guias easd y ada 2012

7/31/2019 Guias Easd y Ada 2012

1/16

Management of Hyperglycemia in Type 2Diabetes: A Patient-Centered ApproachPosition Statement of the American Diabetes Association (ADA) and

the European Association for the Study of Diabetes (EASD)SILVIO E. INZUCCHI, MD1

RICHARD M. BERGENSTAL, MD2

JOHN B. BUSE, MD, PHD3

MICHAELA DIAMANT, MD, PHD4

ELE FERRANNINI, MD5

MICHAEL NAUCK, MD6

ANNE L. PETERS, MD7

APOSTOLOS TSAPAS, MD, PHD8

RICHARD WENDER, MD9

DAVID R. MATTHEWS, MD, DPHIL10,11,12

Glycemic management in type 2 di-abetes mellitus has become increas-ingly complex and, to some extent,

controversial, with a widening array of

pharmacological agents now available (1

5),mounting concerns about their potentialadverse effects and new uncertainties re-garding the benefits of intensive glycemiccontrol on macrovascular complications(69). Many clinicians are therefore per-plexed as to the optimal strategies for theirpatients. As a consequence, the AmericanDiabetes Association (ADA) andtheEuropean

Association for the Study of Diabetes (EASD)convened a joint task force to examine theevidence and develop recommendations forantihyperglycemic therapy in nonpregnantadults with type 2 diabetes. Several guide-

line documents have been developed bymembers of these two organizations (10)and by other societies and federations(2,1115). However, an update wasdeemed necessary because of contemporary

information on the benefits/risks of glycemiccontrol, recent evidence concerning efficacyand safety of several new drug classes(16,17), the withdrawal/restriction of others,

and increasing calls for a move toward morepatient-centered care (18,19).This statement has been written in-

corporating the best available evidenceand, where solid support does not exist,using the experience and insight of thewriting group, incorporating an extensivereview by additional experts (acknowl-edged below). The document refers toglycemic control; yet this clearly needs tobe pursued within a multifactorial riskreduction framework. This stems from thefact that patients with type 2 diabetes are atincreased risk of cardiovascular morbidity

and mortality; the aggressive managementof cardiovascular risk factors (blood pres-sure and lipid therapy, antiplatelet treat-ment, and smoking cessation) is likely tohave even greater benefits.

These recommendations should beconsidered within the context of the needs,preferences, and tolerances of each patient;individualization of treatment is the cor-nerstone of success. Our recommenda-tions are less prescriptive than and not asalgorithmic as prior guidelines. This fol-lows from the general lack of comparative-effectiveness research in this area. Ourintent is therefore to encourage an appre-ciation of the variable and progressive

nature of type 2 diabetes, the specifi

c roleof each drug, the patient and diseasefactors that drive clinical decision making(2023), and the constraints imposed byage and comorbidity (4,6). The implemen-tation of these guidelines will requirethoughtful clinicians to integrate currentevidence with other constraints and im-peratives in the context of patient-specificfactors.

PATIENT-CENTEREDAPPROACHdEvidence-based advicedepends on the existence of primary

source evidence. This emerges onlyfrom clinical trial results in highly selectedpatients, using limited strategies. It doesnot address the range of choices available,or the order of use of additional therapies.Even if such evidence were available, thedata would show median responses andnot address the vital question of whoresponded to which therapy and why (24).Patient-centered care is defined as an ap-proach to providing care that is respectfulof and responsive to individual patientpreferences, needs, and values and ensur-ing that patient values guide all clinical de-cisions (25). This should be the organizingprinciple underlying health care for indi-viduals with any chronic disease, but givenour uncertainties in terms of choice or se-quence of therapy, it is particularly appro-priate in type 2 diabetes. Ultimately, it ispatients who make the final decisions re-garding their lifestyle choices and, to somedegree, the pharmaceutical interventionsthey use; their implementation occurs inthe context of the patients real lives andrelies on the consumption of resources(both public and private).

c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c

From the 1Section of Endocrinology, Yale University School of Medicine and Yale-New Haven Hospital,New Haven, Connecticut; the 2International Diabetes Center at Park Nicollet, Minneapolis, Minnesota; the3Division of Endocrinology, University of North Carolina School of Medicine, Chapel Hill, North Carolina;the 4Diabetes Center/Department of Internal Medicine, VU University Medical Center, Amsterdam, theNetherlands; the 5Departmentof Medicine, University of Pisa School of Medicine, Pisa, Italy;6DiabeteszentrumBad Lauterberg, Bad Lauterberg im Harz, Germany; the 7Division of Endocrinology, Keck School of Medicine,University of Southern California, Los Angeles, California; the 8Second Medical Department, Aristotle Uni-versity Thessaloniki, Thessaloniki, Greece; the 9Department of Family and Community Medicine, Jefferson

Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania; the 10Oxford Centre for Diabetes,Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, U.K.; the 11National Institute forHealth Research (NIHR), Oxford Biomedical Research Centre, Oxford, U.K.; and the 12Harris ManchesterCollege, University of Oxford, Oxford, U.K.

Corresponding author: Silvio E. Inzucchi, [email protected]: 10.2337/dc12-0413This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10

.2337/dc12-0413/-/DC1.S.E. Inzucchi and D.R. Matthews were co-chairs for the Position Statement Writing Group. R.M. Bergenstal,

J.B. Buse, A.L. Peters , and R. Wender were the Writ ing Gr oup for the ADA. M. Diamant, E. Fer rannini,M. Nauck, and A. Tsapas were the Writing Group for the EASD.

This article is being simultaneously published in 2012 in Diabetes Care and Diabetologia by the AmericanDiabetes Association and the European Association for the Study of Diabetes.

2012by the American DiabetesAssociationand Springer-Verlag. Readers may use this article as longas thework is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

care.diabetesjournals.org DIABETES CARE 1

R e v i e w s / C o n s e n s u s R e p o r t s / A D A S t a t e m e n t s

P O S I T I O N S T A T E M E N T

Diabetes Care Publish Ahead of Print, published online April 19, 2012
mailto:[email protected]://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-0413/-/DC1http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-0413/-/DC1http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/http://creativecommons.org/licenses/by-nc-nd/3.0/http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-0413/-/DC1http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/dc12-0413/-/DC1mailto:[email protected]


2/16

Patient involvement in the medicaldecision making constitutes one of thecore principles of evidence-based medi-cine, which mandates the synthesis of bestavailable evidence from the literature withthe clinicians expertise and patients owninclinations (26).During theclinical encoun-ter, the patients preferred level of involve-

ment should be gauged and therapeuticchoices explored, potentially with the uti-lization of decision aids (21). In a shareddecision-making approach, clinician andpatient act as partners, mutually exchanginginformation and deliberating on options, inorder to reach a consensuson the therapeu-tic course of action (27). There is good ev-idence supporting the effectiveness of thisapproach (28). Importantly, engaging pa-tients in health care decisions may enhanceadherence to therapy.

BACKGROUND

Epidemiology and health careimpactBoth the prevalence and incidence of type 2diabetes are increasing worldwide, particu-larly in developingcountries, in conjunctionwith increased obesity rates and westerni-zation of lifestyle. The attendant economicburden for health care systems is skyrocket-ing, owing to the costs associated with treat-ment and diabetes complications. Type 2diabetes remains a leading cause of car-diovascular disorders, blindness, end-stage

renal failure, amputations, and hospitaliza-tions. It is also associatedwith increased riskof cancer, serious psychiatric illness, cogni-tive decline, chronic liver disease, acceler-ated arthritis, and other disabling or deadlyconditions. Effective management strategiesare of obvious importance.

Relationship of glycemic controlto outcomesIt is well established that the risk of micro-vascular and macrovascular complicationsis related to glycemia, as measured byHbA1c; this remains a major focus of ther-apy (29). Prospective randomized trialshave documented reduced rates of micro-vascular complications in type 2 diabeticpatients treated to lower glycemic targets.In the UK Prospective Diabetes Study(UKPDS) (30,31), patients with newly di-agnosed type 2 diabetes were randomizedto two treatment policies. In the standardgroup, lifestyle intervention was the main-stay with pharmacological therapy usedonly if hyperglycemia became severe. In themore intensive treatment arm, patients wererandomly assigned to either a sulfonylurea

or insulin, with a subset of overweightpatients randomized to metformin. Theoverall HbA1c achieved was 0.9% lowerin the intensive policy group comparedwith the conventional policy arm (7.0%vs. 7.9%). Associated withthis difference inglycemic controlwas a reduction in theriskof microvascular complications (retinopa-

thy, nephropathy, neuropathy) with inten-sive therapy. A trend toward reduced ratesof myocardial infarction in this group didnot reach statistical significance (30). Bycontrast, substantially fewer metformin-treated patients experienced myocardialinfarction, diabetes-related and all-causemortality (32), despite a mean HbA1c only0.6% lower than the conventional policygroup. The UKPDS 10-year follow-updemonstrated that the relative benefit ofhaving been in the intensive managementpolicy group was maintained over a de-cade, resulting in the emergence of statisti-cally significant benefits on cardiovasculardisease(CVD) endpoints andtotal mortalityin those initially assigned to sulfonylurea/insulin, and persistence of CVD benefitswith metformin (33), in spite of the factthat the mean HbA1c levels between thegroups converged soon after the ran-domized component of the trial hadconcluded.

In 2008, three shorter-term studies[Action to Control Cardiovascular Risk inDiabetes (ACCORD) (34), Action in Dia-betes and Vascular Disease: Preterax and

Diamicron Modified-Release ControlledEvaluation (ADVANCE) (35), Veterans Af-fairs Diabetes Trial (VADT) (36)] reportedthe effects of two levels of glycemic controlon cardiovascular end points in middle-aged and older individuals with well-established type 2 diabetes at high risk forcardiovascular events. ACCORD and VADTaimed for an HbA1c,6.0% using complexcombinations of oral agents and insulin.

ADVANCE aimed for an HbA1c #6.5%using a less intensive approach based onthe sulfonylurea gliclazide. None of thetrials demonstrated a statistically signif-icant reduction in the primary combinedcardiovascular end points. Indeed, in

ACCORD, a 22% increase in total mortalitywith intensive therapy was observed,mainly driven by cardiovascular mortality.

An explanation for this finding has re-mained elusive, although rates of hypogly-cemia were threefold higher with intensivetreatment. It remains unclear, however, ifhypoglycemia was responsible for the ad-verse outcomes, or if other factors, such asmore weight gain, or simply the greatercomplexity of therapy, contributed. There

weresuggestionsin these trials that patientswithout overt CVD, with shorter durationof disease, and lower baseline HbA1c,benefited from the more intensive strat-egies. Modest improvements in somemicrovascular end points in the studieswere likewise demonstrated. Finally, ameta-analysis of cardiovascular out-

comes in these trials suggested that everyHbA1c reduction of;1% may be associ-ated with a 15% relative risk reduction innonfatal myocardial infarction, butwithout benefits on stroke or all-causemortality (36).

Overview of the pathogenesis oftype 2 diabetes

Any rise in glycemia is the net result ofglucose influx exceeding glucose outflowfrom the plasma compartment. In the fast-ing state, hyperglycemia is directly relatedto increased hepatic glucose production.In the postprandial state, further glucoseexcursions result from the combinationof insufficient suppression of this glucoseoutput and defective insulin stimulationof glucose disposal in target tissues, mainlyskeletal muscle. Once the renal tubulartransport maximum for glucose is excee-ded, glycosuria curbs, though does notprevent, further hyperglycemia.

Abnormal islet cell function is a keyand requisite feature of type 2 diabetes. Inearly disease stages, insulin production isnormal or increased in absolute terms,

but disproportionately low for the degreeof insulin sensitivity, which is typicallyreduced. However, insulin kinetics, suchas the ability of the pancreatic b-cell torelease adequate hormone in phase withrising glycemia, are profoundly compro-mised. This functional islet incompetenceis the main quantitative determinant ofhyperglycemia (37) and progresses overtime. In addition, in type 2 diabetes, pan-creatic a-cells hypersecrete glucagon, fur-ther promoting hepatic glucose production(38). Importantly, islet dysfunction is notnecessarily irreversible. Enhancing insulinaction relievesb-cell secretory burden, andany intervention that improves glycemiadfrom energy restriction to, most strikingly,bariatric surgerydcan ameliorate b-celldysfunction to an extent (39). More re-cently recognized abnormalities in the in-cretin system (represented by the guthormones, glucagon-like peptide 1 [GLP-1],and glucose-dependent insulinotropicpeptide [GIP]) are also found in type 2diabetes, but it remains unclear whetherthese constitute primary or secondary de-fects (40). In most patients with type 2

2 DIABETES CARE care.diabetesjournals.org

Position Statement


3/16

diabetes, especially the obese, insulin re-sistance in target tissues (liver, muscle,adipose tissue, myocardium) is a promi-nent feature. This results in both glucoseoverproduction and underutilization.Moreover,an increaseddelivery of fatty acidsto the liver favors their oxidation, whichcontributes to increased gluconeogenesis,

whereas the absolute overabundance of lip-ids promotes hepatosteatosis (41).

Antihyperglycemic agents are directedat one or more of the pathophysiologicaldefects of type 2 diabetes, or modifyphysiological processes relating to appetiteor to nutrient absorption or excretion.Ultimately, type 2 diabetes is a diseasethat is heterogeneous in both pathogenesisand in clinical manifestationda pointto beconsidered when determining the optimaltherapeutic strategy for individual patients.

ANTIHYPERGLYCEMICTHERAPY

Glycemic targetsThe ADAs Standards of Medical Care inDiabetes recommends lowering HbA1cto ,7.0% in most patients to reduce theincidence of microvascular disease (42).This can be achieved with a mean plasmaglucose of;8.38.9 mmol/L (;150160mg/dL); ideally, fasting and premeal glu-cose should be maintainedat,7.2 mmol/L(,130 mg/dL) and the postprandial glu-cose at ,10 mmol/L (,180 mg/dL).

More stringent HbA1c targets (e.g., 6.06.5%) might be considered in selectedpatients (with short disease duration, longlife expectancy, no significant CVD) if thiscan be achieved without significant hypo-glycemia or other adverse effects of treat-ment (20,43). Conversely, less stringentHbA1c goalsde.g., 7.58.0% or evenslightly higherdare appropriate for pa-tientswith a history of severehypoglycemia,limited life expectancy, advanced complica-tions, extensive comorbid conditions andthose in whom the target is difficult to attaindespite intensive self-management educa-tion, repeated counseling, and effectivedoses of multiple glucose-lowering agents,including insulin (20,44).

The accumulated results from theaforementioned type 2 diabetes cardio-vascular trials suggest that not everyonebenefits from aggressive glucose man-agement. It follows that it is important toindividualize treatment targets (5,3436).The elements that may guide the clinicianin choosing an HbA1c target for a specificpatient are shown in Fig. 1. As mentionedearlier, the desires and values of the

patient should also be considered, sincethe achievement of any degree of glucosecontrol requires active participation andcommitment (19,23,45,46). Indeed, anytarget could reflect an agreement betweenpatient and clinician. An important relatedconcept is that the ease with which moreintensive targets are reached influencestreatment decisions; logically, lower tar-gets are attractive if they can be achievedwith less complex regimens and no orminimal adverse effects. Importantly, uti-lizing the percentage of diabetic patientswho are achieving an HbA1c ,7.0% as aquality indicator, as promulgated by vari-ous health care organizations, is inconsis-tent withthe emphasis on individualizationof treatment goals.

Therapeutic optionsLifestyle. Interventions designed to im-pact an individuals physical activity lev-els and food intake are critical parts oftype 2 diabetes management (47,48). Allpatients should receive standardized

general diabetes education (individual orgroup, preferably using an approved cur-riculum), with a specific focus on dietaryinterventions and the importance of in-creasing physical activity. While encourag-ing therapeutic lifestyle change is importantat diagnosis, periodic counseling shouldalso be integrated into the treatmentprogram.

Weight reduction, achieved throughdietary means alone or with adjunctivemedical or surgical intervention, improvesglycemic control and other cardiovascularriskfactors.Modestweightloss(5 10%)con-tributes meaningfully to achieving improvedglucose control. Accordingly,establishingagoal of weight reduction, or at least weightmaintenance, is recommended.

Dietary advice must be personalized(49). Patients should be encouraged to eathealthy foods that are consistent with theprevailing population-wide dietary rec-ommendations and with an individualspreferences and culture. Foods high infiber(such as vegetables, fruits, whole grains, and

Figure 1dDepiction of the elements of decision making used to determine appropriate efforts toachieve glycemic targets. Greater concerns about a particular domain are represented by in-creasing height of the ramp. Thus, characteristics/predicaments toward the left justify morestringent efforts to lower HbA1c, whereas those toward the right are compatible with lessstringent efforts. Where possible, such decisions should be made in conjunction with the patient,reflecting his or her preferences, needs, and values. This scale is not designed to be appliedrigidly but to be used as a broad construct to help guide clinical decisions. Adapted with per-mission from Ismail-Beigi et al. (20).


Inzucchi and Associates


4/16

Table

1dPropertiesofcurrentlyavail

ableglucose-loweringagentsthatmayg

uidetreatmentchoiceinindividualpatientswithtype2diabetesmellitus

Class

Compound(s)

Cellularmechanism

Primaryphysiological

action(s)

Advantages

Disadvantages

Cost

Biguanides

c

Metformin

ActivatesAMP-kinase

c

Hepaticglucose

production

c

Extensiv

eexperience

c

Noweig

htgain

c

Nohypoglycemia

c

LikelyCVDevents

(UKPDS)

c

Gastrointestinalsideeffects

(diarrhea,abdo

minal

cramping)

c

Lacticacidosisrisk(rare)

c

VitaminB12

deficiency

c

Multiplecontraindications:

CKD,acidosis,

hypoxia,

dehydration,etc.

Low

Sulfonylureas

2ndgeneration

c

Glyburide/

glibenclamid

e

c

Glipizide

c

Gliclazideb

c

Glimepiride

ClosesKATP

channels

onb-cellplasma

membranes

c

Insulinsecretion

c

Extensiv

eexperience

c

Microvascularrisk

(UKPDS)

c

Hypoglycemia

c

Weightgain

c

?Bluntsmyocardialischemic

preconditioning

c

Lowdurability

Low

Meglitinides

(glinides)

c

Repaglinide

c

Nateglinide

ClosesKATP

channels

onb-cellplasma

membranes

c

Insulinsecretion

c

Postprandialglucose

excur

sions

c

Dosingflexibility

c

Hypoglycemia

c

Weightgain

c

?Bluntsmyocardialischemic

preconditioning

c

Frequentdosings

chedule

High

Thiazolidinedionesc

Pioglitazone

c

Rosiglitazonec

Activatesthenuclear

transcriptionfactor

PPAR-g

c

Insulinsensitivity

c

Nohypoglycemia

c

Durability

c

HDL-C

c

Triglycerides

(pioglitazone)

c

?

CVD

events

(ProA

CTIVE,

pioglitazone)

c

Weightgain

c

Edema/heartfailure

c

Bonefractures

c

LDL-C(rosiglita

zone)

c

?

MI(meta-analyses,

rosiglitazone)

c

?

Bladdercancer

(pioglitazone)

Highe

a-Glucosidase

inhibitorsa

c

Acarbose

c

Miglitol

c

Voglibose

b,d

Inhibitsintestinal

a-glucosidase

cSlowsintestinal

carbohydrate

digestion/absorption

c

Nohypoglycemia

c

Postprandialglucose

excur

sions

c

?

CVD

events

(STOP-NIDDM)

c

Nonsystemic

c

Generallymodest

HbA1c

efficacy

c


(flatulence,d

iarrhea)

c

Frequentdosings

chedule

Moderate

DPP-4inhibitors

c

Sitagliptin

c

Vildagliptina

c

Saxagliptin

c

Linagliptin

c

Alogliptin

b,d

InhibitsDPP-4activity,

increasingpostprandial

activeincretin(GLP-1,

GIP)concentrations

c

Insulinsecretion

(glucose-dependent)

c

Glucagonsecretion

(glucose-dependent)

c

Nohypoglycemia

c

Welltolerated

c

Generallymodest

HbA1c

efficacy

c

Urticaria/angioedema

c

?Pancreatitis

High

Continued

on

p.

5


Position Statement


5/16

Table

1dContinued

Class

Compound(s)

Cellularmechanism

Primaryphysiological

action(s)

Advantages

Disadvantages

Cost

Bileacid

sequestrantsa

c

Colesevelam

Bindsbileacidsin

intestinaltract,

increasinghepatic

bileacidproduction;

?activationoffarnesoid

Xreceptor(FXR)inliver

cU

nknown

c?

Hepaticglucose

production

c?

Incretinlevels

c

Nohypoglycemia

c

LDL-C

c

Generallymodest

HbA1c

efficacy

c

Constipation

c

Triglycerides

c

May

absorption

ofother

medications

High

Dopamine-2

agonistsa

c

Bromocriptine

(quick-release)

d

Activatesdopaminergic

receptors

cM

odulateshypothalamic

regulationofmetabolism

c

Insulinsensitivity

c

Nohypoglycemia

c

?

CVD

events

(CyclosetSafety

Trial)

c

Generallymodest

HbA1c

efficacy

c

Dizziness/syncope

c

Nausea

c

Fatigue

c

Rhinitis

High

GLP-1receptor

agonists

c

Exenatide

c

Exenatide

extended

release

c

Liraglutide

ActivatesGLP-1

receptors

c

Insulinsecretion

(glucose-dependent)

c

Glucagonsecretion

(glucose-dependent)

cSlowsgastricemptying

c

Satiety

c

Nohypoglycemia

c

Weightreduction

c

?Potent

ialfor

impro

vedb-cell

mass/function

c

?Cardio

vascular

protectiveactions

c


(nausea/vomiting)

c

?Acutepancreatit

is

c

C-cellhyperplasia

/medullary

thyroidtumors

inanimals

c

Injectable

c

Trainingrequirem

ents

High

Amylinmimeticsa

c

Pramlintided

Activatesamylin

receptors

c

Glucagonsecretion

cSlowsgastricemptying

c

Satiety

c

Postprandialglucose

excur

sions

c

Weightreduction

c

Generallymodest

HbA1c

efficacy

c


(nausea/vomiting)

c

Hypoglycemiaunless

insulindoseis

simultaneously

reduced

c

Injectable

c

Frequentdosings

chedule

High

Insulins

c

HumanNPH

c

HumanRegular

c

Lispro

c

Aspart

c

Glulisine

c

Glargine

c

Detemir

c

Premixed

(severaltypes)

Activatesinsulin

receptors

c

Glucosedisposal

c

Hepaticglucose

production

c

Universallyeffective

c

Theoreticallyunlimited

efficacy

c

Microvascularrisk

(UKPDS)

c

Hypoglycemia

c

Weightgain

c

?Mitogeniceffects

c

Injectable

c

Trainingrequirem

ents

c

Stigma(forpatients)

Variablef

aLimiteduseintheU.S./

Europe.

bNotlicensedintheU.S.c

Prescribinghighlyrestrictedinthe

U.S.;withdrawninEurope.

dNotlicensedinEurope.eTobeavailableasagenericproductin2012,w

ithexpectedsignificant

reductionsincost.fD

ependsontype(analogs

.

humaninsulins)anddosage.CKD,c

hronick

idneydisease;CVD,cardiovasculardisease;DPP-4,d

ipeptidylpeptidase4;GIP,g

lucose-depen

dentinsulinotropicpeptide;

GLP-1,g

lucagon-likepeptide1;HDL-C,H

DL

-cholesterol;LDL-C,L

DL-cholesterol;PPAR,peroxisomeproliferatoractivatedreceptor;ProACTIVE,ProspectivePioglitazoneClinicalTrialinMacrovascularEvents(60);

STOP-NIDDM,

StudytoPreventNon-Insulin-DependentDiabetesMellitus(134);UKPDS,

UKProspectiveDiabetesStudy(2933).




6/16

legumes), low-fat dairy products, and freshfish should be emphasized. High-energyfoods, including those rich in saturatedfats, and sweet desserts and snacks shouldbe eaten less frequently and in loweramounts (5052). Patients who eventuallylose and keep weight off usually do so afternumerous cycles of weight loss and relapse.

The health care team should remain non-judgmental but persistent, revisiting andencouraging therapeutic lifestyle changesfrequently, if needed.

As much physical activity as possibleshould be promoted, ideally aiming for atleast 150 min/week of moderate activityincluding aerobic, resistance, and flexi-bility training (53). In older individuals,or those with mobility challenges, solong as tolerated from a cardiovascularstandpoint, any increase in activity levelis advantageous.

At diagnosis, highly motivated pa-tients withHbA1c already near target (e.g.,,7.5%) could be given the opportunityto engage in lifestyle change for a periodof 36 months before embarking onpharmacotherapy (usually metformin).Those with moderate hyperglycemia orin whom lifestyle changes are anticipatedto be unsuccessful should be promptlystarted on an antihyperglycemic agent(also usually metformin) at diagnosis,which can later be modified or possiblydiscontinued if lifestyle changes are suc-cessful.

Oral agents and noninsulin injectables.Important properties of antihyperglyce-mic agents that play a role in the choice ofdrug(s) in individual patients are summa-rized in Table 1. Ultimately, the aims ofcontrolling glycemia are to avoid acuteosmotic symptoms of hyperglycemia, toavoid instability in blood glucose overtime, and to prevent/delay the develop-ment of diabetes complications withoutadversely affecting quality of life. Infor-mation on whether specific agents havethis ability is incomplete; an answer tothese questions requires long-term, large-scale clinical trials

dnot available for most

drugs. Effects on surrogate measures forglycemic control (e.g., HbA1c) generallyreflect changes in the probability of de-veloping microvascular disease but notnecessarily macrovascular complications.Particularly from a patient standpoint,stability of metabolic control over timemay be another specific goal.

Metformin, a biguanide, remains themost widely used first-line type 2 diabetesdrug; its mechanism of action predomi-nately involves reducing hepatic glucose

production (54,55). It is generally consid-ered weight-neutral with chronic use anddoes not increase the risk of hypoglycemia.Metformin is associated with initial gastro-intestinal side effects, and caution is ad-vised to avoid its use in patients at risk forlactic acidosis (e.g., in advanced renal in-sufficiency, alcoholism), a rare complica-

tion of therapy. As noted earlier, theremay be some cardiovascular benefitsfrom this drug, but the clinical trial dataare not robust.

The oldest oral agent class is the sulfo-nylurea insulin secretagogues. Throughthe closure of ATP-sensitive potassiumchannels on b-cells, these drugs stimulateinsulin release (56). While effectivein con-trolling glucose levels, their use is associ-ated with modest weight gain and risk ofhypoglycemia. In addition, studies havedemonstrated a secondary failure ratethat may exceed other drugs, ascribed toan exacerbation of islet dysfunction (57).Shorter-acting secretagogues, the megliti-nides (or glinides), stimulate insulin re-lease through similar mechanisms butmay be associated with less hypoglycemia(58). They require more frequent dosing,however.

Thiazolidinediones (TZDs) are per-oxisome proliferatoractivated receptor gactivators (59) that improve insulin sen-sitivity in skeletal muscle and reduce he-patic glucose production (54,55). Theydo not increase the risk of hypoglycemia

and may be more durable in their effective-ness than sulfonylureas and metformin(57). Pioglitazone appeared to have a mod-est benefit on cardiovascular events as asecondary outcome in one large trial in-volving patients with overt macrovasculardisease (60). Another agent of this class,rosiglitazone, is no longer widely availableowing to concerns of increased myocardialinfarction risk (61). Pioglitazone has re-cently been associated with a possible in-creased risk of bladder cancer (62).Recognized side effects of TZDs includeweight gain, fluid retention leading toedema and/or heart failure in predisposedindividuals, and increased risk of bonefractures (57,60).

Drugs focused on the incretin systemhave been introduced more recently (63).The injectable GLP-1 receptor agonistsmimic the effects of endogenous GLP-1,thereby stimulating pancreatic insulin se-cretion in a glucose-dependent fashion,suppressing pancreatic glucagon output,slowing gastric emptying, and decreasingappetite. Their main advantage is weightloss, which is modest in most patients but

can be significant in some. A limiting sideeffect is nausea and vomiting, particularlyearly in the course of treatment. Concernsregarding an increased risk of pancreatitisremain unresolved. The oral dipeptidylpeptidase 4 (DPP-4) inhibitors enhancecirculating concentrations of activeGLP-1 and GIP (64). Their major effect

appears to be in the regulation of insulinand glucagon secretion; they are weightneutral. Typically, neither of the incretin-based classes cause hypoglycemia bythemselves.

Two agents that are used infrequentlyin the U.S. and Europe are thea-glucosidaseinhibitors (AGIs),which retard gut carbohy-drate absorption (65), and colesevelam, abile acid sequestrant whose mechanism ofglucose-lowering action remains poorlyunderstood and whose major additionalbenefit is LDL-cholesterol reduction(66).Both have gastrointestinal effects, mainlyflatulence with AGIs and constipationwith colesevelam. The dopamine agonistbromocriptine is only available in the U.S.as an antihyperglycemic agent (67). Itsmechanism of action and precise roleare unclear. The amylinagonist, pramlintide,is typically reserved for patients treatedwith intensive insulin therapy, usually intype 1 diabetes mellitus; it decreases post-prandial glucose excursions by inhibitingglucagon secretion and slowing gastricemptying (68).

The glucose-lowering effectiveness of

noninsulin pharmacological agents is saidto be high for metformin, sulfonylureas,TZDs, and GLP-1 agonists (expectedHbA1c reduction ;1.01.5%) (1,69,70),and generally lower for meglitinides,DPP-4 inhibitors, AGIs, colesevelam,and bromocriptine (;0.51.0%). How-ever, older drugs have typically beentested in clinical trial participants withhigher baseline HbA1c, which is itself as-sociated with greater treatment emergentglycemic reductions, irrespective of ther-apy type. In head-to-head studies, anydifferential effects on glucose control aresmall. So agent- and patient-specific prop-erties, such as dosing frequency, side-effectprofiles, cost, and other benefits oftenguide their selection.Insulin. Due to the progressive b-celldysfunction that characterizes type 2 di-abetes, insulin replacement therapy is fre-quently required (71). Importantly, mostpatients maintain some endogenous insu-lin secretion even in late stages of disease.

Accordingly, the more complex and in-tensive strategies of type 1 diabetes arenot typically necessary (72).


Position Statement


7/16

Ideally, the principle of insulin use isthe creation of as normal a glycemic profileas possible without unacceptable weightgain or hypoglycemia (73). As initial ther-apy, unless the patient is markedly hyper-glycemic and/or symptomatic, a basalinsulin alone is typically added (74). Basalinsulin provides relatively uniform insulin

coverage throughout the day and night,mainly to control blood glucose by sup-pressing hepatic glucose production inbetween meals and during sleep. Eitherintermediate-acting (neutral protamineHagedorn [NPH]) or long-acting (insulinglargine [A21Gly,B31Arg,B32Arg hu-man insulin] or insulin detemir [B29Lys(-tetradecanoyl),desB30 human insulin])formulations may be used. The latter twoare associated with modestly less overnighthypoglycemia (insulin glargine, insulin de-temir) than NPH and possibly slightly lessweight gain (insulin detemir), but aremore expensive (75,76). Of note, the dos-ingof these basal insulin analogsmay differ,with most comparative trials showing ahigher average unit requirement with insu-lin detemir (77).

Although the majority of patientswith type 2 diabetes requiring insulintherapy can be successfully treated withbasal insulin alone, some, because of pro-gressive diminution in their insulin secre-tory capacity, will require prandial insulintherapy with shorter-acting insulins. Thisis typically provided in the form of the

rapid insulin analogs, insulin lispro(B28Lys,B29Pro human insulin), insulinaspart (B28Asp human insulin), or insulinglulisine (B3Lys,B29Glu human insulin),which may be dosed just before the meal.They result in better postprandial glucosecontrol than the less costly human regularinsulin, whose pharmacokinetic profilemakes it less attractive in this setting.

Ideally, an insulin treatment programshould be designed specifically for an in-dividual patient, to match the supply ofinsulin to his or her dietary/exercise hab-its and prevailing glucosetrends,as revealedthrough self-monitoring. Anticipated glucose-lowering effects should be balanced withthe convenience of the regimen, in thecontext of an individuals specific therapygoals (Fig. 1).

Proper patient education regardingglucose monitoring, insulin injectiontechnique, insulin storage, recognition/treatment of hypoglycemia, and sickday rules is imperative. Where available,certified diabetes educators can be in-valuable in guiding the patient throughthis process.

Implementation strategiesInitial drug therapy. It is generallyagreed that metformin, if not contraindi-cated and if tolerated, is the preferred and

most cost-effective first agent (42) (Fig. 2and Supplementary Figs.). It is initiated at,or soon after, diagnosis, especially in pa-tients in whom lifestyle intervention alonehas not achieved, or is unlikely to achieve,HbA1c goals. Because of frequent gastroin-testinal side effects, it should be started at alow dose with gradual titration. Patientswith a high baseline HbA1c (e.g., $9.0%)have a low probability of achieving a near-normal target with monotherapy. It maytherefore be justified to start directlywith a combination of two noninsulinagents or with insulin itself in this circum-stance (78). If a patient presents with sig-nificant hyperglycemic symptoms and/orhas dramatically elevated plasma glucoseconcentrations (e.g., .16.719.4 mmol/L[.300350 mg/dL]) or HbA1c (e.g.,$10.012.0%), insulin therapy should bestrongly considered from the outset. Suchtreatment is mandatory when catabolicfeatures are exhibited or, of course, ifketonuria is demonstrated, the latter re-flecting profound insulin deficiency. Im-portantly, unless there is evidence of type 1diabetes, once symptoms are relieved,

glucotoxicity resolved, and the metabolicstate stabilized, it may be possible to taperinsulin partially or entirely, transferring tononinsulin antihyperglycemic agents, per-haps in combination.

If metformin cannot be used, anotheroral agent could be chosen, such as asulfonylurea/glinide, pioglitazone, or a

DPP-4 inhibitor; in occasional cases whereweightloss is seen as an essential aspect oftherapy, initial treatment with a GLP-1receptor agonist might be useful. Whereavailable, less commonly used drugs (AGIs,colesevelam, bromocriptine) might also beconsidered in selected patients, but theirmodest glycemic effects and side-effectprofiles make them less attractive candi-dates. Specific patient preferences, char-acteristics, susceptibilities to side effects,potential for weight gain and hypoglycemiashould play a major role in drug selection(20,21). (See Supplementary Figs. for ad-aptations of Fig. 2 that address specificpatient scenarios.)Advancing to dual combination therapy.Figure 2 (and Supplementary Figs.) alsodepicts potential sequences of escalatingglucose-lowering therapy beyond met-formin. If monotherapy alone does notachieve/maintain an HbA1c target over;3 months, the next step would be toadd a second oral agent, a GLP-1 recep-tor agonist, or basal insulin (5,10). No-tably, the higher the HbA1c, the morelikely insulin will be required. On average,

any second agent is typically associatedwith an approximate further reduction inHbA1c of;1% (70,79). If no clinicallymeaningful glycemic reduction (i.e., non-responder) is demonstrated, then, adher-ence having been investigated, that agentshould be discontinued, and anotherwith a different mechanism of actionsubstituted. With a distinct paucity oflong-term comparative-effectiveness trialsavailable, uniform recommendations onthe best agent to be combined with metfor-min cannotbe made (80). Thus, advantagesand disadvantagesof specific drugs foreachpatient should be considered (Table 1).

Some antihyperglycemic medicationslead to weight gain. This may be associ-ated with worsening markers of insulinresistance and cardiovascular risk. Oneexception may be TZDs (57); weight gainassociated with this class occurs in asso-ciation with decreased insulin resistance.

Although there is no uniform evidence thatincreases in weight in the range observedwith certain therapies translate into a sub-stantially increased cardiovascular risk, itremains important to avoid unnecessary

KEY POINTS

c Glycemic targets and glucose-loweringtherapies must be individualized.

c Diet, exercise, and education remainthe foundation of any type 2 diabetestreatment program.

c Unless there are prevalent contra-indications, metformin is the op-timal first-line drug.

c After metformin, there are limiteddata to guide us. Combinationtherapy withan additional 12oralor injectable agents is reasonable,aiming to minimize side effectswhere possible.

c Ultimately, many patients will requireinsulin therapy alone or in com-bination with other agents tomaintain glucose control.

c All treatment decisions, where possi-

ble, should be made in conjunctionwiththe patient, focusing on his/herpreferences, needs, and values.

c Comprehensive cardiovascular riskreduction must be a major focus oftherapy.




8/16

weight gain by optimal medication selec-tion and dose titration.

For all medications, considerationshould also be given to overall tolerability.Even occasional hypoglycemia may bedevastating, if severe, or merely irritating,if mild (81). Gastrointestinal side effects

may be tolerated by some, but not others.Fluid retention may pose a clinical ormerely an aesthetic problem (82). Therisk of bone fractures may be a specific con-cern in postmenopausal women (57).

It must be acknowledged that costsare a critical issue driving the selection of

glucose-lowering agents in many environ-ments. For resource-limited settings, lessexpensive agents should be chosen. How-ever, due consideration should be alsogiven to side effects and any necessarymonitoring, with their own cost impli-cations. Moreover, prevention of morbid

Figure 2d

Antihyperglycemic therapy in type 2 diabetes: general recommendations. Moving from the top to the bottom of the figure, potentialsequences of antihyperglycemic therapy. In most patients, begin with lifestyle changes; metformin monotherapy is added at, or soon after, diagnosis(unless there are explicit contraindications). If the HbA1c target is not achieved after;3 months, consider oneof thefive treatment options combinedwith metformin: a sulfonylurea, TZD, DPP-4 inhibitor, GLP-1 receptor agonist, or basal insulin. (The order in the chart is determined by historicalintroductionand routeof administration and is not meant to denote any specific preference.) Choice is based on patient anddrug characteristics, withthe over-riding goalof improving glycemic control while minimizingside effects. Shared decision making with the patientmay help in the selection oftherapeutic options. The figure displays drugs commonly used both in the U.S. and/or Europe. Rapid-acting secretagogues (meglitinides) may beused in place of sulfonylureas. Other drugs not shown (a-glucosidase inhibitors, colesevelam, dopamine agonists, pramlintide) may be used whereavailable in selected patients but have modest efficacyand/or limiting side effects. In patients intolerant of, or with contraindications for, metformin,select initial drug from other classes depicted and proceed accordingly. In this circumstance, while published trials are generally lacking, it isreasonable to consider three-drug combinations other than metformin. Insulin is likely to be more effective than most other agents as a third-linetherapy, especially when HbA1c is very high (e.g., $9.0%). The therapeutic regimen should include some basal insulin before moving to morecomplex insulin strategies (Fig. 3). Dashed arrow line on the left-hand side of the figure denotes the option of a more rapid progression from a two-drug combination directly to multiple daily insulin doses, in those patients with severe hyperglycemia (e.g., HbA1c$10.012.0%). DPP-4-i, DPP-4inhibitor; Fxs, bone fractures; GI, gastrointestinal; GLP-1-RA, GLP-1 receptor agonist; HF, heart failure; SU, sulfonylurea. aConsider beginning at thisstage in patients with very high HbA1c (e.g.,$9%). bConsider rapid-acting, nonsulfonylurea secretagogues (meglitinides) in patients with irregularmeal schedules or who develop late postprandial hypoglycemia on sulfonylureas. cSee Table 1 for additional potential adverse effects and risks, underDisadvantages. dUsually a basal insulin (NPH, glargine, detemir) in combination with noninsulin agents. eCertain noninsulin agents may becontinued with insulin (see text). Refer to Fig. 3 for details on regimens. Consider beginning at this stage if patient presents with severe hyperglycemia($16.719.4 mmol/L [$300350 mg/dL]; HbA1c$10.012.0%) with or without catabolic features (weight loss, ketosis, etc.).


Position Statement


9/16

long-term complications will likely reducelong-term expenses attributed to thedisease.Advancing to triple combination ther-apy. Some studies have shown advantagesof adding a third noninsulin agent to atwo-drug combination that is not yet orno longer achieving the glycemic target(8386). Not surprisingly, however, at

this juncture, the most robust responsewill usually be with insulin. Indeed, sincediabetes is associated with progressiveb-cell loss, many patients, especially thosewith long-standing disease, will eventuallyneed to be transitioned to insulin, whichshould be favored in circumstances wherethe degree of hyperglycemia (e.g., $8.5%)makes it unlikely that another drug will beof sufficient benefit (87). If triple combina-tion therapy exclusive of insulin is tried, thepatient should be monitored closely, withthe approach promptly reconsidered if itproves to be unsuccessful. Many monthsof uncontrolled hyperglycemia shouldspecifically be avoided.

In using triple combinations the es-sential consideration is obviously to useagents with complementary mechanismsof action (Fig. 2 and Supplementary Figs.).Increasing the number of drugs heightensthe potential for side effects and drugdruginteractions, raises costs, and negatively im-pacts patient adherence. The rationale, ben-efits,and side effects of each new medicationshould be discussed with the patient. Theclinical characteristics of patients more or

less likely to respond to specific combina-tions are, unfortunately, not well defined.Transitions to and titrations of insulin.Most patients express reluctance to be-ginning injectable therapy, but, if thepractitioner feels that such a transition isimportant, encouragement and educationcan usually overcome such reticence. In-sulin is typically begun at a low dose (e.g.,0.10.2 U kg21 day21), although largeramounts (0.30.4Ukg21 day21) are rea-sonable in the more severely hyperglyce-mic. The most convenient strategy iswith a single injection of a basal insulin,with the timing of administration depen-dent on the patients schedule andoverallglucose profile (Fig. 3).

Although extensive dosing instruc-tions for insulin are beyond the scope ofthis statement, most patients can be taughtto uptitrate their own insulin dose basedon several algorithms, each essentially in-volving theaddition of a small dose increaseif hyperglycemia persists (74,76,88). Forexample, the addition of 12 units (or, inthose already on higher doses, incrementsof 510%) to the daily dose once or twice

weeklyif thefasting glucose levelsare abovethe preagreed target is a reasonable ap-proach (89). As the target is neared, dosageadjustments should be more modest andoccur less frequently. Downward adjust-ment is advisable if any hypoglycemia oc-curs. During self-titration, frequent contact(telephone, e-mail) with the clinician maybe necessary. Practitioners themselves can,of course, also titrate basal insulin, but thiswould involve more intensive contact withthe patient than typically available in rou-tine clinical practice. Daily self-monitoringof blood glucose is of obvious importanceduring this phase. After the insulin dose isstabilized, the frequency of monitoringshould be reviewed (90).

Consideration should be given to theaddition of prandial or mealtime insulincoverage when significant postprandial

glucose excursions (e.g., to.10.0 mmol/L[.180 mg/dL]) occur. This is suggestedwhen the fasting glucose is at target butthe HbA1c remains above goal after 36months of basal insulin titration (91). Thesame would apply if large drops in glucoseoccur during overnight hours or in be-tween meals, as the basal insulin dose isincreased. In thisscenario, the basal insulindose would obviously need to be simulta-neously decreased as prandial insulin is ini-tiated. Although basal insulin is titratedprimarily against the fasting glucose, gen-erally irrespective of the total dose, practi-tioners should be aware that the need forprandial insulin therapy will becomelikelythemore the daily dose exceeds 0.5 U kg21

day21, especially as it approaches 1 U kg21

day21. The aim with mealtime insulin is toblunt postprandial glycemic excursions,

Figure 3dSequential insulin strategies in type 2 diabetes. Basal insulin alone is usually theoptimal initial regimen, beginning at 0.10.2 units/kg body weight, depending on the degree ofhyperglycemia. It is usually prescribed in conjunction with one to two noninsulin agents. Inpatients willing to take more than one injection and who have higher HbA1c levels($9.0%), twice-daily premixed insulin or a more advanced basal plus mealtime insulin regimen could also beconsidered (curved dashed arrow lines). When basal insulin has been titrated to an acceptablefasting glucose but HbA1c remains above target, consider proceeding to basal plus mealtime in-sulin, consisting of one to three injections of rapid-acting analogs (see text for details). A lessstudied alternativedprogression from basal insulin to a twice-daily premixed insulindcould bealso considered (straight dashed arrow line); if this is unsuccessful, move to basal plus mealtimeinsulin. Thefiguredescribes the number of injections required at each stage, togetherwith the relativecomplexity andflexibility. Once a strategy is initiated, titration of the insulin dose is important, withdose adjustments made based on the prevailing glucose levels as reported by the patient. Noninsulinagents may be continued, although insulin secretagogues (sulfonylureas, meglitinides) are typicallystopped once more complex regimens beyond basal insulin are utilized. Comprehensive educationregarding self-monitoring of blood glucose, diet, exercise, and the avoidance of, and response to,hypoglycemia are critical in any patient on insulin therapy. Mod., moderate.




10/16

which can be extreme in some individuals,resulting in poor control during the day.Such coverage may be provided by one oftwo methods.

The most precise and flexible prandialcoverage is possible with basal-bolustherapy, involving the addition of premealrapid-acting insulin analog to ongoing

basal insulin. One graduated approachis to add prandial insulin before themeal responsible for the largest glucoseexcursiondtypically that with the greatestcarbohydrate content, often, but not always,the evening meal (92). Subsequently, a sec-ond injection can be administered before themeal with the next largest excursion (oftenbreakfast). Ultimately, a third injection maybe added before the smallest meal (oftenlunch) (93). The actual glycemic benefitsof these more advanced regimens afterbasal insulin are generally modest in typicalpatients (92). So, again, individualizationof therapy is key, incorporating the degreeof hyperglycemia needing to be ad-dressed and the overall capacities of thepatient. Importantly, data trends fromself-monitoring may be particularly help-ful in titrating insulins and their doseswithin these more advanced regimens tooptimize control.

A second, perhaps more convenientbut less adaptable method involves pre-mixed insulin, consisting of a fixed com-bination of an intermediate insulin withregular insulin or a rapid analog. Tradi-

tionally, this is administered twice daily,before morning and evening meals. Ingeneral, when compared with basal insu-lin alone, premixed regimens tend tolower HbA1c to a larger degree, but oftenat the expense of slightly more hypogly-cemia and weight gain (94). Disadvan-tages include the inability to titrate theshorter- from the longer-acting compo-nent of these formulations. Therefore,this strategy is somewhat inflexible butmay be appropriate for certain patientswho eat regularly and may be in needof a simplified approach beyond basal in-sulin (92,93). (Anolder andless commonlyused variation of this two-injection strategyis knownas split-mixed, involving a fixedamount of intermediate insulin mixed bythe patient with a variable amount of regu-lar insulin or a rapid analog. This allows forgreater flexibility in dosing.)

The key messages from dozens ofcomparativeinsulin trials in type2 diabetesinclude the following:

1. Any insulin will lower glucose andHbA1c.

2. All insulins are associated with someweight gain and some risk of hypo-glycemia.

3. The larger the doses and the moreaggressive the titration, the lower theHbA1c, but often with a greater likeli-hood of adverse effects.

4. Generally, long-acting insulin analogs

reduce the incidence of overnight hy-poglycemia, and rapid-acting insulinanalogs reduce postprandial glucoseexcursions as compared with corre-sponding human insulins (NPH, Reg-ular), but they generally do not result inclinically significantly lower HbA1c.

Metformin is often continued whenbasal insulin is added, with studies dem-onstrating less weight gain when the twoare used together (95). Insulin secretago-gues do not seem to provide for additionalHbA1c reduction or prevention of hypo-glycemia or weight gain after insulin isstarted, especially after the dose is titratedand stabilized. When basal insulin isused, continuing the secretagogue mayminimize initial deterioration of glycemiccontrol. However, secretagogues shouldbe avoided once prandial insulin regi-mens are employed. TZDs should be re-duced in dose (or stopped) to avoidedema and excessive weight gain, al-though in certain individuals with largeinsulin requirements from severe insulinresistance, these insulin sensitizers may be

very helpful in lowering HbA1c and mini-mizing the required insulin dose (96).Data concerning the glycemic benefits ofincretin-based therapy combined withbasal insulin are accumulating; combina-tionwith GLP-1 receptor agonists may behelpful in some patients (97,98). Onceagain, the costs of these more elaboratecombined regimens must be carefullyconsidered.

OTHER CONSIDERATIONS

AgeOlder adults (.6570 years) often have ahigher atherosclerotic disease burden, re-duced renal function, and more comor-bidities (99,100). Many are at risk foradverse events from polypharmacy andmay be both socially and economicallydisadvantaged. Life expectancy is reduced,especially in the presence of long-termcomplications. They are also more likelyto be compromised by hypoglycemia; forexample, unsteadiness may result in fallsand fractures (101), and a tenuous cardiacstatus may deteriorate into catastrophic

events. It follows that glycemic targets forelderly with long-standing or more com-plicated disease should be less ambitiousthan for the younger, healthier individuals(20). If lower targets cannot be achievedwith simple interventions, an HbA1c of,7.58.0% may be acceptable, transition-ing upward as age increases and capacity

for self-care, cognitive, psychological andeconomic status, and support systemsdecline.

While lifestyle modification can besuccessfully implemented across all age-groups, in the aged, the choice of anti-hyperglycemic agent should focus ondrug safety, especially protecting againsthypoglycemia, heart failure, renal dys-function, bone fractures, and drugdruginteractions. Strategies specifically mini-mizing the risk of low blood glucose maybe preferred.

In contrast, healthier patients withlong life expectancy accrue risk for vas-cular complications over time. Therefore,lower glycemic targets (e.g., an HbA1c,6.57.0%) and tighter control of bodyweight, blood pressure, and circulatinglipids should be achieved to prevent ordelay such complications. This usually re-quires combination therapy, the early in-stitution of which may have the bestchance of modifying the disease processand preserving quality of life.

Weight

The majority of individuals with type 2diabetes are overweight or obese (;80%)(102). In these, intensive lifestyle inter-vention can improve fitness, glycemiccontrol, and cardiovascular risk factorsfor relatively small changes in bodyweight (103). Although insulin resistanceis thought of as the predominate driver ofdiabetes in obese patients, they actuallyhave a similar degree of islet dysfunctionto leaner patients (37). Perhaps as a result,the obese may be more likely to requirecombination drug therapy (20,104).

While common practice has favored met-formin in heavier patients, because ofweight loss/weight neutrality, this drugis as efficacious in lean individuals (75).TZDs, on the other hand, appear to bemore effective in those with higher BMIs,although their associated weight gainmakes them, paradoxically, a less attractiveoption here. GLP-1 receptor agonists areassociated with weight reduction (38),which in some patients may be substantial.

Bariatric surgery is an increasinglypopular option in severe obesity. Type 2diabetes frequently resolves rapidly after


Position Statement


11/16

these procedures. The majority of patientsare able to stop some, or even all, of theirantihyperglycemic medications, althoughthe durability of this effect is not known(105).

In lean patients, consideration shouldbe given to the possibility of latent autoim-mune diabetes in adults (LADA), a slowly

progressive form of type 1 diabetes. Theseindividuals, while presenting with mildhyperglycemia, often responsive to oralagents, eventually develop more severehyperglycemia and require intensive insu-lin regimens (106). Measuringtitres of islet-associated autoantibodies (e.g., anti-GAD)may aid their identification, encouraging amore rapid transition to insulin therapy.

Sex/racial/ethnic/genetic differencesWhile certain racial/ethnic features thatincrease the risk of diabetes are well recog-nized [greater insulin resistance in Latinos(107), more b-cell dysfunction in East

Asians (108)], using this information tocraft optimal therapeutic strategies is in itsinfancy. This is not surprising given thepolygenic inheritance pattern of the dis-ease. Indeed, while matching a drug smechanism of action to the underlyingcauses of hyperglycemia in a specific patientseems logical, there are few data that com-pare strategies based on this approach(109). There are few exceptions, mainlyinvolving diabetes monogenic variants of-ten confused with type 2 diabetes, such as

maturity-onset diabetes of the young(MODY), several forms of which respondpreferentially to sulfonylureas (110).

While there are no prominent sex differ-ences in theresponse to various antihyper-glycemic drugs, certain side effects (e.g.,bone loss with TZDs) may be of greaterconcern in women.

ComorbiditiesCoronary artery disease. Given the fre-quency with which type 2 diabetic patientsdevelop atherosclerosis, optimal manage-ment strategies for those with or at high riskfor coronary artery disease (CAD) areimportant. Since hypoglycemia may ex-acerbate myocardial ischemia and maycause dysrhythmias (111), it follows thatmedications that predispose patients tothis adverse effect should be avoided, ifpossible. If they are required, however, toachieve glycemic targets, patients shouldbe educated to minimize risk. Because ofpossible effects on potassium channels inthe heart, certain sulfonylureas have beenproposed to aggravate myocardial ischemiathrougheffectson ischemicpreconditioning

(112), but the actual clinical relevance of thisremains unproven. Metformin may havesome cardiovascular benefits and wouldappear to be a useful drug in the settingof CAD, barring prevalent contraindica-tions (32). In a single study, pioglitazonewas shown to reduce modestly major ad-verse cardiovascular events in patients

with established macrovascular disease.It may therefore also be considered, unlessheart failure is present (60). In very pre-liminary reports, therapy with GLP-1 re-ceptor agonists and DPP-4 inhibitors hasbeen associated with improvement in ei-ther cardiovascular risk or risk factors, butthere are no long-term data regarding clin-ical outcomes (113). There are very limiteddata suggesting that AGIs (114) and bromo-criptine (115) may reduce cardiovascularevents.Heart failure. With an aging populationand recent decreases in mortality aftermyocardial infarction, the diabeticpatientwith progressive heart failure is an in-creasingly common scenario (116). Thispopulation presents unique challengesgiven their polypharmacy, frequent hos-pitalizations, and contraindications tovarious agents. TZDs should be avoided(117,118). Metformin, previously contra-indicated in heart failure, can nowbe usedif the ventricular dysfunction is not se-vere, if patients cardiovascular status isstable, and if renal function is normal(119). As mentioned, cardiovascular ef-

fects of incretin-based therapies, includ-ing those on ventricular function, arecurrently under investigation (120).Chronic kidney disease. Kidney diseaseis highly prevalent in type 2 diabetes, andmoderate to severe renal functional im-pairment (eGFR,60 mL/min) occurs inapproximately 2030% of patients(121,122). The individual with progres-sive renal dysfunction is at increased riskfor hypoglycemia, which is multifactorial.Insulin and, to some degree, the incretinhormones are eliminated more slowly, asare antihyperglycemic drugs with renalexcretion. Thus, dose reduction may benecessary, contraindications need to beobserved, and consequences (hypoglyce-mia, fluid retention, etc.) require carefulevaluation.

Current U.S. prescribing guidelineswarn against the use of metformin inpatients with a serum creatinine $133mmol/L ($1.5 mg/dL) in men or 124mmol/L ($1.4 mg/dL) in women. Metfor-min is eliminated renally, and cases of lacticacidosis have been described in patientswith renal failure (123). There is an

ongoing debate, however, as to whetherthese thresholds are too restrictive andthat those with mildmoderate renal im-pairment would gain more benefit thanharm from using metformin (124,125). Inthe U.K., the National Institute for Healthand Clinical Excellence (NICE) guidelinesare less proscriptive and more evidence-

based than those in the U.S., generally al-lowing use down to a GFR of 30 mL/min,with dose reduction advised at 45 mL/min(14). Given the current widespread report-ing of estimated GFR, these guidelinesappear very reasonable.

Most insulin secretagogues undergosignificant renal clearance (exceptions in-clude repaglinide and nateglinide) andthe risk of hypoglycemia is thereforehigher in patients with chronic kidneydisease (CKD). For most of these agents,extremecautionis imperative at moreseveredegrees of renal dysfunction. Glyburide(known as glibenclamide in Europe),which has a prolonged duration ofaction and active metabolites, shouldbe specifically avoided in this group.Pioglitazone is not eliminated renally, andtherefore there are no restrictions for usein CKD. Fluid retention may be a concern,however. Among the DPP-4 inhibitors,sitagliptin, vildagliptin, and saxagliptinshare prominent renal elimination. In theface of advanced CKD, dose reduction isnecessary. One exception is linagliptin,which is predominantly eliminated enter-

ohepatically. For the GLP-1 receptor ago-nists exenatide is contraindicated in stage45 CKD (GFR,30 mL/min) as it is re-nally eliminated; the safety of liraglutide isnot established in CKD though pharmaco-kinetic studies suggest that drug levels areunaffected as it does not require renal func-tion for clearance.

More severe renal functional impair-ment is associated with slower elimina-tion of all insulins. Thus doses need to betitrated carefully, with some awarenessfor the potential for more prolongedactivity profiles.Liver dysfunction. Individuals with type2 diabetes frequently have hepatosteatosisas well as other types of liver disease(126). There is preliminary evidence thatpatients with fatty liver may benefit fromtreatment with pioglitazone (45,127,128).It should not be used in an individual withactive liver disease or an alanine transami-naselevel above 2.5 times the upper limitofnormal. In those with steatosis but milderliver test abnormalities, this insulin sensi-tizer may be advantageous. Sulfonylureascan rarely cause abnormalities in liver tests




12/16

but are not specifically contraindicated;meglitinides can also be used. If hepaticdisease is severe, secretagogues should beavoided because of the increased risk ofhypoglycemia. In patients with mild he-patic disease, incretin-based drugs can beprescribed, except if there is a coexistinghistory of pancreatitis. Insulin has no re-

strictions for use in patients with liver im-pairment and is indeed thepreferred choicein those with advanced disease.Hypoglycemia. Hypoglycemia in type 2diabetes was long thought to be a trivialissue, as it occurs less commonly than intype 1 diabetes. However, there is emerg-ing concern based mainly on the resultsof recent clinical trials and some cross-sectional evidence of increased risk ofbrain dysfunction in those with repeatedepisodes. In the ACCORD trial, the fre-quency of both minor and major hypo-glycemia was high in intensively managedpatients

dthreefold that associated with

conventional therapy (129). It remainsunknown whether hypoglycemia wasthe cause of the increased mortality inthe intensive group (130,131). Clearly,however, hypoglycemia is more danger-ous in the elderly and occurs consistentlymore often as glycemic targets are low-ered. Hypoglycemia may lead to dys-rhythmias, but can also lead to accidentsand falls (which are more likely to be dan-gerous in the elderly) (132), dizziness(leading to falls), confusion (so other ther-

apies may not be taken or taken incor-rectly), or infection (such as aspirationduring sleep, leading to pneumonia). Hy-poglycemia may be systematically under-reported as a cause of death, so the trueincidence may not be fully appreciated.Perhaps just as importantly, additional con-sequences of frequent hypoglycemia in-clude work disability and erosion of theconfidence of the patient (and that of familyor caregivers)to liveindependently. Accord-ingly, in at-risk individuals, drug selectionshould favor agents that do not precipitatesuch events and, in general, blood glucosetargets may need to be moderated.

FUTURE DIRECTIONS/RESEARCH NEEDSdFor antihyper-glycemic management of type 2 diabetes,the comparative evidence basis to date isrelatively lean, especially beyond metfor-min monotherapy (70). There is a significantneed for high-quality comparative-effec tive ness research, not only regardingglycemic control, but also costs and thoseoutcomes that matter most to patientsdquality of life and the avoidance of morbid

and life-limiting complications, especiallyCVD (19,23,70). Another issue about whichmore data are needed is the concept of du-rability of effectiveness (often ascribed tob-cell preservation), which would serveto stabilize metabolic control and decreasethe future treatment burden for patients.Pharmacogenetics may very well inform

treatment decisions in the future, guidingthe clinician to recommend a therapy for anindividual patient based on predictors ofresponse and susceptibility to adverse ef-fects. We need more clinical data on howphenotype and other patient/disease char-acteristics should drive drug choices. Asnew medications are introduced to thetype 2 diabetes pharmacopeia, their benefitand safety should be demonstrated in stud-ies versus best current treatment, substan-tial enough both in size and duration toprovide meaningful data on meaningfuloutcomes. It is appreciated, however, thathead-to-head comparisons of all combina-tions and permutations would be impossi-bly large (133). Informed judgment and theexpertise of experienced clinicians willtherefore always be necessary.

AcknowledgmentsdThis position statementwas written by joint request of the ADA andthe EASD Executive Committees, which haveapproved the final document. The process in-volved wide literature review, three face-to-facemeetings of the Writing Group, several tele-

conferences, and multiple revisions via e-mailcommunications.We gratefully acknowledge the following

experts who provided critical review of adraft of this statement: James Best, MelbourneMedical School, The University of Melbourne,Melbourne, Australia; Henk Bilo, Isala Clinics,Zwolle, the Netherlands; John Boltri, WayneState University School of Medicine, Detroit,MI; Thomas Buchanan, Keck School ofMedicine, University of Southern California,Los Angeles, CA; Paul Callaway, University ofKansas School of Medicine-Wichita, Wichita,KS; Bernard Charbonnel, University of Nantes,Nantes, France; Stephen Colagiuri, The Uni-

versity of Sydney, Sydney, Australia; SamuelDagogo-Jack, The University of Tennessee HealthScience Center, Memphis, TN; Margo Farber,Detroit Medical Center, Detroit, MI; CynthiaFritschi, College of Nursing, University of Illi-nois at Chicago, Chicago, IL; Rowan Hillson,The Hillingdon Hospital, Uxbridge, U.K.;Faramarz Ismail-Beigi, Case Western ReserveUniversity School of Medicine/ClevelandVA Medica l Cen ter, Cle veland, OH; DevanKansagara, Oregon Health & Science University/Portland VA Medical Center, Portland, OR;Ilias Migdalis, NIMTS Hospital, Athens,Greece; Donna Miller, Keck School of Medicine,University of Southern California, Los Angeles,

CA; Robert Ratner, MedStar Health ResearchInstitute/Georgetown University School ofMedicine, Washington, DC; Julio Rosenstock,Dallas Diabetes and Endocrine Center at Medi-cal City, Dallas, TX; Guntram Schernthaner,Rudolfstiftung Hospital, Vienna, Austria; RobertSherwin, Yale University School of Medicine,New Haven, CT; Jay Skyler, Miller School ofMedicine, University of Miami, Miami, FL;

Geralyn Spollett, Yale University School ofNursing, New Haven, CT; Ellie Strock, In-ternational Diabetes Center, Minneapolis, MN;Agathocles Tsatsoulis, University of Ioannina,Ioannina, Greece; Andrew Wolf, University ofVirginia School of Medicine, Charlottesville,VA; Bernard Zinman, Mount Sinai Hospital /University of Toronto, Toronto, ON, Canada.The American Association of Diabetes Edu-cators, American College of Physicians, andThe Endocrine Society, and several other or-ganizations who wished to remain anony-mous nominated reviewers who providedinput on the final draft. Such feedback doesnot constitute endorsement by these groupsor these individuals. The final draft was alsopeer reviewed and approved by the ProfessionalPractice Committeeof the ADAand thePanel forOverseeing Guidelines and Statements of theEASD. We are indebted to Dr. Sue Kirkman ofthe ADA for her guidance and support duringthis process. We also thank Carol Hill and MaryMerkin for providing administrative assistance.Funding

The three face-to-face meetings and thetravel of some of the writing group were sup-ported by the EASD and ADA. D.R. Matthewsacknowledges support from the National In-stitute for Health Research.

Duality of interestDuring the past 12 months, the followingrelationships with companies whose productsor services directly relate to the subject matterin this document are declared:

R.M. Bergenstal: membership of scientificadvisory boards and consultation for or clinicalresearch support with Abbott Diabetes Care,Amylin, Bayer, Becton Dickinson, BoehringerIngelheim, Calibra,DexCom, Eli Lilly, Halozyme,Helmsley Trust, Hygieia, Johnson & Johnson,Medtronic, NIH, Novo Nordisk, Roche, Sanofi,and Takeda (all under contracts with hisemployer). Inherited stock in Merck (heldby family)

J.B. Buse: research and consulting withAmylin Pharmaceuticals, Inc.; AstraZeneca;Biodel Inc.; Boehringer Ingelheim; Bristol-Myers Squibb Company; Diartis Pharmaceuticals,Inc.; Eli Lilly and Company; F. Hoffmann-LaRoche Ltd; Halozyme Therapeutics; Johnson& Johnson; Medtronic MiniMed; Merck &Co., Inc.; Novo Nordisk; Pfizer Inc.; Sanofi;and TransPharma Medical Ltd (all undercontracts with his employer)

M. Diamant: member of advisory boards ofAbbott Diabetes Care, Eli Lilly, Merck Sharp &Dohme (MSD), Novo Nordisk, Poxel Pharma.Consultancy for: Astra-BMS, Sanofi. Speakerengagements: Eli Lilly, MSD, Novo Nordisk.


Position Statement


13/16

Through Dr. Diamant, the VU Universityreceives research grants from Amylin/EliLilly, MSE, Novo Nordisk, Sanofi (all undercontracts with the Institutional ResearchFoundation)

E. Ferrannini: membership on scientificadvisory boards or speaking engagements for:Merck Sharp & Dohme, Boehringer Ingelheim,GlaxoSmithKline, BMS/AstraZeneca, Eli Lilly &

Co., Novartis, Sanofi. Research grant supportfrom: Eli Lilly & Co. and Boehringer Ingelheim

S.E. Inzucchi: advisor/consultant to: Merck,Takeda, Boehringer Ingelheim. Research fund-ing or supplies to Yale University: Eli Lilly,Takeda. Participation in medical educationalprojects, for which unrestricted funding fromAmylin, Eli Lilly, Boehringer Ingelheim, Merck,Novo Nordisk, and Takeda was received by YaleUniversity

D.R. Matthews: has received advisoryboard consulting fees or honoraria from NovoNordisk, GlaxoSmithKline, Novartis, Eli Lilly,Johnson & Johnson, and Servier. He has re-search support from Johnson & Johnson andMerck Sharp & Dohme. He has lectured forNovo Nordisk, Servier, and Novartis

M. Nauck: has received research grants (tohis institution) from AstraZeneca, BoehringerIngelheim, Eli Lilly & Co., Merck Sharp &Dohme, Novartis Pharma, GlaxoSmithKline,Novo Nordisk, Roche, and Tolerx. He has re-ceived consulting and travel fees or honorariafor speaking from AstraZeneca, Berlin-Chemie,Boehringer Ingelheim, Bristol-Myers Squibb,Diartis, Eli Lilly & Co., F. Hoffmann-La RocheLtd, Intarcia Therapeutics, Merck Sharp &Dohme, Novo Nordisk, Sanofi-Aventis Pharma,and Versartis

A.L. Peters: has received lecturing fees and/or fees for ad hoc consulting from Amylin, Lilly,Novo Nordisk, Sanofi, Takeda, BoehringerIngelheim

A. Tsapas: has received travel grant, edu-cational grant, research grant and lecture feesfrom Merck Serono, Novo Nordisk, and No-vartis, respectively

R. Wender: declares he has no duality ofinterestContribution statement

All the named writing group authors con-tributed substantially to the document in-cluding each writing part of the text. They wereat the face-to-face meetings and teleconferences.

All authors supplied detailed input and ap-proved the final version. S.E. Inzucchi and D.R.Matthews directed, chaired, and coordinatedthe input with multiple e-mail exchanges be-tween all participants.

References1. Bolen S, Feldman L, Vassy J, et al. Sys-

tematic review: comparative effective-ness and safety of oral medications fortype 2 diabetes mellitus. Ann Intern Med2007;147:386399

2. Bergenstal RM, Bailey CJ, Kendall DM.Type 2 diabetes: assessing the relative

risks and benefits of glucose-loweringmedications. Am J Med 2010;123:374.e9374.e18

3. Nyenwe EA, Jerkins TW, Umpierrez GE,Kitabchi AE. Management of type 2 di-abetes: evolving strategies for the treat-ment of patients with type 2 diabetes.Metabolism 2011;60:123

4. Nolan JJ. Consensus guidelines, algo-

rithms and care of the individual patientwith type 2 diabetes. Diabetologia 2010;53:12471249

5. Blonde L. Current antihyperglycemictreatment guidelines and algorithms forpatients with type 2 diabetes mellitus.Am J Med 2010;123(Suppl.):S12S18

6. Greenfield S, Billimek J, Pellegrini F,et al. Comorbidity affects the relationshipbetween glycemic control and cardiovas-cular outcomes in diabetes: a cohort study.Ann Intern Med 2009;151:854860

7. Matthews DR, Tsapas A. Four decades ofuncertainty: landmark trials in glycaemiccontrol and cardiovascular outcome intype 2 diabetes. Diab Vasc Dis Res 2008;5:216218

8. Skyler JS, Bergenstal R, Bonow RO,et al.; American Diabetes Association;American College of Cardiology Founda-tion; American Heart Association. Intensiveglycemic control and the prevention ofcardiovascular events: implications ofthe ACCORD, ADVANCE, and VAdiabetes trials: a position statement ofthe American Diabetes Association and ascientific statement of the American Col-lege of Cardiology Foundation and theAmerican Heart Association. Diabetes Care2009;32:187192

9. Yudkin JS, Richter B, Gale EA. Intensifiedglucose control in type 2 diabetesdwhoseagenda? Lancet 2011;377:12201222

10. Nathan DM, Buse JB, Davidson MB, et al.;American Diabetes Association; EuropeanAssociation for the Study of Diabetes.Medical management of hyperglycaemiain type 2 diabetes mellitus: a consensusalgorithm for the initiation and adjust-ment of therapy: a consensus statementfrom the American Diabetes Associationand the European Association for theStudy of Diabetes. Diabetologia 2009;52:1730

11. IDF Clinical Guidelines Task Force.Global Guideline for Type 2 Diabetes.Brussels, International Diabetes Federa-tion, 2005

12. Rodbard HW, Jellinger PS, Davidson JA,et al. Statement by an American Associa-tion of Clinical Endocrinologists/AmericanCollege of Endocrinology consensus panelon type 2 diabetes mellitus: an algorithmfor glycemic control. Endocr Pract 2009;15:540559

13. Berard LD, Booth G, Capes S, Quinn K,Woo V. Canadian Diabetes Association2008 Clinical Practice Guidelines for thePrevention and Management of Diabetes

in Canada. Canadian Journal of Diabetes2008;32:S1S201

14. NICE. Type 2 Diabetes: The Managementof Type 2 Diabetes: NICE Clinical Guide-line 87. National Institute for Health andClinical Excellence, 2009

15. Home P, Mant J, Diaz J, Turner C;Guideline Development Group. Man-agement of type 2 diabetes: summary

of updated NICE guidance. BMJ 2008;336:13061308

16. Davidson JA. Incorporating incretin-based therapies into clinical practice:differences between glucagon-like pep-tide 1 receptor agonists and dipeptidylpeptidase 4 inhibitors. Mayo Clin Proc2010;85(Suppl.):S27S37

17. DeFronzo RA. Current issues in thetreatment of type 2 diabetes.Overviewofnewer agents: where treatment is going.Am J Med 2010;123(Suppl.):S38S48

18. Murad MH, Shah ND, Van Houten HK,et al. Individuals with diabetes preferredthat future trials use patient-importantoutcomes and provide pragmatic infer-ences. J Clin Epidemiol 2011;64:743748

19. Glasgow RE, Peeples M, Skovlund SE.Where is the patient in diabetes perfor-mance measures? The case for includingpatient-centered and self-managementmeasures. Diabetes Care 2008;31:10461050

20. Ismail-Beigi F, Moghissi E, Tiktin M,Hirsch IB, Inzucchi SE, Genuth S. In-dividualizing glycemic targets in type 2diabetes mellitus: implications of recentclinical trials. Ann Intern Med 2011;154:554559

21. Mullan RJ, Montori VM, Shah ND, et al.The diabetes mellitus medication choicedecision aid: a randomized trial. ArchIntern Med 2009;169:15601568

22. Schernthaner G, Barnett AH, BetteridgeDJ, et al. Is the ADA/EASD algorithm forthe management of type 2 diabetes(January 2009) based on evidence oropinion? A critical analysis. Diabetologia2010;53:12581269

23. Gandhi GY, Murad MH, Fujiyoshi A,et al. Patient-important outcomes in re-gistered diabetes trials. JAMA 2008;299:25432549

24. Smith RJ, Nathan DM, Arslanian SA,

Groop L, Rizza RA, Rotter JI. Individu-alizing therapies in type 2 diabetes mel-litus based on patient characteristics:what we know and what we need toknow. J Clin Endocrinol Metab 2010;95:15661574

25. Committee on Quality of Health Care inAmerica: Institute of Medicine. Crossingthe Quality Chasm: A New Health Systemfor the 21st Century. Washington, DC,The National Academies Press, 2001

26. Guyatt GH, Haynes RB, Jaeschke RZ,et al.; Evidence-Based Medicine WorkingGroup. Users Guides to the Medical Lit-erature: XXV. Evidence-based medicine:




14/16

principles for applying the Users Guidesto patient care. JAMA 2000;284:12901296

27. Tsapas A, Matthews DR. N of 1 trials indiabetes: making individual therapeuticdecisions. Diabetologia 2008;51:921925

28. Shah ND, Mullan RJ, Breslin M, YawnBP, Ting HH, Montori VM. Translating

comparative effectiveness into practice:the case of diabetes medications. MedCare 2010;48(Suppl.):S153S158

29. Stratton IM, Adler AI, Neil HA, et al.Association of glycaemia with macro-vascular and microvascular complica-tions of type 2 diabetes (UKPDS 35):prospective observational study. BMJ2000;321:405412

30. Turner RC, Holman RR, Cull CA, et al.;UK Prospective Diabetes Study (UKPDS)Group. Intensive blood-glucose controlwith sulphonylureas or insulin com-pared with conventional treatment andrisk of complications in patients withtype 2 diabetes (UKPDS33). Lancet 1998;352:837853

31. UKPDS Group. UK Prospective DiabetesStudy VIII: study design, progress andperformance. Diabetologia 1991;34:877890

32. Turner RC, Holman RR, Cull CA, et al.;UK Prospective Diabetes Study (UKPDS)Group. Effect of intensive blood-glucosecontrol with metformin on complica-tions in overweight patients with type 2diabetes (UKPDS 34). Lancet 1998;352:854865

33. Holman RR,Paul SK,Bethel MA, MatthewsDR, Neil HA. 10-year follow-up of in-tensive glucose control in type 2 diabetes.N Engl J Med 2008;359:15771589

34. Gerstein HC, Miller ME, Byington RP,et al.; Action to Control CardiovascularRisk in Diabetes Study Group. Effects ofintensive glucose lowering in type 2 di-abetes. N Engl J Med 2008;358:25452559

35. Patel A, MacMahon S, Chalmers J, et al.;ADVANCE Collaborative Group. Inten-sive blood glucose control and vascularoutcomes in patients with type 2 diabetes.N Engl J Med 2008;358:25602572

36. Turnbull FM, Abraira C, Anderson RJ,

Byington RP, Chalmers JP, DuckworthWC, et al . Intensive glucose control andmacrovascular outcomes in type 2 di-abetes. Diabetologia2009;52:22882298.Erratum 52:2470

37. Ferrannini E, Gastaldelli A, Miyazaki Y,Matsuda M, Mari A, DeFronzo RA. Beta-cell function in subjects spanning therange from normal glucose tolerance toovert diabetes: a new analysis. J ClinEndocrinol Metab 2005;90:493500

38. Nauck MA. Incretin-based therapies fortype 2 diabetes mellitus: properties, func-tions, and clinical implications. Am J Med2011;124(Suppl.):S3S18

39. Ferrannini E. Thestunned beta cell: a briefhistory. Cell Metab 2010;11:349352

40. Nauck MA. Unraveling the science ofincretin biology. Am J Med 2009;122(Suppl.):S3S10

41. Groop LC, Ferrannini E. Insulin actionand substrate competition. Baillieres ClinEndocrinol Metab 1993;7:10071032

42. American Diabetes Association. Stand-

ards of medical care in diabetesd

2011.Diabetes Care 2011;34(Suppl. 1):S11S61

43. Akalin S, Berntorp K, Ceriello A, et al.;Global Task Force on Glycaemic Control.Intensive glucose therapy and clinicalimplications of recent data: a consensusstatement from the Global Task Force onGlycaemic Control. Int J Clin Pract 2009;63:14211425

44. Lee SJ, Eng C. Goals of glycemic controlin frail older patients with diabetes.JAMA 2011;305:13501351

45. Ahmed MH, Byrne CD. Current treat-ment of non-alcoholic fatty liver disease.Diabetes Obes Metab 2009;11:188195

46. May C, Montori VM, Mair FS. We needminimally disruptive medicine. BMJ2009;339:b2803

47. Anderson JW, Kendall CW, Jenkins DJ.Importance of weight management intype 2 diabetes: review with meta-analysisof clinical studies. J Am Coll Nutr 2003;22:331339

48. Klein S, Sheard NF, Pi-Sunyer X, et al.;American Diabetes Association; NorthAmerican Association for the Study ofObesity; American Society for ClinicalNutrition. Weight management throughlifestyle modification for the preventionand management of type 2 diabetes: ra-tionale and strategies: a statement of theAmerican Diabetes Association, the NorthAmerican Association for the Study ofObesity, and the American Society forClinical Nutrition. Diabetes Care 2004;27:20672073

49. Bantle JP, Wylie-Rosett J, Albright AL,et al.; American Diabetes Association.Nutrition recommendations and in-terventions for diabetes: a positionstatement of the American Diabetes As-sociation. Diabetes Care 2008;31(Suppl.1):S61S78

50. Elmer PJ, Obarzanek E, Vollmer WM,

et al.; PREMIER Collaborative ResearchGroup. Effects of comprehensive lifestylemodification on diet, weight, physicalfitness, and blood pressure control:18-month results of a randomized trial.Ann Intern Med 2006;144:485495

51. Gordon NF, Salmon RD, Franklin BA,et al. Effectiveness of therapeutic lifestylechanges in patients with hypertension,hyperlipidemia, and/or hyperglycemia.Am J Cardiol 2004;94:15581561

52. Wing RR, Tate DF, Gorin AA, RaynorHA, Fava JL. A self-regulation programfor maintenance of weight loss. N EnglJ Med 2006;355:15631571

53. Boul NG, Haddad E, Kenny GP, WellsGA, Sigal RJ. Effects of exercise on gly-cemic control and body mass in type 2diabetes mellitus: a meta-analysis of con-trolled clinical trials. JAMA 2001;286:12181227

54. Bailey CJ,Turner RC.Metformin. N EnglJ Med 1996;334:574579

55. Lamanna C, Monami M, Marchionni N,

Mannucci E. Effect of metformin oncardiovascular events and mortality: a meta-analysis of randomized clinical trials.Diabetes Obes Metab 2011;13:221228

56. Bryan J, Crane A, Vila-Carriles WH,Babenko AP, Aguilar-Bryan L. Insulinsecretagogues, sulfonylurea receptors andK(ATP) channels. Curr Pharm Des 2005;11:26992716

57. Kahn SE, Haffner SM, Heise MA, et al.;ADOPT Study Group. Glycemic dura-bility of rosiglitazone, metformin, orglyburide monotherapy. N Engl J Med2006;355:24272443

58. Gerich J, Raskin P, Jean-Louis L,Purkayastha D, Baron MA. PRESERVE-b:two-year efficacy and safety of initialcombination therapy with nateglinide orglyburide plus metformin. Diabetes Care2005;28:20932099

59. Yki-Jrvinen H. Thiazolidinediones. N EnglJ Med 2004;351:11061118

60. Dormandy JA, Charbonnel B, EcklandDJ, et al.; PROactive investigators. Sec-ondary prevention of macrovascularevents in patients with type 2 diabetesin the PROactive Study (PROspectivepioglitAzone Clinical Trial In macro-Vasc ular Even ts): a randomi sed con-trolled trial. Lancet 2005;366:12791289

61. Nissen SE, Wolski K. Rosiglitazone re-visited: an updated meta-analysis of riskfor myocardial infarction and cardiovas-cular mortality. Arch Intern Med 2010;170:11911201

62. Lewis JD, Ferrara A, Peng T, et al. Risk ofbladder cancer among diabetic patientstreated with pioglitazone: interim reportof a longitudinal cohort study. DiabetesCare 2011;34:916922

63. Drucker DJ, Nauck MA. The incretinsystem: glucagon-like

guias easd y ada 2012

Documents