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Interventions That RestoreAwareness of Hypoglycemia inAdults With Type 1 Diabetes:A Systematic Review andMeta-analysisDiabetes Care 2015;38:1592–1609 | DOI: 10.2337/dc15-0102

OBJECTIVE

Impaired awareness of hypoglycemia (IAH) increases the risk of severe hypogly-cemia (SH) sixfold and affects 30% of adults with type 1 diabetes (T1D). Thissystematic review and meta-analysis looks at the educational, technological,and pharmacological interventions aimed at restoring hypoglycemia awareness(HA) in adults with T1D.

RESEARCH DESIGN AND METHODS

We searched The Cochrane Library, MEDLINE, Embase, Science Citation IndexExpanded, Social Sciences Citation Index, PsycINFO, and CINAHL from inceptionuntil 1 October 2014. Included studies described HA status at baseline. Outcomemeasures were SH rates, change in HA, counterregulatory hormone responses,and glycemic control.

RESULTS

Forty-three studies (18 randomized controlled trials, 25 before-and-after studies)met the inclusion criteria, comprising 27 educational, 11 technological, and 5pharmacological interventions. Educational interventions included structured di-abetes education on flexible insulin therapy, including psychotherapeutic andbehavioral techniques. These were able to reduce SH and improve glycemic con-trol, with greater benefit from the latter two techniques in improving IAH. Tech-nological interventions (insulin pump therapy, continuous glucose monitoring,and sensor-augmented pump) reduced SH, improved glycemic control, and re-stored awareness when used in combination with structured education and fre-quent contact. Pharmacological studies included four insulin studies and onenoninsulin study, but with low background SH prevalence rates.

CONCLUSIONS

This review provides evidence for the effectiveness of a stepped-care approach inthemanagement of patients with IAH, initially with structured diabetes educationin flexible insulin therapy, which may incorporate psychotherapeutic and behav-ioral therapies, progressing to diabetes technology, incorporating sensors andinsulin pumps, in those with persisting need.

1Diabetes Department, King’s College Hospital,London, U.K.2Diabetes Research Group, King’s College London,London, U.K.3Division of Health and Social Care Research, De-partment of Primary Care and Public Health Sci-ences, King’s College, London, U.K.

Corresponding author: Ester Yeoh, [email protected].

Received 15 January 2015 and accepted 27March 2015.

This article contains Supplementary Data onlineat http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-0102/-/DC1.

© 2015 by the American Diabetes Association.Readers may use this article as long as the workis properly cited, the use is educational and notfor profit, and the work is not altered.

Ester Yeoh,1 Pratik Choudhary,2

Munachiso Nwokolo,2 Salma Ayis,3 and

Stephanie A. Amiel2

1592 Diabetes Care Volume 38, August 2015

SYSTEM

ATICREV

IEW

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http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc15-0102/-/DC1


Hypoglycemia remains the major limit-ing factor toward achieving good glyce-mic control (1). Recurrent hypoglycemiareduces symptomatic and hormone re-sponses to subsequent hypoglycemia(2), associated with impaired awarenessof hypoglycemia (IAH). IAH occurs in upto one-third of adults with type 1 diabe-tes (T1D) (3,4), increasing their risk ofsevere hypoglycemia (SH) sixfold (3)and contributing to substantial morbid-ity, with implications for employment(5), driving (6), and mortality. Distribu-tion of risk of SH is skewed: one studyshowed that 5% of subjects accountedfor 54% of all SH episodes, with IAH oneof the main risk factors (7). “Dead-in-bed,” related to nocturnal hypoglyce-mia, is a leading cause of death in peoplewith T1D ,40 years of age (8).Although small research studies have

shown that meticulous avoidance of hypo-glycemia can improve awareness of hypo-glycemia (9), achieving this in clinicalpractice is difficult and hard to sustain.Strategies used include educational ap-proaches, using biopsychosocial or behav-ioral therapies; technological interventions,such as continuous subcutaneous insulininfusion (CSII), continuousglucosemonitor-ing (CGM), and sensor-augmented pumps(SAP); and pharmacotherapies.This systematic review assessed the

clinical effectiveness of treatment strate-gies for restoring hypoglycemia aware-ness (HA) and reducing SH risk in thosewith IAH and performed a meta-analysis,where possible, for different approachesin restoring awareness in T1D adults. In-terventions to restore HA were broadlydivided into three categories: educational(inclusive of behavioral), technological,and pharmacotherapeutic.

RESEARCH DESIGN AND METHODS

Search Strategy, Study Selection, andInclusion CriteriaA systematic literature search in the data-bases of The Cochrane Library, MEDLINE,Embase, Science Citation Index Ex-panded, Social Sciences Citation Index,PsycINFO, and CINAHL was performedfrom inception until 1 October 2014. Ad-ditional studies were identified by hand-searching reference lists of included trialsand systematic reviews and contactingexperts in the field. Search terms andtheir synonyms used were type 1 diabe-tes mellitus, hypoglycemia, low glucose,hypoglycemia unawareness, impaired

awareness of hypoglycemia, avoidanceof hypoglycemia, and awareness (Supple-mentary Table 1).

The recommendations of the Centrefor Reviews and Dissemination for Sys-tematic Reviews (10) were followed. Allrandomized controlled trials (RCTs),nonrandomized controlled trials, andbefore-and-after studies that assessedinterventions to restore HA were in-cluded. Case series and case reportswere excluded.

Inclusion criteria were adults (age$18)with T1D using accepted criteria (11).Studies must have described HA statusat baseline by validated scoring systemssuch as the Clarke (12) orGold (13) scores.In studies that did not use these scores,accuracy of blood glucose (BG) estimatewas allowed as a surrogate measure ofawareness status. Studies performed inpeople with type 2 diabetes, involvingfewer than five participants, those aged,18 years, or who had,1 month follow-up were excluded.

Islet and pancreas transplantationswere excluded because intractable recur-rent severe hypoglycemia is a proven in-dication for these interventions (14,15).

Data Collection and ExtractionTwo authors (E.Y. and M.N.) indepen-dently assessed abstracts and titles foreligibility and extracted data, with differ-ences in interpretation resolved by a thirdreviewer (P.C.) and consensus after dis-cussion. Full texts of studies that fulfilledinclusion criteria were obtained and dataextracted using a standardized data ex-traction table. Relevant missing informa-tion was sought from article author(s).

Interventions were classified into pa-tient education (including diabetes educa-tion classes, psychological interventions,behavioral therapy); use of technology(CSII, CGM sensors, retrospective or real-time [RT]), and pharmacological therapies(insulin analogs andotherpharmacologicalagents). For studies with more than oneintervention (e.g., combining educationand technology), the technological inter-vention was considered the primary inter-vention with a further description of allinterventions.

Outcome measures were categorizedinto SH rates (defined as events requir-ing external assistance [16]), restora-tion of HA (Gold [13] or Clarke [12]scores), subjective recognition of low BGby participants or improved autonomic or

neuroglycopenic symptoms, responsesto hypoglycemia assessed by symptomscores (17), counterregulatory hormoneresponses, and changes to glycemic con-trol measured by HbA1c.

Quality AssessmentTo assess the quality of included studies,Preferred Reporting Items for SystematicReviews and Meta-Analyses (PRISMA)guidelines were used for RCTs (18) andMeta-analysis of Observational Studies inEpidemiology (MOOSE) guidelines for ob-servational studies (19). Instead of a scoreallocated to each study for quality as-sessment, we assessed the strength ofevidences using the four domains sug-gested by the Agency for Healthcare Re-search andQuality guidelines (20): risk ofbias, consistency of effect sizes, direct-ness of link between interventions andoutcomes, and precision or the certaintyof effect in relation to a specific outcome.Additional Agency for Healthcare Researchand Quality domains include assessmentof a dose-response association, existenceof confounders, strength of association,and publication bias. The first three ofthese are more relevant to observationalstudies thanRCTs. The strengthofevidencewas based on a global assessment of all ofthese domains and studies graded as high,moderate, low, or insufficient. A study wasconsidered of high quality if it was a well-conductedRCT, prospective,with a low riskof bias, and accounted for confounderssuch as age and diabetes duration.

Data Synthesis and AnalysisIf interventions studied had sufficientdata, MedCalc software was used toperform a meta-analysis pooling the stan-dardized mean difference (SMD). If stud-ies did not directly report the mean andSD for change from baseline to 12monthsfor the outcomes of interest, these werecalculated. Where outcomes were mea-sured on different scales, SMDs werecombined,wherepossible. Studies report-ing outcomes in a measure that was notsuitable for inclusion into themeta-analysisare presented as a summary of findingsand analyzed in a narrative synthesis.

In the meta-analysis, heterogeneitywas assessed using the I2 statistic. Effectsizes were pooled by using fixed-effectsand random-effects models. The twomodels used different assumptions.The former assumes there is one trueeffect size that is shared by all of theincluded studies, and the latter, by

care.diabetesjournals.org Yeoh and Associates 1593



http://care.diabetesjournals.org

contrast, assumes that the true effectcould vary from study to study.

RESULTS

Study SelectionThe database search identified 1,683 ab-stracts until 1 October 2014 (Fig. 1). Re-view of titles and abstracts identified 57full-text articles meeting the inclusion cri-teria. A further two articles were re-trieved from reference lists of includedarticles, of which one met inclusion crite-ria. Forty-three studies were included inthe final systematic review, summarizedin Table 1.

Summary of the Included StudiesPatient educationwas the primary inter-vention in 27 included studies (8 RCTs);

11 (6 RCTs) were based on technology,and 5 (all RCTs) examined pharmaco-therapeutics. In four studies combiningmultiple interventions (e.g., educationwith technology with/without pharma-cotherapy), one intervention was classi-fied as primary and the other thecomparator. Studies with long-termfollow-up or different outcomes wereanalyzed separately.

Thirteen studies were conducted inNorth America and Canada, 10 in theU.K., 19 elsewhere in Europe, and 1 inAustralia. Numbers of subjects enrolledwere generally ,100, with 10 studiesinvolving $100 subjects. Follow-upranged from 1 to 12 months, withlong-term follow-up (.1 year) reportedfor eight studies.

Qualitative Summary of Interventions

Education

This represented the largest interven-tion group: 27 relevant studies used aneducational approach to restore HA.

Education Before-and-After. Therewere 20studies in this category: 8 in unselectedpopulations with T1D (4,21–27) and 12 inparticipantswith IAH at baseline (9,28–38).Eight studies (22,23,24,26,29,30,33,34)were long-term, durations ranging be-tween 1 and 3 years.

In unselected populations with T1D,some educational programs were basedon well-established structured educationin insulin self-management, such as theGerman Diabetes Treatment and TrainingProgram (DTTP), designed in Dusseldorf(39) and adopted elsewhere in Germany(25); Dose Adjustment For Normal Eating(DAFNE) (21); and the Tayside insulinman-agement course (4), an adaptation fromBournemouth type 1 intensive education(BERTIE), whereas others were basedon psychoeducational programs, suchas Blood Glucose Awareness Training(BGAT) (22–24,26), delivered in individualor group settings. All of these approaches,based on adult learning principles, re-sulted in significant reductions in SH ratesof between 15% and 75% in four studies(4,21,22,24), with one showing a trendtoward a lower frequency of low BG read-ings that was not statistically significant(25). BGAT showed improved ability andaccuracy index in recognizing symptomsof low BG (22). The DAFNE (21) andTayside (4) studies were large-scale regis-try data with more than 1,000 patients,followed up for a year, showing general-izability of the interventions. One yearafter DAFNE, the rate of IAH had fallenfrom 39.9% to 33%, with awareness re-stored in 43% of participants reportingIAH at baseline; the Tayside registryshowed improvement in HA in 25% of par-ticipants, although in both studies IAH wasdefined without a known validated score.Glycemic control improved or was main-tained at target level, uninfluenced bythe method of delivery of the structurededucation (individual or group setting).

Only one study assessed effect of ed-ucation on counterregulatory hormoneresponses (27), comparing hypoglyce-mia rates in intensively treated (definedas CSII therapy or multiple daily insulin[MDI] injections, 4–7 BG tests, andweekly contact with the treatmentFigure 1—Flowchart of the systematic review and meta-analysis.

1594 Interventions to Restore Hypoglycemia Awareness Diabetes Care Volume 38, August 2015

Table

1—Su

mmary

ofthe43studiesthatwere

includedin

thefinalsy

stematicreview

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Educationalinterven

tion(before-and-after

studies)

deZoysa,20

14(28)

DAFN

E-HART:

Psychotherap

euticgroup

education(m

otivational

interviewingandcogn

itive

beh

avioraltherap

y),6

sessionsin

patients

with

IAHandSH

.

N=24

;1year

54.4

67.9;

30.7

611

.9Decreased

med

ianSH

from

3(0–10

4)to

0(0–3)

even

ts/

patient/year.MeanSH

18.96

(27.3)

to0.47

8(0.947

)ep

isodes/patient/year.

9of20

(45%

)regained

HA

withGold/Clarkescore

,4.

Gold

score

from

5.66

1.4

to4.56

1.9(P

,0.029

).Clarkescore

from

5.46

1.2

to3.86

1.8(P

,0.001

).

Nochan

gein

HbA1c:

baseline7.86

1.2%

toen

d7.86

1.1%

(P=0.80

).

Jordan,20

13(4)

Taysideinsulin

managem

ent

course:

Structuredgroup

education,1

day

of

educationper

weekfor4

consecutive

weeks.

N=21

0;24

months

456

13.9;

med

ian16

.5(0.5–58

.7)

Decreased

proportionwithSH

(20.3%

to5.4%

).Number

with

$1SH

per

year

was

25to

4patients.

Decreasein

number

of

patients

withHU(34.36

47.8%to

8.66

28%,

P,

0.001

).

Med

ianHbA1c

reduction:8.7%(7.8–

9.7)to

8.2%(7.6–8.9)

(P,

0.00

1).

Hopkins,20

12(21)

DAFN

Eaudit:Structured

diabetes

grouped

ucation

program

,5-day

coursein

flexibleinsulin

therapy.

N=1,16

3;12

months

41.5

613

.7;

18.0

612

.1Decreased

meanSH

:1.76

8.5to

0.66

3.7ep

isodes/person/

year

(P,

0.00

1,n

=53

9).

Improvedhypoglycem

iarecognitionin

those

with

HUin

43%,n

otdefi

ned

accordingto

scoresbutno

symptomsat

BG,54

mg/dL(n

=21

5).

ImprovedHbA1c:8.56

1.4%to

8.26

1.3%

at1year

(P,

0.001

,n=63

9).

Hernandez,2

008(29)

Self-awaren

essed

ucationon

bodycues

associated

with

variouslevelsofglycem

ia.

Eigh

t3-h,b

iweekly

sessions,follow-upstudy

ofHernandez,2

003.

N=29

;18

months

50.5

614

.6;

26.5

(range

10–47

)

Decreased

meanSH

(req

uiring

assistan

ce):13

.33(17.4)to

7.1

(11.59

)(P

=0.478

);meanSH

(hospitalization):0.76(2.19)

to0.19(0.40)

(P=0.370

,n=23

).

Improveddetectionof

symptom

cues

of

euglycem

iaand

hypoglycem

ia.

ImprovedHbA1c:8.86

1.5%to

8.06

1.5%

(P=0.00

2,n

=23

).

Kubiak,20

06(31)

IGwithhypoglycem

ia-specific

educationprogram

(6lessons,45

min)vs.CG

(con

ventionaleducation,

2lessons,45

min).

N=20

7;6months

34.3

612

.9(CG)

vs.37

.06

14.1

(IG);16

.26

9.3

(CG)vs.16.4610.6

(IG)

Decreased

meanSH

inIG:1.16

4.5to

0.16

0.5(P

,0.01,

n=

92);CG:1

.36

4.5to

0.96

5.3

(P=NS,n=85

)butno

difference

inSH

between

groups(P

=0.26).

Using

modified

Goldscore:

visualanalog

scale18.5cm

(0=totalunawareness,18.5=

perfectaw

areness),H

AremainedstaticinIG

(126

4.8to

11.76

5.1,P=NS)but

deterioratedinCG

(11.56

5.6to

10.06

4.7,P,

0.01);

between-groupP=0.06.

Improved

HbA

1cinboth

groups;nodifference

betw

eenIG:6.86

1.6%

to6.36

0.9%

(P,

0.01)andCG

:6.86

1.5%

to6.26

1.3%

(P,

0.05);

betw

een-grou

pP=

0.67.

Broers,20

05(22)

DutchadaptationofBGAT-III

(6weekly1.5–2hsessions);

groupvs.individualsetting.

Psychoed

ucational

interven

tion,follow-up

studyto

Broers,20

02.

N=59

;12

months

43.8

69.4;

22.7

610

.7Decreased

SHep

isodes/year:

7.96

7.5to

1.76

2.4ingroup

vs.6.66

7.6to

0.36

8.5in

individualBGAT(P

=0.001

,n=26

).

Improvedrecognitionof

hypoglycem

iain

both

groups(27.96

24.6%to

42.1

623

.7%)and

individualBGAT(35.36

33.7%to

42.4

625

.6%)

(P=0.02).

Nochan

gein

HbA1c:

7.36

1.2%to

7.36

1.3%in

groupvs.

7.26

0.9%to

7.56

1.1%in

individual

BGAT(P

=0.30).

Con

tinuedon

p.15

96



Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Hernandez,2

003(30)

Refer

toHernandez,2

008.

N=29

;6months

50.5

614

.6;

23.8

611

.0DecreasedmeanSH

requiring

assistan

ce:13.3

617.4

to9.4

614.8

(P=0.454,n=

25);requiringhospitalization:

0.8

62.2

to0.16

0.4

(P=0.227).

Noincrease

inability

todetecthypoglycem

iabut

subjectscould

iden

tify

norm

alBGmore

accurately.

Nochan

gein

HbA1c:

8.96

1.5%to

8.66

1.4%(P

=0.074

).

Broers,20

02(23)

Refer

toBroers,20

05.

N=59

;6weeks

43.8

69.4;

22.7

610

.7Nomeasure

ofSH

butim

proved

decisiononwhen

notto

drive

when

BGwas

lowandto

raise

BGduringhypoglycem

ia.

Accuracy

index

ofBG

perceptionincreasedfrom

8.7

to13.9%(P

=0.11);

improvedrecogn

itionof

hyp

oglycem

icep

isodes

from

32.1

to39.2%

(P=0.12).

Nochan

gein

HbA1c:

7.36

1.2%to

7.26

1.2%(P

=0.80,

n=42

).

Fritsche,

2001

(32)

Hypoglycem

iaavoidance

for4

months,raised

preprandial

andbed

timeBGtargets,

SMBG$5times/day;

contacted

biweeklyfor

insulin

dose

adjustmen

t.

N=10

;4months

466

16;

206

10BaselineSH

2.06

0.6ep

isodes

inthe4monthsbefore

the

studyto

0.Red

ucedfreq

uen

cyofBG,70

mg/dL:8.46

0.9

to1.46

0.3ep

isodes/w

eek

(P,

0.001

).

Improvedautonomicand

neu

roglycopen

icsymptom

scoresduring

hypoglycem

icclam

p.No

chan

gein

epinep

hrineand

norepinep

hrineresponses.

IncreasedHbA1c:6.86

0.3%to

7.76

0.3%

(P,

0.00

01).

Cox,20

01(24)

BGAT-IIpsychoed

ucational

groupprogram

,follow-up

studyofCox,19

95.

N=73

;12

months

38.3

69.1;

19.5

610

.5Decreased

meanSH

episodes/

month:1.66

2.0to

1.16

2.0

(P,

0.002

).Booster

interven

tiondid

notaffect

theseben

efits.

Improvedpercentage

detectionoflowBGfrom

346

29%to

446

27%(P

,0.005

).

Nochan

gein

HbA1c:

10.2

62.0%to

10.26

1.9%(P

=NS).

Dagogo-Jack,19

99(33)

Avoidance

ofhypoglycem

ia,

3-year

follow-upstudyof

Dagogo-Jack,19

94.

N=4;

3years

26.8

64.7;

15.5

64.4

In2patients,B

G,59mg/dLwas

2.6

60.6%compared

with

13.2

61.4%at

baselin

ean

d4.8

62.3%at

reversalofHU

at1year.NoreportonSH

.

Improvemen

tin

neu

rogenic

andneu

roglycopen

icsymptomsscore

at1year

postreversalfrom

preinterven

tion.

Slightincrease

inHbA1c:7.46

0.2%

atbaselineto

7.66

0.8%.

Fritsche,

1998

(25)

5-day

inpatientdiabetes

educationprogram

(DTTP),

2560

-min

lessonson

flexibleinsulin

therapy,

carbohydrate

counting,

correctionandprevention

ofhypo

-and

hyperglycemia.

N=54

;3months

33.7

611

.7;

11.7

69.3

Tren

dtowardlower

freq

uen

cyof

lowBG,70

mg/dLin

patients

withrepeatedSH

vs.those

withnohistory

ofSH

.

Improvedaccuracy

index

of

BGestimationin

patients

withSH

butno

improvemen

tin

thegroup

withoutSH

.

Decreased

HbA1c:8.06

0.3%to

7.16

0.2%

(P,

0.05

).

Con

tinuedon

p.15

97


Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Fanelli,19

97(35)

Avoidance

ofhypoglycem

iafor6monthsin

patients

withT1D(8

without

diabeticautonomic

neu

ropathy[DAN],13

with

DAN)and15

subjects

withoutT1D.

N=21

T1D

(+15healthy

volunteers);

6months

36.9

64.3;

226

4Decreased

freq

uen

cyof

hypoglycem

iaacrossallgroups

;20

to;2ep

isodes/patient-

month.SH

did

notoccur.

Improvedautonomicand

neu

roglycopen

icsymptomsin

allgroups.

Responseswerelower

inDAN+than

DAN2

patients.

Plasmaep

inep

hrine

responsesto

hypoglycem

iaim

provedinDAN2

butnot

sign

ificantin

DAN+.

Responsesremained

lower

than

insubjectswithout

T1D.

IncreasedHbA1cin

all

groupsbutremained

within

therap

eutic

target:6.26

0.3%

to6.96

0.2%(P

,0.05).

Liu,19

96(36)

Avoidance

ofhypoglycem

iawithless

strict

glycem

iccontrolandhigher

BG

targets,SM

BG4times

daily

withmodificationofinsulin

doses.

N=7T1D

(+12healthy

volunteers);

3months

366

3;18

64

NoSH

duringthestudyperiod,no

baselinerate.Decreased

number

ofep

isodes

of

hypoglycem

ia,54

mg/dL,

from

mean4.7(SE1.3)to

1.9

(SE0.5)/patient/week

(P,

0.05).

Improvedsymptomsscores

forsw

eatingandlack

of

concentration.Im

proved

GHandep

inep

hrine

responsesbutnochanges

inglucagon

,norepinephrine,

andcortisol.

IncreasedHbA1c:6.96

0.3%to

8.06

0.3%

(P,

0.05

).

Cox,19

95(26)

BGAT-II,refer

toCox,20

01.

N=10

0;6months

38.2

69.0;

19.3

610

.4Im

provedlowBGindex

(predictor

offuture

SHoccurren

ce)in

patients

withHAbutnot

sign

ificantforHUgroup.No

reportofSH

.

Betteraccuracy

indetecting

BGfluctuationsandlowBG

levels.Those

withreduced

HAhad

improveddetection

oflowBG.

Notavailable.

Davis,1

994(27)

Conventionalinsulin

therapy

vs.intensive

insulin

therapy.

N=5;

6–10

months

27.6

66.6;

9.66

6.2

Freq

uen

cyofhypoglycem

iaduringconventionaltherapy

vs.intensive

insulin

therapy

was

0.6vs.2.2ep

isodes/

patient/weekbased

on

symptomaticeven

tsorBG

,59

mg/dLreported

toclinician.

Red

uctionin

total

hypoglycem

iasymptom

scoreswithintensive

insulin

therap

y,withno

reversalonreinstitutionof

conventionaltherapy.

Lower

plasm

aglucose

tostim

ulate

plasm

aep

inep

hrinesecretion

duringintensive

therap

ycompared

withinitial

conventionaltherapy

withoutcomplete

reversal

onreinstitutionof

conventionaltherapy.

HbA1cin

conventional

group:9

.56

1.2%vs.

6.66

0.2%in

intensive

insulin-

treatedgroup

(P,

0.00

01),then

to9.76

0.9%

withconventional

treatm

ent

(P,

0.00

5).

Con

tinuedon

p.15

98



Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Dagogo-Jack,19

94(34)

Refer

toDagogo

-Jack,19

99.

Originalgroupof18

patients

(6HA,6

HU,6

healthyvolunteers).

N=12

T1D

(+6healthy);

3months

26.5

64.2;

16.9

63.6

ProportionofBG,59

mg/dL

decreased

from13

.26

1.4%to

4.86

2.3%(P

,0.02).

Increase

intotaln

eurogenic

andneu

roglycopen

icsymptomsscore

responses

tohypoglycem

ia.No

sign

ificantincreasesin

neu

roen

docrineresponses

(epinep

hrine,

pancreatic

polypep

tide,

glucagon,G

H,

andcortisol)after

interven

tion.

Increase

inHbA1c:7.46

0.2%to

7.96

0.2%(P

,0.001

)after3

monthsofavoidance

ofhypoglycem

iain

HUgroup.

Cranston,1

994(9)

Avoidan

ceofhypoglycem

iafor3weeks

in2groupsof

patients:A)goodglycem

iccontrol(HbA1c,7%

)and

B)poorglycem

iccontrol

(HbA1c8.2%

withwide

fluctuationsofBG).

N=12

;4months

Age

range

28–55

;durationrange

11–32

years

Freq

uen

cyofhypoglycem

iafell

from

21per

month

ingroupA

and14

per

month

ingroupBto

nonein

either

group.

Improved

symptom

sscores

after3weeks

ofno

hypo

glycem

ia.Improved

glucosethresholdfor

recognitionof

hypo

glycem

iaingrou

pA

from

glucosethresholdof

2.36

0.18

to3.46

0.23

mmol/L

(P=0.0005)and

from

2.46

0.25

to3.36

0.14

mmol/L

(P=0.015)

ingrou

pB.Improved

coun

terregulatoryho

rmon

e(adrenaline,no

radrenaline,

GH)respon

ses.

Nosign

ificantchan

gein

HbA1cduring

interven

tionperiod;

groupA:6

.56

0.17%

to6.96

0.25%

(P=

0.32)

andgroupB:

8.26

0.18%

to8.76

0.32%

(P=0.26).

Fanelli,19

94(38)

Intensive

insulin

therapy

(physiologicinsulin

replacemen

tand

continuoused

ucation)

withavoidance

of

hypoglycem

ia.

N=21

T1D(16

inIG,5

inCG)

(+20healthy

volunteers);

12months

336

2;11

.46

1.8

Decreased

freq

uen

cyof

hypoglycem

ia(,

72mg/dL)in

IGfrom

0.526

0.05to

0.05

episodes/patient/day

vs.no

decreasein

freq

uen

cyof

hypoglycem

iainCG.B

aseline9

patients

had

atleast1SH

duringtheyear

before

studyto

noep

isodes

ofSHduringstudy.

Improvem

entinautonomic

symptom

sinIG,glucose

thresholdforautono

mic

symptom

sat

baselinefrom

2.46

0.06

to36

0.06

mmol/L

at3monthsand

maintainedat

1year

(P,

0.05).Nochange

inCG

.Im

proved

counterregulatory

horm

ones

(adrenaline,

cortisol,G

H)responses

inIG

maintainedat

1-year

follow-up,butno

tno

rmalized

tohealthy

volunteers.N

ochanges

inCG

.

IncreasedHbA1cin

IGbutstillwithin

target

(5.8

60.2%

to6.96

0.1,P

,0.05

,n=16

).CG:H

bA1cshowed

no

increase

over3

months.

Con

tinu

edon

p.15

99


Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Fanelli,19

93(37)

Avoidance

ofhypoglycem

iawithadjustmen

tofdoses

ofinsulin

aimingforhigher

fasting,preprandial,and

bed

timeBGtargets.

N=8T1D

(+12healthy

volunteers);

3months

266

2;56

0.6

Decreased

freq

uen

cyof

hypoglycem

iafrom

0.496

0.05at

baselineto

0.04

60.03

episodes/patient/day

at3

months(P

,0.05).Baseline2

patientshad

atleast1SH

inthe

year

precedingstudyto

noSH

duringstudy.

Improvedneu

roen

docrine

andsymptom

responses

withnodifference

inautonomicglycem

icthresholdscompared

with

healthyvolunteers.

Epinep

hrineresponses

increasedfrom

baseline

butstilllower

than

inhealthyvolunteers.

IncreasedHbA1c:5.86

0.3%to

6.96

0.2%

at3months(P

,0.05

).

Educationinterven

tion(RCTstudies)

Hermanns,20

13(42)

Grouped

ucationprogram

PRIM

AS(IG)vs.DTTP(CG).

N=16

0(n

=81

inIG,79inCG);

6mon

ths

45.4

613

.6;

19.5

613

Red

uctionofSH

inboth

groups.

SHrequiring3rdparty

assistan

ce/patient/year:CG:

0.316

1.5to

0.016

0.1(P

=0.096

)vs.IG:0.29

60.9to

0.066

0.2(P

=0.04);no

between-groupdifference

(P=

0.179

).SH

requiringmed

ical

assistan

ce/patient/year:CG:

0.096

0.3to

0.016

0.1(P

=0.058

)vs.IG:0.19

60.7to

0.06

60.2(P=0.125)(P=0.214

forbetw

een-grou

pdifference).

Improvemen

tinHA(m

odified

Clarkescore)in

both

groups:CG:1.56

1.6to

1.26

1.3(P

=0.010

)vs.IG:

1.86

1.7to

1.36

1.2(P

=0.00

3)butnobetween-

grou

pdifference

(P=0.981).

ImprovedHbA1cin

PRIM

ASgroup:8.36

1.1%to

7.96

1.0%

(P=0.00

4)vs.no

change

inCG:8.16

1.0%to

8.16

1.0%

(P=0.571

)(P

=0.012

betweengroups).

Hermanns,20

10(43)

HyPOS(IG)vs.stan

dard

education(CG),long-term

follow-upstudyof

Hermanns,20

07;85

.6%

wereHUat

baseline.

N=16

4(n

=84

inHyPOS,

n=80

inCG);

31months

466

12.5;

21.4

610

.9Lower

inciden

ceofSH

inHyPOS

vs.CG:0.16

0.2vs.0.26

0.4

episodes/patient/year

(P=

0.04);26

.5%ofpatients

had

1SH

episodein

CGvs.12

.5%in

HyPOS(OR0.4,95

%CI0.2–0.9,

P=0.04).

Notreported

.Nodifference

inglycem

iccontrol:CG:

7.36

1.1%vs.

HyPOS:7.16

0.9%

(P=0.18

).

Hermanns,20

07(44)

Refer

toHermanns,20

10.

N=16

4(n

=84

inHyPOS,

n=80

inCG);

6months

466

12.5;

21.4

610

.9Nodifference

inratesofSH

inCG

vs.H

yPOSgroup,number

ofSH

episodes/patient/year

inCG:

3.66

3.6to

1.26

2.0vs.IG:

3.56

3.6to

0.96

1.9(P

=0.264

);reducedSH

inboth

groups(81.1to

37.7%vs.78

.3to

34.8%),nodifference

betweengroups(P

=0.119

).

Greater

improvemen

tin

HyPOSgrouponmodified

Goldscore

(0–10

;10=fully

HA):CG:4.3to

5.3;IG:4.3

to6.1(P=0.015

).Im

proved

detectionoflowBGand

treatm

entoflowBG.

Increasedintensity

of

hypoglycem

iasymptoms

scoresin

HyPOSgroup.

HbA1cim

provedin

CG

(7.4

61.1to

7.16

0.9,P

=notreported

)andremained

unchangedin

HyPOS

(7.2

60.9to

7.26

0.8,P

=0.21).

Con

tinuedon

p.16

00



Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Schachinger,20

05(45)

Randomized

toBGAT–III(IG

)vs.

physician-guided

self-help

controlintervention(CG).

N=11

1(n

=56

inBGAT,n=55

inCG);

12months

46.4

613

.8;

22.9

612

.1Red

ucedfreq

uen

cyofSH

(episodes/6

months):BGAT:

1.616

3.49to

0.136

0.33vs.

CG:1.766

3.71to

1.786

4.56

(P=0.04

).

Improvedrecognitionoflow,

high,andoverallBGin

BGATvs.CG.Detectionof

lowBGim

provedin

BGAT:

52.7

621

.8%to

65.2

625

.2%butdeterioratedin

CG:53.56

28.0%to

48.06

25.5%(P

=0.005

).

Nochange

inHbA1c:

6.9%

maintained

inboth

groups.

Cox,20

04(46)

Randomized

toSM

BG+

HAATT

(7-w

eekgroup

psychoed

ucational

program

vs.SM

BG(CG).

N=60

(n=30

ineach

group);

18months

38.1

69.3;

13.9

68.5

Red

ucedSH

(2.0to

0.4/subjectin

HAATT

vs.1.8to

1.7in

CG,

P=0.03).

ImproveddetectionoflowBG

(52to

70%forHAATT

vs.58

to55

%in

CG,P=0.00

5).

Nochange

inHbA1c:

HAATT

group8.1to

9.0%

andCG8.0to

8.1%

(P=NS).

Kinsley,1

999(47)

BGATvs.cholesterol

awaren

ess(CG)in

patients

enrolledinto

anintensive

diabetes

treatm

ent

program

.

N=47

(n=25

inBGAT,n=22

inCG);

4months

34.8

68;

96

3Increasedfreq

uen

cyof

hypo

glycem

iaBG,3.9mmol/L

inboth

groups,0.506

0.08to

0.686

0.06ep

isodes/day

(P,

0.05)in

CGvs.0.456

0.06to

0.696

0.07ep

isodes/

day

(P,

0.001)in

BGAT(P

=NSbetwee

ngroups).Nodata

onSH

.

Increasedneurogenicand

neuroglycopenicsymptom

scores

butdidnotdiffer

betweenCG

andBG

AT

groups

before

orafter4

monthsof

intensivediabetes

therapy.Increased

epinephrineresponse

inBG

ATgrouptohypoglycem

ia.

ImprovedHbA1cin

both

groups:9.06

1.1%

to7.86

0.8%(P

,0.00

1)in

CGand

9.16

1.4%to

7.96

1.1%

inBGAT

(P,

0.001

)(P

=NS

betweengroups).

Cox,19

94(48)

Long-term

follow-upofBGAT

patientswithaproportion

ofpatients

receivingBGAT

booster

training.

N=41

(n=14

inBGAT,n=14

inBGAT+booster,

n=13

inCG

);4.9years

42.9

63.5;

16.3

62.8

BGATsubjectshad

fewer

automobile

crashes

than

controlsubjects:15

%in

BGAT

had

atleast1automobile

crash

vs.42%

inCG.SHnotreported

.

BGATpatientshadbetter

estim

ationof

BGlevelsthan

controlsubjects.Percentage

lowBG

s(,

50mg/dL),

detected

byBG

AT+booster,

BGAT,andCG

was

85,

50,and

43%,respectively

(P,

0.02).BG

AT+booster

was

moreaw

areof

hypoglycem

iathan

BGATalone.

Improved

HbA

1covertim

e:BGAT:12.3to

10.2%

andCG

:11.4to

9.9%

.

Technologicalinterven

tion(before-and-after

studies)

Choudhary,20

13(55)

Retrospective

auditofRT-

CGM

use:33patientswere

onCSIIbefore

starting

CGM,1

onMDI,1

converted

toCSIIwithin

2monthsofstartingCGM.

N=35

;12

months

43.2

612

.4;

29.6

613

.6Decreased

med

ianSH

rate

from

4.0(IQR0.75–

7.25

)ep

isodes/

patient-year

to0.0(0.0–1.25,

P,

0.00

1);mean8.16

13to

0.66

1.2ep

isodes/year

(P=0.00

5).

19patients

(54%

)reported

subjectiveim

provemen

tin

awaren

ess,13

nochange,

3slightworsen

ingin

awaren

ess.Paired

Gold

scoresunchangedfor

19/34subjects:5.06

1.5

vs.5.06

1.9(P

=0.67).

ImprovedHbA1c:8.16

1.2%

to7.86

1.0%

(P=0.007

).

Con

tinu

edon

p.16

01


Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Gim

enez,20

10(52)

CSIIuse

inpatientswith.4

nonsevere

hypoglycem

iaeven

tsper

week(inthelast

8weeks)and.2SH

even

tsin

last

2years.

N=20

;24

months

34.0

67.5;

16.2

66.6

SHfellfrom

baselineof1.256

0.44per

subject/yearto0.056

0.22

(P,

0.001

).

ImprovedClarkescore,

baseline5.456

1.19

to1.66

2.03(P

,0.00

1).At

baseline,

19subjectswere

HUaccordingto

Clarke

test,andat

24months,3of

20wereHU.

Nochange

inHbA

1c:

6.66

1.0%

atbaseline

to6.36

0.9%

.

Leinung,20

10(56)

Retrospective

studyonCGM

use

onHbA1candSH

rates.

N=10

4;2.3years

43.2

612

.8;

24.9

612

Red

uctionin

SHwithOR0.40

(95%

CI0.24

–0.65

).64

.4%withIAHat

baseline

nottrackedovertime.

ImprovedHbA1c:7.66

1.1%to

7.26

0.8%

(P,

0.00

1).

Ryan,2

009(54)

CGM

use

inpatientswithSH

.N=18

;2months

52.0

62.3;

29.4

62.8

SHdropped

from

16ep

isodes

inbaselinemonth

to3during

studymonth

when

onCGM

(P=0.064

).

Modified

-HYPOscore

dropped

from

8576

184

to36

66

86(P

=0.023

).

Nochan

gein

HbA1c:

8.46

0.3%to

8.26

0.3%.

Hubinger,19

91(53)

Patien

tsstartedonCSIIwith

chan

gesin

HA.

N=16

;6months

29.5

69.5;

126

6NoSH

reported

.7of16

patients

onCSII

developed

HUafter6

monthsofCSII.

ImprovedHbA1cin

HU

group:8.46

2.3%to

7.76

1.0%;HA

group:8.26

0.9%to

7.86

0.9%.

Technologicalinterven

tion(RCTstudies)

Little,2

014(63)

HypoCOMPaSS:

Optimized

MDIvs.CSIIwithor

withoutRT-CGM

inSH

(23

2factorialdesign).All

patients

received

structureddiabetes

and

hypoglycem

iaed

ucation,

weeklytelephonecontact,

andmonthlyclinicvisits.

N=96

;6months

48.6

612

.2;

28.9

612

.3Overallstudypopulation,

decreased

SHfrom

8.96

13.4

to0.86

1.8ep

isodes/patient/

year

(P,

0.001

);nobetween-

groupdifferences.

Overallstudypopulation

decreased

Gold

score:

5.16

1.1to

4.16

1.6(P

,0.00

1);nobetween-group

differences.

Nochange

inHbA

1c:8.26

1.2%

to8.16

1.0%

.

Ly,20

13(58)

SAP+LG

Svs.CSIIonlyin

patients

withHU.

N=95

;6months

18.6

611

.8;

11.0

68.9

Red

ucedmeanSH

inCSII:1.426

3.05to

0.546

1.66(P

=0.346

);totalSHeven

ts:23

.5to

7.MeanSH

inLG

S:1.46

62.18to

0.626

1.19

(P=0.076

);total

even

ts:20

to8.

Improvemen

tin

Clarkescore

inboth

groups:CSII:6.46

61.71

to5.546

1.71(P

=0.05

3);LG

S:6.336

1.72to

4.17

61.40(P

=0.002

)(P=

0.04

forbetween-group

sign

ificance

foren

dHU

score).Nodifference

inep

inep

hrineresponse

tohypoglycem

iabetween

groups.

HbA

1cwas

similarinboth

groups

atbaselineand

didnotchange

atend

ofstudy.CSII:7.41

60.73%to

7.20

60.57%

(P=0.249);SAP:7.49

60.61%to

7.33

60.77%(P

=0.266).

Con

tinuedon

p.16

02



Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Leelarathna,20

13(59)

HypoCOMPaSSclam

pstudy

(refer

toLittle,2

014).

N=18

;6months

506

9;34

.96

10.8

Annualized

SHrateswerelower

duringstudyperiod:4(IQR

0–7)

vs.0(0–0)

(P=0.001

).

Decreased

Goldscores:

baseline5.26

0.2vs.4.36

0.4(P

=0.009);7

of18

participantsshow

edHU

reversal.G

lucose

threshold

atwhich

subjectsfelt

hypoglycem

icimproved:

2.66

0.1mmol/Latbaseline

to3.16

0.2mmol/L

(P=

0.017).Improved

autonomic

andneuroglycopenic

symptom

sscores.Improved

metanephrineresponse.

Nochan

gein

HbA1c:

8.16

0.2%baseline

vs.8.26

0.2%

(P=0.66).

Kovatchev,2

011(62)

SMBG

with

HHCdevice

providingfeedback,

random

ized

todifferent

sequences:1-2-3or

2-3-1

(1:routineSM

BG,2:added

estim

ated

HbA

1c,

hypoglycem

iariskandglucose

variability,3:estim

ates

ofsymptom

spotentially

related

tohypoglycem

ia).

N=12

0;

12months

39.2

614

.4;

20.3

612

.9Red

ucedinciden

ceof

symptomaticmoderate/SH

from

5.72

to3.74

episodes/

person/m

onth

(P=0.01

9),

especially

inthose

withHU

(6.44to

3.71

episodes,

P=0.04

5).

Notreported

onfollow-up.

ImprovedHbA1c:8.0

to7.6%.

Thomas,20

07(60)

Randomized

tooptimized

MDI(preprandialinsulin

lispro

andpre-evening

mealglargine),C

SII,or

education.

N=21

;6months

436

10;

256

10Further

SHwas

preventedin

5of

7(71%

)participantsin

each

group(P

=0.06).Inciden

ceof

SHwas

0.6(analog),0

.9(CSII),

3.7(education)ep

isodes/

patient/year.

ImprovedHA:ed

ucation

group:7withHUto

2(P

=0.06);analoggroup:7to

4(P

=0.25);CSIIgroup:7

to3

(P=0.13).Restorationof

HAin3analog(43%

),4CSII

(57%

),and5ed

ucation

(71%

)patients.

Nochange

inHbA

1cin

educationgroup:8.56

1.1%

to8.36

1.0%

(P=0.54)vs.improved

HbA

1cinanalog

group:

8.66

1.1%

to7.66

0.7%

(P=0.04)vs.

improved

HbA

1cin

CSII:8.56

1.9%

to7.46

1.0%

(P=0.06).

Kanc,19

98(61)

Randomized

crossoverstudy

to2groups:A)bed

time

NPH

vs.B

)nighttimeCSII.

N=14

T1D

(+12healthy

volunteers);

4months

Med

ian31

.5(20–45

);med

ian

12.5

(7–20

)

Episodes

withBG,63

mg/dL

duringthelast6weeks

ofboth

treatm

entp

eriodswas

lower

inCSIIthan

bed

timeNPH

group:

16.1

63.1vs.23

.66

3.3(P

=0.03

).SH

outcomenot

reported

.

Auton

omicsymptom

sappeared

earlierat

higher

BGlevelsinCSIIthaninNPH

grou

p:3.16

0.1mmol/Lvs.

2.86

0.2mmol/L(P=0.02).

Nodifferencesbetw

eenCSII

andNPH

forhypo

glycem

icthresholds

for

neuroglycopenicsymptom

s.

Nodifferencesinend

HbA

1cbetw

eenCSII

andNPH

:7.26

0.2vs.

7.16

0.2%

(P=0.2).

Con

tinu

edon

p.16

03


Table

1—Continued

Firstauthor,year

(ref.)

Interven

tion,b

rief

description

N;

studyduration

Age

(years);

diabetes

duration

(years)

SHrates

HAscore

HbA1c

Pharmacologicalinterven

tion(allRCTstudies)

Heller,20

02(64)

Randomized

crossovertrial,

lispro

withNPH

vs.human

solubleinsulin

(SI)with

NPH

.

N=13

;4monthsin

each

study

arm

336

3;12

62

Nodifference

inratesof

symptomatichypoglycem

ia,

noSH

inboth

groups.

Nosign

ificantdifferencesin

totalsym

ptom

scoresor

counterregulatory

horm

oneresponsesduring

hypoglycem

iaclam

p.

HbA1cnotdifferent

betweenSI(6.6

60.3%)andlispro

(6.1

60.2%)and

from

baseline(6.1

60.3%;P=0.077

).Fanelli,20

02(66)

Randomized

crossovertrial,2

differentinsulin

regimen

s:A)split

regimen

of4daily

insulin

injections(3

bolus

plusbed

timeNPH

)vs.B)

mixed

regimen

of3daily

insulin

injection(3

bolus

plusmixed

regularinsulin

andNPH

atdinner).

N=22;

4monthsin

each

study

arm

296

3;14

62

Red

ucednocturnalhypoglycem

iawithsplit

regimen

(0.106

0.02

vs.0.286

0.04ep

isodes/

patient-day

formixed

regimen

,P=0.002

).NoSH

ineither

group.

Autonomicsymptom

scores

increasedearlierwithsplit

regimen

than

withmixed

regimen

(BGthreshold:

3.06

0.1mmol/Lvs.2.96

0.1mmol/L,P=0.010

).Similarneu

roglycopen

icsymptomsthreshold

inboth

groups.

BetterHbA1cwithsplit

vs.mixed

insulin

regimen

(7.0

60.11%

vs.7.56

0.15%

,P=0.004

).

Ferguson,2

001(65)

Randomized

crossovertrial:

insulin

lispro

vs.regu

lar

human

insulin

inpatients

withHUandhistory

of

freq

uen

tSH

.

N=40

;6monthsin

each

study

arm

466

11;

25.8

69.8

Tren

dtowardlower

SH(55in

lispro

vs.84

inregu

larinsulin,

P=0.087

).

InitialG

old

score

4.66

1.8

butnofollow-upGold

score

postinterven

tion.

NodifferencesinHbA1c:

9.36

1.0in

regular

insulin

vs.9.16

0.83%

inlispro

group

(P=NS)

from

9.06

1.1%at

baseline.

Janssen

,20

00(67)

Mixinsulin

(75%

lispro,25

%neu

tralprotaminelispro

[NPL]insulin–HM

insulin)

before

mealsandNPL

insulin

atbed

timevs.

human

regularinsulin

before

mealsandNPH

atbed

time.

N=35

;5–6months

31.1

68.6;

13.7

68.1

Nodifferencesin

hypoglycem

iafreq

uen

cy.SH

occurred

in1

patientin

each

group.

HM

therap

yassociated

with

slightlylower

total

epinep

hrineresponse,and

autonomicsymptom

response

occurred

atalower

BGleveld

uring

experim

ental

hypoglycem

ia.

NodifferencesinHbA1c:

7.26

0.5%to

7.26

0.7%(HM)vs.6.76

0.5%to

6.76

0.6%

(regularinsulin)(P

=0.5;adjusted

for

baselineperiod).

Chalon,19

99(68)

Propranolol:20

mgtw

ice

aday

forfirst2weeks,

followed

by30

mgtw

ice

aday

forthenext2weeks

vs.placebo.

N=16

;4weeks

39.3

63.6;

datanotavailable

Nodifference

innumber

of

hypoglycem

icep

isodes

inplacebogroup(12.66

1.6)

vs.

propranolol(10

.76

1.4)over4

weeks

(P=NS).

More

sweatinginpropranolol

groupduringbiochem

ical

hypoglycem

iacompared

withplacebo.

Notreported

.

CG,controlgroup;GH,growth

horm

one;

HU,h

ypoglycem

ic-unaw

are;

IG,interven

tiongroup;NS,notsign

ificant;OR,oddsratio.



team) against conventional insulin ther-apy (defined as twice-daily insulin injec-tions, 1 to 2 daily BG tests, and monthlyclinic visits, in five subjects, four beingswitched to CSII). This showed that in-tensive therapy was associated with im-proved HbA1c but resulted in a reductionin epinephrine and symptom responsesto experimental hypoglycemia, neitherof which was fully restored on returnto conventional therapy, despite wors-ening of HbA1c.Twelve studies in people with IAH

were small: between 5 and 30 peoplein 11 studies (9,28–30,32–38), although1 study had .100 people (31). Follow-up was 3–12 months, with longer-termfollow-up data of 18 months (29) and 3years (33) was available for two studies.In seven studies (9,32,34–38), the edu-cational content comprised strict avoid-ance of hypoglycemia by using doseadjustment, raised glucose targets,and/or intensive professional contactin frequent clinic visits and regular(even daily) telephone contact. All stud-ies were able significantly to reduce/eliminate SH and improve awareness,providing proof of principle of reversibil-ity of IAH. Although autonomic and neu-roglycopenic symptom scores improvedto levels seen in control subjects with-out diabetes, counterregulatory hormoneresponses did not improve in two ofseven studies (32,34). Dagogo-Jack et al.(33) looked at the sustainability of HA res-toration at 3 years, monitoring four of sixoriginal participants. Reversal of hypo-glycemia unawareness was sustainedbeyond the period of active interventiondespite no regular contact with partici-pants, suggesting that skills acquiredunder supervision for hypoglycemia pre-vention may become ingrained. In threestudies (32,34,36), improvement in HAwas at the expense of worsened glyce-mic control, with HbA1c rising signifi-cantly to suboptimal values, whereas itremained within therapeutic targets intwo (35,37) and showed no significantchange in one (9).Four of 12 studies with baseline IAH

used a psychoeducational approach to re-store awareness (28–31). BGAT, based onwork byCox et al. (40), focuseson increas-ing self-awareness of personal cues forhypoglycemia. The DAFNE-HypoglycemiaAwareness Restoration Training (HART)pilot study (28) incorporates motivationalinterviewing and cognitive behavioral

therapies to address behavioral issuesfound to promote and sustain IAH (41).All of these approaches successfully re-duced SH and improved awareness. Al-though the BGAT studies did not reportany prior structured education, theDAFNE-HART program, in particular, re-cruited people with very high rates ofSH, despite having had structured educa-tion, and demonstrated success of psy-chotherapeutic approaches in thesepeople without deterioration in glycemiccontrol. Neither study assessed counter-regulatory hormone responses.

Education RCTs.Of seven education RCTs(42–48), four recruited unselected pa-tients [BGAT (45,47,48) and Programfor Diabetes Education and Treatmentfor a Self-Determined Living With Type1 Diabetes (PRIMAS) (42)] and three re-cruited those with IAH [HyPOS (43,44)and Hypoglycemia Anticipation, Aware-ness and Treatment Training (HAATT)(46)]. The longest follow-up was 4.9years in the BGAT programs (48). Inthe U.S.-based BGAT studies, BGAT wascompared against general diabeteseducation (49), a stress-managementtraining program (48), and education un-related to glycemic control (cholesteroleducation) (47). These studies did notreport baseline SH rates (47,48) andpeople with SH in the preceding 2 yearsof the study were excluded fromthe Kinsley et al. (47) study. In theEuropean-BGAT study (45), peoplewith recurrent SH were encouraged toparticipate: SH fell by 88% in the BGATgroup compared with the physician-guided self-help control group, whichshowed no reduction in SH rates.A head-to-head comparison betweenPRIMAS (42), a new German educationprogram with additional aspects of goal-setting, motivation, and greater hypogly-cemia focus, against the well-establishedDTTP (39) showed equivalent reduc-tions in SH in both intervention and con-trol groups. There was no consistentfinding in improvement in HA status,with PRIMAS and BGAT-Kinsley showingimprovements with control and inter-vention but no between-group differences(42,47), whereas other BGAT studies hadan additional 15–30% improvement in HAin the intervention versus control group(45,48). Thesedifferences can be attributedto the different comparator arms: thePRIMAS study (42), in particular, compared

the new educational method with theDTTP, a well-established program (39).Of note, the DTTP structured educationprogram on flexible insulin therapy in-cludes education on hypoglycemia avoid-ance. Observational studies of the DTTPwith longer-term follow-up showed amarked reduction in SH rates by ;50%in unselected patients with T1D (50) andan even greater reduction of 70–80% inSH rates in those with three or more epi-sodes of SH in the year before DTTP (51).Their principleswere adapted into severalof the programs included in this analysis.

Counterregulatory hormones to hypo-glycemia were only measured in onestudy, with improved epinephrine re-sponse to hypoglycemia in the BGATgroup despite no between-group differ-ences in hypoglycemia symptom scores(47). Glycemic control improved in theU.S.-based BGAT studies (47,48) in bothcontrol and intervention groups, butshowed no change in the European-BGAT (45). PRIMAS showed improvementin HbA1c only in the intervention arm (42).

Three studies specifically recruited par-ticipants with IAH: HyPOS (43,44) andHAATT (46). Similar to PRIMAS, HyPOScompared a biopsychosocial educationprogram with a standard education pro-gram, specifically in patients with previousSH. Both groups showed similar reduc-tions in SH at 6 months, but the reductionin SH in theHyPOSgroupwas greater com-pared with the control group in long-term(2.5 years) follow-up (43,44). Therewas nodifference in long-term glycemic control.The HAATT study compared a psychoedu-cational program to self-monitoring ofblood glucose (SMBG) in Bulgaria, whereSMBG was not routinely available. Thisstudy showed a reduction in SH andimproved detection of low BG in the in-tervention group despite no significantchange in HbA1c between the two groups,implying that the psychoeducational com-ponent of the study was vital in reducingSH and improving awareness (46).

Technology

Technology Before-and-After.Of five stud-ies that used technology as the primaryintervention, two evaluated CSII (52,53)and three RT-CGM prospectively (54)and retrospectively (55,56). Four ofthese studies recruited people with SHand IAH at baseline and showed signifi-cant reductions in SH postintervention(52,54–56). In contrast, an earlier study


by Hubinger et al. (53) recruited thosestarting CSII for poor metabolic controland evaluated the effect of CSII on HAstatus. IAH developed in 43% of theseparticipants after 6 months on CSII,with an improvement of HbA1c of0.5%. In Gimenez et al. (52), peoplewith IAH and repeated nonsevere orSH were started on CSII. There was im-provement in Clarke score for HA, withparticipants scoring similarly after treat-ment to controls without IAH, with nodeterioration in glycemic control.Of two RT-CGM studies, an observa-

tional study of 35 participants with recur-rent SH showed no change in awarenessstatus using Gold scores, despite a signif-icant reduction in SH, although 54% ofparticipants reported subjective improve-ment in awareness status (55). The otherstudy (54) showed improvement in hypo-glycemia awareness but used a differentscore, the HYPO-score (57). There wasimprovement in HbA1c in the RT-CGMstudies that were studied retrospectivelywith longer duration ($12 months)(55,56), but no change in HbA1c in theprospective study with a much shorterduration of 2 months (54).Technology RCTs. Six RCTs evaluatedtechnology as the primary intervention(58–63). All except one (62) includedIAH or prior episodes of SH in their inclu-sion criteria. Kovatchev et al. (62) did notspecify SH or IAH in their inclusion crite-ria, but 39.2% of their subjects had IAH.SHwas defined according to American Di-abetes Association definitions (16) exceptin the Ly et al. (58) study, which definedSH as hypoglycemia resulting in seizuresor coma and moderate hypoglycemia ashypoglycemia requiring assistance fortreatment. Their population includedadolescents, and the authors were con-tacted for data restricted to participantsaged$18 years, reported here.Baseline assessments of HA status

were performed using Clarke (58,60) orGold scores (59,63) except in Kanc et al.(61), which was based on patient-reported inability to perceive autonomichypoglycemia warning symptoms, and inone study where assessment was notspecified (62).The Comparison of Optimised MDI

versus Pumps with or without Sensors inSevere hypoglycaemia (HypoCOMPaSS) tri-al (59,63) and Thomas et al. (60) comparedCSII against optimized MDI and education,with additional RT-CGM, against SMBG.

Both studies includedahighdegreeof sup-port and education from the researchers.Ly et al. (58) compared sensor-augmentedpump (SAP) with a sensor-driven auto-mated insulin suspension (low-glucosesuspend [LGS]) against conventional CSII,and Kanc et al. (61) compared nighttimeCSII with bedtime NPH insulin. In studiesthat provided structured education orfeedback in addition to technology toall participants, SH was reduced and HAstatus improved in all intervention arms,with technology (CSII or RT-CGM) havingno additional benefit (59,60,63). In theadults from Ly et al. (58), there was anequivalent reduction in SH incidence inSAP and in conventional CSII but greaterimprovement in HA status with SAP. De-spite greater frequency of visits com-pared with routine care, the follow-upof the participants in all of these studiesdid not differ between arms. Kovatchevet al. (62) investigated the utility of ahandheld computer (HHC) device thatprovided continual education feedbackassociated with predicted risk of hypo-glycemia and glucose variability data.Use of the HHC and predictive datawere associated with reduction in SH,greater in those with hypoglycemia un-awareness at baseline, with an increasein the BG estimation accuracy index.

Of studies conducting hyperinsulinemic-hypoglycemic clamps, one showed anincrease in plasma metanephrine re-sponses to hypoglycemia (59), and twoshowed no significant differences inhormone responses (58,61).

In all studies comparing CSII with in-sulin analog therapy, there was no de-terioration or differences in glycemiccontrol in any of the intervention armswhen compared with control despite re-ductions in SH and improvements in HAstatus. In the Kovatchev et al. (62) studyof the HHC, there was significant reduc-tion in HbA1c, especially in those withbaseline HbA1c .8% (64 mmol/mol).

Pharmacotherapy

Pharmacotherapy RCT. Five studies wereidentified, all of which were conductedmore than 10 years ago. Four studiescompared short-acting and long-actinganalog insulin against conventional sol-uble (SI) or NPH insulin (64–67). Onenoninsulin study was identified, investi-gating propranolol to restore HA (68).There was no mention of any changein education between the arms.

SH did not occur in three of thesestudies (64,66,68); two had no statisti-cally significant change in SH rates be-tween study arms (65,67). There was noconsistent finding in changes in hypogly-cemia symptom scores during hypoglyce-mic clamp studies between comparatorarms in the insulin studies (64–67). Thestudy on propranolol reported increasedsweating during hypoglycemia with pro-pranolol (68). There were no significantdifferences in counterregulatory hor-mones responses between lispro and SI(64) or SI before meals and NPH at bed-time versus the premix formulation of lis-pro, HM insulin (75% lispro and 25%neutral protamine lispro [NPL]) withmeals and NPL at bedtime (67). Therewas, however, a higher peak plasma epi-nephrine response when NPH was deliv-ered separately at bedtime comparedwith a combined SI and NPH with dinner(66). Counterregulatory hormones werenot measured in the remaining two stud-ies (65,68).

There were no significant changes inglycemic control in the three lispro stud-ies (64,65,67). HbA1cwas lower at the endof the treatment period in the split-NPHdosing (66). Changes in HbA1c were notreported in the propranolol study, whichlasted only 1 month.

Meta-analysisA meta-analysis for educational inter-ventions on change in mean SH ratesper person per year was performed.Combining before-and-after and RCTstudies, six studies (n = 1,010 people)were included in the meta-analysis(Fig. 2) (21,28,31,42,43,45). We evalu-ated the active interventions used inthe RCTs as individual before-and-aftertrials, because all included some educa-tional component, a structured curricu-lum, and information around causesand prevention of hypoglycemia. ForSchachinger et al. (45), the control groupwas not structured education, so it hasnot been included (there was a slight in-crease in SH in the control group).

A random-effects meta-analysis re-vealed an effect size of a reduction inSH rates of 0.44 per patient per yearwith 95% CI 0.253–0.628. From the RCTstudies (Hermanns et al. [42,43]), whichcompared new structured education inter-ventions PRIMAS and HyPOS against theestablished DTTP flexible insulin therapyprogram, we can conclude that any form



of structured educational interventionin flexible insulin self-managementhas a beneficial and equivalent effectin reducing SH rates. Heterogeneity be-tween studies was significant, with I2

statistic of 68.58% (95% CI 34.2–85;P = 0.0023). Supplementary Table 2A andB lists the SMD, the95%CI of the individualstudies, and the test for heterogeneity.

Risk of Bias and Strength of EvidenceMost of the educational interventionswere observational andmostly retrospec-tive, with few RCTs. The overall risk of biasis considered medium to high and thestudy quality moderate. Most, if not all,of the RCTs did not use double blindingand lacked information on concealment.The strength of association of the effect ofeducational interventions is moderate.The ability of educational interventionsto restore IAH and reduce SH is consistentand direct with educational interventionsshowing a largely positive outcome. Thereis substantial heterogeneity betweenstudies, and the estimate is imprecise, asreflected by the large CIs. The strength ofevidence is moderate to high.There were approximately equal num-

bers of observational and RCTs of techno-logical interventions. These trials werewell conducted, with two RCTs of almost100 patients selected for hypoglycemia

unawareness. The overall risk of biaswas considered low to medium, withmoderate study quality. Double blindingwas not possible, and there was lack ofinformation on concealment in the RCTs.Combining all of these studies into a sin-gle meta-analysis was not appropriatebecause CSII, RT-CGM, and SAP are alldifferent categories of technological in-terventions, with variable reporting ofoutcomes in each category. Further-more, provision of education at baselineprovides a degree of confounding. InCGM studies, the ability of CGM to re-duce SH is consistent and direct, withall included studies showing a positiveoutcome and reduction in SH rates. Thestrength of evidence is thus moderateto high. However, the ability to im-prove or restore hypoglycemia un-awareness is uncertain and the strengthof evidence is low. The strength of ev-idence for the ability of CSII to reduceSH and restore hypoglycemia aware-ness is moderate to high, with a gener-ally positive effect of CSII. However,when patients were provided educa-tion and optimized MDI therapy, CSIIappeared not to provide any additionalbenefit.

All of the pharmacological interven-tion studies were RCTs. Lack of informa-tion on concealment was present, but

the overall risk of bias was consideredlow to medium and the study qualitywas high. However, the strength of evi-dence for insulin analogs to reduce SHwas low because SH was an exclusioncriterion for many of the included stud-ies. The strength of evidence of insulinanalogs to restore hypoglycemia aware-ness was low, with no consistent out-come seen.

Strengths and LimitationsTo our knowledge, this study representsthe first systematic review and meta-analysis of the different interventionsavailable for reversing IAH in T1D andincludes a comprehensive and expan-sive literature search. Despite this, thereare still limitations. A large proportion ofstudies did not report the type of diabe-tes education subjects received beforethe study intervention, and it is possiblethat a proportion of patients would havereceived previous structured educationand that some may have had ongoingeducation given the duration of diabe-tes in most studies. Another limitation isstudy heterogeneity and the inconsis-tent reporting of outcome measures,in particular, in SH rates and measuresof HA status, in noneducation studies,preventing a more comprehensivemeta-analysis. SH rates were reportedas mean (SD), median (interquartilerange [IQR]), odds ratios, and propor-tion of subjects with reduced SH. HAwas reported as Gold and Clarke scores,and BG estimation accuracy and the pro-portion of subjects who had improvedawareness was often subjectively as-sessed. Some studies reported a modi-fied Gold score with a score from 0 to 10on a visual analog scale. In studies re-porting Gold and Clarke scores, weused Clarke scores as themain reportingoutcome. In studies that reported Goldscores only, we grouped the outcomes,because Gold and Clarke scores havebeen shown to be well correlated (69).Even so, it was not possible to perform ameta-analysis due to study heterogene-ity. There were also large differences inparticipant numbers, variable follow-updurations, and differing baseline preva-lence rates of SH/IAH.

CONCLUSIONS

In an unselected population with noprior diabetes education, structured ed-ucation or BGAT can reduce SH and im-prove glycemic control. There is early

Figure 2—Forest plot of meta-analysis of SMDs in SH rates (per person per year) in each studyand the overall pooled estimate. The horizontal lines represent the SMD. The size of box isproportional to the weight of that study. The diamond indicates the weighted mean difference,and the lateral tips of the diamond indicate the associated SMD.




evidence that such programs can alsoachieve these outcomes when providedas reeducation some years after the initialexposure (70). In patients with estab-lished IAH, BGAT and other psychothera-peutic programs, such as HyPOS andHAATT, are also effective. There was nodifference between structured educationprograms in flexible insulin therapy andprograms with a psychological approachwhen compared head to head, and thismay be because in teaching users the ba-sics of insulin pharmacodynamics andhow to adjust their insulin regimensaround their lifestyles to achieve glucosetargets that exclude hypoglycemia, hypo-glycemia exposure is lessened. There isperhaps a need to seek the common fac-tors in successful programs to distill theessential elements of any new programs.Meanwhile, DAFNE-HART had a muchhigher baseline level of SH than any ofthe other studies and was the only studythat took people who were IAH despiteprior education. Although a small non-randomized study, it demonstratedthat a psychobehavioral therapeutic ap-proach can have a sustained effect on SHand nonsevere hypoglycemic episodes inpeople whose IAH seems resistant toother interventions (28).Thus, in unselected populations with

T1D, structured education in flexible in-sulin usage reduces SH and may reducethe proportion of people with IAH andSH. In those with IAH, further educationor BGAT reduces SH, with the greatestreductions seen in programs with a be-havioral component.CSII can reduce SH with greater reduc-

tions in those with greater SH at baseline(52), although there was evidence that inan unselected population, CSII and im-proved control may cause some deterio-ration of awareness (53). In observationalstudies, CGM showed a reduction in SH,even in those who remained in IAH de-spite education and CSII (55). In RCTs oftechnology, HypoCOMPaSS showed thatin the presence of frequent contact, CSII,CGM, and SAP resulted in similar and sig-nificant reductions in SH by 57% with areduction in Clarke scores by ;2 pointscomparedwith optimizedMDI and SMBG(63). A RCT of LGS compared with CSII inyoung people with IAH showed improvedawareness and reduced SH with LGS-enabled SAP (58).Most studies with technology, such as

CSII or CGM, were done in patients who

had received prior education. Thus, inpeople with IAH despite prior education,CSII, CGM, and, in particular, sensor-augmented pump therapy with LGS provideadditional benefits. The HypoCOMPaSSstudy (63) is in keeping with earlier stud-ies by Cranston et al. (9) and Fanelli et al.(37) highlighting the importance of closeand frequent contact, suggesting thatthis has a larger effect than any ofthe technological components tested.HypoCOMPaSS clearly illustrates thevalue of a holistic approach to the man-agement of people with IAH, using struc-tured education as a core foundationcombined with optimized MDI and theuse of CSII in selected individuals, to pro-vide far greater advantages than one in-tervention alone.

We thus propose a stepped-care algo-rithm that may guide the health careprofessional in choosing the appropriateintervention when faced with a personwith IAH (Fig. 3). We would argue thatstep onedprovision of structured edu-cation in flexible insulin therapydshould be available to any person withT1D but that additional resourcesfor individuals with higher care needsmay be focused in centers where themore intensive interventions combiningpsychoeducational and technological in-terventions are available, to which peo-ple with IAH and SH posteducation canbe referred.

For future research, we would recom-mend that outcome measures such as SHrates and HA scores should be reported

in a standardized manner to allow futuresystematic reviews and meta-analyses.Because incidence and prevalence of SHrates are not normally distributed, themedian (IQR) SH ratemay bemore appro-priate than the mean (SD) commonlyused. Measures of assessment of HAshould also be standardized using Goldor Clarke scores because these havebeen shown to correlate well with clinicaland clamp findings and each other. Theproportion of patients with baseline IAHand then improved awareness should bereported as well as Gold or Clarke scoresand their change.

Future research may be needed tocompare structured education, possiblyusing psychotherapeutic techniques, andoptimizedMDI using insulin analogs, withcomparisons against new diabetes tech-nologies such as LGS-enabled SAP.

In summary, although research-based1:1 intensive professional support canrestore awareness and impaired coun-terregulation of IAH, group-based edu-cational interventions can also improvehypoglycemia awareness and reduce SHrates in up to 45% of people with IAH,without deteriorating overall glycemiccontrol. Psychotherapeutic techniquesmay provide additional benefit, in par-ticular in improving HA status, and largeRCTs using this approach should be con-ducted. Use of technology in diabetes,either better warning systems throughCGM or through improved insulindelivery via CSII, can reduce SH ratesand improve HA without worsening

Figure 3—Proposed algorithm for the selection of interventions in patients with IAH and SH. Thegray shading indicates recommendation based on expert opinion, with as yet no completedevidence.



glycemic control, but without restoringcounterregulatory hormone responses.A stepped approach is recommended inthe management of people with IAH.

Acknowledgments. The authors thank theauthors of the original cited studies who werecontacted for sharing the information requiredfrom their studies.Funding. E.Y. received fellowship funding aspart of the HealthManpower Development Planaward from Khoo Teck Puat Hospital, AlexandraHealth Pte, Ltd. (Singapore). M.N. receivedPhD funding as part of a Diabetes UK projectgrant. S.A. is partially supported by the NationalInstitute for Health Research (NIHR) BiomedicalResearch Centre based at Guy’s and St Thomas’NHSFoundation Trust andKing’s College, London.None of the funding or supportive agencies wereinvolved in the design or conduct of the study;collection, management, analysis, or interpreta-tion of the data; or preparation, review, or ap-proval of the manuscript. The views expressedare those of the author(s) and not necessarilythose of the funding agencies.Duality of Interest. P.C. has been on advisoryboards and received speaking honoraria/travelsupport and performed studies for pumpmanufacturers (Medtronic, Roche, Animas Inc,Cellnovo). M.N. has received travel supportfrom Roche and Lilly UK. No other potentialconflicts of interest relevant to this article werereported.Author Contributions. E.Y., P.C., and M.N.undertook the literature search and reviewed theabstracts and full articles. E.Y. wrote the manu-script. S.A. performed and supervised the statisticalanalysis. S.A.A. conceived the idea for the review.All authors designed the study, contributed tothe discussion, and critically reviewed the finalmanuscript.Prior Presentation. Parts of the study weresubmitted in abstract form to the 8th Interna-tional Conference on Advanced Technologies &Treatments for Diabetes, Paris, France, 18–21February 2015, and to the Diabetes UK Profes-sional Conference 2015, London, U.K., 11–13March 2015.

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