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Figure 1.
Flowchart of Continuous Glucose Monitoring Study Completion
Flowchart of Continuous Glucose Monitoring Study Completion

All enrolled participants started the run-in phase; 28 did not proceed to randomization for the reasons indicated in the figure. The number eligible for screening who did not sign the informed consent form was not recorded.

Figure 2.
Hemoglobin A1c Values at Baseline and 24 Weeks, by Group
Hemoglobin A1c Values at Baseline and 24 Weeks, by Group

A, Scatterplot of 24-week hemoglobin A1c (HbA1c) levels by baseline HbA1c level. The horizontal line at 7.0% represents the American Diabetes Association HbA1c goal for adults with type 1 diabetes. Points below the diagonal line represent cases in which the 24-week HbA1c level was lower than the baseline HbA1c level, points above the diagonal line represent cases in which the 24-week HbA1c level was higher than the baseline HbA1c level, and points on the diagonal line represent cases in which the 24-week and baseline HbA1c values were the same. B, Cumulative distribution of 24-week HbA1c values. For any given 24-week HbA1c level, the percentage of cases in each treatment group with an HbA1c value at that level or lower can be determined from the figure. To convert HbA1c to the SI units of mmol/mol, multiply the HbA1c percentage value × 10.93 and subtract 23.5 from the product.

Table 1.  
Baseline Participant Characteristics
Baseline Participant Characteristics
Table 2.  
Primary Outcome and Hemoglobin A1c Outcomes at 12 and 24 Weeksa
Primary Outcome and Hemoglobin A1c Outcomes at 12 and 24 Weeksa
Table 3.  
Continuous Glucose Monitoring Metrics
Continuous Glucose Monitoring Metrics
1.
Miller  KM, Foster  NC, Beck  RW,  et al; T1D Exchange Clinic Network.  Current state of type 1 diabetes treatment in the US: updated data from the T1D Exchange clinic registry.  Diabetes Care. 2015;38(6):971-978.PubMedGoogle ScholarCrossref
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Battelino  T, Conget  I, Olsen  B,  et al; SWITCH Study Group.  The use and efficacy of continuous glucose monitoring in type 1 diabetes treated with insulin pump therapy: a randomised controlled trial.  Diabetologia. 2012;55(12):3155-3162.PubMedGoogle ScholarCrossref
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Battelino  T, Phillip  M, Bratina  N, Nimri  R, Oskarsson  P, Bolinder  J.  Effect of continuous glucose monitoring on hypoglycemia in type 1 diabetes.  Diabetes Care. 2011;34(4):795-800.PubMedGoogle ScholarCrossref
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Bergenstal  RM, Tamborlane  WV, Ahmann  A,  et al; STAR 3 Study Group.  Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes.  N Engl J Med. 2010;363(4):311-320.PubMedGoogle ScholarCrossref
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Tamborlane  WV, Beck  RW, Bode  BW,  et al; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group.  Continuous glucose monitoring and intensive treatment of type 1 diabetes.  N Engl J Med. 2008;359(14):1464-1476.PubMedGoogle ScholarCrossref
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Beck  RW, Hirsch  IB, Laffel  L,  et al; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group.  The effect of continuous glucose monitoring in well-controlled type 1 diabetes.  Diabetes Care. 2009;32(8):1378-1383.PubMedGoogle ScholarCrossref
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Grunberger  G, Abelseth  JM, Bailey  TS,  et al.  Consensus statement by the American Association of Clinical Endocrinologists/American College of Endocrinology Insulin Pump Management Task Force.  Endocr Pract. 2014;20(5):463-489.PubMedGoogle ScholarCrossref
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Pickup  J.  Insulin pumps.  Int J Clin Pract Suppl. 2011;65(170):16-19.PubMedGoogle ScholarCrossref
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Foster  NC, Miller  KM, Tamborlane  WV, Bergenstal  RM, Beck  RW; T1D Exchange Clinic Network.  Continuous glucose monitoring in patients with type 1 diabetes using insulin injections.  Diabetes Care. 2016;39(6):e81-e82. PubMedGoogle ScholarCrossref
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Clarke  WL, Cox  DJ, Gonder-Frederick  LA, Julian  D, Schlundt  D, Polonsky  W.  Reduced awareness of hypoglycemia in adults with IDDM: a prospective study of hypoglycemic frequency and associated symptoms.  Diabetes Care. 1995;18(4):517-522.PubMedGoogle ScholarCrossref
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Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group.  Validation of measures of satisfaction with and impact of continuous and conventional glucose monitoring.  Diabetes Technol Ther. 2010;12(9):679-684.PubMedGoogle ScholarCrossref
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Little  RJA, Rubin  DB.  Statistical Analysis With Missing Data. New York, NY: John Wiley & Sons; 1987.
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Rosenbaum  PR, Rubin  DB.  Reducing bias in observational studies using subclassification on the propensity score.  J Am Stat Assoc. 1984;79(387):516-524.Google ScholarCrossref
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Kovatchev  BP, Cox  DJ, Farhy  LS, Straume  M, Gonder-Frederick  L, Clarke  WL.  Episodes of severe hypoglycemia in type 1 diabetes are preceded and followed within 48 hours by measurable disturbances in blood glucose.  J Clin Endocrinol Metab. 2000;85(11):4287-4292.PubMedGoogle Scholar
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Fiallo-Scharer  R, Cheng  J, Beck  RW,  et al; Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group.  Factors predictive of severe hypoglycemia in type 1 diabetes: analysis from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized control trial dataset.  Diabetes Care. 2011;34(3):586-590.PubMedGoogle ScholarCrossref
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Brod  M, Wolden  M, Christensen  T, Bushnell  DM.  A nine country study of the burden of non-severe nocturnal hypoglycaemic events on diabetes management and daily function.  Diabetes Obes Metab. 2013;15(6):546-557.PubMedGoogle ScholarCrossref
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Davis  RE, Morrissey  M, Peters  JR, Wittrup-Jensen  K, Kennedy-Martin  T, Currie  CJ.  Impact of hypoglycaemia on quality of life and productivity in type 1 and type 2 diabetes.  Curr Med Res Opin. 2005;21(9):1477-1483.PubMedGoogle ScholarCrossref
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Fulcher  G, Singer  J, Castañeda  R,  et al.  The psychosocial and financial impact of non-severe hypoglycemic events on people with diabetes: two international surveys.  J Med Econ. 2014;17(10):751-761.PubMedGoogle ScholarCrossref
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Battelino  T, Liabat  S, Veeze  HJ, Castañeda  J, Arrieta  A, Cohen  O.  Routine use of continuous glucose monitoring in 10 501 people with diabetes mellitus.  Diabet Med. 2015;32(12):1568-1574.PubMedGoogle ScholarCrossref
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Bailey  TS, Chang  A, Christiansen  M.  Clinical accuracy of a continuous glucose monitoring system with an advanced algorithm.  J Diabetes Sci Technol. 2015;9(2):209-214.PubMedGoogle ScholarCrossref
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Christiansen  M, Bailey  T, Watkins  E,  et al.  A new-generation continuous glucose monitoring system: improved accuracy and reliability compared with a previous-generation system.  Diabetes Technol Ther. 2013;15(10):881-888.PubMedGoogle ScholarCrossref
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Zisser  HC, Bailey  TS, Schwartz  S, Ratner  RE, Wise  J.  Accuracy of the SEVEN continuous glucose monitoring system: comparison with frequently sampled venous glucose measurements.  J Diabetes Sci Technol. 2009;3(5):1146-1154.PubMedGoogle ScholarCrossref
Original Investigation
January 24/31, 2017

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

Author Affiliations
  • 1Jaeb Center for Health Research, Tampa, Florida
  • 2Oregon Health & Science University, Portland
  • 3Park Nicollet Institute, International Diabetes Center, St Louis Park, Minnesota
  • 4Diabetes & Glandular Disease Clinic, San Antonio, Texas
  • 5Division of Endocrinology, Henry Ford Medical Center, Detroit, Michigan
  • 6Washington University in St Louis, St Louis, Missouri
  • 7Behavioral Diabetes Institute, San Diego, California
  • 8Joslin Diabetes Center, Boston, Massachusetts
  • 9Dexcom Inc, San Diego, California
JAMA. 2017;317(4):371-378. doi:10.1001/jama.2016.19975
Key Points

Question  For adults with type 1 diabetes who are using multiple daily insulin injections, does continuous glucose monitoring improve hemoglobin A1c (HbA1c) levels compared with self-monitored blood glucose management?

Findings  In a randomized clinical trial of 158 adults with type 1 diabetes, there was a significantly greater decrease in HbA1c level during 24 weeks with continuous glucose monitoring vs usual care (–1.0% vs –0.4%).

Meaning  Continuous glucose monitoring resulted in better glycemic control compared with usual care, but further research is needed to assess clinical outcomes, as well as effectiveness, in a typical clinical population.

Abstract

Importance  Previous clinical trials showing the benefit of continuous glucose monitoring (CGM) in the management of type 1 diabetes predominantly have included adults using insulin pumps, even though the majority of adults with type 1 diabetes administer insulin by injection.

Objective  To determine the effectiveness of CGM in adults with type 1 diabetes treated with insulin injections.

Design, Setting, and Participants  Randomized clinical trial conducted between October 2014 and May 2016 at 24 endocrinology practices in the United States that included 158 adults with type 1 diabetes who were using multiple daily insulin injections and had hemoglobin A1c (HbA1c) levels of 7.5% to 9.9%.

Interventions  Random assignment 2:1 to CGM (n = 105) or usual care (control group; n = 53).

Main Outcomes and Measures  Primary outcome measure was the difference in change in central-laboratory–measured HbA1c level from baseline to 24 weeks. There were 18 secondary or exploratory end points, of which 15 are reported in this article, including duration of hypoglycemia at less than 70 mg/dL, measured with CGM for 7 days at 12 and 24 weeks.

Results  Among the 158 randomized participants (mean age, 48 years [SD, 13]; 44% women; mean baseline HbA1c level, 8.6% [SD, 0.6%]; and median diabetes duration, 19 years [interquartile range, 10-31 years]), 155 (98%) completed the study. In the CGM group, 93% used CGM 6 d/wk or more in month 6. Mean HbA1c reduction from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (repeated-measures model P < .001). At 24 weeks, the adjusted treatment-group difference in mean change in HbA1c level from baseline was –0.6% (95% CI, –0.8% to –0.3%; P < .001). Median duration of hypoglycemia at less than <70 mg/dL was 43 min/d (IQR, 27-69) in the CGM group vs 80 min/d (IQR, 36-111) in the control group (P = .002). Severe hypoglycemia events occurred in 2 participants in each group.

Conclusions and Relevance  Among adults with type 1 diabetes who used multiple daily insulin injections, the use of CGM compared with usual care resulted in a greater decrease in HbA1c level during 24 weeks. Further research is needed to assess longer-term effectiveness, as well as clinical outcomes and adverse effects.

Trial Registration  clinicaltrials.gov Identifier: NCT02282397

Introduction

Quiz Ref IDOnly approximately 30% of individuals with type 1 diabetes meet the American Diabetes Association goal of hemoglobin A1c (HbA1c) level of 7.5% (58 mmol/mol) for children (<18 years) and 7.0% (53 mmol/mol) for adults (≥18 years),1 indicating the need for better approaches to diabetes management. Continuous glucose monitoring (CGM) with glucose measurements as often as every 5 minutes, plus low and high glucose level alerts and glucose trend information, has the capability of better informing diabetes management decisions than blood glucose meter testing performed several times a day. Randomized clinical trials have demonstrated the benefit of CGM in adults with type 1 diabetes, but not consistently in children, to improve glycemic control as measured by HbA1c level and to reduce hypoglycemia.2-6 These previous trials have either completely or predominantly included insulin pump users,2,4,5 although the majority of adults with type 1 diabetes deliver insulin via injections.7,8

Only a small proportion of individuals with type 1 diabetes who inject insulin use CGM, although the limited available observational data suggest that the glycemic benefit may be comparable to that for pump users. In T1D Exchange registry 2015 data, mean HbA1c level in the 410 adult insulin injecters using CGM was similar to that in 2316 pump users using CGM (7.6% vs 7.7%, respectively) and lower than mean HbA1c level in the 6222 injection users not using CGM (7.6% vs 8.8%; P < .001).9

Whether individuals receiving insulin injections would be willing to regularly wear CGM sensors and would derive glycemic benefits from CGM needs investigation. Accordingly, this randomized multicenter clinical trial was conducted to evaluate the effect of CGM in adults with type 1 diabetes who have elevated HbA1c levels and use multiple daily injections of insulin.

Methods

The trial was conducted at 24 endocrinology practices in the United States (19 community-based and 5 academic centers). The protocol and Health Insurance Portability and Accountability Act–compliant informed consent forms were approved by institutional review boards (central commercial board for 17 sites and local boards for the other 7 sites). Written informed consent was obtained from each participant. The protocol is provided online and the statistical analysis plan is available in Supplement 1.

Study Participants

Major eligibility criteria included age 25 years or older, diagnosis of type 1 diabetes treated for at least 1 year with multiple daily insulin injections, central laboratory–measured HbA1c level of 7.5% to 10.0%, no home use of a personal CGM device in the 3 months before the trial, and a negative pregnancy test for women of childbearing potential (eTable 1 in Supplement 2 has a complete listing of the inclusion and exclusion criteria).

Synopsis of Study Design

Each participant was required to complete a 2-week prerandomization phase using a CGM system that was configured to record glucose concentrations not visible to the participant (referred to as a “blinded” CGM). Eligibility required that the blinded CGM be worn on at least 85% of possible days, the CGM be calibrated at least 2 times per day, and blood glucose meter testing (with a study-provided meter and test strips) be performed at least 3 times daily. Fourteen participants did not meet these criteria and did not continue into the randomized trial (Figure 1). One participant had a sudden death during the prerandomization phase.

On the study website, after verification of eligibility from data entered, each participant was assigned randomly from a computer-generated sequence to either the CGM or control group in a 2:1 ratio, with a permuted block design (block sizes of 3 and 6) stratified by HbA1c level (<8.5% and ≥8.5%). A 2:1 randomization was used rather than 1:1 to provide a larger sample size for a separate follow-on randomized trial assessing glycemic benefits of initiating pump therapy in CGM users using insulin injections.

Quiz Ref IDParticipants in the CGM group were provided with a CGM system (Dexcom G4 Platinum CGM System with an enhanced algorithm, software 505, Dexcom Inc) that measured glucose concentrations from interstitial fluid in the range of 40 to 400 mg/dL every 5 minutes for up to 7 days. Participants in both groups were provided with a Bayer Contour Next USB meter and test strips. The CGM group was instructed to use the CGM daily, calibrate the CGM twice daily, and verify the CGM glucose concentration with the blood glucose meter before injecting insulin (as per the regulatory labeling of the device at the time the trial was conducted). General guidelines were provided to participants about using CGM, and individualized recommendations were made by their clinician about incorporating CGM trend information into their diabetes management. The control group was asked to perform home blood glucose monitoring at least 4 times daily. Participants in both groups were provided general diabetes management education, and clinicians were encouraged to review downloaded glucose data at each visit to inform treatment recommendations, which were at clinician discretion and not prescriptive in the protocol. eTable 2 in Supplement 2 describes the participant education as well as guidelines for clinicians. CGM guidelines for participants are included in Supplement 1.

Follow-up visits for both treatment groups occurred after 4, 12, and 24 weeks. The CGM group had an additional visit 1 week after randomization. The control group had 2 additional visits 1 week before the 12- and 24-week visits, at which a CGM sensor in blinded mode was inserted to collect glucose data for 1 week. Telephone contacts for both groups occurred 2 and 3 weeks after randomization.

Hemoglobin A1c level was measured at baseline, 12 weeks, and 24 weeks at the Northwest Lipid Research Laboratories, University of Washington, Seattle, with the Diabetes Control and Complications Trial standardized analyzer (TOSOH, Biosciences Inc).

Outcomes

The primary outcome was change in the central laboratory–measured HbA1c level. Prespecified secondary outcomes included percentage of participants with HbA1c level less than 7.0%; CGM-measured time in range (70-180 mg/dL), duration of hypoglycemia (<70 mg/dL, <60 mg/dL, and <50 mg/dL), duration of hyperglycemia (>180 mg/dL, >250 mg/dL, and >300 mg/dL), and glucose variability (coefficient of variation); change in hypoglycemia unawareness10; and change in frequency of blood glucose meter testing (longitudinal changes in blood glucose meter testing were not assessed). Prespecified exploratory outcomes included CGM-measured mean glucose concentration and the following binary HbA1c outcomes to assist in translation of the primary HbA1c analysis to a participant level: HbA1c level less than 7.5% and relative HbA1c reduction greater than or equal to 10%. Post hoc outcomes included HbA1c reduction of 1% or more, HbA1c level less than 7.0% or reduction of 1% or more, CGM-measured area above the curve 70 mg/dL and area under the curve 180 mg/dL, change in insulin dose, and change in body weight.

Satisfaction with CGM was assessed by completion at 24 weeks of the CGM Satisfaction Survey (44 items on a 1-5 Likert scale, with the computed score representing the mean of the 44 items and subscales of benefits and lack of hassles).11 Quality-of-life and health economic outcomes will be reported in separate articles.

Safety outcomes included severe hypoglycemia (defined as an event that required assistance from another person to administer carbohydrate, glucagon, or other resuscitative actions), diabetic ketoacidosis, and serious adverse events regardless of causality.

Statistical Methods

A sample size of 147 for the 2:1 randomization was calculated to have 90% power to detect a difference in mean HbA1c level between treatment groups, assuming a population difference of 0.4%, standard deviation of the 24-week values of 0.7 adjusted for the correlation between baseline and 24-week values (based on data from the Juvenile Diabetes Research Foundation CGM randomized trial5), and a 2-sided α level of .05. Sample size initially was increased to 169 to account for potential loss to follow-up. When it was recognized by the coordinating center that the trial completion rate was higher than anticipated, the recruitment goal was changed to a minimum of 150, with the approval of the steering committee and the sponsor.

Analyses followed the intent-to-treat principle. The following change was made from the protocol and statistical analysis plan before the data lock: the primary analysis was a treatment group comparison of the change in HbA1c level from baseline to 24 weeks, adjusted for baseline HbA1c level and clinical site as a random effect, in a repeated-measures linear model in the protocol and with analysis of covariance in the statistical analysis plan; both are reported in this article. Confounding was assessed by repeating the analysis, including potential confounding variables as covariates. The Rubin method was used to impute for missing data.12 Exploratory analyses were conducted to assess for interaction between the treatment effect on the change in HbA1c level from baseline to 24 weeks and baseline factors by including interaction terms in analysis of covariance models. The following changes were made from the protocol and statistical analysis plan during the peer-review process: in post hoc analyses, binary HbA1c outcomes were evaluated with propensity scores13 instead of logistic regression, adjusted for baseline HbA1c level and clinical site; and for secondary, exploratory, and post hoc analyses, 99% CIs instead of 95% CIs are reported.

For CGM outcomes, treatment group comparisons using the CGM data collected in each group for 7 days at 12 and 24 weeks were made with analysis of covariance models based on ranks using van der Waerden scores if the metric was skewed, adjusted for the corresponding baseline value, baseline HbA1c level, and clinical site as a random effect. Similar analyses were performed separately for daytime and nighttime. Frequency of blood glucose monitoring was compared between groups with an analysis of covariance model, adjusted for the baseline frequency and clinical site as a random effect.

Statistical methods for other analyses are described in table footnotes. Standard deviations are reported for means and interquartile ranges (IQRs) for medians where applicable. Reported point estimates are unadjusted unless otherwise noted. Analyses were conducted with SAS version 9.4. All P values are 2 sided. P < .05 was considered significant for the primary analysis and P < .01 for all other analyses to account for multiple comparisons (with 99% CIs accordingly provided).

SI Unit Conversions

Throughout, to convert HbA1c to the SI units of mmol/mol, multiply the HbA1c percentage value × 10.93 and subtract 23.5 from the product. For example, an HbA1c value of 7.0% corresponds to 53 mmol/mol. To convert glucose to mmol/L, multiply the values × 0.0555.

Results

Between October 2014 and December 2015, 158 participants were assigned to the CGM group (n = 105) or control group (n = 53). Mean age was 48 years (SD, 13) (range, 26-73 years, with 34 participants [22%] ≥60 years); 44% were women. Median diabetes duration was 19 years (IQR, 10-31 years), and mean baseline HbA1c level was 8.6% (SD, 0.6%; range, 7.5%-9.9%). Participant characteristics according to randomized group are shown in Table 1.

The 24-week primary study outcome visit was completed by 102 participants (97%) in the CGM group and all 53 (100%) in the control group (Figure 1). Overall visit completion was 99% and 98%, respectively. Three participants in the CGM group (4 total visits) and 3 in the control group (3 total visits) had additional visits, not required in the protocol, for diabetes management.

Among the 102 participants in the CGM group who completed the trial, median CGM use was 7.0 d/wk (IQR, 7.0-7.0) at 4, 12, and 24 weeks; only 2 (2%) discontinued CGM before the 24-week visit. During month 6 (weeks 21-24), CGM use was 6 or more d/wk for 93% of the 102 participants (eTable 3 in Supplement 2). No participant in the control group initiated unblinded CGM use before the primary outcome.

According to meter downloads, mean blood glucose self-monitoring was 5.1 tests per day (SD, 1.8) in the CGM group and 5.1 tests per day (SD, 1.4) in the control group during the baseline period of blinded CGM wear and 3.6 tests per day (SD, 1.6) and 4.6 tests per day (SD, 1.6), respectively, at 24 weeks (adjusted mean difference for the change, –1.0; 99% CI, –1.7 to –0.4; P < .001).

Glycemic Control and Other Outcomes
Primary Outcome

Mean reduction in HbA1c level from baseline was 1.1% at 12 weeks and 1.0% at 24 weeks in the CGM group and 0.5% and 0.4%, respectively, in the control group (primary analysis repeated-measures P < .001). At 24 weeks, the adjusted treatment group difference in mean change in HbA1c level was –0.6% (95% CI, –0.8% to –0.3%; P < .001) (Table 2). For each treatment group, baseline and 24-week HbA1c values for each participant are shown in Figure 2A, and the cumulative distribution of the 24-week HbA1c values is shown in Figure 2B.

Secondary, Exploratory, and Post Hoc HbA1c Outcomes

The greater HbA1c improvement in the CGM group also was reflected in multiple participant-level secondary, exploratory, and post hoc HbA1c outcomes (Table 2). There was no significant interaction of the effect of treatment on 24-week HbA1c level according to baseline HbA1c, age, education level, or type of site (eTable 4 in Supplement 2).

Secondary and Exploratory CGM Outcomes

As secondary outcomes, CGM metrics for time in the range of 70 to 180 mg/dL, hyperglycemia, hypoglycemia, and glycemic variability favored the CGM group compared with the control group (Table 3, eTable 5 in Supplement 2). In exploratory analyses, hypoglycemia treatment group differences favored the CGM group during both daytime and nighttime, but hyperglycemia treatment group differences favoring the CGM group were present only during the daytime (eTables 6 and 7 in Supplement 2).

Other Analyses

At 24 weeks, in post hoc analyses there were no significant differences between the CGM group and control group in median change in total daily insulin dose per kilogram of body weight (–0.02 vs 0.03 U/kg; P = .23), median ratio of long-acting to rapid-acting daily insulin dose (0.9 vs 1.0; P = .54), proportion of participants with an increase in number of injections of rapid-acting insulin per day (26% vs 26%; P = .90), or mean change in body weight (1.7 vs 0.7 kg; mean difference, 1.0 kg; 99% CI, –0.7 to 2.8; P = .12) (eTable 8 in Supplement 2). Clarke Hypoglycemia Unawareness scores did not differ between groups (mean difference, –0.1; 99% CI, –0.7 to 0.5; P = .64).

Severe Hypoglycemia and Other Adverse Events

Severe hypoglycemic events occurred in 2 participants in each group (P = .67). There were no occurrences of diabetic ketoacidosis. Other serious adverse events, unrelated to the study intervention, occurred in 2 participants in the CGM group and none in the control group (eTable 9 in Supplement 2).

CGM Satisfaction

In the CGM group, satisfaction with use of CGM was high, as indicated by the mean (SD) score of 4.2 (0.4) on the CGM Satisfaction Survey, with mean (SD) scores of 4.2 (0.5) on the benefits subscale and 4.3 (0.5) on the subscale for lack of hassles (eTable 10 in Supplement 2).

Discussion

Quiz Ref IDAmong adults with type 1 diabetes using multiple daily insulin injections, the use of CGM compared with usual care resulted in a greater decrease in HbA1c level during 24 weeks. The HbA1c benefit in the CGM group was consistently present across the age range of 26 to 73 years, the baseline HbA1c level range of 7.5% to 9.9%, and all education levels. In addition, CGM use was associated with a high degree of participant satisfaction with CGM, increased time with glucose concentrations between 70 and 180 mg/dL, decreased time with glucose concentrations less than 70 mg/dL, and decreased glycemic variability, measured with the coefficient of variation. The trial was not designed to demonstrate a benefit in reducing clinical severe hypoglycemia events, and the low event rate in the control group precluded a meaningful analysis. However, less biochemical hypoglycemia, as was observed in the trial, has been associated with a lower risk for subsequent severe hypoglycemic events14,15 and improved quality of life.16-18

The amount of CGM use by the participants was high (median CGM use 7 d/wk in month 6) despite a protocol approximating usual practice, with only 1 visit after week 4 and no visits or other protocol-specified contacts between 12 and 24 weeks. The amount of use was similar to or greater than the frequency of use in pump-using adults with type 1 diabetes in previous trials and observational studies,2-5,19 which could be related to CGM accuracy being significantly improved from the generation of sensors in previous trials.20-22 The observed benefits of CGM occurred despite the CGM group’s having significantly less blood glucose meter testing per day than the control group.

Quiz Ref IDThe magnitude of benefit of CGM on HbA1c levels relative to control in this trial of insulin injection users is comparable to the magnitude of benefit of CGM observed in pump users in previous randomized trials.2,4,5 This finding was not a foregone conclusion. Insulin injection users have less flexibility in adjusting their insulin delivery in response to CGM glucose concentrations and trends than do pump users. Basal insulin delivery for pump users is continuous, can be programmed to vary at different times of the day, and can be temporarily changed in response to decreasing or increasing glucose concentrations or planned activities such as exercise. In contrast, injection users have fixed basal insulin based on the absorption of their long-acting insulin and can make adjustments only to rapid-acting insulin boluses.

Quiz Ref IDThe strengths of the trial included a high retention rate, high adherence to treatment group assignment, central laboratory measurement of HbA1c level, a protocol approximating usual clinical practice, and participation in the trial by both community-based and academic sites. Assignment to the CGM and control groups could not be blinded because of the nature of the intervention; however, the groups had a similar number of visits. The 0.4% mean improvement in HbA1c level in the control group likely reflects both a study effect related to clinical trial participation and more structured training in using blood glucose monitoring in adjusting insulin regimens than was occurring for these individuals before the study.

This study also had several limitations. In light of the eligibility criteria, the results may not apply to individuals with type 1 diabetes who are younger than 26 years or have HbA1c levels outside the range of 7.5% to 9.9% and should not be applied to individuals with type 2 diabetes who receive multiple daily injections of insulin. The informed consent process and the run-in phase had the potential to exclude individuals who might be less adherent with CGM than the cohort that was studied.

Conclusions

Among adults with type 1 diabetes who use multiple daily insulin injections, the use of CGM compared with usual care resulted in a greater decrease in HbA1c level during 24 weeks. Further research is needed to assess longer-term effectiveness, as well as clinical outcomes and adverse effects.

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Article Information

Corresponding Author: Roy W. Beck, MD, PhD, Jaeb Center for Health Research, 15310 Amberly Dr, Ste 350, Tampa, FL 33647 (rbeck@jaeb.org).

Author Contributions: Dr Beck had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Beck, Riddlesworth.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Riddlesworth, Kollman.

Obtained funding: Price.

Administrative, technical, or material support: All authors.

Supervision: All authors.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dexcom Inc provided funding for the trial to each investigator’s institution. Dr Beck reports receiving a study grant from Dexcom and that his institution received supplies for research from Dexcom and Abbott Diabetes Care for other studies. Dr Ahmann reports receiving grants for the study and consulting for Dexcom Inc; receiving grants for research support from Medtronic, Novo Nordisk, Lexicon, and Sanofi; consulting for Novo Nordisk, Sanofi, and AstraZeneca; and serving on advisory boards for Lilly, Janssen, and AstraZeneca. Dr Bergenstal reports receiving a study grant from Dexcom and NIH; reports serving on the advisory boards for and/or receiving study funding from Abbott Diabetes Care, AstraZeneca, Becton Dickinson, Boehringer Ingelheim, Calibra, Eli Lilly, Halozyme, Hygieia, Johnson & Johnson, Medtronic, Novo Nordisk, Roche, Sanofi, and Takeda; and reports holding stock in Merck. Ms Kruger reports holding stock in Dexcom. Dr McGill reports receiving grant funding from Novartis, Novo Nordisk, Lexicon, Bristol-Myers Squibb, and Dexcom; and consulting fees from Boehringer Ingelheim, Dexcom, Lilly, Merck, Novo Nordisk, Intarcia, Dynavax, Valeritas, Janssen, and Calibra. Dr Polonsky reports consulting for Dexcom. Dr Wolpert reports receiving grant funding from Abbott Diabetes Care. Dr Price is an employee of Dexcom, Inc and reports holding stock in the company. No other disclosures were reported.

DIAMOND Participating Clinical Sites: Personnel are listed as (I) for study investigator and (C) for study coordinator. Sites are listed in order by number of participants randomized in the study. The number of participants randomized is noted in parentheses, preceded by the site location and site name. Joslin Diabetes Center, Boston, MA (24): Elena Toschi (I); Howard Wolpert (I); Astrid Atakov-Castillo (C); Edvina Markovic (C). Research Institute of Dallas, Dallas, TX (17): Stephen Aronoff (I); Satanya Brooks (C); Gloria Martinez (C); Angela Mendez (C); Theresa Dunnam (C). Iowa Diabetes & Endocrinology Research Center, Des Moines, IA (13): Anuj Bhargava (I); Kathy Fitzgerald (I); Diana Wright (I); Teck Khoo (I); Pierre Theuma (I); Tara Herrold (C); Debra Thomsen (C). International Diabetes Center – HealthPartners Institute, Minneapolis, MN (13): Richard Bergenstal (I); Marcia Madden (I); Kathleen McCann (C); Arlene Monk (C), Char Ashanti (C). Rocky Mountain Diabetes and Osteoporosis Center, Idaho Falls, ID (12): David Liljenquist (I); Heather Judge (C); Jean Halford (C). Henry Ford Medical Center Division of Endocrinology, Detroit, MI (10): Davida Kruger (I); Shiri Levy (I); Arti Bhan (I); Terra Cushman (C); Heather Remtema (C). Washington University in St Louis, St Louis, MO (10): Janet McGill (I); Olivia Jordan (C); Carol Recklein (C). Portland Diabetes & Endocrinology Center, Portland, OR (8): Fawn Wolf (I); James Neifing (I); Jennifer Murdoch (I); Susan Staat (C); Tamara Mayfield (C). Diabetes & Glandular Disease Clinic, San Antonio, TX (7): Mark Kipnes (I); Stacie Haller (C); Terri Ryan (C). Atlanta Diabetes Associates, Atlanta, GA (5): Bruce Bode (I); Jennifer Boyd (I); Joseph Johnson (I); Nitin Rastogi (C); Katherine Lindmark (C). Oregon Health & Science University, Portland, OR (5): Andrew Ahmann (I); Bethany Klopfenstein (I); Farahnaz Joarder (I); Kathy Hanavan (I); Jessica Castle (I); Diana Aby-Daniel (I); Victoria Morimoto (I); Donald DeFrang (C); Bethany Wollam (C). Amarillo Medical Specialists LLP, Amarillo, TX (5): William Biggs (I); Lorena Sandoval (C); Robin Eifert (C); Becky Cota (C). Accent Clinical Trials, Las Vegas, NV (4): Quang Nguyen (I); Alejandra Martinez (C); Cathy Duran (C). Columbus Regional Research Institute, Endocrine Consultants PC, Columbus, GA (4): Steven Leichter (I); Emily Evans (C). East Coast Institute for Research LLC, Jacksonville, FL (4): Scott Segel (I); David Sutton (I); Miguel Roura (I); Rebecca Rosenwasser (C); Jennifer McElveen (C); Emily Knisely (C); Anne Johnson (C). Mountain Diabetes and Endocrine Center, Asheville, NC (4): Wendy Lane (I); Stephen Weinrib (I); Kaitlin Ramsey (C); Lynley Farmer (C); Mindy Buford (C). Diabetes & Endocrine Associates PC, Omaha, NE (3): Sarah Konigsberg (I); Jennifer Rahman (C). Physicians Research Associates LLC, Lawrenceville, GA (2): A. Ola Odugbesan (I); Karla Wardell (C); Carolyn Paulus (C). Consano Clinical Research, San Antonio, TX (2): Michelle Welch (I); Daniel Katselnik (I); Greg Danet (C). Marin Endocrine Care & Research Inc, Greenbrae, CA (2): Linda Gaudiani (I); Natalie Woods (C); Jesse Cardozo (C). Coastal Metabolic Research Centre, Ventura, CA (1): Ronald Chochinov (I); Graciela Hernandez (I); Gabriel Garcia (C); Jessica Rios-Santiago (C). Laureate Medical Group at Northside, LLC, Atlanta, GA (1): Kate Wheeler (I); Jennifer Kane (C); Terri Eubanks (C). Granger Medical Clinic, West Valley, UT (1): Michelle Litchman (I); Kim Martin (C); Heather Holtman (C); Carrie Briscoe (C). Advanced Research Institute, Ogden, UT (1): Jack Wahlen (I); Jon Winkfield (I); Hilary Wahlen (C); Emily Hepworth (C); David Winkfield (C); Sue Owens (C).

Coordinating Center: Jaeb Center for Health Research, Tampa, FL: Katrina Ruedy; Roy W. Beck; Craig Kollman; Tonya Riddlesworth; Thomas Mouse. Sponsor: Dexcom Inc, San Diego, CA: David Price; Eileen Casal; Claudia Graham. Quality-of-Life Collaborator: University of California, San Diego, La Jolla, CA: William Polonsky.

Funding/Support:Dexcom Inc provided funding for the trial to each investigator’s institution.

Role of the Funder/Sponsor: Dr Price, a Dexcom employee, participated in the steering committee, which was responsible for designing the study, writing the protocol, reviewing and approving the manuscript, and interpreting the data. Dexcom did not participate in collection, management, analysis, and interpretation of the data; or, except for the role of Dr Price as a coauthor, in the preparation or revision of the manuscript or in the decision to submit the manuscript for publication. Dexcom staff participated in onsite audit visits. All other monitoring was performed by staff of the Jaeb Center for Health Research.

Meeting Presentation: The trial results were presented at the American Diabetes Association meeting, June 12, 2016, New Orleans, Louisiana.

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