Introduction

Diabetes mellitus (DM) and its associated

disease outcomes are a growing concern

worldwide. The current global prevalence of DM

for all ages has been estimated at 2.8 percent and

is predicted to reach 4.4 percent by 2030.1 There

is intense interest in identifying and treating risk

factors that may prevent the onset of this disease

and minimize morbidity. 

Impaired fasting glucose (IFG) and impaired

glucose tolerance (IGT) are the intermediate

metabolic states between normal and diabetic

glucose homeostasis. These conditions are

thought to be the precursors of DM, but the

progression to overt disease is not straightforward.

The risk for both macrovascular and

microvascular complications increases across the

distribution of blood glucose concentrations well

below the overt DM, and the risk is more

strongly associated with post-challenge

hyperglycemia than fasting glucose levels.

However, it is unclear whether this “glucose

effect” is independent of classical risk factors, such

as blood pressure and lipids, or occurs due to

abnormalities of other metabolites, such as free

fatty acids. 

Objective of This Systematic Review

The goal of this systematic review is to evaluate

the state of the evidence in the areas of the

diagnosis, prognosis, and treatment of IFG or

IGT. This evidence report was requested by the

American College of Physicians-American Society

of Internal Medicine; other partners were the

American Academy of Pediatrics and the

American Academy of Family Physicians. 

Key Questions 

Preliminary questions were subsequently

modified and refined in consultation with the

partner medical agencies, the Agency for

Healthcare Research and Quality, and McMaster

University Evidence-based Practice Center. The

revised key questions are as follows:

1. Diagnosis—What is the reliability of the

diagnosis of IFG or IGT (e.g., does

individual variability or measurement error

require multiple measurements to ensure

reliability of diagnosis)? What is the

relationship between IFG and IGT?

2. Prognosis—For those identified with IFG

or IGT, what are the short- and long-term

risks for developing the following outcomes:

a) Progression to DM or reversion towards

normal glucose tolerance or fasting

glucose level.

b) Cardiovascular events and stroke (fatal

and nonfatal).

c) Microvascular disease, specifically

retinopathy and nephropathy as

measured by proteinuria,

microalbuminuria, elevated creatinine,

albumin-to-creatinine ratio in the urine,

dialysis, or renal transplant.

Does this risk vary by subpopulation, such as

sex, race, obesity, age or other risk factors

(e.g., blood pressure, elevated lipid levels)? 

3. Treatment—What is the effectiveness of

pharmaceutical and behavioral interventions

for reducing the risks associated with IFG or

IGT on the following outcomes: 

Evidence Report/Technology Assessment

Number 128

Diagnosis, Prognosis, and Treatment of Impaired

Glucose Tolerance and Impaired Fasting Glucose

Summary

Authors: Santaguida PL, Balion C, Hunt D, Morrison K, Gerstein H, Raina P, 

Booker L, Yazdi H

Agency for Healthcare Research and Quality

Advancing Excellence in Health Care • www.ahrq.gov

Agency for Healthcare Research and Quality Evidence-Based

Practice
2

a) Delay in onset of DM or reversion towards normal

glucose tolerance or fasting glucose level. 

b) Reducing risk for cardiovascular events and stroke

(fatal and nonfatal).

c) Reducing risk for microvascular disease, including

early markers such as retinopathy/proteinuria. 

d) Improving other metabolic parameters, independently

associated with increased risk, such as blood pressure

and lipid levels.

Are some treatments more effective than others for any of

the above outcomes, and does the effectiveness of

interventions vary by subpopulation (e.g., age, sex, and

obesity)?

4. Pediatric population—What is known of the

development of IFG or IGT in the pediatric population?

Methods

Eligibility Criteria

Primary studies were eligible if they evaluated subjects with

IGT or IFG, were published after 1978, and were written in

the English language. Excluded publications included

systematic reviews, narrative reviews, editorials, letters to the

editor, unpublished position papers, consensus conference

reports, and practice guidelines. 

Study design eligibility varied with the research question:

• Diagnosis—All study designs with a maximum of 8-week

retest for reproducibility were eligible. 

• Prognosis—Any prospective cohorts, or randomized or

controlled clinical trials (RCTs) were eligible for evaluation

(with a minimum followup of 1 year). 

• Treatment—Only RCTs that analyzed the effects of

lifestyle, behavioral, or pharmaceutical treatment (with a

minimum followup of 6 months) were eligible. 

• Pediatric population—All study designs for children age

0 to 18 years were eligible.

The study had to include an IFG or IGT group as the study

population or analyzed as a subgroup. The specific criteria

reference (for example, WHO-85) used within a study was

checked relative to the procedures described in the methods

and results sections of each study. The following

inclusion/exclusion criteria were used for the testing procedure

for dysglycemia: 

• All testing must have been done on venous blood plasma

or venous blood serum, not on whole blood or on

capillary samples. 

• For oral glucose tolerance testing (OGTT), the subject

must have been given 75 g of oral glucose (1.75 g per kg

to maximum of 75 g for children) and measurement taken

at 2 hours post-glucose ingestion (2-hr PG). 

• All measurements must have been done in a laboratory

and not with a point-of-care device or not undertaken in

an acute care setting, such as an emergency ward following

a myocardial infarction (MI) or pneumonia. 

Study outcomes included glycemic disturbances, nonfatal

cardiac outcomes, fatal cardiac outcomes, mortality, lipid and

blood pressure disorders, amputation, nephropathy, and ocular

problems.

Literature Search Strategy

A comprehensive search was undertaken to capture all

relevant studies. In addition to MEDLINE®, HealthSTAR,

CINAHL®, AMED (alternative medicines), PsycINFO®, and

EMBASE®, the personal files of the local research team and the

reference lists of included articles were searched from 1979

onward.2

Study Selection and Extraction

The title and abstract lists and the full-text papers were

screened using the eligibility criteria, standardized forms, and a

guide manual. Data from the Access database were

summarized into summary tables, which included data about

the general study characteristics (study design, location, source

of funding, population, mean age, and diagnosis criteria),

interventions, and outcomes assessed. 

Studies were grouped according to classification of the IFG

and IGT status. Five categories were considered, including: 1)

isolated IGT (I-IGT), 2) isolated IFG (I-IFG), 3) non-isolated

IGT, 4) non-isolated IFG, and 5) combined IGT/IFG. 

A classification of I-IGT indicates that 2-h OGTT level was

between 7.8 and 11.0 mmol/L and the fasting plasma glucose

(FPG) level was less than 6.1 mmol/L. Similarly, the I-IFG

classification indicates that the 2-h OGTT level was less than

7.8 mmol/L and the FPG level was between 6.1 and 7.0

mmol/L. 

The isolated classifications indicate that both forms of

glucose testing were undertaken and only one of the two tests

was abnormal. Each eligible study was rated for quality using

standardized instruments.3,4

Results 

The original search yielded 25,521 citations for all four

questions combined. From these, 1,243 proceeded to full-text

screening. After the final eligibility screening, data were

extracted from a total of 156 studies.

Key Question 1: Diagnosis 

Fifty-three studies provided data on the reproducibility of

repeat testing of fasting glucose or OGTTs, comparison of IGT

diagnosis by different criteria, and the relationship between

IGT and IFG diagnosis in the same population.
Reproducibility of IGT and IFG Tests. Five reports of

four studies5-9 assessed the reproducibility of the OGTT for

diagnosis of IGT and three reports of two studies6,7,9 assessed

the reproducibility of FPG for the diagnosis of IFG in

publications after 1978. All repeat tests were done within 6

weeks of the first test. The populations studied were mostly

Caucasians,5-7 except for two reports of one study on Hong

Kong Chinese.8,9

The study populations were subgroups of larger studies and

did not provide detailed characterization for the subgroup. All

studies used the same classification criteria. IGT was FPG <

7.8 mmol/L and 2-hr PG 7.8 to 11.0 mmol/L and IFG was

FPG 6.1 to 6.9 mmol/L. 

The kappa coefficients for IGT ranged from 0.04 to 0.56,

indicating poor to moderate agreement. The proportion of

participants classified as IGT by the first OGTT and upon

repeat testing ranged from 33 percent to 48 percent. A similar

proportion (range 39.3 percent to 46.2 percent) of participants

was reclassified as normal glucose tolerance, with the remainder

reclassified as DM (range 6 percent to 12.6 percent). 

Two studies retested participants based on FPG for IFG.6,9

The kappa coefficients for these studies were 0.22 and 0.44,

indicating fair to moderate reproducibility. The proportions of

participants classified as IFG by the first FPG and upon repeat

testing were 63.7 percent and 51.4 percent, respectively. The

reclassified subjects had mostly normal fasting glucose with

some newly diagnosed DM. Two studies that evaluated

coefficient of variation for biological variation (CVI

) for repeat

testing gave similar CVI for FPG (6 percent and 6.3 percent)

and 2-hr PG (18 percent and 16.6 percent) concentrations,

indicating consistency in variation between the different

populations studied.5,7 

Comparison of IGT diagnosis using different criteria.

Only four studies10-13 provided data for a comparison between

diagnosis using different IGT criteria (i.e., using both IFG and

2-hr PG concentrations for classification). Studies that assessed

IGT based on the 2-hr PG concentration only (WHO

epidemiological criteria) were excluded.14

The characteristics of the study populations represent a

broad spectrum of populations (Asian, Dutch, Pima Indians,

and women with previous gestational DM). The IGT criteria

included were WHO-85, WHO-98, and WHO-99. All of

these criteria use a 2-hr PG range of 7.8 to 11.0 mmol/L, but

the WHO-85 criteria use an FPG cutpoint of < 7.8 mmol/L

whereas both the WHO-98 and WHO-99 criteria use a

cutpoint of < 7.0 mmol/L. More IGT diagnoses were made

using a FPG cutpoint of < 7.8 mmol/L (13.6 percent to 31.5

percent) than 7.0 mmol/L (8.3 percent to 29.7 percent). There

were fewer cases of I-IGT (6.0 percent to 11.9 percent)

compared to IGT regardless of the FPG cutpoint. 

Relationship between IGT and IFG. Forty-nine studies

provided data on the relationship between diagnostic criteria

for IGT and IFG. Most studies were prospective cohort studies

(n = 14) and cross-sectional studies (n = 31). Data were

extracted to give seven classifications: 

1) IGT—2-hr PG 7.8 to 11.0 mmol/L.

2) IGT—FPG < 7.8 mmol/L and 2-hr PG 7.8 to 11.0

mmol/L.

3) IGT—FPG < 7.0 mmol/L and 2-hr PG 7.8 to 11.0

mmol/L.

4) IFG—FPG 6.1 to 6.9 mmol/L.

5) I-IGT—FPG < 6.1 mmol/L and 2-hr PG 7.8 to 11.0

mmol/L.

6) I-IFG—FPG 6.1 to 6.9 mmol/L and 2-hr PG < 7.8

mmol/L.

7) Combined IFG/IGT—FPG 6.1 to 6.9 mmol/L and 2-hr

PG 7.8 to 11.0 mmol/L.

Comparison of studies that present both IGT and I-IGT

data show that the number of participants in the IGT

classification is approximately 40 percent greater than in the IIGT group (p < 0.0001). Also, IGT classification using the

limited criteria, which omits the fasting plasma glucose value,

classified 10 percent more participants as IGT (p = 0.0033).

Evaluation of studies containing data for all classification

categories (n = 16) show a change in proportion between each

classification group and between studies. In general, the

proportion of participants decreased with increased stringency

of the diagnostic criteria—that is, IGT as 2-hr PG > IGT as

FPG and 2-hr PG > I-IGT > IFG > I-IFG > IFG/IGT. 

The prevalence of IGT and IFG varied greatly among

studies ranging from a few percent to over 30 percent.

Comparisons between categories of IGT and IFG were

significant (p < 0.01) for all combinations except for I-IGT

versus IFG and I-IFG versus IGT/IFG. Correlations were

much higher for IGT and I-IGT than for IFG and I-IFG. 

Key Question 2: Prognosis 

A total of 104 studies met the initial eligibility criteria. From

these, only some provided sufficient data (frequency counts)

versus a reference group of subjects with normal glucose to

estimate the following: 

• Annualized risk per 100 persons in the exposed group.

• Unadjusted annualized relative risk (RR), with the

confidence interval (CI).

• Risk differencei

• Attributable risk (AR), expressed as a percentage for the

observed study duration. 

All included studies prospectively followed cohorts; 90 were

observational studies and 14 were RCTs (placebo arm only).

The duration of followup varied from 1 year to 18 years. Five

3

i Risk differences are discussed in the full evidence report.
4

studies15-19 evaluated women only, and nine studies20-28 evaluated

men only. The mean age and the ranges varied significantly

among studies, but most included middle-aged and older

subjects. There was a broad representation of populations.

The measures of risk were calculated from data provided in

prospective studies that included both normal and dysglycemic

people in either observational studies or the placebo arm of

RCTs. The risk estimates for all outcomes were classified into

five diagnostic groups: 1) IGT, 2) I-IGT, 3) IFG, 4) I-IFG, and

5) combined IFG/IGT. Findings are summarized for three

main outcomes: progression to DM, cardiovascular disease

(CVD) outcomes (fatal and nonfatal), and mortality.

Risk for progression to DM. The number of studies that

provided data for the five classification groups varied. Studies

with IGT subjects (n = 36) were the most numerous, whereas

five studies included people with IFG and three studies

included people with I-IGT, I-IFG, and both IGT/IFG. 

Annualized risk per 100 persons in the exposed groups. The

minimum and maximum annualized risk estimates for each of

the five dysglycemic classification groups are as follows:

• IGT group—1.83 (minimum) to 34.12 (maximum)

• I-IGT group—4.35 to 6.35

• IFG group—1.60 to 23.44

• I-IFG group—6.07 to 9.15

• IGT/IFG group—9.96 to 14.95. 

Two studies and four RCTs had high annualized risk

estimates, and these included populations with many risk

factors for DM. The variation in the annualized risk per 100

persons observed are likely related to the different populations,

mean age, and the sample sizes evaluated within these studies. 

Unadjusted annualized relative risk. Three of the 28 studies29-31

within the IGT classification group were nonsignificant,

indicating no association with IGT and progression to DM.

Most of these studies had small sample sizes. In the remaining

studies, the unadjusted annualized RR with 95 percent CI

varied as a function of the diagnostic groups in the following

manner: 

• IGT group— range 3.58 (95 percent CI 2.12 to 6.06) to

10.60 (6.38 to 17.60)

• I-IGT group—3.51 (2.22 to 5.54) to 8.63 (5.46 to 13.64)

• IFG group—2.40 (1.71 to 3.37) to 9.04 (6.28 to 13.03)

• I-IFG group 5.05 (2.86 to 8.90) to 9.85 (6.65 to 14.60)

• IGT/IFG group—5.50 (2.86 to 8.90) to 20.69 (12.51 to

34.22). 

There were fewer studies in the IFG and I-IFG diagnostic

categories than for IGT, and, as such, interpretation across

classification groups may be limited. 

Meta-analysis was undertaken with unadjusted annualized

RR for DM where sufficient numbers of studies were available

for combining. The pooled estimates with the 95 percent CI

are as follows: 

• IGT group—6.02 (95 percent CI 4.66 to 7.38)

• I-IGT group—5.55 (3.15 to 7.95)

• IFG group—4.70 (2.71 to 6.70)

• I-IFG group—7.24 (5.30 to 9.17)

• IGT/IFG group—12.21 (4.32 to 20.10). 

All pooled estimates were significant. Heterogeneity tests

were significant for all of the dysglycemic groups except for the

I-IFG group. Sensitivity analyses did not affect the significance

of the Q test for heterogeneity. 

Attributable risk in the exposed group. High estimates of AR

were calculated for the outcome of DM in dysglycemic

individuals. Estimates for each dysglycemic group are as

follows: 

• IGT group—range 52.8 percent to 97.0 percent

• I-IGT group—68.8 percent to 86.6 percent

• IFG group—57.3 percent to 86.9 percent

• I-IFG group—77.1 percent to 88.5 percent

• IGT/IFG group—78.6 percent to 93.3 percent.

Risk for nonfatal CVD outcomes. Estimates of risk for

any nonfatal CVD outcomes were based on six studies. The

outcomes characterizing CVD included atherothrombosis,

nonstenotic atherosclerosis, clinical MI, percutaneous

transluminal coronary angioplasty (PTCA), stroke, unstable

angina, heart failure, and combinations of these (major event or

any event). Study durations varied from 5 to 9 years and

studies were published from 1998 forward. Three of the five

studies18,32,33 evaluating IFG as the risk factor are RCTs. 

Annualized risk per 100 persons in the exposed groups.

Estimates of annualized risk per 100 persons varied between the

types of CVD events. The highest observed annualized risk

was within the only IGT study for the outcome of nonstenotic

atherosclerosis.34 The lowest observed annualized risk was for

stroke in people with IFG.18 The annualized risk estimates for

any nonfatal CVD event are as follows: IGT group—11.58 to

12.39; IFG group—0.63 to 9.68. 

Unadjusted annualized relative risk. Only two studies had

significant unadjusted annualized RRs. The single study within

the IGT group had similar RR and CI estimates: 2.43 (95

percent CI 1.44 to 4.10) and 2.46 (1.46 to 4.12) for both

atherothrombosis groups.34 Five studies evaluated subjects in

the IFG group and RR estimates varied from 1.24 (1.08 to

1.43) to 1.41 (1.17 to 1.69). 

In a meta-analysis, nonfatal CVD outcomes were combined

according to these subgroups: 1) PTCA and coronary artery

bypass graft, 2) stroke, and 3) any other major cardiovascular

event. Tests for heterogeneity were not significant. Only one

combination for the IFG of any major cardiovascular event was

significant with an overall estimate of 1.28 (CI 1.15 to 1.41, p

= 0.0001). 
Attributable risk in the exposed group. The AR for CVD

outcomes was higher in the IGT group (range 52.8 percent to

52.9 percent) than in the IFG group (0 percent to 32.9

percent).

Risk for fatal CVD outcomes. Eight studies reported fatal

CVD outcomes. Some studies subdivided the outcomes into

ischemic heart disease, cardiocerebrovascular disease, and

coronary heart disease (CHD). There were no eligible studies to

evaluate the I-IFG and IFG/IGT combined classifications. The

duration of the studies varied from 7 to 18 years. Three of the

studies21,25,27 were based on a male-only cohort (Paris Police

study) for the IGT, I-IGT, and IFG groups. Similarly, one

study within the IFG group included only postmenopausal

women with a history of MI.18 Two other studies in the IFG

group recruited subjects with a history of either MI or

CHD.35,36

Annualized risk per 100 persons in the exposed groups. The

annualized risks in the exposed group per 100 persons are as

follows: IGT group—0.06 to 0.76; I-IGT group—0.23 to

0.34; IFG group—0.10 to 1.54. The differences in annualized

risk are likely a function of the different study populations and

categorizations of the CVD mortality subgroup classification. 

Unadjusted annualized relative risk. Only four studies25,35,37,38

had unadjusted annualized RRs that were significant. The

calculated estimates are as follows: 

• IGT group— range 1.67 (95 percent CI 1.23 to 2.26) to

3.08 (1.47 to 6.47)

• I-IGT group—1.59 (1.07 to 2.28) to 1.72 (1.23 to 2.41)

• IFG group—1.32 (1.04 to 1.67)ii

In a meta-analysis, within the IGT group, CVD and

ischemic heart disease were grouped and the pooled overall

estimate of relative risk was 1.66 (95 percent CI 1.21 to 2.11).

Within the IFG group, estimates for the CHD/CVD subgroup

(1.25 [0.99 to 1.51] and ischemic-related disease subgroup

(1.27 [1.06 to 1.54]) were pooled; these estimates did not differ

substantively. Overall, the pooled estimates do not provide

evidence of a significant association with IFG or IGT and fatal

CVD outcomes. 

Attributable risk in the exposed group. The AR for fatal CVD

outcomes varied as follows: IGT group—range 24.8 percent to

67.3 percent; I-IGT group—36.8 percent to 41.2 percent; IFG

group—11.8 percent to 39.5 percent. With the exception of

one study,38 the AR did not exceed 41 percent. Tominaga et

al.38 evaluated CVD outcome in both the IGT and IFG groups

concurrently, and the AR was 67.3 percent and 39.5 percent,

respectively.

Risk for mortality. In general, most studies reporting

mortality outcomes had the largest sample sizes and the longest

followup duration (up to 18 years). Eligible studies included

the IGT, I-IGT and IFG classifications; the I-IGT group was

based on two studies on the same cohort. 

Annualized risk per 100 persons in the exposed group. The

annualized risks per 100 persons for mortality (all-cause, cancer,

and cirrhosis categories) are as follows: IGT group—0.09 to

2.44; I-IGT group—0.10 to 1.34; and IFG group—0.56 to

1.39. 

Unadjusted annualized relative risk. The all-cause mortality

estimates along with 95 percent CI are as follows: 

• IGT group—range 1.36 (95 percent CI 1.12 to 1.66) to

3.18 (1.79 to 5.63)

• I-IGT group—1.60 (1.33 to 1.92) to 7.19 (3.37 to 15.37)

• IFG group—1.18 (1.03 to 1.35) to 1.45 (1.27 to 1.66). 

One study showed a strong association between I-IGT and

the outcome of death due to cirrhosis (RR 7.19)25 for male

police officers and also showed the highest AR (86 percent) for

mortality outcomes. Three studies21,35,38 evaluated both all-cause

mortality and CVD mortality; both the RR and the AR

estimates were approximately double in magnitude for the

CVD-related mortality relative to all causes with the exception

of one study.

38 Two studies27,39 compared all-cause mortality to

cancer-related deaths, and the RR and AR did not differ

substantively for these two mortality outcomes. 

Meta-analysis for all-cause mortality in the IGT and IFG

groups was undertaken. The overall pooled estimates were 1.48

(95 percent CI 1.09 to 1.86) for the IGT group and 1.21 (95

percent CI 1.05 to 1.36) for the IFG group. 

Attributable risk in the exposed group. The ARs for all-cause

mortality are as follows: IGT group—range 0 percent to 67.2

percent; I-IGT group—35.1 percent to 86.0 percent; IFG

group—13.9 percent to 61.2 percent. The single study with an

AR equal to 0 percent has been previously noted for its sample

size issues. As with the other risk metrics for mortality, the AR

was highest (86 percent) for cirrhosis-related mortality.

Key Question 3: Treatment

Twenty-three reports of 14 RCTs published between 1992

and 2003 evaluated lifestyle or pharmacotherapeutic

interventions in adults with IFG or IGT. Duration of followup

ranged from 6 months to 6 years. Studies involved 14 to 3,234

participants from Europe, North America, Australia, and Asia

with their mean ages ranging from 37.5 to 70 years.

Interventions included diet and exercise, oral hypoglycemic

agents (metformin, acarbose, and chromium), a statin

(pravastatin), and an ACE inhibitor (enalapril). Outcomes

included progression to DM or reversion to normal glucose

tolerance, cardiovascular events, mortality, and effects on blood

pressure and lipid levels. 

5

ii Based on a single study.
Progression to DM or reversion to normal. Most studies

of the effects of lifestyle or pharmacotherapeutic interventions

involved people with IGT.

Lifestyle interventions. Six RCTs evaluated the effect of

lifestyle interventions on the risk for developing DM or

reverting to normal glucose tolerance in adults with IGT.

Intensive combined diet and exercise programs that involved

frequent study visits were compared with lifestyle advice alone

in five studies.40-44 One study41 compared an exercise program

with advice alone, and two studies16,41 evaluated the effect of

dietary intervention alone. One trial, the Diabetes Prevention

Program, also included a metformin arm.40

All but one of the trials that evaluated a combined diet and

exercise program found a significant reduction in the risk for

developing DM, or a higher rate of reversion to normal glucose

tolerance, with aggressive lifestyle modification. The absolute

risk reduction of progressing to DM per year in the studies was

between 1.6 percent and 7.1 percent, corresponding to a

number needed to treat for 1 year to prevent a case of DM

between 14 and 62. Dietary intervention alone significantly

reduced the risk for progressing to DM in one trial41 but had

no effect in a second study.45 The trial41 that evaluated an

exercise intervention alone showed a significantly reduced rate

of progression to DM (absolute risk reduction 3.9 percent,

number needed to treat 25.5, relative risk reduction 37

percent). 

Pharmacotherapeutic interventions. Four RCTs evaluated the

effects of pharmacotherapeutic interventions on the risk for

developing DM in people with IGT.

40,46-48 These studies assessed

the effect of acarbose and metformin. 

The study46 with acarbose demonstrated a reduced risk of

progressing to DM (32 percent versus 42 percent; relative risk

reduction 0.25, 95 percent CI 0.10 to 0.37). This effect did

not vary by age, sex, or body mass index (BMI). The study

also demonstrated an increased rate of reversion to normal

glucose tolerance with acarbose relative to placebo (35 percent

versus 31 percent, p < 0.0001). 

A large study40 found a significantly reduced risk for

progressing to DM when taking metformin relative to placebo

(7.8 percent versus 11.0 percent per year; relative risk reduction

0.31, 95 percent CI 0.17 to 0.43). Two smaller studies47,48 in

people with IGT found no difference in those treated with

metformin. 

The effect of enalapril in people with IFG and left

ventricular dysfunction was assessed in a retrospective post-hoc

subgroup analysis. This study49 found a decreased risk for

progression to DM in the enalapril arm relative to the placebo

arm (3.3 percent versus 48 percent, p = 0.0001). The effect of

pravastatin on the development of DM in people with IFG and

a previous MI was assessed in a retrospective post-hoc subgroup

analysis. This study found no effect on the rate of development

of DM, based on a fasting blood glucose level of ≥ 7 mmol/L,

or reported use of oral hypoglycemic medication or insulin.

Lifestyle versus pharmacotherapeutic interventions in people

with IGT. Only one trial to date, the Diabetes Prevention

Program,40 has directly compared lifestyle intervention with

pharmacotherapeutic intervention for the prevention of

diabetes in people with IGT. It found a significantly lower risk

for progressing to DM with aggressive lifestyle intervention

compared with taking metformin (4.8 percent versus 7.8

percent per year; relative risk reduction 0.39, 95 percent CI

0.24 to 0.51), especially in individuals 60 years of age or older.

Cardiovascular event outcomes. No RCTs of lifestyle

interventions evaluated cardiovascular outcomes.

Pharmacotherapeutic interventions in people with IGT. A

single trial50 evaluated the effect of acarbose on cardiovascular

event rates in people with IGT. 

The primary outcome found a significant reduction in the

risk for developing a major cardiovascular event in the acarbose

arm compared with the placebo arm of the study (relative risk

reduction 0.49, 95 percent CI 0.05 to 0.72, absolute risk

reduction 2.5 percent).

Pharmacotherapeutic interventions in people with a previous

MI and IFG. Two post-hoc retrospective subgroup analyses

evaluated the effect of pravastatin therapy on cardiovascular

event rates in people with a previous MI and IFG. In one

trial,32 the rate of cardiovascular death or nonfatal MI was

significantly lower in the pravastatin group; the relative risk was

not significantly different from the values for the post MI

patients. In a second trial18 the relative risk for the outcome of

cardiovascular death or a nonfatal MI in individuals with IFG

was also not significantly different from those within

individuals with normal fasting glucose levels at baseline. 

Mortality outcomes. One trial41 reported the effect of

lifestyle intervention on total mortality rates in individuals with

IGT. One trial18 reported the effect of statin therapy on

mortality rates in individuals with a previous MI and IFG. In

both trials, mortality rates did not differ significantly between

groups.

Effects on blood pressure and lipid levels. All studies

involved people with IGT. 

Lifestyle interventions. Three RCTs43,44,51 evaluated the effect

of lifestyle interventions on blood pressure and lipid levels.

Significant differences (decline) in blood pressure (systolic and

diastolic) were found in two studies and in lipid levels (ratio of

total to HDL cholesterol and serum triglycerides only) in one

study.

Pharmacotherapeutic interventions. Four RCTs reported the

effects of oral hypoglycemic agents on blood pressure and lipid

levels. Two trials47,48 reported the effects of metformin on blood

pressure levels in people with IGT and demonstrated no

significant effect of metformin on blood pressure or lipid levels.

6
7

One study46,50 reported the effects of acarbose therapy on blood

pressure and lipid levels in people with IGT and found

significant differences in blood pressure (systolic and diastolic)

and hypertension (defined as a blood pressure of at least 140/90

on two consecutive visits or the addition of antihypertensive

medications between visits). The trial noted a significant

reduction in triglyceride levels. A trial of chromium52 found no

significant effects on lipid levels. 

Key Question 4: Pediatric Population 

All articles that met the general criteria (English language,

full-text publication, published since 1979, and results for IFG

or IGT analyzed separately from other study populations) and

included children with IFG or IGT were collected (36 articles).

Of these, a subset of five articles met the criteria for diagnosis,

prognosis, or treatment according to the criteria outlined in the

methodology. These articles are included in the analysis of their

respective sections above. 

Four articles included within the analysis (one diagnosis,

three prognosis) included participants 15 to 18 years of age, but

the pediatric data were not presented separately.17,53-55 These

studies were therefore excluded from the pediatric analysis.

Nineteen studies were excluded for the following reasons: nine

discussed cystic fibrosis,56-64 one discussed endemic fluorosis,65

one dealt with Turner’s syndrome,66 six related to type 1 DM

risks,55,67-71 and no specific pediatric data could be extracted in

two articles.72,73

Thus, 13 of 36 articles had extractable pediatric data in

articles relevant to either the prevalence, diagnosis, prognosis, or

treatment of IFG and/or IGT. The information from these

articles forms the basis of the analysis that follows.

Most studies (12 out of 13) addressed the prevalence of IFG

or IGT in various at-risk populations and in the population at

large. Two studies compared IFG and IGT diagnosis in

children. Four studies examined longitudinal followup of a

cohort of children and addressed the prognosis of IFG or IGT.

One study examined treatment in an open-label trial with

metformin. 

Prevalence. As DM in childhood was initially recognized in

Aboriginal populations, most prevalence studies examine these

groups. Population-based prevalence of IGT in childhood

Aboriginal populations varies from 3.5 percent74 in Tuvalu to

6.25 percent of Australian Aboriginals aged 7 to 18 years.75

The prevalence of IFG has been studied in one populationbased study. The Third National Health and Nutrition

Examination Survey (NHANES III), conducted from 1988 to

1994, measured fasting glucose in 1,083 adolescents age 12 to

19. IFG (glucose 6.1 – 6.9 mmol/L) was present in 1.8

percent (n = 20/1,083). Of these 20 children, 4 were nonHispanic white, 9 were non-Hispanic black, and 7 were

Mexican American. The majority of the children were

overweight (mean BMI at 86th percentile), but the range

extended from the 10th to 99th percentile. Prevalence of IGT

in children not “at-risk” is available from the control group of a

single study in which 2.5 percent of 80 children age 10 to 16

had IGT.76

The prevalence of IGT in obese children has been examined

in two studies77,78 of children referred to a tertiary care center for

obesity management; IGT was found in 25 percent of children

(age 4 to 10 years) and 21 percent of adolescents (age 11 to 18

years) in a U.S. study and in 4.2 percent of 6- to 18-year-olds

using the same diagnostic criteria in an Italian population. In

the U.S. study, 51 percent of those with IGT were nonHispanic white, 30 percent were non-Hispanic black, and 19

percent were Hispanic (compared to 58 percent, 23 percent,

and 19 percent, respectively, in the population studied).

“Silent” DM was diagnosed in four participants (two nonHispanic black and two Hispanic). 

Other “at-risk” populations have been identified. These

include children with a history of DM in first degree relatives.

In a study of 150 Latino children with a family history of DM,

28 percent were noted to have IGT.

79 Furthermore, 25 percent

of Hispanic children whose sibling had type 2 DM had IGT.

Offspring of mothers with pregestational or gestational DM

(ODM) also have a higher prevalence of IGT. In a

longitudinal study, the prevalence of IGT in ODM was 1.2

percent in children < 5 years (n = 168), 5.4 percent in 5- to 9-

year-olds (n = 111), and 19.3 percent (95 percent CI 12.1 to

28.6) in 10- to 16-year-olds (compared to 2.5 percent [95

percent CI 0.4 to 8.1] in controls).76 Although the control

group was somewhat lighter (BMI 20.3 ± 4.0 versus 22.8 ± 5.4

kg/m2) and had 37 percent of participants other than

Caucasian compared to 51 percent in the ODM group, it is

unlikely that these differences would account for the difference

in IGT prevalence. Within this same cohort, 36 percent of

those in the ODM group have had at least one abnormal

OGTT result by 14 to 17 years of age.80

Finally, 11 of 21 adolescents with polycystic ovary syndrome

had abnormal OGTT results (9 IGT, 2 DM). 

The prevalence of IGT is related to increasing age in several

studies, but few studies have examined children less than 10

years of age. Children under 10 with obesity have IGT rates

comparable to adolescents, although type 2 DM is reported

with much less frequency in this young group. Two

longitudinal studies with repeated OGTT in Aboriginal and

ODM children suggest that rates of IGT increase with

increasing age, particularly during the peripubertal period. 

Diagnosis. A comparison of IGT with IFG is presented in

two articles,77,78 and IFG and hemoglobin A1c are compared in

the NHANES III study.

81 In obese children, 6.6 percent of

children78 and less than 0.08 percent of children and

adolescents77 with IGT had IFG, indicating that this method of

screening for IGT is very insensitive. 
8

Similarly, hemoglobin A1c is a poor screen for IFG in

children. The reproducibility of OGTT testing has not been

well studied. Sinha et al.77 showed that, upon retesting, 10 of

10 children (4 with normal glucose tolerance and 6 with IGT)

had the same categorization 3 months later. One article82

included in the full review for reproducibility of diagnosis that

included adolescents concluded that the reliability of test results

was likely lower in younger populations.

Prognosis. The prognosis of IGT in childhood and

adolescence has not been well studied. Three studies had

longitudinal data in IGT, but the numbers were very small and

did not allow a prediction or rate of conversion from IGT to

DM. All of these longitudinal studies were in high-risk

populations (two in Aboriginal populations in the United

States and the South Pacific) and one in ODM. 

Treatment. Treatment of IGT in childhood has been

examined in a single small open-label trial of metformin for 3

months in 15 adolescents with polycystic ovary syndrome and

IGT.83 Eight of 15 children had normal glucose tolerance when

re-evaluated after 3 months of metformin therapy. This was

associated with a significant decline in BMI, although there was

no significant change in fat mass. 

Discussion

Diagnosis 

An accurate diagnosis of DM is required because the

consequences for the individual are considerable and lifelong.

The diagnosis of IFG or IGT is used as a risk indicator for

future DM and/or CVD. The problem with these arbitrary

classifications is that test reproducibility is poor, and this

encourages repeat testing that adds to the uncertainty and

confusion of the diagnosis when results are different. 

Reproducibility of IGT and IFG. The observed

reproducibility for both IGT and IFG classification in these

studies was roughly 50 percent. The kappa coefficients for the

IGT category were quite low and indicate overall fair

agreement. The potential factors contributing to the variation

and poor reproducibility were not assessed for this review. 

The probability that a significant change has occurred in

serial measurements can be estimated by calculating the

reference change value (RCV). For FPG, the RCV = 21/2 * 1.96

* (1.42 + 6.32)

1/2 or 17.9 percent. For 2-hr PG, the RCV = 21/2

* 1.96 * (1.42 + 16.62)

1/2 or 46.4 percent. The difference

between two fasting glucose values would therefore need to be

greater than 17.9 percent to be significantly different. A lower

RCV would increase the sensitivity to change, or reduce the

variation noise, and could be achieved if the analytical and/or

the biological variation are lowered. In the best case scenario,

the lowest biological variability reported for fasting glucose was

an FPG CVI of 4.8 percent.84 If this value is used along with

an intra-laboratory imprecision of 1 percent and no bias, the

RCV can be reduced to 13.6 percent. This is the very best or

lowest amount of variation possible for a fasting plasma glucose

measurement. 

Comparison of IFG and IGT diagnosis. This review also

compared among studies the proportion of participants

classified as IGT (2-hr PG), IGT (FPG and 2-hr PG), I-IGT,

IFG, I-IFG, and IGT/IFG. Comparisons among these

categories were statistically significant except for I-IGT versus

IFG and I-IFG versus IGT/IFG. This exemplifies the

importance of clearly distinguishing categories as this can affect

the proportion of study subjects and the conclusions from

prognosis and treatment data. 

The reproducibility for both IGT and IFG categorization is

poor by both observed and kappa analysis. Because of the large

variability in glucose measurement, the absolute FPG and 2-hr

PG measurements may be more informative than

categorization into IFG and IGT, respectively. Comparison of

IGT and IFG categories shows a wide degree of variation

among populations. The prevalence of IGT is greater than for

IFG in almost all studies. High-risk populations have an equal

or greater proportion of IFG compared to IGT diagnoses.

Statistically, the proportion of study participants classified as

IGT by 2-hr PG alone is greater than if the diagnostic criteria

of both 2-hr PG and FPG are used. This will affect the

conclusions of prognosis and possibly treatment data in

population studies using only the 2-hr PG concentration

(WHO epidemiological criteria).

Prognosis 

This review provides further evidence of the relevance of the

OGTT as a diagnostic test. Despite the many shortcomings of

the OGTT reviewed here, it detects a very high-risk group for

future DM and may either need to be more accessible to

clinicians or replaced by a simpler test that provides comparable

predictive information. The OGTT also detects a group at risk

for CVD; and if IGT is causally related to CVD, the AR

estimates suggest that its treatment may reduce CVD risk by as

much as 20 percent to 40 percent. 

These studies highlight the relevance of fasting and postchallenge glucometabolic abnormalities to clinically relevant

outcomes. Intervention studies have already shown that DM

can be prevented in these individuals with some interventions.

Risk for progression to DM. The results of this systematic

review clearly show that IGT, IFG, I-IGT, I-IFG, and

combined IGT/IFG are strong risk factors for future DM. The

combined group has the strongest risk factor, and this

observation is not surprising given the fact that the diagnostic

threshold for DM is just a farther point along the dysglycemic

spectrum than the threshold for either IFG or IGT.

Nevertheless, these large risk estimates clearly do suggest that

any clinical approach directed at preventing DM should

include a policy of detecting IFG or IGT. They do not support
suggestions that measures of glucose are not necessary to detect

individuals at risk for future DM. However, such a policy may

be useful to reduce the number of individuals who require a

glucose test.

Risk for CVD outcomes. The reviewed studies provide

confirmation that IFG or IGT are risk factors for fatal and

nonfatal CVD and are consistent with other studies that were

excluded because whole blood or capillary samples were used to

assay glucose levels. Moreover, the suggestion that IGT is a

greater risk factor for CVD than IFG is supported by this

systematic review but is based on the findings of a single

study.85 This is not surprising given the fact that IGT is

detected in response to stressing the physiology with a

nonphysiological glucose load, thus exposing a degree of

metabolic dysregulation that would not be apparent on the

basis of fasting glucose levels alone.

Treatment 

Prevention of DM: lifestyle interventions. This

systematic review clearly demonstrates that DM can be

prevented or delayed with lifestyle modification. All but one of

the five studies that evaluated a combined diet and exercise

program found significant benefits, with a pooled relative risk

of 54 percent for progression to diabetes. The only trial to

show no effect of a combined diet and exercise intervention was

of short duration (6-month followup). Interventions with diet

or exercise alone showed mixed results between studies. Efforts

to modify dietary intake and activity levels in individuals at

increased risk for developing DM are clearly warranted. 

Prevention of DM: pharmacotherapeutic interventions.

Only four trials to date have evaluated the effect of

pharmacotherapeutic interventions on the risk for developing

DM in individuals with IGT. Two of these studies, one

involving acarbose and one involving metformin, demonstrated

reduced rates of progression to DM with a relative risk

reduction of about 25 percent. Given this relative paucity of

information, recommendation of pharmacological intervention

for the prevention of DM would seem premature at this time. 

Pediatric Population

Despite the paucity of population-based studies, several

cohort studies in high-risk groups suggest that IGT is a

significant and potentially growing problem in the pediatric

population. Indeed, larger proportions of children may have

IGT than is currently recognized. It is critical to acquire an

understanding of the precursors of type 2 DM development in

children and youth. However, few conclusions can be made

based on the current pediatric literature. Further investigation

of prevalence in children and adolescents is necessary to clarify

the magnitude of the problem.

Diagnosis. The reproducibility of the diagnosis of IGT

with OGTT testing and the clinical significance of IFG versus

IGT have not been widely examined in the pediatric literature.

Although young age has been implicated as a predictor of poor

reproducibility of OGTT results in adults, suggesting that

reproducibility may be worse in adolescents and children, this

was not the experience in one small pediatric study (n = 10).77

Clearly, further investigation of the reliability of diagnostic

criteria for IFG and IGT is warranted. Furthermore, given the

importance of the prevention of type 2 DM, it may be

advantageous to identify children who have disturbed glucose

metabolism (insulin resistance and/or beta cell dysfunction)

before they develop IFG or IGT. 

Prognosis. An understanding of how disturbed glucose

metabolism progresses to IGT and to type 2 DM is key to the

primary prevention of DM. Currently, details of this

progression are completely lacking in the pediatric population.

Prevalence data for type 2 DM suggest prognosis may vary with

age, pubertal status, and ethnicity. Family history of DM,

exposure to a diabetic environment in utero, fitness and

physical activity, fat distribution, and characteristics of

nutritional intake may also influence the prognosis of IFG and

IGT. Longitudinal studies are required to examine mid- and

long-term outcomes of IGT and the determinants of outcome

in multiple ethnic groups and across a broad age range.

Investigation of other metabolic outcomes in children and

adolescents with IFG and IGT would further improve our

understanding of disturbance in health in this population.

Better understanding of the prognosis of IGT in children and

adolescents will clarify the need for intervention and contribute

to optimal intervention study design. 

Treatment. A single study has described the

pharmacological treatment of IGT, and no randomly controlled

lifestyle intervention has been reported in the pediatric age

group. Given the increasing rates of IFG/IGT, research on the

optimal approach to the management of these children should

be a research priority. This research should compare lifestyle

intervention and pharmacotherapy and identify optimal

methodologies for young populations and their families.

Although glycemic status is a key outcome variable, other

metabolic and psychosocial outcomes should also be examined. 

Conclusions

Analysis from this systematic evidence review suggests the

following:

• Diagnosis—The reproducibility for both IGT and IFG

categorization is poor. Therefore the absolute FPG and 2-

hr PG measurement may be more informative than

categorization into IFG and IGT respectively. The

distribution of study participants in the IGT category

varies significantly with the diagnostic criteria used. This

will affect findings in epidemiological studies evaluating

prognosis and treatment. 

• Prognosis—Many studies consistently show that both

IFG and IGT are strong risk factors for the development

9
of DM. Fewer studies also show that they are risk factors

for future CVD and all-cause mortality. 

• Treatment—There is evidence that combined diet and

exercise, as well as drug therapy (metformin, acarbose),

may be effective at preventing progression to DM in IGT

subjects. 

• Pediatric population—IGT is relatively common in

childhood, particularly in children who are overweight.

Further clarification of population-based prevalence and

investigation to improve understanding of the diagnosis,

clinical significance, and optimal management of IFG and

IGT in childhood is required.

Availability of the Full Report

The full evidence report from which this summary was taken

was prepared for the Agency for Healthcare Research and

Quality (AHRQ) by the McMaster Evidence-based Practice

Center under Contract No. 290-02-0020. It is expected to be

available in September 2005. At that time, printed copies may

be obtained free of charge from the AHRQ Publications

Clearinghouse by calling 800-358-9295. Requesters should ask

for Evidence Report/Technology Assessment No. 128,

Diagnosis, Prognosis, and Treatment of Impaired Glucose Tolerance

and Impaired Fasting Glucose. In addition, Internet users will be

able to access the report and this summary online through

AHRQ’s Web site at www.ahrq.gov.

Suggested Citation

Santaguida PL, Balion C, Hunt D, Morrison K, Gerstein H,

Raina P, Booker L, Yazdi H. Diagnosis, Prognosis, and

Treatment of Impaired Glucose Tolerance and Impaired Fasting

Glucose. Summary, Evidence Report/Technology Assessment

No. 128. (Prepared by the McMaster Evidence-based Practice

Center under Contract No. 290-02-0020). AHRQ Pub. No

05-E026-1. Rockville, MD: Agency for Healthcare Research

and Quality. August 2005.

References

1. Wild S, Roglic G, Green A, et al. Global prevalence of diabetes:

estimates for the year 2000 and projections for 2030. Diabetes Care

2004 May;27(5):1047-53.

2. Reference Manager [computer program]. ISI Research Soft. 10.

Carlsbad, CA, USA: ISI Research Soft; 2001.

3. Oremus M, Wolfson C, Perrault A, et al. Interrater reliability of the

modified Jadad quality scale for systematic reviews of Alzheimer’s

disease drug trials. Dement Geriatr Cogn Disord 2001

May;12(3):232-6.

4. MacKay M, Scanlan A, Olsen L, et al. Looking for the evidence: a

systematic review of prevention strategies addressing sport and

recreational injury among children and youth. J Sci Med Sport

2004 Mar;7(1):58-73.

5. Mooy JM, Grootenhuis PA, de Vries H, et al. Intra-individual

variation of glucose, specific insulin and proinsulin concentrations

measured by two oral glucose tolerance tests in a general Caucasian

population: the Hoorn Study. Diabetologia 1996 Mar;39(3):298-

305.

6. de Vegt F, Dekker JM, Stehouwer CD, et al. Similar 9-year

mortality risks and reproducibility for the World Health

Organization and American Diabetes Association glucose tolerance

categories: the Hoorn Study. Diabetes Care 2000 Jan;23(1):40-4.

7. Farrer M, Fulcher G, Albers CJ, et al. Patients undergoing coronary

artery bypass graft surgery are at high risk of impaired glucose

tolerance and diabetes mellitus during the first postoperative year.

Metabolism 1995 Aug;44(8):1016-27.

8. Ko GTC, Chan JCN, Woo J, et al. The reproducibility and

usefulness of the oral glucose tolerance test in screening for diabetes

and other cardiovascular risk factors. ANN CLIN BIOCHEM

1998;35(1):62-7.

9. Ko GT, Chan JC, Woo J, et al. Use of the 1997 American Diabetes

Association diagnostic criteria for diabetes in a Hong Kong Chinese

population. Diabetes Care 1998 Dec;21(12):2094-7.

10. de Vegt F, Dekker JM, Jager A, et al. Relation of impaired fasting

and postload glucose with incident type 2 diabetes in a Dutch

population: The Hoorn Study. JAMA 2001 Apr 25;285(16):2109-

13.

11. Gabir MM, Hanson RL, Dabelea D, et al. The 1997 American

Diabetes Association and 1999 World Health Organization criteria

for hyperglycemia in the diagnosis and prediction of diabetes.

Diabetes Care 2000 Aug;23(8):1108-12.

12. Qiao Q, Nakagami T, Tuomilehto J, et al. Comparison of the

fasting and the 2-h glucose criteria for diabetes in different Asian

cohorts. Diabetologia 2000 Dec;43(12):1470-5.

13. Kousta E, Lawrence NJ, Penny A, et al. Implications of new

diagnostic criteria for abnormal glucose homeostasis in women with

previous gestational diabetes. Diabetes Care 1999 Jun;22(6):933-7.

14. Alberti KGMM, Zimmet PZ. Definition, diagnosis and

classification of diabetes mellitus and its complications part 1:

Diagnosis and classification of diabetes mellitus - Provisional report

of a WHO consultation. Diabet Med 1998 Jul;15(7):539-53.

15. Norman RJ, Masters L, Milner CR, et al. Relative risk of

conversion from normoglycaemia to impaired glucose tolerance or

non-insulin dependent diabetes mellitus in polycystic ovarian

syndrome. Hum Reprod 2001 Sep;16(9):1995-8.

16. Wein P, Beischer N, Harris C, et al. A trial of simple versus

intensified dietary modification for prevention of progression to

diabetes mellitus in women with impaired glucose tolerance. Aust

N Z J Obstet Gynaecol 1999;39(2):162-6.

17. Pettitt DJ, Narayan KM, Hanson RL, et al. Incidence of diabetes

mellitus in women following impaired glucose tolerance in

pregnancy is lower than following impaired glucose tolerance in the

non-pregnant state. Diabetologia 1996 Nov;39(11):1334-7.

18. Goldberg RB, Mellies MJ, Sacks FM, et al. Cardiovascular events

and their reduction with pravastatin in diabetic and glucoseintolerant myocardial infarction survivors with average cholesterol

levels: subgroup analyses in the cholesterol and recurrent events

(CARE) trial. The Care Investigators. Circulation

1998;98(23):2513-9.

19. Larsson H, Lindgarde F, Berglund G, et al. Prediction of diabetes

using ADA or WHO criteria in post-menopausal women: a 10-year

follow-up study. Diabetologia 2000 Oct;43(10):1224-8.

20. Charles MA, Eschwege E, Thibult N, et al. The role of nonesterified fatty acids in the deterioration of glucose tolerance in

Caucasian subjects: results of the Paris Prospective Study.

Diabetologia 1997 Sep;40(9):1101-6.

10
21. Balkau B, Eschwege E, Ducimetiere P, et al. The high risk of death

by alcohol related diseases in subjects diagnosed as diabetic and

impaired glucose tolerant: the Paris Prospective Study after 15 years

of follow-up. J Clin Epidemiol 1991;44(6):465-74.

22. Fontbonne A, Tchobroutsky G, Eschwege E, et al. Coronary heart

disease mortality risk: plasma insulin level is a more sensitive marker

than hypertension or abnormal glucose tolerance in overweight

males. The Paris Prospective Study. Int J Obes 1988;12(6):557-65.

23. Fontbonne AM, Eschwege EM. Insulin and cardiovascular disease.

Paris Prospective Study. Diabetes Care 1991 Jun;14(6):461-9.

24. Fontbonne A, Eschwege E. Insulin-resistance, hypertriglyceridaemia

and cardiovascular risk: the Paris Prospective Study. Diabete Metab

1991 May;17(1 Pt 2):93-5.

25. Balkau B, Eschwege E, Fontbonne A, et al. Cardiovascular and

alcohol-related deaths in abnormal glucose tolerant and diabetic

subjects. Diabetologia 1992 Jan;35(1):39-44.

26. Balkau B, Eschwege E, Papoz L, et al. Risk factors for early death in

non-insulin dependent diabetes and men with known glucose

tolerance status. BMJ 1993 Jul 31;307(6899):295-9.

27. Balkau B, Forhan A, Eschwege E. Two hour plasma glucose is not

unequivocally predictive for early death in men with impaired

fasting glucose: more results from the Paris Prospective Study.

Diabetologia 2002 Sep;45(9):1224-30.

28. Charles MA, Fontbonne A, Thibult N, et al. Risk factors for

NIDDM in white population. Paris prospective study. Diabetes

1991 Jul;40(7):796-9.

29. Ammari F, Batieha A, Jaddou PHH, et al. A natural history of

impaired glucose tolerance in North Jordan. Practical Diabetes

International 1998;15(5):139-40.

30. Puavilai G, Tiewtranon V, Pensuwan S, et al. Impaired glucose

tolerance in Thai adults: status of glucose tolerance after 2-year

follow up. J Med Assoc Thai 1987 Mar;70 Suppl 2:68-76.

31. Inoue I, Takahashi K, Katayama S, et al. A higher proinsulin

response to glucose loading predicts deteriorating fasting plasma

glucose and worsening to diabetes in subjects with impaired glucose

tolerance. Diabet Med 1996;13(4):330-6.

32. Keech A, Colquhoun D, Best J, et al. Secondary prevention of

cardiovascular events with long-term pravastatin in patients with

diabetes of impaired fasting glucose: Results from the LIPID trial.

Diabetes Care 2003;26(10):2713-21.

33. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin,

and cardiovascular disease: subgroup analysis from the Department

of Veterans Affairs high-density lipoprotein intervention trial (VAHIT). Arch Intern Med 2002;162(22):2597-604.

34. Bonora E, Kiechl S, Oberhollenzer F, et al. Impaired glucose

tolerance, Type II diabetes mellitus and carotid atherosclerosis:

prospective results from the Bruneck Study. Diabetologia 2000

Feb;43(2):156-64.

35. Fisman EZ, Motro M, Tenenbaum A, et al. Impaired fasting

glucose concentrations in nondiabetic patients with ischemic heart

disease: a marker for a worse prognosis. Am Heart J 2001

Mar;141(3):485-90.

36. Tenenbaum A, Motro M, Fisman EZ, et al. Status of glucose

metabolism in patients with heart failure secondary to coronary

artery disease. Am J Cardiol 2002;90(5):529-32.

37. Saydah SH, Loria CM, Eberhardt MS, et al. Subclinical states of

glucose intolerance and risk of death in the U.S. Diabetes Care

2001 Mar;24(3):447-53.

38. Tominaga M, Eguchi H, Manaka H, et al. Impaired glucose

tolerance is a risk factor for cardiovascular disease, but not impaired

fasting glucose. The Funagata Diabetes Study. Diabetes Care 1999

Jun;22(6):920-4.

39. Saydah SH, Loria CM, Eberhardt MS, et al. Abnormal glucose

tolerance and the risk of cancer death in the United States. Am J

Epidemiol 2003 Jun 15;157(12):1092-100.

40. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the

incidence of type 2 diabetes with lifestyle intervention or

metformin. N Engl J Med 2002;346(6):393-403.

41. Pan XR, Li GW, Hu YH, et al. Effects of diet and exercise in

preventing NIDDM in people with impaired glucose tolerance. The

Da Qing IGT and Diabetes Study. Diabetes Care 1997;20(4):537-

44.

42. Liao D, Asberry PJ, Shofer JB, et al. Improvement of BMI, body

composition, and body fat distribution with lifestyle modification in

Japanese Americans with impaired glucose tolerance. Diabetes Care

2002 Sep;25(9):1504-10.

43. Lindstrom J, Eriksson JG, Valle TT, et al. Prevention of diabetes

mellitus in subjects with impaired glucose tolerance in the finnish

diabetes prevention study: results from a randomized clinical trial. J

Am Soc Nephrol 2003;14(7 Suppl 2):S108-S113

44. Oldroyd JC, Unwin NC, White M, et al. Randomised controlled

trial evaluating the effectiveness of behavioural interventions to

modify cardiovascular risk factors in men and women with impaired

glucose tolerance: outcomes at 6 months. Diabetes Res Clin Pract

2001;52(1):29-43.

45. Weber-Hamann B, Hentschel F, Kniest A, et al. Hypercortisolemic

depression is associated with increased intra-abdominal fat.

Psychosomatic-Medicine 2002;64(2):274-7.

46. Chiasson JL, Josse RG, Gomis R, et al. Acarbose for prevention of

type 2 diabetes mellitus: the STOP-NIDDM randomised trial.

Lancet 2002;359(9323):2072-7.

47. Lehtovirta M, Forsen B, Gullstrom M, et al. Metabolic effects of

metformin in patients with impaired glucose tolerance. Diabet Med

2001;18(7):578-83.

48. Li CL, Pan CY, Lu JM, et al. Effect of metformin on patients with

impaired glucose tolerance. Diabet Med 1999;16(6):477-81.

49. Vermes E, Ducharme A, Bourassa MG, et al. Enalapril reduces the

incidence of diabetes in patients with chronic heart failure: insight

from the Studies of Left Ventricular Dysfunction (SOLVD).

Circulation 2003 Mar 11;107(9):1291-6.

50. Chiasson JL, Josse RG, Gomis R, et al. Acarbose treatment and the

risk of cardiovascular disease and hypertension in patients with

impaired glucose tolerance: the STOP-NIDDM trial. JAMA

2003;290(4):486-94.

51. Eriksson J, Tuominen J, Valle T, et al. Aerobic endurance exercise or

circuit-type resistance training for individuals with impaired glucose

tolerance? Horm Metab Res 1998 Jan;30(1):37-41.

52. Uusitupa MI, Mykkanen L, Siitonen O, et al. Chromium

supplementation in impaired glucose tolerance of elderly: effects on

blood glucose, plasma insulin, C-peptide and lipid levels. Br J Nutr

1992;68(1):209-16.

53. Nagi DK, Knowler WC, Charles MA, et al. Early and late insulin

response as predictors of NIDDM in Pima Indians with impaired

glucose tolerance. Diabetologia 1995 Feb;38(2):187-92.

54. Motala AA, Omar MA, Gouws E. High risk of progression to

NIDDM in South-African Indians with impaired glucose tolerance.

Diabetes 1993 Apr;42(4):556-63.

55. Rosenbloom AL, Hunt SS. Prognosis of imparied glucose tolerance

in children with stress hyperglycemia, symptoms of hypoglycemia,

or asymptomatic glucosuria. J Pediatr 1982 Sep;101(3):340-4.

11
www.ahrq.gov

AHRQ Pub. No. 05-E026-1

August 2005

ISSN 1530-440X

56. Solomon MP, Wilson DC, Corey M, et al. Glucose intolerance in

children with cystic fibrosis. J Pediatr 2003 Feb;142(2):128-32.

57. Cucinotta D, De Luca F, Gigante A, et al. No changes of insulin

sensitivity in cystic fibrosis patients with different degrees of glucose

tolerance: an epidemiological and longitudinal study. European

Journal of Endocrinology 1994 Mar;130(3):253-8.

58. Rakotoambinina B, Delaisi B, Laborde K, et al. Insulin responses to

intravenous glucose and the hyperglycemic clamp in cystic fibrosis

patients with different degrees of glucose tolerance. Pediatr Res

1994;36(5):667-71.

59. Austin A, Kalhan SC, Orenstein D, et al. Roles of insulin resistance

and beta-cell dysfunction in the pathogenesis of glucose intolerance

in cystic fibrosis. J Clin Endocrinol Metab 1994;79(1):80-5.

60. Cucinotta D, De Luca F, Arrigo T, et al. First-phase insulin

response to intravenous glucose in cystic fibrosis patients with

different degrees of glucose tolerance. J Pediatr Endocrinol

1994;7(1):13-7.

61. Peraldo M, Fasulo A, Chiappini E, et al. Evaluation of glucose

tolerance and insulin secretion in cystic fibrosis patients. Horm Res

1998;49(2):65-71.

62. Milla CE, Warwick WJ, Moran A. Trends in pulmonary function in

patients with cystic fibrosis correlate with the degree of glucose

intolerance at baseline. Am J Respir Crit Care Med 2000 Sep;162(3

Pt 1):891-5.

63. Garagorri JM, Rodriguez G, Ros L, et al. Early detection of

impaired glucose tolerance in patients with cystic fibrosis and

predisposition factors. J Pediatr Endocrinol Metab 2001;14(1):53-

60.

64. Arrigo T, Cucinotta D, Conti NS, et al. Longitudinal evaluation of

glucose tolerance and insulin secretion in non-diabetic children and

adolescents with cystic fibrosis: results of a two-year follow-up. Acta

Paediatr 1993 Mar;82(3):249-53.

65. Trivedi N, Mithal A, Gupta SK, et al. Reversible impairment of

glucose tolerance in patients with endemic fluorosis. Diabetologia

1993;36(9):826-8.

66. Haeusler G, Frisch H. Growth hormone treatment in Turner’s

syndrome: Short and long-term effects on metabolic parameters.

Clin Endocrinol (Oxf) 1992;36(3):247-54.

67. Schulz B, Witt S, Hildmann W, et al. Islet cell antibodies in

individuals at increased risk for IDDM. Exp Clin Endocrinol 1984

Apr;83(2):192-8.

68. Gale EA, European Nicotinamide Diabetes Intervention Trial

Group. Intervening before the onset of Type 1 diabetes: baseline

data from the European Nicotinamide Diabetes Intervention Trial

(ENDIT). Diabetologia 2003 Mar;46(3):339-46.

69. Ratzman K-P, Strese J, Rjasanowski I. Prevalence of islet cell

antibodies (ICA) and islet cell surface antibodies (ICSA) in children

and adolescents with antecedent mumps infection. Exp Clin

Endocrinol 1984;83(2):199-202.

70. Rakotoambinina B, Timsit J, Deschamps I, et al. Insulin responses

to intravenous glucose, intravenous arginine and a hyperglycaemic

clamp in ICA-positive subjects with different degrees of glucose

tolerance. Diabetes Metab 1997 Feb;23(1):43-50.

71. Lorini R, Alibrandi A, Vitali L, et al. Risk of type 1 diabetes

development in children with incidental hyperglycemia: A

multicenter Italian study. Diabetes Care 2001 Jul;24(7):1210-6.

72. Hanley AJ, McKeown-Eyssen G, Harris SB, et al. Cross-sectional

and prospective associations between abdominal adiposity and

proinsulin concentration. J Clin Endocrinol Metab 2002

Jan;87(1):77-83.

73. Harris SB, Zinman B, Hanley A, et al. The impact of diabetes on

cardiovascular risk factors and outcomes in a native Canadian

population. Diabetes Res Clin Pract 2002;55(2):165-73.

74. Zimmet PZ, Collins VR, Dowse GK, et al. Hyperinsulinaemia in

youth is a predictor of Type 2 (non-insulin-dependent) diabetes

mellitus. Diabetologia 1992;35(6):534-41.

75. Braun B, Zimmermann MB, Kretchmer N, et al. Risk factors for

diabetes and cardiovascular disease in young Asutralian Aborigines.

Diabetes Care 1996 May;19(5):472-9.

76. Silverman BL, Metzger BE, Cho NH, et al. Impaired glucose

tolerance in adolescent offspring of diabetic mothers: relationship to

fetal hyperinsulinism. Diabetes Care 1995 May;18(5):611-7.

77. Sinha R, Fisch G, Teague B, et al. Prevalence of impaired glucose

tolerance among children and adolescents with marked obesity. N

Engl J Med 2002 Mar 14;346(11):802-10.

78. Invitti C, Guzzaloni G, Gilardini L, et al. Prevalence and

concomitants of glucose intolerance in European obese children and

adolescents. Diabetes Care 2003 Jan;26(1):118-24.

79. Goran MI, Bergman RN, Avila Q, et al. Impaired glucose tolerance

and reduced beta-cell function in overweight Latino children with a

positive family history for type 2 diabetes. J Clin Endocrinol Metab

2004 Jan;89(1):207-12.

80. Silverman BL, Rizzo TA, Cho NH, et al. Long-term effects of the

intrauterine environment. The Northwestern University Diabetes in

Pregnancy Center. Diabetes Care 1998 Aug;21 Suppl 2:B142-B149

81. Fagot-Campagna A, Saaddine JB, Flegal KM, et al. Diabetes,

impaired fasting glucose, and elevated HbA1c in U.S. adolescents:

the Third National Health and Nutrition Examination Survey.

Diabetes Care 2001 May;24(5):834-7.

82. Swai ABM, McLarty DG, Kitange HM, et al. Study in Tanzania of

impaired glucose tolerance: Methodological myth? Diabetes

1991;40(4):516-20.

83. Arslanian SA, Lewy V, Danadian K, et al. Metformin therapy in

obese adolescents with polycystic ovary syndrome and impaired

glucose tolerance: amelioration of exaggerated adrenal response to

adrenocorticotropin with reduction of insulinemia/insulin resistance.

J Clin Endocrinol Metab 2002 Apr;87(4):1555-9.

84. Widjaja A, Morris RJ, Levy JC, et al. Within- and between-subject

variation in commonly measured anthropometric and biochemical

variables. Clin Chem 1999;45(4):561-6. 

85. Hassan IA, Wickramasinghe YA, Spencer SA. Effect of a change in

global metabolic rate on peripheral oxygen consumption in

neonates. Archives of Disease in Childhood: Fetal & Neonatal

Edition 2003 Mar;88(2):F143-F146