Continuous subcutaneous insulin infusion therapy and ... · Continuous subcutaneous insulin infusion therapy and multiple daily insulin ... structured education and support are important

REVIEW

Continuous subcutaneous insulin infusion therapy and multiple daily insulininjections in type 1 diabetes mellitus: a comparative overview and futurehorizonsHood Thabita,b and Roman Hovorkaa,c

aWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge, Cambridge, UK; bDepartment of Diabetes & Endocrinology,Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK; cDepartment of Paediatrics, University of Cambridge, Cambridge, UK

ABSTRACTIntroduction: Continuous subcutaneous insulin infusion (CSII) therapy is currently accepted as atreatment strategy for type 1 diabetes. Transition from multiple daily injection therapy (MDI;including basal-bolus regimens) to CSII is based on expectations of better metabolic control andfewer hypoglycaemic events. Evidence to date has not been always conclusive.Areas covered: Evidence for CSII and MDI in terms of glycaemic control, hypoglycaemia andpsychosocial outcomes is reviewed in the adult and paediatric population with type 1 diabetes.Findings from studies on threshold-based insulin pump suspension and predictive low glucosemanagement (PLGM) are outlined. Limitations of current CSII application and future technologicaldevelopments are discussed.Expert opinion: Glycaemic control and quality of life (QOL) may be improved by CSII compared toMDI depending on baseline HbA1c and hypoglycaemia rates. Future studies are expected toprovide evidence on clinical and cost effectiveness in those who will benefit the most. Training,structured education and support are important to benefit from CSII. Novel technologicalapproaches linking continuous glucose monitoring (CGM) and CSII may help mitigate againstfrequent hypoglycaemia in those at risk. Development of glucose-responsive automated closed-loop insulin delivery systems may reduce the burden of disease management and improveoutcomes in type 1 diabetes.

ARTICLE HISTORYReceived 2 September 2015Accepted 28 October 2015

KEYWORDSContinuous subcutaneousinsulin infusion; insulinpump; multiple dailyinjections; type 1 diabetes

1. Introduction

Type 1 diabetes is a chronic autoimmune conditioncharacterised by the inflammation and destruction ofpancreatic B-cell, leading to absolute insulin deficiencyand hyperglycaemia. The Diabetes Control andComplication Trial (DCCT) and Epidemiology ofDiabetes Interventions and Complications (EDIC) fol-low-up studies have had major influences on clinicalpractice.[1,2] Improvement of glycaemic control byintensive insulin therapy in DCCT significantly reducedthe risk of microvascular complications, while EDIC fol-lowing the DCCT cohort demonstrated the beneficialeffects of intensive insulin therapy, which persisted17 years later, with a reduced risk of cardiovascularevents by 42%. The intensive treatment group in theDCCT received multiple daily insulin injection therapy(MDI) or continuous subcutaneous insulin infusion (CSII)therapy. Participants in the DCCT treated with CSIIachieved and maintained relatively lower glycated hae-moglobin (HbA1c) levels compared to MDI users.However, the rate of severe hypoglycaemia was notably

higher in the group receiving intensive treatment byaround two- to three-fold.

An important difference to current practice is thatmodern recommended MDI therapy, known as basal-bolus regimen (once or twice daily injections of long-acting insulin analogues combined with rapid-actinginsulin analogues at mealtimes), is not comparable tothe older insulin therapy used in the DCCT. Moderninsulin analogues have faster and less-variable insulinaction profiles compared to older human insulins.[3]The use of insulin analogues has been shown toreduce the relative rate of hypoglycaemia events by29%, in those at highest risk.[4] Along with compre-hensive diabetes self-care and structured education,clinical outcomes may therefore differ from earlierstudies. As more expensive technology becomes inte-grated with day-to-day healthcare delivery, clinicaland cost-effectiveness needs to be demonstrated.The present article outlines the current evidence ofCSII and MDI in the adult and paediatric populationwith type 1 diabetes from the perspective of

CONTACT Roman Hovorka [email protected]

EXPERT OPINION ON DRUG DELIVERY, 2016VOL. 13, NO. 3, 389–400http://dx.doi.org/10.1517/17425247.2016.1115013

© 2015 Taylor & Francis

measured glycaemic outcomes and quality of life(QOL) impact on people with type 1 diabetes andcaregivers. The issues and limitations surroundingCSII application in clinical practice are discussed,together with updates on technological develop-ments and recommendations for future research toaddress unanswered questions.

2. Insulin therapy and delivery methods inclinical practice

2.1 Multiple daily injections

Evidence of intensive insulin therapy in reducing therisk of long-term diabetes-related complications wasfirst shown in the DCCT, and has subsequently beenconfirmed by other studies.[5] The MDI regimen ofthe DCCT control group consisted one or two fixeddoses of insulin that did not vary with meals,whereas the MDI regimen of the interventiongroup consisted of three or more daily insulin injec-tions adjusted according to self-monitoring bloodglucose results, dietary intake and anticipated exer-cise. As mentioned earlier, this has been supersededby modern insulin analogues administered in a man-ner replicating the endogenous insulin secretoryprofile by the healthy pancreas known as thebasal-bolus MDI regimens. This consists of subcuta-neous long-acting or basal insulin to maintain glu-cose homeostasis between meals and normalise theglucose levels during the fasting period, and quickor rapid-acting insulins to provide prandial insulin

cover during meals. Basal-bolus regimens are nowwidely advocated by professional clinical bodies andare currently the primary strategy for intensive insu-lin therapy in type 1 diabetes. Subcutaneous insulinpreparations currently available in clinical practice aspart of the basal bolus strategy include soluble (reg-ular) human insulin, Neutral Protamine Hagedorn(NPH) insulin and analogue insulins. These are sub-divided according to the duration of action intointermediate/long-acting insulins and quick/rapid-acting insulins.

NPH is a neutral suspension insulin created by theaddition and crystallisation of protamine with regularinsulin.[6] Its pharmacokinetic is more in keeping withan intermediate-acting rather than long-acting insulin.NPH insulin has an onset of action of approximately 2–4 h. It reaches peak plasma concentration at 4–10 hwith duration of action up to 10–18 h. It has severaldisadvantages; its peak action in plasma is often asso-ciated with nocturnal hypoglycaemia if given at night,and its pharmacokinetics is less predictable as subcuta-neous absorption of NPH insulin can vary by up to80%.[7]

The first long-acting insulin analogue introduced inclinical practice was glargine.[8] In glargine, the aminoacid of regular insulin, glycine, is substituted for aspar-agine at position 2. It is less soluble at physiologic pHbut more soluble at acidic pH, due to the addition ofarginine residues to the B chain. As glargine precipi-tates at neutral pH, this leads to slower absorptionfollowing subcutaneous administration. Its pharmaco-kinetics is relatively peakless compared to NPH insulin,and has a duration of action of approximately 20–24 h.[9] Another long-acting analogue currently being usedin clinical practice is insulin detemir, in which theamino acid threonine of regular insulin is removed atB30, and fatty acid acylation of lysine can be found atB29. This acylation allows the molecule to bind toalbumin in plasma, thereby prolonging the durationof action of detemir in the systemic circulation.[10] Itshalf-life is slightly less than glargine (duration of action18–22 h), thereby necessitating twice-daily administra-tion by most MDI users. In contrast to glargine it doesnot form a precipitate after subcutaneous injectionand has a neutral pH. A recent addition to the basalinsulin analogue family is degludec, in which theDesB30 human insulin is acylated with hexadecandioicacid and forms stable di-hexamer compounds in thepresence of phenol and zinc. The di-hexamer com-pounds initially self-associate into depot of multi-hex-amer chains at the injection site, followingsubcutaneous injection and dispersion of phenol. The

Article highlights• Continuous subcutaneous insulin infusion (CSII) therapy

involves infusion of rapid-acting insulin analogue accordingto a preprogrammed basal profile to mimic basal insulinsecretion, and meal boost insulin to manage post-prandialglucose excursions.

• Glycaemic control is improved by CSII in those suboptimallycontrolled by multiple daily injection (MDI) therapy with agreater treatment effect at high baseline HbA1c.

• Most trials were not powered to demonstrate significantdifferences in hypoglycaemia due to low reported baselinerates of hypoglycaemia; however, those with the greatesthypoglycaemia burden at baseline benefitted significantlyfrom CSII use.

• Findings from qualitative studies and validated quality of lifequestionnaires in adults and adolescents with type 1 diabetesas well as parents indicate that the majority of CSII usersexperienced higher diabetes treatment satisfaction and dia-betes-related quality of life measures compared to MDI, withvery low discontinuation rates of CSII therapy.

• Further innovations in CSII technology are anticipated withthe advent of threshold suspend features and closed-loopinsulin delivery systems, which may further improve clinicaloutcomes.

This box summarises key points contained in the article.

390 H. THABIT AND R. HOVORKA

diffusion of zinc then causes the multi-hexamericdepots to slowly and continuously release monomericcompounds of insulin degludec. As a result, insulindegludec has a prolonged half-life of 25 h, and clinicalstudies have shown a four-fold reduction in day-to-daywithin-subject pharmacodynamic variability, comparedto insulin glargine.[11]

Example of quick-acting insulin is regular (human)insulin. Regular insulin has an onset of action of 30–60 min; therefore, it is advised to be administered sub-cutaneously 30 min prior to a meal. Its duration ofaction after injection is approximately 5–8 h. In contrast,rapid-acting insulins, which are insulin analogues, havefaster onset than regular insulin (5–15 min), with fasterpeak concentration (0.5–2 h) and shorter duration ofaction (3–5 h).[12] Examples of these are insulin aspart,lispro and glulisine. Rapid-acting insulin analogues uti-lise various strategies to reduce insulin self-association,leading to earlier hypoglycaemic action compared toregular insulin. Among these strategies are introducingcharge repulsion (in insulin aspart and glulisine) andstearic manipulation (lispro). As these analogues havesignificantly reduced lag-phase, they can be adminis-tered subcutaneously immediately with meals, there-fore allowing greater convenience and flexibility forusers, although optimal postprandial glucose excur-sions are more likely to be achieved if given 15 minbefore a meal.[13]

2.2 CSII therapy

CSII was first used in type 1 diabetes in the 1970s.[14,15] Early generation CSII devices were bulky, unreli-able and delivered a single basal insulin infusion rate,with manually triggered boosts or boluses at mealtimes. Over the years, CSII devices have become smal-ler, more reliable and sophisticated, infusing rapid orquick-acting insulin at preselected infusion rates withmultiple programmable basal profiles to mimic basalinsulin secretion. Modern CSII devices have a numberof bolus delivery profile options, allowing different infu-sion rate patterns at mealtimes, and an integrated on-board calculator, which recommend insulin bolus dosebased on manually entered glucose value, carbohydratecontent and amount of insulin still active on board.[16]

The advantage of CSII compared to MDI is theplanned and immediate adjustments that can bemade to insulin delivery, in concordance with the vary-ing degree of glycaemia levels that may occur through-out the day. Examples include gradual increase ininsulin infusion rate overnight to address the dawnphenomenon and temporary suspension or decreasein insulin infusion rate following increased physical

activity or fasting. Conventional CSII devices consist ofa subcutaneous infusion set (catheter and tubing sys-tem), insulin reservoir (both replaced every 2–3 days)and a portable electromechanical pump. A recent inno-vation in CSII design has been the advent of the patchor “tubing-less” (“tubing-minimal”) pump, which inte-grates the infusion set, reservoir unit, pump and auto-mated inserter into a single unit, which adheres directlyto the user’s skin, allowing more discretion and free-dom of movement.

The uptake of CSII in clinical practice varies globally,with an estimated 20–25% of type 1 diabetes in the USand Norway using CSII, to around 6% in the UK.[17,18]This may partly be explained by differences in theprovision of service and support cost in different coun-tries.[19] The National Health Service in the UK providesfunding for CSII based on recommendations from theNational Institute for Health and Clinical Excellence(NICE) technology appraisal committee. NICE supportsCSII use in adults and children ≥12 years of age withtype 1 diabetes whose HbA1c remains above 69 mmol/mol (8.5%) or suffers from recurrent disabling hypogly-caemia during attempts to achieve target hbA1c level,despite optimised basal-bolus insulin therapy and bestefforts from the patient and diabetes team. CSII isrecommended in children younger than 12 years andfor whom MDI is considered impractical or inappropri-ate, with the expectation of reverting to trial of MDIbetween ages 12 and 18 years. NICE also includes pro-vider-specific recommendations such as the availabilityof a trained specialist team of diabetes specialist nurse,dietician and diabetologist, and user engagement withstructured education programmes tailored for CSIIapplication.

These recommendations are not exclusive to the UKhowever, and are broadly in line with recommendationsin other developed countries.[20] Despite its potentialbenefits, CSII implementation requires significant com-mitment and governance due to the underlying risksand inherent costs associated with CSII therapy.Examining the evidence for efficacy, safety as well ascost-effectiveness of CSII is therefore important to bet-ter understand its role and benefits in the managementof type 1 diabetes.

3. Evidences from paediatric studies

3.1 Glycaemic control

Two large paediatric diabetes registries, the T1DRegistry in the US and the Prospective DiabetesFollow-up Registry in Germany and Austria, recentlyevaluated the clinical outcomes of participants under

EXPERT OPINION ON DRUG DELIVERY 391

the age of six on CSII and MDI.[21] The T1D Registryshowed that those on CSII had significantly lower aver-age HbA1c levels and were more likely to achieve levelsless than 7.5%. The Prospective Diabetes Follow-upRegistry however showed no difference between CSIIand MDI. The CSII and MDI groups in the T1D Registryhad comparable age, BMI z score and total daily insulindose, whilst CSII users in the Prospective DiabetesFollow-up Registry were significantly younger(4.9 years vs. 5.3 years, p < 0.001). Between the tworegistries, HbA1c levels’ discrepancy was the greatestamong MDI than among CSII users. Long-term glycae-mic control in 345 children on CSII was compared withmatched controls on MDI in a single-centre observa-tional study.[22] Despite the similar glycaemic controlat baseline (HbA1c 8% in both groups), CSII users hadsignificantly lower HbA1c throughout the follow-upperiod compared with the MDI group (mean HbA1cdifference 0.7% over 5 years).

Limited numbers of randomised controlled studiescomparing CSII with MDI have been performed inthe paediatric population. Early randomised con-trolled studies included participants using regularinsulin rather than analogues in the CSII group, orearly-generation CSII with limited capacity to alterthe basal rates and bolus profiles.[23,24] This limitsthe generalisability to modern CSII application andpractice. A recent meta-analysis evaluated rando-mised controlled studies comparing glycaemic con-trol in children and adolescents on CSII using rapid-acting analogues, and MDI therapy receiving at leastthree injections per day (with long- and rapid-actinganalogues or NPH and regular insulin). The pooledmean between-group difference in HbA1c changefrom baseline was not significantly different [meanbetween-group HbA1c difference −0.14% (95% CI,−0.48 to 0.20)] and was comparable among adoles-cents >12 years and children <12 years.[41] A criti-cism of most comparative studies and meta-analysesis the inclusion of MDI participants not on a recom-mended analogue-based basal-bolus MDI regimen ascomparator for CSII (see Table 1). This may introducea bias in favour of CSII given the perceived benefitsof analogues against regular and NPH insulin, andargumentation that analogue-based basal-bolus MDImay have comparable glycaemic effects to CSII.[25]

3.2 Hypoglycaemia

Due to the heterogeneity in reporting and definition ofhypoglycaemia, only studies with data on severe hypo-glycaemia deemed clinically significant (associated withseizure or loss of consciousness [32]) will be stated. In

an observational study (n = 255), significant reductionin the incidence rate of severe hypoglycaemia wasshown in CSII users compared to MDI users on NPHinsulin (31.8/100-patient-years vs. 46.1/100-patient-years, p = 0.04).[33] This was confirmed by anotherlong-term observational study of over 1160 person-years of follow-up, which showed a significantly lowerrate of severe hypoglycaemia by 30% in CSII user com-pared with MDI (7.2 vs. 10.2 per 100 patient-years,p = 0.013).[22]

A meta-analysis of randomised controlled studiesin participants on MDI and on CSII with insulinanalogues reported a similar rate of severe hypogly-caemia between the treatment group, but had anotably wide confidence interval [pooled incidencerate ratio based upon events per person-year of 0.99(95% CI, 0.57–1.71)].[41] Hypoglycaemia rates areknown to increase with diabetes duration, and aschildren generally have a shorter duration of dia-betes than adults, the baseline rates of severe hypo-glycaemia in this population are considerably lower.[34,35] Studies included in the meta-analysis were ofshort duration (less than 6 months) with lowreported baseline rates of severe hypoglycaemia,and thus were not statistically powered to showany significant difference between treatmentgroups.

3.3 QOL and carers’ perspective

In a prospective pre- and post-CSII study involvingchildren and adolescents between ages 4 and16 years, significant increase in diabetes-specific QOLwas shown across the whole age range following tran-sition to CSII.[36] Formal comparisons using validatedmeasures in six randomised controlled studies foundcomparable effects on general QOL, but CSII users hadhigher treatment satisfaction measures compared withMDI.[41] The strength of evidences is limited by thedifferent measures used to assess QOL outcomes. Acomprehensive battery of cognitive tests was appliedto children aged 6–16 years in a pilot uncontrolledstudy at baseline and 6–8 weeks after starting CSII.[37]The study reported significant improvements in scoresrelated to perceptual reasoning, selective attention,divided attention, cognitive flexibility and workingmemory. Several small randomised controlled studies(n = 16–38 participants), which included parental dia-betes-specific QOL scores, showed no significant differ-ence between the CSII and MD groups.[38,39] However,in one study an increase in QOL scores in the fathers ofthe CSII group was reported at the 6-month follow-upperiod.[40]


4. Evidences from adult studies

4.1 Glycaemic control

A Cochrane review of adults with type 1 diabetesshowed significant difference in HbA1c favouringCSII compared to MDI [weighted mean difference−0.3% (95% CI, −0.1 to −0.4)].[24] In a subgroup ana-lysis of medium-term-duration studies (1–6 months),an estimated mean difference of HbA1c of −0.3%(95% CI, −0.5 to −0.1) in favour of CSII was reported,whereas in studies longer than 6 months the meandifference was relatively smaller (−0.2% [95% CI, −0.4to 0.1]). A recent meta-analysis of randomised con-trolled studies compared CSII using insulin analogues,with MDI.[41] A significant decrease of HbA1c infavour of the CSII group was found (combined meanbetween-group difference −0.30% [95% CI, −0.58% to

−0.02%]). The degree of HbA1c reduction was greaterin studies with higher HbA1c before CSII initiation.Retrospective analysis of data over 5 years from 272CSII users confirmed that higher HbA1c at the start ofCSII intervention led to significantly greater HbA1creduction compared to the MDI control group(HbA1c reduction of 0.25% [95% CI, 0.11–0.39] inparticipants with baseline HbA1c of 9.0% and BMI of25 kg/m2).[42]

4.2 Hypoglycaemia

Estimated effects on hypoglycaemia may be misleadingas most studies were limited by participant numbers,duration and frequency of hypoglycaemic episodes,thus statistically underpowered. As studies used differ-ent scales and definitions for non-severe

Table 1. Summary of studies comparing CSII with analogue- or NPH-based basal-bolus MDI regimens with HbA1c and hypogly-caemia endpoints.

Reference Population Study design CSII intervention MDI regimenNumber ofparticipants

Studyduration Main findings

deVries et al. [26] Adults Randomisedparalleldesign

CSII therapy withrapid- actinginsulin analogue

NPH-basedbasal insulinplusmealtimeaspart

62 16 weeks Mean HbA1c was 0.84% (95% CI, −1.31 to−0.36) lower in the CSII group comparedwith the MDI group (p = 0.002). Number ofpatients with severe hypoglycaemiaepisodes was similar in either group.

Hoogma et al.[27]

Adults Randomisedparalleldesign


NPH-basedbasal insulinplusmealtimelispro

272 6 months Hba1c values were similar at baseline(8.3 ± 1.1 vs. 8.2 ± 1.4%), and reducedsignificantly in the CSII compared to theMDI group (7.45 vs. 7.67%, p < 0.001). CSIIusers had significantly fewer severehypoglycaemia events (0.5 vs. 0.2 eventsper patient year, p < 0.001)

Skogsberg et al.[28]

Paediatrics Randomisedparalleldesign


NPH-basedbasal insulinplusmealtimeaspart

72 24 months HbA1c was similar at baseline (8.2 ± 0.4%in the CSII group and 8.4 ± 0.5% in theMDI group, p = 0.57). There was nosignificant difference in HbA1c after24 months (6.5 ± 0.4 vs. 6.7 ± 0.5%,p = 0.66). There were no significantdifferences in severe hypoglycaemiabetween the two groups.

Bolli et al. [29] Adults Randomisedparalleldesign


Analogue-based basalbolustherapy

50 24 weeks Mean A1C reduction was similar in the twogroups (CSII −0.7 ± 0.7%; MDI−0.6 ± 0.8%) with a baseline-adjusteddifference of −0.1% (95% CI, −0.5 to 0.3).The incidence of overall hypoglycaemiaevents was similar in either group.

Doyle et al. [30] Paediatrics Randomisedparalleldesign



32 16 weeks HbA1c levels in the CSII group significantlydecreased from 8.1 ± 1.2% to 7.2 ± 1.0% at16 weeks (p < 0.02 vs. baseline andp < 0.05 vs. MDI group). No significantdifference in HbA1c was observed in theMDI group. Five episodes of severehypoglycaemia occurred in the MDI group,and none in the CSII group.

Bergenstal et al.[31]

Adults andpaediatrics

Randomisedparalleldesign

Sensor-augmentedpump therapy withrapid-acting insulinanalogue


495 12 months Baseline mean HbA1c level (8.3% in bothgroups) decreased to 7.5% in the sensor-augmented pump therapy group(−0.8 ± 0.8 percentage points), comparedwith 8.1% in the injection-therapy group(−0.2 ± 0.9 percentage points). Between-group difference was −0.6 percentagepoints (95% confidence interval CI, −0.7 to−0.4; p < 0.001). Rate of severehypoglycaemia did not differ between thetwo groups.


hypoglycaemia, only studies reporting severe hypogly-caemia events will be summarised.

A Cochrane review reported a lower incidence ofsevere hypoglycaemia events for CSII than MDI, butno meta-analysis of the data was provided.[24] In ameta-analysis that included randomised controlledand before/after studies of participants with significantrisk of severe hypoglycaemia (initial rate >10 episodes/100 patients years of treatment), those on CSII had asignificantly reduced rate of severe hypoglycaemiacompared to MDI (rate ratio of 2.89 [95% CI, 1.45–5.76] for randomised controlled trials (RCTs) and 4.34[2.87–6.56] for before/after studies).[34] Sub-analysisshowed that older participants and those with a highfrequency of hypoglycaemia at baseline had the great-est reduction in severe hypoglycaemia. A meta-analysisof three RCTs comparing CSII using insulin analoguesand MDI showed a similar pooled incidence of severehypoglycaemia in both groups.[41] The confidenceinterval of the pooled odds ratio was notably wide[0.74 (95% CI, 0.30–1.83)], likely due to the small num-ber of participants involved in each study (less than 50in each intervention group) and the relatively low ratesof severe hypoglycaemia episodes.

4.3 Quality of life

In a randomised controlled study, 50 participants onNPH-based insulin therapy were randomised toeither lispro-based CSII or lispro and glargine-basedMDI for 24 weeks.[29] Diabetes treatment-satisfac-tion scores were significantly higher in those onCSII. The 5-Nations trial randomised 272 participantsto CSII or NPH-based MDI, in which the CSII groupshowed significantly higher overall scores for dia-betes-specific QOL domains and improvement inmental health perceptions.[27] Observational studieshave similarly reported significant improvements inQOL and treatment satisfaction scores in CSII userscompared to MDI.[43,44] A large case-control studyinvolving 481 CSII and 860 MDI users (of which 90%were on glargine-based MDI) from 62 centres con-firmed the findings from smaller aforementionedstudies, with higher diabetes-treatment satisfactionscores as well as less fear of hypoglycaemia in CSIIusers.[43]

Findings from formal validated measures of QOL arein concordance with anecdotal evidence observed inusual clinical practice, where most CSII users self-reportimprovements in well-being and mood when transi-tioned from MDI to CSII. Discontinuation rate for CSII,either by choice or otherwise, is reportedly low at mostclinical centres.[45] This highlights the potential

psychosocial benefits of CSII on the life of those withtype 1 diabetes, beyond glycaemic control per se.

5. Combining insulin delivery with continuousglucose monitoring: what benefit does it add?

5.1 Continuous glucose monitoring with multipledaily insulin injections

Real-time continuous glucose monitoring (CGM) allowsusers to make immediate adjustments to their insulindoses, food intake and physical activity by inspectingglucose values and trends, and by responding to lowand high glucose alarms. The present generation ofreal-time CGM devices utilises a minimally invasive sub-cutaneously implanted needle-type amperometricenzyme electrode to measure interstitial glucose con-centration by detecting changes in the electric currentcaused by the enzymatic catalysation of glucose byglucose oxidase into hydrogen peroxide, and displaynew glucose readings every 1–5 min.[46]

Comparative analyses of CGM in CSII versus MDIusers are challenging as most studies included partici-pants who were on mixed modes of insulin delivery, orwere using either real-time or retrospective CGM (sen-sor values were masked to participants). TheHypoCompass study was a 24-week 2 × 2 factorialRCT that studied the effects of different methods ofinsulin delivery and glucose monitoring on restoringhypoglycaemia awareness and preventing severe hypo-glycaemia in participants with hypoglycaemia unaware-ness (Gold score ≥4).[47] A sub-analysis comparingCGM-MDI with CGM-CSII therapy showed no significantdifferences at follow-up in biochemical hypoglycaemiameasures, severe hypoglycaemia episodes, Gold scoresand HbA1c. However, the analysis is weakened by thefact that it did not differentiate between real-time andretrospective CGM users in the CSII and MDI groups. Nopublished studies to date have evaluated CGM effec-tiveness with MDI compared to CSII alone.

5.2 Sensor-augmented pump

Sensor-augmented pump therapy (SAP) combines real-time CGM with CSII, an example of which is theParadigm Veo (Medtronic Diabetes, Northridge, CA,USA). SAP provides users with real-time CGM glucoseprofile whilst using CSII, making it a useful adjunctivetool to aid with retrospective and immediate insulindose adjustments. Capillary glucose measurements arestill needed, however, to inform any pre-meal or correc-tion insulin boluses. The first large multicentre RCT, theSTAR3 study, compared the efficacy of SAP with MDI in


children and adults.[31] Subjects on SAP achieved lowerHbA1c levels (7.5% vs. 8.1%, p < 0.001), withoutincreased incidence of hypoglycaemia. Improvementin Hba1c was still observed at the 18-month follow-up.[48] In a 26-week study comparing SAP with MDI,87 adults with type 1 diabetes were randomised toeither SAP or MDI therapy with rapid-acting insulinanalogue before meals and long-acting analogues orhuman insulin.[49] The study showed a significantimprovement in the primary outcome (mean differencein change in HbA1c after 26 weeks) in favour of SAP(−1.21% (95% CI, −1.52 to −0.90, p < 0.001). Theimprovement in HbA1c was achieved without increas-ing time spent hypoglycaemic (CGM values below4.0 mmol/l), with between-group difference 0.0% (95%CI, −1.6 to 1.7, p = 0.96).

The benefit of adding CGM to CSII was confirmedby a meta-analysis of four randomised controlled stu-dies ranging between 15 weeks and 1-year duration,which reported a greater reduction in HbA1c for SAPthan MDI (combined mean between-group differencefrom baseline −0.68% [95% CI, −0.81 to −0.54).[41] Theauthors were unable to perform a pooled analysis onthe incidence of severe hypoglycaemia due to thedifferent measures used by the included studies, andas a result we were unable to draw a definitive con-clusion. A large (n = 263) single-arm observationalstudy showed that benefits of SAP persisted after36 months in terms of HbA1c improvements(decreased from 8.7% to 7.3%, p < 0.001), as well astreatment satisfaction (improvement in DiabetesTreatment Satisfaction Questionnaire score by 9points, p < 0.001).[50]

5.3 Threshold-based insulin pump suspension andpredictive low glucose management

SAP with automated insulin suspension represents thefirst step towards automated glucose-responsive insulindelivery systems. The low-glucose suspend (LGS) function(Paradigm Veo, Medtronic Diabetes, Northridge, CA, USA)allows insulin to be automatically suspended for up to 2 hwhen sensor glucose falls below a present threshold,which is determined by the user or health-care provider,and the hypoglycaemic alarm is not acknowledged.There are no published data comparing LGS with MDI,with SAP being the active comparator in randomisedcontrolled studies. Post-marketing studies in childrenand adults have reported reduced duration of hypogly-caemia, especially in those at the greatest risk of noctur-nal low-glucose events.[51,52] LGS led to a significantlylower rate of second and subsequent hypoglycaemia

episodes, as well as a lower rate of hypoglycaemia eventsoverall. Despite the temporary insulin suspension, noevidence of increased ketosis or deterioration in HbA1cwas observed. The ASPIRE In-Home was a large rando-mised controlled study that evaluated the effects of LGScompared with SAP on HbA1c and nocturnal hypogly-caemia in patients at risk with at least two nocturnalhypoglycaemic events during the run-in phase.[53] Themean area under the curve for nocturnal hypoglycaemicevents was lower by 37.5% compared to SAP with com-parable HbA1c, thus confirming that LGS can reducenocturnal hypoglycaemia episodes without deteriorationof glycaemic control.

The predictive low glucose management (PLGM)function of the Medtronic 640G CSII device was recentlyintroduced into clinical practice in Europe. In compar-ison to LGS, the hypoglycaemia-prediction algorithmand automatic pump suspension of the PLGM systemenable insulin delivery to be suspended when hypogly-caemia is predicted and insulin delivery automaticallyrestarted when hypoglycaemia risk recedes. Preliminaryefficacy and safety data in an outpatient setting over21 nights showed that PLGM reduced the proportion ofnights with sensor glucose <3.9 mmol/l by 40%.[54]Mean overnight glucose and morning fasting glucosewere reported to be higher than control nights (withoutPLGM). The investigators had to modify the hypoglycae-mia-prediction horizon of the algorithm twice duringthe experiment, as pump suspensions occurred fre-quently, leading to elevated overnight and morningglycaemia levels. A randomised controlled study evalu-ated PLGM use at home compared to conventional SAPfor 42 nights.[55] The primary endpoint of the study,percentage of nights with at least one sensor glucosevalues <3.3 mmol/l, was approximately halved by PLGM(odds ratio 0.52 [95% CI, 0.43–0.64]; p < 0.001). Therewas no difference in overnight sensor glucose levels>10 mmol/l (57 vs. 59% of nights, p = 0.17). Currentresults suggest that the use of LGS or PLGM systemsdoes not mitigate against overnight or early morninghyperglycaemia.

6. Limitations and potential solutions

6.1 Technical and mechanical issues

Despite the technological applications in modern CSIIdevices such as alerts and alarms for catheter occlusionor pump failures, CSII users may still be exposed tosignificant and potentially life-threatening conditions ifthere is lack of vigilance. As there is no subcutaneousdepot of long-acting insulin during CSII use, interrup-tion of insulin delivery due to catheter displacement,


catheter/tubing occlusion, battery failure or depletionof insulin supply puts the user at risk of diabetic ketoa-cidosis, especially if the interruption is prolonged. In across-sectional survey of 92 CSII users, nearly halfreported some form of pump mechanism malfunction.[56] This includes unintended stoppage of CSII deliveryand keypad/button problems on the CSII device.Approximately 10% of those surveyed also reportedfrequent kinking or blockage of the infusion set, withan increasing trend associated with the use of the infu-sion set for longer than 3 days. This highlights theimportance of user and health-care provider adherenceto proper CSII care and practice guidelines to mitigateagainst potential and relatively common hazards. It alsounderpins the need for regulation of CSII devices toensure safety standards are met and to improve thereliability of CSII components by manufacturers.[57]

6.2 Insulin absorption and pharmacokinetics

Subcutaneous absorption and action of insulin via CSIImay be altered by local site reactions such as inflam-mation or lipohypertrophy. The quantitative effects oflipohypertrophy on changes in insulin pharmacoki-netics and pharmacodynamics are still poorly under-stood due to the lack of well-conducted studies in thisarea.[58] As a potential source of glycaemic variability,this may be of significant clinical concern given that arecent survey of CSII users revealed that approximatelyone in four might have lipohypertrophy.[56] Thereforeidentifying and avoiding user-driven factors such asrepeated injections/infusion with needles/catheters atthe same body site should be common practice for allCSII users and healthcare professionals providing clin-ical care. Future development of alternative infusiondelivery mechanism such as intra-dermal microneedleor use of hyaluronidase enzyme may accelerate theaction and improve the pharmacokinetic consistencyof insulin analogues used in CSII devices.[59,60]

6.3 Cost-effectiveness

The higher cost of CSII compared to MDI presentsanother limitation to its wider use. In the UK, theannualised cost of CSII with a 4–6-year warranty isapproximately £1700 greater than MDI.[61] Thisincludes the unit cost of CSII device and consumablesrelated to infusion sets and reservoirs; however, it doesnot factor in expenditures on staff and education time.Utilising the Centre for Outcomes Research (CORE)model and based on assumptions of Hba1c as well asQOL improvements, NICE in the UK deems CSII to becost-effective based on a willingness to pay threshold

of £20,000–£30,000 per quality-adjusted life yeargained.[45] The estimated cost per quality-adjustedlife year improves in favour of CSII, if the expectedreduction in HbA1c is greater due to the expectedreduced complications risk and health-care costs. TheCORE model outcome assumes an average age of40 years at baseline and is greatly influenced byHbA1c reduction rather than indices or impact of hypo-glycaemia. The existing economic model does not ade-quately address the paediatric population or theindividual and societal burden in those at greatest riskof hypoglycaemia, such as loss of productivity at workor school and mental health issues related to fear ofhypoglycaemia. There is therefore a need to reappraisethe analysis of CSII cost-effectiveness with various sta-keholders so that those who may benefit the most fromCSII are also included.

7. Expert opinion

The ongoing debate of CSII and MDI use in clinicalpractice has stemmed from the growing need byclinicians as well as health care service providers toascertain the relative benefit of one interventionagainst the other. Clinicians and people with type 1diabetes face significant challenges when intensifyinginsulin therapy to reduce the risk of complications.The overall evidence currently point towards modestimprovements in HbA1c level, severe hypoglycaemiarates and QOL measures in favour of CSII comparedto MDI, but also that CSII may benefit some morethan others. An important limitation is that manystudies do not provide adequate information relatedto the extent of patient education, and whether self-management skills provided to both groups werecomparable. Some analyses included participants noton analogue-based basal-bolus MDI regimens, andinformation on adherence to skills such as carbohy-drate counting are lacking. These insufficiencies mayconfound reported outcomes, highlighting the needfor well-designed powered studies with the compara-tor following “best clinical practice” and ensuringequal provisions for self-management skills and edu-cation among CSII and MDI users.

In reviewing the data to address clinical decision-making, few studies and meta-analysis currently focuson those with significant and proven clinical need.Analysis should be focused on groups with the highestbaseline HbA1c and hypoglycaemia burden rather thanthose who are already managing well on MDI, as it isthe former rather than latter who may benefit the mostwhen transitioned to CSII. Due to the relatively shorterduration of diabetes and hypoglycaemia exposure in


the paediatric population, there is still a need for well-conducted statistically powered studies. This is espe-cially true given the benefit of CSII to date in terms oflifestyle flexibility and psychosocial impact for parentsand children with type 1 diabetes. Early evidence arealso starting to emerge about the potential benefit ofCSII in lowering cardiovascular mortality compared toMDI.[62] The exact mechanism however is unknown,and the finding remains to be verified and replicatedin other cohorts.

The importance of self-empowerment and educationhas to be addressed in any form of insulin therapy intype 1 diabetes. Observational studies have shown thatthose who are motivated to invest the time and effort,and are well-educated in their diabetes self-care, aremore likely to achieve better glycaemic control.Family-centred, structured education programme inspecialist centres and routine clinical care among thepaediatric population have shown more personalengagement by family members around diabetes-related tasks; however, the improvements in HbA1cwere relatively modest.[63,64] In addition, ensuringoptimal training and education to families and thoseneeding it the most can be challenging, as reported bya qualitative study evaluating the feasibility of an edu-cation programme carried out across paediatric clinicsin the UK.[65] Among the reported barriers were orga-nisational difficulties and time-commitment by staffmembers, reflecting real-world feasibility issues. Adultdiabetes education courses such as Dose Adjusted forNormal Eating (DAFNE) in the UK, which are deliveredby trained diabetes educators, have shown benefits inglycaemic control and QOL.[66,67] Optimisation of MDItherapy using programmes such as DAFNE shouldtherefore be offered to all adults with type 1 diabetes.

The support and engagement to optimise their MDItherapy should be continuous during the course oftheir care with both parties fully involved, rather thanto be used as a short-term bridge before CSII initiation.Transitioning to CSII, users and healthcare providersshould acknowledge that realising the full potential ofCSII involves similar if not more commitment to self-care, as well as a good knowledge base of insulintherapy. Trained pump educators should be availableto provide support after transitioning to CSII, for exam-ple in downloading and reviewing glucose/insulin datafrom CSII devices, and helping make appropriate adjust-ments to insulin delivery settings. Future studies deter-mining the benefits of CSII over MDI following exposureto structured educational programmes should ensurethat such programmes cater for comprehensive CSIItraining and retraining.

Further innovation in diabetes technology is antici-pated. The advent of SAP shows that integration ofCSII with real-time CGM may provide additional ben-efit to glycaemic control in both adults and youthwith type 1 diabetes, provided CGM use is high andconsistent. Automated insulin delivery suspension atlow or predicted low CGM levels may confer addi-tional protection against hypoglycaemia, especially inthose at greatest risk. Rapid progress in also beingmade in the development of closed-loop insulin deliv-ery systems, also known as the “artificial pancreas”,which uses a control algorithm that automaticallysmoothly modulates (increases and decreases) CSIIinsulin delivery based on real-time CGM values.[68]Results from closed-loop clinical studies conductedin controlled research facility and unsupervisedhome settings have been promising.[69–71] Recentlya 3-month application of closed-loop insulin deliveryin real-world free-living conditions showed significantimprovements in glycaemic control and reduction ofhypoglycaemia events compared to optimised SAP.[72] Larger and longer multicentre studies are beingplanned, and closed-loop insulin delivery systems mayact as a “bridge” until a biological cure for type 1diabetes is found.

Advances in diabetes treatment and technology havethe potential to reduce the considerable demands type 1diabetes management has on people with type 1 dia-betes and their caregivers. In those unable to achievetheir glycaemic goal in spite of sufficient support, CSIImay benefit them whilst potentially improving theirQOL. Well-conducted studies in those who would likelybenefit from CSII most are still needed to provide furtherguidance and information to health-care providers, andevidence for its use in clinical practice.

Declaration of interest

The authors were supported by JDRF, Seventh FrameworkProgramme of the European Union, Diabetes UK, NationalInstitute for Health Research Cambridge Biomedical ResearchCentre and Wellcome Strategic Award (100574/Z/12/Z). RHovorka reports having received speaker honoraria fromMinimed Medtronic, Eli Lilly, BBraun and Novo Nordisk, ser-ving on advisory panel for Eli Lilly, receiving license fees fromBBraun and Medtronic; having served as a consultant toBBraun, Sanofi-Aventis, and Profil; and patents in the field. HThabit declares no competing financial interests exist. Theauthors have no other relevant affiliations or financial involve-ment with any organisation or entity with a financial interestin or financial conflict with the subject matter or materialsdiscussed in the manuscript apart from those disclosed.


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http://dx.doi.org/10.1056/NEJMoa1509351

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