Reviews/C

o m me

n ta

ries

/ Pos

itio

State

m e nts

The Diabetes
Design
THE DIABETES

Prevention
for a clinical
RESEARCH GROUP

Program
of type 2 diabetes
with metformin is diagnosed or glucose 1997 (ADA) criteria to the or placebo) by fasting tolerance American (1). or delaying Diabetes (FPG) the development tions combined in preventing of diabetes. plasma testing Diabetes glucose according Association

and methods
PREVENTION PROGRAM

trial in the prevention

The Diabetes Prevention Program is a randomized clinical trial testing strategies to prevent or delay the development of type 2 diabetes in high-risk individuals with elevated fasting plasma glucose concentrations and impaired glucose tolerance. The 27 clinical centers in the u.s. are recruiting at least 3,000 participants of both sexes, ~50% of whom are minority patients and 20% of whom are >65 years old, to be assigned at random to one of three intervention groups: an intensive lifestyle intervention focusing on a healthy diet and exercise and two masked medication treatment groups~metformin or placebo-combined with standard diet and exercise recommendations. Participants are being recruited during a 2 2I3~year period, and all will be followed for an additional 3 1/3 to 5 years after the close of recruitment to a common closing date in 2002. The primary outcome is the development of diabetes, diagnosed by fasting or post-challenge plasma glucose concentrations meeting the 1997 American Diabetes Association criteria. The 3,000 participants will provide 90% power to detect a 33% reduction in an expected diabetes incidence rate of at least 6.5% per year in the placebo group. Secondary outcomes include cardiovascular disease and its risk factors; changes in glycemia, j3-cell function, insulin sensitivity, obesity, diet, physical activity, and health-related quality of life; and occurrence of adverse events. A fourth treatment group~troglitazone combined with standard diet and exercise recommendations-was included initially but discontinued because of the liver toxicity of the drug. This randomized clinical trial will test the possibility of preventing or delaying the onset of type 2 diabetes in individuals at high risk. Diabetes Care 22:623-634,1999

Secondary Secondary differences groups glycemia, ity, obesity, lar disease research between and j3-cell its risk function, activity, goals the include three assessing treatment changes sensitivintake, in

in the development

of cardiovascufactors; insulin nutrient

physical

and health-related quality of life; occurrence of adverse events.

and

Subgroup research goals Other research goals include assessing the consistency of the effects of the interventions by baseline demographic, clinical, biochemical, and psychosocial attributes.

STUDY
Eligibility

DESIGN criteria
is for at least -20% approximately the Asian and following American, exclusion half of to be half ethnic Hispanic, and criteria 1. to group old, to be women, and of

ype

2 diabetes affecting

is a common an estimated

chronic 12% of

People (IGT), an normoglycemia by an oral The was of Diabetes

with

impaired

glucose category (1,3), test Program several type

tolerance between defined (OGTT) diabetes. (DPP) stratein

An aim of recruitment the study >65 be years composed Indian, Islander. inclusion trial are based

T
renal,

disease

intermediate glucose

40- to 74-year-old (1). It is a major cause ity and morbidity ophthalmic, treatment hyperglycemia, and disease present type or maintained. and

people in the U.S. of premature mortalto cardiovascular, neurologic diseases. can 2 diabetes

and diabetes tolerance

due

are at increased developed with

risk of developing Prevention to compare or delay IGT.

minorities: American Pacific The for They ing the were

African-American,

Although improve glycemia achieved vascular already policy tion more developing and

of type

normalization Furthermore, at high than

gies to prevent individuals

2 diabetes

glycohemoglobin and its risk factors in individuals 2 diabetes rather

is rarely macroare often risk of a be

summarized on the goals individuals with risk with

in Table of 1) recruitwith conditions shorten conduct

RESEARCH Primary
The primary efficacy

GOALS

nondiabetic

a high and 2) that effects life of

risk of progression excluding individuals increase the might from the dent

to type 2 diabetes of adverse severely the the assessment criterion Eligible diagnosis pregnancy), 1985 criteria, (7.0 glucose

(2). Therefore, early detecmight

of prevention treatment effective

research and (an

goal is a comparison safety of each lifestyle of three inter-

of diabetes complications.

of the vention

the interventions, interfere or affect 2 diabetes. main 75-g no entry prior trial, type The

in preventing

microvascular

interventions

intensive lifestyle

expectancy,

and macrovascular

or standard

recommenda-

for inci-

is IGT based individuals of diabetes be nondiaWorld Health and mg/dl 2-h (7.8 and have IGT:

on a single
A complete affiliations Address Washington Received list of the members of the Diabetes Prevention can be found in APPENDIX 2. correspondence and reprint requests to Reprint University, Biostatistics Center, 6110 Executive for publication 17 September 1998 Program Research Group and their professional The George

OGTT.

must (other betic FPG

have than

Requests, DPP Coordinating Center, Blvd., #750, Rockville, MD 20852. in revised form 30 November

during (WHO) mg/dl plasma

by 1997 <126

ADA and

and accepted

1998.

Organization post-load

Abbreviations: plasma glucose; Kidney Diseases;

ADA, American Diabetes Association; DPP, Diabetes Prevention Program; FPG, fasting IGT, impaired glucose tolerance; NlDDK, National Institute of Diabetes and Digestive and OGTT, oral glucose tolerance test; WHO, World Health Organization. shows conventional and systeme International (SO units and conversion

mmol/l) >140

A table elsewhere in this issue factors for many substances.

mmol/l) and <200 mg/dl (1,3). In addition, to include

(11.1 mmol/l) individuals at

DIABETES CARE, VOLUME 22, NUMBER 4, APRIL 1999

623

Diabetes

Prevention

Program

Table I~Inclusion

and exclusion

criteria

particularly must lower

high

risk mg/dl. limit only

of diabetes, However, American for FPG

the FPG there is no Indians high risk of (4). of the 1997. for postand DPP in the criteria crithe (1). years, years to 2 diaof is but <140 in of diais directed >35 an FPG 2-h mg/dl

be 95~125 eligibility enrolling they have

in the clinical

Inclusion Age >25 BMI >24 Elevated Exclusion Diabetes at baseline mg/dl* >200 mg/dl based on 75-g OGTT by a physician and confirmed by other medication, other than and/or disease Class> during increase clinical data, other than FPG >126 years kg/m2 (>22 glucose kg/m2 among 140~199 mg/dl*), Asian Americans) mg/dl except based on 75-g OGTT) Indian centers in the American

centers because

an unusually before criteria criteria mmol/l) An

type 2 diabetes new The <140 load <200 mg/dl. would

even at lower levels ofFPG the release in June required and 140 additional enrolled for IGT

IGT (2-h plasma

The DPP began ADA diagnostic 1985 WHO (7.8 (3). 7% been ofFPG

FPG (95~125

used

DPP eligibility mg/dl plasma mg/dl Only have These their

at that time glucose;::

2-h plasma glucose Diabetes diagnosed during Ever used Medical pregnancy antidiabetic

requirement pregnancy risk of intervention likely to limit life span of heart Functional or third degree DPP before teria because mg/dl. DPP, but betes pressure> treatment 180 mmHg > 1.4 mg/dl or diastolic unless or >1.3 in women) elevation) bowel disease) inflammatory blood pressure> 105 mmHg is considered or urine good the betes Indians gestational >24 or daily use of bronchodilators and of the trial BMI by randomization project that might except interfere with DPP weight loss for any reason postpartum Asian kg/m2 may in the past 5 years, for men, the prognosis mg/dl

was for the FPG to be 100-139 of those ineligible >126 this change in eligibility mg/dl assessment

conditions

Cardiovascular Hospitalization

disease for treatment Association block branch in past 6 months 2

by the new remain

New York Heart Left bundle Aortic Systolic Cancer protein Anemia Hepatitis Other Recent Chronic Conditions Unable Unwilling Participation Weight Unable Pregnancy Currently Currently Pregnancy Unwilling Unwilling Major Excessive Medications Thiazide j3-Blockers, Niacin, Selective Other Thyroid hormone Other Fasting endocrine plasma stenosis blood requiring >2 + )| (hematocrit (based gastrointestinal or significant disease infection

participants outcome with most

AV block

will be done Although

the new criteria aged risk

recruitment was set at >25 such with

at overweight age criterion groups in early include

individuals at high adulthood, women

Renal disease

(creatinine <36%

for women,

for type

in men or <33% or serum (pancreatitis, surgery

as American a history with

on history disease

transaminase

and young diabetes because

(4). The BMI criterion individuals risk for type candidates at >22 of their were effects disease lower 2 diabetes

abdominal

Pulmonary

with dependence (e.g., HIV, active with clinic intervention

on oxygen tuberculosis) staff research

BMIs are at a lower weight-loss criterion Americans Most reduce significant exclusion goals

not be suitable was set

for the The for risk to to in the with failure risk Also as kg/m2 high chosen related

or behaviors to communicate to accept in another

likely to affect conduct treatment assignment

of the interventions. because criteria Individuals heart stenosis,

of diabetes

at this range

of BMIs (5).

loss of > 10% in past 6 months to walk 0.25 pregnant nursing anticipated to undergo disorder intake, either conditions acute miles in 10 min or within or within during pregnancy 3 months 6 weeks and childbearing

the risk of adverse ischemic are lifestyle physical

the interventions. postpartum of having completed possible nursing pregnancy promptly of the trial or report measures, if potentially fertile Table intensive increased are excluded the assessment for diabetes excluded well for lowering inhibitors treated serum triglycerides indicated for weight serum reduction thyroid-stimulating. during during 1), aortic

with clinically (defined because Individuals heart increased (6,7). women, pregnancy because to be safe are (8), Because indion a and drugs or uncontrolled requires

the course testing contraceptive

hypertension

excluded intervention activity. or congestive of their metformin or nursing anticipate been shown and with IGT Such meet

to take adequate alcohol

psychiatric

renal insufficiency or chronic of lactic acidosis as women the course not pregnancy used often agents using basis may

because with who

and medical diuretics systemic in doses serotonin disease,

likely to confound

are pregnant

indicated systemic re-uptake

of the program, or nursing.

Glucocorticoids, prescription

met form in has in doses as indicated Thiazide by abnormal commonly which these viduals daily other

weight-loss suboptimally disorders triglyceride

medications

diuretics to treat cause coexists thiazides if they criteria

j3-blockers IGT.

hypertension (9~13),

(e.g., Cushing's >600 mg/dl,

syndrome, despite

acromegaly)

treatment

or j3-blockers glycemic

are ineligible.

individuals treatment

*WHO criteria (3) were used to exclude diabetes (FPG > 140 mg/dl or 2-h plasma glucose >200 mg/dl) until June 1997, and the FPG inclusion range was 100~139 mg/dl. |Since March 1998, a creatinine clearance of >75 ml/min, based on a 24-h urine collection, was required for eligibility for potential volunteers who were or would become >80 years of age during the study.

may be included eligibility is changed

after their

to other

antihypertensive

624

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

The Diabetes

Prevention

Program

Research

Group

Table

2~Staged

screening

process

for determination

of eligibility

is allowed domization

from

the

OGTT
4.

in step

2 to ran-

at step

Step 1 2

Assessment

Comments questionnaire measurement Initial Fasting Definitive medication assessment or casual, use pressure mg/dl and creatinine, count, for eligibility by telephone history,

Outcomes Primary by the plasma Although selected of type individuals in the early diabetes betes individuals outcome every 75-g ever or dysrhythmia Diabetes 6 months OGTT. symptoms (14) outcome. 1997 ADA the to identify 2 diabetes, recruited stages or other at entry. is defined and FPG The criteria during eligibility individuals a small into primary outcome of diabetes for FPG an OGTT criteria at high proportion may of type forms of diaall such or 2-h (1). were risk of be 1 of the DPP is the development

Prescreening Single glucose

in the field or at the clinic of age, medical

Interview
Physical OGTT Other laboratory assays measurements

assessment

glucose

Assess

BMI and blood

FPG 95~125

2-h plasma glucose 140~199 mg/dl Liver function tests, electrolytes, serum plasma triglycerides, complete hormone, blood thyroid-stimulating urinalysis

the DPP

of development specific Therefore, as diabetes by performing measured with to identify

Run-in/behavioral Clinical evaluation human

trial

3-week trial of compliance and recordkeeping History Assessed and physical for acute ischemia

with pill taking

(1). It is not feasible

the primary of any type. testing FPG whendiabetes an annual

examination

Electrocardiogram

is assessed is also consistent

Serum Review

chorionic checklist

Rule out pregnancy If eligible, then randomize

gonadotropin eligibility

are noted polyphagia). withoUt without metabolism. Recruitment Clinic-specific priate include phone systems. information interpersonal effective ods ment for problem to monitor response 1996, manual Monitoring Diabetes eases to end recruitment media, groups workshops and cultural strategies target recruitment mail, approand telecare held for the identified use of mass contacts and or social Recruitment investigators and assistance and skills populations through were known adverse effects on glucose vides about progress ing (Table consent opportunity from 3-week included ticipants diet and Data mination during screening lection began approval the external and the after Food this and Kidney and date, in June and by the Data of DisDrug in the and phone process, are plete judged on pant to within evaluation ticipant
Staged informed screening consent process and

(e.g., polyuria, These tests that the either study 1997 FPG >200

polydipsia, or are performed treatare omitted for diaor 2-h FPG If the

interruption except meet (i.e.,

of the assigned drugs

increasing the DPP through process for

amounts to recruitment step includes of relevant discussion facilitating to the or

of information as and they screen-

ment results betes plasma both of A is

participants in the verbal

the morning

of the test. If the FPG or OGTT ADA criteria >126 mg/dl), within mg/dl a second

2). Each

informed and written and

glucose tests are

descriptions

information a decision next step. period with

or OGTT participant the primary ticipant ment.

dinating

is performed diagnostic is considered outcome. will continue

6 weeks. reached

of questions

of diabetes, to have Otherwise,

the volunteer, to proceed run-in, in step

employment for the DPP

or health

whether

the partreatof a subset

practice,

on the assigned masking, at random

a repeat

staff to share sensitivity. methfor recruitdeveloped a timely systems

3 to give prospective and activity. related baseline to eligibility data process. minimizes on by potential placing (e.g., complex are The keeping records

parpill takof

To maintain chosen
Center has

on recruitment,

a trial of compliance only) physical directly and the

participants or semiannual

by the Coorannual

ing (placebos

OGTT
for up condition Particithe suswhen antidiais not of data to

transmission developing solving,

of information, support were

test. The FPG are

annual

OGTT and

deterstaged colless tele-

semiannual 6 weeks that pants study pended an ized could who will until

postponed tolerance.

and clinic-specific Procedures and provide

collected

in case affect have

of a temporary glucose outcome pregnant

methods.

screening process

recruitment to problems.

the data participants simpler, a 10-min

become

during

burden clinic staff

assessment after delivery. To insure any during

Participant after

recruitment and

6~8 weeks

completion Committee, Board, and Digestive and

of the protocol

expensive

assessments interview) while later. potentially step each 2, step etc. more

OGTT

is performed. initiated

standardpregnancy

of operations

earlier

in the

screening must combe moving progress a particiclinical (Table the 2) parlikelithe

assessment before

of OUtcomes, the OGTT. FPG diabetes and

DPP Steering

assessments 1 and

betic medication is stopped possible, may the until occurs, primary ments an For remain

the NationalInstitute

done

A participant eligible In is flexible, schedule

If this

all the components

of step before e.g., contrast,

two elevated to define Investigators

determinations in place participants outcome is confirmed. of diabetes and to unmasked measureand HbA1c' FPG is

(NIDDK),

be used OGTT. masked progression If the

Administration. first half of 1999. of all participants until the middle

Recruitment Treatment are planned of 2002.

is anticipated follow-up to continue

~ 2 2/3 years

to primary to diabetes outcome are

at step

3 may

and electrocardiogram interest and minimize during

primary care

at his or her convenience. hood time informed of changes to consider fashion, in health

To maintain

participants, and plasma participants

DPP investigators, to subsequent glucose in whom

providers

baseline volunteers in weeks

the diagnosis of those

assessment,

yet to give potential participation a window

A four-step combined screening, recruitment, and informed consent process pro-

of 3~13

< 140 mg/dl,

all study-related

oral glucose

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

625

Diabetes

Prevention

Program

tolerance continue annual dations continued physician and introduced,

testing visits,

is terminated, with coded treatment

participants FPG at semiis recommenmedication and his/her is optithat mg/dl are disfor naire is intensified, glucose urine

Kidney creatinine sample Physical composition. evaluate tionnaire intake ments hip diameter, substudy computed ceral at albumin

function. are used activity, Two the level is used

Urinary

albumin in an

and

tially lifestyle

the

same

as those is more for the

of the

standard

to be followed original if the agree, with are reinforced,

concentrations excretion.

untimed urinary and body to and quesnutrient measurewaist and, and in a sagittal

recommendation, goals

but the approach intensive. lifestyle reduction weight physical intensive a weight body and eating

to determine nutrition, (16~18) are frequency

to implementation The intervention ~ achieve through activity, ~ achieve activity alent erate

participant monitoring of blood (15).

standardized of physical food to determine weight, abdominal thicknesses, participants, scanning

questionused activity,

are to: and maintain 7% healthy and and to maintain

self-monitoring control progress and

assessments

of at least

of initial

the goal of achieving In the event 2: 140 referred medicines are to FPG

mal glycemic participants continued appropriate of the study to be followed lect other semiannual Secondary comes disease; insulin position, health talityand events, specified cose cemia, and betes. include glycemia mmol/l), quired improvement j3-Cell function ing and 30-min during plasma is used the include changes

a semiquantitative (19). include circumference, skin-fold of some tomography Body

a level of physical (equivmodas walking of achieving and exercise to maxiinterin support diet, skills; for interto culin they the are of a the intensive through (such

on two occasions, diabetes

study patients

composition

of at least to ~700 intensity

150 min/week

height,

kcal/week) activity

care (15) Participants

independent continue to colFPG

protocol. outcome visits. outcomes.

or bicycling). Recognizing long-term behaviors lifestyle mize active exercise, frequent behavior ventions tural changes intervention by using behavior diet and interventions: and (no less than change; that differences, communities intervention; protocol certain help maintain support. ongoing staff. intervention with training is conducted in nutrition, who and modification participant first 24 weeks monthly at least remainder at least contacts the by case exermeet contact every represent information stratesetting, and goal solving, Individualizadifferent flexibilare and weeks. initially to and 2 a flexibility to and on (in the difficulty in eating weight,

at scheduled data,

intervals including

abdominal for vis-

fat content. Health-related quality of life. The Beck Inventories Study assess 36-item mood, support (20), short general quality-ofutilization, of be will include comand (21), are Depression Outcomes and used and a social to

and in body

The

secondary risk profile body

outand comintake; and Mor-

is designed the following training modification monthly) and exercise sensitive acceptable in which

cardiovascular in glycemia, renal

Anxiety form naire

success

j3-cell function,

the Medical

sensitivity, physical economics morbidity,

function,

question-

activity, and nutrient quality are also monitored. including parameters In addition during throughout

and health-related

of life. Safety

adjustment, life issues. Health costs, health

health-related Resource and diabetes safety serum

are flexible,

cardiovascular the study, at gluliver are evaluated to plasma average value outcomes of fasting mg/dl than diabetes, that

economics. utilities, to prevent

are monitored intervals.

effectiveness

specific and group

and the following Glycemia. measured to monitored to assess Specific

treatments determined. Safety. function plete blood (as needed), events Lifestyle Standard treatment mation sion with importance vention ticipants Pyramid equivalent and

implemented; structured pants and vidually achieve emphasis and receive the

a combination which

of individual all particiinformation) strategies goals; indiand participant

a combination common

Periodic tests,

tests creatinine,

the OGTT, recent

reflect

HbA Ie is glyfor diawill hyper(7.8 reand

to test its relationship its predictive secondary

to the OGTT,

count, and pregnancy testing as well as recording of adverse interval interventions lifestyle assignment) recommendation. (regardless written individual addressing Specifically, to follow receive After of sesthe parinforall participants a 20- to 30-min case manager 2 diabetes. of a healthy history.

to tailor specific

the study A Lifestyle

self-esteem, intervention training

empowerment, Resource and for support materials and

the development at a level Le., a level for diagnosis in glucose and

social

of 2: 140 greater of

Core

developed

randomization, and

provides intervention The managers cise, with the (with months program). about gies stimulus relapse tion

tolerance insulin

to normal. sensitivity.

j3-Cell function

their of type

is estimated from the fastplasma insulin and glucose and Fasting disease profile and smoking tissue from the fasting insulin Caran hemoactiplasma

lifestyle

for the prethe Food

or behavior an individual in the in-person throughout participant

for at least 16 thereafter of the

OGTT

are encouraged

sessions

proinsulin. as a surrogate risk

for insulin is assessed

sensitivity. by car-

guidelines and to consume the of a National Cholesterol Educastep 1 diet (22); to lose 5~10% through to increase 5 days a combination their each activity week; All parto stop. annuThe on obesity indeweight

Cardiovascular diovascular diovascular electrocardiogram, static protein, vator), derived tion particle ures and and fibrinogen, history fibrinolytic

rish profile. symptoms, history, plasminogen profile, (fullj3

tion Program of their initial gradually activity ticipants These ally with Intensive intensive previous and type pendently with such

The initial

16 sessions and behavior

of diet and exercise;

a core curriculum, such

with general

a goal of at least 30 min of an as walking alcohol intake.

diet and exercise control, prevention

factors

(C-reactive including quantificamg/dl), Disease LDL measblood blood

as self-monitoring, problem training.

and to avoid

excessive

lipoprotein

who smoke recommendations

are encouraged are reviewed intervention. intervention suggesting

j3 quantification size, and

is facilitated

by use of several how to achieve

if triglycerides Cardiovascular include by and carotid

are >400 disease. intimal

all participants. lifestyle lifestyle literature increase (23). is based that both

approaches ity in deciding in diet encouraged exercise The through and

to self-monitoring exercise. to achieve goals within goal

LDL apolipoprotein-B. wall thickness arm systolic

the changes

All participants the weight-loss the first 24 is attempted in dietary

assessed pressure, pressure.

ultrasonography, ankle:brachial

a sedentary 2 diabetes

lifestyle the The

may risk goals

of developing are essen-

weight-loss

a reduction

fat intake

626

DIABETES CARE, VOLUME 22, NUMBER 4, APRIL 1999

The Diabetes

Prevention

Program

Research

Group

<25% occur is added.

of calories. with

If weight then

loss

does

not goal is

for information, assessment vidual ideas ence. group the skills, participant Clinic protocol

training

in counseling situations,

and of indiand adherto and

fat restriction,

a calorie intervention

problem-solving or clinic

The focus a gradual activities vised exercise achieve are given exercise (performed coronary >40 not who ease years using have risk provided

of the exercise in brisk intensity. sessions participants goal

for the tool box for medication data are reviewed of poor identified can be so that patterns

increase of similar exercise but to help goal,

walking Two

or other superare their also and of tests aged

by the workadherence early

participate. Inactive participants continue to be contacted to remind them of the opportunity to reenter the DPP and to complete the final assessment at the end of the DPP.
Concomitant Concomitant medical treatment illnesses conditions conditions that could do not provide the program of concomitant that could affect when providers affect are defined requiring most other guidelines outcomes clinical or ancilhealth for Treatare conlactaalternate as or conditions protocol. Since assists

group

per week achieve can own the type tolerance preexisting in men

participants

interventions Retention Several been some ments. and child randomly potential identified,

can be implemented.

the exercise flexibility to perform. heart and hormone at least factors) exercise individuals goal, new may may tapes or a "tool strategies

on their

implementation

in choosing Exercise and with

obstacles such

to retention masking time

have with of

of the research centers care ments lary care, therapy discouraged

as dissatisfaction treatment, and include which are based

all primary

in individuals disease,

assigned Other barriers care,

of the test results, costs and of transportation, elder the target retention barriers removal. and

commitand to

in following study

postmenopausal replacement two are coronary used

women therapy heart disthe

the demands parking, vary Steps resources are fostered consider-

conditions. appropriate pregnancy,

to modify

ably among maximize ing these

populations.

treatments ditions tion, and

are available. were considered:

The following

individual's For achieving exercise to add Strategies items exercise equipment, structured diets, Group terly during lasting related ioral help 4~6 issues. approaches

program. having box" approach incentives Additional loaning home

on recogniz-

difficulty or is used

and committing retention array which and group according Quarterly within professional

hypertension, cardiovascular Women to practice of the

dyslipidemia, diseases.

smoking, potential are in study monand rantak-

or maintaining

the weight-loss for the participant. such aerobic exercise

for their by

Adherence education interest, availability motivational and rewards judgment a sense

of child-bearing reliable unknown risks

a comprehensive procedures, responsiveness, of the programs, deployed clinic. of each

of participant require continuous staff, to and the activities, newsletthe

asked view drugs itoring monthly domized placebo)

contraception of the Safety tests Women while the

include value. include other

as

of nominal

tool box

on the fetus and mother. includes menstrual to the drug who become pregnancy diaries. treatments pregnant about drugs who

enrolling eating visits. are and courses weeks These and

the facility, plans,

participant and liquid

in a formula quarcourse

(including to treatment potential and disconto become until nursand (25) and gluand

class at an exercise or home

use of more

ters are given Program were several to reflective and crepancies trained basic an approach

to participants and Recruitment in motivational to changing principles,

to encourage the DPP. Coordinators interviewing, based on including skillful (24). by between Dis-

ing medication to allow effects study tinued. pregnant,

are unmasked

of community

counseling

also with

offered each

of the study medication For women medication

on the fetus, want

maintenance, weight courses achieve exercise

is permanently is discontinued

focusing loss, and goals.

on topics or behavthe

behavior,

to exercise, participants

are designed maintain

listening, are the and

expression of ambivalence developed

of empathy, increasing present parand/or efforts, systo the out, thus semifor and or of is of Questionstudy positive

acceptance

the completion ing; medication Standard treatment are used, j3-adrenergic discouraged cose tolerance The intervention Cholesterol dietary after, whether ing during 6 months, lipid agents.

of the pregnancy is not unmasked. guidelines

weight-loss Adherence mined manager, assessments, activity Drug are the and and

for diagnosis in adults agents agents they diuretic

to the intervention monitoring weight and diet. self-reported by

is deterthe case

awareness showing behavior ticipants attendance as well

of consequences discrepancy important level are in place trigger goals.

of behaviors,

of hypertension except that blocking because (9~13). and plans standard diet Education 12 months, profiles are individuals Individuals qualify follow-up

through measuring

at the 6-month physical

are strongly

Procedures whose

to identify recovery monitoring

may worsen intensive meet the

of adherence hierarchy

should as a graded

lifestyle National for there(22). At

interventions

of recovery

Metformin are started increased dosage

and

its corresponding treatments. of 850

placebo They daily The

efforts. tem having protocol qualifying naires is annually, purposes retention negative to

A computer-based allows and identification with likely those problems

Program and used whose them Program qualify

standards annually

pharmacological at a dose to 850

of participants adherence to drop efforts. end of the at baseline, adherence interventions. of a large portion the and longer study validity actively

management

of dyslipidemia

mg once daily.

mg twice if necessary study and

to determine lar lipid-lowerlipid for drug (22) levels therhave Their deciuse of will folbecause (26).

can be adjusted to pill

because

for recovery and of and impact at the

of gastrointestinal Adherence assessed interview ication enhance tocol pants. by by

symptoms. medication a structured A Medprowas formed of particiclinic case staff, managers, network behavior. counts Workgroup

are administered predicting determining of study

apy based Cholesterol reached

on the guidelines Education a DPP secondary

of the National outcome. to aid clinical which The

of pill-taking Resource adherence promoting group This

to the medication retention supports

Since the

the retention

lipid levels are unmasked sions about low these nicotinic pharmacotherapy, guidelines glucose

while

participants findings, those

throughout power mechanisms who no

key to the statistical the DPP to recover

(22). intolerance

specifically providing

the medication

are in place

acid is strongly

discouraged

a communication

it can worsen

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

627

Diabetes

Prevention

Program

Standard reduce overall pants referred interested. smoking health are cardiovascular

approaches by discussing disease benefits given

are

followed its impact

to on the

defined 100 studies tional

by the ADA criteria combined margin

(1) was 7.7 per in the six size rate particrecused for an addi-

Statistical analyses comes (33). include assigned participant's treatment The

analysis of primary

plan. and

The

principal out-

person-years

of follow-up (4). To allow of error,

secondary

and emphasizing of quitting. materials programs incidence population cessation disease in this diseases an effect

Particiand if is

the DPP sample conversion among lifestyle were

will use the intent-to-treat approach The intent-to-treat analyses will all participants treatment regimen. principal analysis of the DPP Separate cumulative calculated the groups test will (34). will analysis of diabetes. estimated will be and of time to confirmed productincifor each be For cenof adherence in their group to the randomly of a assigned regardless

self-help

was based of 6.5 per ipants ommendations The

on an expected 100 person-years

to smoking

assigned

to the standard plus placebo. assumptions

Cardiovascular likely with study who dial ment coronary continue except intensive ticipants cise exercise ification who during diagnosis exercise cardiologic ment not impeded to be IGT (27), outcomes, experience infarction, for increased and

following

these have

and their on DPP Participants of myocaror treat(e.g., or to

treatments

may

to determine the sample ~ The primary outcome firmed criteria

to one

size goal: is time to the conof diabetes by ADA

be a life-table development limit dence life-table curves

or vice versa. new unstable heart graft) DPP intervention. resume risk may their transluminal episodes angina,

development (1). are

three

~ Participants
of the

uniformly
treatment

randomized
groups dur-

treatment compared the primary will sored" the 6

group using

coronary artery bypass

disease angioplasty

a log-rank analysis,

percutaneous

ing

a 2 2/3~year participants

period, are (Le.,

and after

all ranfor time the close

outcome complete Participants their as of their prior outcome groups event, development

participants

are eligible interventions,

domized

followed

be considered if they DPP without

"administratively the full duration confirmed who follow-up

following for participants lifestyle may testing, of the not until which exercise new-onset

an additional of randomization for each years). ~ The sided) for three type with three person par-

3 1/3 years is between rate

randomized These DPP

to the exerby

follow-up

development prematurely visits before will be visit. of for for the

3 1/3 and (two-

of diabetes. discontinue confirmed censored diabetes Mortality the primary mortality treatment composite development tality, same mary methods outcome.

program

is estimated result angina program.

I error pairwise assigned

(@) is 0.05 adjustment

of diabetes last follow-up to the development

in modPatients pectoris and until their their Treatis

a Bonferroni groups.

(30) of the lifestyle time to

comparisons to the standard plus with rate assigned placebo, a diabetes of 6.5 per of diabetes

develop

treatment

may be a competing (35). as a competing defined occurs described

risk event To account risk as first, event, confirmed

the DPP are referred and/or program of cardiac interventions,

for appropriate

~ In those

recommendation the development tially opment person-years. ~ For participants distributed hazard

is discontinued is complete. with participation. patients

is exponendevel100

will be compared or all-cause

on the morthe

evaluation by DPP

j3-blockers

of diabetes

whichever

using

to the intensive intervention hazLe., to >33%,

above

for the prioutcomes morbidity) life-table primary regrespoten(e.g., baseline site). to assess recurrent and forth tolerof

Biostatistical considerations Sample size goal. Several published studies have examined the rates of conversion from IGT to diabetes defined by WHO criteria (3). There were 21 studies identified that allowed computation of the participant-years of follow-up and the incidence rates of diabetes by the person-years of follow-up. Overall, the conversion rates ranged as follows: 2.3 per 100 person-years among Japanese populations, 3 per 100 person-years for Caucasians and MexicanAmericans, 4.7 per 100 person-years for Nauruans, 4.0 per 100 person-years for women with a history of gestational diabetes, and between 10 and 11 per 100 person-years for Asian Indians and Pima Indians (23,28~29). In data from six population-based cohorts provided to the DPP for calculation of conversion rates from IGT to diabetes (4) defined by WHO criteria (3), the overall conversion rate was 5.8 per 100 person-years of follow-up. To decrease the required sample size, a criterion of IGT with elevated FPG was chosen for eligibility in the DPP. For participants with an elevated FPG of 95~125 mg/dl, the conversion rate from IGT to diabetes

lifestyle groups, ard <4.33 With tive sample statistical Assuming prematurely visits before betes ization pants, with rate

or the per these power that

metformin diabetes by

development

is reduced

Secondary (e.g., mortality, will be analyzed methods outcome. sion model

time to event cardiovascular using the same above

100 person-years. assumptions, is 2,279 randomized their development loss hazard the total effecto achieve participants 90% (31).

described

for the hazards to evaluate outcomes

size necessary

A proportional will be used

participants follow-up of diarate

tial covariables and secondary risk fasting Graphical Some population and and history

that may modify time to event defined 2-h glucose, assumption. may normal based data involve back events, as moving and recurrent by of gestational

the primary race/ethnicity clinical

discontinue confirmed an exponential

diabetes, will be used

of < 10 per 100 person-years,

the random-

goal of the DPP is 2,834 particiwhich was increased to 3,000 (1,000 to per group). treatment groups. treatment differand manageis stratified randomizaprobability and treatment to of is To the three to anticipated populations in participant An adaptive a high the the

procedures processes such IGT

the proportionality events, between ance. of statistical counting

participants Assignment ensure groups ences possible ment, tion by clinical of balance unpredictable group the

balance with in the adaptive center. procedure

among respect participant

glucose

For these

the family (36). measures blood of life). preva(e.g., visits analyses

models processes

on the theory techniques lipids, quality

differences

will be applied analysis repeated fasting activity,

randomization provides by

Longitudinal will be used data These lence over (e.g., pressure, of time

to analyze glycemia,

in treatment

assignments

physical include a discrete

adjusting probabilities in

analyses

of the point characteristic repeated rank

allocation actual

according numbers (32).

imbalance assigned

hypertension) (37),

at successive multivariate

participants

to the groups

628

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

The Diabetes

Prevention

Program

Research

Group

of quantitative the form) OGTT) measures or Medical

(2-h

plasma Study

glucose (score 36-item visits

during from the short (38),

ordinal over

NIDDK project office. gram officer participates efforts involved col and Steering of the conduct committee Committee consists each This Center, of the DPP DPP

The NIDDK proin the scientific Group and is of the protosubcommittees. is the representaGroup. and The the rep-

to the Coordinating compiled data reports crepancies grams forms Central resources laboratory) ing Center, from all clinical

Center, centers.

where

they

are with edit with proall

into the DPP master are sent within to each forms. clinical

database Weekly center audit

Outcomes

Research

successive

in the development of the DPP. and

a parametric linear random (39) to compare participant time (e.g., rate and of change normality to compare linear (41) be used I error by The the when linearity techniques under work tion The probability primary the data Monitoring corresponding (42) boundary which at the using firmed mation number accrued number unknown, time participant the type time the of the fraction information (40). lan-DeMets will of a type outcome are taken Board.

effects model slopes over under and slopes framefuncthe the of Data a

out-of-range

values,

inconsistencies, Monthly

and dis-

in FPG) assumption, participant models spending

The

Steering

tive body Committee gator from Coordinating resentative. makes trative bers detailed

Research

produce more detailed edits across for an individual participant. resources. (e.g., are where the Data central transmitted they from via biochemistry

of the Principallnvesticlinical and committee and oversees comprised Group, center sets the NIDDK

central direct into

a generalized

policies, Group. of memdevelop and make Commit-

telecommunications the DPP master

link to the Coordinatare compiled database. ~ Treatment in including complications, Prevention be preferable, modification considerable causes and both have in the relative of diabetes its dispre-

approach

to adjust for testing looks external

decisions, aspects of the policies

the adminis-

of the DPP Research Research and

interim spending

Subcommittees,

DISCUSSION is often adverse ease, mature outcomes, neurological death. therefore, through Despite people in most and to be (44).

function

procedures

unsuccessful

preventing vascular and

to an O'Brien and Fleming will be used. The rate at I error is spent interim test (i.e., is a function available (Le., analysis to conthe inforof the events the accrued information of total total to be total is analysis time of total information of the time). For an interim of diabetes), fraction diabetes to on the (43). be

recommendations tee. The chairpersons are members which work reviewed planning and Studies, ventions, Presentations, Recruitment and Data toring advice vant Eligibility. monitoring Board to the and serves of the and phase

to the Steering of the as the Planning forum

of the subcommittees Committee, in which is The active procedures: Conditions, Publications Coordinators, and The and Screening Data review the Moniand the the initially following the protocol Ancillary Interand

of type 2 diabetes and may be of risk importance of type ethnic insulin These metabolic the and disease aimed at facof 2 variation

would, possible tors among genetic diabetes, groups, resistance appear

subcommittees coordinated. were study to develop

log-rank is the entire events

subcommittees detailed

during

development time in the of of confirmed

and environmental all populations j3-cell the patients

Concomitant Outcomes, Program

DPP. Since of the

dysfunction.

underlying

an estimate exposure

Retention, board.

will be based

fraction

abnormalities (45,46). Thus, reducing j3-cell ficial of type Target prevention A goal should is of insulin function in delaying 2 diabetes groups

leading to interventions resistance are anticipated or preventing

preserving to be benemost cases

provides NIDDK fields, who It consists

external

MANAGEMENT
Organization Clinical pating tigator, additional dietitians, gists, and units. ble data resource istry others. center and central Center design, processing. the Central Coding Center, Center, Resource firm. and and resource is responsianalysis, and Central BiochemCenter, Carotid Lifestyle WorkThese readthey treatThe Coordinating for biostatistical storage units Laboratory, and include centers. clinical a Program staff to carry recruitment nurses, Each of the 27 particiand protocol physiolocollectors, centers has a PrincipalInvesCoordinator out exercise data the coordinators,

Steering in releand by the

Committee. medical director tion Board ethics

of experts biostatistics, appointed Prior the Data material

in all populations. and goals for activities the health

biomedical

were

of the NIDDK. reviewed all study validity Its principal the emerging treatment safety. the board the that Based may on

to the initiaMonitoring to ensure and safety of the DPP and parto the or considera-

of recruitment,

diabetes

prevention or improve

be to maintain

that may include physicians,

the scientific of participants. to monitor to assess ticipant tions, NIDDK that Data Clinical ment one lected into staff newly mitted computers, at the on the and

of the study results these

behaviorists,

responsibility

of individuals by preventing disease primary several vent outcomes 2 diabetes, diseases mortality and

at high risk of type 2 diabetes or delaying the onset of the associated feasible type complications. strategies The to preof type and renal and all-cause may not treatment mortality, of the the factors j3-cell help the prito compare Secondary

effectiveness recommend

goal of the DPP is, thus, currently 2 diabetes. the complications as cardiovascular risk factors, Because duration assess

Coordinating

or delay such

protocol

be modified

include and their rates.

the DPP be terminated. management centers. system consists one paper local checked consistency. entered weekly and Coordinating forms computer A remote at each data manageof microcenter Data and colof a network clinical Center. are

Nutrition Grading

the DPP to test and or

Electrocardiogram Ultrasound Tomography Resource group, units serve and

have effects

sufficient

Reading Core,

Center,

Computed

on late complications will also on delaying measures insulin

Scan Reading Medication a public as central for samples with

the study treatments development and

the effects lessening risk to may

relations laboratories collected centers,

double-entered center and of the link ranges copies data

of cardiovascular Measurements and related sensitivity

by clinical

surrogate

of cardiovascular

ing centers performed provide ment' and

and studies

for allowed Electronic updated

disease. function explain mary

in the clinical assistance retention

internal

recruitment,

are trans-

the mechanism outcome

by which

of participants.

via telecommunications

was achieved.

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

629

Diabetes

Prevention

Program

Although require posing caused currently conditions, ventions logistic uals trial dictate who disease. at high vinue susceptible

prevention individuals

of diabetes of the many

might predisthat are are interThe clinical

insulin The tions has been

sensitivity feasibility

and

promote loss.

long-term interven2 diabetes Sweden, IGT were

improvement panied els, and, ment mental overall reduction action which

in insulin cases,

sensitivity of plasma

is accominsulin lev-

modification physiologic by genetic unknown) addressing constraints

throughout abnormalities factors (most and

the lives of

maintenance

of weight

by a lowering in some of blood profiles level,

of behavioral of type in Malmo, groups Men The with diet rate men and

is also accompanied and improveMetformin therefore, has increthe of in for (58). and,

for the prevention demonstrated of two IGT (50).

by lowering in lipid only a small

pressure

of which

socioeconomic to design factors.

in a study men treated program ment of by IGT with with with

of middle-aged exercise

effect on the postprandial lowering

it is impractical

glucose glycemic plus

all these

an intensive in these intervention

effect is due to the on its mechanism in France, risk factors is an excellent for a very major occurs or who other many well seriis in are major can Based in whom because is <5% (61). metformin Drugs in this be with on a the Based was class tissue troglitathis class it or studonly

of a randomized close type

for 5 years.

of developwas only half group not proin out The uncerwere not in their exercise clinical China, were 6-year in the diet alone, The than

in FPG. Based a I-year metformin

tests of interventions are relatively the DPP will enroll IGT and elevated by insulin hyperinsulinemia in the nondiabetic is no longer secretion

in individto the onset volunteers FPG. that 2 diabetes

of diabetes this study

study

that of a nonrandomized for whom vided. This demonstrating a diet -exercise effect of treatment, tain because assigned medical at random conditions reponed with interventions alone, or both on a clinic incidence intervention receiving no were the three of the group effects

comparison was

improved (59), this drug

Thus, of having

type 2 diabetes intervention Metformin years outside understood ous adverse extremely when the patients undergoing side effect testinal minimized appropriate large drug on number must these

risk of developing

is important program however, and for

primarily of carrying 5 years. remains

candidate. has the safety rare, drug with and been U.S. profile. even used with The acidosis, then

the feasibility

is accompanied compensatory tains When glycemia the OGTT has been tion studies betes with who Thus, included
Selection interventions

resistance

mainrange.

glycemia insulin

the treatment

groups differed and

effect is lactic is used (60). (60), usually

which

sufficient hyperof

to compensate (47). Despite well

for insulin to the the high repeat

resistance, point

at baseline. of diet in a randomized IGT in Da-Qing, involving basis (51). groups no significant in combination of diabetes

inappropriately The relates

worsens (48),

of diabetes value ofIGT popula-

Preventive have been in which exercise assigned or cumulative in all three control and between there trial in adults

renal surgery

insufficiency

test variability in many

the prognostic established

of metformin symptoms and titration

to gastroin-

which tolerated trials,

(23). The incidence in subsets who risk FPG such higher as those

of type 2 diaof individuals are obese factors (4). were

is even higher IGT, have these

of dosage. of patients

was lower

of clinical

it appears of gas-

concentrations criteria.

that the percentage trointestinal selected

additional

interventions, differences groups.

be discontinued side effects considerations,

in the eligibility
of the lifestyle

intervention drug

as a drug exclusively sensitivity was the only clinical that

treatment by (62). agent

in the DPP.

Selection Drugs development six classes: diones, carbohydrate

interventions to prevent belonged 2) thiazolidine4) inhibitors 5) fatty acid of oxithe to

Thiazolidinediones. work insulin zone under

Individuals with greater BMI or abdominal fat distribution and those who are less physically active are more likely to develop type 2 diabetes (23). Changes in diet and an increasingly sedentary lifestyle, with consequent increased body mass, have been associated with the development of type 2 diabetes in recently industrialized populations and in migrating populations that previously had a low prevalence of diabetes. Thus, it is hypothesized that lifestyle interventions aimed at reducing weight and increasing physical activity may help to prevent type 2 diabetes (44). A goal of losing;::; 7% of body weight was selected for the DPP because losses of this magnitude have been achieved and maintained in previous clinical trials and appear to improve insulin sensitivity and glycemic control in individuals with type 2 diabetes. The physical activity goal of 150 min/week of moderate activity such as walking (equivalent to ~700 kcal/week) is in agreement with the national physical activity recommendations of the Centers for Disease Control and Prevention and the American College of Sports Medicine (49). Modest increases in exercise improve

considered

as a means

enhancing Because within

of type 2 diabetes 1) biguanides, absorption,

3) sulfonylureas,

development in IGT, improves ranging depending type

in the U.S., 2 diabetes, troglitazone sensitivity, 50 to 100%

was considered ies show polycystic successfully with effects improvement, of insulin drug tions treated improves ering and studies with normal treatment blood has been an increase In 1997, treating Drug type insulin IGT, and with also lowers both (63,64). ovarian

for the DPP. Clinical syndrome, insulin from used and

dase inhibitors 6) weight-loss had to have lowering able safety problems Biguanides. sidered vated on glucose

and anti-lipolytic drugs, and agents. To be selected, drugs a proven record of efficacy similar an acceptuntoward coneffects elein in in people to those

glycemia profile,

to be enrolled

in the DPP, have and not create

on the measure (63~65). postprandial with IGT sensitivity by a lowglucose individuals from after IGT to of in with for and 3 months decline triglycerides along levels (65,66). Food The insulin concentra-

sensitivity plasma fasting

in adherence Metformin, homeostasis in this category,

or retention. the only drug has beneficial by suppressing glucose production glucose tract insulin lowers senof effect (54,55). insulindirectly without This

glycemia

In individuals insulin postprandial (64,66). convened tolerance and A modest plasma observed, HDL accompanied

troglitazone, and

rates of hepatic of delaying

strikingly, levels ~80% (64,66). pressure consistently in plasma

type 2 diabetes est effect

(52). It may also have a modor inhibiting gastrointestinal may improve treatment the that direct

of fasting

In short-term

absorption from the (53). Finally, metforrnin sensitivity plasma sitivity In some (7). glucose Any

of troglitazone-treated glucose

can also improve on insulin

insulin

by ameliorating studies individuals, insulin weight

hyperglycemia resistant improved concomitant

resistance metformin

of nondiabetic sensitivity, loss even (56,57).

troglitazone 2 diabetes

was approved by the Long-term

Administration

in the US

630

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

The Diabetes

Prevention

Program

Research

Group

safety were

data

are

lacking, no the and

although serious side frequency

in

pre-

Minority Health National Indian Control nies, centers

Health, and Health Institute

the National on Aging.

Institute

or Child and the the

glycemia middle pants loss, invited lessons the the over with

with or 2002. basic

semiannual To provide inrormation and group

visits these about exercise,

until

the

marketing

studies,

effects of side

Human Service, and support. two

Development, the Centers the American pharmaceutical and

particiweight they are with of or and within the with par-

observed,

In addition,

effects was comparable with that or placebo (67). A few cases of irreversible liver failure were lance, ment. ideal reported however, Given mechanism as one DPP in post marketing necessitating function the acceptable one dose or action, or the was drug toxicity, to liver the during sarety troglitazone treatments however, during medeffects, of liver ror only surveilcareful treatprofile, an was in its

ror Disease Diabetes compa-

healthy and

eating, printed

and Prevention, Bristol-Myers and

to quarterly

sessions components The objective

Association, contribute

materials

addressing

Squibb

Parke-Davis, to the clinical Center except is proror the which and is the

principal lifestyle time

educational intervention. follow-up and cohort during told they but in glycemia, cohort and

monitoring the need selected use Other ication because or considered insulin because which side ranted effect. 2 diabetes.

All support

the Coordinating Agreement, by the

continued cardiovascular the

is to assess adverse and the

differences

per day, and

vided through Southwestern supported Indian Health

the NIDDK using the mechanism American Indian Center, NIDDK

insulinemia, events between

or the Cooperative directly

troglitazone group other were troglitazone,

the DPP. Due in the recruitment classes

troglitazone control The double-placebo

concurrent treated

discontinued The other were were side

Service.

of participants

(see APPENDIX 1). of drugs. considered Sulfonylureas because They they This were were can risk Dedication This the paper Principal is dedicated Investigator to the memory Clinical St. Louis. to the of curiosor Dr. Julio Center He made planning, ity were V. Santiago at Washington (1942~1997), of the University, who was not selected seriously or type however,

the DPP. were remained or placebo their their not taking masked assignactive or

categories or concerns

pharmacologic-treated

ticipants active ment. placebo placebo and as to their

for safety,

efficacy.

metformin discontinued continue but

of the role of deficient not chosen, cause and was study

They

troglitazone

secretion

in the pathogenesis

extraordinary contributions design, and implementation and intellectual to all or us. The original inspirational 1 ~ four to the three

metrormin. of the troglitazone placebo control development cohort group or dia-

hypoglycemia, life-threatening deemed healthy. Obesity and physrisk them, modinsulin predicting pharmasuch not treatbeen unwarwith or people

the DPP. His warmth

Comparison the concurrent ror time

can be a serious in a prevention otherwise

to confirmed

APPENDIX design addition fourth included group

study arms. In the drug mg

IGT who

treatment described the standard with

betes (e.g., ease) three data

and other development

time to event outcomes or cardiovascular dislife-table analyses The described in glycemia, risk ractors and the between concurrent analyin outcomes participants this treatand secondary the because early. methods or the for the to assess insulinewithin the

above, the of 400

will use the same for the principal groups. techniques over time treatment analysis analyses

CONCLUSIONS
ical inactivity factors however, been Insulin secretion, cologically. ment can adequately to test both with ification for type clearly

received combined given Because

lifestyle

described

are potentially 2 diabetes.

modifiable Modirying and

intervention troglitazone once and drug. son separate daily.

longitudinal

at a fixed dose tablets were drug are easily

is very challenging, established and reduces resistance the The tested. clinical behavioral emphasis compliance. clinical to treatment trial on The to the incidence metabolic hypothesis diabetes

it has not such

for metrormin distinguishable, ror each each took peractive to a or a with railure in the subplus drug.

principal differences mia, the and

will also be used

whether impaired defects that has trials and

troglitazone placebos To maintain assigned to

of diabetes.

prepared masking,

cardiovascular cohort cohort group. and exclude

troglitazone control will

medication troglitazone

troglitazone placebo the ment DPP ses of primary assigned

type 2 diabetes,

can also be treated

metformin troglitazone, placebo placebo One troglitazone requiring presence sequently reviewed Board, lack

plus a placebo active corresponding corresponding DPP liver of other died. by which the developed participant

corresponding to metformin, to each treated hepatic and, illness,

The principal

prevent

to troglitazone,

Randomized ments, enhancing domized approaches

are needed drug treatand three with

was discontinued

measuring DPP test

transplantation complicating This DPP benefits Data that,

APPENDIX
Members

2
Group

is a ran-

case was immediately Monitoring given the in sarety adverse or conNIDDK in were assign(active was for partici-

of the Research

of individuals

IGT and other high-risk type 2 diabetes. These diet, cemia rormin. effective or type tremendous complications exercise, and The and insulin goal

characteristics for treatments include or hyperglywith at high and metrisk the its the most

concluded

or established

or this drug of intensive

treatment resistance is to determine in those so that or this

the DPP and the inability surveillance event, tinuation suspended the DPP pants unmasked to prevent was unacceptable. the risk to other

this severe participants the The this 585 drug

interventions 2 diabetes, burden

On the Boards treatment

in the future disease

recommendation, the randomized to their plus their and on 4 June

therefore, troglitazone 1998. to study They

can be reduced.

intervention medication placebo) be will

Acknowledgments~ ported through by the National the NIDDK,

The

DPP

is supor Health on

ment,

The rollowing individuals and institutions constitute the Diabetes Prevention Program Research Group (*Principal Investigator; Program Coordinator): ** Pennington Biomedical Research Center~ G.A. Bray, MD*, I.W. Culbert, BSN, RN, CCRC**, C.M. Champagne, PhD, RD, L. Dawson, B. Eberhardt, RD, LDN, F.L. Greenway, MD, F.G. Guillory, LPN, A.A. Hebert, RD, M.L. Jeffirs, LPN, B.M. Kennedy, MPA, J.C. Lovejoy, PhD, L.H. Morris, BS, L.E. Melancon, BA, BS, L. Reed,

Institutes

troglitazone discontinued.

metformin

J.

Pe rault, D.H. Ryan, MD, D.A. Sanford,

the Office or Research

rollowed

LPN, KG. Smith, BS, MT, L.L. Smith, BS,

DIABETES CARE, VOLUME 22,

NUMBER 4, APRIL 1999

631

Diabetes

Prevention

Program

].A. St.Amant, RTR, R.T. Tulley, PhD, P.C. Vicknair, MS, RD, D. Williamson, PhD, and ].]. Zachwieja, PhD; University of ChicagoK.S. Polonsky, MD*, M.J. Matulik, RN, BSN**, B. Clarke, MD, C. DeSandre, BA, D.A. Ehrmann, MD, R.M. Hilbrich, RD, W.L. McNabb, EdD, D. Morrone, RN, BSN, A.R. Semenske, MS, RD, K.A. Stepp, MS, and].A. Tobian, MD, PhD; Jefferson Medical College~ P.G. Watson, RN, ScD*,].F. Caro, MD, B.J. Goldstein, MD, PhD, C.M. Graziani, MD, E.J. Kunkel, MD, c.A. Laine, MD, D.Z. Louis, MS, K.A. Smith, BSN, ]. Spandirfer, MD, and E.J. Yuen, MBA; University of Miami~ R.B. Goldberg, MD*, P. Rowe, MPA**,]. Calles, MSEd, R.P. Donahue, PhD, H.]. Florez, MD, A. Giannella, RD, MS, P. O'Hara, PhD, and R. Prineas, MD, PhD; The University of Texas Health Science Center~ S.M. Haffner, MD, MPH*, M.G. Montez, RN, MSHP, CDE**, H. Miettinen, MD, PhD, C.M. Mobley, PhD, and L.A. Mykkanen, MD, PhD; University of ColoradoR.F. Hamman, MD, DrPH*, P.V. Nash, MS**, B.N. Calonge, MD, MPH, ].0. Hill, PhD, B.T. Jortberg, MS, RD, CDE, ].G. Regensteiner, PhD,]. Reusch, MD, C.M. Schiltz, MS, RN, RD, H. Seagle, MS, RD, and B. VanDorsten, PhD; Joslin Diabetes Center~ E.S. Horton, MD*, K.E. Lawton, RN* *, R.A. Arky, MD, M. Bryant, ].P. Burke, BSN, E. Caballero, MD, K.M. Callaphan, BA, O.P. Ganda, MD, T. Franklin, S.D. Jackson, MS, RD, A.M. Jacobsen, MD, L.M. Kula, RD, M. Kocal, RN, CDE, M.A. Malloy, BS, M. Nicosia, MS, RD, C.F. Oldmixon, RN,]. Pan, BS, MPH, M. Quitingon, S. Rubtchinsky, BS, E.W. Seely, MD, D. Schweizer, BSN, D. Simonson, MD, F. Smith, MD, C.G. Solomon, MD, MPH, and]. Warram, MD; University of Washington~ S.E. Kahn, MB, ChB*, B.K. Montgomery, RN, BSN**, M. Berger, BS, E.J. Boyko, MD, W.Y. Fujimoto, MD, C.J. Greenbaum, MD, R.H. Knopp, MD, B.S. McCann, PhD, E.W. lipkin, MD, T.T. Nguyen, BA,].P. Palmer, MD, R.S. Schwartz, MD, C. Talbot-Lawson, RN, and D. Wan, MS, RD; University of Tennessee~ A.E. Kitabchi, PhD, MD*, M.E. Murphy, RN, MS, CDE, MBA**, W.B. Applegate, MD, MPH, M. Bryer-Ash, MB, MRCp, FRCp, S.L. Frieson, RN, R. lmseis, MD, c.L. Kennedy, PhD, H.C. Lambeth, RN, BSN, L.c. Lichtermann, RN, BSN, H. Oktaei, MD, M.L. O'Toole, PhD, L.M.K. Rutledge, RN, BSN, A.R. Sherman, MS, RD, CDE, C.M. Smith RD, MPH, ].E. Soberman, MD, and B.J. Williams-Cleaves,

MD; Northwestern University Medical School~ B.E. Metzger, MD*, M.K. Johnson, MS, RN**, M. Fitzgibbon, PhD, D. Heard, MA, C.K.H. Johnson, MS, RN, D. McPherson, MD, M.E. Molitch, MD, M. Moore, MS, RD, T. Pius, MD, and P.A. Schinleber, RN, MS; Massachusetts General Hospital~ D.M. Nathan, MD*, C. McKitrick, BSN* *, K. Abbott, E. Anderson, MS, RD, E. Cagliero, MD, M. Cohen, MS, PT, S. Crowell, BSN, L. Delahanty, MS, RD, E. Levina, BA, T. Michel, MS, PT,]. O'Keefe, PhD, A. Poulos, BA, L. Ronan, MD, M. Rosal, PhD, M. Salerno, BA, C. Shagensky, BA, B. Steiner, EdM, and A. Young, MPH, CHES; University of California, San DiegoJ.M. Olefsky, MD*, M.L. CarrionPetersen, RN, BSN *, E. Barrett -Connor, * MD, M. Beltran, RN, BSN, CDE, K. Caenepeel, S.V. Edelman, MD, R.O. Ford,]. Garcia, R.R. Henry, MD, M. Hill,]. Home, RD, D. Leos, S. Mudaliar, MD, A. Pollard, and]. Torio; St. Luke's-Roosevelt Hospital~ F.X. Pi-Sunyer, MD* ,].E. Lee, MS**, D.B. Allison, PhD, N.J. Aronoff, MS, RD, I.M. Barreras,].P. Crandall, MD, S.T. Foo, MD, S.J. Orlando, BA, K. Parkes, RN, E.S. Rooney, BA, G.E.H. Van Wye, MA, and K.A. Viscovich, ANP; Indiana University~ M.J. Prince, MD*, S.M. Kukman, RN, CDE**, Y.F. Dotson, BS, E.S. Fineberg, MD, ].c. Guare, PhD, ].M. Ignaut, MA, M.A. Jackson, M.s. Kirkman, MD, D.G. Marrero, PhD, B.D. Porter, MSN, N.D. Rowland, BS, MS, and M.L. Wheeler, RD; Medlantic Research Institute~ R.E. Ramer, MD*, G. Youssef, RD, CDE**, M. Bronsord, MS, RD, CDE, W.W. Cheatham, MD, G. Boggs, MSN, RN, C. Evans, C. Levatan, MD, T. Kellum, MS, RD, CDE, A.K. Nair, BS, and M.D. Passaro, MD; UCLA Medical School/University of Southern California~ M.F. Saad, MD*, A. Khan, MD**,A.Aziz, MD, B. Bernaba, MD, M.D. Budgett, C. Cosenza, RD,].E. Hagar, BS, K. lsagholian, MD, S.D. Jinagouda, MD, V.V. Kamdar, MD, D. Kumar, MD, Q. Khawaja, MD, B.L. Kelada, MD, G. Lui, A.R. Marston, PhD, V. Mehta, MD, A.R. Sharma, MD, K. Szamos, RD, A. Vargas, B. Vargas, and N. Zambrana; Washington University, St. LouisS. Dagogo-Jack, MD*, A.E. Santiago, RN** ,].5. Brendle, MT, E.B. Fisher Jr., PhD, D.C. Gherardini, RN, ].M. Heins, RD, ].M. Marsala, RN, c.c. Raspberry, MSW,],V. Santiago, MD, and c.L. Stephan, RN; Johns Hopkins School of Medicine~ C.D. Saudek, MD*, V.L. Bradley, BA *, F.L. Brancati, MD, MHS, s. * Cappelli, BA, ].B. Charleston, RN, MSN,

R.R. Rubin, PhD, K.]. Stewart, EdD, and E. Sullivan, MEd, RN; University of New Mexico School of Medicine~ D. S. Schade, MD*, K.S. Adams, RN, MSN**, L.F. Atler, PhD, D.A. Bowling, P.]. Boyle, MD, M.R. Burge, MD, ].L. Canady, RN, CDE, L. Chai, RN, R.l. Dorin, MD, E. Facio, M. Guillen, RD, M. Gutierrez, RD, C. Johannes, RN, CDE, P. Katz, LPN, C. King, R. McCalman, RD,A. Rassam, MD, W. Senter, RD, and D. Waters, PhD; Albert Einstein College ofMedicine~ H. Shamoon, MD*, ].0. Brown, RN, MPH, MSN**, L. Cox, MS, RD, H. Duffy, MS, C-ANp, S. Engel, MD, A. Friedler, BS, C.J. HowardCentury, BS, MA, N. Longchamp, LPN, D. Pompi, BA, E.A. Walker, RN, DNSc, ]. Wylie-Rosett, EdD, RD, and]. Zonszein, MD; University of Pittsburgh~ R.R. Wing, PhD*, M.K. Kramer, BSN, MPH**, S. Barr, BS, L. Clifford, BS, R. Culyba, BS, M. Frazier, L. Harris, RN, S. Harrier, MLT, W. Henderson, RN, BSN, S. Jeffries, RN, MSN, G. Koenning, MS, RD, K. Maholic, BS, M. Mullen, MPH, RD, A. Noel, BS, T. Orchard, MBBCh, c.F. Smith, PhD, M. Smith, RN, BSN,]. Viteri, MS, T. Wilson, BA, K.V. Williams, MD, MPH, and]. Zgibor, MPH; University of Hawaii~ R.F. Arakaki, MD*, R.W. Latimer, BSN, MPH**, N.K. Baker-Ladao, BS, R.M. Beddow, MD, L.M. Dias, D.A. Dupont, L.L. Fukuhara, BSN, RN, M.K. Mau, MD, S.K. adorn, MPH, RD, R.U. Perry, and ].5. Tokunaga, BS; Southwest American Indian Center for Diabetes Prevention~ W.c. Knowler, MD, DrPH*; Salt River/Gila River: M.A. Hoskin, MS, RD**, V.L. Andre, RN, FNp, K.]. Acton, MD, MPH, S. Antone, N.M. Baptisto, P.H. Bennett, MB, FRCp, E.c. Bird, MPH, RD, T.S. Dacawyma, PTR, R.L. Hanson, MD, MPH, M.C. Jackson, RMA, RPT, P.A. Jay, K.M. Kobus, RNC-ANp, ]. Roumain, MD, MPH, D.H. Rowse, MD, R.]. Roy, and M. Yazzie, BA; Zuni: N.J. Cooeyate* *, M. Chavez, RN, AS, B.A. Broussard, RD, MPH, MBA, CDE, ].M. Ghahate, G. Hughte, L.E. Ingraham, MS, RD, LN, R.S. Kaskalla, D. Kessler, MD, Y. Nashboo, and S. Poirier, MD; Shiprock: c.A. Percy, RN, MS**, R. Barber, M.B. Benson, RN, BSN, R. Duncan, RD, M. Glass, MD, D. Gohdes, MD, W. Grant, MD, E. Horse, T. Morgan, and M. Reidy, MD; Data Coordinating Center (George Washington University Biostatistics Center)~ R. Bain, PhD*,]. Bambad, T. Brenneman, C. Dunegan, S.L. Edelstein, ScM, K.L. Grimes, S.Jones, T.L.Jones, H. Klepac,].M. Lachin, ScD, P. Mucik, R. Orlosky,]. Rochon, PhD,

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e.E. Stimpson, and C. Van Aerden; National Institute of Diabetes and Digestive and Kidney Diseases Program Office~ R. Eastman, MD, S. Garfield, PhD, and M. Harris, PhD; National Institute on Aging~ R. Andres, MD; Centers for Disease Control and Prevention~ M. Engelgau, MD, V. Narayan, MD, and D. Williamson, PhD; University of Michigan~ W. Herman, MD; Central Units: Central Biochemistry Laboratory~ W.L. Chandler, MD, S.M. Marcovina, PhD, ScD*, and 1. McMillan, BS; Epicare Center (Bowman Gray School of Medicine)~ PM. Rautaharju, MD, PhD*, and F.S. Razack Rautaharju, PhD; Nutrition Coding Center (University of South Carolina)~ E.]. Mayer-Davis, PhD*; Central Carotid Ultrasound Unit (New England Medical Center)~ D.H. O'Leary, MD*, L.R.e. Funk, MS, and K.A. O'Leary; Computed Tomography~scan Reading Unit (University of Colorado Health Sciences Center)~ A.L. Scherzinger, PhD, and E.R. Stamm, MD*; Lifestyle Resource Core (University of Pittsburgh)~ B.P Gillis, MS, RD, A.M. Kriska, PhD, e. Huffmyer, A. Meier, MS, RD, E.M. Venditti, PhD and R.R. Wing, PhD*; Design Committees (Chairpersons)~ Ancillary Studies: S.M. Haffner, MD, MPH, Concomitant Conditions: R.E. Ratner, MD, Intervention: ].M. Olefsky, MD,].V. Santiago, MD, Outcomes: e.D. Saudek, MD, Publications and Presentations: w.e. Knowler, MD, DrPH, Program Coordinator: M.G. Montez, RN, MSHP, CDE, Recruitment/Retention: W.Y. Fujimoto, MD, Screening/Eligibility: R.F. Hamman, MD, DrPH, Steering Committee: D.M. Nathan, MD.

5.

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Bethesda, MD, National Institute of Health, National Heart, Lung, and Blood Institute, 1993 Treatment of hypertriglyceridemia: NIH Consensus Development Conference summary. Arteriosclerosis 4:296-301, 1984 Balkau B, Shipley M, Jarrett RJ, Pyorala K, Pyorala M, Forhan A, Eschwege E: High blood glucose concentration is a risk factor for mortality in middle-aged nondiabetic men. Diabetes Care 21:360-367, 1998 Yudkin JS, Alberti KGMM, Mclarty DG, Swai GPM: Impaired glucose tolerance.

DJ: Thiazide-associated metabolic abnormalities and estrogen replacement therapy:

an epidemiological analysis of postmenopausal women in Rancho Bernardo, California. J Clin Endocrinol Metab
78:1O59~1O63, 1994 14. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359~362, 1993 15. American Diabetes Association: Standards of medical care for patients with diabetes mellitus (Position Statement). Diabetes Care 20 (Suppl. 1):S5~S13, 1997 16. Kriska AM, Knowler WC, laPorte RE, Drash AL, Wing RR, Blair SN, Bennett PH, Kuller LH: Development of questionnaire to examine relationship of physical activity and diabetes in Pima Indians. Diabetes Care 13:401-411,1990 17. Kriska AM, Casperson C], Eds.: Modifiable activity questionnaire. Taken from "A Collection of Physical Activity Questionnaires
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