Evidence-Informed ClinicalPractice Recommendations forTreatment of Type 1 DiabetesComplicated by ProblematicHypoglycemiaDiabetes Care 2015;38:1016–1029 | DOI: 10.2337/dc15-0090

Problematic hypoglycemia, defined as two or more episodes per year of severehypoglycemia or as one episode associated with impaired awareness of hypoglyce-mia, extremeglycemic lability, ormajor fear andmaladaptivebehavior, is a challenge,especially for patients with long-standing type 1 diabetes. Individualized therapy forsuch patients should include a composite target: optimal glucose control withoutproblematic hypoglycemia. Therefore, we propose a tiered, four-stage algorithmbased on evidence of efficacy given the limitations of educational, technological, andtransplant interventions. All patientswith problematic hypoglycemia should undergostructured or hypoglycemia-specific education programs (stage 1). Glycemic andhypoglycemia treatment targets should be individualized and reassessed every 3–6months. If targets are not met, one diabetes technologydcontinuous subcutaneousinsulin infusion or continuous glucose monitoringdshould be added (stage 2). Forpatients with continued problematic hypoglycemia despite education (stage 1) andone diabetes technology (stage 2), sensor-augmented insulin pumps preferably withan automated low-glucose suspend feature and/or very frequent contact with aspecialized hypoglycemia service can reduce hypoglycemia (stage 3). For patientswhose problematic hypoglycemia persists, islet or pancreas transplant should beconsidered (stage 4). This algorithm provides an evidence-informed approach to re-solving problematic hypoglycemia; it should be used as a guide, with individualpatient circumstances directing suitability and acceptability to ensure the prudentuse of technology and scarce transplant resources. Standardized reporting of hypo-glycemia outcomes and inclusion of patients with problematic hypoglycemia in stud-ies of new interventions may help to guide future therapeutic strategies.

TYPE 1 DIABETES AND PROBLEMATIC HYPOGLYCEMIA: BALANCING THEEFFECTIVENESS AND SAFETY OF INTERVENTIONS

Hypoglycemia is a common and greatly feared complication of type 1 diabetes (T1D)(1–4). Severe hypoglycemia (SH), an event that because of profound neuroglycope-nia requires the assistance of another person for recovery (5), is experienced by one-third of patients with T1D at least once a year (6–9). Many such events are singleepisodes caused by insulin dosing errors, exercise, and alcohol (Table 1). Conversely,problematic hypoglycemia is a condition in which episodes of SH are unpredictable,cannot be easily explained or prevented, and, therefore, have a significant negative

1Diabetes Research Group, King’s College Lon-don, London, U.K.2Department ofMedicine, Division of Endocrinol-ogy, Diabetes, and Metabolism, University ofPennsylvania Perelman School of Medicine, Phil-adelphia, PA3Department ofMedicine, Division of Endocrinol-ogy, University of Alberta, Edmonton, Canada4Endocrinology and Metabolism Department,INSERM U1190, European Genomics Institutefor Diabetes, Lille University Hospital, Lille Cedex,France5Diabetes Research Institute, Scientific InstituteOspedale San Raffaele, Milan, Italy6Immunology and Diabetes Unit, St. Vincent’sInstitute, University of Melbourne, Melbourne,Australia7Diabetes Clinic and Research Center, Vrije Uni-versiteit Brussel, Brussels, Belgium8Department of Diabetes and Clinical Nutrition,Kyoto University, Kyoto, Japan9Diabetes Center, Institute for Clinical and Exper-imental Medicine, Prague, Czech Republic10Department of Endocrinology and Diabetol-ogy, University of Zurich, Zurich, Switzerland11Schulze Diabetes Institute and Department ofSurgery, University of Minnesota, Minneapolis,MN

Corresponding author: Bernhard J. Hering,bhering@umn.edu.

Received 14 January 2015 and accepted 9March2015.

P.C., M.R.R., P.A.S., and M.-C.V. contributedequally as primary authors.

R.L. and B.J.H. contributed equally as seniorauthors.

© 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.

See accompanying articles, pp. 968,971, 979, 989, 997, 1008, 1030, and1036.

Pratik Choudhary,1 Michael R. Rickels,2

Peter A. Senior,3

Marie-Christine Vantyghem,4

Paola Maffi,5 Thomas W. Kay,6

Bart Keymeulen,7 Nobuya Inagaki,8

Frantisek Saudek,9 Roger Lehmann,10

and Bernhard J. Hering11

1016 Diabetes Care Volume 38, June 2015

TYPE1DIABETES

ATACROSSROADS

impact on health and quality of life (QoL).The criteria of problematic hypoglycemiainclude two ormore episodes of SH in the

past 12 months or one episode of SH inthe past 12 months associated with im-paired awareness of hypoglycemia (IAH),

extreme glycemic lability, or major fearand maladaptive behavior. Simple toolsare available clinically to quantitate IAH

Table 1—Identification and initial assessment of people with problematic hypoglycemia

Identification of patients with T1D andproblematic hypoglycemia

Assessment of hypoglycemia risk should be performed annually for allpatients with T1D. Frequently, episodes of hypoglycemia are notreported to physicians. Health care planners should consider whetherappropriate referral pathways exist for patients experiencing SH(patients attended by emergency medical services or emergencydepartment physicians or dispensed glucagon injections by theirpharmacist). Number of calls for an ambulance or glucagon injectionsduring the past month and past year should be considered as well aswhether injuries may have been due to unidentified hypoglycemia.

History of hypoglycemia Frequency of episodesNocturnal hypoglycemiaEpisodes of SHAbility to detect episodesPresence of adrenergic and neuroglycopenic symptoms of hypoglycemiaPrecipitating factors (e.g., insulin dosing errors, exercise, alcohol)

Review diabetes self-care Adequate frequency of SBGM?Appropriate diet?

Review for presence of riskfactors for SH Older age

Long duration of diabetesRenal impairmentLow BMIIAH (Clarke or Gold scores $4)Erratic, unpredictable blood glucose levelsVery low HbA1c

Initial assessment of people identified withproblematic hypoglycemia

Insulin therapyInsulin preparations Use of regular and NPH insulins have greater risk for hypoglycemia than

insulin analogsPremixed insulins are not recommended

Insulin dosing Inappropriate balance between basal and bolus dosesExcessive correction dosesInappropriate timing of insulinLack of adjustment for (prior) exercise and/or heatOverestimation of meal size or carbohydrate content

Insulin administration LipohypertrophyIntramuscular injectionNeedle lengthInjection technique

Physiologic/other causesDiabetes complications HAAF

GastroparesisMalabsorption Celiac disease

Pancreatic exocrine insufficiencyEndocrinopathies Adrenal insufficiency

HypopituitarismFactitious Misuse of insulin

Alcohol excessAutoimmune Insulin autoimmune syndromeMetabolic Renal failure

Hepatic failureInborn errors of metabolism

Psychological/psychosocial Fear of hyperglycemia/diabetes complicationsFear of hypoglycemiaDenial, not willing to attend educational programs or to use technologyDepression or other psychiatric problemsCognitive impairment

This approach may identify some reversible causes for hypoglycemia, which can be addressed relatively easily. It may also identify some individualsfor whom some of the interventions described in this article are contraindicated or who require specific nonendocrine interventions.

care.diabetesjournals.org Choudhary and Associates 1017

(10,11), hypoglycemia severity (12), andglycemic lability (12).Recurrent hypoglycemia impairs

counterregulatory hormonal responsesto and awareness of hypoglycemia, pre-disposing patients to more frequenthypoglycemia and SH (13). IAH, whichincreases in prevalence with diabetesduration, is found in 20–40% of patientswith T1D (11,14–16) and increases therisk of SH by 6–20-fold (6,10,11). Recur-rent SH (two or more episodes annually)is reported by 21% of patients with T1D(6) and by 66% of patients whose T1D iscomplicated by IAH (11). Recurrent hy-poglycemia can cause significant mor-bidity (4,17) and mortality. Amongindividuals with T1D, 4–10% of alldeaths are attributed to SH (18,19),and risk of death 5 years after an epi-sode of SH is increased 3.4-fold in thosewho report SH (20).The risk factors for SH depend mainly

on residual C-peptide secretion, which re-duces glycemic variability (21–23). Re-lated to residual C-peptide secretion arethe patient’s age at onset of T1D and dis-ease duration (21). Other risk factorsinclude autonomic failure, insulin sensi-tivity, BMI, genetics, andpsychosocial fac-tors (24) (Table 1). In the Diabetes Controland Complications Trial, residual endoge-nous insulin secretion was associatedwith a reduced risk of SH, regardless oftreatment intensity (25). Unfortunately,most patients with T1D lose all measur-able C-peptide within 10–15 years afterdiagnosis (26),making itmore challengingfor those with long-standing (.15 years)T1D to avoid hypoglycemia.Besides a reduction of microangio-

pathic complications, long-term follow-upof the Diabetes Control and Complica-tions Trial cohort demonstrated a re-duction in cardiovascular morbidity (27)and all-cause mortality (28) in patientswith an HbA1c ,7.0% (53 mmol/mol),which concurs with Swedish and Aus-trian registries (29,30). However, evenat that HbA1c level, the residual risk forcardiovascular and all-cause mortalityremained twice as high in patients withT1D than in nondiabetic control subjects(29–31). A large U.S. registry of.20,000patients demonstrated a U-shaped rela-tionship between SH and HbA1c level,with the lowest risk of SH occurringwhen the HbA1c level is between 7.0%(53 mmol/mol) and 7.5% (58 mmol/mol)(9). Therefore, the selection of glycemic

targets in each patient should be individ-ualized to the lowest HbA1c level thatdoes not cause SH, that preserves hypo-glycemia awareness, and that avoidslong-term micro- and macrovascularcomplications (32).

The objectives of this review articleare to examine the evidence on educa-tional, technological, and transplantinterventions in patients with T1Dcomplicated by problematic hypoglyce-mia (Table 2) and to propose clinicalpractice recommendations (Table 3)in a tiered, four-stage treatment algo-rithm (Fig. 1). To achieve these ob-jectives, an international group ofendocrinology clinician-investigatorswith expertise in evaluating all threetreatment categories in this patientpopulation was formed to critically ap-praise the available evidence and toformulate a consensus approach.

EDUCATIONAL INTERVENTIONS

Muhlhauser et al. (33) demonstratedthat intensified insulin therapy, whencombined with a 5-day teaching pro-gram, improved glycemic control with-out increasing SH. A similar programwascalled Dose Adjustment For Normal Eat-ing (DAFNE) (16). Such educational in-terventions typically consist of a 30- to40-h group-learning curriculum basedon adult learning principles around car-bohydrate counting, frequent self-monitoring of blood glucose (SMBG), andadjustment of insulin doses in responseto exercise, alcohol, and illness. To dif-ferentiate it from fixed-dose multipledaily injections (MDIs), active adjust-ment of insulin doses is often termed“functional insulin therapy.”

Large-scale audits of educational in-terventions in various countries foundreliable and sustained (up to 6 years)reductions in the incidence of SH by50–70% as well as an improvement inthe mean HbA1c level to ;7.6% (60mmol/mol) in unselected patients withT1D (16,34). A subanalysis of 341 pa-tients with three or more episodes ofSH in the prior year demonstrated re-ductions in both the incidence of SH(from 6.1 to 1.4 per patient annually)and the mean length of hospitalization(from 8.6 to 3.9 days per patient annu-ally) as well as improvements in themean HbA1c level (34,35). The DAFNEprogram showed similar reductions inthe incidence of SH, with restoration of

hypoglycemia recognition in 43% of pa-tients reporting IAH at baseline.

Blood glucose awareness training(BGAT) is a psychoeducational programdeveloped by Cox et al. (36) to increaseself-awareness of personal cues for de-tecting hypoglycemia. Originally devel-oped as 8 weekly sessions, BGAT hasundergone numerous iterations andhas been successfully piloted as an onlineprogram. It has consistently resulted inimproved detection of hypoglycemia, es-pecially in patients with IAH and sus-tained reductions in SH and even inthose with a high incidence of SH at base-line (37,38).

Few studies have examined educa-tional interventions specifically in pa-tients with IAH (Table 2). In the early1990s, three small studies demonstratedimprovement in symptom responses,with some (but variable) improvementin epinephrine responses after meticu-lous avoidance of hypoglycemia (39–42).Those improvements were achieved byextensive re-education, physiologic distri-bution of insulin with MDIs, and, mostimportantly, intensive contact and sup-port (up to four telephone calls per day)from the study team.

Three large randomized clinical trials(RCTs) specifically recruited patientswith problematic hypoglycemia. Coxet al. (43) randomized Bulgarian patientswith very little access to SMBG and atleast three episodes of SH annually toSMBG with and without hypoglycemiaanticipation, awareness, and treatmenttraining (HAATT) and found that the in-cidence of SH decreased with HAATT butnot with increased SMBG alone.

Hermanns et al. (44) randomized 164patients with more than one episode ofSH or with IAH despite MDI and continu-ous subcutaneous insulin infusion (CSII)to either a hypoglycemia-specific educa-tion program (HyPOS) or a standard edu-cation program. They demonstratedgreater improvement in awareness withHyPOS with a trend to a lower incidenceof SH 1 year after completing HyPOS thatbecame statistically significant at 31months of follow-up.

Decision making is central to hypogly-cemia avoidance, andqualitative researchhas identified fear of hypoglycemia andlack of concern regarding hypoglycemiaas important factors beyond skills andeducation that predispose to IAH (45,46).These findings may explain the success

1018 Type 1 Diabetes Complicated by Hypoglycemia Diabetes Care Volume 38, June 2015

Table

2—Keyinterven

tionstudiesin

hypoglyce

mia

unaw

are

patients

withT1D

Baseline

Endofstudy

Referen

ceInterven

tionand

durationoffollow-up

Studydesignandduration

No.and

durationof

diabetes

(years)

HbA1c(%

)SH

rate

and

awaren

essscore

HbA1c(%

)SH

rate

and

awaren

essscore

Commen

ts

Fanelli

etal.(42)

Chan

gefrom

twicedaily

toMDIregimen

Dailycontact

Re-ed

ucation

Prospective,singlecenter

Before

andafter

1-year

follow-up

n=21

(11.46

1.8)

5.86

0.1

(norm

al3.8–5.5)

9of21

had

SHin

previousyear

Allhad

IAH

6.96

0.1

(norm

al3.8–5.5)

NoSH

in12

-month

follow-up

10-fold

reductionin

mild

hypoglycem

iceven

ts

Restoration

ofsymptom

andcoun

terregulatory

horm

onerespon

ses;

sustainedto

1year

Cranston

etal.(40)

Intensive

insulin

therapy

Freq

uen

tcontact

Intensive

education

Prospective,singlecenter

Before

andafter

4-month

follow-up

n=12

men

(11–

32)

GroupA:

6.96

0.3

GroupB:

8.76

0.3

N/A

AtleastthreeCBG,3with

nosymptoms

in2weeks

Nosign

ificant

deterioration

(numbersnot

reported

)

SH:N/A

Restorationofsymptoms

andim

provemen

tin

counterregulatory

responsesafter3

weeks

ofnoCBG,3.0

mmol/L

Mean4.16

1.1monthsof

freq

uen

tcontact

required

toachieve

3weeks

ofhypoglycem

iaavoidance

Dagogo-Jack

etal.(41)

Scrupulousavoidance

ofiatrogenic

hypoglycem

ia

Prospective,singlecenter

Before

andafter

3-month

follow-up

n=6

(15.56

4.4)

Age

,35

8.36

1.0

10.6

63.7AllIAH

9.86

1.1

SHnotreported

60%reductionin

CBG

,3.3mmol/L

Restoredsymptombutnot

horm

onalresponsesat

3months

Hermanns

etal.(44)

HyPOSvs.control

interven

tion,w

ith

mostpatientsalso

movingto

CSIIwith

more

than

oneSH

orIAH

with.10

years

ofT1D

RCT

6months(31-month

follow-upreported

separately)

n=16

4,85.3%

withT1D

(HyPOS:

20.2

610

.8Control:

22.1

610

.9)

HyPOS:

7.26

0.9

Control:

7.46

1.1

HyPOS:3.56

3.6/patient-

year

Clarkescore

4.8

Control:3.66

36/patient-

year

Clarkescore

5.0

HyPOS:7.16

0.9

Control:7.36

1.1

HyPOS:0.96

1.9/

patient-year

Clarkescore

2.3

Control:0.66

1.2/

patient-year

Clarkescore

3.0

30%reductionin

mild

hypoglycem

iawith

HyPOS;further

31-

month

follow-upshows

sustained

ben

efitin

HyPOSoverstan

dard

education

Cox et

al.(43)

HAATvs.control

IncreasedSM

BGand

monthlyvisits

Noprevious

educationorSM

BG

RCT

18-m

onth

follow-up

n=60

(13)

HAATT:

8.16

0.7

Control:

8.06

0.7

HAATT:2.0

Control:1.8

HAATT:8.0

Control:8.1

HAATT:0.4

Control:1.7

Hypoglycem

ia-specific

educationprogram

perform

edbetterthan

freq

uen

tcontact

Little etal.(48)

HypoCOMPaSSMDIvs.

CSIIandSM

BGvs.

CGM

in23

2design

Both

arms:ed

ucation

andmonthlyvisits

plustelephone

support

RCT

24-m

onth

follow-up

n=96

(28–

30)

8.26

1.2

8.96

13.4

77%had

SHin

prioryear

Gold

score

5.16

1.1

8.16

1.2

0.86

1.9

20%had

SHin

prioryear

Gold

score

4.16

1.6

Nodifferencesam

ongCSII,

CGM,andSA

PCGM

had

slightlygreater

reductionin

mild

and

SH,b

uthigher

baseline

than

SMBG

Con

tinuedon

p.10

20

care.diabetesjournals.org Choudhary and Associates 1019

Table

2—Continued

Baseline

Endofstudy

Referen

ceInterven

tionand

durationoffollow-up

Studydesignandduration

No.and

durationof

diabetes

(years)

HbA1c(%

)SH

rate

and

awaren

essscore

HbA1c(%

)SH

rate

and

awaren

essscore

Commen

ts

Pedersen-

Bjergaard

etal.(56)

HypoAnastudy

[Analoginsulin

(detem

irandaspart)vs.

human

insulin

(NPH

andregu

lar)]

Multicen

ter,open

-lab

el,

crossoverRCT(1:1)

2-year

follow-up

n=15

98.06

1.0

Allhad

2ormore

episodes

ofSH

inprioryear

Decreaseof0

.13%

with

analogtreatm

ent

compared

with

human

insulin

(P=0.02

)

Insulin

analogs:10

5ep

isodes

ofSH

Human

insulin:13

6ep

isodes

ofSH

Absolute

rate

reductionof

0.51

episodes

ofSH

per

patient-yearwithinsulin

analogs

Lyet

al.(65)

CSIIvs.SA

Pin

young

patientswithIAH

RCT

6-month

follow-up

n=95

(11.0)

7.46

0.2

SAP-LGS:6SH

and

0.22

/patient-year

Clarkescore

5.96

1.5

CSII:6SH

and0.25/

patient-year

Clarkescore

6.46

1.5

7.46

0.2in

both

arms

SAP-LG

S:0even

ts=0/

patient-year

Clarkescore

4.7(4.0–5.1)

CSII:6even

ts=0.26/

patient-year

Clarkescore

5.1(5.5–6.4)

Youngpatients

with

shortdurationSA

P-LG

SreducedSH

compared

withCSIIalone,

although

even

trates

werelow

Reduced

time,70

and

,60

mg/dL

inLG

Sarm

deZoysa

etal.(47)

DAFN

E-HART

6sessionsbased

on

cogn

itivebeh

avioral

therap

yand

motivational

interviewing

1-year

follow-up

Smalltrial;2sites

Uncontrolledpilot

clinicaltrial

n=24

(316

12)

Previous

DAFN

E8

CSII

7.86

1.1

Med

ian3.0(0–10

3)Clarkescore

5.46

1.2

Ryanscore

948

7.86

1.2

Med

ian0(0–3)

70%reported

no

further

SHClarkescore

3.86

1.8

Ryanscore

372

9of20restoredaw

aren

ess

SomeacceptedCSIIor

CGM,whichthey

were

resistan

tto

previously

Choudhary

etal.(66)

Observationalclinical

auditofCGM

inpatientswithSH

despiteprevious

DAFN

EandCSII

1-year

follow-up

Retrospective

audit

n=35

(29.66

13.6)

8.16

1.2

SH8.16

13.6/patient-year

Gold

score

5.16

1.5

7.66

1.0

0.66

1.2/patient-year

Gold

score

5.26

1.9

54%reported

subjective

improvemen

tin

awaren

ess

Red

uctionin

SHwithCGM

23of35

usedSA

P-LG

S3withSH

onSA

Phad

no

further

episodes

on

SAP-LG

S

Gim

enez

etal.(58)

CSIIanded

ucation

program

with2–3-

month

follow-up

Small,uncontrolled

pilottrial

2-year

follow-up

n=20

(16.2)

6.76

1.1

1.256

0.4/patient-year

Clarkescore

5.56

1.2

6.36

0.9

SH0.05/patient-year

at2years

Clarkescore

1.66

2.03

16of19

restored

awaren

ess

Red

ucedmild

hypoglycem

iaTime,70

mg/dL

reducedfrom

13.7to9.1%

Samann

etal.(35)

Structureded

ucation

5-day

course(DTTP)

9,58

3patients

at96

centers

1-year

follow-up

Subgroupanalysisof

patientswith3or

more

SHat

baseline

n=34

1(18.76

11.1)

7.46

1.9

6.16

9.6/patient-year

7.26

1.5

1.46

5.4/patient-year

56%had

1,20

%had

2,andonly15

%had

more

than

3SH

even

tsRed

ucedtimein

hospital

8.66

15.4to

3.96

10.7

days/patient-year

Con

tinu

edon

p.10

21

1020 Type 1 Diabetes Complicated by Hypoglycemia Diabetes Care Volume 38, June 2015

of frequent contact and behavioral inter-ventions such as BGAT and HAATT. TheDAFNE-Hypoglycemia Awareness Res-toration Training (HART) pilot studyevaluated a different strategy built onbehavioral changes identified throughqualitative interviewing in patients withIAH (46), incorporating aspects of BGATbut delivered using cognitive behavioraltherapy and motivational interviewingtechniques. Of the 24 patients with SHdespite previous treatments (includingDAFNE), 17 experienced complete reso-lution of SH, and the remaining 7 experi-enced significant reductions in theincidence of SH (47).

The ComparisonofOptimizedMDI Ver-sus Pumps With or Without Sensors inSevere Hypoglycemia (HypoCOMPaSS)trial randomized 96 patients with long-standing (mean duration 28 years) dia-betes, IAH, and previous recurrent SH(mean 8.9 episodes per patient annually)in a 2 3 2 fashion to SMBG or real-timecontinuous glucosemonitoring (RT-CGM)and MDI or CSII (48). All four armsunderwent a 2-h standardized educa-tion program emphasizing rigorousavoidance of hypoglycemia, includingadvice on never delaying treatment,recognizing times of increased risk, de-tecting subtle symptoms, and confirm-ing low readings through frequentSMBG. In addition, all patients hadweekly telephone contact andmonthly face-to-face visits with thestudy team. The educational interven-tion led to significant reductions in SH(from 8.9 to 0.8 episodes per patientannually) and to improvement inawareness scores irrespective of treat-ment allocation.

Thus, current data highlight the impor-tance of structured education as an es-sential baseline strategy to reduce theproportion of patients with problematichypoglycemia. Relatively inexpensiveprograms such as BGAT and DAFNE canreduce the incidence of SH by 50% andimprove HbA1c levels and QoL in patientswith long-standing (.15 years) T1D whocontinue to experience SHwith associatedIAH and excessive glycemic variabilitydespite effective education and intensiveinsulin therapy. Intensive and frequentcontact with health care providers appearsto be the most effective therapy, yet suchpatients still have a higher incidence of SHthan the general T1D population so mayrequire more advanced therapies.

Table

2—Continued

Baseline

Endofstudy

Referen

ceInterven

tionand

durationoffollow-up

Studydesignandduration

No.and

durationof

diabetes

(years)

HbA1c(%

)SH

rate

and

awaren

essscore

HbA1c(%

)SH

rate

and

awaren

essscore

Commen

ts

Hopkins

etal.(16)

Structureded

ucation

program

inflexible

insulin

therapy(U.K.

DAFN

E)5-day

course

1-year

follow-up

IAHsubgroupreported

Retrospective

audit

n=21

5(Durationnot

reported

)

N/A

3.66

13.6/patient-year

N/A

1.36

5.9/patient-year

Improvedaw

aren

essof

hypoglycem

iaat

ablood

glucose.3mmol/L

O’Connell

etal.(92)

Islettreatm

ent(961

644

5kIEQ

)Antithym

ocyte

globulin

followed

by

tacrolim

us+

mycophen

olate

mofetil

2patients

had

1treatm

ent,7had

2treatm

ents,and

8had

3isletgrafts

3-centerobservational

study

1-year

follow-up

n=17

Durationnot

reported

8.36

2.0

Hyposcore

2,97

66

3,49

46.56

1.3

2of17

patients

with

graftfailure

had

SH82

%achievedcomposite

endpointofHbA1c,7%

andabsence

ofSH

at1

year

Brooks

etal.(93)

Islettreatm

ent(535

kIEQ

)Observational

multicen

tertrial

2-year

follow-up

n=20

30(16.5–38

.5)

8.0

(7.0–9.6)

20(7–50

)6.2(5.7–8.4)

0.3(0–1.6)

70%maintained

composite

endpointof

HbA1c,7%

andnoSH

at2years

CBG,cap

illarybloodglucose;DTTP,d

iabetes

teachingandtreatm

entprogram

;kIEQ

,kilo

isleteq

uivalen

t;N/A,notavailable.

care.diabetesjournals.org Choudhary and Associates 1021

TECHNOLOGICAL INTERVENTIONS

Before implementing diabetes technolo-gies in treatment, insulin therapies shouldbe optimized, with preference given to in-sulin analogs. Most studies of insulin ana-logs have excluded high-risk patients withprior SH or IAH (49) and used a noninfe-riority design and strict, treat-to-targetdosing algorithms (50) so are likely tohave underestimated benefits for patientswith problematic hypoglycemia. Rapid-acting insulin analogs (aspart, glulisine, lis-pro)with faster onset and shorter durationthan regular insulin are associated with a20% reduction in the incidence of SH and a45% reduction in the incidence of noctur-nal hypoglycemia (51). Basal analogs,which have less intraindividual variabilityin bioavailability than neutral protamineHagedorn (NPH) insulin (52), are also ef-fective, providing a 27% reduction in theincidence of SH and a 31% reduction inthe incidence of nocturnal hypoglycemiacompared with NPH insulin (53,54). Newerbasal insulin analogs (e.g., degludec andU300 glargine) may be even less variableand further reduce hypoglycemia risk.Studies of degludec found a 25% reductionin the incidence of symptomatic nocturnalhypoglycemia but no difference in the in-cidence of SH (55). In the single trial con-ducted in patients with problematichypoglycemia, insulin analogs reducedthe incidence of SH by 29% comparedwith regular and NPH insulin (56).The effectiveness of CSII in patients

with problematic hypoglycemia has notbeen tested in robust RCTs, but a meta-analysis found a fourfold reduction in theincidence of SH and a 0.6% improvementin HbA1c levelwith CSII (57). Older age andmore frequent episodes of SH were inde-pendentpredictors of a reduced incidenceof SH with CSII. A small pilot study of CSIIin 19 patients with IAH demonstratedrestoration of awareness in 16 at 1 year(58).Although a cornerstone of therapy in

T1D, SMBG may only be effective in re-ducing the incidence of SH when com-bined with education (e.g., HAATT) (43).Although blinded CGM may be useful asa diagnostic tool to identify periods ofhypoglycemia, a systematic review ofblinded CGM versus SMBG did not dem-onstrate improved HbA1c levels and wasunable to analyze hypoglycemia rates(because of heterogeneity in definitionsand assessment of hypoglycemia) (59).

In contrast, a meta-analysis showed thatRT-CGM, which can alert patients to im-pending hypoglycemia, decreased HbA1clevels without increasing hypoglycemicepisodes (60). Because patientswith priorSH or IAH were excluded from this study,the proportion with major hypoglycemicepisodes was numerically lower with RT-CGM but was not significantly differentfrom the proportion with SMBG.

In the context of intensive educationand frequent contact, no differences in re-ducing the incidence of SH or in restoringawareness were found between MDI ver-sus CSII and SBGM versus RT-CGMS in theHypoCOMPaSS trial. CGM tended to showgreater reductions in the incidence of SHpossibly because of a higher incidence ofSH at baseline (48). A substudy of theHypoCOMPaSS trial found improvementsin symptom and catecholamine responsesto experimental hypoglycemia, withtrends to greater improvements withCSII and to a lesser degree with CGM (61).

Clinical trials of sensor-augmentedpumps (SAPs), which are CSII deviceswith an integrated CGM system, havefound superior glycemic control but nodifference in the incidence of SH com-pared with MDI (and SMBG) (62). Manypatients were noted to sleep throughnocturnal alarms (63). One RCT of a de-vice with an automated threshold-suspend feature (where insulin deliveryis automatically suspended for up to 2 hif the sensor glucose falls below a pre-specified threshold) demonstrated a38% reduction in the duration of noctur-nal hypoglycemia (64) compared withSAP. Another RCT in children and adoles-cents with IAH showed a reduction in theincidence of SH with SAP compared withCSII alone but no improvement in theepinephrine response to experimentalhypoglycemia (65). A small observa-tional study demonstrated significantreductions in the incidence of SH (from8.1 to 0.6 episodes per patient annually)using SAP in patients with IAH but noimprovement in awareness (66).

Clinical trials of fully automated inte-grated CGM/CSII technologies (artificialpancreas) have been reported (67,68).Somehaveuseddual pumps to administerboth insulin and glucagon, although glu-cagon was not required to protect fromnocturnal hypoglycemia in a head-to-head study (69). Although potentially ofgreat benefit, these technologies havenot yet been evaluated in patients with

problematic hypoglycemia and are notyet commercially available.

TRANSPLANT INTERVENTIONS

Pancreas and, now, islet transplants caneffectively prevent hypoglycemia and re-store normoglycemia and may stabilizethe complications of T1D (70–75). Patientswith T1D who undergo an islet or a pan-creas transplant exhibit recovery of physi-ologic islet cell hormonal responses toinsulin-induced hypoglycemia wherebyendogenous insulin secretion is sup-pressed and glucagon secretion restored(76,77), although in islet transplant recipi-ents, the glucagon response remains par-tial likely due to lower islet mass beingtransplanted as evidenced from b-cell se-cretory capacity testing (78,79). Both isletand pancreas transplant recipients alsohave improved epinephrine and normal-ized autonomic symptom responses tohypoglycemia, providing evidence ofamelioration of hypoglycemia-associatedautonomic failure (HAAF) (76,77). Theseimproved counterregulatory defensemechanisms may be sustained for morethan a decade of pancreas graft function(80). Most importantly, islet and pancreastransplantation have been shown to nor-malize the endogenous (predominantlyhepatic) glucose production response toinsulin-induced hypoglycemia (77,81),thereby affording recipients protectionand recovery from low blood glucose.

Pancreata procured from leaner andyounger donors often are preferredfor whole-organ pancreas transplants,whereas islets can be isolated from obeseand older donors (82) unsuitable forwhole-organ transplants, thereby increas-ing the proportion of donated organs thatcan contribute to the treatment of T1D.Thus, islet and pancreas transplants areevolving as complementary approachesto b-cell replacement for the eliminationof problematic hypoglycemia in T1D.

Most pancreas transplants are per-formed simultaneously with a kidneytransplant. Simultaneous pancreas-kidney (SPK) transplants confer superiorlong-term graft function compared withpancreas transplant alone or pancreastransplant after a kidney transplant. The5-year pancreas graft survival rate for re-cipients of pancreas transplant alone andpancreas transplant after a kidney trans-plant is between 55 and 70%; for SPKrecipients, it is .85% (83). With SPKtransplants, most recipients can expect

1022 Type 1 Diabetes Complicated by Hypoglycemia Diabetes Care Volume 38, June 2015

amelioration of problematic hypoglyce-mia for more than a decade (83–85).Pancreas transplants are usually under-

taken in patientswho are relatively young(,50 years) and nonobese (,30 kg/m2)and who do not have coronary artery dis-ease. These patient selection criteria min-imize operative mortality (,1%) andreduce early technical pancreas graftloss (;10%) (86,87). Removal of techni-cally failed grafts and routine complica-tions of abdominal surgery have led to areoperation rate as high as 40% (85).Islet transplantation, a minimally inva-

sive procedure, allows for inclusion ofolder patients and patients with coronaryartery disease who would be ineligiblefor a whole-pancreas transplant. In non-obese recipients, the target islet dose of$5,000 islet equivalents/kg can be iso-lated from a deceased donor pancreas(71).Most islet transplants are performedin nonuremic patients with T1D and prob-lematic hypoglycemia and related exces-sive glycemic lability (12,71,88). Carefulselection of patients and protocol optimi-zation have led to substantial clinical im-provements (71). Importantly, refinedrecipient treatment has improved long-term outcomes of islet transplants; insu-lin independence can now be maintainedfor 5 years in 50% of recipients (89,90).Although restoring insulin indepen-

dence remains an important objective,several multicenter clinical trials of islettransplants in patients with T1D and prob-lematic hypoglycemia, including the phase3 licensure trial of human islets conductedby the Clinical Islet Transplantation Con-sortium, have adopted a combination ofnear-normal glycemic control (HbA1c,7.0% [53 mmol/mol]) together with theelimination of SH as the primary end pointand the clinically relevant dual goal of in-tervention (91–93). After having reportedsuccessful achievement of that goal in 82%of patients at 1 year (92) and in 70% at 2years posttransplant (93), islet transplantsare now approved and reimbursed in sev-eral countries for the treatment of prob-lematic hypoglycemia in T1D. In the U.S.,although a phase 3 trial of islet transplantsin this patient population has beencompleted, a formal license applicationawaits submission, review, and approval.Even with partial islet graft function,

the endogenous glucose production re-sponse to insulin-induced hypoglycemiaimproves (94), so islet grafts protectagainst problematic hypoglycemia even

when insulinmay be required tomaintainnear-normoglycemia. This protectionfrom hypoglycemia has been confirmedin CGM studies showing a near absenceof time at glucose ,70 mg/dL/,3.9mmol/L (77). The reductions in mean glu-cose, glucose variability, and time spenthypoglycemic (,54mg/dL/,3.0mmol/L)relative to T1D were similar for bothinsulin-independent and insulin-requiringislet recipients (95), and those reductionswere sustained for 18 months in onestudy (96). Importantly, Vantyghemet al. (23) showed that minimal islet graftfunction is sufficient to abrogate hypogly-cemia (,54 mg/dL/,3.0 mmol/L), con-firming that even suboptimal function(requiring insulin) significantly improvesmean glucose and glucose variability.That the islet graft imparts these glycemiccontrol benefits has been further sup-ported by the demonstration of sig-nificant continuous associations withstimulated C-peptide levels in islet trans-plant recipients (97). This avoidance ofhypoglycemia with islet or pancreastransplants as documented by CGM bestexplains the documented reversal of HAAFas well as the recovery of glucose counter-regulation and hypoglycemia symptomrecognition, thereby reversing the vicioushypoglycemia-begets-hypoglycemia cyclein T1D (98). Data from the CollaborativeIslet Transplant Registry indicate thatproblematic hypoglycemia amelioratedfor the duration of islet graft function is

currently retained in 90% of recipients at4 years posttransplant (71).

In addition to procedural risks andlimited organ availability, the currentneed for lifelong immunosuppressivetherapy represents a major limitationto widespread implementation ofb-cell replacement therapies for pa-tients with problematic hypoglycemiarefractory to educational and techno-logical interventions. Because kidneytransplant recipients are already com-mitted to immunosuppressive therapy,the addition of an islet or pancreastransplant may be considered tonormalize glycemia, stabilize diabetescomplications, and prevent recurrentdiabetic nephropathy. In such T1D kidneytransplant recipients, islet transplan-tation can be considered simultaneously with or after a kidney trans-plant for patients who are not surgicalcandidates for or willing to accept therisks of a pancreas transplant (85). At 5years (99) and 13 years (85) post-transplant, the insulin independencerate was higher for pancreas than for isletrecipients; however, the islet recipientsexperienced significantly fewer opera-tive complications, and both the pan-creas and islet recipients experiencedsignificantly improved glycemic controland a reduction of .90% in the inci-dence of SH (85).

Thus, regardless of b-cell replace-ment approach (pancreas or islets), the

Figure 1—Proposed treatment algorithm for patients with T1D and problematic hypoglycemia.

care.diabetesjournals.org Choudhary and Associates 1023

majority of recipients can anticipateamelioration from problematic hypogly-cemia for at least 5 years together withnear-normal glycemic control. In fact,islet and pancreas transplants are theonly approaches to date that conferboth sustained recovery from HAAFand restoration of glucose counterregu-lation (by endogenous glucose produc-tion) and, thereby, reliable protectionfrom SH in patients with long-standing(.15 years) T1D.

TREATMENT ALGORITHM

The treatment algorithm has to takeinto account the number of patientswith T1D who have problematic or re-current SH, existing educational toolsand technologies to reduce hypoglyce-mia, and the available resources for var-ious treatment strategies, includingtransplants. Individual countries or re-imbursement plans might need to adaptthe algorithm in accordance with theirresources.Individualized treatment targetsmust

balance the risk of complications withthat of hypoglycemia in an effort toachieve the lowest attainable HbA1c

level without problematic hypoglycemia(32). Published studies have indicatedthat educational and technological in-terventions can prevent SH while main-taining HbA1c levels between 7.2 and8.0% (55 and 64 mmol/mol) (Table 2).Many patients rarely or never inform

their physician about episodes of hypo-glycemia (100); therefore, health carepractitioners must routinely inquireabout a given patient’s frequency ofand risk factors for hypoglycemia andglycemic lability (12) and must screenfor impaired awareness. Commonlyused validated scores are those byClarke et al. (10) and Gold et al. (11)where a score $4 indicates hypoglyce-mia unawareness, but increasingly,other measures are used, such as glu-cose SD (.40 mg/dL/.2.8 mmol/L)(23), low blood glucose index (101), oraverage daily risk range (102).

THE FOUR STAGES OF THEPROPOSED TIERED ALGORITHM

Stage 1All MDI therapy patients using SMBGshould have routine evaluation of hypo-glycemia awareness status using vali-dated scores along with assessment of

glycemic control. Patients with prob-lematic hypoglycemia should be regu-larly evaluated for possible underlyingcauses of hypoglycemia (Table 1), forthe presence of hypoglycemia unaware-ness, and for meeting their own individ-ual HbA1c level and other treatmenttargets (32). If the patient is not at tar-get, first-line therapy is a structurededucation or hypoglycemia-specific ed-ucation program (Fig. 1). A robustevidence base supports functional insu-lin therapy (33) through educationalprograms such as DAFNE (16) and be-havioral interventions such as BGAT(36). These programs reduce the inci-dence of SH by 50–70% and restorehypoglycemia awareness in up to 40%of patients (Table 2). Some data suggestadditional benefits with programs fo-cused on hypoglycemia avoidance,such as HyPOS, over standard educa-tion. The choice of insulin in patientswith SH has been tested in only onetrial, which demonstrated a 29% re-duction in SH using analogs comparedwith regular or NPH insulin (56). But nodata exist so far regarding the impacton IAH of newer insulins, such as de-gludec, U300 glargine, or pegylatedinsulin (103).

Stage 2Robust evidence exists for the use of CSIIas second-line therapy to reduce SH (57).Although a paucity of randomized evi-dence supports the use of RT-CGM andless evidence supports the use of RT-CGMin patients with T1D for the purpose ofreducing the incidenceof SH, this technol-ogy offers a logical step forward for indi-vidual patients. Limitations to the use oftechnology must be considered, and datasuggest that CGM must be used continu-ously for sustained benefit (104).

Stage 3If the composite treatment target of noSH, Clarke score ,4, and HbA1c ,8.0%(64 mmol/mol) is still not met (Fig. 1),the use of SAP, preferably with low-glucose suspension (LGS), and/or veryfrequent contact with a specialized hy-poglycemia service should be consid-ered for third-line therapy (Fig. 1).Small-scale nonrandomized trials ofpsychoeducational therapies such asDAFNE-HART and BGAT suggested thatthey offer further benefit, especially in

patients with behavioral contributors torecurrent SH (39–41).

Because most trials of SAP in T1D ex-cluded patients with problematic hypo-glycemia, only anecdotal evidencesupports the use of SAP alone for reduc-ing the incidence of SH in this patientpopulation. Studies using threshold sus-pension of insulin were successful in re-ducing hypoglycemia over and aboveSAP alone, suggesting that this may bethe preferred evidence-based option inpatients with T1D and problematic hy-poglycemia (64,65). In patients with on-going problematic hypoglycemia, veryfrequent and intensive contact with anexpert diabetes team can restore theirawareness of symptoms and, to someextent, counterregulatory responses,but such contact may not always be fea-sible in the clinical scenario. Weekly tomonthly contact as offered in theHypoCOMPaSS trial seem to be effectivein reducing the incidence of SH, but res-torationof awareness ismodest (Table 2).

The algorithmproposed in Fig. 1 showsthe level of evidence supporting each in-tervention. The system should be flexible,and clinicians will make individual deci-sions based on specific circumstances,taking into account the preference ofthe patient as well as the patient’s in-volvement and possibilities. For certainpatients with behavioral issues, furtherbehavioral programs such as BGAT,HyPOS, or DAFNE-HART may be benefi-cial. For others, more expensive treat-ment such as CSII with and withoutRT-CGM may be more appropriate.

Stage 4Pancreas and islet transplants, thefourth-line therapy, are very effectivein achieving the composite target ofeliminating SH with near-normal HbA1clevels, but lifelong immunosuppressivetherapy and its possible complicationsrepresent a major limiting factor. Be-cause islet and pancreas transplantsare both effective in preventing SHand achieving near-normoglycemia,the optimal treatment option will re-quire individualized discussion of multi-ple factors, including the proceduralrisks (which are higher for a pancreastransplant), importance of insulin inde-pendence, waiting time, and sensitiza-tion. Some contraindications to apancreas transplant (age .50 years,high cardiac risk) are common in

1024 Type 1 Diabetes Complicated by Hypoglycemia Diabetes Care Volume 38, June 2015

patients with problematic hypoglyce-mia; they may only be eligible for anislet transplant. Yet, a small proportionof patients may be ineligible for an islettransplant because of their weight orinsulin requirements. The transplantteam should consider each patient’spreferences and perceptions of risksand benefits.In the absence of contraindications,

the main determinant of which type oftransplant to choose is the patient’s kid-ney function. A living donor kidneytransplant might be the best optionfor a given patient with chronic kidneydisease followed by either an islet or apancreas transplant (105). If a living do-nor is not available, then a simultaneousdeceased donor kidney transplant andislet or pancreas transplant may be in-dicated (Fig. 2).For patients requiring a kidney trans-

plant, it is clear that both pancreasand islet transplants, either simulta-neously or sequentially, are effective inpreventing SH and protecting the kidneygraft from hyperglycemia (85). How-ever, how best to treat problematichypoglycemia in patients with an inter-mediate estimated glomerular filtrationrate (eGFR) (30–60 mL/min) (Fig. 2) isunclear because the immunosuppres-sive therapy required after a pancreasor islet transplant can increase the riskof end-stage renal failure in these pa-tients (106,107).

Currently, organ donation rates in theU.S. and Europe are stalled at between10 and 35 donors per million population(108,109), yet potentially 1,000 patientswith T1D per million population are af-fected by recurrent SH (6–9). The organshortage is the second major factor (inaddition to lifelong immunosuppression)limiting b-cell replacement. Until newsources of b-cells are available, b-cell re-placement bymeans of a whole-pancreastransplant or an isolated islet transplantwill be limited to a carefully selectedgroup of patients with problematic hypo-glycemia refractory to medical and tech-nological interventions.

Byrne et al. (110) demonstrated thatspecialized clinics with expertise in hy-poglycemia management are essentialto concentrating limited transplant re-sources for patients who need themmost. Of 36 patients with recurrentSH referred to a specialized hypoglyce-mia service, 47.2% experienced resolu-tion of their problematic hypoglycemiawith optimal medical therapy, andanother 25% achieved clinically rele-vant improvement. Of those highlyselected patients, however, 27.8%required a transplant despite havingelevated HbA1c levels of 8.0% (64mmol/mol) and despite having accessto all educational and technologicalinterventions.

Another crucial factor is the reimburse-ment policy of each country or insurance

plan. If an expensive technology optiondoes not deliver the expected resultswithin a 6-month period, it may bediscontinued. In many countries, CSII isreimbursed by health insurance, but RT-CGM is not. The same is true for b-cellreplacement; in many countries, pan-creas transplants are reimbursed, butonly in a much smaller number of coun-tries are islet transplants reimbursed. Thecost-effectiveness of these technologieshas not been tested in larger populations;it will take many years to prove the costsavings or at least the cost-effectiveness,although QoL improves in most trials.

CLINICAL RESEARCH NEEDS

As new insulin analogs and devices be-come available, we recommend includ-ing in future trials and studies patientswith recent SH or IAH and then sepa-rately reporting changes in HbA1c level,SH, and IAH in those with prior problem-atic hypoglycemia. Doing so would allowdata on the impact of new therapies inthis complex group of patients to be-come available sooner. Also crucial inevaluating new therapies are robuststudies of changes in symptoms, coun-terregulatory hormone responses, andendogenous glucose production re-sponses to experimental hypoglycemia.

Educational interventions have theevidence base to be recommended asfirst-line therapy. Further investigationinto appropriate baseline factors thatmay aid personalization of treatment isdesirable. In the home studies usingsingle- or dual-hormone closed-loopsystems now taking place, the role ofsuch systems in patients with problem-atic hypoglycemia remains to be tested.

The effectiveness of CSII with SMBGand CGM with MDI in preventing SH inpatients with IAH remains to becompared in larger trials. AlthoughHypoCOMPaSS suggests equivalence,the technology selection may dependon the availability of systems, reim-bursement policies, and patient choice.Also remaining to be studied is whichpatients with persistent problematichypoglycemia despite structured edu-cation should use SAP as the nextintervention.

In the field of transplantation, areasthat require further clinical researchinclude improvement of islet engraft-ment to prolong graft survival and

Figure 2—Transplant options for patients with T1D (expert consensus). CGMS, continuousglucose monitoring system. +eGFR .30 and ,60 mL/min/1.73 m2: islet or pancreas trans-plantation alone, high risk for developing end-stage renal disease under calcineurin-basedimmunosuppression. *All transplant types: living kidney and deceased donor islet or pancreasafter kidney transplantation, simultaneous pancreas or islet kidney transplantation, or de-ceased donor kidney alone and islet or pancreas after kidney transplantation.

care.diabetesjournals.org Choudhary and Associates 1025

minimization of immunosuppressionthrough antigen-specific immunotherapy,adoptive transfer of immunoregulatorycells, and use of biocompatible immune-isolating devices. Moving forward, pre-clinical work is already showing potentialfor expanding the role of transplantationthrough the use of alternate tissuesources, such as porcine islet xenograftsor human stem cell–derived insulin-secreting cells.

CONCLUSIONS

Problematic hypoglycemia is anothercomplication of long-term T1D, causingmorbidity and mortality in a significantproportion of patients. It is important toscreen patients for problematic hypogly-cemia using validated tools and to imple-ment individualized therapeutic targetsbased on the balance between glycemiccontrol and hypoglycemia risk. Problem-atic hypoglycemia can be resolved withappropriate educational and technologicalinterventions inmost patientswith accept-able glycemic control; however, in a subsetof patients, transplants offer the only so-lution. Especially for that subset, existinginterventions need to be more thoroughlyevaluated and new therapies developed.

Acknowledgments. The authors thankMary E.Knatterud, University of Minnesota, for experteditorial assistance.

Funding. P.C. is supported in part by DiabetesUK grants 14/0004865 and 13/0005643. M.R.R. issupported in part by U.S. Public Health Serviceresearch grants R01-DK-091331 and U01-DK-070430 from the National Institutes of Health.P.A.S. is supported by the Academic AlternateRelationship Plan and in part by Alberta InnovatesHealth Solutions and JDRF. M.-C.V. is supportedby the French Ministry of Health (PHRC 2001,2008, and 2009), European Community (FondEuropeen de Developpement Regional), ConseilRegional Nord Pas de Calais (IFR 114), EuropeanFP7, JDRF, Societe Francophone du Diabete, As-sociation de Recherche pour le Diabete, andAgence de Biomedecine. T.W.K. is supported bytheNationalHealth andMedical ResearchCouncil(APP1037321), JDRF, Diabetes Australia ResearchTrust, Operational Infrastructure Support schemeof the Victorian Government, and NationallyFunded Centres scheme. F.S. is supported inpart by Ministry of Health of the Czech Republicgrant NT14020-3/2013. B.J.H. is supported in partby U.S. Public Health Service research grants U01-AI-065193 and U01-AI-102463 from the NationalInstitutes of Health and by research grants 17-2012-527 and 17-2013-495 from JDRF.Duality of Interest. P.C. has participated onadvisory boards for Medtronic, Johnson andJohnson, and Roche regarding insulin pumpsand CGM and has participated in commercialresearch funded by Medtronic. P.A.S. has re-ceived research support from Novo Nordisk andEli Lilly and consulting fees from Eli Lilly, Med-tronic, and Novo Nordisk and is on the speakersbureau for Animas, Eli Lilly, Novo Nordisk, andSanofi. No other potential conflicts of interestrelevant to this article were reported.Author Contributions. P.C., M.R.R., P.A.S., andM.-C.V. researched data, conducted the system-atic review, identified studies for inclusion in thereview and rated their quality, and contributedto the writing, review, editing, and final approvalof themanuscript. P.M., T.W.K., B.K., N.I., and F.S.contributed to the design of the review and

writing, editing, and final approval of the manu-script. R.L. researched data, conducted the sys-tematic review, identified studies for inclusion inthe review and rated their quality, led thedevelopment of the comprehensive treatmentalgorithm, and contributed to the writing, review,editing, and final approval of the manuscript.B.J.H. developed the concept of a comprehen-sive treatment algorithm for patients with T1Dand problematic hypoglycemia in collaborationwith councilors of the International Pancreasand Islet Transplant Association, assembled thewriting team, researched data, conducted thesystematic review, identified studies for inclu-sion in the review and rated their quality, led thewriting of the manuscript, and contributed tothe review, editing, and final approval of themanuscript.

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Table 3—Proposed clinical practice recommendations for the treatment ofpatients with T1D complicated by problematic hypoglycemia

1 Routinely provide to allMDI therapy patientswith T1D usingSMBG structured and curriculum-based educationalprograms that reduce the incidence of SH and restoreawareness in a significant proportion of patientswith IAH.

2 Add one diabetes technology, preferably CSII with SMBG orMDI with CGM, where available, with appropriateeducation, training, and support to patients withproblematic hypoglycemia to reduce the incidence of SHand maintain or improve HbA1c.

3 Use SAPs, preferably with an automated threshold-suspendfeature, where available, or very frequent contact witha specialized hypoglycemia service in patients whoseproblematic hypoglycemia persists despite the use ofstructured education and other diabetes technologies.

4 Consult with transplant program (and payer) about theeligibility of selected patientswith persistent problematichypoglycemia for an islet or a pancreas transplant whenother interventions have not been effective andwhen therisk-benefit ratio is deemed favorable.

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97. Brooks AM, Oram R, Home P, Steen N, ShawJA. Demonstration of an intrinsic relationshipbetween endogenous C-peptide concentrationand determinants of glycemic control in type 1diabetes following islet transplantation. Diabe-tes Care 2015;38:105–11298. Cryer PE. Hypoglycemia begets hypoglyce-mia in IDDM. Diabetes 1993;42:1691–169399. Gerber PA, Pavlicek V, Demartines N, et al.Simultaneous islet-kidney vs pancreas-kidneytransplantation in type 1 diabetes mellitus: a 5year single centre follow-up. Diabetologia 2008;51:110–119100. Ostenson CG, Geelhoed-Duijvestijn P,Lahtela J, Weitgasser R, Markert Jensen M,Pedersen-Bjergaard U. Self-reported non-severe hypoglycaemic events in Europe. DiabetMed 2014;31:92–101101. Kovatchev BP, Cox DJ, Gonder-Frederick LA,Young-Hyman D, Schlundt D, Clarke W. Assess-ment of risk for severe hypoglycemia amongadults with IDDM: validation of the low bloodglucose index. Diabetes Care 1998;21:1870–1875

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106. Maffi P, Bertuzzi F, De Taddeo F, et al.Kidney function after islet transplant alone intype 1 diabetes: impact of immunosuppressivetherapy on progression of diabetic nephropa-thy. Diabetes Care 2007;30:1150–1155107. Ojo AO, Held PJ, Port FK, et al. Chronicrenal failure after transplantation of a nonrenalorgan. N Engl J Med 2003;349:931–940108. Klein AS, Messersmith EE, Ratner LE,Kochik R, Baliga PK, Ojo AO. Organ donationand utilization in the United States, 1999-2008. Am J Transplant 2010;10:973–986109. Matesanz R, Domınguez-Gil B, Coll E, de laRosa G, Marazuela R. Spanish experience as aleading country: what kind of measures weretaken? Transpl Int 2011;24:333–343110. Byrne ML, Hopkins D, Littlejohn W, et al.Outcomes for adults with type 1 diabetes re-ferred with severe hypoglycaemia and/or re-ferred for islet transplantation to a specialisthypoglycaemia service. Horm Metab Res 2015;47:9–15

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