levels at 0900 h being associated with poorer age-related cognitive ability in a small group of elderly, healthy male volunteers (4). Conversely, manipulations that reduce plasma glucocorticoid concentrations or their effects on target tissues can attenuate cognitive decline with ageing in rodents (5,6). Elevated glucocorticoid levels have widespread effects within the central nervous system, including deleterious effects on the structure and function of the hippocampus, a key locus for cognitive function, which also highly expresses glucocorticoid receptors (7,8).Several studies have demonstrated that people with type 2 diabetes have activation of the HPA axis, manifested by elevated basal plasma cortisol levels (9,10), higher late-night salivary cortisol levels (11), elevated ACTH levels (12), increased cortisol levels following overnight dexamethasone suppression (13,14), and impaired habituation of cortisol levels to repeated stress (15). These findings are consistent with a central dysregulation of the HPA axis in type 2 diabetes. The elevated plasma cortisol levels are associated with metabolic abnormalities in diabetes (16) and with complications of diabetes, including retinopathy, neuropathy, and nephropathy (17).Investigators have started to explore whether altered HPA axis activity contributes to cognitive impairment in diabetes. Impaired central negative feedback control of the HPA axis, as indicated by higher cortisol levels after 1.5 mg dexamethasone administration, was related to declarative memory impairments, possibly reflecting hippocampal dysfunction, in 30 individuals with type 2 diabetes compared with age-, sex-, and education-matched control subjects (18). However, the association between cortisol and cognitive function disappeared after adjustment for glycemic control (A1C). The same investigators reported similarly impaired HPA axis feedback control in association with verbal declarative memory deficits in 41 subjects with type 2 diabetes (1). In the latter study, the subjects with type 2 diabetes also had reduced hippocampal and prefrontal volumes, but there were no significant associations between the cortisol measurements and magnetic resonance image findings (1).Despite these findings from animal and human studies, information from large-scale epidemiological studies of representative populations is lacking, which could confirm or refute an association between circulating plasma cortisol levels and age-related cognitive impairment. We therefore examined the relationship between fasting cortisol and both late-life cognitive ability and estimated lifetime cognitive change in a large, representative study population of people with type 2 diabetes (the Edinburgh Type 2 Diabetes Study [ET2DS]). The ET2DS has the advantage over many previous epidemiological studies of having detailed cognitive testing in a range of cognitive domains and very extensive phenotyping for potential confounding or mediating factors.     

Cognitive Function in Adolescents and Young Adults With Youth-Onset Type 1 Versus Type 2 Diabetes: The SEARCH for Diabetes in Youth Study

OBJECTIVEPoor cognition has been observed in children and adolescents with youth-onset type 1 (T1D) and type 2 diabetes (T2D) compared with control subjects without diabetes. Differences in cognition between youth-onset T1D and T2D, however, are not known. Thus, using data from SEARCH for Diabetes in Youth, a multicenter, observational cohort study, we tested the association between diabetes type and cognitive function in adolescents and young adults with T1D (n = 1,095) or T2D (n = 285).RESEARCH DESIGN AND METHODSCognition was assessed via the National Institutes of Health Toolbox Cognition Battery, and age-corrected composite Fluid Cognition scores were used as the primary outcome. Confounder-adjusted linear regression models were run. Model 1 included diabetes type and clinical site. Model 2 additionally included sex, race/ethnicity, waist-to-height ratio, diabetes duration, depressive symptoms, glycemic control, any hypoglycemic episode in the past year, parental education, and household income. Model 3 additionally included the Picture Vocabulary score, a measure of receptive language and crystallized cognition.RESULTSHaving T2D was significantly associated with lower fluid cognitive scores before adjustment for confounders (model 1; P < 0.001). This association was attenuated to nonsignificance with the addition of a priori confounders (model 2; P = 0.06) and Picture Vocabulary scores (model 3; P = 0.49). Receptive language, waist-to-height ratio, and depressive symptoms remained significant in the final model (P < 0.01 for all, respectively).CONCLUSIONSThese data suggest that while youth with T2D have worse fluid cognition than youth with T1D, these differences are accounted for by differences in crystallized cognition (receptive language), central adiposity, and mental health. These potentially modifiable factors are also independently associated with fluid cognitive health, regardless of diabetes type. Future studies of cognitive health in people with youth-onset diabetes should focus on investigating these significant factors.     

Overnight Closed-Loop Insulin Delivery in Young People With Type 1 Diabetes: A Free-Living,Randomized Clinical Trial

OBJECTIVE

To evaluate feasibility, safety, and efficacy of overnight closed-loop insulin delivery in free-living youth with type 1 diabetes.

RESEARCH DESIGN AND METHODS

Overnight closed loop was evaluated at home by 16 pump-treated adolescents with type 1 diabetes aged 12–18 years. Over a 3-week period, overnight insulin delivery was directed by a closed-loop system, and on another 3-week period sensor-augmented therapy was applied. The order of interventions was random. The primary end point was time when adjusted sensor glucose was between 3.9 and 8.0 mmol/L from 2300 to 0700 h.

RESULTS

Closed loop was constantly applied over at least 4 h on 269 nights (80%); sensor data were collected over at least 4 h on 282 control nights (84%). Closed loop increased time spent with glucose in target by a median 15% (interquartile range −9 to 43; P < 0.001). Mean overnight glucose was reduced by a mean 14 (SD 58) mg/dL (P < 0.001). Time when glucose was <70 mg/dL was low in both groups, but nights with glucose <63 mg/dL for at least 20 min were less frequent during closed loop (10 vs. 17%; P = 0.01). Despite lower total daily insulin doses by a median 2.3 (interquartile range −4.7 to 9.3) units (P = 0.009), overall 24-h glucose was reduced by a mean 9 (SD 41) mg/dL (P = 0.006) during closed loop.

CONCLUSIONS

Unsupervised home use of overnight closed loop in adolescents with type 1 diabetes is safe and feasible. Glucose control was improved during the day and night with fewer episodes of nocturnal hypoglycemia.     

Factors Predictive of Use and of Benefit From Continuous Glucose Monitoring in Type 1 Diabetes

OBJECTIVE

To evaluate factors associated with successful use of continuous glucose monitoring (CGM) among participants with intensively treated type 1 diabetes in the Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Randomized Clinical Trial.

RESEARCH DESIGN AND METHODS

The 232 participants randomly assigned to the CGM group (165 with baseline A1C ≥7.0% and 67 with A1C <7.0%) were asked to use CGM on a daily basis. The associations of baseline factors and early CGM use with CGM use ≥6 days/week in the 6th month and with change in A1C from baseline to 6 months were evaluated in regression models.

RESULTS

The only baseline factors found to be associated with greater CGM use in month 6 were age ≥25 years (P < 0.001) and more frequent self-reported prestudy blood glucose meter measurements per day (P < 0.001). CGM use and the percentage of CGM glucose values between 71 and 180 mg/dl during the 1st month were predictive of CGM use in month 6 (P < 0.001 and P = 0.002, respectively). More frequent CGM use was associated with a greater reduction in A1C from baseline to 6 months (P < 0.001), a finding present in all age-groups.

CONCLUSIONS

After 6 months, near-daily CGM use is more frequent in intensively treated adults with type 1 diabetes than in children and adolescents, although in all age-groups near-daily CGM use is associated with a similar reduction in A1C. Frequency of blood glucose meter monitoring and initial CGM use may help predict the likelihood of long-term CGM benefit in intensively treated patients with type 1 diabetes of all ages.Despite recent advances in insulin delivery and home blood glucose monitoring, many individuals with type 1 diabetes fail to achieve recommended A1C target levels (1,2). Further, hypoglycemia is a problem for many patients with type 1 diabetes (3) and can be a significant deterrent to achieving and maintaining tight glycemic control (4,5). Thus, the introduction of real-time continuous glucose monitoring (CGM) systems was received with great interest because these devices may have the potential to increase the proportion of patients who are able to maintain target A1C values while simultaneously limiting their risk of severe hypoglycemia. The first real-time CGM device, the GlucoWatch Biographer (6), was difficult to use, in large part because of skin reaction and frequent skipping of glucose measurements that prevented patients from using it as a tool for day-to-day diabetes management. More recently, several new real-time CGM systems have been introduced that have improved accuracy, functionality, and user tolerance.In a multicenter randomized controlled trial, our Juvenile Diabetes Research Foundation (JDRF) Continuous Glucose Monitoring Study Group evaluated the effectiveness of CGM compared with standard blood glucose monitoring in 451 adults and children ≥8 years old with type 1 diabetes, 322 of whom had baseline A1C ≥7.0% and 129 of whom had baseline A1C <7.0% (7). Among subjects with baseline A1C level ≥7.0%, we found that CGM substantially improved A1C levels during 6 months of follow-up without increasing the frequency of hypoglycemia in adults ≥25 years of age. However, the efficacy of this device as a tool to help participants <25 years of age lower their A1C levels was much more limited (8). Among the subjects with baseline A1C <7.0%, we found that the CGM group had a reduction in hypoglycemia on most measures compared with the control group and was able to maintain mean A1C levels at 6.4%, whereas A1C increased in the control group (9). The present analyses were conducted to determine which demographic, clinical, and psychosocial factors were associated with successful CGM use and A1C improvement in the 232 CGM-group subjects.     

Heterogeneity of Responses to Real-Time Continuous Glucose Monitoring (RT-CGM) in Patients With Type 2 Diabetes and Its Implications for Application

OBJECTIVE

To characterize glucose response patterns of people who wore a real-time continuous glucose monitor (RT-CGM) as an intervention to improve glycemic control. Participants had type 2 diabetes, were not taking prandial insulin, and interpreted the RT-CGM data independently.

RESEARCH DESIGN AND METHODS

Data were from the first 12 weeks of a 52-week, prospective, randomized trial comparing RT-CGM (n = 50) with self-monitoring of blood glucose (n = 50). RT-CGM was used in 8 of the first 12 weeks. A1C was collected at baseline and quarterly. This analysis included 45 participants who wore the RT-CGM ≥4 weeks. Analyses examined the RT-CGM data for common response patterns—a novel approach in this area of research. It then used multilevel models for longitudinal data, regression, and nonparametric methods to compare the patterns of A1C, mean glucose, glycemic variability, and views per day of the RT-CGM device.

RESULTS

There were five patterns. For four patterns, mean glucose was lower than expected as of the first RT-CGM cycle of use given participants’ baseline A1C. We named them favorable response but with high and variable glucose (n = 7); tight control (n = 14); worsening glycemia (n = 6); and incremental improvement (n = 11). The fifth was no response (n = 7). A1C, mean glucose, glycemic variability, and views per day differed across patterns at baseline and longitudinally.

CONCLUSIONS

The patterns identified suggest that targeting people with higher starting A1Cs, using it short-term (e.g., 2 weeks), and monitoring for worsening glycemia that might be the result of burnout may be the best approach to using RT-CGM in people with type 2 diabetes not taking prandial insulin.In a 12-month, prospective, randomized controlled trial of real-time continuous glucose monitoring (RT-CGM) in people with type 2 diabetes and not taking prandial insulin, we demonstrated that intermittent RT-CGM used for a period of 12 weeks was associated with a clinically significant reduction in A1C during the same period of time compared with premeal and bedtime self-monitoring of blood glucose (SMBG) and that the improvement in A1C was sustained for at least 40 weeks after the active intervention ended (1,2). Previous studies of RT-CGM for people with type 2 diabetes (3–5), although smaller and including mostly patients taking prandial insulin, have observed similar improvements in glycemia.Owing to fluctuations around the mean, people with the same A1C can have different glycemic variability (6,7). Some researchers have proposed that higher glycemic variability may increase the risk for diabetes complications (8–10) through increased oxidative stress (11,12). However, these studies of RT-CGM in people with type 2 diabetes did not address whether glycemic variability was also reduced concomitantly with A1C and did not report whether there were different patterns of responses to using the device and when the responses might have occurred. Were responses immediate or gradual, temporary or sustained, marked or modest? These questions are important because their answers may inform clinicians how RT-CGM might be implemented in practice for people with type 2 diabetes who are not taking prandial insulin.Thus, the present analysis sought to answer those questions through an in-depth investigation of each participant’s raw glucose data from their RT-CGM and identification of common response patterns. This led to a new typology describing glucose responses, which we verified by statistical analyses of measures of mean glucose, glycemic variability, and patient engagement with the RT-CGM device.     

The Use of an Automated,Portable Glucose Control System for Overnight Glucose Control in Adolescents and Young Adults With Type 1 Diabetes

OBJECTIVE

A key milestone in progress towards providing an efficacious and safe closed-loop artificial pancreas system for outpatient use is the development of fully automated, portable devices with fault detection capabilities to ensure patient safety. The ability to remotely monitor the operation of the closed-loop system would facilitate future physician-supervised home studies.

RESEARCH DESIGN AND METHODS

This study was designed to investigate the efficacy and safety of a fully automated, portable, closed-loop system. The Medtronic Portable Glucose Control System (PGCS) consists of two subcutaneous glucose sensors, a control algorithm based on proportional-integral-derivative with insulin feedback operating from a BlackBerry Storm smartphone platform, Bluetooth radiofrequency translator, and an off-the-shelf Medtronic Paradigm Veo insulin pump. Participants with type 1 diabetes using insulin pump therapy underwent two consecutive nights of in-clinic, overnight, closed-loop control after a baseline open-loop assessment.

RESULTS

Eight participants attended for 16 overnight studies. The PGCS maintained mean overnight plasma glucose levels of 6.4 ± 1.7 mmol/L (115 ± 31 mg/dL). The proportion of time with venous plasma glucose <3.9, between 3.9 and 8 (70 and 144 mg/dL), and >8 mmol/L was 7, 78, and 15%, respectively. The proportion of time the sensor glucose values were maintained between 3.9 and 8 mmol/L was greater for closed-loop than open-loop (84.5 vs. 46.7%; P < 0.0001), and time spent <3.3 mmol/L was also reduced (0.9 vs. 3%; P < 0.0001).

CONCLUSIONS

These results suggest that the PGCS, an automated closed-loop device, is safe and effective in achieving overnight glucose control in patients with type 1 diabetes.Intensive management of type 1 diabetes is necessary to achieve near-normal glucose levels to obtain A1C values associated with a reduced risk of microvascular and macrovascular complications. Large-scale studies have revealed that in some patients, such efforts are associated with an increased risk of severe hypoglycemia (1). The effects of intensive management on the incidence of severe hypoglycemia may be even greater in children and adolescents (2), particularly in the setting of diminished counterregulatory hormone responses (3,4). Despite the development of insulin analogs and increasing use of insulin pump therapy, approximation of physiologic insulin delivery has not been achievable by most. Presently, children with an A1C <7% spend approximately one-quarter of each 24-h period with glucose levels >11.1 mmol/L (200 mg/dL) (3). Even with use of sensor-augmented pump therapy, the epitome of technology currently available to patients, one-third or less patients achieve an A1C target <7% (5,6), and the incidence of severe hypoglycemia is not reduced.Currently, there are two principal approaches to β-cell replacement therapy. Islet-cell transplantation has demonstrated promising results in recovery of hypoglycemia awareness and reduction in episodes of hypoglycemia (7). Unfortunately, there are risks associated with immunosuppressive therapy (8), and currently, <75% of patients are insulin-independent 4 years after transplant (7). The second and, arguably, more promising therapeutic approach to β-cell replacement is a closed-loop artificial pancreas incorporating a continuous glucose sensor, insulin pump, and control algorithm.Commercially available insulin pumps and glucose sensors are considered sufficiently accurate for use in a closed-loop system (9,10). Despite the delays inherent in absorption and action of insulin delivered subcutaneously, previous studies have demonstrated superiority of such systems over standard pump therapy (11–18). Automation of insulin delivery is not a novel concept (11,12); however, the closed-loop system in many reports was not fully automated. In some studies, sensor glucose was entered manually every 5 to 15 min (15–17) or changes to the pump delivery rate were made manually by a physician or research nurse (13–17). Furthermore, insulin delivery in studies published to date was based on a control algorithm contained in a desktop or laptop computer (11–18), implying that the system was not readily portable or practical in an ambulatory setting. A key milestone in progress toward making a closed-loop artificial pancreas system available for outpatient use is the development of fully automated, portable devices with fault detection capabilities to ensure safety. An additional desirable feature of these devices is the ability to remotely monitor the operation of the closed-loop system via data transmitted over a wireless network, facilitating future physician-supervised home studies.The Medtronic Portable Glucose Control System (PGCS) is a portable, automated, closed-loop device consisting of a BlackBerry Storm smartphone (Research in Motion, Waterloo, ON, Canada), an unmodified Medtronic Paradigm Veo insulin pump, two MiniLink REAL-Time Transmitters (Medtronic Minimed, Northridge, CA) modified to transmit at 1-min rather than 5-min intervals, two Enlite glucose sensors (Medtronic Minimed), and a Medtronic custom-built radiofrequency translator, as illustrated in Fig. 1.Open in a separate windowFigure 1The components of the Medtronic PGCS.In this study, we describe the safety and efficacy of the PGCS, an automated closed-loop device, focusing on overnight glucose control in adolescents and young adults with type 1 diabetes.     

Pregnancy Outcomes in Youth With Type 2 Diabetes: The TODAY Study Experience

OBJECTIVE

We evaluated pregnancy outcomes, maternal and fetal/neonatal, during the Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study.

RESEARCH DESIGN AND METHODS

The TODAY study was a randomized controlled trial comparing three treatment options for youth with type 2 diabetes. Informed consent included the requirement for contraception, including abstinence; this was reinforced at each visit. Following informed consent, self-reported data related to the mother’s prenatal care and delivery and the infant’s health were retrospectively collected. When permitted, maternal medical records and infant birth records were reviewed.

RESULTS

Of the 452 enrolled female participants, 46 (10.2%) had 63 pregnancies. Despite continued emphasis on adequate contraception, only 4.8% of the pregnant participants reported using contraception prior to pregnancy. The mean age at first pregnancy was 18.4 years; the mean diabetes duration was 3.17 years. Seven pregnancies were electively terminated; three pregnancies had no data reported. Of the remaining 53 pregnancies, 5 (9.4%) resulted in early pregnancy loss, and 7 (13%) resulted in loss with inadequate pregnancy duration data. Two pregnancies ended in stillbirth, at 27 and 37 weeks, and 39 ended with a live-born infant. Of the live-born infants, six (15.4%) were preterm and eight (20.5%) had a major congenital anomaly.

CONCLUSIONS

Despite diabetes-specific information recommending birth control and the avoidance of pregnancy, 10% of the study participants became pregnant. Pregnancies in youth with type 2 diabetes may be especially prone to result in congenital anomalies. Reasons for the high rate of congenital anomalies are uncertain, but may include poor metabolic control and extreme obesity.     

Association Between Excessive Daytime Sleepiness and Severe Hypoglycemia in People With Type 2 Diabetes: The Edinburgh Type 2 Diabetes Study

OBJECTIVE

Sleep-disordered breathing and sleepiness cause metabolic, cognitive, and behavioral disturbance. Sleep-disordered breathing is common in type 2 diabetes, a condition that requires adherence to complex dietary, behavioral, and drug treatment regimens. Hypoglycemia is an important side effect of treatment, causing physical and psychological harm and limiting ability to achieve optimal glycemic control. We hypothesized that sleep disorder might increase the risk of hypoglycemia through effects on self-management and glucose regulation.

RESEARCH DESIGN AND METHODS

People with type 2 diabetes (n = 898) completed questionnaires to assess sleep-disordered breathing, daytime sleepiness, and occurrence of severe hypoglycemia.

RESULTS

Subjects who scored highly on the Epworth Sleepiness Scale were significantly more likely to have suffered from severe hypoglycemia. This was a significant predictor of severe hypoglycemia in regression analysis including the variables age, sex, duration of diabetes, HbA_1c, BMI, and treatment type.

CONCLUSIONS

Daytime sleepiness may be a novel risk factor for hypoglycemia.Hypoglycemia is an adverse side effect of insulin and sulfonylurea treatment for type 2 diabetes. Factors influencing risk of severe hypoglycemia (requiring external assistance) include duration of diabetes (1), duration of insulin treatment (2), renal impairment (2), age (1), comorbidities (3), and impaired awareness of hypoglycemia (4). Sleep-disordered breathing with associated daytime somnolence is reported in up to 75% of people with type 2 diabetes (5) and is linked to a range of cardiovascular and metabolic morbidities (6). We hypothesized that sleep disorder and increased daytime sleepiness would be associated with increased frequency of severe hypoglycemia in people with diabetes.     

Incremental Value of Continuous Glucose Monitoring When Starting Pump Therapy in Patients With Poorly Controlled Type 1 Diabetes: The RealTrend study*

OBJECTIVE

To compare the improvements in glycemic control associated with transitioning to insulin pump therapy in patients using continuous glucose monitoring versus standard blood glucose self-monitoring.

RESEARCH DESIGN AND METHODS

The RealTrend study was a 6-month, randomized, parallel-group, two-arm, open-label study of 132 adults and children with uncontrolled type 1 diabetes (A1C ≥8%) being treated with multiple daily injections. One group was fitted with the Medtronic MiniMed Paradigm REAL-Time system (PRT group), an insulin pump with integrated continuous subcutaneous glucose monitoring (CGM) capability, with instructions to wear CGM sensors at least 70% of the time. Conventional insulin pump therapy was initiated in the other group (continuous subcutaneous insulin infusion [CSII] group). Outcome measures included A1C and glycemic variability.

RESULTS

A total of 115 patients completed the study. Between baseline and trial end, A1C improved significantly in both groups (PRT group −0.81 ± 1.09%, P < 0.001; CSII group −0.57 ± 0.94%, P < 0.001), with no significant difference between groups. When the 91 patients who were fully protocol-compliant (including CGM sensor wear ≥70% of the time) were considered, A1C improvement was significantly greater in the PRT group (P = 0.004) (PRT group −0.96 ± 0.93%, P < 0.001; CSII group −0.55 ± 0.93%, P < 0.001). Hyperglycemia parameters decreased in line with improvements in A1C with no impact on hypoglycemia.

CONCLUSIONS

CGM-enabled insulin pump therapy improves glycemia more than conventional pump therapy during the first 6 months of pump use in patients who wear CGM sensors at least 70% of the time.The long-term clinical benefit of tight glycemic control in type 1 diabetic patients has been demonstrated in several reports by the Diabetes Control and Complications Trial (1,2). To achieve this goal, insulin analogs, basal-bolus multiple daily injections (MDI), and insulin pumps for continuous subcutaneous insulin infusion (CSII) have proved to be important tools for lowering glucose variability and improving glycemic control, leading to higher treatment satisfaction in patients with type 1 diabetes (3–5).Nevertheless, intensive treatment of type 1 diabetes often does not succeed in achieving target A1C levels ≤7.0% (6). Increased self-monitoring of blood glucose (SMBG) levels is correlated with better A1C levels (7,8), but for practical reasons most patients do not perform more than five to seven glucose measurements per day. Consequently, postprandial hyperglycemia and nocturnal hypoglycemia often remain unnoticed, even in individuals with well-controlled diabetes (9–11). Hence, detecting and treating these events might improve the patient''s glycemic control and have an impact on quality of life.Continuous glucose monitoring (CGM) provides information from a subcutaneous glucose sensor on interstitial glucose levels. A typical CGM system incorporates alarms for high and low glucose levels and displays glucose trend information graphically, allowing patients to anticipate hypo- and hyperglycemic events. Recent studies have shown that wearing such devices is associated with improved glycemic control in patients undergoing intensive therapy for type 1 diabetes (12,13) and in patients treated by CSII (14); however, no study has investigated the benefit of CGM in patients with poor metabolic control using MDI upon initiation of pump therapy. In this trial we randomly initiated pump therapy in patients with insufficient metabolic control despite optimized basal-bolus injection regimens with either the MiniMed Paradigm REAL-Time insulin pump (PRT), an insulin pump that can receive and display CGM data from a separate subcutaneous glucose sensor, or conventional CSII, and compared glycemic outcomes after 6 months.