Randomized comparison of self-monitored blood glucose (BGM) versus continuous glucose monitoring (CGM) data to optimize glucose control in type 2 diabetes.

AIMS: Evaluate whether structured BGM testing (BGM) or real-time CGM (CGM) lead to improved glucose control (A1c). Determine which approach optimized glucose control more effectively. METHODS-MULTI-ARM PARALLEL: trial of three type 2 diabetes (T2D) therapies ± metformin: (1) sulfonylurea (SU), (2) incretin (DPP4 inhibitor or GLP-1 agonist), or (3) insulin. After a baseline CGM, 114 adult subjects were randomized to either BGM (4 times daily) or CGM (24/7) for 16 weeks with therapies adjusted every 4 weeks. RESULTS: A1c means decreased from 8.19 to 7.07 (1.12% difference) with CGM (n = 59) and 7.85 to 7.03 (0.82% difference) with BGM (n = 55) (p < 0.001). BGM and CGM groups showed significant improvements in time in range and glucose variability-with no significant difference between the two groups. Clinically important hypoglycemia (<50 mg/dL) was significantly reduced for the CGM group compared with BGM (p < 0.01), particularly in subjects taking insulin or therapies with higher hypoglycemic risk (SU). CONCLUSION: In T2D, structured, consistent use of glucose data regardless of device (structured BGM or CGM) leads to improvements in A1c control. CGM is more effective than BGM in minimizing hypoglycemia particularly for those using higher hypoglycemic risk therapies.

EVALUATION OF INSULIN GLARGINE AND EXENATIDE ALONE AND IN COMBINATION: A RANDOMIZED CLINICAL TRIAL WITH CONTINUOUS GLUCOSE MONITORING AND AMBULATORY GLUCOSE PROFILE ANALYSIS.

Objective: Characterize the effectiveness of insulin glargine alone, exenatide alone, or combined in subjects taking stable doses of metformin and evaluate their impact on hemoglobin A1C, hypoglycemia, weight, and glucose variability. Methods: Open-label, randomized, parallel-arm study of adults with type 2 diabetes naïve to both insulin and glucagon-like peptide 1 (GLP-1) agonist who were not at A1C goal despite treatment with metformin. This prospective interventional study employed blinded continuous glucose monitoring ambulatory glucose profile (AGP) reports over 32 weeks. Subjects were randomized to treatment with glargine (Iglar), exenatide (GLP-1), or combination of glargine and exenatide (Iglar + GLP-1). At midpoint, those not at A1C target had the second medication added; those on Iglar + GLP-1 continued therapy optimization. Results: Decreases in A1C were: 7.6 to 6.2% for Iglar + GLP-1, 7.5 to 6.6% for Iglar, and 7.5 to 6.4% for GLP-1. Iglar + GLP-1 achieved A1C targets faster (14 to 16 weeks) but had more hypoglycemia. Hypoglycemia rates increased slightly for all arms. Weight loss was achieved in all regimens including GLP-1. Glucose variability was not reduced to the same extent in the Iglar arm as the GLP-1 arm. Conclusion: Addition of Iglar and/or GLP-1 to metformin for patients not at treatment goal was safe and effective. The order of medication addition needs to consider individualized AGP patterns and goals. Iglar + GLP-1 resulted in rapid A1C lowering, whereas GLP-1 was noted to have less hypoglycemia. Weight loss was most pronounced in GLP-1 monotherapy, suggesting that GLP-1 may mitigate the weight gain of Iglar. Any treatment with GLP-1 showed significant decreases in glucose variability. Abbreviations: A1C = hemoglobin A1c; AGP = ambulatory glucose profile; CGM = continuous glucose monitoring; GLM = general linear model; GLP-1 = glucagon-like peptide 1 (exenatide); Iglar = insulin glargine; SGLT2 = sodium-glucose cotransporter 2; SMBG = self-monitoring blood glucose; SU = sulfonylurea; T2D = type 2 diabetes mellitus.

Technology Applications: Use of Digital Health Technology to Enable Drug Development.

PURPOSE: This pilot study developed and evaluated the feasibility, usability, and perceived satisfaction with an end-user mobile medical application and provider web portal. The two interfaces allowed for remote monitoring, provided daily guidance in the management of hypertension and diarrhea, and allowed for rapid management of adverse events during a clinical trial of olaparib and cediranib. PATIENTS AND METHODS: eCO (eCediranib/Olaparib) was designed for patient self-reported, real-time management of hypertension and diarrhea using remote monitoring. eCO links to a Bluetooth-enabled blood pressure (BP) monitor and transmits data to a secure provider web portal. eCO use was assessed for suitability, usability, and satisfaction after 4 weeks using a 17-item questionnaire. Metrics regarding patient-reported BP and diarrhea events were analyzed. RESULTS: Sixteen patients enrolled in the pilot. A total of 98.2% of expected BP values were reported: 94.2% via Bluetooth and 5.8% entered manually. Twelve patients experienced 21 BP events (systolic BP > 140 and/or diastolic BP > 90 mmHg on two consecutive readings); data from cycle 1 were comparable to the study database. Thirteen patients reported diarrhea (more than one stool per 24 hours over baseline) categorized as grade 1 or 2, which was comparable to the study database. Survey analysis showed that patients had statistically significant, positive responses to the use of the eCO application. Patients indicated eCO use made them feel more involved in their care and better connected to their health care team. The only aspect of the application that did not show a statistically significant positive response was the process of reporting diarrhea. CONCLUSION: The eCO application was designed to assist in managing acute treatment-related events most often associated with treatment discontinuation, need for drug holidays, or dose interruption. Hypertension and diarrhea events reported via eCO allowed rapid provider response and a positive overall patient experience.

Diurnal glucose exposure profiles of patients treated with lixisenatide before breakfast or the main meal of the day: An analysis using continuous glucose monitoring.

BACKGROUND: In the parent study of this analysis, patients with type 2 diabetes received lixisenatide before breakfast or the main meal of the day. This substudy was designed to examine the effect of lixisenatide administered before breakfast or the main meal of the day on continuously assessed 24-hour patient glucose profiles. METHODS: A subset of patients from the parent study underwent 2 14-day periods of continuous glucose monitoring (CGM) at the start and end of the 24-week study. Ambulatory glucose profile analysis was used to measure changes over time in detailed aspects of the glucose profiles. The breakfast group consumed a standardized meal during both CGM periods to determine change in 4-hour glycemic response. RESULTS: Data were available for 69 patients in the substudy, 40 from the original breakfast group and 29 from the main meal group. Between baseline and end of study, mean (standard deviation) total glucose exposure decreased from 4198.1 (652.3) to 3681.2 (699.6) mg/dL*24 h in the breakfast group (P < .0001) and from 4127.9 (876.8) to 3880.9 (1165.0) mg/dL*24 h in the main meal group (P = .0224). For patients included in the substudy, HbA1c decreased by approximately 0.6% in both groups. Mean (standard deviation) 4-hour total glucose exposure fell by 168.9 (158.4) mg/dL*4 h (P < .0001) from baseline. CONCLUSIONS: This analysis demonstrates that lixisenatide has beneficial effects on components of the 24-hour glucose profile, which endure beyond the meal at which it is administered. Continuous glucose monitoring analysis detects changes not captured using HbA1c alone.

Safety and efficacy of insulin therapy delivered via a 4mm pen needle in obese patients with diabetes.

OBJECTIVE: To determine whether insulin delivered via a 4-mm × 32-gauge pen needle (PN) provides equivalent glycemic control as 8-mm × 31-gauge and 12.7-mm × 29-gauge PNs in obese (body mass index ≥30) patients with diabetes. PATIENTS AND METHODS: This prospective, multicenter, randomized, open-label, 2-period, crossover, equivalence, home-based study was conducted from October 26, 2010, through May 31, 2012. After a 3-week wash-in period, eligible patients aged 18 to 80 years with a hemoglobin A1c (HbA1c) level of 5.5% to 9.5% (37-80 mmol/mol) were randomized to compare either 4- vs 8-mm PNs or 4- vs 12.7-mm PNs, using each of the 2 assigned PNs for 12 weeks in random order. The primary outcome was change in HbA1c level, with equivalence limits of ±0.4%. RESULTS: The 274 patients randomized (mean ± SD age, 56.7±11.0 years) had a mean ± SD body mass index of 37.0±6.1 (range, 29.1-59.9) and took up to 350 U of insulin daily; 226 patients were included in the modified intention-to-treat analysis. Mean (95% CI) changes in HbA1c levels with the 4-mm PN were -0.08% (-0.21 to 0.06) and -0.10% (-0.19 to 0.00) vs the 8- and 12.7-mm PNs, respectively, within equivalence margins. The 4-mm PN was less painful than the larger PNs (P<.05), with similar leakage rates reported (4.1%-4.3%). Patients preferred the 4-mm PN over the 12.7-mm PN (P<.05) but not significantly vs the 8-mm PN. There were no differences between PNs in insulin doses and hypoglycemic or hyperglycemic adverse event rates. CONCLUSION: The 4-mm × 32-gauge PN provides equivalent glycemic control as 8- and 12.7-mm PNs in obese patients with diabetes, with less pain and no increase in leakage. Shorter PNs should be considered in all insulin-requiring patients with diabetes, including those who are obese. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01231984.

A feasibility study of a 3-day basal-bolus insulin delivery device in individuals with type 2 diabetes.

OBJECTIVE: This study tested the feasibility of transition from multiple daily injections (MDI) to a 3-day, basal-bolus insulin delivery device (PaQ) for type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: Twenty MDI-treated individuals with T2D with HbA(1c) ≤9% (75 mmol/mol) were enrolled in a single-center, single-arm pilot study, lasting three 2-week periods: baseline (MDI), transition to PaQ, and PaQ therapy. Feasibility of use, glycemic control, safety, and patient satisfaction were assessed. RESULTS: Nineteen participants transitioned to PaQ treatment and demonstrated competency in assembling, placing, and using the device. Self-monitored blood glucose and blinded continuous glucose-monitoring data showed glycemic control similar to MDI. Study participants reported high satisfaction and device acceptance. CONCLUSIONS: PaQ treatment is both feasible and acceptable in individuals with T2D. Transition from MDI is easy and safe. PaQ treatment might lead to better therapy adherence and improvements in glycemic control and clinical outcomes.

Diurnal glucose profiles using continuous glucose monitoring to identify the glucose-lowering characteristics of colesevelam HCl (Welchol).

OBJECTIVES: The study's purpose was to identify the antihyperglycemic affects of colesevelam-HCl (C-HCl) by characterizing the diurnal and postprandial glucose patterns in type 2 diabetic subjects treated concomitantly with metformin, sulfonylurea, or a combination of metformin/sulfonylurea. A secondary aim was to determine whether C-HCl significantly increased the risk of hypoglycemia. METHODS: A prospective, randomized, double-blind, placebo-controlled, crossover study employing continuous glucose monitoring (CGM) with ambulatory glucose profile (AGP) analysis was undertaken. Fifteen males and 6 females, age 60 ± 8 years, treated with metformin (n = 8), sulfonylurea (n = 2), or combination (n = 11) participated. RESULTS: Treatment with C-HCl led to reductions in glycated hemoglobin (HbA1c) (7.5 ± 0.3 to 7.0 ± 0.4% P<.0001), LDL (90.9 ± 18.6 to 68.9 ± 15.2 mg/dL, P<.0007) and total cholesterol (169.2 ± 24.4 to 147.8 ± 21.5 mg/dL, P<.001). Significantly lower normalized diurnal (21 mg/dL/hour, P = .0006), nocturnal (19 mg/dL/hour, P = .0005), and daytime (22 mg/dL/hour, P = .0008) glucose exposure was detected immediately upon C-HCl administration. Additionally, there was a significant (P<.004) decline in postprandial glucose excursions (averaging 15% or -36 mg/dL/hour) pronounced at dinner following C-HCl administration. There was a nonsignificant increase in the incidence of hypoglycemia (0.4-1%), with no difference due to antihyperglycemic medications. CONCLUSIONS: AGP analysis of CGM visually and quantitatively showed immediate and midterm impacts of C-HCl on basal and postprandial glucose patterns. This suggests a multifactorial glucose-lowering mechanism for C-HCl affecting both meal-related and basal glucose levels.

Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the ambulatory glucose profile.

Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes mellitus. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardizing the analysis and presentation of glucose monitoring data, with the initial focus on data derived from continuous glucose monitoring systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile, and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This article provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients.

Recommendations for standardizing glucose reporting and analysis to optimize clinical decision making in diabetes: the Ambulatory Glucose Profile (AGP).

Abstract Underutilization of glucose data and lack of easy and standardized glucose data collection, analysis, visualization, and guided clinical decision making are key contributors to poor glycemic control among individuals with type 1 diabetes. An expert panel of diabetes specialists, facilitated by the International Diabetes Center and sponsored by the Helmsley Charitable Trust, met in 2012 to discuss recommendations for standardization of analysis and presentation of glucose monitoring data, with the initial focus on data derived from CGM systems. The panel members were introduced to a universal software report, the Ambulatory Glucose Profile (AGP), and asked to provide feedback on its content and functionality, both as a research tool and in clinical settings. This paper provides a summary of the topics and issues discussed during the meeting and presents recommendations from the expert panel regarding the need to standardize glucose profile summary metrics and the value of a uniform glucose report to aid clinicians, researchers, and patients.

International Forum for the Advancement of Diabetes Research and Care, April 29-30, 2011, Athens, Greece.

The International Forum for the Advancement of Diabetes Research and Care brought together distinguished international experts in diabetes to discuss diverse trends and emerging issues in diabetes therapy and management. The plenary sessions on the first day focused on trends in insulin therapy, the role of glucagon-like peptide-1 receptor agonists in diabetes treatment, the relationship between diabetes and cardiovascular risk, and the challenges associated with the development of clinically relevant treatment guidelines. Interactive breakout sessions addressed the following topics: microvascular complications of diabetes; the need for a team approach to patient education; optimal management of Asian people with diabetes; the role of continuous glucose monitoring in assessing glucose variability; and lessons learned from biosimilar drugs. The plenary sessions on the second day covered self-monitoring of blood glucose, treatment and prevention of type 1 diabetes, and future directions for diabetes therapy. The meeting represented an excellent forum for the presentation of new research and the exchange of ideas aimed at improving outcomes for people with diabetes.

Diurnal glucose patterns of exenatide once weekly: a 1-year study using continuous glucose monitoring with ambulatory glucose profile analysis.

OBJECTIVE: To use continuous glucose monitoring (CGM) to characterize diurnal glucose patterns produced by a novel formulation of exenatide consisting of biodegradable polymeric microspheres that entrap exenatide and provide extended release enabling once-weekly administration. METHODS: We performed a subgroup analysis of patients with type 2 diabetes who participated in a multicenter trial (DURATION-1: Effects of Exenatide Long-Acting Release on Glucose Control and Safety in Subjects With Type 2 Diabetes Mellitus) comparing once-weekly with twice-daily formulations of exenatide. We are the only center to use CGM with ambulatory glucose profile (AGP) analysis to characterize glucose exposure, variability, and stability in participants assigned to exenatide once weekly. RESULTS: Seven of the 303 patients in the larger study population were included in the subgroup analysis. Mean age (57.6 +/- 7 years), weight (102 +/- 17 kg), body mass index (34 +/- 3 kg/m2), and duration of diabetes (5 +/- 2 years) were comparable to characteristics of the larger study population. At 30 weeks and 52 weeks, participants treated with exenatide once weekly had a mean reduction in hemoglobin A1c level of 1.3 +/- 0.3% and 1.0 +/- 0.3%, respectively (P<.05). CGM analysis revealed a significant (P<.01) decrease in diurnal glucose exposure for 4 participants during nocturnal and daytime periods. Excess glucose exposure (compared with reference values) decreased in 6 of 7 participants, as did glucose variability. Glucose stability improved in 5 participants. The percentage of glucose values less than 70 mg/dL initially increased during the first half of the study then decreased to baseline levels by study end. CONCLUSIONS: Individual glucose profiles revealed that changes in hemoglobin A1c did not consistently parallel alterations in glucose exposure, variability, and stability. AGPs provided a visual representation of improved glucose responses to exenatide once weekly.

Evaluating the accuracy, reliability, and clinical applicability of continuous glucose monitoring (CGM): Is CGM ready for real time?

BACKGROUND: This study was designed to assess the accuracy, reliability, and contribution to clinical decision-making of two commercially available continuous glucose monitoring (CGM) devices using a novel analytical approach. STUDY DESIGN: Eleven individuals with type 1 diabetes and five with type 2 diabetes wore a Guardian RT (GRT) (Medtronic Minimed, Northridge, CA) or DexCom STS Continuous Monitoring System (DEX) (San Diego, CA) device for 200 h followed by an 8-h laboratory study. A subset of these subjects wore both devices simultaneously. RESULTS: Subjects produced 1,902 +/- 269 readings during the ambulatory phase. During the laboratory study we found: lag time of 21 +/- 5 min for GRT and 7 +/- 7 min for DEX (P < 0.005); mean absolute relative difference of 19.9% and 16.7%, respectively, for GRT and DEX; and glucose exposure (the ratio of study device/laboratory reference device [YSI Instruments, Inc., Yellow Springs, OH] area under the curve) of 95 +/- 6% for GRT and 101 +/- 13% for DEX. Reliability measured during laboratory study showed 82% for DEX and 99% for GRT. Clarke Error Grid analysis (YSI reference) showed for GRT 59% of values in zone A, 34% in zone B, and 7% in zone D and for DEX 70% in zone A, 28% in zone B, 1% in zone C, and 1% in zone D. Bland-Altman plots (YSI standard) yielded for DEX 3 mg/dL (95% confidence interval, -78 to 84 mg/dL) and for GRT -21 mg/dL (95% confidence interval, -124 to 82 mg/dL). Six of eight subjects completed both home and laboratory simultaneous use of DEX and GRT. Lag times were inconsistent between devices, ranging from 0 to 32 min; area under the curve revealed a tendency for DEX to report higher total glucose exposure than GRT for the same patient. CONCLUSIONS: CGM detects abnormalities in glycemic control in a manner heretofore impossible to obtain. However, our studies revealed sufficient incongruence between simultaneous laboratory blood glucose levels and interstitial fluid glucose (after calibrations) to question the fundamental assumption that interstitial fluid glucose and blood glucose could be made identical by resorting to algorithms based on concurrent blood glucose levels alone.

Characterizing glucose exposure for individuals with normal glucose tolerance using continuous glucose monitoring and ambulatory glucose profile analysis.

BACKGROUND: Efforts to mimic euglycemia depend upon targets from epidemiologic studies that rely on episodic measurements reduced to statistical summaries, leaving open the question, "What is normal glycemia?" We postulated that portrayal of euglycemia was possible through application of continuous glucose monitoring (CGM) and a novel analytical tool, the ambulatory glucose profile (AGP). METHODS: Individuals with normal glucose tolerance (NGT) and with diabetes used CGM for 30 days. AGP analysis, which graphs CGM data by time without regard to date, was used to characterize glucose exposure, variability, and stability. RESULTS: Sixty-two subjects completed the study, employing CGM for 28 +/- 4 days averaging 99 +/- 18 (range, 33-125) readings per day. NGT subjects (n = 32) had a mean CGM of 102 +/- 7 mg/dL, ranging between 94 and 117 mg/dL and averaging 105 +/- 8 mg/dL daytime and 97 +/- 6 mg/dL overnight. Glucose variability, as expressed by the interquartile range, was 21 +/- 4 mg/dL (range, 14-29 mg/dL). Stability in glycemic control (hourly change in the median) for NGT subjects averaged 3 +/- 1 mg/dL/h. Subjects with diabetes (n = 30) were significantly higher on all glycemic characteristics with the exception of the percentage of hypoglycemic (CGM <70 mg/dL) episodes for type 2 diabetes (2.9%), compared to 2.7% for subjects with NGT. CONCLUSIONS: CGM technologies enabled collection of verified data under normal living conditions, providing an exceptional vantage point from which to obtain important clinical information. This will facilitate an understanding of the range of euglycemic patterns, provide a sensitive means of detecting impaired glucose tolerance, and help set realistic treatment goals for individuals with diabetes.