Long-Term Safety, Tolerability, andWeight Loss AssociatedWithMetforminin the Diabetes Prevention ProgramOutcomes StudyTHE DIABETES PREVENTION PROGRAMRESEARCH GROUP*

OBJECTIVEdMetformin produced weight loss and delayed or prevented diabetes in theDiabetes Prevention Program (DPP). We examined its long-term safety and tolerability alongwith weight loss, and change in waist circumference during the DPP and its long-term follow-up.

RESEARCH DESIGN AND METHODSdThe randomized double-blind clinical trial ofmetformin or placebo followed by a 7–8-year open-label extension and analysis of adverseevents, tolerability, and the effect of adherence on change in weight and waist circumference.

RESULTSdNo significant safety issues were identified. Gastrointestinal symptoms were morecommon in metformin than placebo participants and declined over time. During the DPP,average hemoglobin and hematocrit levels were slightly lower in the metformin group than inthe placebo group. Decreases in hemoglobin and hematocrit in the metformin group occurredduring the first year following randomization, with no further changes observed over time.During the DPP, metformin participants had reduced body weight and waist circumferencecompared with placebo (weight by 2.06 6 5.65% vs. 0.02 6 5.52%, P , 0.001, and waistcircumference by 2.13 6 7.06 cm vs. 0.79 6 6.54 cm, P , 0.001 in metformin vs. placebo,respectively). The magnitude of weight loss during the 2-year double-blind period was directlyrelated to adherence (P , 0.001). Throughout the unblinded follow-up, weight loss remainedsignificantly greater in the metformin group than in the placebo group (2.0 vs. 0.2%, P, 0.001),and this was related to the degree of continuing metformin adherence (P , 0.001).

CONCLUSIONSdMetformin used for diabetes prevention is safe and well tolerated. Weightloss is related to adherence to metformin and is durable for at least 10 years of treatment.

Diabetes Care 35:731–737, 2012

Metformin is an established treat-ment for diabetes with a goodsafety profile (1). Its most com-

mon side effects are gastrointestinal (1).These symptoms are generally transient,resolve spontaneously, and can often beavoided by gradual escalation of dosage.Metformin treatment has not been associ-ated with hypoglycemia unless used in

conjunction with other glucose-loweringmedicines (sulfonylureas or insulin). InU.S. clinical trials, about 4% of partici-pants were unable to continue metformindue to adverse effects. Serious adverseevents are infrequent and generally limitedto lactic acidosis, which occurs only inpersons with renal or hepatic insufficiencyor other contraindications. Metformin is

associated with weight loss when used totreat diabetes and thus differs from a num-ber of other antidiabetic medications thatare associated with weight stability or gain(2,3). To date, metformin is indicated onlyfordiabetesmanagement andnot forweightloss in individuals with or without diabetes.

In the Diabetes Prevention Program(DPP), metformin reduced the develop-ment of diabetes by 31% over an average of2.8 years of follow-up (4,5). The long-termfollow-up of the DPP, the DPP OutcomesStudy (DPPOS), included an open-labelextension of metformin treatment in thoserandomly assigned to metformin in theDPP. After a median of 10 years of follow-up since DPP randomization, both the life-style and metformin intervention groupshad significantly less diabetes than theplacebo group (6). During the DPP, par-ticipants randomized to metformin expe-rienced an average 2.1-kg weight loss (4).Weight loss was a strong predictor of dia-betes prevention in both themetformin andplacebo groupswithweight loss accountingfor 64% of the metformin versus placeboeffect on diabetes prevention (7). Weightloss in the metformin group was main-tained throughout the combined DPP andDPPOS periodwithmetformin participantshaving an average 2.5-kg weight loss overtime (6). This report updates these findingsby documenting the long-term safety andtolerability of metformin, and in a post hocanalysis, it tests the hypothesis that greateradherence to metformin is associated withgreater weight loss and reduction in waistcircumference in participants randomly as-signed to metformin compared with thoserandomly assigned to placebo.

RESEARCH DESIGN ANDMETHODSdBetween 1996 and 1999,3,234 participants from 27 clinics in theU.S. were enrolled in the DPP; the 2,155randomly assigned to the metformin(1,073) or placebo (1,082) arms are in-cluded in this analysis (8). Participantswere $25 years of age, had a BMI $24kg/m2 ($22 kg/m2 in Asian Americans),elevated fasting glucose (95–125 mg/dL),

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

Corresponding author: Diabetes Prevention Program Coordinating Center, dppmail@bsc.gwu.edu.Received 8 July 2011 and accepted 20 December 2011.DOI: 10.2337/dc11-1299. Clinical trial reg. nos. NCT00004992 (DPP) and NCT00038727 (DPPOS),

clinicaltrials.gov.This article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10

.2337/dc11-1299/-/DC1.A slide set summarizing this article is available online.*A complete list of the members of the Diabetes Prevention Program Research Group, centers, and staff can be

found in the Supplementary Data online, and members of the writing group are listed in the APPENDIX.The opinions expressed are those of the investigators and do not necessarily reflect the views of the funding

agencies.© 2012 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 thework is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

See accompanying articles, pp. 663, 717, and 723.

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E p i d e m i o l o g y / H e a l t h S e r v i c e s R e s e a r c hO R I G I N A L A R T I C L E

and impaired glucose tolerance (140–199mg/dL) 2 h after a 75-g oral glucose load.Participants were excluded for a prior di-agnosis of diabetes or conditions or med-ications that would impair their ability toparticipate or affect weight loss. All partici-pants gave written informed consent as ap-proved by each institutional review board.

Metformin or matching placebo wasinitiated at 850-mg once per day andincreased by 1 month to 850-mg twicedaily unless gastrointestinal symptomswarranted a longer titration period. Stan-dard lifestyle recommendations andwritten information on healthy eating,healthy weight, and physical activity wereprovided annually (4). Case managerspromoted adherence to the DPP studymedications using a brief structured in-terview and a standard problem-solvingapproach.

The first phase of the DPP was com-pleted in 2001 after an average of 3.2years of follow-up on the advice of theData and Safety Monitoring Board due tothe effectiveness of the lifestyle and met-formin interventions in preventing di-abetes (4). After the DPP results wereannounced, participants underwent a 1- to2-week study/drug washout period fol-lowed by a repeat glucose tolerance test(9). Subsequently, they were unblindedand offered a 6-month, 16-session, group-implemented program with content identi-cal to the original DPP lifestyle intervention(10). All DPP participants, regardless ofwhether diabetes had developed, were en-couraged to join the DPPOS, and 88% did(6). Participants followed their originaltreatment assignments, and all were offeredquarterly group lifestyle classes. Placebotreatment was terminated. Participantsinitially assigned to metformin continuedtaking study-provided open-label metfor-min unless there were contraindications,or fasting plasma glucose was$140mg/dLin the DPP, or HbA1c was$7% during theDPPOS, which required management out-side of the protocol.

A summary of data collection duringthe DPP and the DPPOS can be found inSupplementary Appendix Table 1. Ad-verse events were ascertained as follows:1) During the DPP but not the DPPOS, allstudy participants were queried everyquarter by asking “During the intervalsince the last visit, has the participanthad any new symptoms, injuries, illnessor side effects, or worsening of pre-existingconditions?” Responses were coded usingthe U.S. Food and Drug Administration’s(FDA) COSTART (Coding Symbols for

a Thesaurus of Adverse Reaction Terms)coding system. Possible hypoglycemicevents were identified by searchingfor “HYPOGLY,” “CONSCIOUS,” and“COMA,” and for possible anemia as“ANEMIA” or “B12.” Serious adverseevents (SAEs) were handled as definedby the FDA. 2) Gastrointestinal symptomswere identified annually throughout theDPP and the DPPOS by asking partici-pants about any stomach pain, bloating,nausea, diarrhea, or loss of appetite. 3)Gastrointestinal symptoms attributed tostudy medication were ascertained duringthe DPP and for those participants activelytaking metformin during the DPPOS.

Weight was measured twice yearlyand waist circumference annually (4,8).Hemoglobin and hematocrit were mea-sured annually in each clinic’s laboratoryon all participants randomized to medica-tion during the DPP and for participantsactively taking metformin during theDPPOS. Low hematocrit was defined as,40% in men and ,36% in womenand low hemoglobin as ,13 mg/dL inmen and ,12 mg/dL in women.

Statistical analysisAnalyses are presented in two parts: 1) thefirst 2 years of the double-blind random-ized placebo-controlled trial and 2) thecomplete follow-up period since random-ization, including the open-label phase,lasting an additional 7–8 years (until 27August 2008, the closing date for thisanalysis). Two years was selected becauseall participants completed two full yearsin the double-blind period in the DPP andfor comparability with many other drugtrials for weight loss. We also show theresults at 9 years, theminimum combinedDPP + DPPOS follow-up time. We exam-ine the weight and waist circumferencechanges stratified by level of adherenceto placebo and metformin during the2-year blinded phase and to metforminthroughout both phases.

Adherence tometformin was assessedat all regularly scheduled clinic visits andrecorded as $80% (adherent) or ,80%(nonadherent) of assigned pills taken,based on pill counts. Four categories oflong-term adherence were defined (Table1). Participants were censored from themetformin adherence grouping whenstudy-supplied metformin was discontin-ued due to uncontrolled hyperglycemia,and diabetes drug treatment was managedoutside the protocol. All participants, otherthan those censored, were included in theadherence measures regardless of reasons

for low adherence (e.g., safety or standardcontraindications) to explore fully the ex-posure to metformin and weight loss.

For the assessment of long-term met-formin safety and tolerability, all visitsafter the diagnosis of diabetes were ex-cluded in order to avoid confounding bydiabetes treatment (e.g., by use of non-study drugs).

Fixed-effects models with the as-sumption of normally distributed errorswere used to compute repeated-measuresadjusted means in body weight and waistcircumference among the adherence cat-egories and treatment groups. Models wereadjusted for baseline weight and waistcircumference (11). Generalized estimatingequations were used to assess symptomsand adverse events over time by treatmentgroup (11).

RESULTS

DPPdresults from the double-blindphaseCharacteristics of the DPP participantshave been reported (4). The proportion ofparticipants taking $80% of the pre-scribed dose over time during the DPPwere lower in the metformin (71%) thanin the placebo group (77%) (P , 0.001).

Medication adherence varied by race/ethnicity with African American partici-pants having the lowest adherence duringboth the DPP (metformin and placebo)and the full follow-up period (metforminonly) (Table 1). Men were more adherentto metformin during the DPP but not overthe total follow-up period. No differenceswere observed among placebo partici-pants. At the end of year 1, weight lossin the metformin group was 2.7 6 4.7%(mean 6 SD) compared with a loss of0.43 6 4.7% in the placebo group (P ,0.001). After 2 years, weight loss was2.16 5.7% in the metformin group com-pared with 0.02 6 5.5% (P , 0.001) inthe placebo group. Waist circumferencewas reduced at year 1 in the metformingroup by 2.26 6.2 cm vs. 0.716 5.6 cmin the placebo group (P, 0.001) and at 2years by 2.1 6 7.1 cm in the metformingroup vs. 0.79 6 6.5 cm in the placebogroup (P, 0.001 for both time periods).At year 1, 29% in the metformin grouphad lost$5% of their initial body weight,comparedwith 13% of the placebo group,and at 2 years, 26% of the metformin and14% of the placebo group had lost $5%of baseline body weight (P , 0.001 forboth time periods). The percentage losing$10% of their body weight at 1 year was

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8% for the metformin versus 4% for theplacebo group and at 2 years was 10% forthe metformin and 5% for the placebogroup (P, 0.001 for both time periods).

Figure 1 shows changes in bodyweight and waist circumference in eachtreatment group according to pill-takingadherence during the 2-year double-blindphase. Seventy-two percent of themetfor-min group and 74% of the placebo groupwere in the $50% adherent or highly ad-herent categories (Table 1), although fewerplacebo participants were highly adherent.Adherence was strongly associated withweight loss in the metformin-treated group.The durability of weight loss was also af-fected by adherence. Average weight ofhighly adherent participants was 3.5 60.35% below baseline at 2 years, very closeto their 1-year weight loss. Those with lowadherence had returned to baseline weightby year 2 (Fig. 1A) (P , 0.001). Placeboparticipants in all adherence subgroupsremainedwithin 1%of their baselineweight,

on average, over the 2 years (Table 1),except for the 7% who were highly adher-ent with placebo, who had a small weightgain of 1.2% (P , 0.05 for the highly ad-herent compared with the.50% adherentgroup; all other P values.0.05). The asso-ciations of adherence to medication withchanges in waist circumference were notstatistically significant for either themetfor-min or placebo groups. (Fig. 1C and D).

Results including DPPOSdopen-label treatmentDuring the total follow-up period, 62% ofthe metformin participants were in the$50% or highly adherent categoriescompared with 72% in the 2-year double-blind phase (Table 1). Placebo was discon-tinued when the open-label phase beganand adherence could not be assigned.

Among placebo participants, bodyweight was relatively stable but waist cir-cumference increased after the fourth year,continuing throughout the entire open-label

follow-up (Fig. 2). Over the total follow-up, average weight loss from baseline inthe metformin treatment group, inde-pendent of adherence, was 2.0% (1.9 kg).Among those highly adherent to metfor-min, weight loss from baseline was 3.5%(3.1 kg). Among those with partial adher-ence to metformin, weight loss was inter-mediate between the highly adherentgroup and those on placebo. In the lowadherence group, weight initially fell,followed by weight change similar tothe placebo participants until 5 years, fol-lowed by weight increase. The percent ofmetformin participants who lost at least5% was positively associated with metfor-min adherence (Table 1).Waist circumfer-ence remained significantly lower thanat baseline in the highly adherent group(P, 0.05) through the 7-year visit, whereasin the partially adherent groups it waslower up to the 4-year visit, and in thelow-adherence group only through 2 years.Although weight and waist changes over

Table 1dDistribution of adherence to metformin and placebo overall and by race/ethnicity and sex during the DPP (2 years) andfor the DPP + DPPOS combined (9 years), and percent of the DPP/DPPOS participants achieving greater than 5% weight lossduring each time period

Adherence through DPP 2-yeardouble-blind phase

Adherence throughDPP + DPPOS combination

Lowadherence

,50%adherent

.50%adherent

Highlyadherent P

Lowadherence

,50%adherent

.50%adherent

Highlyadherent P

Total sample distribution* Metformin 12.3 15.8 45.5 26.5 d 11.7 26.6 37.0 24.7 dPlacebo 11.7 13.9 67.5 6.9 d d

Race/ethnicityCaucasian Metformin 11.8 14.5 44.0 29.7 0.029 11.0 25.2 35.5 28.2 0.011

Placebo 10.6 9.6 72.0 7.8 ,0.001 dAfrican American Metformin 15.4 16.7 50.7 17.2 15.4 30.8 38.9 14.9

Placebo 15.5 20.0 58.6 5.9Hispanic Metformin 11.7 16.7 43.2 28.4 11.1 21.6 42.0 25.3

Placebo 12.5 16.7 64.3 6.5Asian Metformin 16.7 11.1 47.2 25.0 16.7 30.6 27.8 25.0

Placebo 12.2 14.3 65.3 8.2Native American Metformin 3.8 26.9 46.2 23.1 3.8 36.5 36.5 23.1

Placebo 6.8 25.4 66.1 1.7SexMale Metformin 11.3 11.6 45.7 31.4 0.009 10.5 24.8 37.2 27.5 n.s.

Placebo 9.9 14.3 68.7 7.2 n.s. dFemale Metformin 12.8 17.9 45.4 23.9 12.4 27.5 36.9 23.2

Placebo 12.6 13.7 66.9 6.8Percent at .5% weightloss at 2 or 9 years** Metformin 13.3 19.6 27.9 33.2 ,0.001 23.1 27.1 32.2 48.1 ,0.001

Placebo 14.6 15.2 14.7 6.5 n.s. 27.0

Data are percent. Long-term adherence was computed for 2 years and for the DPP + DPPOS combined and defined as follows: adherent, had taken at least 80% of theirprescribed pills since the previous visit; low adherence, participants who may have taken some medication but never reported taking $80% of their pills; ,50%adherent, participants who were adherent at.0% but,50% of their visits;.50% adherent, participants who were adherent at$50% but,90% of their visits; andhighly adherent, participants whowere adherent at$90% of their visits. n.s., not significant. *Percent distribution among all randomized participants through 2 yearsof the DPP or throughout the DPP + DPPOS follow-up. **Percent at .5% weight loss at 2 years for the DPP and 9 years for the DPP + DPPOS. The 9-year resultsinclude the 790 metformin participants by adherence category and the combined 783 placebo participants who had a year 9 visit out of the 924 metformin and 932placebo participants who joined the DPPOS.

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time varied by race/ethnicity and sex, therewas no interaction between level of ad-herence and either race/ethnicity or sexindicating that the effect of metforminadherence on weight loss was consistentacross race/ethnic groups and in men andwomen.

Safety and tolerabilityDuring the DPP (through year 4), reportsof gastrointestinal symptoms were morecommon amongmetformin comparedwithplacebo participants (average 28% vs. 16%,P = 0.01) (Fig. 3A). Metformin participantsself-reported “study medication-related”gastrointestinal symptoms more frequentlythan placebo participants (9.5% vs. 1.1%,P , 0.001) (Fig. 3A). Both types of gas-trointestinal symptom reports declinedthroughout the DPP. Rates of gastrointes-tinal symptoms were similar betweengroups by years 6 through 9 (P . 0.10).These results persisted after excluding allvisits for participants who had low adher-ence to the study medication. Although re-ported symptoms varied by race/ethnicityand sex, changes in symptoms over timewere similar by demographic group (datanot shown).

No unexpected adverse events or treat-ment group differences in adverse eventswere identified, either by the study’s Dataand Safety Monitoring Board or in thisanalysis. Adverse events during the DPP

were previously reported (4). The rateof gastrointestinal symptoms was higherin the metformin group. Nonseriousadverse events for hypoglycemia andanemia during the DPP were also un-common and similar in metformin andplacebo participants, with seven metfor-min participants and eight placebo partic-ipants ever reporting hypoglycemia, andfifty metformin participants and thirty-eight placebo participants ever reportinganemia. SAEs potentially related to studymedication were rare. There were threeSAE reports for anemia (two metforminand one placebo participant), and therewere none for lactic acidosis or hypogly-cemia during nearly 18,000 patient-yearsof follow-up.

During the DPP, average hemoglobinand hematocrit levels were the same atbaseline and over time were slightly lowerin the metformin group than in the pla-cebo group (hemoglobin: 13.6 vs. 13.8mg/dL; hematocrit: 40.6 vs. 41.1%; P ,0.001 for both). Hemoglobin and hemat-ocrit levels varied by race/ethnicity andsex; however, changes over time were sim-ilar by demographic group (data notshown). The percent of participants withlow hemoglobin was not significantly dif-ferent between metformin and placeboparticipants (11.2 vs. 7.6%, P = 0.17)whereas the percent of participants withlow hematocrit was higher in metformin

than placebo participants (12.6 vs. 8.4%,P = 0.035). Among metformin partici-pants, changes in hemoglobin and he-matocrit occurred during the first yearfollowing randomization with no furtherchanges observed over time.

CONCLUSIONSdWe report the lon-gest follow-up to date of metformin onbody weight changes and on safety andtolerability. Metformin used in over-weight or obese individuals with elevatedfasting glucose and impaired glucose tol-erance was associated with modest butdurable weight loss and was safe and welltolerated over many years.

On an intent-to-treat basis, metforminproduced a significant weight loss thatpersisted during the 2-year double-blindtreatment period and for the entire durationof follow-up. Long-term follow-up wasexcellent at 92%, in contrast with otherweight loss drug trials (12). Effects of met-formin onweight have been reported in sev-eral trials in diabetes (2,3,13,14,15), one inobese adolescents (16), and in a recentmeta-analysis (17). One report included changesinwaist-to-hip circumference ratio, andonlythree provided data for more than 1 year offollow-up. In a meta-analysis of metforminandweight loss, weight change at 1 year was21.52 kg (95% CI 22.82 to 20.21) (17).The mean weight change at 1 year in our

Figure 1dEffect of adherence to metformin or placebo on percent weight change (A and B) andchange inwaist circumference (C andD) during 2 years of treatment during the double-blind phase ofthe DPP.

Figure 2dChange in weight (A) and changein waist circumference (B) throughout the DPPand the DPPOS by placebo and adherence tometformin.

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study was22.7 kg in the metformin groupand20.4 kg in the placebo group.

Adherence to metformin improved themagnitude of weight lossdbut not waistcircumferencedduring the first 2 years.Adherence to placebo did not affect weightloss, suggesting thatmetformin, rather thannonspecific adherence to positive healthbehaviors, was the relevant factor.

Waist circumference increased in allgroups after year 2, except for the highlyadherent participants where the increasebegan after 5 years and waist circumfer-ence remained lower than baseline. Sincebody weight did not increase, this sug-gests that central adiposity increased byredistribution of body fat.

Metformin participants in the lowadherence group lost weight but placeboparticipants with low adherence did not.Many of those in the low adherence met-formin group took some metformin but

not enough to be labeled “adherent.” Inaddition, those with low adherence inthe placebo group may have personalitytraits related to accepting advice, abilityto change habits, etc., whereas low adher-ence in the metformin group may also berelated to gastro-intestinal side effects.Therefore, one would not expect thosewith low adherence in the two groups tohave the same characteristics.

Metformin lowers glucose and re-duces risk for diabetes in part throughweight loss (2,7,16,17). Although basalenergy metabolism is highly correlatedwith body mass, early studies showedthat despite appreciable reductions inbody weight with metformin treatment,basal energy expenditure remains un-changed (18). This is because metformin-induced weight loss is almost exclusivelyconfined to reductions in adipose mass(2,16,18) with little change in lean tissue.

This pattern is different from that seenwith caloric restriction, which tends to in-duce loss of lean tissue as well as adiposetissue. Metformin has several effects on en-ergymetabolism that parallel physical exer-cise. Both exercise andmetformin stimulatephosphorylation of AMP-activated proteinkinase (AMPK) (19). AMPK is an importantregulator of mitochondrial biogenesis (20),hepatic and muscle fatty acid oxidation,glucose transport, insulin secretion, and li-pogenesis (21). Whether metformin di-rectly affects energy expenditure fromphysical activity is unknown. Metforminmight also influence weight loss throughreduced food intake owing to irritation ofthe gastrointestinal tract, which maymotivate a reduction in food intake orchange in nutritional preference.

Adherence to metformin was high. Inthe double-blind phase of the trial, 72%were highly adherent, and throughout theentire trial, 62% of the metformin groupwas highly adherent.

No significant safety issues were iden-tified. Both hemoglobin and hematocritdeclined slightly in the metformin groupover the first year after randomization andstabilized after that. Metformin participantsreported more gastrointestinal symptomsthan placebo participants, however theseabated over time and both types of gastro-intestinal symptom reports were similarbetween groups by the latter years of theDPPOS.

One potential bias is that 12% of DPPparticipants chose not to continue intothe DPPOS. It is likely that some of thosewho discontinued the study or who con-tinued but chose not to take open-labelmetformin did so because of side effects,which may have influenced the safety andtolerability profile of metformin duringthe open-label DPPOS period.

In summary, metformin produces ahighly significant reduction in body weightand waist circumference with minimalsafety issues and limited issues of tolerabil-ity (22). The weight reduction persists forup to 10 years and is related to adherence tometformin. Waist circumference initiallydeclines, then steadily increases after a na-dir at 12–36months in all groups except inthe highly adherent group, in which thisincreasewas delayed for 5 years.Metforminwas well tolerated with few side effects.

AcknowledgmentsdThe National Instituteof Diabetes and Digestive and Kidney Diseases(NIDDK) of the National Institutes of Healthprovided funding to the clinical centers and

Figure 3dSelf-reported gastrointestinal (GI) problems (A) and gastrointestinal symptoms at-tributed to study medication (B) through the DPP and the DPPOS.

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DPP Research Group

the DPP Coordinating Center for the designand conduct of the study, and collection,management, analysis, and interpretation ofthe data. The Southwestern American IndianCenters were supported directly by the NIDDK,including its Intramural Research Program, andthe Indian Health Service. The General ClinicalResearch Center Program, National Center forResearch Resources, supported data collectionatmany of the clinical centers. Funding was alsoprovided by the National Institute of ChildHealth and Human Development; the NationalInstitute on Aging; the National Eye Institute;the National Heart, Lung, and Blood Institute;the Office of Research onWomen’s Health; theNational Institute on Minority Health andHealth Disparities; the Centers for DiseaseControl and Prevention; and the AmericanDiabetes Association.Bristol-Myers Squibb and Parke-Davis pro-

vided additional funding and material supportduring the DPP. Lipha (Merck-Sante) pro-vided medication, and LifeScan Inc. donatedmaterials during the DPP and the DPPOS.P.W.F. was supported in part by grants fromNovo Nordisk, the Swedish Heart-LungFoundation, the Swedish Diabetes Association,and the Swedish Research Council. No otherpotential conflicts of interest relevant to thisarticle were reported.The full research group designed and un-

dertook the study. G.A.B. researched data,participated in the reviewing and modifying ofdata analyses, drafted the first draft, wrote themanuscript, reviewed and edited the manu-script, and is the guarantor of the manuscriptand, as such, had full access to all the data inthe study and takes responsibitility for theintegrity of the data and the accuracy of thedata analysis. S.L.E. researched data, partici-pated in the reviewing and modifying of dataanalyses, performed all statistical analyses,wrote the manuscript, and reviewed and edi-ted the manuscript. J.P.C. researched data,participated in the reviewing and modifying ofdata analyses, wrote the manuscript, and re-viewed and edited the manuscript. V.R.A.participated in the reviewing and modifying ofdata analyses and reviewed and edited themanuscript. P.W.F. participated in the re-viewing and modifying of data analyses, wrotethe manuscript, and reviewed and edited themanuscript. W.F. participated in the review-ing and modifying of data analyses andreviewed and edited the manuscript. E.H. re-searched data, participated in the reviewingand modifying of data analyses, and reviewedand edited the manuscript. S.J. participated inthe reviewing and modifying of data analysesand reviewed and edited the manuscript.M.M. participated in the reviewing and mod-ifying of data analyses and reviewed andedited the manuscript. S.M. participated in thereviewing and modifying of data analyses andreviewed and edited the manuscript. F.X.P.-S.researcheddata, participated in the reviewing andmodifying of data analyses, and reviewed andedited the manuscript. N.H.W. researched

data, participated in the reviewing andmodifying of data analyses, wrote the man-uscript, and reviewed and edited the manu-script. W.C.K. researched data, participatedin the reviewing and modifying of dataanalyses, wrote the manuscript, and reviewedand edited the manuscript.The research group gratefully acknowledges

the commitment and dedication of the par-ticipants of the DPP and the DPPOS.

APPENDIXdMembers of the writinggroup are George A. Bray, MD1; Sharon L.Edelstein, ScM2; Jill P. Crandall, MD3;Vanita R. Aroda, MD4; Paul W. Franks,MD5,6; Wilfred Fujimoto, MD7; EdwardHorton, MD8; Susan Jeffries, BSN, MSN9;Maria Montez, RN, MSHP, CDE, CCRA10;SunderMudaliar,MD11; F. Xavier Pi-Sunyer,MD12; Neil H. White, MD13; and WilliamC. Knowler, MD, DrPH14.

From the 1Pennington BiomedicalResearch Center, Baton Rouge, Louisiana;2The George Washington University Bio-statistics Center, Rockville, Maryland; the3Albert Einstein College of Medicine,Bronx, New York; the 4Medstar HealthResearch Institute, Hyattsville, Maryland;the 5Lund University Diabetes Center,Skåne University Hosptial, Malmö, Sweden;the 6Harvard School of Public Health,Boston, Massachusetts; the 7Universityof Washington, Seattle, Washington; the8Joslin Diabetes Center, Boston, Massachu-setts; the 9University of Pittsburgh, Pitts-burgh, Pennsylvania; the 10University ofTexas Health Sciences Center at SanAntonio, San Antonio, Texas; the 11Uni-versity of California, San Diego, San Diego,California; the 12St. Luke’s-RooseveltHospital Center, New York, New York; the13Washington University School of Medi-cine, St. Louis, Missouri; and the14NationalInstitute of Diabetes and Digestive andKidney Diseases, Phoenix, Arizona.

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