Reproducibility of IGT and IFG Tests

Five reports of four studies^5–9 assessed the reproducibility of the OGTT for diagnosis of IGT and three reports of two studies^{6, 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 studies^10–13 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.

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 studies^{18, 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:

1.

PTCA and coronary artery bypass graft.

2.

Stroke.

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 studies^{21, 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 studies^{25, 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 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.
• 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 studies^{21, 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 studies^{27, 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.

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 studies^{16, 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% 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 studies^{47, 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% 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.

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 RCTs^{43, 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 trials^{47, 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 study^{46, 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.

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 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 had IGT.⁷⁶

The prevalence of IGT in obese children has been examined in two studies^{77, 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.

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.