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Effect of initiating use of an insulin pump in adults with


type 1 diabetes using multiple daily insulin injections and
continuous glucose monitoring (DIAMOND): a multicentre,
randomised controlled trial
Roy W Beck, Tonya D Riddlesworth, Katrina J Ruedy, Craig Kollman, Andrew J Ahmann, Richard M Bergenstal, Anuj Bhargava, Bruce W Bode,
Stacie Haller, Davida F Kruger, Janet B McGill, William Polonsky, David Price, Elena Toschi, for the DIAMOND Study Group*

Summary
Background The benefit of initiation of insulin pump therapy (continuous subcutaneous insulin infusion; CSII) in Lancet Diabetes Endocrinol 2017
patients with type 1 diabetes using continuous glucose monitoring (CGM) has not been studied. We aimed to assess Published Online
glycaemic outcomes when switching from multiple daily injections (MDI) to CSII in adults with type 1 diabetes July 12, 2017
http://dx.doi.org/10.1016/
using CGM.
S2213-8587(17)30217-6
See Online/Comment
Methods In this multicentre, randomised controlled trial, 75 adults with type 1 diabetes in the CGM group of the http://dx.doi.org/10.1016/
DIAMOND trial were randomly assigned via the study website using a computer-generated sequence to continue S2213-8587(17)30235-8
MDI or switch to CSII, with continuation of CGM, for 28 weeks. The primary outcome was CGM-measured time in *Study group listed in appendix
the glucose concentration range of 70180 mg/dL (39100 mmol/L). This study is registered with ClinicalTrials.gov, Jaeb Center for Health
number NCT02282397. Research, Tampa, FL, USA
(R W Beck MD,
T D Riddlesworth PhD,
Findings Between April 14, 2015, and May 5, 2016, 37 participants were randomly assigned to the CGM plus CSII K J Ruedy MSPH, C Kollman PhD);
group and 38 participants were randomly assigned to the CGM plus MDI group. The study was completed by Oregon Health and Science
36 (97%) of 37 participants in the CGM plus CSII group and 35 (92%) of 38 participants in the CGM plus MDI University, Portland, OR, USA
group. Mean CGM use was 67 days per week (SD 08) in the CGM plus CSII group and 69 days per week (03) in (Prof A J Ahmann MD); Park
Nicollet Institute International
the CGM plus MDI group (p=086). No participants in the CGM plus CSII group who completed the trial Diabetes Center, Minneapolis,
discontinued CSII. Over the follow-up period, mean time in the glucose concentration range of 70180 mg/dL MN, USA (R M Bergenstal MD);
(39100 mmol/L) was 791 min per day (SD 157) in the CGM plus CSII group and 741 min per day (225) in the Iowa Diabetes and
CGM plus MDI group (adjusted mean treatment group difference: 83 min, 95% CI 17149; p=001). Participants in Endocrinology Research Center,
Des Moines, IA, USA
the CGM plus CSII group had a greater reduction in CGM-measured mean glucose (p=0005) and hyperglycaemia (A Bhargava MD); Atlanta
(on four metrics: p=0007 for >180 mg/dL [>100 mmol/L], p=002 for >250 mg/dL [>139 mmol/L], p=004 for Diabetes Associates, Atlanta,
>300 mg/dL [>166 mmol/L], and p=002 for the area under the curve for 180 mg/dL [100 mmol/L]), but also an GA, USA (B W Bode MD);
increase in CGM-measured hypoglycaemia (p=00001 for <70 mg/dL [<39 mmol/L], p=00002 for <60 mg/dL Diabetes and Glandular Disease
Clinic, San Antonio, TX, USA
[<33 mmol/L], p=00009 for <50 mg/dL [<28 mmol/L], p=00002 for the area over the curve for 70 mg/dL (S Haller CDE); Henry Ford
[39 mmol/L]). Mean HbA1c change from baseline to 28 weeks was 03% (SD 09; 33 mmol/mol [SD 98]) in the Medical Center Division of
CGM plus CSII group and 01% (04; 11 mmol/mol [44]) in the CGM plus MDI group (p=032). Severe Endocrinology, Detroit, MI,
USA (D F Kruger MSN); Division
hypoglycaemia occurred in one participant in the CGM plus MDI group, and diabetic ketoacidosis and severe
of Endocrinology, Metabolism
hyperglycaemia occurred in one participant each in the CGM plus CSII group. and Lipid Research Washington
University in St Louis, St Louis,
Interpretation Our findings show that glycaemic control measured by time in the glucose range of 70180 mg/dL MO, USA (Prof J B McGill MD);
Behavioral Diabetes Institute,
(39100 mmol/L) is improved by initiation of CSII in adults with type 1 diabetes. However, biochemical
San Diego, CA, USA
hypoglycaemia also was increased in the study, which will be important to consider when incorporating these results (W Polonsky PhD); Dexcom,
into clinical practice. San Diego, CA, USA
(D Price MD); and Joslin
Diabetes Center, Boston, MA,
Funding Dexcom.
USA (E Toschi MD)
Correspondence to:
Introduction users of insulin pumps to make better use of the features of Dr Roy W Beck, Jaeb Center for
Use of continuous glucose monitoring (CGM) has been their pumps, as evidenced by an increase in the number of Health Research, 15310 Amberly
shown to consistently reduce HbA1c with either no increase rapid-acting insulin boluses, more frequent use of the Drive, Tampa, FL 33647, USA
t1dstats5@jaeb.org
or a decrease in hypoglycaemia. Most outcome studies bolus calculator, and more frequent use of temporary basal
evaluating CGM have been done primarily with participants rates or suspension of basal rates.
using an insulin pump for insulin management.13 Addition The DIAMOND4 and GOLD5 studies were the first
of CGM for people managing their diabetes with insulin randomised trials of CGM focused entirely on adults with
pumps has clear potential benefits, as shown in the type 1 diabetes using multiple daily insulin injections
SWITCH crossover trial,3 which showed that CGM enabled (MDI). In both studies, which used the G4 sensor (Dexcom,

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Research in context
Evidence before this study no corresponding improvement in HbA1c for participants in the
We searched PubMed for reports of clinical trials in any CGM plus CSII group, and the CGM plus CSII group had greater
language published up to March 31, 2017, using the search mean time spent in the hypoglycaemic range (<70 mg/dL
terms (continuous subcutaneous insulin infusion OR CSII) [<39 mmol/L], <60 mg/dL [<33 mmol/L], <50 mg/dL
AND (continuous glucose monitoring OR CGM) AND [<28 mmol/L] and area over the curve for 70 mg/dL
(type 1 diabetes) with clinical trial as a filter. Although [39 mmol/L]); the frequency of severe hypoglycaemia (defined
several clinical trials have evaluated the benefit of initiating as an event that required assistance from another person to
CGM in individuals with type 1 diabetes using an insulin pump, administer carbohydrate, glucagon, or other resuscitative
we did not identify any previously published clinical trials actions) was not higher than in the CGM plus MDI group. We
assessing the effect of changing from multiple daily injections also showed that in a protocol approximating usual clinical
(MDI) to continuous subcutaneous insulin infusion (CSII) in practice, CGM use is high and sustainable irrespective of insulin
continuous glucose monitoring (CGM) users. delivery method, and that its glycaemic benefits are
maintained.
Added value of this study
To our knowledge, this is the first randomised trial of Implications of all the available evidence
experienced CGM users who changed their insulin delivery CSII should be considered in adults with type 1 diabetes using
method from MDI to CSII. Compared with a control group that MDI for insulin delivery and CGM for glucose monitoring for
continued on MDI, our results show an association between whom there is a desire to improve glycaemic control. Future
CSII use and improvements in CGM-measured time in range, studies should assess whether glycaemic control can be
mean glucose, and time in hyperglycaemia. However, there was improved without an increase in hypoglycaemia.

San Diego, CA, USA), CGM use significantly reduced Of 102 participants in the CGM group who completed
HbA1c, CGM-measured hypoglycaemia, and CGM- the original trial, 75 continued in this follow-on trial. Of
measured hyperglycaemia compared with a control group 27 participants who were not included, ten were using
who used self-monitoring of blood glucose. In the 100 units or more of insulin per day; two had insufficient
DIAMOND study,4 there was a high degree of CGM CGM use in the previous 28 days; 14 were eligible, but
perseverance, with 93% of participants using CGM for chose not to continue; and one was withdrawn by the
See Online for appendix 6 days or more per week during the last month of the study site (appendix). One participant was enrolled in
24-week study despite no scheduled visits or phone contact this follow-on trial despite not meeting the total daily
with the clinics study staff between 12 weeks and 24 weeks. insulin eligibility restriction; the participant was using
Insulin-pump therapy (or continuous subcutaneous 101 units of insulin per day.
insulin infusion; CSII) has been shown to reduce HbA1c Ethics Committee approval was obtained for all
concentrations and to reduce severe hypoglycaemic participating clinical sites. The protocol and Health
events in high-risk individuals.6 Whether or not there is Insurance Portability and Accountability Act-compliant
glycaemic benefit of CSII in adults with type 1 diabetes informed consent forms were approved by institutional
already using CGM has not been studied. Accordingly, review boards (appendix). Written informed consent was
the DIAMOND study was designed with a 28-week obtained from all participants.
follow-on randomised trial in which participants in the
CGM group were randomly assigned to continue MDI or Randomisation and masking
initiate CSII. All 75 participants continued using the G4 Platinum
CGM System with an enhanced algorithm, software 505
Methods (Dexcom, San Diego, CA, USA). On the study website,
Study design and participants after programmatic verification of eligibility from data
This multicentre, randomised controlled trial was done entered, each participant was randomly assigned (1:1) to
at 20 endocrinology practices in the USA (15 community- either CSII or continuation of MDI using a computer-
based and five academic centres). generated sequence maintained in an encrypted database
Participants in the CGM group in the initial DIAMOND and a random permuted block design (block sizes of two
randomised trial were eligible for this trial if they used and four) stratified by HbA1c (70% [53 mmol/mol],
CGM on 21 of the last 28 days of the initial trial and used 71% [54 mmol/mol] to 74% [57 mmol/mol], and 75%
MDI of less than 100 units per day of insulin. Eligibility [58 mmol/mol]). We used HbA1c as the stratification
criteria for the initial trial included age 25 years or older, variable as a surrogate for time in range because it was
diagnosis of type 1 diabetes being treated with MDI for at more readily available.
least 1 year, and central-laboratory measured HbA1c of The CGM plus CSII group was provided with an
75100% (5886 mmol/mol). The full eligibility and Insulet OmniPod (Insulet, Billerica, MA, USA) insulin
exclusion criteria have been published previously.4 pump and pods. Pump training was done according to

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the study sites routine practice and customised to each assistance from another person to administer
participants need, including a training visit after 2 weeks carbohydrate, glucagon, or other resuscitative actions),
to troubleshoot any use or device issues and to modify diabetic ketoacidosis, and serious adverse events,
pump settings. Training included use of an OmniPod irrespective of causality. Psychosocial and economic
training checklist to ensure pertinent topics were outcomes will be reported separately.
reviewed and discussed with participants. Pump basal By the nature of the intervention, participants, clinic
rate settings and bolus calculator settings were staff, and data analysts were not masked to treatment
determined by the investigators or clinicians within the group assignment. Individuals in the laboratory who
clinical practices and were not standardised per protocol. measured HbA1c concentrations were masked to group
Participants in both groups were provided with sensors, assigment.
blood glucose meters, and glucose test strips (Abbott
Freestyle; Alameda, CA, USA), built into the Omnipod Statistical analysis
Personal Diabetes Manager (Insulet) for the CGM plus The sample size was determined by the number of
CSII group; and Bayer Contour Next USB (Ascenia participants completing the original trial. The trial was
Diabetes Care, Parsippany, NJ, USA) for the CGM plus projected to have at least 80% power with a type 1 error
MDI group. Both groups were given instructions on rate of 5% (two-sided) to show a treatment group
carbohydrate counting and had reviews of diabetes difference in the primary outcome of time in glucose
management guidelines using CGM. Instructions for concentration target range if the true population
CGM use were the same as in the original trial and difference is at least 75% (108 min per day), assuming
included the importance of not stacking insulin, of an SD of 80% (115 min per day) for time in range and a
reflecting on which diabetes management decisions minimum of 50 participants completing the trial.
worked well, and of noting which decisions did not work.4 The primary analysis was a treatment group
Follow-up visits for both treatment groups occurred comparison using a linear regression model with the
after 6 weeks, 14 weeks, and 28 weeks. Participants in the change in time in glucose concentration target range
CGM plus CSII group had an additional visit after (using all data after the first 4 weeks) as the outcome
2 weeks to troubleshoot pump issues. Data from CGM, adjusting for baseline time in range, baseline HbA1c
blood glucose metres, and pumps were uploaded from concentration, and clinical site as a random effect. We
the devices at each visit and reviewed by the clinical team. assessed confounding by repeating the analysis including
Insulin adjustments in both groups were individualised baseline variables imbalanced between treatment groups
on the basis of the glucose data. HbA1c concentration was as covariates. We did exploratory analyses to assess the
measured at baseline (the end of the initial trial), interaction between the treatment effect on the change in
14 weeks, and 28 weeks at the Northwest Lipid Research time in range and baseline factors by including
Laboratories, University of Washington (Seattle, WA, interaction terms in linear regression models. We
USA) using the Diabetes Control and Complications assessed the interaction between the treatment effect on
Trial standardised analyser (TOSOH Biosciences, South the change in time in range and the time of day by
San Francisco, CA, USA). including both the day and night time in range in a
repeated measures model adjusting for the baseline time
Outcomes in range, baseline HbA1c concentration, and clinical site
The primary outcome was change in CGM-measured as a random effect. Two per-protocol analyses were done:
time in the glucose range of 70180 mg/dL prespecified analysis including participants meeting
(39100 mmol/L) from baseline using all available these criteria (completion of the 28-week examination
CGM data after the first 4 weeks of the trial. Prespecified within 30 days, CGM usage averaging a minimum of
secondary outcomes included change in HbA1c from 6 days per week, insulin pump being used at the time of
baseline; percentage of participants with HbA1c less than the 28-week visit [CGM plus CSII group], and insulin
70% (<53 mmol/mol) at 14 weeks and 28 weeks; CGM- pump not used at any time during the trial [CGM plus
measured mean glucose concentration, time in MDI group]); and post-hoc analysis excluding participants
hyperglycaemia (>180 mg/dL [100 mmol/L], >250 mg/dL who started an oral glucose-lowering agent after
[>139 mmol/L], >300 mg/dL [>166 mmol/L]), time in randomisation, who initiated CSII when assigned to the
hypoglycaemia (<70 mg/dL [<39 mmol/L], <60 mg/dL CGM plus MDI group, or had less than 72 h of follow-up
[<33 mmol/L], <50 mg/dL [<28 mmol/L]), and CGM data.
coefficient of variation; self-reported hypoglycaemia For the additional CGM outcomes, we made treatment
unawareness;7 change in total daily insulin dose; and group comparisons using linear regression models based
change in bodyweight. Insulin data were obtained for the on ranks using van der Waerden scores if the metric was
CGM plus CSII group by downloading data from the skewed, adjusting for the corresponding baseline value,
pump and by self-report for the CGM plus MDI group. baseline HbA1c concentration, and clinical site as a
Safety outcomes were frequencies of severe random effect. The treatment group comparison of
hypoglycaemia (defined as an event that required change in HbA1c was made using a linear regression

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model adjusting for baseline HbA1c concentration and Role of the funding source
clinical site as a random effect, and binary HbA1c The study was designed by the authors in collaboration
outcomes were compared using logistic regression with the funder. The funder reviewed the report and
models adjusting for baseline HbA1c concentration and provided comments for the authors to consider, but had
clinical site as a random effect. We calculated the adjusted no approval rights for the report. The corresponding
differences for the binary outcomes as in Kleinman and author had full access to all the data in the study and had
Norton8 and CIs were calculated with a bias-corrected final responsibility for the decision to submit for
bootstrap. We compared the frequency of blood glucose publication.
monitoring between treatment groups using a linear
regression model adjusting for the baseline value and Results
clinical site as a random effect. Between April 14, 2015, and May 5, 2016, 37 participants
Analyses were done in SAS (version 9.4). All p values were randomly assigned to the CGM plus CSII group
are two-sided. CIs are 95% for the primary outcome and and 38 participants were randomly assigned to the CGM
99% for all other outcomes. plus MDI group. Mean age of all participants at the time
This study is registered with ClinicalTrials.gov, number of randomisation was 46 years (SD 14; range 2672),
NCT02282397. 35 (47%) of 75 participants were women, and 65 (87%) of
75 participants were non-Hispanic white people. Mean
CGM plus CSII CGM plus MDI
(n=37) (n=38)
CGM plus CSII CGM plus MDI
Age, years (n=37) (n=38)
Mean (SD) 46 (15) 45 (12) (Continued from previous column)
Range 2672 2668 Blood glucose meter testing in 38 (18) 37 (14)
Diabetes duration, years previous 7 days, tests per day*
Median (IQR) 22 (1229) 15 (629) 1 severe hypoglycaemia event 0 2 (5%)
during initial trial
Range 357 349
1 diabetic ketoacidosis event during 0 0
Women 16 (43%) 19 (50%)
initial trial
Race or ethnicity*
Use of non-insulin glucose-lowering 2 (5%) 1 (3%)
White, non-Hispanic 31 (86%) 34 (89%) medication
Black, non-Hispanic 2 (6%) 3 (8%) Total daily insulin units per kg bodyweight
Hispanic or Latino 2 (6%) 0 Median (IQR) 072 067
More than one race 1 (3%) 1 (3%) (050089) (055077)
Annual household income, US$ Range 035117 031100
<50000 11 (30%) 12 (32%) Short-acting or rapid-acting insulin injections per day
50000 to <100000 12 (32%) 8 (21%) 3 20 (54%) 20 (54%)
100000 5 (14%) 6 (16%) 4 17 (46%) 17 (46%)
Did not specify unknown 9 (24%) 12 (32%) Long-acting or intermediate-acting insulin injections per day
Education* 1 26 (70%) 27 (71%)
Less than bachelors degree 15 (43%) 16 (44%) 2 11 (30%) 11 (29%)
Bachelors degree 16 (46%) 16 (44%)
Data are n (%) or mean (SD), unless otherwise specified. CGM=continuous glucose
Higher than bachelors degree 4 (11%) 4 (11%) monitoring. CSII=continuous subcutaneous insulin infusion. MDI=multiple daily
BMI* 29 (3) 27 (5) injections. *Missing race for one participant in CGM plus CSII group; missing
education for two in each group; missing BMI for two in CGM plus CSII group and
Time in glucose concentration range 70180 mg/dL (39100 mmol/L)
one in CGM plus MDI group; missing blood glucose meter testing for two in CGM
Min per day 708 (162) 762 (224) plus CSII group. Due to missing central laboratory HbA1c data, an imputed HbA1c
Proportion of day 49% (11) 53% (16) value (based on the local laboratory value) was used for one participant in the
CGM plus CSII group. One participant in each group used metformin; one
Mean central laboratory HbA1c concentration
participant in the CGM plus CSII group used a glucagon-like peptide-1 receptor
% 76% (07%) 76% (09%) agonist. One participant in the CGM plus MDI group was only using one injection
mmol/mol 60 (77) 60 (98) of short-acting insulin per day because they were on a low-carb diet;
19 participants had rapid-acting insulin lispro and 18 participants had aspart in
<70% (<53 mmol/mol) 6 (16%) 9 (24%)
the CGM plus CSII group; 23 participants had lispro and 15 had aspart in the CGM
70% to <75% 8 (22%) 9 (24%) plus MDI group; and one participant in each group used afrezza; 29 participants
(53 to <58 mmol/mol) had long-acting insulin glargine (20 once per day and nine twice per day), four
75% (58 mmol/mol) 23 (62%) 20 (53%) had insulin detemir (two once per day and two twice per day), and none had
insulin degludec in the CGM plus CSII group; 27 participants had insulin glargine
CGM use in previous 28 days, days 69 (02) 69 (04)
(21 once per day and six twice per day), seven had insulin detemir (four once per
per week
day and three twice per day), and one had insulin degludec in the CGM plus MDI
6 days per week 37 (100%) 37 (97%) group; two participants in each group used isophane (NPH) insulin.
(Table 1 continues in next column)
Table 1: Baseline characteristics

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CGM-measured time in glucose range 70180 mg/dL


(39100 mmol/L) at baseline was 736 min per day 102 patients were in the CGM group
and completed the initial trial
(SD 196; equivalent to 51% of the day) and mean baseline
HbA1c was 76% (SD 08; 60 mmol/mol [SD 8]). In the
CGM plus MDI group, 27 (71%) of 38 participants used 27 not included
10 were using 100 units or more of insulin per day
one injection of long-acting insulin per day and 11 (29%) 2 had insufficient CGM usage in the previous 28 days
of 38 used two injections per day (table 1). The 14 were eligible, but did not continue
1 was withdrawn by the study site
75 participants in this trial were similar to the 105 original
participants in the initial DIAMOND randomised trial in
mean age (46 years [SD 14] vs 46 years [14]), female sex 75 enrolled
(47% [n=35] vs 45% [n=47]), white race or ethnic origin
(88% [n=66] vs 86% [n=90]), and education level (college
degree or higher: 56% [n=74] vs 53% [n=53]).
37 randomly assigned to CGM plus CSII 38 randomly assigned to CGM plus MDI
The 28-week primary study outcome visit was
completed by 36 (97%) of 37 participants in the CGM
plus CSII group and 35 (92%) of 38 participants in the 36 completed week 2 visit
CGM plus MDI group (figure). All 36 participants in the 1 missed visit
CGM plus CSII group who completed the trial were
using CSII at the end of the trial. Two participants in the 1 lost to follow-up 2 lost to follow-up
CGM plus MDI group initiated CSII before the primary
outcome was assessed (one after 6 weeks and one after
26 weeks) and two in the CGM plus MDI group started a 34 completed week 6 visit 36 completed week 6 visit
2 missed visit
non-insulin glucose-lowering medication during follow-
up. Mean CGM use (pooled CGM data downloaded at the
6-week, 14-week, and 28-week visits) was 67 days 35 completed week 14 visit 36 completed week 14 visit
1 missed visit
per week (SD 08; n=36) in the CGM plus CSII group,
and 69 days per week (03; n=35) in the CGM plus MDI
group (p=086; table 2). During weeks 2528, 33 (94%) of 1 lost to follow-up
35 participants in the CGM plus CSII group and 34 (97%)
of 35 participants in the CGM plus MDI group used
36 completed week 28 visit 35 completed week 28 visit
CGM for 6 days per week or more (table 2). Based on 1 lost to follow-up* 3 lost to follow-up
meter downloads, mean blood glucose self-monitoring
was 38 tests per day (SD 18) in the CGM plus CSII Figure: Trial profile
group and 37 tests per day (14) in the CGM plus MDI CGM=continuous glucose monitoring. CSII=continuous subcutaneous insulin infusion. MDI=multiple daily
group at baseline and 30 (27) in the CGM plus CSII injections. *97% of participants completed the study. 92% of participants completed the study.
group and 32 (14) in the CGM plus MDI group at
28 weeks (p=092). The beneficial effect of CSII on time in range was
During follow-up, mean time in range 70180 mg/dL reflected in a greater reduction in CGM-measured mean
(39100 mmol/L) was 791 min per day (SD 157) in the glucose (p=0005) and in all four hyperglycaemia metrics
CGM plus CSII group and 741 min per day (225) in the (p=0040007; table 3). However, there also was an
CGM plus MDI group, representing a mean change from increase in CGM-measured hypoglycaemia in the CGM
baseline of 78 min per day (185) in the CGM plus CSII plus CSII group compared with the CGM plus MDI
group and 17 min per day (105) in the CGM plus MDI group (p<0001 on all four hypoglycaemia metrics;
group (adjusted mean treatment group difference table 3). In the CGM plus CSII group, there was a net
favouring the CGM plus CSII group: 83 min [95% CI decrease in hypoglycaemia (<70 mg/dL [<39 mmol/L])
17149], p=001; table 3). Adjusting for the baseline at the end of this trial compared with the initial baseline
imbalance in diabetes duration did not alter the result. blinded CGM data, from a median of 73 min per day to
Results were similar when analysed separately at 14 weeks 47 min per day at 28 weeks (52 weeks from randomisation
and 28 weeks and in two per-protocol analyses (appendix). in the original trial). The treatment group difference in
The treatment group difference in time in range hypoglycaemia was largest in participants with less
70180 mg/dL (39100 mmol/L) was predominately baseline hypoglycaemia (pinteraction=004) and higher
seen during the daytime (0600 h to 2200 h; appendix), baseline HbA1c (pinteraction=00001; appendix). Compared
with little difference between groups overnight (2200 h to with the blinded baseline CGM data from the initial
0600 h, p<00001 for day vs night; table 4). In subgroup study (before unblinded CGM was started), mean
analyses, the beneficial effect of CSII on the time in range improvement in time in glucose concentration range
outcome was greatest in participants with higher baseline 70180 mg/dL (39100 mmol/L) at 28 weeks (52 weeks
HbA1c concentration (pinteraction=0006; table 4). from randomisation in the initial trial) was 136 min

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Baseline* Week 6 Week 14 Week 28 Overall Overall p value


CGM plus CGM plus CGM plus CGM plus CGM plus CGM plus CGM plus CGM plus CGM plus CGM plus
CSII (n=37) MDI (n=38) CSII (n=34) MD (n=36) CSII (n=35) MDI (n=35) CSII (n=35) MDI (n=35) CSII (n=36) MDI (n=35)
Mean days per week 69 (02) 69 (04) 66 (13) 69 (04) 69 (04) 69 (03) 67 (13) 69 (04) 67 (08) 69 (03) 086
Did not use 0 0 1 (3%) 0 0 0 1 (3%) 0 0 0
<1 day 0 0 0 0 0 0 0 0 0 0
1 to <2 days 0 0 0 0 0 0 0 0 0 0
2 to <3 days 0 0 0 0 0 0 0 0 0 0
3 to <4 days 0 0 1 (3%) 0 0 0 0 0 1 (3%) 0
4 to <5 days 0 0 0 0 0 0 1 (3%) 0 2 (6%) 0
5 to <6 days 0 1 (3%) 1 (3%) 1 (3%) 2 (6%) 1 (3%) 0 1 (3%) 0 1 (3%)
6 to <7 days 5 (14%) 4 (11%) 2 (6%) 4 (11%) 1 (3%) 2 (6%) 4 (11%) 6 (17%) 6 (17%) 12 (34%)
7 days 32 (86%) 33 (87%) 29 (85%) 31 (86%) 32 (91%) 32 (91%) 29 (83%) 28 (80%) 27 (75%) 22 (63%)
6 days 37 (100%) 37 (97%) 31 (91%) 35 (97%) 33 (94%) 34 (97%) 33 (94%) 34 (97%) 33 (92%) 34 (97%)

Data are mean (SD) or n (%). CGM=continuous glucose monitoring. CSII=continuous subcutaneous insulin infusion. MDI=multiple daily injections. *Baseline refers to time of randomisation for this trial.
Missing CGM data downloads for one participant in the CGM plus MDI group at 14 weeks (broken receiver) and one participant in the CGM plus CSII group at 28 weeks (device malfunction). Mean of weeks 6,
14, and 28. Treatment group comparison based on a linear regression model adjusted for baseline CGM use and clinical site as a random effect; because of a skewed distribution, this model is based on ranks
using van der Waerden scores.

Table 2: Days of CGM use in the 28 days before baseline visit

Baseline* Pooled follow-up* Adjusted mean p value


difference (95% or
99% CI)
CGM plus CSII (n=37) CGM plus MDI (n=38) CGM plus CSII (n=36) CGM plus MDI (n=36)
Length of data, h 628 (576 to 648) 637 (618 to 655) 1702 (1515 to 1843) 1713 (16341776)
Time in range 70180 mg/dL (39100 mmol/L)
Min per day 708 (162) 762 (224) 791 (157) 741 (225) 83 (17 to 149) 001
Proportion of day 49% (11) 53% (16) 55% (11) 51% (16) 6% (1 to 10) 001
Mean glucose concentration 0005
mg/dL 185 (24) 178 (31) 172 (22) 182 (33) 14 (26 to 1)
mmol/L 103 (13) 99 (17) 95 (12) 101 (18) 08 (14 to 01)
Hyperglycaemia
>180 mg/dL (>100 mmol/L), min per day 661 (557 to 836) 601 (467 to 793) 614 (455 to 694) 660 (457 to 823) 0007
>250 mg/dL (>139 mmol/L), min per day 260 (176 to 371) 220 (105 to 309) 175 (120 to 274) 221 (115 to 299) 002
>300 mg/dL (>166 mmol/L), min per day 110 (56 to 165) 61 (25 to 104) 61 (30 to 102) 69 (32 to 109) 004
180 mg/dL (100 mmol/L), area under curve 32 (22 to 42) 25 (14 to 36) 22 (16 to 32) 27 (15 to 36) 002
Hypoglycaemia
<70 mg/dL (<39 mmol/L), min per day 34 (25 to 58) 41 (23 to 75) 49 (34 to 79) 32 (15 to 51) 00001
<60 mg/dL (<33 mmol/L), min per day 14 (9 to 27) 16 (11 to 30) 23 (15 to 41) 12 (6 to 25) 00002
<50 mg/dL (<28 mmol/L), min per day 4 (2 to 10) 4 (2, 12) 9 (4 to 17) 4 (2 to 9) 00009
70 mg/dL (39 mmol/L), area above curve 025 (017 to 045) 028 (018 to 050) 039 (025 to 071) 021 (010 to 043) 00002
Coefficient of variation 39% (37% to 42%) 37% (35% to 42%) 39% (37% to 43%) 37% (33% to 39%) 025

Data are median (IQR), mean (SD), or n (%), unless otherwise specified. 95% CI for the primary outcome of time in range and 99% CI for mean glucose. CGM=continuous glucose monitoring. CSII=continuous
subcutaneous insulin infusion. MDI=multiple daily injections. *Baseline refers to time of randomisation for this trial; pooled follow-up combines all data collected in follow-up excluding the first 4 weeks for all
participants randomly assigned, and excludes one participant in the CGM plus CSII group and two in the CGM plus MDI group with less than 72 h of follow-up data (none of whom completed the study). 95% CIs
for the primary outcome; 99% CIs for mean glucose and all other secondary outcomes. Treatment group comparisons based on linear regression models adjusted for the corresponding baseline value, baseline
HbA1c, and clinical site as a random effect; because of skewed distributions, the models for the hyperglycaemia, hypoglycaemia, and coefficient of variation are based on ranks using van der Waerden scores.

Table 3: CGM outcome metrics

per day (SD 248) in the CGM plus CSII group and 81 min plus MDI group (p=032; appendix). Among participants
per day (167) in the CGM plus MDI group. with baseline HbA1c of 75% (58 mmol/mol) or higher,
Mean HbA1c change from baseline to 28 weeks was 03% mean change in HbA1c from baseline to 28 weeks was
(SD 09; 33 mmol/mol [SD 98]) in the CGM plus CSII 01% (07; 11 mmol/mol [77]) in the CGM plus CSII
group and 01% (04; 11 mmol/mol [44]) in the CGM group (n=22) and 01% (05; 11 mmol/mol [55]) in the

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CGM plus CSII CGM plus MDI Adjusted mean pinteraction


difference (99% CI)
n Mean change from n Mean change from
baseline* (SD) baseline* (SD)
Time in range 70180 mg/dL (39100 mmol/L) 005
<53% 20 11% (11%) 19 1% (8%) 10% (3% to 18%)
53% 16 2% (12%) 17 4% (6%) 1% (7% to 10%)
Time in hypoglycaemia <70 mg/dL (<39 013
mmol/L)
<3% 25 8% (13%) 19 1% (8%) 9% (1% to 17%)
3% 11 1% (11%) 17 2% (6%) 1% (9% to 11%)
HbA1c 0006
<75% (<58 mmol/mol) 14 3% (12%) 17 3% (6%) 2% (10% to 7%)
75% (58 mmol/mol) 22 11% (10%) 19 1% (8%) 11% (3% to 18%)
Age, years 007
<50 20 9% (15%) 21 2% (9%) 9% (1% to 17%)
50 16 1% (9%) 15 1% (5%) 1% (8% to 10%)
Blood glucose meter testing 073
<3 times per day 11 3% (13%) 16 1% (9%) 3% (8% to 13%)
3 to <5 times per day 15 3% (13%) 13 3% (7%) 6% (3% to 16%)
5 times per day 8 10% (12%) 7 1% (4%) 6% (7% to 20%)
Education 062
<Bachelors degree 15 7% (15%) 15 2% (6%) 8% (2% to 17%)
Bachelors degree 19 5% (12%) 19 1% (9% 5% (3% to 14%)
Clarke hypoglycaemia unawareness score|| 090
Reduced awareness or uncertain (score 3) 13 4% (10%) 14 2% (5%) 5% (5% to 16%)
Aware (score 2) 23 6% (14%) 22 1% (9%) 6 (2% to 14%)
Hypoglycaemia fear score** 019
13 21 7% (15%) 18 3% (6%) 9% (0% to 17%)
14 15 4% (10%) 18 1% (8%) 2% (7% to 11%)
Time of CGM event <00001
Daytime (0600 h to 2200 h) 36 7% (14%) 36 2% (8%) 8% (2% to 15%)
Night time (2200 h to 0600 h) 36 2% (14%) 36 0% (9%) 1% (8% to 6%)
Centre effect NA NA NA NA NA 073

CGM=continuous glucose monitoring. CSII=continuous subcutaneous insulin infusion. MDI=multiple daily injections. *Using data from all those randomly assigned in this
trial collected after the first 4 weeks; excludes one participant in the CGM plus CSII group and two in the CGM plus MDI group with less than 72 h of follow-up data (none of
whom completed the study). Treatment group comparison for time of day made by including both the day and night time in range in a repeated measures model adjusted
for baseline time in range, baseline HbA1c, and clinical site as a random effect; all other treatment group comparisons made by including an interaction term in each linear
regression model adjusted for baseline time in range, baseline HbA1c, and clinical site as a random effect; the model for the subgroup based on time in range less than
70 mg/dL (<39 mmol/L) did not adjust for baseline time in range since time in hypoglycaemia less than 70 mg/dL (<39 mmol/L) and time in range 70180 mg/dL
(39100 mmol/L) are highly correlated in this result (r=068); continuous variable used for all subgroup factors other than education and site. Median values prespecified in
statistical analysis plan. Blood glucose meter testing data was missing for two participants in the CGM plus CSII group; education missing for two in the CGM plus CSII group
and two in the CGM plus MDI group; hypoglycaemia unawareness score missing for one participant in the CGM plus CSII group. ||The Clarke hypoglycaemia unawareness
questionnaire has eight items with a total score of 07; higher score denotes less awareness. **The hypoglycaemia fear questionnaire contains 18 items on issues related to
diabetes that the participant worries about; higher score denotes higher fear.

Table 4: Change in time in range 70180 mg/dL (39100 mmol/L) by baseline subgroups

CGM plus MDI group (n=18; p=049). The correlations overall mean change in HbA1c over the 52-week period
between change in HbA1c from baseline to 28 weeks with from randomisation in the original trial was 08% (08;
change from baseline to follow-up in time in hypoglycaemia 87 mmol/mol [87]) in the CGM plus CSII group and
70180 mg/dL (39100 mmol/L), time in range greater 09% (08; 99 mmol/mol [87]) in the CGM plus
180 mg/dL (>100 mmol/L), mean glucose concentration, MDI group.
and glucose concentration area under the curve for Data for insulin dosing, bodyweight, and
180 mg/dL (100 mmol/L) ranged from 063 to 066. The hypoglycaemia unawareness are reported in the

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appendix. Median change in total daily insulin dose was increase in hypoglycaemia with CSII, there was still a
018 units/kg per day in the CGM plus CSII group median net reduction of time with a concentration of less
compared with 001 units/kg per day in the CGM plus than 70 mg/dL (<39 mmol/L) compared with the
MDI group (p<00001). Mean number of boluses per blinded CGM data before the initiation of CGM in the
day at 28 weeks was 43 (SD 19) in the CGM plus CSII original DIAMOND trial (ie, 52 weeks before the
group and 36 (10) in the CGM plus MDI group, with completion of this trial). A previous meta-analysis6
the average number of boluses per day increasing by one showed a lower rate of severe hypoglycaemia in pump
or more in 17 (47%) of 36 participants in the CGM plus users with type 1 diabetes not using CGM than in
CSII group versus seven (21%) of 35 participants in the injection users.
CGM plus MDI group (p=027). Mean change in The benefit of CSII on glycaemic control has been shown
bodyweight was 00 kg (SD 36) in the CGM plus CSII in three meta-analyses of numerous studies comparing
group and 06 kg (34) in the CGM plus MDI group initiation of CSII therapy with insulin injection therapy for
(p=042). Hypoglycaemia unawareness did not differ adults with type 1 diabetes not using CGM for glucose
between groups at 28 weeks (p=076). monitoring.911 Similarly, studies have shown the benefit of
Four adverse events were reported in this study. A severe initiation of CGM compared with routine blood glucose
hypoglycaemic event occurred in one participant in the monitoring in insulin pump users13,12 or of initiation of
CGM plus MDI group (participant had an insulin bolus, both CSII and CGM together with sensor-augmented
but fell asleep before eating dinner; CGM device alarmed, pump therapy compared with use of injections plus blood
but did not wake the participant) and none in the CGM glucose monitoring.13 However, to our knowledge, this is
plus CSII group. There was one occurrence of diabetic the first clinical trial assessing initiation of CSII in existing
ketoacidosis and one hospital admission for CGM users.
For the T1D Exchange registry hyperglycaemia without diabetic ketoacidosis that In the US-based T1D Exchange registry, mean HbA1c
see https://t1dexchange.org/ occurred in the CGM plus CSII group, which were concentrations were reported to be lower in CSII users
pages/resources/clinic-registry/
presumed to be due to the insulin pump, although than in MDI users and, among CSII users, lower in those
attribution in the diabetic ketoacidosis case was using CGM versus those not using CGM.14 The primary
inconclusive because an insulin bolus also was missed. outcome in the present trial of time in the range of
One participant in the CGM plus CSII group reported a 70180 mg/dL (39100 mmol/L) can be compared with
skin reaction related to the insulin pump insertion site, previous CGM trials that reported this metric as a
which was deemed a non-serious adverse event. No other secondary outcome. The present trial of CGM users found
adverse events were reported. an improvement in time in range of 83 min per day with
CSII compared with MDI. In the initial DIAMOND trial of
Discussion MDI users, time in range improved by 77 min per day with
This multicentre randomised trial was done to establish CGM compared with blood glucose monitoring.4 In
whether switching from MDI to CSII in adults with previous trials of mainly CSII users, time in range
type 1 diabetes using CGM would improve glycaemic improved by about 100 min per day with CGM compared
control. For the primary outcome, CSII increased CGM- with blood glucose monitoring.1,3
measured time in the glucose concentration range of There were two hospital admissions among the CGM
70180 mg/dL (39100 mmol/L) by an average of plus CSII participantsone for diabetic ketoacidosis and
83 min per day (proportion of day 6%) more than MDI. the other for severe hyperglycaemia. Both events were
The beneficial effect was seen predominately during the probably related to impaired insulin delivery from the
daytime, with little difference between groups overnight. insulin pump. Impaired insulin delivery is a potential
Improved glycaemic control also was reflected in a complication of using CSII, and patient education is
reduction in mean glucose concentration and important to enable identification of impaired pump
hyperglycaemia, but not in HbA1c. The benefit of CSII on function early enough to restore insulin delivery with
glycaemic control was most evident in participants who injections and replacement of the infusion set or pod.
started this trial with worse glycaemic controlie, those Although the trial was not powered to assess HbA1c
who had the greatest room for improvement. differences between groups, we expected HbA1c results to
Although participants in the CGM plus CSII group had parallel those of glucose concentration time in range,
no severe hypoglycaemic events, the reduction in mean glucose concentration, and time in hyperglycaemia,
hyperglycaemia with CSII was associated with an because HbA1c concentrations mainly reflect the amount
increase in CGM-measured time in hypoglycaemia and severity of hyperglycaemia that is present. Although
(<70mg/dL [<39 mmol/L], <60 mg/dL [<33 mmol/L], discordance between HbA1c and mean glucose
<50 mg/dL [<28 mmol/L], and area over the curve for 70 concentration for an individual is not uncommon, mean
mg/dL [39 mmol/L]) compared with MDI. Presumably HbA1c for a group is typically correlated with mean
the increase in hypoglycaemia reflected the tighter amount of hyperglycaemia, as evidenced by the
control achieved with CSII, but could also reflect correlation of change in HbA1c with change in mean
inappropriate management of CSII therapy. Despite this glucose concentration in the study data. We have

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interrogated the data at length to try to understand the unrelated to the present work. DFK has received grants and consulting
absence of a relation in this study, but have been unable fees from Dexcom, and holds stock in Dexcom. JBM reports grant
funding from Novartis, Lexicon, and Pfizer; and personal fees from
to explain this discordance (data not shown). Boehringer Ingelheim, Lilly, Merck, Novo Nordisk, Janssen, and Calibra.
Strengths of our trial include a high retention rate, high WP reports personal fees from Dexcom. DP is an employee of Dexcom
adherence to treatment group assignment, high adherence and holds stock ownership. RWB, TDR, KJR, CK, BWB, SH, and ET
to CGM use in both groups, participation in the trial by declare no competing interests.
both community-based and academic sites, and a protocol Acknowledgments
approximating usual clinical practice in the visit schedule Dexcom provided funding for the trial to each of the investigators
institutions.
and by not requiring downloading of pump data or
prescribing a structured approach to adjusting basal rates References
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Contributors
11 Misso ML, Egberts KJ, Page M, OConnor D, Shaw J. Continuous
RWB contributed to data interpretation and the writing and editing of
subcutaneous insulin infusion (CSII) versus multiple insulin
the report. TDR did statistical analysis and contributed to the writing
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and editing of the report. KJR, CK, AJA, RMB, AB, BWB, SH, DFK, 2010; 1: CD005103.
JBM, WP, DP, and ET contributed to data interpretation and reviewed
12 Pickup JC, Freeman SC, Sutton AJ. Glycaemic control in type 1
and edited the report. diabetes during real time continuous glucose monitoring compared
Declaration of interests with self monitoring of blood glucose: meta-analysis of randomized
AJA reports personal fees from Dexcom, during the conduct of the controlled trials using individual patient data. BMJ 2011; 343: d3805
study; other fees from Medtronic and Dexcom, and personal fees from 13 Bergenstal RM, Tamborlane WV, Ahmann A, et al, for the STAR3
Trividia Health. RMB is an employee of HealthPartners Institute, Park Study Group. Effectiveness of sensor-augmented insulin-pump
therapy in type 1 diabetes. N Engl J Med 2010; 363: 31120.
Nicollet Health Services; sits on the advisory board for Abbott Diabetes
Care, AstraZeneca, Becton Dickinson, Boehringer Ingelheim, Calibra, 14 Foster NC, Miller KM, Tamborlane WV, Bergenstal RM, Beck RW,
for the T1D Exchange Clinic Network. Continuous glucose
Eli Lilly, Hygieia, Johnson & Johnson, Medtronic, Novo Nordisk, Roche,
monitoring in patients with type 1 diabetes using insulin injections.
Sanofi, Takeda, and ResMed; and holds stock in Merck. AB reports fees Diabetes Care 2016; 39: e8182.
from Dexcom and grants from the Jaeb Center for Health Research

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