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.     

The Cost-Effectiveness of Continuous Glucose Monitoring in Type 1 Diabetes

OBJECTIVE

Continuous glucose monitoring (CGM) has been found to improve glucose control in type 1 diabetic patients. We estimated the cost-effectiveness of CGM versus standard glucose monitoring in type 1 diabetes.

RESEARCH DESIGN AND METHODS

This societal cost-effectiveness analysis (CEA) was conducted in trial populations in which CGM has produced a significant glycemic benefit (A1C ≥7.0% in a cohort of adults aged ≥25 years and A1C <7.0% in a cohort of all ages). Trial data were integrated into a simulation model of type 1 diabetes complications. The main outcome was the cost per quality-adjusted life-year (QALY) gained.

RESULTS

During the trials, CGM patients experienced an immediate quality-of-life benefit (A1C ≥7.0% cohort: 0.70 quality-adjusted life-weeks [QALWs], P = 0.49; A1C <7.0% cohort: 1.39 QALWs, P = 0.04) and improved glucose control. In the long-term, CEA for the A1C ≥7.0% cohort, CGM was projected to reduce the lifetime probability of microvascular complications; the average gain in QALYs was 0.60. The incremental cost-effectiveness ratio (ICER) was $98,679/QALY (95% CI −60,000 [fourth quadrant] to −87,000 [second quadrant]). For the A1C <7.0% cohort, the average gain in QALYs was 1.11. The ICER was $78,943/QALY (15,000 [first quadrant] to −291,000 [second quadrant]). If the benefit of CGM had been limited to the long-term effects of improved glucose control, the ICER would exceed $700,000/QALY. If test strip use had been two per day with CGM long term the ICER for CGM would improve significantly.

CONCLUSIONS

Long-term projections indicate that CGM is cost-effective among type 1 diabetic patients at the $100,000/QALY threshold, although considerable uncertainty surrounds these estimates.The Diabetes Control and Complication Trial (DCCT) established the clinical benefits of intensive glucose control in type 1 diabetes (1). Despite the availability of insulin pumps and insulin analogues, achieving optimal glucose control, while avoiding hypoglycemia, continues to be a significant challenge for patients.An important component of glucose control is glucose monitoring. Conventional self-glucose monitoring permits patients to periodically measure capillary glucose. This leaves patients unaware of postprandial hyperglycemia and asymptomatic nocturnal hypoglycemia (2). Newer continuous glucose monitoring (CGM) technology, which measures glucose levels in subcutaneous tissue, has the potential to overcome these challenges and increase the likelihood that patients with diabetes can achieve and maintain optimal glucose control without symptomatic hypoglycemia. While there are potential advantages of CGM, the technology does have some disadvantages, including discomfort from the probe, ongoing use of conventional monitoring, potential overestimation of the frequency of overnight low glucose levels, and high costs (3).Recently, parallel multicenter trials comparing CGM with conventional self-glucose monitoring alone were conducted in patients with A1C ≥7.0% (A1C ≥7.0% cohort) and in patients with A1C <7.0% (A1C <7.0% cohort) (4). In the A1C ≥7.0% cohort, CGM was found to significantly reduce average A1C levels (−0.53 [95% CI −0.71 to −0.35], P < 0.001) in adults (aged ≥25 years) (5). In the A1C <7.0% cohort, CGM helped intervention patients maintain their A1C at 6.5%, while control patients experienced an increase in A1C of 0.3% (6). The purpose of this study is to evaluate the cost-effectiveness of CGM technology compared with standard glucose monitoring in the type 1 diabetic patients from the societal perspective.     

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 Effect of Continuous Glucose Monitoring in Well-Controlled Type 1 Diabetes

OBJECTIVE

The potential benefits of continuous glucose monitoring (CGM) in the management of adults and children with well-controlled type 1 diabetes have not been examined.

RESEARCH DESIGN AND METHODS

A total of 129 adults and children with intensively treated type 1 diabetes (age range 8–69 years) and A1C <7.0% were randomly assigned to either continuous or standard glucose monitoring for 26 weeks. The main study outcomes were time with glucose level ≤70 mg/dl, A1C level, and severe hypoglycemic events.

RESULTS

At 26 weeks, biochemical hypoglycemia (≤70 mg/dl) was less frequent in the CGM group than in the control group (median 54 vs. 91 min/day), but the difference was not statistically significant (P = 0.16). Median time with a glucose level ≤60 mg/dl was 18 versus 35 min/day, respectively (P = 0.05). Time out of range (≤70 or >180 mg/dl) was significantly lower in the CGM group than in the control group (377 vs. 491 min/day, P = 0.003). There was a significant treatment group difference favoring the CGM group in mean A1C at 26 weeks adjusted for baseline (P < 0.001). One or more severe hypoglycemic events occurred in 10 and 11% of the two groups, respectively (P = 1.0). Four outcome measures combining A1C and hypoglycemia data favored the CGM group in comparison with the control group (P < 0.001, 0.007, 0.005, and 0.003).

CONCLUSIONS

Most outcomes, including those combining A1C and hypoglycemia, favored the CGM group. The weight of evidence suggests that CGM is beneficial for individuals with type 1 diabetes who have already achieved excellent control with A1C <7.0%.Over the past 15 years, the use of rapid and long-acting insulin analogs, improvements in insulin pumps, and more frequent home blood glucose monitoring have had a positive impact on the ability to achieve target A1C levels in type 1 diabetes. However, the rates of severe hypoglycemia remain too high and the occurrence of such events is often followed by a decline in glycemic control due to fears of further hypoglycemic episodes (1). Hypoglycemia remains the major limiting factor for achieving euglycemia in type 1 diabetes (2).The introduction of new real-time continuous glucose monitoring (CGM) systems has generated 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 the risk of severe hypoglycemia. In a randomized trial of 322 adults and children with type 1 diabetes and baseline A1C level ≥7.0%, our Juvenile Diabetes Research Foundation (JDRF) Continuous Glucose Monitoring Study Group reported that CGM substantially improved A1C levels without increasing the frequency of hypoglycemia in adults ≥25 years of age, whereas the lowering of A1C levels in children and adolescents was more limited (3). As with virtually every other study of a new drug or device in the treatment of type 1 diabetes, this study excluded individuals already reaching target A1C levels <7.0% because lowering of A1C was the primary outcome of interest. Consequently, our study group also conducted a separate, concurrent randomized trial to evaluate the efficacy and safety of CGM in adults and children with type 1 diabetes who already had successfully achieved A1C levels <7.0% with intensive insulin therapy.     

Hypoglycemia Unawareness in Older Compared With Middle-Aged Patients With Type 2 Diabetes

OBJECTIVE

Older patients with type 2 diabetes are at a particularly high risk for severe hypoglycemic episodes, and experimental studies in healthy subjects hint at a reduced awareness of hypoglycemia in aged humans. However, subjective responses to hypoglycemia have rarely been assessed in older type 2 diabetic patients.

RESEARCH DESIGN AND METHODS

We tested hormonal, subjective, and cognitive responses (reaction time) to 30-min steady-state hypoglycemia at a level of 2.8 mmol/l in 13 older (≥65 years) and 13 middle-aged (39–64 years) type 2 diabetic patients.

RESULTS

Hormonal counterregulatory responses to hypoglycemia did not differ between older and middle-aged patients. In contrast, middle-aged patients showed a pronounced increase in autonomic and neuroglycopenic symptom scores at the end of the hypoglycemic plateau that was not observed in older patients (both P < 0.01). Also, seven middle-aged patients, but only one older participant, correctly estimated their blood glucose concentration to be <3.3 mmol/l during hypoglycemia (P = 0.011). A profound prolongation of reaction times induced by hypoglycemia in both groups persisted even after 30 min of subsequent euglycemia.

CONCLUSIONS

Our data indicate marked subjective unawareness of hypoglycemia in older type 2 diabetic patients that does not depend on altered neuroendocrine counterregulation and may contribute to the increased probability of severe hypoglycemia frequently reported in these patients. The joint occurrence of hypoglycemia unawareness and deteriorated cognitive function is a critical factor to be carefully considered in the treatment of older patients.Hypoglycemia is the limiting factor in the glycemic management of diabetes (1). For a long time hypoglycemia was assumed a major problem only in patients suffering from type 1 diabetes (2); however, there is increasing evidence that hypoglycemic episodes are a critical factor also in type 2 diabetes (3,4). Older subjects aged >65 years, who represent the majority of type 2 diabetic patients, appear at a particularly high risk of experiencing severe hypoglycemia (3,4). Previous studies (5–7) have shown weakened perception of hypoglycemia-related symptoms in healthy older (i.e., nondiabetic older subjects, aged 65–80 years) as compared with younger subjects (aged 24–49 years). Of note, in aged humans, the perception of hypoglycemic symptoms was found to simultaneously occur with the impairment of cognitive functions during a stepwise reduction of blood glucose levels (7), contrasting the well-known hierarchical succession of central nervous responses to hypoglycemia in younger healthy adults who normally perceive hypoglycemic symptoms at higher glucose levels than cognitive dysfunction (4). The concurrence of glycemic thresholds for the onset of symptoms and of cognitive dysfunction may be expected to increase the risk for severe hypoglycemic episodes since it likely prevents behavioral counteractions (e.g., the intake of carbohydrates) (3).To date only one study (8) has assessed subjective responses to standardized hypoglycemia in older type 2 diabetic patients (aged 72 ± 1 years), revealing an impairment in the perception of hypoglycemic symptoms that was comparable to that of age-matched healthy control subjects. Although this finding points to a decrease in hypoglycemia awareness that develops in the course of aging also in type 2 diabetic patients, this assumption has not yet been experimentally elucidated. Moreover, in the previous studies in healthy subjects (5–7), the age gap between experimental groups was rather large, raising the question as to the perception of hypoglycemia in middle-aged subjects. On this background, we examined whether older (aged ≥65 years) as compared with middle-aged (aged 39–64 years) type 2 diabetic patients differ in their subjective response to hypoglycemia and how hypoglycemia awareness in these age-groups relates to hormonal and cognitive effects of hypoglycemia.     

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.     

青少年1型糖尿病患者动态血糖监测的护理

1型糖尿病是在遗传易感性的基础上,通过外界环境因素（最常见的为病毒感染）作用而引发机体自身免疫功能紊乱,导致胰岛B细胞的损伤和破坏,最终使胰岛素分泌绝对不足而引发的一种疾病。由于胰岛功能较差,往往导致血糖波动大,故此类患者的血糖监测尤为重要。     

The Effect of Real-Time Continuous Glucose Monitoring in Pregnant Women With Diabetes: A randomized controlled trial

OBJECTIVE

To assess whether intermittent real-time continuous glucose monitoring (CGM) improves glycemic control and pregnancy outcome in unselected women with pregestational diabetes.

RESEARCH DESIGN AND METHODS

A total of 123 women with type 1 diabetes and 31 women with type 2 diabetes were randomized to use real-time CGM for 6 days at 8, 12, 21, 27, and 33 weeks in addition to routine care, including self-monitored plasma glucose seven times daily, or routine care only. To optimize glycemic control, real-time CGM readings were evaluated by a diabetes caregiver. HbA_1c, self-monitored plasma glucose, severe hypoglycemia, and pregnancy outcomes were recorded, with large-for-gestational-age infants as the primary outcome.

RESULTS

Women assigned to real-time CGM (n = 79) had baseline HbA_1c similar to that of women in the control arm (n = 75) (median 6.6 [range 5.3–10.0] vs. 6.8% [5.3–10.7]; P = 0.67) (49 [34–86] vs. 51 mmol/mol [34–93]). Forty-nine (64%) women used real-time CGM per protocol. At 33 weeks, HbA_1c (6.1 [5.1–7.8] vs. 6.1% [4.8–8.2]; P = 0.39) (43 [32–62] vs. 43 mmol/mol [29–66]) and self-monitored plasma glucose (6.2 [4.7–7.9] vs. 6.2 mmol/L [4.9–7.9]; P = 0.64) were comparable regardless of real-time CGM use, and a similar fraction of women had experienced severe hypoglycemia (16 vs. 16%; P = 0.91). The prevalence of large-for-gestational-age infants (45 vs. 34%; P = 0.19) and other perinatal outcomes were comparable between the arms.

CONCLUSIONS

In this randomized trial, intermittent use of real-time CGM in pregnancy, in addition to self-monitored plasma glucose seven times daily, did not improve glycemic control or pregnancy outcome in women with pregestational diabetes.Pregnancy in women with pregestational diabetes is still associated with adverse perinatal outcomes largely attributed to maternal hyperglycemia, including large-for-gestational-age infants, preterm delivery, and perinatal morbidity (1–4). Large-for-gestational-age infants to mothers with diabetes are at increased risk for birth trauma, transient tachypnea, and neonatal hypoglycemia (5), and maternal diabetes in pregnancy is associated with later-life morbidity in the offspring (6). The major barrier in the strive for strict maternal glycemic control is the risk of severe hypoglycemia (1), occurring up to five times more frequently in early pregnancy than in the period prior to pregnancy in women with type 1 diabetes (7).Real-time continuous glucose monitoring (CGM) measures interstitial glucose in an ongoing fashion and offers the possibility of hyper- and hypoglycemic alarms. Studies of nonpregnant patients with type 1 diabetes indicate that real-time CGM lowers HbA_1c (8–19) and may reduce the tendency to biochemical hypoglycemia (9). Pregnant women with diabetes may also profit from real-time CGM, but experience is still limited (20–26). A randomized controlled trial evaluating intermittent use of a previous CGM system (not real-time) on top of routine pregnancy care reported improved glycemic control and a reduced risk of large-for-gestational-age infants in the intervention arm (27). Against this background, it is tempting to suggest that women with pregestational diabetes would benefit even more from the use of real-time CGM in pregnancy.In this investigator-driven trial, we therefore aimed to assess whether intermittent real-time CGM, as part of routine pregnancy care, could improve maternal glycemic control and pregnancy outcome in an unselected cohort of women with pregestational type 1 or type 2 diabetes.     

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.     

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.     

应用动态血糖监测系统评估2型糖尿病的无症状低血糖

目的评估2型糖尿病（T2DM）患者的无症状低血糖。方法应用动态血糖监测系统（CGMS）监测1147例血糖控制稳定的T2DM患者连续3d（65—72h）的血糖变化。结果①无症状低血糖发生率25．54％,占低血糖60．8％（697例）,与病程呈指数曲线正相关（r=0．913,tr=3．636,P〈0．05）;②平均血糖（MBG）与无症状低血糖发生率呈双曲线负相关（r=-0．963,P〈0．01）;③随着最大血糖波动幅度（LAGE）增大,无症状低血糖发生率增高;④低血糖发生率男女相仿,与年龄呈负相关（男r=旬．929,tr=5．613,P〈0．01。女r=m．824,tr=3．251,P〈0．01）;⑤老年组MBG水平明显高于非老年组（t=6．81,P〈0．01）,低血糖发生率明显低于非老年组（x^2=60．37,P〈0．01）。结论①2型糖尿病患者无症状低血糖发生率高,且随病程延长而增高。MBG控制越低、最大血糖波动幅度越大,无症状低血糖发生率越高;②放宽老年DM患者血糖控制要求,提高MBG水平可有效降低其低血糖发生率;③cGMS能及时准确发现无症状低血糖。     

应用动态血糖监测评估2型糖尿病的低血糖

目的评估2型糖尿病（T2DM）患者治疗中的低血糖、无症状低血糖。方法应用动态血糖监测系统（CGMS）监测1147例血糖控制稳定的T2DM患者血糖（BG）变化。结果2型糖尿病患者：低血糖发生率37．23％,其中无症状低血糖60．80％（697人次）,与病程呈指数曲线负相关。平均血糖（MBG）与低血糖发生率呈指数曲线负相关,与无症状低血糖发生率呈双曲线负相关。随着日内血糖差值逐渐增大,低血糖发生率呈等级增高。结论①2型糖尿病患者治疗中低血糖发生率高,MBG控制越低、日内BG波动越大,则低血糖、无症状低血糖发生率越高;（2）CGMS能及时准确发现无症状低血糖。     

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.     

Evaluation of an Algorithm to Guide Patients With Type 1 Diabetes Treated With Continuous Subcutaneous Insulin Infusion on How to Respond to Real-Time Continuous Glucose Levels: A randomized controlled trial

OBJECTIVE

To evaluate an algorithm guiding responses of continuous subcutaneous insulin infusion (CSII)–treated type 1 diabetic patients using real-time continuous glucose monitoring (RT-CGM).

RESEARCH DESIGN AND METHODS

Sixty CSII-treated type 1 diabetic participants (aged 13–70 years, including adult and adolescent subgroups, with A1C ≤9.5%) were randomized in age-, sex-, and A1C-matched pairs. Phase 1 was an open 16-week multicenter randomized controlled trial. Group A was treated with CSII/RT-CGM with the algorithm, and group B was treated with CSII/RT-CGM without the algorithm. The primary outcome was the difference in time in target (4–10 mmol/l) glucose range on 6-day masked CGM. Secondary outcomes were differences in A1C, low (≤3.9 mmol/l) glucose CGM time, and glycemic variability. Phase 2 was the week 16–32 follow-up. Group A was returned to usual care, and group B was provided with the algorithm. Glycemia parameters were as above. Comparisons were made between baseline and 16 weeks and 32 weeks.

RESULTS

In phase 1, after withdrawals 29 of 30 subjects were left in group A and 28 of 30 subjects were left in group B. The change in target glucose time did not differ between groups. A1C fell (mean 7.9% [95% CI 7.7–8.2to 7.6% [7.2–8.0]; P < 0.03) in group A but not in group B (7.8% [7.5–8.1] to 7.7 [7.3–8.0]; NS) with no difference between groups. More subjects in group A achieved A1C ≤7% than those in group B (2 of 29 to 14 of 29 vs. 4 of 28 to 7 of 28; P = 0.015). In phase 2, one participant was lost from each group. In group A, A1C returned to baseline with RT-CGM discontinuation but did not change in group B, who continued RT-CGM with addition of the algorithm.

CONCLUSIONS

Early but not late algorithm provision to type 1 diabetic patients using CSII/RT-CGM did not increase the target glucose time but increased achievement of A1C ≤7%. Upon RT-CGM cessation, A1C returned to baseline.Real time-continuous glucose monitoring (RT-CGM) can be integrated with a continuous subcutaneous insulin infusion (CSII) device (1,2). Interstitial glucose readings, with direction and rate of change, are displayed and linked to low and high glucose alarms. Data can be uploaded and reviewed retrospectively. Apart from recent devices with automatic shutoff for low glucose, RT-CGM cannot initiate insulin delivery. Insulin changes must be initiated by the patient or caregiver. Continuous glucose monitoring (CGM) data interpretation can be difficult, and advice guiding insulin or lifestyle change may enhance benefits (3).In this study, we tested the glycemia effects of an algorithm guiding responses to RT-CGM in CSII-using type 1 diabetic subjects. We also evaluated whether glucose changes persisted after RT-CGM withdrawal and whether late algorithm introduction improved glycemia.     

Real-Time Hypoglycemia Prediction Suite Using Continuous Glucose Monitoring: A safety net for the artificial pancreas

OBJECTIVE

The purpose of this study was to develop an advanced algorithm that detects pending hypoglycemia and then suspends basal insulin delivery. This approach can provide a solution to the problem of nocturnal hypoglycemia, a major concern of patients with diabetes.

RESEARCH DESIGN AND METHODS

This real-time hypoglycemia prediction algorithm (HPA) combines five individual algorithms, all based on continuous glucose monitoring 1-min data. A predictive alarm is issued by a voting algorithm when a hypoglycemic event is predicted to occur in the next 35 min. The HPA system was developed using data derived from 21 Navigator studies that assessed Navigator function over 24 h in children with type 1 diabetes. We confirmed the function of the HPA using a separate dataset from 22 admissions of type 1 diabetic subjects. During these admissions, hypoglycemia was induced by gradual increases in the basal insulin infusion rate up to 180% from the subject''s own baseline infusion rate.

RESULTS

Using a prediction horizon of 35 min, a glucose threshold of 80 mg/dl, and a voting threshold of three of five algorithms to predict hypoglycemia (defined as a FreeStyle plasma glucose readings <60 mg/dl), the HPA predicted 91% of the hypoglycemic events. When four of five algorithms were required to be positive, then 82% of the events were predicted.

CONCLUSIONS

The HPA will enable automated insulin-pump suspension in response to a pending event that has been detected prior to severe immediate complications.The Diabetes Control and Complications Trial (DCCT) proved that glucose control in the closer-to-normal range (tight glycemic control) reduced the likelihood of eye, kidney, nerve, and cardiovascular complications of diabetes (1,2). Unfortunately, the DCCT also showed that the incidence of severe hypoglycemia was three times higher in the intensively treated group compared with the standard treatment group (1). In the DCCT, 55% of the severe lows occurred during sleep hours (1). Further, in the adolescent portion of the DCCT, the risk for severe hypoglycemia was even greater, with one episode every 1.17 years (85.7 per 100 patient-years) (2). One report in children found 75% of severe lows to occur during the nighttime hours (3). The high frequency and duration of nocturnal hypoglycemia has been confirmed in clinical research center (CRC) studies, in which frequent laboratory reference glucose values were obtained. For example, in a DirecNet study of exercise-induced nocturnal hypoglycemia, children who did not exercise had a 28% incidence of nocturnal hypoglycemia (glucose <60 mg/dl), and those who exercised had a 48% incidence of nocturnal hypoglycemia (4). In a recent study (5) of bedtime snacks and nocturnal hypoglycemia, on nights when adult subjects did not have a snack, 57% became hypoglycemic (<70 mg/dl), with an average duration of hypoglycemia of over 2.5 h. In this study, the duration of hypoglycemia was as long as 8.75 h.Real-time continuous glucose monitoring (CGM) is becoming available with the Food and Drug Administration (FDA) approval of the MiniMed Guardian, the DexCom STS, and the Abbott Navigator. One of the major perceived benefits of real-time glucose monitoring is the ability of these devices to have alarms for hypoglycemia. For a real-time alarm to be effective, it must awaken a sleeping subject. The first FDA-approved real-time glucose monitor was the GlucoWatch^TM. To determine whether the alarm function on the GlucoWatch was effective in awakening children while they were sleeping, an infrared camera was used to videotape them throughout the night in the CRCs. During this admission, reference glucose values were obtained every half hour to document hypoglycemia. In this study, 71% of youths wearing the watch did not respond to nighttime alarms (6), placing these patients at a risk for nocturnal hypoglycemia despite wearing a real-time continuous glucose sensor. One possible correction of this problem would be to have the sensor send a signal to the pump so that it will stop infusing insulin when pending or real hypoglycemia has been reached and the patient has not responded to alarms. This is the primary focus of the hypoglycemia prediction algorithm.Previous studies (7–9) have shown that when insulin infusion is stopped for 2 h or when an infusion set is disconnected for up to 30 min (7), there is essentially no risk of the patient developing significant ketones or acidosis. Three previous studies (8–10) have demonstrated that turning off an insulin pump for 2 h did not result in diabetic ketoacidosis (DKA). In all three studies, blood β-hydroxybutyrate concentrations were determined using both a meter (Precision Xtra^TM) and the hospital laboratory. In two of the studies (9,10), the continuous subcutaneous insulin infusion pumps were purposely turned off for periods of 4 and 5 h, with a gradual increase in β-hydroxybutyratek concentrations after 2 h to the upper normal range. No cases of DKA occurred in these studies.     

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.