CADTH RAPID RESPONSE REPORT: SUMMARY WITH … Insulin Pumps Final.pdfSAP Sensor augmented pump SD Standard deviation T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus TDD

Service Line: Rapid Response Service

Version: 1.0

Publication Date: October 26, 2018

Report Length: 44 Pages

CADTH RAPID RESPONSE REPORT: SUMMARY WITH CRITICAL APPRAISAL

Insulin Pumps for the Management of Type 2 Diabetes: A Review of Clinical Effectiveness, Cost-Effectiveness and Guidelines

SUMMARY WITH CRITICAL APPRAISAL Insulin Pumps for Type 2 Diabetes 2

Authors: Charlotte Wells, Lorna Adcock

Cite As: Insulin pumps for the management of Type 2 diabetes: a review of clinical effectiveness, cost-effectiveness and guidelines. Ottawa: CADTH; 2018

Oct. (CADTH rapid response report: summary with critical appraisal).

ISSN: 1922-8147 (online)

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Abbreviations

AUC Area under the curve

BMI Body-mass index

CGM Continuous glucose monitoring

CONGA Continuous overlapping net glycemic action

CSII Continuous subcutaneous insulin infusion

dL Decilitre

GRADE The Grading of Recommendations

Assessment

HbA1c Hemoglobin A1c (glycated hemoglobin)

MAGE Mean amplitude of glycemic excursions

MDI Multiple daily injections

Mmol Millimole

QALY Quality adjusted life years

RCT Randomized controlled trial

SAP Sensor augmented pump

SD Standard deviation

T1DM Type 1 diabetes mellitus

T2DM Type 2 diabetes mellitus

TDD Total daily insulin dose

Context and Policy Issues

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by a lack of insulin

production or an inability to adequately use produced insulin, and is the most common form

of diabetes (occurring in 90% of cases) in Canada.1 As of 2017, approximately three million

Canadians are living with T2DM, and it is estimated that each year, 200,000 Canadians are

newly diagnosed.1 Initial management strategies for T2DM can include lifestyle changes,

including weight loss and diet changes.1,2 However, for individuals with poorly controlled

diabetes despite following management strategies, multiple daily injections of insulin are

often required and may escalate to higher doses and more frequent injections. These

injections often become challenging for patients as they are invasive, disruptive, and

uncomfortable.2 Insulin pump therapy (e.g., continuous subcutaneous insulin infusion

[CSII]), in which a portable pump provides a slow basal rate of insulin per day through a

cannula, was originally designed to treat type 1 diabetes (T1DM), but has been increasingly

used in patients with uncontrolled T2DM. The number of T2DM patients using pump

therapy is estimated in the US as being less than 5% of patients.2 Despite the small

percentage of use in patients, a narrative review of insulin pump studies appears to show

satisfaction from patients and improvements in quality of life and psychological burden

when using continuous insulin infusions compared with multiple daily injections.2 However,

the review reported that randomized controlled trials have conflicting results regarding the

clinical effectiveness of this therapy in comparison to usual care.3

The purpose of this review is to evaluate the evidence regarding the clinical effectiveness of

pump therapy when compared to usual subcutaneous injection therapies, evaluate the cost-

effectiveness of pump therapy in the context of T2DM, and identify any evidence-based

guidelines to direct use of this technology. This may assist in decision making related to

access, reimbursement, and coverage decisions relating to insulin pumps for Canadians

with T2DM.


Research Questions

1. What is the clinical effectiveness of insulin pumps for the treatment of type 2 diabetes in children, adolescents, or adults?

2. What is the cost-effectiveness of insulin pumps for the treatment of type 2 diabetes in children, adolescents, or adults?

3. What are the evidence-based guidelines for the use of insulin pumps in the treatment of type 2 diabetes in children, adolescents, or adults?

Key Findings

Twelve studies were identified that addressed clinical-effectiveness, cost-effectiveness, or

evidence-based guidelines relating to pump therapies in patients with type 2 diabetes

mellitus (T2DM). These included one systematic review, nine randomized controlled trials

(RCTs), one economic evaluation, and one evidence-based guideline.

Overall, pump therapies appear to be effective in controlling HbA1c levels and were effective

in diabetes care, but when directly compared with multiple daily injections the results were

mixed. Data from one systematic review and nine RCTs showed that continuous

subcutaneous insulin infusion (CSII), sensor augmented pumps, and closed-loop therapy

appear to lower HbA1c levels and reduce the total daily insulin dose of patients with T2DM,

but differences were not always statistically significant.. Adverse events, including serious

hypoglycemic events appear to be rare, and similar in frequency to usual care (including

multiple daily injections). The overall quality of the clinical studies was low to moderate due

to a lack of blinding of interventions, poor descriptions of randomization methods, and small

sample sizes.

One cost-effectiveness study was identified in the literature, showing that CSII has a

greater than 70% probability of being cost-effective in a Dutch-based analysis. These

analyses were performed specifically for patients with poor glycemic control, and were

based on only one study for the effectiveness measurements.

One evidence based guideline recommended CSII for patients with T2DM with poor

glycemic control and who are likely to comply with therapy. This guideline was of low

quality, with poorly reported methods.

Methods

Literature Search Methods

A limited literature search was conducted on key resources including Ovid Medline,

PubMed, The Cochrane Library, University of York Centre for Reviews and Dissemination

(CRD) databases and a focused Internet search. No methodological filters were applied to

limit retrieval by publication type. Where possible, retrieval was limited to the human

population. The search was limited to English language documents published between

January 1, 2013 and September 26, 2018.

Selection Criteria and Methods

One reviewer screened citations and selected studies. In the first level of screening, titles

and abstracts were reviewed and potentially relevant articles were retrieved and assessed

for inclusion. The final selection of full-text articles was based on the inclusion criteria

presented in Table 1.


Table 1: Selection Criteria

Population Children (ages 5 to 11), adolescents (ages 12 to 18), or adults (age ≥18 years) with Type 2 Diabetes

Intervention Insulin administered via insulin pump

Comparator Q1-2: Insulin administered via manual subcutaneous injections Q3: Not applicable

Outcomes Q1: Clinical effectiveness and safety Q2: Cost-effectiveness Q3: Guidelines

Study Designs Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials, economic evaluations, evidence-based guidelines

Exclusion Criteria

Articles were excluded if they did not meet the selection criteria outlined in Table 1, they

were duplicate publications, or were published prior to 2015.

Critical Appraisal of Individual Studies

The included systematic review (SR) was critically appraised by one reviewer using

AMSTAR II,4 the R were critically appraised using the Downs and Black checklist,5 the

economic evaluation was assessed using the Drummond checklist,6 and the evidence-

based guideline was assessed with the AGREE II instrument.7 A review of the strengths

and limitations of each included study were described narratively.

Summary of Evidence

Quantity of Research Available

A total of 422 citations were identified in the literature search. Following screening of titles

and abstracts, 387 citations were excluded and 35 potentially relevant reports from the

electronic search were retrieved for full-text review. One potentially relevant publication was

retrieved from the grey literature search for full text review. Of these potentially relevant

articles, 24 publications were excluded for various reasons, and 12 publications met the

inclusion criteria and were included in this report. These comprised one SR, nine RCTs,

one economic evaluation, and one evidence-based guideline. Appendix 1 presents the

PRISMA8 flowchart of the study selection. Additional references of potential interest are

provided in Appendix 5.

Summary of Study Characteristics

Additional details regarding the characteristics of included publications are provided in

Appendix 2.

Study Design

One SR9 was identified, which included 5 RCTs ranging in publication date from 2003 to

2014 (search date up to January 2016). The included SR also meta-analyzed the data from

these 5 RCTS, as an individual patient data meta-analysis and meta-regression.9


Nine publications representing seven RCTs, with seven unique patient groups were

identified as relevant to this report.10-18 Two RCTs14,17 were additional or exploratory

analyses using data from the 2014 OpT2mise RCT19 (not included in this review).

One economic evaluation20 was identified. The evaluation was an IMS CORE21 model-

based approach using a lifetime time horizon from both a societal and third party payer

perspective. The model assumed that costs from other sources, such as medications would

be equal between the two groups studied. The cost data was sourced from market data,

Dutch tariffs, and published literature, adjusted for inflation.

One evidence-based guideline, produced by a task force appointed by the Endocrine

Society, was identified that included recommendations regarding CSII for patients with

T2DM.22 Although an SR was commissioned, it appeared to only be applicable to patients

with T1DM, and not to patients with T2DM, although the guideline addresses both

conditions. The evidence used to formulate recommendations related to patients with T2DM

were from both randomized and non-randomized clinical trials, as well as meta-analyses

and uncontrolled data. The evidence base for these recommendations also included the

OpT2mise trial data.19 The quality of the evidence was rated using GRADE.

Country of Origin

The SR and one RCT were conducted in the UK,9,16 three studies were conducted in

China,12,15,18 and two studies (including the subgroup analyses of the OpT2mise trial19)

were conducted in the USA.11,14 One study was conducted in Switzerland10 and one study

was conducted in the Czech Republic.13 The additional analyses of one RCT were

conducted in Spain.17 Although the first author of the economic evaluation was based in

France, the evaluation is on cost-effectiveness in the Netherlands.20 The authors of the

guideline are based in the USA, and the guideline is likely intended for use in the USA, but

the nationality of intended users of the guideline is not reported.22

Patient Population

Systematic Review

The included SR9 included patients with long-standing (not newly-diagnosed) T2DM, who

are not pregnant, and who had data follow-up of greater than two months. The patients

included in the 5 RCTs had an average age of 55.2 years to 66.4 years, an average

diabetes duration of 15.1 years to 16.8 years (not reported in one RCT) and a baseline

HbA1c level of 8.1% (65mmol/mol) to 9.0% (75 mmol/mol). The patients also had a baseline

insulin dose (units/kg) of 0.72 to 1.16.

Primary Studies

All included primary studies recruited adult patients with T2DM.10-18 One study included

patients with T2DM on parenteral nutrition.12 The average age ranged from 47.3 years in

one arm of one study11 to 69.3 years in one arm of one study.16 The subgroup analysis of

the OpT2mise trial19 reported some results by age, into patients greater than or equal to 65

years of age.14

One study specifically included patients with newly diagnosed diabetes,18 and the majority

included patients with long-standing diabetes, ranging from 5.2 years12 to 19.9 years. 14

Men were represented more frequently than women, ranging from a proportion of 51.3%18

in one publication to 70% in two publications. 13,16 Only one study included more female

participants, however the sample size was small (6 females versus 5 males ).11


The body mass index (BMI) (only reported in eight studies10,12-18) of included patients

ranged from 22.34 kg/m2 12 to 36.213. With the exception of one RCT,12 and three of six

arms in another RCT,18 the average BMI for included patients was classified as either

overweight or higher.

Economic Evaluations

The base case for the included economic evaluation20 was from the OpT2mise clinical

trial19, in which included patients had suboptimal control of their diabetes (HbA1c ≥ 8%), the

mean age was 56 years, the mean HbA1c at baseline was 9.0% (75 mmol/mol) and mean

duration of diabetes was 15 years.

Guidelines

The target population for the included guideline22 was for adults with either T1DM or T2DM.

The intended users (patients or physicians) were not reported.

Interventions and Comparators

The included SR analyzed continuous subcutaneous insulin infusion (CSII) as the

intervention of interest, compared with multiple daily injections (MDI).9 The regime of MDI

varied between the 5 included RCTs in the SR, and included different types of insulin, such

as isophane, lispro, glargine, Humulin R, actrapid, Humalog, glulisine, and determir.9

The majority of studies12-14,17,18 used CSII as the intervention of interest. One study used

sensor-augmented pump (SAP) therapy,15 two studies used closed-loop therapy,10,16 and

one study used the Omnipod insulin pump (with either blinded continuous glucose

monitoring [CGM] or unblinded CGM).11 Five studies used insulin aspart,11-13,15,18 one study

used rapid acting insulin analogue (Humalog, Eli Lilly or NovoRapid), 10 one study used

insulin lispro, 16 and two studies (both additional analyses of the OpT2mise trial19) did not

report what type of insulin was used.14,17

The comparator for the majority of RCTs was MDI.12-14,17,18 “conventional subcutaneous

therapy” or “conventional insulin therapy” was the comparator in two RCTs,10,16 whilst

“standard subcutaneous basal glargine” was the comparator in another.11 Long-acting

bedtime bolus of determir was used in one RCT.15 Li et al18 used two different injection

frequencies (3 aspart based vs. 4 glargine daily injections) as comparators to CSII.

The economic evaluation compared the cost-effectiveness of CSII versus MDI.20 This used

the data from the OpT2mise trial in which an insulin pump was compared with MDI (the

regime for MDI from the OpT2mise trial19 was not reported in the economic evaluation, but

was reported in the included SR as aspart, lispro or gluisine before meals and glargine or

determir as basal9).

Outcomes

The outcomes assessed in the included studies were glycemic control and HbA1c

levels,9,11,13,14 total daily insulin dose,9,12,16,18 changes in weight (and BMI),9,13,14 percentage

of time within, above, or below a target glucose range,10,11,15-18 mean sensor glucose

measurement,10,15 incremental area under the curve (AUC),10,12,15-18 time spent in hypo- or

hyperglycemia, mean amplitude of glycemic excursions (MAGE),12,13,15,17,18 continuous

overlapping net glycemic action (CONGA),17 and time to reach glycemic targets or target

blood glucose levels.12,15 Additionally, the odds ratio of reaching the threshold A1c level was


also analyzed in one study.14 Adverse events were also recorded, and included

hypoglycemic events.10-15,18

The economic evaluation reported quality adjusted life-years (QALYs), direct lifetime costs,

incremental cost-effectiveness ratio (ICER), and the cost-effectiveness acceptability

curve.20

Summary of Critical Appraisal

Additional details regarding the strengths and limitations of included publications are

provided in Appendix 3

Systematic Review

The SR was not registered prior to conduction on PROSPERO, but the meta-analysis

portion of the study was registered a priori on Clinicaltrials.gov, thus it appears that the

analysis for the SR was planned ahead of completion. The research question and aim of

the SR is clear and the search strategy was comprehensive, used more than two

databases, was not limited by language, and included searches of reference lists. The

study selection was performed in duplicate, but it was unknown if this included all levels of

the study selection (i.e., both abstract selection and full-text selection), and unclear if this

also included data extraction.

Sources of bias were described (although no specific risk of bias tool used) and quality of

studies were taken into account (only studies with a score ≥3 on the Jadad scale were

eligible). However, the heterogeneity of the studies included in the meta-analysis for HbA1c

level (the primary outcome) was high (I2 = 81.1%), likely due to differing baseline levels of

HbA1c. Additionally, the included studies had different comparators, some included run in

periods whilst others did not, and one study included an older population (a mean age of 10

years greater) compared with the other studies. Therefore, these studies may not have

been appropriate to meta-analyze.

Primary Studies

All of the included studies were RCTs and shared a common strength of randomization of

patients to treatment groups. They also clearly described the aim of the study and main

outcomes measured.10-18 However, only two studies10,16 detailed the randomization

methodology or allocation methods, therefore it is unknown whether the randomization was

appropriately performed or whether investigators were blinded to treatment allocation until

after randomization completion in the remaining studies. The two studies that detailed the

randomization methodology did not conceal assignment of the intervention to investigators.

None of the included RCTs blinded either patients or outcome assessors to intervention

assignment.10-18 This was likely because the nature of the intervention is invasive and

subjecting patients to a large number of injections would be difficult or deemed not feasible.

Nevertheless, this lack of blinding was a limitation of all included publications.

Study sample size was a limitation for some included publications. Power calculations were

performed for two studies,10,16 and likely had sufficient power to detect a statistically

meaningful difference. However, some studies had small sample sizes (N < 40)in treatment

arms, or did subgroup analyses that limited the number of participants in each group. These

small sample sizes were coupled with no power calculations, so it is unknown if there were

enough participants to properly detect a difference for some outcomes.11-15,17,18


Additionally, in all but three studies (in which other medication use was an exclusion

criterium10,15,16), other medications such as acetaminophen were either allowed, or were not

reported. As acetaminophen can interfere with readings of interstitial glucose values and

falsely elevate levels in some CGM monitors,23 this may have affected results.

Economic Evaluation

The research question and the objective of the cost-effectiveness analysis were clearly

stated, and the perspective used and time horizon were clear in the included cost-

effectiveness report.20 The model used was validated 24, used specifically for type 1 and

type 2 diabetes long term outcomes in economics studies. Sensitivity analyses and

discount rates were applied to determine drivers of outcomes. One limitation of the analysis

was that the effectiveness data were based only on one study. Finally, the study was

funded and supported by the manufacturer of the CSII insulin pump used in the

effectiveness study, and many of the authors had affiliations with the manufacturer or had

received funding from the manufacturer. 20

Guidelines

The included guidelines were of very low quality.22 The objective and health question

covered by the guideline was clear, and the guideline used GRADE to assess the evidence

for each recommendation. However the methodology of the SR and the gathering of the

evidence to formulate the recommendations was not reported and not clear. The decision

method for strength of recommendations is not clear, although consensus was apparently

reached through a group meeting, conference calls, and email, but this is not a clear

consensus method. The methodology for formulating the recommendations with the

recommendation task force is also unclear. The views and preferences of the target

population do not appear to have been sought, the target users are not clear, and there are

no details on applicability of the guideline. The recommendations are specific, and the

guideline task force appeared to have multiple individuals from relevant professional

groups, but the role of each individual was not evident. Additionally the roles and expertise

of individuals from committees and members of other organizations that externally reviewed

the guideline drafts are unclear.22

Summary of Findings

Appendix 4 presents a table of the main study findings and authors’ conclusions.

Clinical Effectiveness of Insulin Pumps for T2DM

Ten studies were identified that evaluated clinical effectiveness of insulin pumps for patients

with T2DM.9-18

HbA1c levels and time spent within, above, or below target glucose range

The included SR9 used both a random effects and fixed effects model to analyze individual

patient data from 5 RCTs. Both models found a decrease in mean HbA1c levels, , but this

did not reach statistical significance.9

Seven RCTs analyzed HbA1c levels or time spent within or outside of a target glucose

range.10,11,13-16,18 At 6 months, mean HbA1c levels were significantly decreased in CSII, and

non-significantly decreased in MDI, but when compared to one another, the between-group

difference was not significant (P = 0.20).13 In subgroup analyses of the OpT2mise trial,

comparisons of CSII and MDI in adults with C-peptide levels of >55 ng/mL and adults with


C-peptide levels of ≤ 55 ng/mL showed statistical significance, favouring CSII.14 Subgroup

analyses of CSII versus MDI in adults ≥ 65 years of age showed numerically similar

changes in mean HbA1c levels, but statistical results were not reported.14 The odds ratio of

an individual reaching a threshold A1c level of


significance when compared to MDI three times daily or four times daily.18 The AUC >

250mg/dL was significantly decreased in SAP therapy compared to MDI in one study, (P <

0.05) but P-values for other ranges were not reported.15

Adverse events

Adverse events, primarily hypoglycemic events, were reported in seven studies.10-15,18

Adverse events did not differ between pump therapy and conventional insulin therapy or

MDI, or were not tested, with the exception of one study, where the number of clinically

significant hyperglycemic events (>360 mg/dL) were significantly fewer in closed-loop

therapy in comparison to control (P = 0.03).10

Cost-Effectiveness of CSII versus MDI

The included economic evaluation20 analyzed QALYs gained on a base case and

concluded that the difference between MDI and CSII was not significant (P = 0.43). The

ICER from a third party payer perspective and from a societal perspective was EUR 62,895

and EUR 60,474 respectively. Sensitivity analyses found CSII was most cost-effective in

patients with the poorest glycemic control. At a baseline of 8.5% HbA1c, 9.5% HbA1c, and

10% HbA1c, the ICER was EUR 161,936, EUR 35,837, and EUR 18,610. At a willingness-

to-pay threshold of EUR 80,000, CSII has a >70% probability of being cost-effective.

Guidelines

The included guideline from the Endocrine Society had two recommendations relevant to

T2DM, one recommendation specific to T2DM, and one recommendation for all patients

with either form of diabetes.22 CSII was suggested for T2DM patients who have poor

glycemic control despite intensive insulin therapy and lifestyle modifications, and to those

who have good adherence to monitoring and dosing. In the hospital, it was suggested that

patients continue CSII if the admitting hospital has suitable protocols and procedures.22

Both recommendations were weak recommendations, stemming from low quality

evidence.22

Limitations

One limitation of the included studies was that the majority of RCTs were in hospital

settings with patients being admitted with acute issues. As the majority of T2DM patients

are not continuously hospitalized, this may not reflect insulin use of diabetic patients in

regular practice. Information on outcomes, such as quality of life, were also not found in

identified literature.

Additionally, no included studies were conducted in Canada, limiting the generalizability of

the results to the Canadian context. There were also no data on the use of CSII in children

or adolescents, so no information on this population was available to assist in decision

making. The sole cost-effectiveness study was based in the Netherlands, and may not

directly translate to Canadian costing.

Another limitation of the evidence base was the lack of available guidelines and the low

quality of guidelines identified. The majority of guidelines within the literature search did not

address the use of CSII or insulin pumps in patients with T2DM (usually focusing on

T1DM).


Conclusions and Implications for Decision or Policy Making

One SR and meta-analysis,9 nine RCTs,10-18 one economic evaluation,20 and one evidence-

based guideline were identified.22

Results from one meta-analysis9 found a non-statistically significant effect size for HbA1c

levels, favouring CSII when compared to MDI and no statistical difference for total daily

insulin dose between CSII and MDI. In the RCTs, CSII and closed-loop therapy had mixed

results, with three studies10,16,17 finding a significant difference in time spent within target

glucose range, and the other study finding no significant differences. 11 Subgroup analyses

of adults over the age of 65 were not tested statistically for HbA1c levels14 CSII and SAP

therapy also appeared to reduce time taken to reach glycemic goals when compared to

MDI. 15,18 Hypoglycemic events were the most common adverse event reported. In studies

examining this outcome, hypoglycemic events were similar or favoured pump therapies.10-

15,18 Many of the RCTs had small sample sizes, did not blind the patients or assessors, and

did not detail the methods of randomization. Many of the RCTs also did not control for

medications that may alter the readings of blood glucose.

The included cost-effectiveness study20 found that at a willingness-to-pay threshold of EUR

80,000, CSII has a >70% probability of being cost-effective. These analyses were

performed specifically for patients with poor glycemic control, as the authors used data from

one effectiveness study that included only patients with poor glycemic control and HbA1c

levels above 8.0%. This evaluation was also specific to a Dutch setting.

One evidence based guideline22 recommended CSII for patients with T2DM who have good

compliance and poorly controlled diabetes. However, this guideline is of poor-quality, as the

authors did not properly report the methodology of the SR, did not report consensus

methods or decision-making methods, and did not explore applicability of the guideline.

It is uncertain whether pump therapy provides a greater clinical effectiveness than usual

T2DM care. Research gaps include exploration of CSII or pump therapy in children or

adolescents with T2DM, reporting of quality of life outcomes, and research on pump

therapy in the outpatient setting. Further research addressing these gaps may be useful for

future decision making and help reduce uncertainty regarding pump therapy. Additionally,

research addressing cost-effectiveness outcomes in the Canadian setting are needed to aid

policy makers on decisions and funding regarding pump therapy for patients with T2DM.


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mellitus. Diabetes Technol Ther. 2018;20(1):32-38. 12. Li FF, Zhang WL, Liu BL, et al. Management of glycemic variation in diabetic patients receiving parenteral nutrition by continuous subcutaneous

insulin infusion (CSII) therapy. Sci Rep. 2018;8(1):5888. 13. Chlup R, Runzis S, Castaneda J, Lee SW, Nguyen X, Cohen O. Complex assessment of metabolic effectiveness of insulin pump therapy in patients

with Type 2 diabetes beyond HbA1c reduction. Diabetes Technol Ther. 2018;20(2):153-159. 14. Vigersky RA, Huang S, Cordero TL, et al. Improved Hba1c, total daily insulin dose, and treatment satisfaction with insulin pump therapy compared

to multiple daily insulin injections in patients with Type 2 diabetes irrespective of baseline C-peptide levels. Endocr Pract. 2018;24(5):446-452. 15. Gu W, Liu Y, Chen Y, et al. Multicentre randomized controlled trial with sensor-augmented pump vs multiple daily injections in hospitalized patients

with type 2 diabetes in China: Time to reach target glucose. Diabetes Metab. 2017;43(4):359-363. 16. Thabit H, Hartnell S, Allen JM, et al. Closed-loop insulin delivery in inpatients with Type 2 diabetes: a randomised, parallel-group trial. Lancet

Diabetes Endocrinol. 2017;5(2):117-124. 17. Conget I, Castaneda J, Petrovski G, et al. The impact of insulin pump therapy on glycemic profiles in patients with Type 2 diabetes: data from the

OpT2mise Study. Diabetes Technol Ther. 2016;18(1):22-28. 18. Li FF, Fu LY, Zhang WL, et al. Blood glucose fluctuations in Type 2 diabetes patients treated with multiple daily injections. J Diabetes Res.

2016;2016:1028945. 19. Reznik Y, Cohen O, Aronson R, et al. Insulin pump treatment compared with multiple daily injections for treatment of Type 2 diabetes (OpT2mise): a

randomised open-label controlled trial. Lancet. 2014;384(9950):1265-1272. 20. Roze S, Duteil E, Smith-Palmer J, et al. Cost-effectiveness of continuous subcutaneous insulin infusion in people with Type 2 diabetes in the

Netherlands. J Med Econ. 2016;19(8):742-749. 21. Riemsma R, Corro Ramos I, Birnie R, al. e. Appendix 6 Detailed description of the IMS core diabetes model. Integrated sensor-augmented pump

therapy systems [the MiniMed® Paradigm™ Veo system and the Vibe™ and G4® PLATINUM CGM (continuous glucose monitoring) system] for managing blood glucose levels in Type 1 diabetes: a systematic review and economic evaluation. Southampton (UK): NIHR Journals Library; 2016.

22. Peters AL, Ahmann AJ, Battelino T, et al. Diabetes technology-continuous subcutaneous insulin infusion therapy and continuous glucose monitoring in adults: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2016;101(11):3922-3937.

23. Maahs DM, DeSalvo D, Pyle L, et al. Effect of acetaminophen on CGM glucose in an outpatient setting. Diabetes Care. 2015;38(10):e158-e159. 24. McEwan P, Foos V, Palmer JL, Lamotte M, Lloyd A, Grant D. Validation of the IMS CORE Diabetes Model. Value Health. 2014;17(6):714-724.

https://www.canada.ca/en/public-health/services/publications/diseases-conditions/diabetes-canada-highlights-chronic-disease-surveillance-system.htmlhttps://www.canada.ca/en/public-health/services/publications/diseases-conditions/diabetes-canada-highlights-chronic-disease-surveillance-system.htmlhttp://www.bmj.com/content/bmj/358/bmj.j4008.full.pdfhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1756728/pdf/v052p00377.pdfhttp://handbook-5-1.cochrane.org/chapter_15/figure_15_5_a_drummond_checklist_drummond_1996.htmhttp://handbook-5-1.cochrane.org/chapter_15/figure_15_5_a_drummond_checklist_drummond_1996.htmhttps://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdfhttps://www.agreetrust.org/wp-content/uploads/2017/12/AGREE-II-Users-Manual-and-23-item-Instrument-2009-Update-2017.pdf


Appendix 1: Selection of Included Studies

387 citations excluded

35 potentially relevant articles retrieved

for scrutiny (full text, if available)

1 potentially relevant report retrieved from other sources (grey

literature, hand search)

36 potentially relevant reports

24 reports excluded: -irrelevant population (4) -irrelevant comparator (1) -irrelevant outcomes (3) -study design (14) -already included in at least one of the selected systematic reviews (1) -published in language other than English (1)

12 reports included in review

422 citations identified from electronic literature search and screened


Appendix 2: Characteristics of Included Publications

Table 1: Characteristics of Included Systematic Review and Meta-Analysis

First Author, Publication Year, Country, Funding Source

Study Designs and Numbers of Primary Studies Included

Population Characteristics

Intervention and Comparator(s)

Clinical Outcomes, Length of Follow-Up

Pickup, 20179

UK Funding source NR

5 RCTs included Patients with not newly-diagnosed T2DM who are not pregnant, and have a follow-up of > 2 months CSII n = 303 MDI n = 287

CSII MDIa

Primary outcome:

Glycemic control at study completion (HbA1c)

Secondary outcomes:

Insulin dose (total units per day and units per kilogram)

Weight

CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injection; NR = not reported; RCT = randomized controlled trial; T2DM = type 2

diabetes mellitus

a MDI regimen varied between studies – study 1: Aspart before meals, isophane (NovolinN) once or twice daily as basal; study 2: Lispro before

meals, glargine once daily as basal; study 3: Actrapid or Humulin R before meals, isophane (Insulatard/ Humulin N) as basal; study 4: Humalog Mix

50 (lispro/isophane) three times daily; study 5: Aspart, lispro, or glulisine before meals, glargine or detemir as basal

Table 2: Characteristics of Included Randomized Controlled Trials

First Author, Publication Year, Country, Study Design, Funding Source

Statistical Tests, Population Characteristics

Intervention(s) Comparator(s) Clinical Outcomes, Length of Follow-Up

Bally, 201810 Switzerland Open-label RCT Grant from Diabetes UK, Grant from the Swiss National Science Foundation, the European Foundation for the Study of Diabetes, the JDRF, the National Institute for Health Research Cambridge Biomedical

137 adult (>18 yrs) inpatients with T2DM on general wards at the University Hospital with hyperglycemia requiring subcutaneous insulin therapy Sex, age, BMI (mean ± SD), duration of diabetes: Closed loop group: - 50 male; 20 female - 67.7 ± 10.1 yrs - BMI 32.7 ± 8.2 kg/m2 a - 17.1 ± 11.2 yrs Control group: - 43 male; 23 female - 67.1 ± 13.0 yrs - BMI 32.3 ± 8.1 kg/m2 - 15.5 ± 11.2 yrs

Fully automated, closed-loop system (closed-loop group) delivering rapid-acting insulin analogue (Humalog, Eli Lilly, or NovoRapid, Novo Nordisk) linked to a CGM receiver set at a threshold of 63 mg/dL Usual insulin therapy and sulfonylurea medication were

Conventional subcutaneous therapy (the patients’ usual insulin and other antihyperglycemic therapies) managed by the clinical team and adjusted as needed n = 66

Primary outcome: - Percentage of time

patient glucose measurement was between 100 and 180 mg/dL (5.6 to 10.0 mmol /L)

Secondary outcomes: - Percentage of time that

the glucose measurement was:

> or < the target range;

>360 mg/dL (20.0 mmol/L)





Research Centre, Wellcome Strategic Award Abbott Diabetes Care supplied discounted devices Dr. Bally received financial support from the University Hospital Bern, University of Bern, and the Swiss Diabetes Foundation

discontinued, but other medications continued n = 70

mmol/L)





Sex, age, HbA1c (mean ± SD), diabetes duration Group 1:

- 3 male; 3 female - 47.3 ± 6.2 - 7.9 ± 1.4% - 18.2 ± 11.4 yrs

Group 2:

- 2 male; 3 female - 61.6 ± 9.0 - 8.2 ± 2.7% - 18.1 ± 8.4 yrs

Group 3:

- 2 male; 3 female - 57.4 ± 15.0 - 7.0 ± 0.6% - 18.4 ± 15.8 yrs

Sex: P = 0.94 Age: P = 0.10 Baseline HbA1c: P = 0.53

insulin pump with nonblinded Dexcom CGM Group 1 n = 6 Group 2 n = 5

Li, 201812 China RCT Science and Technology Support Program of Jiangsu Province (No. BL2014010) and a Project funded by the China Postdoctoral Science Foundation (No. 2015M581829).

102 patients with T2DM on parenteral nutrition Sex, age, BMI, HbA1c (mean ± SD), duration of diabetes CSII group:

34 male; 16 female 66.8 ± 9.1 yrs 23.34 ± 3.15 kg/m2

7.7 ± 1.4% 5.2 ± 3.0 yrs MDI group: 31 male; 21 female 65.3 ± 9.3 yrs 22.34 ± 1.51 kg/m2

8.2 ± 1.2% 5.7 ± 2.5 yrs

CSII, insulin aspart 0.05 IU/kg/h (0.01 IU/kg/h given after PN therapy, remaining as a bolus) n = 50

MDI n = 52

- 24-hrs glycemic variation profile (MAGE, mean glucose and SD, incremental AUC > 10 mmol/L and





data19 Medtronic

55.5 ± 9.7 yrs 9.0 ± 0.8% MDI group:

86 male; 77 female 56.4 ± 9.5 yrs 9.0 ± 0.8% Patients ≥ 65 yrs: Sex, age, duration of diabetes (mean ± SD) 38 male; 31 female 68.1 ± 2.64 years 19.9 ± 8.45 yrs

Gu, 201715 China RCT Funding source NR, but some authors are employees of Medtronic

Two-sample t tests and Wilcoxon rank tests 118 adult (18 to 65 yrs) patients with T2DM hospitalized for insulin treatment with ≥1 insulin injection per day and HbA1c levels > 8% at screening Sex, age, BMI, HbA1c (mean ± SD) SAP group: 36 male; 15 female 51 ± 10.2 yr 25 ± 3.1 kg/m2

10 ± 1.6% MDI group: 24 male; 17 female 49 ± 9.6 yr 25 ± 3.3 kg/m2

10 ± 1.2% Loss to followup of 32, 5 patients excluded from analysis. Duration of diabetes NR.

SAP (Medtronic MiniMed Paradigm 722 insulin pump, Sof-sensor glucose sensor and MiniLink Transmitter) delivering fast-acting insulin aspart n = 57

MDI, per day, one bedtime bolus injection of long-acting insulin detemir, three pre-prandial bolus injections of fast-acting insulin aspart n = 61

Primary outcome: - Time taken to achieve

target blood glucose level

Secondary outcomes: - Percentage of patients

achieving target blood glucose levels

3, 5, 14 days

Thabit, 201716 UK Single-centre, open-label, parallel RCT Diabetes UK and the European Foundation

Unpaired t test, Mann-Whitney U test, Fisher’s exact test 40 adult (> 18 yr) patients with T2DM for at least one year recruited from general wards Sex, age, BMI, HbA1c, duration of

Fully automated closed-loop insulin delivery, insulin lispro n = 20

Conventional insulin therapy n = 20

Primary outcome: - Proportion of time

spent in the target glucose concentration range (5.6 to 10.0 mmol/L)

Secondary outcome:

- Time spent <





for the Study of Diabetes. Juvenile Diabetes Research Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, and Wellcome Strategic Award Abbott Diabetes Care supplied discounted devices

diabetes (mean ± SD) Closed loop group: 15 male; 5 female 67.7 ± 10.9 34.1 ± 7.3 kg/m2

8.6 ± 2.3% 15.1 ± 7.6 yrs Control group: 13 male; 7 female 69.3 ± 12.6 32.2 ± 7.8 kg/m2 9.0 ± 1.8% 15.9 ± 7.1 yrs

5.6mmol/L - Time spent > 10

mmol/L - AUC < 3.5mmol/L - Mean sensor glucose - concentration - Total daily insulin dose

72 h

Conget, 201617 Spain RCT Additional analyses for OpT2mise trial19 Medtronic International Trading

Two-sided, two-sample, t test 331 patients with suboptimal glucose control (HbA1c ≥ 8% and ≤12%) Sex, age, BMI, body mass, HbA1c, duration of diabetes (mean ± SD): 56.0 ± 9.6 yrs 9.0 ± 0.8% 15.1 ± 8.0 yrs Sex, age, BMI, HbA1c, duration of diabetes (mean ± SD) CSII group: 94 male; 74 female 55.5 ± 9.7 yrs 33.5 ± 7.5 kg/m2

9.0 ± 0.8% 14.9 ± 8.0 yrs MDI group: 86 male; 77 female 56.4 ± 9.5 yrs 33.2 ± 7.0 kg/m2

9.0 ± 0.8% 15.3 ± 8.0 yrs

CSII n = 168

MDI n = 163

Primary outcome of this additional analysis was glucose profiles Primary outcome of OpT2mise trial:

- Change in mean HbA1c Secondary outcomes:

- Mean 24-h glucose levels

- AUC for hypoglycemia - Time spent in

hypoglycemia and hyperglycemia

- Glucose variability (SD, mean amplitude of glucose excursions, CONGA (over a 60-min interval)

- Impact of CSII on postprandial (4-h) glucose profiles

Li, 201618 China Parallel-group RCT

Independent samples 𝑡-test 243 adult (18 to 80 yr) patients with newly diagnosed or long-standing T2DM admitted to hospital

CSII group, Medtronic insulin pump delivering insulin aspart n = 82

MDI3, aspart 30-based, three injections daily n = 79 newly diagnosed

- 24 h MAGE - 24h mean blood

glucose and SD - Percentage time

duration (%), and the incremental





Nanjing Public Health Bureau project (no. YKK11110), Nanjing Committee of Science and Technology project (no. 201201108), and Jiangsu Provincial Department of Science and Technology project (no. BL2014010)

Sex, age, BMI, HbA1c, duration of diabetes (mean ± SD) CSII group, newly diagnosed: 19 male; 20 female 55.10 ± 10.02 yr 24.55 ± 2.90 kg/m2

9.65 ± 1.81% N/A CSII group, long-standing T2DM: 25 male; 18 female 59.68 ± 8.22 yr 24.73 ± 3.43 kg/m2 8.38 ± 1.68% 12.34 ± 2.07 yrs MDI3 group, newly diagnosed: 18 male; 20 female 52.95 ± 9.63 yr 25.72 ± 3.62 kg/m2 9.99 ± 1.75% N/A MDI3 group, long-standing T2DM: 21 male; 20 female 57.67 ± 10.82 yr 25.17 ± 3.29 kg/m2 8.18 ± 1.58% 11.3 ± 1.14 yrs MDI4 group, newly diagnosed: 19 male; 20 female 52.56 ± 9.97 yr 25.03 ± 2.84 kg/m2 10.13 ± 1.93% N/A MDI4 group, long-standing T2DM: 23 male; 20 female 58.89 ± 11.85 yr 24.66 ± 2.84 kg/m2 8.66 ± 1.73% 13.28 ± 2.54 yrs

newly diagnosed n = 39, long-standing T2DM n = 43

n = 38, long-standing T2DM n = 41 MDI4, glargine based, four injections daily n = 82 newly diagnosed n = 39, long-standing T2DM n = 43

AUC of plasma glucose >10.0mmol/L and


Table 3: Characteristics of Included Economic Evaluation

First Author, Publication Year, Country, Funding Source

Type of Analysis, Time Horizon, Perspective

Decision Problem

Population Characteristics

Intervention and Comparator(s)

Approach

Clinical and Cost Data Used in Analysis

Main Assumptions

Roze, 201620

First author from France, but analysis based on patients in the Netherlands Funded by Medtronic International Sàrl

IMS CORE Diabetes Model Lifetime time horizon Third party-payer perspective Societal perspective

Cost-effectiveness of CSII compared with MDI in patients with T2DM unable to achieve good glycemic control with MDI

Population obtained from the OpT2mise trial19 T2DM patients with suboptimal glucose control (HbA1c ≥ 8% and ≤12%)

CSII MDI

Model-based

Clinical data from the OpT2mise trial19 Cost data sourced from market data, official Dutch tariffs, and published literature (inflated using a consumer price index)

Assumed that other management costs, including other medications, was equal between the two groups

CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injection; RCT = randomized controlled trial; T2DM = type 2 diabetes mellitus

Table 4: Characteristics of Included Guideline

Intended Users, Target Population

Intervention and Practice Considered

Major Outcomes Considered

Evidence Collection, Selection, and Synthesis

Evidence Quality Assessment

Recommendations Development and Evaluation

Guideline Validation

Diabetes Technology-Continuous Subcutaneous Insulin Infusion Therapy and Continuous Glucose Monitoring in Adults: An Endocrine Society Clinical Practice Guideline, 201622

Adults with T1DM and T2DM diabetes

Continuous glucose monitoring and continuous subcutaneous insulin infusion

Glucose control Hypoglycemia

NR GRADE NR NR

GRADE = The Grading of Recommendations Assessment, Development and Evaluation; NR = not reported; RCT = randomized controlled trial


Appendix 3: Critical Appraisal of Included Publications

Table 1: Strengths and Limitations of Systematic Reviews and Meta-Analyses using AMSTAR II4

Strengths Limitations

Pickup, 20179

- Research questions and inclusion criteria explicit - Explicit statement of predefined a priori protocol

registered on ClinicalTrials.gov for the meta-analysis - Search strategy searched at least 2 databases, there

were no language restrictions, keywords were provided, searched lists of articles from manufacturers, and searched reference list

- Study selection performed in duplicate - Individual patient data obtained for meta-analyses - Included studies described - Although no tool used, sources of bias described and

additional trial features investigated - Jadad scale used to assess study quality - Publication bias testing not performed, but justified by

the small number of trials - Conflict of interest and funding conflicts described

- No explanation for inclusion of only RCTs - No search strategy published or MeSH terms, only

keywords - Duplicate study selection not specific (i.e., unknown

whether abstract selection was duplicate, full-text selection was duplicate, or both)

- Unknown if data extraction performed in duplicate - Funding sources of included trials not detailed - Considerable heterogeneity observed for primary

outcome (I2 = 81%), although discussed as likely to be from different baseline HbA1c levels, was likely inappropriate for meta-analysis

- Each trial used differing MDI regimes as comparators, which may affect the appropriateness of combining the trials for meta-analysis

CGM = continuous glucose monitoring; CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections; RCT = randomized controlled trial

Table 2: Strengths and Limitations of Clinical Studies using the Down’s and Black Checklist5


Bally, 201810

- Hypothesis/aim/objective of the study clearly described - Study subjects randomized to intervention groups using

the minimization method - Main outcomes to be measured clearly described - CGM masked to patient and investigators to reflect

usual care in conventional insulin therapy arm - Intervention of interest clearly described - Main findings of the study clearly described - Patient baseline characteristics tested statistically and

found to not differ between the two groups - Adverse events that may be a consequence of the

intervention reported - Intent-to-treat analysis performed - Actual probability values reported, with confidence

intervals - Subjects likely representative of the entire population

from which they were recruited - Staff, places, and facilities where the patients were

treated likely representative of the treatment the majority of patients receive (general ward of hospital)

- Statistical tests used to assess the main outcomes appropriate

- Open label trial, so no blinding of assessors or patients to assigned treatment arm

- Not all characteristics of the patients included in the study clearly described

- Comparator is unclear – conventional insulin therapy may have differed between patients (their “usual care” was continued)

- Randomized intervention assignment not concealed from investigators

- Use of other medications, including acetaminophen, not recorded



- Compliance with the intervention likely to be reliable as procedures performed by clinical team, and pump therapy remained in patient

- Patients in different intervention groups recruited from the same population

- Study likely had sufficient power - Use of other medications, including acetaminophen, not

recorded, but was an exclusion criteria for entry into the study

Chlup, 2018 13

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Interventions of interest clearly described - Main findings of the study clearly described - Important adverse events that may be a consequence

of the intervention reported - Actual probability values reported, with 95% confidence

intervals - Subjects representative of the entire population from

which they were recruited - Blinding in CGM measurements - Statistical tests used to assess the main outcomes

appropriate - Patients in different intervention groups recruited from

the same population

- Not all characteristics of the patients included in the study clearly described, nor were baseline characteristic statistically tested between groups

- Study had no power calculation and very small sample size

- Unknown from which facilities the patients were obtained from or treated, unknown if representative of the treatment the majority of patients receive

- Reliability of compliance with the intervention unknown as frequency of self-monitoring differed between the two groups

- No blinding to the intervention they have received - Randomization sequence unknown/ not reported - Losses of patients to follow-up not taken into account - Use of other medications, including acetaminophen, not

recorded

Levitt, 201811

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Characteristics of the patients included in the study

clearly described and baseline characteristics tested statistically

- Interventions of interest clearly described - Patients placed on specific carbohydrate-controlled diet

with counseling to avoid non-prescribed snacks - Main findings of the study described adequately - Actual probability values reported - Although not blinded to treatment arm, insulin titration

handled by separate diabetes consultation team and not by study investigators

- Compliance with the intervention likely reliable as insulin titration handled by third party


- Losses of patients to follow-up taken into account through intent-to-treat analysis

- Study sample size very small (highest number in study arm of 6)

- Only hypoglycemic events recorded, no other adverse events

- Power calculations performed, but inadequate numbers of patients recruited so there were likely not enough patients to adequately detect a significant clinical difference in effectiveness

- Acetaminophen was administered to some study subjects

- Four subjects dropped out disproportionately in among the pump groups, one of the patients reasoning for drop out not reported

- Study investigators not blinded to treatment group, but not possible due to study design

- Statistical testing methods not reported - Randomization methodology not reported, unknown if

allocation concealed to investigators or patients

Li, 201812

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Some characteristics of the patients included in the

study described and baseline characteristics tested

- Not all characteristics of patients described - Interventions of interest not clearly described (what

pump used) - Open label trial, so no blinding of assessors or patients



statistically - Main findings of the study clearly described - Adverse events that may be a consequence of the

intervention reported - No loss to follow-up of patients - Subjects likely representative of the entire population




- Compliance with the intervention reliable - Patients in different intervention groups recruited from

the same population

to assigned treatment arm - Randomization methodology not reported, unknown if

allocation concealed to investigators or patients - No power calculation, unknown if sample size large

enough - Use of other medications, including acetaminophen, not

recorded

Vigersky, 201814

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Main findings of the study clearly described - Actual probability values reported - Subjects representative of the entire population from

which they were recruited - Staff, places, and facilities where the patients were

treated, representative of the treatment the majority of patients receive



- Comparator is unclear – no information on what MDI regime was given to patients

- Not all characteristics of patients described – e.g., age only described in the abstract of the paper

- No patient characteristics included for group A or B (C-peptide ≤ 55ng/mL and > 55ng/mL)

- Interventions of interest not clearly described (pump mentioned, but unsure of type of insulin or dose)

- No blinding of assessors or patients to assigned treatment arm

- Unknown how randomization performed, unknown if allocation concealed to investigators or patients

- Older patient sample size very small, so no statistical testing performed, only presented narratively

- Sample sizes of each group small, so potentially not enough power to detect a significant difference

- Some patients older than 65 had missing total insulin dose data missing, the characteristics of these patients are not reported

- Only hypoglycemic events recorded, no other adverse events

Gu, 201715

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Interventions of interest clearly described - Main findings of the study clearly described - Important adverse events that may be a consequence

of the intervention reported - Actual probability values reported - Subjects representative of the entire population from

which they were recruited (hospitalized patients) - Staff, places, and facilities where the patients were

treated, representative of the treatment the majority of patients receive in the hospital

- Meal carbohydrate intakes in the hospital were fixed - Statistical tests used to assess the main outcomes

appropriate

- Not all characteristics of the patients included in the study clearly described, nor were baseline characteristics statistically tested between groups

- Characteristics of patients lost to follow-up not described


- Randomization methodology not reported, unknown if allocation concealed to investigators or patients


- Characteristics of withdrawals or exclusions not tested between groups, large number of withdrawals (32 patients).

- No power calculation, unknown if sample size large



- Compliance with the intervention reliable, as patients were withdrawn if compliance was unreliable


- Use of other medications, including acetaminophen, not recorded, but was an exclusion criteria for entry into the study

enough

Thabit, 201716

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Interventions of interest clearly described - Distributions of principal confounders in each group of

subjects to be compared clearly described - Main findings of the study clearly described - Important adverse events and safety endpoints that

may be a consequence of the intervention reported - Characteristics of patients lost to follow-up described - Actual probability values reported - Subjects likely representative of the entire population




- Compliance with intervention likely, as it was an automated closed loop system


- Study subjects randomized to intervention groups by computer generated minimization method

- Intention-to-treat analysis done - Study likely had sufficient power, power calculation

performed - Role of funding source detailed - Use of other medications, including acetaminophen, not

recorded, but was an exclusion criteria for entry into the study

- Open label trial, so no blinding of assessors or patients to assigned treatment arm

- Not all characteristics of the patients included in the study clearly described, nor were baseline characteristics statistically tested between groups

- Randomized intervention assignment not concealed from investigators

- Compliance with the comparator unknown as it was likely administered by the patient

- Insulin type different between the two groups - Closed-loop therapy allowed for low glucose monitoring

alarms and may have mitigated against hypoglycemia better than in the control group

Conget, 201617

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Interventions of interest clearly described? - Main findings of the study clearly described - Important adverse events that may be a consequence

of the intervention reported - Actual probability values reported - Intention-to-treat analysis done - Subjects representative of the entire population from



- Comparator is unclear – no information on what MDI regime was given to patients

- Not all characteristics of patients described - Adverse event not described, but described in a

different publication - Drop outs occurred but reasoning for and statistical

comparison between groups not performed or described, despite intention-to-treat analysis done and description of characteristics being similar between groups


- Randomization methodology not reported, unknown if



- Subjects blinded to the intervention they have received - Blinding of assessors measuring the main outcomes of

the intervention - Statistical tests used to assess the main outcomes

appropriate - Compliance with the intervention reliable - Patients in different intervention groups recruited from

the same population

allocation concealed to investigators or patients - No power calculation, unknown if sample size large

enough - Use of other medications, including acetaminophen, not

recorded

Li, 201618

- Hypothesis/aim/objective of the study clearly described - Main outcomes to be measured clearly described - Baseline characteristics of the patients included in the

study tested statistically - Study period long, resulting in heterogeneous

populations - Interventions of interest clearly described - Main findings of the study clearly described - Subjects representative of the entire population from




- Compliance with the intervention likely reliable as hospital setting, and language used implies third party administered intervention

- Main outcome measures used accurate (valid and reliable)


- Actual probability values not reported - Important adverse events that may be a consequence

of the intervention not reported, aside from hypoglycemia

- Characteristics of patients lost to follow-up not described, unknown if any loss occurred


- Randomization methodology not reported, unknown if allocation concealed to investigators or patients

- No power calculation, unknown if sample size large enough


CGM = continuous glucose monitoring; CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections;

Table 3: Strengths and Limitations of Economic Studies using the Drummond Checklist6


Roze, 201620

- Research question and objective of the cost-analysis were clearly stated

- The perspective and time horizon was clearly stated - The time horizon (length of infant's initial hospital stay)

was clearly stated - The source of the effectiveness data (OpT2mise 19)

clearly stated and some details provided - Details about the model were provided. - Currency and prices were stated to be in EUR and

adjusted for inflation - Sensitivity analyses were conducted and choice of

variables was justified

- Not all details of the design and results of effectiveness study are given

- Effectiveness data based on one single study - Generalizability limited to the Netherlands - Conflict of interest stated, however some of the authors

are employees of the manufacturer (Medtronic) of the CSII pump used. Medtronic also funded the project and supported the analysis.



- The answer to the study question was provided and conclusions based on the data reported were clearly stated

- Discount rate applied in sensitivity analyses and justified

- Sensitivity analyses performed

CGM = continuous glucose monitoring; CSII = continuous subcutaneous insulin infusion; MDI = multiple daily injections;

Table 4: Strengths and Limitations of Guidelines using AGREE II7

Item

Guideline

Diabetes Technology-Continuous Subcutaneous Insulin Infusion

Therapy and Continuous Glucose Monitoring in Adults: An

Endocrine Society Clinical Practice Guideline, 201622

Domain 1: Scope and Purpose AGREE Score (1 to 7)

1. The overall objective(s) of the guideline is (are) specifically described. 6

2. The health question(s) covered by the guideline is (are) specifically described. 6

3. The population (patients, public, etc.) to whom the guideline is meant to apply is specifically described.

7

Domain 2: Stakeholder Involvement

4. The guideline development group includes individuals from all relevant professional groups.

4

5. The views and preferences of the target population (patients, public, etc.) have been sought.

1

6. The target users of the guideline are clearly defined. 1

Domain 3: Rigour of Development

7. Systematic methods were used to search for evidence. 1

8. The criteria for selecting the evidence are clearly described. 1

9. The strengths and limitations of the body of evidence are clearly described. 5

10. The methods for formulating the recommendations are clearly described. 1

11. The health benefits, side effects, and risks have been considered in formulating the recommendations.

2

12. There is an explicit link between the recommendations and the supporting evidence. 5

13. The guideline has been externally reviewed by experts prior to its publication. 3

14. A procedure for updating the guideline is provided. 1

Domain 4: Clarity of Presentation

15. The recommendations are specific and unambiguous. 6


Item

Guideline

Diabetes Technology-Continuous Subcutaneous Insulin Infusion

Therapy and Continuous Glucose Monitoring in Adults: An

Endocrine Society Clinical Practice Guideline, 201622

16. The different options for management of the condition or health issue are clearly presented.

1

17. Key recommendations are easily identifiable. 7

Domain 5: Applicability

18. The guideline describes facilitators and barriers to its application. 1

19. The guideline provides advice and/or tools on how the recommendations can be put into practice.

1

20. The potential resource implications of applying the recommendations have been considered.

1

21. The guideline presents monitoring and/or auditing criteria. 1

Domain 6: Editorial Independence

22. The views of the funding body have not influenced the content of the guideline. 1

23. Competing interests of guideline development group members have been recorded and addressed.

7


Appendix 4: Main Study Findings and Authors’ Conclusions

Table 1: Summary of Findings Included Systematic Review and Meta-Analysis

Main Study Findings Authors’ Conclusion

Pickup, 20179

5 RCTS included in the SR and MA Mean HbA1c levels, covariate adjustment Overall, all trials combined, individual data Random effects model

- –0.40% (95% CI –0.86 to 0.05) - –4.4 mmol/mol (95% CI –9.4 to 0.6), favoring CSII. - I2 = 81.1%

Fixed effects model - –0.30% (95% CI –0.47 to –0.13) - –3.3mmol/mol (95% CI –5.2 to –1.5)

Overall, aggregate data of summary effect sizes

- –0.45% (95% CI –0.81 to –0.09) - –5.0 mmol/mol (95% CI –8.9 to –1.0), favoring CSII.

Fixed effects model - –0.47% (95% CI –0.65 to –0.29) - –5.2mmol/mol (95% CI –7.1 to –3.2)

Insulin requirements Overall, all trials combined, individual data Insulin dose Random effects model

- –0.25 (95% CI –0.31 to 0.19) - I2 = 4.7%

Fixed effects model - –0.0.26 (95% CI –0.31 to –0.20)

Total daily insulin Random effects model

- CSII v. MDI - –24.0 (95% CI –30.6 to 17.5) - I2 = 0% - –0.0.26 (95% CI –0.31 to –0.20)

Weight Mean weight, all trials combined, individual data

- 0.08kg (95% CI –0.33 to 0.48) - I2 = 0%

Mean difference BMI, 4 trials, individual data

- 0.00kg/m2 (95% CI –0.23 to –0.24)

“We show in this individual patient data meta-analysis and meta-regression of five RCTs involving 590 participants with type 2 diabetes that insulin pump therapy achieves better glycemic control than MDI in participants with poor diabetes control at baseline.” p. 719

AUC = area under the curve; BMI = body-mass index; CGM = continuous glucose monitoring; CONGA = continuous overlapping net glycemic action; CSII = continuous

subcutaneous insulin infusion; dL = decilitre; GAD Ab = glutamic acid decarboxylase antibodies; L = litre; MA = meta-analysis; MAGE = mean amplitude of glycemic

excursions; MDI = multiple daily injection; mg = milligram; mmol = millimoles; mo = month; mol =mole; NR = not reported; RCT = randomized controlled trial; SAP =

sensor-augmented pump; SD = standard deviation; SR = systematic review; T2DM = Type 2 diabetes mellitus; TDD = total daily insulin dose; yr = year


Table 2: Summary of Findings of Included Primary Clinical Studies


Bally, 201810

“[Baseline characteristics] …similar with respect to sex, age, body-mass index, glycated hemoglobin level, duration of diabetes, receipt of insulin, and insulin requirements” p. 550 P = NR Sex, age, BMI (mean ± SD): Closed loop group: - 50 male; 20 female - 67.7 ± 10.1 yrs - BMI 32.7 ± 8.2a

Control group: - 43 male; 23 female - 67.1 ± 13.0 yrs - BMI 32.3 ± 8.1 kg/m2

Mean percentage of time in target glucose range (SD): - Closed loop: 65.8% (16.8%) - Control: 41.5% (16.9%) - Difference: 24.3% (2.9%) (95% CI 18.6 to 30.0), P < 0.001

Mean sensor glucose measurement (SD): - Closed loop: 154 (29) mg/dL - Control: 188 (43) mg/dL - Difference : 35 (6) mg per deciliter (95% CI, 23 to 47,

P



- Closed-loop: 129mg/dL (24) - Control: 160 mg/dL (49) - P < 0.001

Daytime (8 am to midnight) Mean percentage of time in target range - Closed-loop: 61.9% (18.9%) - Control: 34.9% (18.6%) - Difference: 26.9% (3.2%) (95% CI, 20.6 to 33.3, P8% [64 mmol/mol] Mean age, BMI, BM, diabetes duration, HbA1c (SD)

- 57.2 (8.0) yrs - 36.2 (7.0) kg/m2 - 106.9 (18.3) kg - 13.3 (4.7) yrs - 9.5% (0.96)% [80 mmol/mol])

CSII group: Mean HbA1c reduction:

- 0.9% ± 1.1% (10 ±12 mmol/mol) (95% CI, –1.6 [–17] to –0.1 [–1])

- P= 0.0312

“Thus, CSII was more effective than MDI (perhaps due to the more physiological mode of basal insulin administration with insulin pump infusion therapy).” p. 157 “The use of CSII therapy in individuals with insulin resistant T2D is both safe and effective for improving glucose control and reducing insulin usage, although without a sustainable reduction in BM, BP, or lipid profile. While an optimum metabolic balance in most of the patients was not reached, treatment adherence and satisfaction were excellent. All subjects decided to continue using CSII therapy.” p. 158



Total daily insulin dose:

- 29.8 ± 28.41 U/d (33% of baseline, 92.1 ± 20.35U/d) BMI reduction: - –0.3 ± 1.94 kg/m2 (95% CI, –1.61 to 0.99) (0.86% of

baseline, 36.2 ± 4.25 kg/m2) Body mass: - -0.78 ± 5.61 kg (95% CI, –4.55 to 2.99) (0.74% of baseline,

104.8 kg ± 16.15) MDI group: Mean HbA1c reduction: - 0.3% ± 3mmol/mol (95% CI, –0.8 [–9] to 0.1 [1])

Total daily insulin dose: - 0.4U/d from baseline (99.0 ± 25.25U/d) - P = NS

BMI reduction: - –0.31 ± 0.70 kg/m2 (95% CI, –0.78 to 0.16) (0.9% of

baseline 36.2 ± 9.07 kg/m2) Body mass: - –1.0± 2.03 kg (95% CI, –2.36 to 0.36) (0.91% of baseline

108.9 ± 20.55kg) Between group difference, 6 months - -0.53% ± 0.9% (1 ± 10 mmol/mol) , in favour of CSII - P = 0.20

Percentage of time spent in hypoglycemia, 6 months - No significant change from baseline, P = NR - CSII: 95% CI = –2.5% to 3.5% - MDI: 95% CI = –2.5% to1.5%

Mean amplitude of glycemic excursions, 6 months - No significant change from baseline, P = NR - CSII: –12.9 (20.6) - MDI: –3.0 (33.6)

Adverse Events:

31 adverse events in 8 patients using CSII (either in the CSII only group or the MDI to CSII crossover group). One event was attributed to diabetes.

Levitt, 201811

Group 1 – basal bolus injection Group 2 – blinded CGM and pump injection Group 3 – unblinded CGM and pump injection Baseline outpatient glycemic control

- Basal bolus: 7.0% ± 0.6% - Blinded CGM and pump: 7.9% ± 1.4% - Unblinded CGM and pump: 8.2% ± 2.7%

“During our study, insulin pump use did not provide superior glucose control over conventional basal-bolus subcutaneous insulin therapy. Inpatient pump initiation was labor intensive and technically challenging, possibly limiting glycemic benefits. Further, the small number enrolled in the study may have impacted our findings.” P. 36



- Basal bolus vs. unblinded and blinded CGM + pump: P = 0.15

- Unblinded pump vs. blinded pump: P = 0.8 - All three groups: P = 0.53

Mean capillary glucose value - Basal bolus: 144.5 ± 19.5mg/dL - Unblinded pump: 191.5 ± 52.3 mg/dL - Blinded pump: 182.7 ± 59.9 mg/dL - Basal bolus vs. unblinded and blinded CGM + pump: P =

0.05 Percentage of time spent in range according to CGM: - < target ( target (>180mg/dL)

o Basal bolus: 18 ± 9 o Unblinded pump: 45 ± 36 o Blinded pump: 23 ± 38

Hypoglycemic events - Capillary glucose data:

o Basal bolus: 3 o Unblinded pump: 0 o Blinded pump: 4 o Blinded vs. Unblinded pump, P = NS o Basal Bolus and blinded pump vs. unblinded,

P = NS - CGM:

o Basal bolus: 9 o Unblinded pump: 4 o Blinded pump: 5 o Blinded vs. Unblinded pump, P = NS o Basal Bolus and blinded pump vs. unblinded,

P = NS - No patients experienced clinically significant severe

hypoglycemia (loss of consciousness, seizure, or death)

Li, 201812

- No significant difference in most baseline characteristics (P = NS)

o Sex: P = 0.38 o Age: P = 0.42 o HbA1c: P = 0.07 o Years of diabetes: P = 0.33

- Body weight and BMI significantly lower in MDI group than CSII group (P = 0.01 and P = 0.04, respectively)

“In conclusion, the administration of insulin via CSII led to a significant decrease in glycemic variations, and insulin doses required by patients receiving PN to maintain euglycemic control when compared to the MDI therapy in patients with T2D who had had gastrointestinal surgery.” P.4



Before operation, glycemic control

- Number of days until control reached, CSII vs. MDI o 2.23 ± 1.82 vs. 4.32 ± 1.17, P < 0.05

- Daily insulin dose, CSII vs. MDI o 0.43 ± 0.22 vs. 0.46 ± 0.25 IU/Kg, P > 0.05

24-hr and 14-hr Glycemic variation profiles - CSII vs. MDI, decrease o 24 hr and 14 hr MAGE, P < 0.01 o 24 hr and 14 hr standard deviation of MG, P < 0.01 o 24 hr and 14 hr SD glucose mmol/L, P 10 mmol/L, P < 0.01 o 24 hrs AUC < 3.9 mmol/L, P = 0.84 o 14 hr AUC < 3.9 mmol/L, P = 0.96

- CSII had lower hourly mean glucose levels than MDI

(all time points P < 0.05) Total daily insulin dose CSII: 25.3 ± 5.0 IU MDI: 32.3 ± 2.9 IU P = 0.00 By body weight:

CSII: 0.4 ± 0.1 UI/kg MDI: 0.5 ± 0.1 UI/kg P = 0.00 Adverse Events:

- No episodes of hypoglycemia - No infection events reported

Vigersky, 201814

- C-peptide level of ≤ 0.55 ng/mL = Group A - C-peptide level of > 0.55 ng/mL = Group B - Baseline A1c levels:

o Group A CSII: 9.0 ± 0.6 (n = 49) o Group B CSII: 9.0 ± 0.8 (n = 112) o Group A MDI: 8.9 ± 0.7 (n = 45) o Group B MDI: 9.0 ± 0.8 (n = 113) o

- Baseline total daily insulin dose o Group A CSII: 83.2 ± 41.8 (n = 44) o Groups B CSII: 124.2 ± 54.5 (n = 106) o Group A MDI: 88.5 ± 42.3 (n = 42) o Group B MDI: 113.0 ± 50.2 (n = 102)

A1c levels, change at 6 months:

- CSII vs MDI - Group A: −0.9 ± 1.1 vs. −0.1 ± 0.9 (P = 0.0006) - Group B: −1.1 ± 1.3 vs. −0.5 ± 1.1 (P < 0.0001)

“The OpT2mise RCT demonstrated that individuals with poorly controlled T2D benefited from CSII with improvement in several important metrics of glycemic control and quality of life. The data show that compared to subjects randomized to MDI, those randomized to CSII have a significant improvement in A1c and a significantly greater likelihood of reaching the A1c thresholds of


Main Study Findings Authors’ C

Documents

CADTH RAPID RESPONSE REPORT: SUMMARY WITH … Insulin Pumps Final.pdfSAP Sensor augmented pump SD Standard deviation T1DM Type 1 diabetes mellitus T2DM Type 2 diabetes mellitus TDD