cost-effectiveness of interventions to prevent and control … · cost-effectiveness of...

Cost-Effectiveness of Interventions toPrevent and Control Diabetes Mellitus:A Systematic ReviewRUI LI, PHD

PING ZHANG, PHD

LAWRENCE E. BARKER, PHD

FARAH M. CHOWDHURY, MPH

XUANPING ZHANG, PHD

OBJECTIVE — To synthesize the cost-effectiveness (CE) of interventions to prevent andcontrol diabetes, its complications, and comorbidities.

RESEARCH DESIGN AND METHODS — We conducted a systematic review of liter-ature on the CE of diabetes interventions recommended by the American Diabetes Association(ADA) and published between January 1985 and May 2008. We categorized the strength ofevidence about the CE of an intervention as strong, supportive, or uncertain. CEs were classifiedas cost saving (more health benefit at a lower cost), very cost-effective (�$25,000 per life yeargained [LYG] or quality-adjusted life year [QALY]), cost-effective ($25,001 to $50,000 per LYGor QALY), marginally cost-effective ($50,001 to $100,000 per LYG or QALY), or not cost-effective (�$100,000 per LYG or QALY). The CE classification of an intervention was reportedseparately by country setting (U.S. or other developed countries) if CE varied by where theintervention was implemented. Costs were measured in 2007 U.S. dollars.

RESULTS — Fifty-six studies from 20 countries met the inclusion criteria. A large majority ofthe ADA recommended interventions are cost-effective. We found strong evidence to classify thefollowing interventions as cost saving or very cost-effective: (I) Cost saving— 1) ACE inhibitor(ACEI) therapy for intensive hypertension control compared with standard hypertension con-trol; 2) ACEI or angiotensin receptor blocker (ARB) therapy to prevent end-stage renal disease(ESRD) compared with no ACEI or ARB treatment; 3) early irbesartan therapy (at the microalbu-minuria stage) to prevent ESRD compared with later treatment (at the macroalbuminuria stage);4) comprehensive foot care to prevent ulcers compared with usual care; 5) multi-componentinterventions for diabetic risk factor control and early detection of complications compared withconventional insulin therapy for persons with type 1 diabetes; and 6) multi-component inter-ventions for diabetic risk factor control and early detection of complications compared withstandard glycemic control for persons with type 2 diabetes. (II) Very cost-effective— 1) intensivelifestyle interventions to prevent type 2 diabetes among persons with impaired glucose tolerancecompared with standard lifestyle recommendations; 2) universal opportunistic screening forundiagnosed type 2 diabetes in African Americans between 45 and 54 years old; 3) intensiveglycemic control as implemented in the UK Prospective Diabetes Study in persons with newlydiagnosed type 2 diabetes compared with conventional glycemic control; 4) statin therapy forsecondary prevention of cardiovascular disease compared with no statin therapy; 5) counselingand treatment for smoking cessation compared with no counseling and treatment; 6) annualscreening for diabetic retinopathy and ensuing treatment in persons with type 1 diabetes com-pared with no screening; 7) annual screening for diabetic retinopathy and ensuing treatment inpersons with type 2 diabetes compared with no screening; and 8) immediate vitrectomy to treatdiabetic retinopathy compared with deferred vitrectomy.

CONCLUSIONS — Many interventions intended to prevent/control diabetes are cost savingor very cost-effective and supported by strong evidence. Policy makers should consider givingthese interventions a higher priority.

Diabetes Care 33:1872–1894, 2010

The cost of diabetes in the U.S. in2007 was $174 billion (1). Many in-terventions can reduce the burden

of this disease. However, health care re-sources are limited; thus, interventionsfor diabetes prevention/control should beprioritized. We wanted to compare theeffectiveness and costs of various inter-ventions to find those that were the mosteffective for the least expense. Cost-effective analysis is a useful tool for thispurpose. Such analyses consist of compil-ing incremental cost-effectiveness ratios(ICERs), which are calculated as a ratio ofthe difference in costs to the difference ineffectiveness between the intervention be-ing evaluated and the comparisonintervention.

With the same health outcome indi-cator, ICERs of interventions are compa-rable. Therefore, these ICERs can make iteasier to decide how to allocate resources.Although many cost-effectiveness (CE)analyses of diabetes interventions havebeen published, their qualities and con-clusions vary. A systematic review, whichappraises individual studies and summa-rizes results, would aid policy makers andclinicians in prioritizing interventions toprevent or treat diabetes and itscomplications.

Few investigators have conductedsystematic reviews of the CE of diabetesinterventions (2–5). The systematicreview presented here, following theCochrane Collaboration’s protocol (6),includes all English language studiesavailable from 1985 to May 2008. Theinterventions included only those recom-mended by the 2008 American DiabetesAssociation (ADA) Standards of MedicalCare in Diabetes (7).

RESEARCH DESIGN ANDMETHODS

Study selection and protocols forreviewWe searched the Medical Literature Anal-ysis and Retrieval System Online (MED-LINE), Excerpta Medica (EMBASE),Cumulative Index to Nursing and AlliedHealth Literature (CINAHL), PsycINFO,Sociological Abstracts (Soc Abs), Web of

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

From the Division of Diabetes Translation, National Center for Chronic Disease Prevention and HealthPromotion, Centers for Disease Control and Prevention, Atlanta, Georgia.

Corresponding author: Rui Li, [email protected] findings and conclusions in this report are those of the authors and do not necessarily reflect the official

positions of the Centers for Disease Control and Prevention.DOI: 10.2337/dc10-0843© 2010 by the American Diabetes Association. Readers may use this article as long as the work 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.

R e v i e w s / C o m m e n t a r i e s / A D A S t a t e m e n t sR E V I E W A R T I C L E

1872 DIABETES CARE, VOLUME 33, NUMBER 8, AUGUST 2010 care.diabetesjournals.org

Science (WOS), and Cochrane databasesto identify relevant studies. We created asearch strategy involving medical subjectheadings. The key words—and what eachindicated—were:

● Indicating diabetes: 26 key words indi-cating the disease of diabetes, such as“type 1 diabetes,” “type 2 diabetes,”“impaired glucose tolerance,” and “in-sulin resistance”;

● Indicating costs: (“cost or expendi-ture”) OR (“costs and cost analysis”) OR(“health care costs”) OR (“cost ofillness”);

● Indicating effectiveness: (“benefit”) OR(“life years”) OR (“quality-adjusted lifeyears”) OR (“disability adjusted lifeyears”);

● Indicating CE analysis: [(key words forcosts) AND (keywords for effective-ness)] OR (“cost-benefit analysis”) OR(“cost-effectiveness analysis”) OR(“cost-utility analysis”) OR (“economicevaluation”).

Database searches were based onmatches in all four keyword categories.Reference lists of all the included articleswere screened for additional citations,and Diabetes Care was reviewed manu-ally, issue by issue, as the journal was ex-pected to be highly relevant.

Criteria for inclusion in the reviewwere 1) original CE analysis; 2) interven-tion directed toward patients with type 1,type 2, or gestational diabetes mellitus(GDM) and recommended in the 2008ADA standards for medical care (7); 3)outcomes were measured as life yearsgained (LYGs) or quality-adjusted lifeyears gained (QALYs); and 4) publicationin the English language occurred betweenJanuary 1985 and May 2008 (2). To en-sure that only studies with acceptablequality were included, we limited theanalysis to studies considered good or ex-cellent according to a 13-item quality-assessment tool based on the BritishMedical Journal authors’ guide for eco-nomic studies (8).

To make ICERs comparable acrossthe studies, all costs are expressed as 2007U.S. dollars with adjustment from othercurrencies, as needed, using the FederalReserve Bank’s annual foreign exchangerates (9) and from other cost years usingthe Consumer Price Index (10). If a studydid not mention the year used in cost cal-culations, we assumed cost was as of oneyear before publication. ICERs were ex-pressed as dollars per QALY or dollars per

LYG and were rounded to the nearesthundred dollars per QALY or LYG.

Classification of cost-effectiveness ofinterventionsInterventions were classified based on thelevel of CE by convention as described inthe literature (2,11,12)—cost saving (anintervention generates a better health out-come and costs less than the comparisonintervention) or cost neutral (ICER � 0);very cost-effective (0 � ICER � $25,000per QALY or LYG); cost-effective($25,000 � ICER � $50,000 per QALY orLYG); marginally cost-effective ($50,000 �ICER � $100,000 per QALY or LYG); ornot cost-effective (�$100,000 per QALY orLYG)—and whether evidence for the inter-vention’s CE was strong, supportive, or un-certain as described below.

There were two grades of evidence in-cluded in the “strong” group. Grade 1 wasdefined as 1) CE of the intervention wasevaluated by two or more studies; 2)study quality was rated good or excellent;3) effectiveness of interventions based onwell-conducted, randomized clinicaltrials with adequate power and gen-eralizable results or meta-analysis or avalidated simulation model; 4) effec-tiveness of interventions rated as level A(clear evidence from well-conducted,generalizable, randomized controlled tri-als that were adequately powered; com-pelling nonexperimental evidence, i.e.,the all or none rule developed by theCentre for Evidence-Based Medicine atthe University of Oxford, U.K.) or levelB (supportive evidence from well-conducted cohort studies or supportiveevidence from a well-conducted case-control study) according to the 2008 ADAstandards of medical care (7); and 5) sim-ilar ICERs reported across the studies.Grade 2 was defined as the same as Grade1 except that the CE was based on onlyone study and the study was rated asexcellent.

We called the level of evidence “sup-portive” if only one study, rated lowerthan excellent, evaluated the CE of theintervention or if the effectiveness of theintervention was supported by eitherlevel C evidence (supportive evidencefrom poorly controlled or uncontrolledstudies, or conflicting evidence with theweight of evidence supporting the recom-mendation) or expert consensus (level E)in ADA recommendations (7). The term“uncertain” was used to describe inter-ventions with inconsistent evidenceabout CE across studies.

Reporting the results of thesystematic reviewWe reported the study results in twoways: 1) summarizing the key featuresand results for each included study; and2) synthesizing the CE of the interven-tions based on the classification criteriadescribed above. For the summary, wegrouped interventions based on their in-tended purposes: a) preventing type 2 di-abetes among high-risk persons; b)screening for undiagnosed type 2 diabetesand GDM; c) management of diabetes andrisk factors for complications; d) screen-ing for and early treatment of complica-tions; and e) treatment of complicationsand comorbidities. We considered caseswhere the same intervention was appliedto different populations or was comparedwith different interventions as differentspecific interventions and reported theICERs separately. This was because bothincremental costs and effectiveness of anintervention, and thus the ICERs, varied ifthe population and/or comparison groupdiffered. If the CE of an intervention wasevaluated from different study perspec-tives, we report the ICERs separately. Wepresented the ICERs in subgroups if theirICERs differed substantially from base-case analysis, and original studies re-ported the ICERs this way. If the studyreported the ICERs only for populationsubgroups, we provided a range and,when available, trend of the ICERs. Fi-nally, if a study used both LYGs andQALYs as study outcome measures, wereported the ICER in both costs per LYGand QALY.

In reporting the synthesized results,we applied the following rules: 1) Weused the median ICER to represent the CEof an intervention if the intervention wasevaluated by more than one study. 2) Wereported the ICERs from the longer ana-lytical time horizon if the interventionwas evaluated from both short- and long-term perspectives. This was appropriatesince many of the benefits of most diabe-tes prevention and control interventionswould come from preventing diabeticcomplications, which occur later in life. 3)We chose the health care system as ourprimary study perspective for the purposeof cross-study and cross-interventioncomparisons. This study perspective in-cluded all the medical costs incurred nomatter who paid. 4) If the ICERs of anintervention differed substantially be-tween the U.S. and other developed coun-tries (mainly European countries,Australia, and Canada), we reported the

Li and Associates

care.diabetesjournals.org DIABETES CARE, VOLUME 33, NUMBER 8, AUGUST 2010 1873

summary results separately by labelingthe ICER for the U.S. or for the othercountries. 5) If the trial on which the CEof an intervention was based was con-ducted in a mixed population with type 1or type 2 diabetes, we assumed the CEwas the same for both types of diabetes.

RESULTS — The search yielded 9,461abstracts. After reviewing the abstractsand subsequent reference tracking, wenarrowed the focus to 197 possible origi-nal CE studies. Further review of the fulltext resulted in 56 CE studies that met ourinclusion criteria. Figure 1 depicts thedata abstraction process.

Table 1 shows the detailed descrip-tion of the CE studies that we includedaccording to intervention type (13–70).

We first grouped similar interventions to-gether, then arranged them chronologi-cally and by the first author’s last name.Some studies that evaluated multiple in-terventions appear in more than one cat-egory. The information used to describeeach study included the intervention be-ing evaluated; comparison intervention,population, and country setting; datasources for the effectiveness of the inter-vention; study methods; quality of thestudy; analytical time horizon; discountrate (a rate that is used to convert futurecosts and benefits into their present val-ues); and ICER.

Thirty-nine of the 56 studies took along-term analytical time horizon, such as20–30 years or lifetime. Nearly all of thestudies with the long-term horizon used

simulation modeling. Only one study wasconducted in a developing country (Thai-land) (57). There were 48 excellent stud-ies and 8 good studies. Only three studiestook perspectives other than the healthcare system.

The interventions evaluated in theseCE studies covered a wide range: lifestyleand medication therapy to prevent type 2diabetes among high-risk individuals(eight studies); screening for undiag-nosed type 2 diabetes or GDM (threestudies); intensive glycemic control (12studies); self-monitoring of blood glucose(one study); intensive hypertension con-trol (four studies); statin therapy for cho-lesterol control (five studies); smokingcessation (one study); diabetic health ed-ucation program (two studies); diabetes

Figure 1—Selection of cost-effectiveness studies for systematic review of interventions to prevent and control diabetes.

Cost-effectiveness of diabetes interventions


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ons

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gor

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ofty

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Life

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$46,

800–

$130

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for

age

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ofty

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$72,

200–

$189

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age

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699,

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quen

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met

hod

$35,

200/

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rm

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omes

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rne

onat

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Inte

nsi

vegl

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ntr

olD

CC

T19

96(6

5)U

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Typ

e1

diab

etes

Inte

nsiv

egl

ycem

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ntro

lth

roug

hin

sulin

man

agem

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self-

mon

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and

outp

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ntvi

sits

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goal

was

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hiev

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1Cle

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sno

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%)

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vent

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lthe

rapy

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sin

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DC

CT

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tice

nter

RC

T(n

�1,

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Life

tim

e3%

$47,

600/

life

year

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50,8

00/

QA

LY

Palm

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al.2

000

(46)

Swit

zerl

and

Typ

e1

diab

etes

Inte

nsiv

ein

sulin

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apy

Con

vent

iona

lins

ulin

ther

apy

Lite

ratu

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view

Life

tim

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orte

dre

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sat

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tabl

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$46,

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fham

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.20

03(5

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Typ

e1

diab

etes

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tino

ussu

bcut

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usin

sulin

inte

rven

tion

for

pers

ons

usin

gin

sulin

pum

p

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tipl

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sulin

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ctio

ns1

syst

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view

1m

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anal

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8ye

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6%$1

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005

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U.K

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CC

T(n

�1,

441)

mai

nly

met

a-an

alys

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60ye

ars

3%$1

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4)U

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CT

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1)Li

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age

atdi

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set;

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R�

33,0

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rag

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year

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ray

etal

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0(3

0)U

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Typ

e2

diab

etes

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nsiv

em

anag

emen

tw

ith

insu

linor

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nylu

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aim

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vent

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nly

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min

gat

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mm

ol/l

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PDS

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RC

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tsa

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intr

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min

gat

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vent

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KPD

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Med

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10.7

year

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savi

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Cen

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for

Dis

ease

Con

trol

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enti

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02(1

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lydi

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type

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tens

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glyc

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cont

rolw

ith

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mol

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vent

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cose

cont

rol(

mai

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gra

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age

atdi

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rag

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year

s;$2

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0–$5

6,00

0/Q

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for

age

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Li and Associates


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2000

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Swed

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Typ

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MI

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fusi

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2008

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LYIn

ten

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KPD

S19

98(6

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Typ

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cont

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year

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ost

savi

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ente

rsfo

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ontr

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even

tion

2002

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U.S

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Typ

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cont

rol

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vera

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154/

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mH

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PDS

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ost

savi

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rke

etal

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5(1

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Typ

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diab

etes

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nsio

nT

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BPco

ntro

lBP

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0/85

mm

Hg,

AC

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niti

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200/

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Late

r�

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erm

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al.1

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U.S

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vast

atin

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son

etal

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urop

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coun

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Typ

e2

diab

etes

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lipid

emia

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Ior

angi

na

Sim

vast

atin

Plac

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indi

ffer

ent

coun

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n:$2

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Gro

ver

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VD

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Men

and

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year

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vast

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AR

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Typ

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Sim

vast

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LDL

chol

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roll

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46m

mol

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–$15

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GC

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even

tion

2002

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U.S

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Typ

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etes

Dys

lipid

emia

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CV

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stor

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tin

Plac

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Ed

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disease management program (two stud-ies); screening to prevent diabetic reti-nopathy (five studies); optimal foot careto prevent foot ulcer and amputation (twostudies); ACE inhibitor (ACEI) or angio-tensin receptor blocker (ARB) therapy toprevent diabetic end-stage renal diseases(ESRD) (15 studies); comprehensive in-terventions using a combination of sev-eral of the above secondary preventioninterventions (two studies); and interven-tions treating diabetic retinopathy andfoot ulcers (two studies).

The classification of the interventionsbased on their level of CE and strength ofevidence is presented in Table 2. For eachintervention, we also described the num-ber of studies that evaluated the CE of thisintervention, its comparison interven-tion, and the study population in whichthe intervention was implemented. Wereported the median and range of the IC-ERs across the studies.

Twenty-six interventions were classi-fied as supported by strong evidence con-cerning their CE (Table 2). Among these,six interventions were cost saving, eightwere very cost-effective, six were cost-effective, two were marginally cost-effective, and four were not cost-effective.These interventions consisted of primaryprevention, screening for undiagnosedtype 2 diabetes, diabetic risk factor con-trol, early prevention of diabetes compli-cations, and treatment of diabetescomplications.

The six cost-saving interventions withstrong evidence were 1) ACEI therapy forintensive hypertension control, as in theUK Prospective Diabetes Study (UKPDS),in persons with type 2 diabetes comparedwith standard hypertension control; 2)ACEI or ARB therapy to prevent ESRD fortype 2 diabetes compared with no ACEIor ARB therapy; 3) early irbesartan ther-apy at the stage of microalbuminuria toprevent ESRD in people with type 2 dia-betes compared with treatment at thestage of macroalbuminuria; 4) compre-hensive foot care to prevent ulcers inmixed population with either type 1 ortype 2 diabetes compared with usual care;5) multi-component interventions for di-abetic risk factor control and early detec-tion of complications compared withconventional insulin therapy for personswith type 1 diabetes; and 6) multi-component interventions for diabetic riskfactor control and early detection of com-plications compared with standard glyce-mic control for persons with type 2diabetes.

Of the eight very cost-effective inter-ventions with strong evidence, six werefor persons with type 2 diabetes, one forpersons with type 1 diabetes, and one fora mixed population with type 1 or type 2diabetes. Interventions for type 2 diabetesincluded: 1) primary prevention throughintensive lifestyle modification; 2) univer-sal opportunistic screening for un-diagnosed type 2 diabetes in AfricanAmericans between 45 and 54 years old;3) intensive glycemic control as imple-mented in UKPDS; 4) statin therapy forsecondary prevention of cardiovasculardisease; 5) smoking cessation; and 6) an-nual screening for diabetic retinopathyand early treatment of it. The interventionfor type 1 diabetes was annual screeningfor diabetic retinopathy and treating thepositive cases. The intervention for mixedpopulation of type 1 and type 2 diabeteswas immediate vitrectomy to treat dia-betic retinopathy compared with deferralof vitrectomy.

The six cost-effective interventionswith strong evidence were 1) one-timeopportunistic targeted screening for un-diagnosed type 2 diabetes in hypertensivepersons aged 45 years and older com-pared with no screening; 2) intensive in-sulin treatment for persons with type 1diabetes compared with conventional gly-cemic control; 3) UKPDS-like intensiveglycemic control applied to the U.S.health care system among adults youngerthan age 54 years with type 2 diabetescompared with conventional glycemiccontrol; 4) intensive glycemic control by aDiabetes Prevention Program (DPP) typeof intensive lifestyle intervention in per-sons with newly diagnosed type 2 diabe-tes compared with conventional glycemiccontrol; 5) statin therapy for primary pre-vention of cardiovascular disease in per-sons with type 2 diabetes compared withno statin therapy; 6) multi-component in-terventions including insulin therapy,ACEI therapy, and screening for retinop-athy in persons with type 1 diabetes com-pared with intensive insulin therapy.

The two marginally cost-effective in-terventions with strong evidence were 1)intensive glycemic control for all U.S. res-idents with type 2 diabetes diagnosed atage 25 years and older compared withusual care; and 2) screening for diabeticretinopathy every two years comparedwith screening every three years in per-sons with type 2 diabetes.

The four interventions with strongevidence of not being cost-effective were1) one-time universal opportunistic

screening for undiagnosed type 2 diabetesamong those aged 45 years and oldercompared with no screening; 2) universalscreening for type 2 diabetes comparedwith targeted screening; 3) intensive gly-cemic control in the U.S. setting for pa-tients diagnosed with diabetes at olderages (55–94 years of age) compared withusual care; and 4) annual screening forretinopathy compared with screening ev-ery two years. All these studies were fortype 2 diabetes.

There were 18 specific interventionsfor which their CEs were based only on“supportive” evidence. Among them, 15were each supported by one CE study, 13were supported by level C or level E evi-dence, and five were supported by level Aor B evidence as defined in the 2008 ADAstandards of medical care in diabetes (7).For those interventions with level A or Bevidence, the CE of each intervention wasevaluated by one study with a quality ofbeing “good.”

In terms of the level of the CE, 10 ofthe 18 specific interventions based on“supportive” evidence were cost-saving,including 1) screening using the sequen-tial method (50-g glucose challenge testfollowed by 100-g glucose tolerance test[GTT]) for GDM in 30-year-old pregnantwomen between 24–28 weeks’ gestationcompared with no screening; 2) screeningfor GDM using the 100-g GTT methodcompared with no screening; 3) the se-quential method compared with 75-gGTT screening for GDM; 4) 100-g GTTcompared with 75-g GTT screening forGDM; 5) diabetes self-management edu-cation for persons with type 1 diabetescompared with no education; 6) full-reimbursement policy for ACEI for pa-tients with type 1 diabetes compared withpatients paying out-of-pocket; 7) full-reimbursement policy for ACEI for pa-tients with type 2 diabetes compared withpatients paying out-of-pocket; 8) screen-ing using a mobile camera at a remote areaand processing data in a reading centercompared with a retina specialist’s visit ina mixed population of type 1 and type 2diabetes; 9) screening for diabetic ne-phropathy and ensuing ACEI or ARBtherapy in persons with type 1 diabetescompared with no screening; and 10) in-tensified foot ulcer treatment in a mixedpopulation with type 1 or type 2 diabetescompared with standard treatment.

Seven of the 18 specific interventionswere very cost-effective: 1) primary pre-vention of type 2 diabetes in women withGDM history through intensive lifestyle

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intervention compared with usual care; 2)universal opportunistic screening for type2 diabetes in African Americans aged25–44 years compared with no screen-ing; 3) 100-g GTT compared with the se-quential screening method for detectingGDM in 30-year-old pregnant womenbetween 24–28 weeks’ gestation; 4) dia-betes self-management education for per-sons with type 2 diabetes compared withno education; 5) disease managementprograms using specialist nurse–led clin-ics to treat and control hypertension orhyperlipidemia in patients with type 2 di-abetes in a city in England or a culturallysensitive case–management training pro-gram to control diabetes and its risk fac-tors in a Latino population with both type1 and type 2 diabetes in a U.S. countycompared with usual care only; 6) self-monitoring of blood glucose (SMBG)three times per day compared with noSMBG in type 2 noninsulin users; and 7)SMBG once per day compared with noSMBG in type 2 noninsulin users. One ofthe 18 specific interventions was cost-effective, i.e., the use of metformin to pre-vent type 2 diabetes in obese persons withimpaired glucose tolerance comparedwith standard lifestyle intervention. Nointerventions in the “supportive” evi-dence category were “marginally cost-effective” or “not cost-effective.”

Current evidence is uncertain on howthe CE of screening for undiagnosed type2 diabetes would change with the age ofthose screened. Two studies evaluated theCE of screening for undiagnosed type 2diabetes; one study reported that cost-effectiveness ratios (CERs) increased withinitial screening age (16) while the otherreported that they decreased with screen-ing age (35).

CONCLUSIONS — Our systematicreview showed that, with few exceptions,ADA-recommended interventions forpreventing or treating diabetes and itscomplications were cost saving, very cost-effective, or cost-effective (i.e., with anICER of less than $50,000 per QALY orLYG), although the strength of evidencevaried. Generally, interventions that costless than $50,000 per QALY are consid-ered an efficient use of resources andworth recommending (11). Interventionswith strong evidence for being cost sav-ing, very cost-effective, or cost-effectiveshould be considered for implementa-tion. Interventions with supportive evi-dence for being cost saving, very cost-effective, or cost-effective should be

adopted if extra resources are available orif similar interventions with strong evi-dence are unavailable or infeasible in aspecific setting.

The one intervention recommendedby the ADA that was shown as not CE wasscreening for type 2 diabetes of all U.S.residents aged 45 years and older. Whenconsidering allocating resources effi-ciently, universal screening for undiag-nosed diabetes should be undertakenwith great caution. The high CE ratio foruniversal screening for undiagnosed type2 diabetes was primarily attributable tothe small gain in health benefit. For exam-ple, screening everyone aged 45 years andolder gained only 0.003 QALY per eligibleperson compared with no screening.However the additional costs associatedwith screening and early treatments wererelatively large ($564 per person). Al-though detecting and treating diabetesearlier can prevent future diabetes-relatedcomplications and their associated medi-cal costs, such savings are relatively small($57 per person). Combining the healthbenefit and costs would yield an ICER ofmore than $1 million per QALY (35). Analternative to broad screening is to focuson screening persons with additional riskfactors, such as hypertension. Such tar-geted screening is shown to be cost-effective when compared with noscreening or universal screening.

Intensive glycemic control for all U.S.residents with type 2 diabetes diagnosedat age 25 years and older is marginally CE.However the cost-effectiveness of this in-tervention varies by age at the time of thediabetes diagnosis. The intervention iscost-effective in persons diagnosed at25–54 years of age. However, intensiveglycemic control for those diagnosed withdiabetes at 55 years of age and older is notcost-effective. In fact, this result is consis-tent with the ADA’s recommendation ofless stringent A1C goals for patients withlimited life expectancies.

The ADA recommended annual eyescreening for diabetic retinopathy. Thisrecommended intervention is very cost-effective compared with no screening inpersons with type 2 diabetes. If consider-ing the efficient allocation of resources,however, screening every other yearmight be a better alternative. Screeningannually leads to a small health benefitbut results in a moderate additional cost.For example, Vijan et al. (69) showedthat, compared with a 2-year screening,annual screening among persons at mod-erate risk (65 years old with A1C level

9%) resulted in an increase of 2–3 days ofsight at a cost of $540–690 per person.However the ADA also stated in its recom-mendation that “less frequent exams (ev-ery 2–3 years) may be consideredfollowing one or more normal eyeexams.”

For the interventions with uncertainCE (including optimal age of startingscreening for type 2 diabetes), followingthe current treatment guidelines may bethe best option until more evidence ontheir CE is available.

The CEs of 43 ADA-recommendedinterventions were evaluated. Of these,25 were in the “strong” evidence category.This number would probably have beenlarger if we had used less stringent criteriato define evidence as being strong. Forexample, evidence on the CE of usingmetformin to prevent type 2 diabetesamong high-risk individuals was consid-ered “supportive” in our current classifi-cation even though the efficacy of theintervention was shown by well-conducted multi-center large clinical tri-als in different country settings (71,72),and its CE was evaluated by “excellent”CE studies (25,34). This intervention wasconsidered to have supportive evidencebecause it ranked lower in the ADA rec-ommendations (7).

Among all the interventions consid-ered, evidence for the CE of primary pre-vention through intensive lifestylemodification was the strongest regardingthe quantity and quality of the CE studiesand efficacy data. Several well-conductedclinical trials have shown the efficacy ofintensive lifestyle modification in pre-venting diabetes in different country set-tings, such as the U.S. DPP (71), FinnishDiabetes Prevention Study (73), China DaQing Diabetes Prevention Study (74), andIndian DPP (72). Eight cost-effectivenessstudies (seven of them rated as excellentquality) have been conducted by differentgroups in different countries based on datafrom these well-conducted clinical trials(15,25,34,36,41,50,59,66). The resultsfrom these studies consistently showed thatintensive lifestyle modification in personswith impaired glucose tolerance was costsaving or very cost-effective in the long run(15,25,34,36,41,50,59). Even in a short-term and one-on-one consulting setting,the intervention remained cost-effective(66). The intervention would be morecost-effective than existing studies show ifthe cost of the lifestyle intervention couldbe reduced. This might be achieved bychanging the setting in which the inter-



vention is provided. Only one studyfound a DPP-like intervention to be mar-ginally cost-effective (25). Even in thisstudy, however, the intervention wouldhave been very cost-effective (23) if donein the type of group environment that ismost likely in a real-world setting. Agroup-based, DPP-style lifestyle interven-tion partnership with the YMCA costs$275 to $325 per participant in the firstyear compared with $1,400 in the one-on-one setting of the DPP trial (75). Pre-venting diabetes, in particular by lifestylemodification, is not only effective but alsoa very efficient use of health careresources.

The CE of an intervention can vary bycountry setting. For example, intensiveglycemic control (with a goal A1C level of7%) in type 2 diabetic patients diagnosedat 25 years of age and older was margin-ally cost-effective in the U.S. but verycost-effective in other developed coun-tries. Although the efficacy data of allstudies of intensive glycemic control intype 2 diabetic patients were based on thesame UKPDS data, the cost data werebased on how residents of the differentcountries used health services and thecost of those services. The incrementalcost of intensive glycemic control wasmuch higher in the U.S. than in the U.K.because of different practice patterns. Pa-tients outside the U.S. did not receive di-abetes disease management services andhad less frequent self-testing and physi-cian office visits than their U.S. counter-parts at the time these studies wereconducted. If using the health services asdescribed in the UKPDS setting but withthe U.S. cost of these services, the CE ofthe intensive glycemic control in the U.S.would resemble that of other developedcountries.

Future economic evaluation of diabe-tes interventions should consider the fol-lowing. First, more studies are needed toevaluate the CE of interventions that fellin the “supportive” evidence category. Forstudies with weaker efficacy data, furtherefficacy studies are needed. Second, thereare also 38 interventions recommendedby the ADA but they have not been eval-uated for their CE or the studies did notmeet the inclusion criteria for our review(list is available upon request from theauthors). The CE of these interventionsshould be assessed. Third, more CE stud-ies are needed that address interventionsin real-world settings. For example, fewstudies considered attrition rate, non-compliance, and dropout rates in evaluat-

ing CE. Fourth, more studies are neededto evaluate the CE of public policychanges. Only two studies evaluated pub-lic insurance reimbursement of ACEItherapy and both found this interventionto be cost saving. Finally, the CE of mul-tiple interventions needs to be evaluated.In most real-world settings, patients re-ceive multiple interventions simulta-neously. Nearly all previous studies onlyevaluated the CE of a single intervention.

This review’s conclusions should beused with caution. First, our conclusionsare based on available information up toMay 2008. More studies have been pub-lished since then. In addition, data onboth the effectiveness and cost of an in-tervention could have changed since thetime the original study was conducted.Using the newly available data couldchange our current conclusion. For ex-ample, in our review, we concluded thatthe CE of optimal age to start screening fortype 2 diabetes was uncertain. A recentlypublished CE study on age at initiation ofscreening for type 2 diabetes, released af-ter our analysis was complete, mightchange that conclusion (76). Another ex-ample is the large decrease in costs formetformin, statins, and ACEIs. Studiesthat evaluate CE using current costs mightlook more favorably on interventions thatinclude statins and ACEIs than those re-ported here. Reevaluating the costs andbenefits of these interventions, using cur-rent-day costs, is beyond the scope of thisstudy. Second, when using the results andconclusions of our review, readers need tobe certain that terms are understood cor-rectly. For example, “intensive insulintreatment” in our review meant “multipleinsulin injection” or “insulin infusion.”Developments in medical technologymight make continuous glucose monitor-ing systems, which record blood glucoselevels throughout the day and night, morecommon. Drugs such as TZD Byetta andGliptin, not available at the time coveredby this review, are increasingly used toachieve intensive glycemic control. TheCE of treatment with these and other newdevices and drugs are unknown. New CEanalyses are needed for these new inter-ventions. Third, not everyone will neces-sarily agree with our classification criteria.Different classification criteria might havechanged some conclusions. Fourth, mostof the CE studies are based on simulationmodeling. Although good-quality simula-tion modeling can provide information ata much lower cost than clinical trials,models are based on assumptions and

represent a simplification of—and there-fore might depart from—reality. Fifth,these CE studies use different methods,which could account for some differencesin CERs. If the results from different mod-els were consistent, we would have moreconfidence in the conclusion on the CE ofthe intervention. Sixth, we used the samethreshold for the classification of the CEof interventions regardless of whether theICERs were expressed as dollars per LYGor dollars per QALY, although they aredifferent measures. The studies that re-ported costs per LYG did not incorporatethe impact of the intervention on qualityof life into the analysis. If they did, thecost per QALY could be higher, lower, orthe same depending on the relative mag-nitude of the health benefit of the inter-vention on quality of life. Seventh, theinterpretation of the CE of an interventionmust include consideration of variablessuch as study population, comparison in-terventions, and country setting. Lastly,our recommendations are based on theCE of the interventions and not their effi-cacy; therefore, these recommendations arenot necessarily the same as the ADA recom-mendations.

The importance of CE in decisionmaking should not be overstated. CE isonly one aspect to consider. CE analysisdoes not address the distribution of costsand the benefits of an intervention, soci-etal or personal willingness to pay, socialand legal aspects, or ethical issues associ-ated with each intervention. All these as-pects are important in formulating publicpolicy. The good news is that our studyshows that a majority of the recom-mended diabetes interventions provideboth health benefits and good use ofhealth care resources.

Acknowledgments— The authors con-ducted this project as part of their jobs as em-ployees of the Centers for Disease Control andPrevention (CDC). The CDC is a federalagency in the U.S. government. The authorshave no financial interest in this project.

Parts of this study were presented at the69th Scientific Sessions of the American Dia-betes Association, New Orleans, Louisiana,5–9 June 2009, and at the Division of DiabetesTranslation 2007 Annual Conference, Atlanta,Georgia, April 30–May 3, 2007.

We thank Drs. Sue Kirkman, Richard Khan,William H. Herman, John Anderson, SusanBraithwaite, Dan Lorber, and Vivian Fonsecafor reviewing the earlier version of this manu-script and providing valuable comments. Wealso thank Elizabeth Lee Greene for her invalu-able editorial assistance.

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