Endocrinología,
Diabetes
y
Nutrición
CONSENSUSDOCUMENT
Consensus
on
insulin
treatmentin
type2
diabetes
,
Consenso
sobre
tratamiento
con
insulina
en
la
diabetes
tipo
2
JuanGirbésBorrás
,
JavierEscaladaSanMartín
,ManelMataCases
,Fernando
Gomez-Peralta
,
SaraArtolaMenéndez
,DiegoFernándezGarcía
,Carlos
OrtegaMillán
,FernandoAlvarezGuisasola
,JuanCarlosFerrer
García
,Patxi
EzkurraLoiola
,FernandoEscobarJiménez
,José
AntonioFornosPérez
,MercedesGalindoRubio
,
ItxasoRicaEchevarría
,EdelmiroMenéndezTorre
a
Unidad
de
Endocrinología
y
Nutrición,
Servicio
de
Endocrinología
y
Nutrición,
Hospital
Arnau
de
Vilanova,
Valencia,
Spain
b
Departamento
de
Endocrinología
y
Nutrición,
Clínica
Universidad
deNavarra,
Pamplona,
Navarra,
Spain
c
Centro
de
Investigación
Biomédica
en
Red-Fisiopatología
dela
Obesidad
y
Nutrición
(CIBERobn),
Instituto
de
Salud
Carlos
III,Madrid,Spain
d
Centro
de
Atención
Primaria
LaMina,
Gerència
d’Àmbit
d’Atenció
Primària
Barcelona
Ciutat,
Institut
Català
dela
Salut,
Sant Adriàde
Besòs,
Barcelona,
Spain
e
Grupo
DAP-Cat,
Unitat
deSuport
a
la
Recerca
Barcelona
Ciutat,
Institut
Universitari
d’Investigació
en
Atenció
Primària
JordiGol(IDIAP
Jordi
Gol),
Barcelona,
Spain
f
Centro
de
Investigación
Biomédica
enRed
de
Diabetes
y
Enfermedades
Metabólicas
Asociadas
(CIBERdem),
Instituto
de
Salud CarlosIII,
Madrid,
Spain
g
Unidad
de
Endocrinología
y
Nutrición,
Hospital
General
de
Segovia,
Segovia,
Spain
h
Medicina
Familiar
y
Comunitaria,
Centro
deSalud
José
Marvá,
Madrid,
Spain
i
Red
de
Grupos
de
Estudio
de
la
Diabetes
enAtención
Primaria
dela
Salud
(RedGDPS),
Spain
j
Servicio
Endocrinología
y
Nutrición,
Hospital
Virgen
dela
Victoria,
Málaga,
Spain
k
Servicio
de
Endocrinología
y
Nutrición,
Hospital
Vithas-Xanit,
Benalmádena,
Málaga,
Spain
l
Medicina
Familiar
y
Comunitaria,
Centro
deSalud
de
Pozoblanco,
Pozoblanco,
Córdoba,
Spain
m
Medicina
Familiar
y
Comunitaria,
Centro
de
Salud
Ribera
del
Órbigo,
Benavides
deÓrbigo,
León,
Spain
n
Sociedad
Espa˜nola
de
Diabetes
y
Sociedad
Espa˜nola
deMedicina
Familiar
y
Comunitaria,
Spain
o
Unidad
de
Endocrinología
y
Nutrición,
Consorcio
Hospital
General
Universitario
de
Valencia,
Valencia,
Spain
p
Medicina
Familiar
y
Comunitaria,
Centro
de
Salud
deZumaia-Gipuzkoa,
Zumaya,
Guipúzcoa,
Spain
q
Servicio
de
Endocrinología
y
Nutrición,
Hospital
Clínico
San
Cecilio,
Universidad
deGranada,
Granada,
Spain
r
Grupo
Berbés
de
Investigación
y
Docencia,
Spain
s
Grupo
de
Diabetes
de
SEFAC,
Spain
t
Fundación
Pharmaceutical
Care,
Spain
Pleasecitethisarticleas:GirbésBorrásJ,EscaladaSanMartínJ,MataCasesM,Gomez-PeraltaF,ArtolaMenéndezS,FernándezGarcíaD,etal.Consensosobretratamientoconinsulinaenladiabetestipo2.EndocrinolDiabetesNutr.2018;65:1---8.
ThecompleteConsensusDocumentisavailableat:http://www.seen.esandhttp://www.sediabetes.org,andasadditionalmaterialin
theJournalwebpage.
∗
Correspondingauthor.
E-mailaddress:
jgirbesb@yahoo.es(J.GirbésBorrás).https://doi.org/10.1016/j.endien.2018.01.0032530-0180/©2018SEENandSED.PublishedbyElsevierEspa˜na,S.L.U.All
rightsreserved.
2
J.
Girbés
Borrás
et
al.
u
Universidad
deSantiago
de
Compostela,
Santiago
deCompostela,
La
Coru˜na,
Spain
v
Servicio
de
Endocrinología
y
Nutrición,
Hospital
Clínico
San
Carlos,
Madrid,
Spain
w
Facultad
de
Enfermería,
Fisioterapia
y
Podología,
Universidad
Complutense
deMadrid,
Madrid,
Spain
x
Sección
de
Endocrinología
Pediátrica,
Hospital
Universitario
de
Cruces,
Baracaldo,
Vizcaya,
Spain
y
Centro
de
Investigación
Biomédica
en
Red
de
Enfermedades
Raras
(CIBERER),
Valencia,
Spain
z
Servicio
deEndocrinología
y
Nutrición,
Hospital
Universitario
Central
deAsturias,
Oviedo,
Asturias,
Spain
Introduction
In
2010,
the
Working
Group
on
Consensus
andClinical
Guide-lines
of
theSpanish
Society
of
Diabetes
(SED)
published
aconsensus
on
drug
treatment
intype
2
diabetes
mellitus(T2DM)
which
was
approved
bydifferent
scientific
bodies.
The
Working
Group
thought
that
itwould
be
useful
to
pub-lish
a
consensus
document
specifically
addressed
to
insulintherapy
in
T2DM.This
document
is
anexecutive
summary
of
amore
com-prehensive
document
approved
by
theboards
oftheSEDand
the
Spanish
Society
of
Endocrinology
and
Nutrition.
Thecomplete
version
may
be
found
on
the
websites
of
both
soci-eties
on
those
of
all
the
other
scientific
bodieswhich
adhereto
the
consensus.
Criteriaforinsulin
therapystartandwithdrawal
When
and
how
should
insulin
therapy
be
given
Start
of
insulin
therapy
Insulin
therapy
may
be
started
at
diagnosis
orduringfollow-up.
---
At
the
start
ofthe
disease,
if
there
is
weight
loss,
severeketonuria,
or
cardinal
symptoms
of
diabetes,
especiallywithHbA
1c
>
9%.---During
follow-up,
transient
or
permanent
insulin
therapymay
be
required.
How
should
insulin
therapy
be
given
There
are
several
options
forstarting
insulin
therapy:---
Basal
insulin.
Oneor
two
doses
of
NPH
insulin,
or
onedoseof
a
basal
analogue:
glargine,
detemir,
and
degludec.---
Prandial
insulin.
Three
doses
of
rapid-acting
insulin
or
anultra-rapid
analogue
before
meals.---
Insulin
mixtures.
Two
or
more
doses
offixed
mixturesof
rapid-acting
or
ultra-rapid
insulin
with
intermediate-acting
insulin.The
first
optionis
currently
theregimen
of
choice.
patients,
adoseof
10
Uor
0.2
U/kg
inobesepatients
of
basal
insulin
at
bedtime
may
be
used
dose
is
adjusted
based
on
basalblood
glucose
levelevery
Table
1
Basal
insulin
therapy.
Adjustment
ofnon-insulin
drugs:
---
Continue
with
the
same
dose:
metformin,
DPP-4i,GLP-1
RA
and/or
SGLT2i---
Consider
discontinuation
or
a
dose
reduction
ofsulfonylureas,
glinides,
and
pioglitazone
Start
with
10
Uor
0.2
U/kg
---
NPH
or
detemir
atbedtime---
Glargina
at
any
time---
Degludec
atany
time
Adjust
the
insulin
dose
based
on
BGIncrease
the
insulin
dose
every
3days
(provided
there
isnohypoglycemia):
--- By2
U
when
thegoal
levels
are
exceeded
for
3
daysconsecutively--- By4
U
when
basal
blood
glucose
>
180
mg/dL
Decrease
the
insulin
dose
every
3---5days
---By
2
U
when
BG
isbelow
a
pre-established
limit
(usually70---90mg/dL)
for
2---3
consecutive
days
Ifhypoglycemia
occurs,
decrease
the
dose
by
4Uor
10%
of the
basal
insulin
dose.
BG:
basalbloodglucoselevel.
three
days
Duly
trained
patients
may
also
performtitration.If
glucose
goals
are
notachieved
with
basal
insulins
atdoses
higher
than
0.5
U/kg
in
3---4
months,
treatment
inten-sification
shouldbe
considered.In
highly
symptomatic
patients
with
marked
basal
hyper-glycemia
(>280---300
mg/dL)
or
ketonuria,
two
doses
of
basalinsulin,
a
biphasic
regimen,
or
basal/bolus
treatment
may
berequired.
Discontinuation
of
insulin
therapy
in
patients
withT2DM
Insomepatients,
insulin
may
be
discontinued
and/orreplaced
by
other
antidiabetic
drugs.
Some
variables
maypredict
theefficacy
ofreplacing
insulin
by
other
antidia-betic
drugs:
a)
insulin
therapy
during
hospital
admission
orconcomitant
disease
with
adequate
prior
blood
glucose
con-trol
with
antidiabetic
drugsother
than
insulin;
b)
insulintherapy
from
thestartwith
sustained
adequate
control;
c)adequate
control
with
nottoo
high
doses
(<0.5
U/kg/day)
Consensus
on
insulin
treatment
intype
2diabetes
3and
diabetes
duration<10
years;
and
d)
patients
undergoingbariatric
surgery.Reduction
should
be
gradual,
e.g.4Uper
week.Finally,
the
decision
should
be
agreed
with
thepatient.If
hyperglycemic
decompensation
occurs,
insulin
should
berestarted.
Insulin
may
be
required
again
inthe
eventofconcomitant
disease.
Insulin
therapy
regimens
Basalinsulin
the
insulins
available.
Basalinsulins
tryto
sim-ulate
the
basal
pattern
to
maintain
patients
close
tonormalfasting
bloodglucose
levels.
Types
of
basal
insulin
---
NPH
insulin.
The
peakaction
of
NPH
insulin
occurs
at4---6
h,and
its
effective
duration
of
action
is
12
h.Itmaybe
administered
as
oneor
two
doses,
combined
with
oraldrugs.
It
may
be
used
inpregnancy.---
Insulin
detemir
is
asoluble
insulin
analogue.
The
durationof
action
is
dose-dependent:
12
h
for
doses
of0.2
U/kg
and20
h
for
doses
of
0.4
U/kg.Inone
thirdof
patients,
twodoses
are
required
to
cover
the24
h
period.---
Insulin
glargine
U-100
is
ananalogue
with
a
slower
onsetof
action
than
NPH
and
a
smoother
action
profile,withno
peaks
andaction
lasting
upto
18---24
h.
Itshould
beadministered
once
daily,
atthe
same
time
every
day.---
Biosimilar
insulin
glargine.
The
summaries
of
the
productcharacteristics
of
glargine
U-100and
biosimilar
glargine100
U/mL
are
almost
superimposable.---
Insulinglargine
U-300.
Glargine
formulation
with
aconcentration
of
300U/mL.
It
has
aflatter
and
longerpharmacodynamic
and
pharmacokinetic
profile
thanglargine
U-100andis
associated
with
less
risk
ofhypoglycemia
andsimilar
HbA
1c
reductions
in
patientswith
T2DM.
Inclinical
trials,
basal
doses
10---18%
higherwere
needed
on
average
as
compared
toglargine
U-300.---
Insulin
degludec
is
ananalogue
with
a
duration
of
actionlonger
than
42h
with
an
intrapatient
variability
four
timeslower
as
compared
to
glargine
U-100,
with
the
same
effi-cacy
but
less
nocturnal
hypoglycemia.
Insulin
degludecshould
be
administered
daily
and
allows
forhighly
flexi-ble
administration,
with
dosing
intervals
ranging
from
8to
40
h.It
is
not
reimbursed
inSpain
as
a
starting
insulin.
Choice
ofstarting
insulinregimen
All
basal
insulins
have
thesame
efficacy,
but
there
aredifferences
regarding
therisk
of
hypoglycemia,
especiallynocturnal
hypoglycemia.
Anychoice
must
be
basedon
thepatient
profile
in
terms
of
safety
and
the
cost
of
the
treat-ment.
Insulincombined
with
other
drugs
Basal
insulin
therapy
is
usually
the
treatment
ofchoice
afterdrugs
other
than
insulin
have
failed.
As
regards
drugs
thatmay
be
used
incombination
with
basal
insulin,
there
are
twooptions
(Fig.
Start
of
insulintherapy
with
basal
insulin
If
thepatient
is
receiving
metformin,
DPP-4
inhibitors
(DPP-4i),
GLP-1
receptor
agonists
GLP-1
RAs),
and/or
SGLT-2inhibitors
(SGLT-2i),
these
shouldbe
continued,
andthediscontinuation
ofpioglitazone
should
be
considered.
Ifsul-fonylureas
(SUs)
are
discontinued,
aninitial
blood
glucoseimpairment
may
occur.
IfSUs
are
continued,
a
reduction
inthe
doseis
advised
because
of
therisk
ofhypoglycemia
(Fig.
Intensification
of
basalinsulin.
Which
non-insulin
drugsshould
beused?
Usually,
patients
are
already
receiving
an
oral
antidiabetic,generally
metformin
with
or
without
SUs
or
DPP-4i.The
mostrecent
guidelines
recommend
theaddition
ofa
GLP-1
RAor
SGLT-2i
as
analternative
to
theaddition
ofnew
insulininjections.
Basal-plus
insulin
regimen
This
consists
ofthe
progressive
addition
of
doses
of
prandialinsulin
(or
analogue),
starting
with
themeal
with
the
great-est
impact
onpostprandial
blood
glucose,
while
maintainingbasal
insulin.
Non-insulin
drugs
may
be
continued,
butSUdiscontinuation
is
preferred
because
ofthe
increased
risk
ofhypoglycemia.
Before
prandial
insulin
is
started,
thebasalglucose
goalshould
have
been
achieved.
Subsequently,
if
HbA
1c
is
ele-vated,
rapid-acting
insulin
(oranalogue)
should
be
added.As
regards
the
starting
dose,Appendix
A,
Table
3
(Supple-mentary
material)
shows
four
options.
The
doses
shouldsubsequently
be
adjusted
(usually
every
oneor
two
weeks)until
anindividualized
postprandial
blood
glucose
goal
isachieved.
Appendix
A,
Table
4
(Supplementary
material)shows
several
possibilities.Once
the
postprandial
goal
isachieved,
if
thegoal
HbA
1c
has
not
been
reached,
an
additional
dose
of
prandial
insulinshould
be
given
at
another
meal.
Basal-bolus
insulin
regimen
When
treatment
with
basal
insulin
or
premixed
insulins
doesnotachieve
the
control
goal
inT2DM,
theclinical
practiceguidelines
recommend
the
addition
of
rapid-acting
insulinbeforemeals.
Meta-analyses
have
not
confirmed
a
greaterhypoglycemic
potency,
but
have
reported
alower
hypo-glycemia
rate
as
compared
toother
regimens.
2shows
apractical
algorithm
for
regimen
start
andadjust-ment.Practical
recommendations:
Bolus
dose
calculation.
Different
systems
have
been
pro-posed
(Appendix
A,
Table
3ofSupplementary
material).
Ourworking
group
considers
thefirst
two
to
be
themost
prudentoptions.
Start
in
patients
usingbasal/NPH
insulin.
A
switch
to
abasal
analogue
and
a20%
reduction
of
theprevious
dose
ofslow-acting
insulin
are
advisedif
control
was
close
to
thegoal
or
a
high
risk
of
hypoglycemia
exists.
Start
in
patients
usingpremixed
insulin.
Administer
50%as
a
slow-acting
insulin
andtheother
50%
as
three
injectionsof
rapid-acting
insulin
before
themain
meals.
Depending
4
J.
Girbés
Borrás
et
al.
Table
2
Classification
and
presentation
of
insulins
inSpain
(December
2017).Product
Trade
name
How
supplied
Ultra-rapid-acting
insulins
(onset
ofaction:
<15min;
usual
duration:
3---5
h)
LisproHumalog
®
KwikPen
®
Five
3-mL
prefilled
pensHumalog
®
vial 10-mL
vialHumalog
®
200
KwikPen
®
Five
3-mL
prefilled
pensAspartNovoRapid
®
FlexPen
Five
3-mL
prefilled
pensNovoRapid
®
vial 10-mL
vialNovoRapid
®
Penfill
®
Five
3-mL
cartridgesNovoRapid
®
PumpCart
®
Five
1.6-mL
cartridgesGlulisineApidra
®
SoloStar
®
Five
3-mL
prefilled
pensApidraJuniorStar
cartridge
®
Five
3-mL
cartridgesApidra
®
solution
for
injection
10-mL
vial
Rapid-acting
insulins
(onset
of
action:
30
min;
usual
duration:
6---8
h)
RegularActrapid
®
InnoLet
®
Five
3-mL
prefilled
pensActrapid
®
vial
10-mL
vialHumulin
regular
®
10-mL
vial
Intermediate-action
insulins
(onset
of
action:
1
h;
usual
duration
12---18
h)
NPHInsulatard
®
FlexPen
®
Five
3-mL
prefilled
pensInsulatard
®
vial
10-mL
vialHumulina
®
NPH
KwikPen
®
Six
3-mL
prefilled
pensHumulina
®
NPH
vial
10-mL
vialInsulindetemir Levemir
®
FlexPen
®
Five
3-mL
prefilled
pensLevemir
®
InnoLet
®
Five
3-mL
prefilled
pens
Long-actinginsulins
(onset
of
action:
1h;
usual
duration
≥
22---26
h)
Glargine
Lantus
®
SoloStar
®
Five
3-mL
prefilled
pensLantus
®
JuniorStar
cartridges
®
Five
3-mL
prefilled
pensLantus
®
vial
10-mL
vialGlargineU-300
Toujeo
®
SoloStar
®
Three
1.5-mL
prefilled
pensGlargine(biosimilar)
Abasaglar
®
KwikPen
Five
3-mL
prefilled
pensDegludecTresiba
®
Flex
Touch
®
Five
3-mL
prefilled
pens
Allinsulins
are
supplied
at
concentrations
of100U/mL
except
for
Humalog
KiwkPen
200
U,
with
a
concentration
of 200U/mL,
and
Toujeo
Solostar,
with
a
concentration
of
300
U/mL.
Standard
insulin
syringes
are
prepared
for concentrations
of
100
U/mL.
Thus,
drawing
insulin
from
these
pens
would
multiply
the
dose
by
three
or
by
two,
with
theresultant
risk
of
hypoglycemia.Insulin
Lantus
100U/mL
and
Abasaglar
(biosimilar)
are
not
exchangeable.
They
should
be
prescribed
by
brand
name.Premixedcombinations
Regular
30%
+
NPH
70%
Humulina
®
30:70
KwikPen
®
Six
3-mL
prefilled
pensMixtard
®
30
InnoLet
®
Five
3-mL
prefilled
pensHumulin
®
30:70
vial
10-mL
vialMixtard
®
30
vial
10-mL
vialLispro25%+Lispro
protamine
75%
Humalog
®
Mix
25
TM
KiwkPen
®
Five
3-mL
pensLispro50%+Lispro
protamine
50%
Humalog
®
Mix
50
TM
KwikPen
®
Five
3-mL
prefilled
pensAspart30%+Aspart-protamine
70%
NovoMix
®
30
FlexPen
®
Five
3-mL
prefilled
pensAspart50%+Aspart-protamine
50% NovoMix
®
50
FlexPen
®
Five
3-mL
prefilled
pensAspart70%+Aspart-protamine
30%
NovoMix
®
70
FlexPen
®
Five
3-mL
prefilled
pens