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: david.matthews@ocdem.ox.ac.uk

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

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.

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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