Evidence Report/Technology Assessment: Number 128
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Introduction / Key Questions / Methods / Results / Discussion / Conclusions / Availability of Full Report / References
Authors: Santaguida PL, Balion C, Hunt D, Morrison K, Gerstein H, Raina P,
Booker L, Yazdi H.
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 straight-forward.
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
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.
Return to Contents
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:
- 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?
- Prognosis—For those identified with IFG
or IGT, what are the short- and long-term
risks for developing the following outcomes:
Does this risk vary by subpopulation, such as
sex, race, obesity, age or other risk factors
(e.g., blood pressure, elevated lipid levels)?
- Progression to DM or reversion towards
normal glucose tolerance or fasting
- Cardiovascular events and stroke (fatal
- Microvascular disease, specifically
retinopathy and nephropathy as
measured by proteinuria,
microalbuminuria, elevated creatinine,
albumin-to-creatinine ratio in the urine,
dialysis, or renal transplant.
- Treatment—What is the effectiveness of
pharmaceutical and behavioral interventions
for reducing the risks associated with IFG or
IGT on the following outcomes:
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
- Delay in onset of DM or reversion towards normal
glucose tolerance or fasting glucose level.
- Reducing risk for cardiovascular events and stroke
(fatal and nonfatal).
- Reducing risk for microvascular disease, including
early markers such as retinopathy/proteinuria.
- Improving other metabolic parameters, independently
associated with increased risk, such as blood pressure
and lipid levels.
- Pediatric population—What is known of the
development of IFG or IGT in the pediatric population?
Return to Contents
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.
inclusion/exclusion criteria were used for the testing procedure
- 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
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
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:
- Isolated IGT (I-IGT).
- Isolated IFG (I-IFG).
- Non-isolated IGT.
- Non-isolated IFG.
- 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
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
Return to Contents
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
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
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
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:
- IGT—2-hr PG 7.8 to 11.0 mmol/L.
- IGT—FPG < 7.8 mmol/L and 2-hr PG 7.8 to 11.0 mmol/L.
- IGT—FPG < 7.0 mmol/L and 2-hr PG 7.8 to 11.0 mmol/L.
- IFG—FPG 6.1 to 6.9 mmol/L.
- I-IGT—FPG < 6.1 mmol/L and 2-hr PG 7.8 to 11.0 mmol/L.
- I-IFG—FPG 6.1 to 6.9 mmol/L and 2-hr PG < 7.8 mmol/L.
- 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 difference.i
- 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 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:
- Combined IFG/IGT.
Findings are summarized for three
main outcomes: progression to DM, cardiovascular disease
(CVD) outcomes (fatal and nonfatal), and mortality.
i. Risk differences are discussed in the full evidence report.
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% CI
varied as a function of the diagnostic groups in the following
- IGT group— range 3.58 (95% 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% CI
are as follows:
- IGT group—6.02 (95% 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
- 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% 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:
- PTCA and coronary artery bypass graft.
- 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
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
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
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% 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% 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
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,
iiBased on a single study.
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.
- IFG group—0.56 to 1.39.
Unadjusted annualized relative risk. The all-cause mortality
estimates along with 95% CI are as follows:
- IGT group—range 1.36 (95% 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% CI 1.09 to 1.86) for the IGT group and 1.21 (95% 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.
Progression to DM or reversion to normal
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
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% 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% CI 0.17 to 0.43). Two smaller studies47,48 in
people with IGT found no difference in those treated with
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% 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% 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.
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
Effects on blood pressure and lipid levels
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
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.
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
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
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 population-based
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 non-Hispanic 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
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 non-Hispanic 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 non-Hispanic 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% CI 12.1 to
28.6) in 10- to 16-year-olds (compared to 2.5 percent [95% 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.
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.
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