-
POSITION STATEMENT
Management of hyperglycaemia in type 2 diabetes, 2015:a
patient-centred approach. Update to a Position Statementof the
American Diabetes Association and the EuropeanAssociation for the
Study of Diabetes
Silvio E. Inzucchi & Richard M. Bergenstal & John B.
Buse & Michaela Diamant &Ele Ferrannini & Michael Nauck
& Anne L. Peters & Apostolos Tsapas &Richard Wender
& David R. Matthews
Received: 15 October 2014 /Accepted: 20 October 2014 /Published
online: 13 January 2015# Springer-Verlag Berlin Heidelberg 2015
Keywords Guidelines . Insulin .Oral agents . Therapy .Type2
diabetes
AbbreviationsCKD Chronic kidney diseaseDPP-4 Dipeptidyl
peptidase 4eGFR Estimated GFR
GLP-1 Glucagon-like peptide 1SGLT2 Sodiumglucose co-transporter
2TZD Thiazolidinedione
In 2012, the American Diabetes Association (ADA) andthe European
Association for the Study of Diabetes(EASD) published a position
statement on the
Michaela Diamant is credited posthumously. Her experience,
wisdom andwit were key factors in the creation of the original 2012
positionstatement; they continued to resonate with us during the
writing of thisupdate.
S. E. Inzucchi and D. R. Matthews were co-chairs for the
PositionStatement Writing Group. R. M. Bergenstal, J. B. Buse, A.
L. Petersand R. Wender were the Writing Group for the American
DiabetesAssociation. M. Diamant, E. Ferrannini, M. Nauck and A.
Tsapas werethe Writing Group for the European Association for the
Study ofDiabetes.
Simultaneous publication: This article is being
simultaneouslypublished in Diabetes Care and Diabetologia by the
American DiabetesAssociation and the European Association for the
Study of Diabetes.Copyright 2014 by the American Diabetes
Association and Springer-Verlag. Copying with attribution allowed
for any non-commercial use ofthe work.
Electronic supplementary material The online version of this
article(doi:10.1007/s00125-014-3460-0) contains an ESM slide set
for thispaper and an abridged version, which is available to
authorised users.
S. E. InzucchiSection of Endocrinology, Yale University School
of Medicine,Yale-New Haven Hospital, New Haven, CT, USA
R. M. BergenstalInternational Diabetes Center at Park Nicollet,
Minneapolis, MN,USA
J. B. BuseDivision of Endocrinology, University of North
Carolina School ofMedicine, Chapel Hill, NC, USA
M. DiamantDiabetes Center/Department of Internal Medicine, VU
UniversityMedical Center, Amsterdam, The Netherlands
Diabetologia (2015) 58:429442DOI 10.1007/s00125-014-3460-0
-
management of hyperglycaemia in patients with type 2diabetes [1,
2]. This was needed because of an increas-ing array of
anti-hyperglycaemic drugs and growinguncertainty regarding their
proper selection and se-quence. Because of a paucity of comparative
effective-ness research on long-term treatment outcomes withmany of
these medications, the 2012 publication wasless prescriptive than
prior consensus reports. We previ-ously described the need to
individualise both treatmenttargets and treatment strategies, with
an emphasis onpatient-centred care and shared decision-making, and
thiscontinues to be our position, although there are now
morehead-to-head trials that show slight variance betweenagents
with regard to glucose-lowering effects. Neverthe-less, these
differences are often small and would be un-likely to reflect any
definite differential effect in an indi-vidual patient.
The ADA and EASD have requested an update to theposition
statement incorporating new data from recent clinicaltrials.
Between June and September of 2014, the WritingGroup reconvened,
including one face-to-face meeting, todiscuss the changes. An
entirely new statement was felt to
be unnecessary. Instead, the group focused on those areaswhere
revisions were suggested by a changing evidence base.This briefer
article should therefore be read as an addendum tothe previous full
account [1, 2].
Glycaemic targets
Glucose control remains a major focus in the management
ofpatients with type 2 diabetes. However, this should always bein
the context of a comprehensive cardiovascular risk factorreduction
programme, to include smoking cessation and theadoption of other
healthy lifestyle habits, blood pressure con-trol, lipid management
with priority to statin medications and,in some circumstances,
antiplatelet therapy. Studies have con-clusively determined that
reducing hyperglycaemia decreasesthe onset and progression of
microvascular complications [3,4]. The impact of glucose control on
cardiovascular compli-cations remains uncertain; a more modest
benefit is likely tobe present, but probably emerges only after
many years ofimproved control [5]. Results from large trials have
alsosuggested that overly aggressive control in older patients
withmore advanced disease may not have significant benefits andmay
indeed present some risk [6]. Accordingly, instead of
aone-size-fits-all approach, personalisation is necessary,balancing
the benefits of glycaemic control with its potentialrisks, taking
into account the adverse effects of glucose-lowering medications
(particularly hypoglycaemia), and thepatients age and health
status, among other concerns. Figure 1displays those patient and
disease factors that may influencethe target for glucose control,
as reflected by HbA1c. The mainupdate to this figure is the
separation of those factors that arepotentially modifiable from
those that are usually not. Thepatients attitude and expected
treatment efforts and access toresources and support systems are
unique in so far as theymayimprove (or worsen) over time. Indeed,
the clinical teamshould encourage patient adherence to therapy
through edu-cation and also try to optimise care in the context of
prevailinghealth coverage and/or the patients financial means.
Otherfeatures, such as age, life expectancy, comorbidities and
therisks and consequences to the patient from an adverse drugevent,
are more or less fixed. Finally, the usual HbA1c goalcut-off point
of 7% (53.0 mmol/mol) has also been inserted atthe top of the
figure to provide some context to the recom-mendations regarding
stringency of treatment efforts.
Therapeutic options (See text box Properties of
availableglucose-lowering agents in the USA and Europe that
mayguide individualised treatment choices in patientswith type 2
diabetes; for other unchanged options, alsorefer to the original
statement [1, 2])
430 Diabetologia (2015) 58:429442
E. FerranniniDepartment of Medicine, University of Pisa School
of Medicine,Pisa, Italy
M. NauckDiabeteszentrumBad Lauterberg, Bad Lauterberg imHarz,
Germany
A. L. PetersDivision of Endocrinology, Keck School of Medicine
of theUniversity of Southern California, Los Angeles, CA, USA
A. TsapasSecond Medical Department, Aristotle University
Thessaloniki,Thessaloniki, Greece
R. WenderAmerican Cancer Society, Atlanta, GA, USA
R. WenderDepartment of Family and Community Medicine, Jefferson
MedicalCollege, Thomas Jefferson University, Philadelphia, PA,
USA
D. R. Matthews (*)Harris Manchester College (University of
Oxford),Mansfield Road, Oxford OX1 3TD, UKe-mail:
[email protected]
D. R. MatthewsOxford Centre for Diabetes, Endocrinology and
Metabolism,Churchill Hospital, Oxford, UK
D. R. MatthewsNational Institute for Health Research (NIHR),
Oxford BiomedicalResearch Centre, Oxford, UK
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Propertiesofavailableglucose-loweringagentsin
theUSA
andEuropethat
may
guideindividu
alised
treatm
entchoicesinpatientswithtype
2diabetes
Class
Com
pound(s)
Cellularmechanism
(s)
Primaryphysiological
action(s)
Advantages
Disadvantages
Costa
Biguanides
Metform
inActivates
AMP-kinase
(?other)
Hepaticglucose
production
Extensive
experience
Gastrointestinalside
effects
(diarrhoea,abdom
inal
cram
ping)
Low
Nohypoglycaemia
Lactic
acidosisrisk
(rare)
CVDevents(U
KPDS)
Vitamin
B12deficiency
Multiplecontraindications:
CKD,acidosis,hypoxia,
dehydration,etc.
Sulfonylureas
2ndgeneration
ClosesKATPchannels
onbetacellplasma
mem
branes
Insulin
secretion
Extensive
experience
Hypoglycaem
iaLow
Glibenclam
ide/
glyburide
Microvascularrisk
(UKPDS)
Weight
Glipizide
?Bluntsmyocardialischaem
icpreconditioning
Gliclazide
bLow
durability
Glim
epiride
Meglitinides
(glinides)
Repaglinide
Nateglinide
ClosesKATPchannels
onbetacellplasma
mem
branes
Insulin
secretion
Po
stprandialglucose
excursions
Hypoglycaem
iaModerate
Dosingflexibility
Weight
?Bluntsmyocardialischaem
icpreconditioning
Frequent
dosing
schedule
TZDs
Pioglitazonec
Activates
thenuclear
transcriptionfactor
PPAR-
Insulin
sensitivity
Nohypoglycaemia
Weight
Low
Rosiglitazoned
Durability
Oedem
a/heartfailure
HDL-C
Bonefractures
Triacylglycerols
(pioglitazone)
LDL-C
(rosiglitazone)
?CVDevents
(PROactive,
pioglitazone)
?MI(m
eta-analyses,
rosiglitazone)
-Glucosidase
inhibitors
Acarbose
Inhibitsintestinal
-glucosidase
Slow
sintestinal
carbohydrate
digestion/absorption
Nohypoglycaemia
Generally
modestH
bA1c
efficacy
Moderate
Miglitol
Po
stprandialglucose
excursions
Gastrointestinalside
effects
(flatulence,diarrhoea)
?CVDevents
(STOP-N
IDDM)
Frequent
dosing
schedule
Non-systemic
Diabetologia (2015) 58:429442 431
-
DPP
-4inhibitors
Sitagliptin
InhibitsDPP
-4activity,
increasing
postprandial
activeincretin
(GLP-1,
GIP)concentrations
Insulin
secretion
(glucose-dependent)
Nohypoglycaemia
Angioedem
a/urticariaand
otherim
mune-mediated
derm
atologicaleffects
High
Vildagliptin
b
Glucagonsecretion
(glucose-dependent)
Welltolerated
?Acutepancreatitis
Saxagliptin
?Heartfailure
hospitalisations
Linagliptin
Alogliptin
Bile
acid
sequestrants
Colesevelam
Binds
bileacidsinintestinal
tract,increasing
hepatic
bile
acid
production
?Hepaticglucose
production
Nohypoglycaemia
Generally
modestH
bA1c
efficacy
High
?Incretin
levels
LDL-C
Constipation
Triacylglycerols
May
absorptionof
other
medications
Dopam
ine-2
agonists
Bromocriptine
(quick
release)d
Activates
dopaminergic
receptors
Modulateshypothalam
ic
regulationof
metabolism
Nohypoglycaemia
Generally
modestH
bA1c
efficacy
High
Insulin
sensitivity
?CVDevents
(CyclosetS
afetyTrial)
Dizziness/syncope
Nausea
Fatigue
Rhinitis
SGLT
2
inhibitors
Canagliflozin
InhibitsSG
LT2in
the
proxim
alnephron
Blocksglucose
reabsorptionby
the
kidney,increasing
glycosuria
Nohypoglycaemia
Genitourinaryinfections
High
Dapagliflozinc
Weight
Po
lyuria
Empagliflozin
Blood
pressure
Volum
e
depletion/hypotension/
dizziness
Effectiv
eatallstages
ofT2D
M
LDL-C
Creatinine(transient)
GLP-1
receptor
agonists
Exenatide
Activates
GLP-1receptors
Insulin
secretion
(glucose-dependent)
Nohypoglycaemia
Gastrointestinalside
effects
(nausea/vomiting/diarrhoea)
High
Exenatide
extended-release
Glucagonsecretion
(glucose-dependent)
Weight
Heartrate
Albiglutide
Slow
sgastricem
ptying
Po
stprandialglucose
excursions
?Acutepancreatitis
Liraglutide
Satiety
So
mecardiovascular
risk
factors
Ccellhyperplasia/medullary
thyroidtumoursin
anim
als
Lixisenatideb
Injectable
Dulaglutide
Trainingrequirem
ents
432 Diabetologia (2015) 58:429442
-
Amylin
mim
etics
Pram
lintided
Activates
amylin
receptors
Glucagonsecretion
Po
stprandialglucose
excursions
Generally
modestH
bA1c
efficacy
High
Slow
sgastricem
ptying
Weight
Gastrointestinalside
effects
(nausea/vomiting)
Satiety
Hypoglycaem
iaunless
insulin
dose
issimultaneouslyreduced
Injectable
Frequent
dosing
schedule
Trainingrequirem
ents
Insulins
Rapid-acting
analogues
Activates
insulin
receptors
Glucose
disposal
Nearlyuniversal
response
Hypoglycaem
iaVariablee
Lispro
Hepaticglucose
production
Theoretically
unlim
ited
efficacy
Weightg
ain
Aspart
Other
Microvascularrisk
(UKPDS)
?Mitogeniceffects
Glulisine
Injectable
Sh
ort-acting
Trainingrequirem
ents
Hum
anRegular
Patient
reluctance
Interm
ediate-acting
Hum
anNPH
Basalinsulin
analogues
Glargine
Detem
ir
Degludecb
Pre-m
ixed
(severaltypes)
a Costisbasedon
lowest-priced
mem
berofthe
class(see
Appendix).bNotlicensedintheUSA
.cInitialconcerns
re:bladdercancerrisk
aredecreasing
aftersubsequentstudy.dNotlicensedin
Europefortype2diabetes.eCostishighlydependentontype/brand
(analogues>human
insulins)anddosage.C
KD,chronickidney
disease;CVD,cardiovasculardisease;D
PP-4,dipeptidyl
peptidase4;
GIP,glucose-dependent
insulinotropicpeptide;GLP-1,glucagon-likepeptide1;
HDL-C,H
DL-cholesterol;L
DL-C,L
DL-cholesterol;M
I,myocardialinfarction;
PPAR-,
peroxisomeproliferator-activated
receptor
;PR
Oactive,ProspectivePioglitazoneClinicalTrialinMacrovascularEvents[26];S
GLT
2,sodium
glucose
co-transporter2;STOP-NID
DM,
StudytoPreventN
on-Insulin-D
ependentDiabetesMellitus
[60];T
2DM,type2diabetesmellitus;T
ZDs,thiazolidinediones;UKPD
S,UKProspectiveDiabetesStudy
[4,61].C
yclosettrial
ofquick-releasebrom
ocriptine[62]
Diabetologia (2015) 58:429442 433
-
Sodiumglucose co-transporter 2 inhibitors The majorchange in
treatment options since the publication of the2012 position
statement has been the availability of a newclass of
glucose-lowering drugs, the sodiumglucose co-trans-porter 2 (SGLT2)
inhibitors [7]. These agents reduce HbA1cby 0.51.0% (5.511
mmol/mol) vs placebo [7, 8]. Whencompared with most standard oral
agents in head-to-headtrials, they appear to be roughly similarly
efficacious withregard to initial HbA1c lowering [912]. Their
mechanism ofaction involves inhibiting the SGLT2 in the proximal
nephron,thereby reducing glucose reabsorption and increasing
urinaryglucose excretion by up to 80 g/day [13, 14]. Because
thisaction is independent of insulin, SGLT2 inhibitors may beused
at any stage of type 2 diabetes, even after insulin secre-tion has
waned significantly. Additional potential advantagesinclude modest
weight loss (~2 kg, stabilising over 612 months) and consistent
lowering of systolic and diastolic
blood pressure in the order of ~24/~12 mmHg [7, 8, 15].Their use
is also associated with reductions in plasma uric acidlevels and
albuminuria [16], although the clinical impact ofthese changes over
time is unknown.
Side effects of SGLT2 inhibitor therapy include genitalmycotic
infections, at rates of about 11% higher in womenand about 4%
higher in men compared with placebo [17]; insome studies, a slight
increase in urinary tract infections wasshown [7, 9, 12, 17, 18].
They also possess a diuretic effect,and so symptoms related to
volume depletion may occur [7,19]. Consequently, these agents
should be used cautiously inthe elderly, in any patient already on
a diuretic, and in anyonewith a tenuous intravascular volume
status. Reversible smallincreases in serum creatinine occur [14,
19]. Increased urinecalcium excretion has been observed [20], and
the UnitedStates Food and Drug Administration (FDA) mandated
afollow-up of upper limb fractures of patients on canagliflozin
More
stringent
Less
stringent
Patient attitude and expected
treatment efforts Highly motivated, adherent, excellent
self-care capacities
Less motivated, nonadherent,poor self-care capacities
Risks potentially associated
with hypoglycaemia and
other adverse drug effects
Low High
Disease durationNewly diagnosed Long-standing
Life expectancy Long Short
Important comorbiditiesAbsent SevereFew / mild
Established vascular
complications Absent SevereFew / mild
Readilyavailable
Limited
Usually not
modifiable
Potentially
modifiable
HbA1c7%a
Patient / disease features
Approach to the managementof hyperglycaemia
Resources and support
system
Fig. 1 Modulation of the intensiveness of glucose lowering in
type 2diabetes. Depiction of patient and disease factors that may
be used by thepractitioner to determine optimal HbA1c targets in
patients with type 2diabetes. Greater concerns regarding a
particular domain are representedby increasing height of the
corresponding ramp. Thus, characteristics/predicaments toward the
left justify more stringent efforts to lower
HbA1c, whereas those toward the right suggest (indeed, sometimes
man-date) less stringent efforts. Where possible, such decisions
should bemade with the patient, reflecting his or her preferences,
needs and values.This scale is not designed to be applied rigidly
but to be used as a broadconstruct to guide clinical
decision-making. Based on an original figureby Ismail-Beigi et al
[59]. aHbA1c 7%=53 mmol/mol
434 Diabetologia (2015) 58:429442
- after an adverse imbalance in cases was reported in
short-termtrials [21]. Small increases in LDL-cholesterol (~5%)
havebeen noted in some trials, the implications of which
areunknown. Due to their mechanism of action, SGLT2 inhibi-tors are
less effective when the estimated GFR (eGFR) is
-
highlow riskneutral / lossGI / lactic acidosis low
Metformin+
Metformin+
Metformin+
Metformin+
Metformin+
highlow riskgainoedema,HF,Fxslow
Thiazolidine-dione
intermediatelow riskneutralrarehigh
DPP-4 inhibitor
highesthigh risk gainhypoglycaemiavariable
Insulin (basal)
Metformin+
Metformin+
Metformin+
Metformin+
Metformin+
Basal insulin +
Sulfonylurea+
TZD
DPP-4-i
GLP-1-RA
Insulinc
or
or
or
or
Thiazolidine-dione
SU
DPP-4-i
GLP-1-RA
Insulinc
Insulin (basal) +
TZD
DPP-4-ior
or
or GLP-1-RA
highlow risklossGIhigh
GLP-1 receptoragonist
Sulfonylurea
highmoderate riskgainhypoglycaemialow
SGLT2 inhibitor
intermediatelow risklossGU, dehydrationhigh
SU
TZD
Insulinc
GLP-1 receptoragonist+
SGLT2 inhibitor+
SU
TZD
Insulinc
Metformin+
Metformin+
or
or
or
or
SGLT2-i
or
or
or
SGLT2-i
Efficacya
Hypo. risk WeightSide effects Costs
Efficacya
Hypo. risk WeightSide effects Costs
or
or
DPP-4inhibitor
SU
TZD
Insulinc
SGLT2-i
or
or
or
SGLT2-i
or
DPP-4-i
Metformin+
GLP-1-RAMealtime insulin
Healthy eating, weight control, increased physical activity and
diabetes education
MetforminMono-therapy
Dualtherapyb
Tripletherapy
Combinationinjectabletherapyd
If HbA1c target not achieved after ~3 months of dual therapy,
proceed to three-drug combination (order not meant to denote
If HbA1c target not achieved after ~3 months of monotherapy,
proceed to two-drug combination (order not meant to denoteany
specific preferencechoice dependent on a variety of patient- and
disease-specific factors):
If HbA1c target not achieved after ~3 months of triple therapy
and patient (1) on oral combination, move to injectables; (2) on
GLP-1-RA, add basal insulin; or (3) on optimally titrated basal
insulin, add GLP-1-RA or mealtime insulin. In refractory patients
consider adding TZD or SGLT2-i:
any specific preferencechoice dependent on a variety of patient-
and disease-specific factors):
++
Fig. 2 Anti-hyperglycaemic therapy in type 2 diabetes: general
recom-mendations. Potential sequences of anti-hyperglycaemic
therapy for pa-tients with type 2 diabetes are displayed, the usual
transition beingvertical, from top to bottom (although horizontal
movement within ther-apy stages is also possible, depending on the
circumstances). In mostpatients, begin with lifestyle changes;
metformin monotherapy is addedat, or soon after, diagnosis, unless
there are contraindications. If theHbA1c target is not achieved
after ~3 months, consider one of the sixtreatment options combined
withmetformin: a sulfonylurea, TZD, DPP-4inhibitor, SGLT2
inhibitor, GLP-1 receptor agonist or basal insulin. (Theorder in
the chart, not meant to denote any specific preference,
wasdetermined by the historical availability of the class and route
of admin-istration, with injectables to the right and insulin to
the far right.) Drugchoice is based on patient preferences as well
as various patient, diseaseand drug characteristics, with the goal
being to reduce glucose concen-trations while minimising side
effects, especially hypoglycaemia. Thefigure emphasises drugs in
common use in the USA and/or Europe.Rapid-acting secretagogues
(meglitinides) may be used in place of sulfo-nylureas in patients
with irregular meal schedules or who develop latepostprandial
hypoglycaemia on a sulfonylurea. Other drugs not shown(-glucosidase
inhibitors, colesevelam, bromocriptine, pramlintide) maybe tried in
specific situations (where available), but are generally
notfavoured because of their modest efficacy, the frequency of
administra-tion and/or limiting side effects. In patients
intolerant of, or with contra-indications for, metformin, consider
initial drug from other classes
depicted under Dual therapy and proceed accordingly. In this
circum-stance, while published trials are generally lacking, it is
reasonable toconsider three-drug combinations that do not include
metformin. Consid-er initiating therapy with a dual combination
when HbA1c is 9%(75 mmol/mol) to more expeditiously achieve target.
Insulin has theadvantage of being effective where other agents may
not be and should beconsidered a part of any combination regimen
when hyperglycaemia issevere, especially if the patient is
symptomatic or if any catabolic features(weight loss, any ketosis)
are evident. Consider initiating combinationinjectable therapy with
insulin when blood glucose is 16.719.4 mmol/l(300350 mg/dl) and/or
HbA1c 1012% (86108 mmol/mol). Poten-tially, as the patients glucose
toxicity resolves, the regimen can besubsequently simplified. aSee
Appendix for description of efficacycategorisation. bConsider
initial therapy at this stage when HbA1c 9%(75 mmol/mol). cUsually
a basal insulin (e.g. NPH, glargine,[A21Gly,B31Arg,B32Arg human
insulin] detemir [B29Lys(-tetradecanoyl),desB30 human insulin],
degludec [des(B30)LysB29(-Glu N-hexadecandioyl) human insulin]).
dConsider initial therapy at thisstagewhen blood glucose is
16.719.4 mmol/l (300350mg/dl) and/orHbA1c 1012% (86108 mmol/mol),
especially if patient is symptom-atic or if catabolic features
(weight loss, ketosis) are present, in which casebasal
insulin+mealtime insulin is the preferred initial regimen.
DPP-4-i,DPP-4 inhibitor; Fxs, fractures; GI, gastrointestinal;
GLP-1-RA, GLP-1receptor agonist; GU, genito-urinary infections; HF,
heart failure; hypo.,hypoglycaemia; SGLT2-i, SGLT2 inhibitor; SU,
sulfonylurea
436 Diabetologia (2015) 58:429442
-
those individuals with baseline HbA1c levels well above tar-get,
who are unlikely to successfully attain their goal
usingmonotherapy. A reasonable threshold HbA1c for this
consid-eration is 9% (75 mmol/mol). Of course, there is no
provenoverall advantage to achieving a glycaemic target more
quick-ly by a matter of weeks or even months. Accordingly, as
longas close patient follow-up can be ensured, prompt
sequentialtherapy is a reasonable alternative, even in those with
baselineHbA1c levels in this range.
Combination injectable therapy (see Figs 2 and 3) In
certainpatients, glucose control remains poor despite the use of
threeanti-hyperglycaemic drugs in combination. With long-stand-ing
diabetes, a significant diminution in pancreatic insulinsecretory
capacity dominates the clinical picture. In any pa-tient not
achieving an agreed HbA1c target despite intensivetherapy, basal
insulin should be considered an essential com-ponent of the
treatment strategy. After basal insulin (usually incombination with
metformin and sometimes an additionalagent), the 2012 position
statement endorsed the addition ofone to three injections of a
rapid-acting insulin analogue dosedbefore meals. As an alternative,
the statement mentioned that,in selected patients, simpler (but
somewhat less flexible) pre-mixed formulations of intermediate- and
short/rapid-actinginsulins in fixed ratios could also be considered
[44]. Overthe past 3 years, however, the effectiveness of
combiningGLP-1 receptor agonists (both shorter-acting and newer
week-ly formulations) with basal insulin has been demonstrated,with
most studies showing equal or slightly superior efficacyto the
addition of prandial insulin, and with weight loss andless
hypoglycaemia [4547]. The available data now suggestthat either a
GLP-1 receptor agonist or prandial insulin couldbe used in this
setting, with the former arguably safer, at leastfor short-term
outcomes [45, 48, 49]. Accordingly, in thosepatients on basal
insulin with one or more oral agents whosediabetes remains
uncontrolled, the addition of a GLP-1 recep-tor agonist or mealtime
insulin could be viewed as a logicalprogression of the treatment
regimen, the former perhaps amore attractive option in more obese
individuals or in thosewho may not have the capacity to handle the
complexities of amulti-dose insulin regimen. Indeed, there is
increasing evi-dence for and interest in this approach [50]. In
those patientswho do not respond adequately to the addition of a
GLP-1receptor agonist to basal insulin, mealtime insulin in a
com-bined basalbolus strategy should be used instead [51].
In selected patients at this stage of disease, the addition ofan
SGLT2 inhibitor may further improve control and reducethe amount of
insulin required [52]. This is particularly anissue when large
doses of insulin are required in obese, highlyinsulin-resistant
patients. Another, older, option, the ad-dition of a TZD (usually
pioglitazone), also has aninsulin-sparing effect and may also
reduce HbA1c [53,54],but at the expense of weight gain, fluid
retention
and increased risk of heart failure. So, if used at thisstage,
low doses are advisable and only with verycareful monitoring of the
patient.
Concentrated insulins (e.g. U-500 Regular) also have a rolein
those individuals requiring very large doses of insulin perday, in
order to minimise injection volume [55]. However,these must be
carefully prescribed, with meticulous commu-nication with both
patient and pharmacist regarding properdosing instructions.
Practitioners should also consider the significant expenseand
additional complexity and costs of multiple combinationsof
glucose-lowering medications. Overly burdensome regi-mens should be
avoided. The inability to achieve glycaemictargets with an
increasingly convoluted regimen shouldprompt a pragmatic
reassessment of the HbA1c target or, inthe very obese,
consideration of non-pharmacological inter-ventions, such as
bariatric surgery.
Of course, nutritional counselling and diabetes self-management
education are integral parts of any thera-peutic programme
throughout the disease course. Thesewill ensure that the patient
has access to information onmethods to reduce, where possible, the
requirements forpharmacotherapy, as well as to safely monitor and
con-trol blood glucose levels.
Clinicians should also be wary of the patient with
latentautoimmune diabetes of adulthood (LADA), which may
beidentified by measuring islet antibodies, such as those
againstGAD65 [56]. Although control with oral agents is possible
fora variable period of time, these individuals, who are
typicallybut not always lean, develop insulin requirements
fasterthan those with typical type 2 diabetes [57] and
pro-gressively manifest metabolic changes similar to thoseseen in
type 1 diabetes. Ultimately, they are optimallytreated with a
regimen consisting of multiple daily in-jections of insulin,
ideally using a basalbolus approach(or an insulin pump).
Figure 3 has been updated to include proposed dosinginstructions
for the various insulin strategies, including theaddition of
rapid-acting insulin analogues before meals or theuse of pre-mixed
insulin formulations.
Other considerations
As emphasised in the original position statement, opti-mal
treatment of type 2 diabetes must take into accountthe various
comorbidities that are frequently encoun-tered in patients,
particularly as they age. These includecoronary artery disease,
heart failure, renal and liverdisease, dementia and increasing
propensity to (andgreater likelihood of experiencing untoward
outcomesfrom) hypoglycaemia. There are few new data to furtherthis
discussion. As mentioned, new concerns about
Diabetologia (2015) 58:429442 437
-
DPP-4 inhibitors and heart failure and the issuesconcerning
SGLT2 inhibitors and renal status should
be taken into consideration [29]. Finally, cost can bean
important consideration in drug selection. As the
Start: Divide current basal dose into 2/3 AM, 1/3 PM or 1/2 AM,
1/2 PM.
Adjust: dose by 12 U or 1015% once to twice weekly until SMBG
target reached.
For hypo.: Determine and address cause; corresponding dose by 24
U or 1020%.
Start: 10 U/day or 0.10.2 U kg1 day1.
Adjust: 1015% or 24 U once to twice weekly to reach FBG
target.
For hypo.: Determine and address cause; dose by 4 U or
1020%.
(usually with metformin+/-other non-insulin agent) Low
Mod.
High
More flexible Less flexible
injections
Flexibility
1
2
3+
Start: 4 U, 0.1 U/kg, or 10% basal dose. If HbA1c
-
prices of newer medications continue to increase, prac-titioners
should take into account patient (and societal)resources and
determine when less costly, generic prod-ucts might be
appropriately used.
Future directions
More long-term data regarding the cardiovascular impactof our
glucose-lowering therapies will be available overthe next 13 years.
Information from these trials willfurther assist us in optimising
treatment strategies. Alarge comparative effectiveness study in the
USA isnow assessing long-term outcomes with multiple agentsafter
metformin monotherapy, but results are not antic-ipated until at
least 2020 [58].
The recommendations in this position statement will obvi-ously
need to be updated in future years in order to provide thebest and
most evidence-based recommendations for patientswith type 2
diabetes.
Acknowledgements This position statement was written by
jointrequest of the ADA and the EASD Executive Committees,
whichhave approved the final document. The process involved
wideliterature review, one face-to-face meeting of the Writing
Groupand multiple revisions via e-mail communications. We
gratefullyacknowledge the following experts who provided critical
reviewof a draft of this update: James Best, Lee Kong Chian School
ofMedicine, Singapore; Henk Bilo, Isala Clinics, Zwolle, the
Neth-erlands; Andrew Boulton, Manchester University, Manchester,UK;
Paul Callaway, University of Kansas School of Medicine-Wichita,
Wichita, KS, USA; Bernard Charbonnel, University ofNantes, Nantes,
France; Stephen Colagiuri, The University ofSydney, Sydney, NSW,
Australia; Leszek Czupryniak, MedicalUniversity of Lodz, Lodz,
Poland; Margo Farber, University ofMichigan Health System and
College of Pharmacy, Ann Arbor,MI, USA; Richard Grant, Kaiser
Permanente Northern California,Oakland, CA, USA; Faramarz
Ismail-Beigi, Case Western ReserveUniversity School of
Medicine/Cleveland VA Medical Center,Cleveland, OH, USA; Darren
McGuire, University of TexasSouthwestern Medical Center, Dallas,
TX, USA; Julio Rosenstock,Dallas Diabetes and Endocrine Center at
Medical City, Dallas,TX, USA; Geralyn Spollett, Yale University
School of Medicine,New Haven, CT, USA; Agathocles Tsatsoulis,
University of Ioan-nina, Ioannina, Greece; Deborah Wexler,
Massachusetts GeneralHospital, Boston, MA, USA; Bernard Zinman,
Lunenfeld-Tanenbaum Research Institute, University of Toronto and
MountSinai Hospital, Toronto, ON, Canada. The final draft was also
peerreviewed and approved by the Professional Practice Committee of
theADA and the Panel on Guidelines and Statements of the EASD.
Funding The face-to-face meeting was supported by the EASD. D.
R.Matthews acknowledges support from the National Institute for
HealthResearch.
Duality of interest During the past 12 months, the following
relation-ships with companies whose products or services directly
relate to thesubject matter in this document are declared:
R. M. Bergenstal: membership of scientific advisory
board,consultat ion services or clinical research support with
AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck & Co.,
NovoNordisk, Roche, Sanofi, and Takeda (all under contracts with
hisemployer). Inherited stock in Merck & Co. (previously held
byfamily)
J. B. Buse: research and consulting with AstraZeneca;
BoehringerIngelheim; Bristol-Myers Squibb Company; Eli Lilly and
Company;Johnson & Johnson; Merck & Co., Inc.; Novo Nordisk;
Sanofi; andTakeda (all under contracts with his employer)
E. Ferrannini:membership on scientific advisory boards or
speakingengagements for Merck Sharp & Dohme, Boehringer
Ingelheim,GlaxoSmithKline, Bristol-Myers Squibb/AstraZeneca, Eli
Lilly & Co.,Novartis, and Sanofi. Research grant support from
Eli Lilly & Co., andBoehringer Ingelheim
S. E. Inzucchi:membership on scientific/research advisory boards
forBoehringer Ingelheim, AstraZeneca, Intarcia, Lexicon, Merck
& Co., andNovo Nordisk. Research supplies to Yale University
from Takeda. Par-ticipation in medical educational projects, for
which unrestricted fundingfrom Boehringer Ingelheim, Eli Lilly, and
Merck & Co. was received byYale University
D. R. Matthews: has received advisory board consulting feesor
honoraria from Novo Nordisk, GlaxoSmithKline, Novartis,Johnson
& Johnson, and Servier. He has research support fromJohnson
& Johnson. He has lectured for Novo Nordisk, Servier,and
Novartis
M. Nauck: research grants to his institution from
Berlin-Chemie/Menarini, Eli Lilly, Merck Sharp & Dohme,
Novartis, AstraZeneca,Boehringer Ingelheim, GlaxoSmithKline, Lilly
Deutschland, and NovoNordisk for participation in multicenter
clinical trials. He has receivedconsulting fees and/or honoraria
for membership in advisory boards and/or honoraria for speaking
from Amylin, AstraZeneca, Berlin-Chemie/Menarini, Boehringer
Ingelheim, Bristol-Myers Squibb, Diartis Pharma-ceuticals, Eli
Lilly, F. Hoffmann-La Roche, GlaxoSmithKline, Hanmi,Intarcia
Therapeutics, Janssen, Merck Sharp & Dohme, Novartis,
NovoNordisk, Sanofi, Takeda, and Versartis, including reimbursement
fortravel expenses
A. L. Peters: has received lecturing fees and/or fees for ad
hocconsulting from AstraZeneca, Bristol-Myers Squibb, Janssen, Eli
Lilly,Novo Nordisk, Sanofi, and Takeda
A. Tsapas: has received research support (to his institution)
fromNovo Nordisk and Boehringer Ingelheim, and lecturing fees
fromNovartis, Eli Lilly and Boehringer Ingelheim
R. Wender: declares he has no duality of interest
Contribution statement All the named Writing Group authors
con-tributed substantially to the document. All authors supplied
detailed inputand approved the final version. S. E. Inzucchi and D.
R. Matthewsdirected, chaired and coordinated the input with
multiple e-mail ex-changes between all participants.
Appendix
The following scale was developed to categorise efficacy ofthe
anti-hyperglycaemic drug classes, with data predominatelybased on
placebo-controlled trials in monotherapy. The Writ-ing Group
acknowledges that this schema is somewhat arbi-trary and that there
are many different ways to assess theHbA1c-lowering effect of
agents, including head-to-head tri-als. The results of all such
trials are influenced by baselineHbA1c, drug type and dose,
duration of treatment, wash-outfrom other anti-hyperglycaemic
therapies, as well as adher-ence among participants to study
medication and diet and
Diabetologia (2015) 58:429442 439
-
exercise, among other factors. Accordingly, it remains
chal-lenging to evaluate and compare the potency of
anti-hyperglycaemic drugs. Moreover, mean differences betweenmost
agents, with some exceptions, are modest. Such datawould be
unlikely to reflect with any certainty the differentialeffect of a
specific drug at a precise point in the treatmentcourse in an
individual patient.
The following scale was developed to categorise cost of
theanti-hyperglycaemic drug classes, using an online retail
phar-macy tool for New Haven, Connecticut, in October 2014.
Wequeried the lowest-priced member of each class at the
highestprescribed dose for a 30-day supply. Insulin was assigned
avariable category, given the very wide range in cost, depen-dent
on formulation and dose. The Writing Group acknowl-edges that this
schema is also somewhat arbitrary but feels thatit constitutes a
reasonable valuation of healthcare expendi-tures. Costs are always
of concern to health providers, thoughthese may not be apparent to
an individual patient covered bya health service, and may vary
based on insurance coverageand other factors.
References
1. Inzucchi SE, Bergenstal RM, Buse JB et al (2012) Management
ofhyperglycemia in type 2 diabetes: a patient-centered approach:
posi-tion Statement of the American Diabetes Association (ADA) and
theEuropean Association for the Study of Diabetes (EASD).Diabetes
Care 35:13641379
2. Inzucchi SE, Bergenstal RM, Buse JB et al (2012) Management
ofhyperglycaemia in type 2 diabetes: a patient-centered
approach.Position statement of the American Diabetes Association
(ADA)and the European Association for the Study of Diabetes
(EASD).Diabetologia 55:15771596
3. Stratton IM, Adler AI, Neil HA et al (2000) Association of
glycaemiawith macrovascular and microvascular complications of type
2 dia-betes (UKPDS 35): prospective observational study. BMJ
321:405412
4. UKPDS Group (1998) Intensive blood-glucose control
withsulphonylureas or insulin compared with conventional
treatmentand risk of complications in patients with type 2 diabetes
(UKPDS
33). UK Prospective Diabetes Study (UKPDS) Group. Lancet
352:837853
5. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA
(2008)10-year follow-up of intensive glucose control in type 2
diabetes.N Engl J Med 359:15771589
6. Gerstein HC, Miller ME, Byington RP et al (2008) Effects of
inten-sive glucose lowering in type 2 diabetes. N Engl J Med
358:25452559
7. Vasilakou D, Karagiannis T, Athanasiadou E et al
(2013)Sodiumglucose cotransporter 2 inhibitors for type 2
diabetes:a systematic review andmeta-analysis. Ann InternMed
159:262274
8. Stenlf K, Cefalu WT, Kim KA et al (2013) Efficacy and safety
ofcanagliflozin monotherapy in subjects with type 2 diabetes
mellitusinadequately controlled with diet and exercise. Diabetes
Obes Metab15:372382
9. Schernthaner G, Gross JL, Rosenstock J et al
(2013)Canagliflozin compared with sitagliptin for patients with
type2 diabetes who do not have adequate glycemic control
withmetformin plus sulfonylurea: a 52-week randomized
trial.Diabetes Care 36:25082515
10. Roden M, Weng J, Eilbracht J et al (2013) Empagliflozin
monother-apy with sitagliptin as an active comparator in patients
with type 2diabetes: a randomised, double-blind,
placebo-controlled, phase 3trial. Lancet Diabetes Endocrinol
1:208219
11. Nauck MA, Del Prato S, Meier JJ et al (2011) Dapagliflozin
versusglipizide as add-on therapy in patients with type 2 diabetes
who haveinadequate glycemic control with metformin: a
randomized,52-week, double-blind, active-controlled noninferiority
trial.Diabetes Care 34:20152022
12. Cefalu WT, Leiter LA, Yoon KH et al (2013) Efficacy and
safety ofcanagliflozin versus glimepiride in patients with type 2
diabetesinadequately controlled with metformin (CANTATA-SU): 52
weekresults from a randomised, double-blind, phase 3
non-inferiority trial.Lancet 382:941950
13. Bakris GL, Fonseca VA, Sharma K, Wright EM (2009) Renal
sodi-um-glucose transport: role in diabetes mellitus and potential
clinicalimplications. Kidney Int 75:12721277
14. Ferrannini E, Solini A (2012) SGLT2 inhibition in
diabetesmellitus: rationale and clinical prospects. Nat Rev
Endocrinol8:495502
15. Rosenstock J, Seman LJ, Jelaska A et al (2013) Efficacy and
safety ofempagliflozin, a sodium glucose cotransporter 2 (SGLT2)
inhibitor,as add-on to metformin in type 2 diabetes with mild
hyperglycaemia.Diabetes Obes Metab 15:11541160
16. Chino Y, Samukawa Y, Sakai S et al (2014) SGLT2 inhibitor
lowersserum uric acid through alteration of uric acid transport
activity inrenal tubule by increased glycosuria. BiopharmDrugDispos
35:391404
17. Nyirjesy P, Sobel JD, Fung A et al (2014) Genital mycotic
infectionswith canagliflozin, a sodium glucose co-transporter 2
inhibitor, inpatients with type 2 diabetes mellitus: a pooled
analysis of clinicalstudies. Curr Med Res Opin 30:11091119
18. Johnsson KM, Ptaszynska A, Schmitz B, Sugg J, Parikh SJ,List
JF (2013) Vulvovaginitis and balanitis in patients withdiabetes
treated with dapagliflozin. J Diabetes Complicat 27:479484
19. Monami M, Nardini C, Mannucci E (2014) Efficacy and safety
ofsodium glucose co-transport-2 inhibitors in type 2 diabetes: a
meta-analysis of randomized clinical trials. Diabetes Obes Metab
16:457466
20. Weir MR, Kline I, Xie J, Edwards R, Usiskin K (2014)
Effectof canagliflozin on serum electrolytes in patients with type
2diabetes in relation to estimated glomerular filtration
rate(eGFR). Curr Med Res Opin 30:17591768
21. FDA briefing document (2013) Invokana (canagliflozin)
tablets.[NDA 204042], US Food and Drug Administration
Mean HbA1c reduction Efficacy category
Potential of >2% (>22 mmol/mol) Very high
>12% (>1122 mmol/mol) High
>0.51% (>5.511 mmol/mol) Intermediate
0.5% (5.5 mmol/mol) Low
Daily cost in US$ Cost category
-
22. Neal B, Perkovic V, de Zeeuw D et al (2013) Rationale,
design, andbaseline characteristics of the Canagliflozin
CardiovascularAssessment Study (CANVAS)a randomized
placebo-controlledtrial. Am Heart J 166:217223.e11
23. Balaji V, Seshiah V, Ashtalakshmi G, Ramanan
SG,Janarthinakani M (2014) A retrospective study on
findingcorrelation of pioglitazone and incidences of bladder
cancerin the Indian population. Indian J Endocrinol Metab
18:425427
24. Kuo HW, Tiao MM, Ho SC, Yang CY (2014) Pioglitazone use
andthe risk of bladder cancer. Kaohsiung J Med Sci 30:9497
25. Wei L, MacDonald TM, Mackenzie IS (2013) Pioglitazoneand
bladder cancer: a propensity score matched cohort study.Br J Clin
Pharmacol 75:254259
26. Dormandy JA, Charbonnel B, Eckland DJ et al (2005)
Secondaryprevention of macrovascular events in patients with type 2
diabetes inthe PROactive Study (PROspective pioglitAzone Clinical
Trial InmacroVascular Events): a randomised controlled trial.
Lancet 366:12791289
27. Colhoun HM, Livingstone SJ, Looker HC et al (2012)
Hospitalisedhip fracture risk with rosiglitazone and pioglitazone
use comparedwith other glucose-lowering drugs. Diabetologia
55:29292937
28. Scirica BM, Bhatt DL, Braunwald E et al (2013) Saxagliptin
andcardiovascular outcomes in patients with type 2 diabetes
mellitus.N Engl J Med 369:13171326
29. Scirica BM, Braunwald E, Raz I et al (2014) Heart failure,
saxagliptinand diabetes mellitus: observations from the SAVOR -
TIMI 53randomized trial. Circulation 130:15791588
30. White WB, Cannon CP, Heller SR et al (2013) Alogliptin after
acutecoronary syndrome in patients with type 2 diabetes. N Engl J
Med369:13271335
31. White WB, Pratley R, Fleck P et al (2013) Cardiovascular
safety ofthe dipetidyl peptidase-4 inhibitor alogliptin in type 2
diabetesmellitus. Diabetes Obes Metab 15:668673
32. Egan AG, Blind E, Dunder K et al (2014) Pancreatic safety
ofincretin-based drugsFDA and EMA assessment. N Engl J
Med370:794797
33. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010)
Risk offatal and nonfatal lactic acidosis with metformin use in
type 2diabetes mellitus. Cochrane Database Syst Rev (4):CD002967.
doi:10.1002/14651858.CD002967.pub4
34. Lipska KJ, Bailey CJ, Inzucchi SE (2011) Use of metformin in
thesetting of mild-to-moderate renal insufficiency. Diabetes Care
34:14311437
35. Nye HJ, HerringtonWG (2011) Metformin: the safest
hypoglycaemicagent in chronic kidney disease? Nephron Clin Pract
118:c380c383
36. Pilmore HL (2010) Review: metformin: potential benefits and
use inchronic kidney disease. Nephrology 15:412418
37. Lu WR, Defilippi J, Braun A (2013) Unleash metformin:
reconsid-eration of the contraindication in patients with renal
impair-ment. Ann Pharmacother 47:14881497
38. National Institute for Health and Care Excellence (2009)
Type 2diabetes: the management of type 2 diabetes [CG87]. NICE,
London
39. Groop PH, Del Prato S, Taskinen MR et al (2014)
Linagliptintreatment in subjects with type 2 diabetes with and
withoutmild-to-moderate renal impairment. Diabetes Obes Metab
16:560568
40. Phung OJ, Sobieraj DM, Engel SS, Rajpathak SN (2014)
Earlycombination therapy for the treatment of type 2 diabetes
mellitus:systematic review and meta-analysis. Diabetes Obes Metab
16:410417
41. Musso G, Gambino R, Cassader M, Pagano G (2012) A
novelapproach to control hyperglycemia in type 2 diabetes: sodium
glu-cose co-transport (SGLT) inhibitors: systematic review and
meta-analysis of randomized trials. Ann Med 44:375393
42. Goring S, Hawkins N, Wygant G et al (2014) Dapagliflozin
com-pared with other oral anti-diabetes treatments when added to
metfor-min monotherapy: a systematic review and network
meta-analysis.Diabetes Obes Metab 16:433442
43. Bosi E, Ellis GC, Wilson CA, Fleck PR (2011) Alogliptin as a
thirdoral antidiabetic drug in patients with type 2 diabetes and
inadequateglycaemic control on metformin and pioglitazone: a
52-week, ran-domized, double-blind, active-controlled,
parallel-group study.Diabetes Obes Metab 13:10881096
44. Holman RR, Thorne KI, Farmer AJ et al (2007) Addition
ofbiphasic, prandial, or basal insulin to oral therapy in type 2
diabetes.N Engl J Med 357:17161730
45. Eng C, Kramer CK, Zinman B, Retnakaran R (2014)
Glucagon-likepeptide-1 receptor agonist and basal insulin
combination treatmentfor the management of type 2 diabetes: a
systematic review andmeta-analysis. Lancet.
doi:10.1016/S0140-6736(14)61335-0
46. Diamant M, Nauck MA, Shaginian R et al (2014)
Glucagon-likepeptide 1 receptor agonist or bolus insulin with
optimized basalinsulin in type 2 diabetes. Diabetes Care
37:27632773
47. Buse JB, Bergenstal RM, Glass LC et al (2011) Use of
twice-dailyexenatide in basal insulin-treated patients with type 2
diabetes: arandomized, controlled trial. Ann Intern Med
154:103112
48. Balena R, Hensley IE, Miller S, Barnett AH (2013)
Combinationtherapy with GLP-1 receptor agonists and basal insulin:
a systematicreview of the literature. Diabetes Obes Metab
15:485502
49. Charbonnel B, Bertolini M, Tinahones FJ, Domingo MP, Davies
M(2014) Lixisenatide plus basal insulin in patients with type 2
diabetesmellitus: a meta-analysis. J Diabetes Complicat
28:880886
50. LaneW,Weinrib S, Rappaport J, Hale C (2014) The effect of
additionof liraglutide to high-dose intensive insulin therapy: a
randomizedprospective trial. Diabetes Obes Metab 16:827832
51. Davidson MB, Raskin P, Tanenberg RJ, Vlajnic A, Hollander
P(2011) A stepwise approach to insulin therapy in patients with
type2 diabetes mellitus and basal insulin treatment failure. Endocr
Pract17:395403
52. Rosenstock J, Jelaska A, Frappin G et al (2014) Improved
glucosecontrol with weight loss, lower insulin doses, and no
increasedhypoglycemia with empagliflozin added to titrated multiple
dailyinjections of insulin in obese inadequately controlled type 2
diabetes.Diabetes Care 37:18151823
53. Charbonnel B, DeFronzo R, Davidson J et al (2010)
Pioglitazone usein combination with insulin in the prospective
pioglitazone clinicaltrial in macrovascular events study
(PROactive19). J Clin EndocrinolMetab 95:21632171
54. Shah PK, Mudaliar S, Chang AR et al (2011) Effects of
intensiveinsulin therapy alone and in combination with pioglitazone
on bodyweight, composition, distribution and liver fat content in
patients withtype 2 diabetes. Diabetes Obes Metab 13:505510
55. Davidson MB, Navar MD, Echeverry D, Duran P (2010)
U-500regular insulin: clinical experience and pharmacokinetics in
obese,severely insulin-resistant type 2 diabetic patients. Diabetes
Care 33:281283
56. Hawa MI, Buchan AP, Ola T et al (2014) LADA and CARDS:
aprospective study of clinical outcome in established adult-onset
au-toimmune diabetes. Diabetes Care 37:16431649
57. Zampetti S, Campagna G, Tiberti C et al (2014) High GADA
titerincreases the risk of insulin requirement in LADA: a 7-years
offollow-up (NIRAD Study 7). Eur J Endocrinol 171:697704
58. Nathan DM, Buse JB, Kahn SE et al (2013) Rationale and
design ofthe glycemia reduction approaches in diabetes: a
comparative effec-tiveness study (GRADE). Diabetes Care
36:22542261
59. Ismail-Beigi F, Moghissi E, Tiktin M, Hirsch IB, Inzucchi
SE, GenuthS (2011) Individualizing glycemic targets in type 2
diabetes mellitus:implications of recent clinical trials. Ann
Intern Med 154:554559
60. Chiasson JL, Gomis R, HanefeldM, Josse RG,Karasik A,
LaaksoM;STOP-NIDDM Trial Research Group (1998) The STOP-NIDDM
Diabetologia (2015) 58:429442 441
-
Trial: an international study on the efficacy of an
alpha-glucosidaseinhibitor to prevent type 2 diabetes in a
population with impairedglucose tolerance: rationale, design, and
preliminary screening data.Diabetes Care 21:17201725
61. UKPDSGroup (1998) Effect of intensive blood-glucose control
withmetformin on complications in overweight patients with type
2
diabetes (UKPDS 34). UK Prospect Diabetes Study (UKPDS)Group
Lancet 352:854865
62. Gaziano JM, Cincotta AH, O'Connor CM et al (2010)
Randomizedclinical trial of quick-release bromocriptine among
patientswith type 2 diabetes on overall safety and
cardiovascularoutcomes. Diabetes Care 33:15031508
442 Diabetologia (2015) 58:429442
Management...Glycaemic targetsTherapeutic options (See text box
Properties of available glucose-lowering agents in the USA and
Europe that may guide individualised treatment choices in patients
with type 2 diabetes; for other unchanged options, also refer to
the original statement [1, 2])Implementation strategiesOther
considerationsFuture directionsAppendixReferences