Pioglitazone does not enhance the effectiveness of lifestyle modification in preventing conversion of impaired glucose tolerance to diabetes in Asian Indians: results of the Indian Diabetes Prevention Programme-2 (IDPP-2)

Aims/hypothesis  The objective of this prevention programme was to study whether combining pioglitazone with lifestyle modification would enhance the efficacy of lifestyle modification in preventing type 2 diabetes in Asian Indians with impaired glucose tolerance. Methods  In a community-based, placebo-controlled 3 year prospective study, 407 participants with impaired glucose tolerance (mean age 45.3 ± 6.2 years, mean BMI 25.9 ± 3.3 kg/m²) were sequentially grouped to receive either: lifestyle modification plus pioglitazone, 30 mg (n = 204) or lifestyle modification plus placebo (n = 203). The participants and investigators were blinded to the assignment. The primary outcome was development of diabetes. Results  At baseline, both groups had similar demographic, anthropometric and biochemical characteristics. At year 3, the response rate was 90.2%. The cumulative incidence of diabetes was 29.8% with pioglitazone and 31.6% with placebo (unadjusted HR 1.084 [95% CI 0.753–1.560], p = 0.665). Normoglycaemia was achieved in 40.9% and 32.3% of participants receiving pioglitazone and placebo, respectively (p = 0.109). In pioglitazone group, two deaths and two non-fatal hospitalisations occurred due to cardiac problems; in the placebo group there were two occurrences of cardiac disease. Conclusions/interpretation  Despite good adherence to lifestyle modification and drug therapy, no additional effect of pioglitazone was seen above that achieved with placebo. The effectiveness of the intervention in both groups was comparable with that of lifestyle modification alone, as reported from the Indian Diabetes Prevention Programme-1. The results are at variance with studies that showed significant relative risk reduction in conversion to diabetes with pioglitazone in Americans with IGT. An ethnicity-related difference in the action of pioglitazone in non-diabetic participants may be one explanation. Trial registration: ClinicalTrials.gov NCT00276497 Funding: This study was funded by the India Diabetes Research Foundation     

Metabolic response to oral lipid overload in diabetes and impaired glucose tolerance

Post-prandial hyperglycemia and hypertriglyceridemia have been related to atherogenesis. The aim of this study was to evaluate the response of plasma lipoproteins to a lipid overload in subjects with diabetes (DM), impaired glucose tolerance (IGT) and normals (N). Seventy-seven subjects were selected, 36-85 years, plasma glucose (G)<140 mg/dl and triglycerides (TG)<150 mg/dl; those without diabetes underwent a glucose tolerance test (GTT), which classified them into three groups: N, 2h G<140 mg/dl, n=37; IGT, 2h G 140-200mg/dl, n=20; and DM, previous diabetes or 2h G>200mg/dl, n=20. They were submitted to a clinical evaluation and an oral lipid overload (1000 kcal, 58% fat). Fasting, 4 and 6-h blood samples after the meal were collected for G, insulinaemia (I), TG, cholesterol and their fractions, and HOMA-IR. Fasting and post-lipid overload lipoproteins were similar between groups, but 6h TG was still high in DM versus IGT and N as compared to their 4h values. There was a positive correlation between fasting TG versus 6h TG (r=0.78, p<0.001). We conclude that individuals with impaired glucose tolerance and with diabetes mellitus have a slower plasma reduction of triglycerides after lipid overload, as well as an altered glucose and post-prandial insulin response.     

High incidence of type 2 diabetes and increasing conversion rates from impaired fasting glucose and impaired glucose tolerance to diabetes in Mauritius

OBJECTIVE: To describe the incidence of different stages of glucose intolerance in a population from Mauritius followed over 11 years. RESEARCH DESIGN, METHODS AND SUBJECTS: Population-based surveys were undertaken in the multi-ethnic nation of Mauritius in 1987, 1992 and 1998 with 5083, 6616 and 6291 participants, respectively. Questionnaires, anthropometric measurements, and a 2-h 75-g oral glucose tolerance test were included. Three cohorts aged between 25 and 79 years with classifiable glucose tolerance data were identified; 3680 between 1987 and 1992, 4178 between 1992 and 1998, and 2631 between 1987 and 1998. Glucose tolerance was classified according to WHO 1999 criteria. RESULTS: The incidence rate of type 2 diabetes was higher between 1992 and 1998 than between 1987 and 1992. In men, the incidence was similar between cohorts (24.5 and 25.4 per 1000 person-years) whereas the incidence increased in women (23.3 and 16.4 per 1000 person-years). The incidence of diabetes peaked in the 45-54 year age group and then plateaued or fell. The incidences of impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) decreased in both men and women. Of normoglycaemic subjects at baseline, more women than men developed IGT and more men than women developed IFG. Of those labelled as IFG in 1987, 38% developed diabetes after 11 years. The corresponding figure for IGT was 46%. CONCLUSIONS: In this study, we report changes in incidence rates of glucose intolerance over a 11-year period. In particular, differences between men and women were observed. The increased incidence of IGT in women compared with men, and increased incidence of IFG in men compared with women was consistent with, and explains the sex biases seen in the prevalences of these states.     

Significance of impaired glucose tolerance in an Asian Indian population: a follow-up study

A prospective study was undertaken in 107 Indians with impaired glucose tolerance (IGT) for a period ranging from 2 to 10 years. On follow-up, 32% still had an impaired glucose tolerance, 32% reverted to normal glucose tolerance and 36% developed diabetes. Careful dietary adherence and weight reduction were found to favour normalisation of glucose tolerance. Poor dietary adherence, persistent obesity and weight gain were found to precipitate diabetes. The study stresses the need for intensive diet therapy in individuals with IGT. Insulin responses were heterogeneous in IGT and non-predictive of the follow-up changes in glucose tolerance.     

Progression from impaired fasting glucose and impaired glucose tolerance to diabetes in a high-risk screening programme in general practice: the ADDITION Study,Denmark

AIMS/HYPOTHESIS: To estimate the 1-year progression rates from both IFG and IGT to diabetes in individuals identified in a pragmatic diabetes screening programme in general practice (the ADDITION Study, Denmark [Anglo-Danish-Dutch Study of Intensive Treatment in People with Screen-Detected Diabetes in Primary Care]). METHODS: Persons aged 40-69 years were screened for type 2 diabetes based on a high-risk, stepwise strategy. At baseline, anthropometric measurements, blood samples and questionnaire data were collected. A total of 1,160 persons had IFG or IGT at baseline: 811 (70%) accepted re-examination after 1 year. Glucose tolerance classification was based on the 1999 WHO definition. At follow-up, diabetes was based on one diabetic glucose value of fasting blood glucose or 2-h blood glucose. RESULTS: At baseline, 308 persons had IFG and 503 had IGT. The incidence of diabetes was 17.6 and 18.8 per 100 person-years in the two groups, respectively. CONCLUSIONS/INTERPRETATION: IFG and IGT identified in general practice during a stepwise, high-risk screening programme for type 2 diabetes have high 1-year progression rates to diabetes. Consequently, intensive follow-up and intervention strategies are recommended for these high-risk individuals.     

Metabolic syndrome does not increase angiographic restenosis rates after drug-eluting stent implantation

Metabolic syndrome (MS) is associated with an increased risk of coronary heart disease, stroke, and cardiovascular mortality; but its effect on patients undergoing cardiac revascularization is still unclear. Robust evidence demonstrates that diabetes mellitus and insulin resistance are among the main risk factors for restenosis in patients requiring percutaneous myocardial revascularization. The recent advent of drug-eluting stents (DESs) has significantly reduced the incidence of restenosis compared with bare-metal stents, both in nondiabetic and in diabetic patients. The aim of the study was to evaluate the effect of MS on the risk of binary restenosis in DES implant recipients. One hundred eighty-nine recipients of successful DES implants performed between January and March 2005 for stable coronary artery disease underwent 1-year clinical and angiographic follow-up. Body mass index (BMI), blood pressure, fasting blood glucose, and lipid profile were determined. Metabolic syndrome was defined according to the National Cholesterol Education Program Adult Treatment Panel III criteria, with the waist criterion being substituted by a BMI>or=28.8 kg/m2. Metabolic and anthropometric information for MS diagnosis was available for 148 of 189 patients; 87 of 148 patients (58%) had MS. Patients with MS had higher BMI (28.4+/-3.8 vs 26+/-2.7 kg/m2, P<.0001), systolic blood pressure (133+/-14 vs 124+/-14 mm Hg, P=.0004), and fasting glucose (113+/-37 vs 92+/-17 mg/dL, P<.0001). They also had higher serum triglycerides (154+/-94 vs 113+/-43, P=.0018) and lower high-density lipoprotein cholesterol levels (39+/-9 vs 46+/-10, P<.0001). Rates of restenosis (10.5% vs 8.1%, P=not significant [NS]), target vessel revascularization (10.5% vs 11.3%, P=NS), and major adverse cardiac events (11.6% vs 14.5%, P=NS) were not significantly different in patients with MS compared with those without MS, nor was any association found between increased end point risk and presence of MS. When patients were subdivided into 6 subgroups by the presence of 0, 1, 2, 3, 4, or 5 of the MS components, restenosis rates were not significantly different among subgroups. In conclusion, MS is not associated with higher rates of restenosis, target vessel revascularization, or major adverse cardiac events; and no additional MS feature was associated with an increased risk.     

Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in the Kashmir Valley of the Indian subcontinent

This cross-sectional population survey was undertaken to determine the prevalence of type 2 diabetes and impaired glucose tolerance in subjects aged 40 years or more in Kashmir Valley, India. The study was carried out in two phases. In phase one, 6091 randomly selected subjects, 40 years or older, from all six districts of the valley were surveyed for prevalence of known diabetes mellitus. In phase two, 5083 subjects, 40 years or older, were screened with oral glucose tolerance test for prevalence of undiagnosed (asymptomatic) diabetes mellitus and impaired glucose tolerance. Abnormalities of carbohydrate intolerance were determined as recommended by WHO. Of 6091 subjects interviewed, 115 were known cases of diabetes mellitus with an overall prevalence of 1.89% (1.98% in males and 1.77% in females). Results of glucose tolerance test revealed that mean fasting as well as mean 2 h blood glucose was significantly more in females as compared to males (4.68+/-0.91 and 6.40+/-2.12 vs. 4.49+/-0.96 and 5.94+/-2.03 mmol/l, respectively, P < 0.0001). Of 5083 subjects who were subjected to glucose tolerance test (GTT), 627 (12.34%) had an abnormal test; with 411 (8.09%) having impaired glucose tolerance (IGT) and 216 (4.25%) having diabetes mellitus. The prevalence of IGT as well as of diabetes was significantly more in females as compared to males (P < 0.001). Subjects who had family history of diabetes had a significantly higher prevalence of abnormal GTT. Prevalence of known diabetes as well as that of abnormal GTT steadily increased with age, with a highest prevalence in the age group of > or = 70 years (P < 0.001). Obese subjects had a significantly higher basal as well as 2 h blood glucose in males as well as in females. Subjects with diabetes on GTT had a higher waist/hip ratio. Overall the prevalence of diabetes as well as IGT was significantly higher in the urban population. We conclude that 1.89% of the general population have known diabetes, 4.25% have undiagnosed diabetes and 8.09% have impaired glucose tolerance test; making the total load of abnormal glucose tolerance 14.23% in Kashmir Valley. In subjects greater than 40 years of age having a family history of diabetes, obesity, higher age (50 years or above), female sex, and urban origin have more chance (odds ratio: 4.65, 2.30, 1.87, 1.49 and 1.16, respectively) of developing abnormal glucose tolerance.     

The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1)

Aims/hypothesis Lifestyle modification helps in the primary prevention of diabetes in multiethnic American, Finnish and Chinese populations. In a prospective community-based study, we tested whether the progression to diabetes could be influenced by interventions in native Asian Indians with IGT who were younger, leaner and more insulin resistant than the above populations. Methods We randomised 531 (421 men 110 women) subjects with IGT (mean age 45.9±5.7 years, BMI 25.8±3.5 kg/m²) into four groups. Group 1 was the control, Group 2 was given advice on lifestyle modification (LSM), Group 3 was treated with metformin (MET) and Group 4 was given LSM plus MET. The primary outcome measure was type 2 diabetes as diagnosed using World Health Organization criteria. Results The median follow-up period was 30 months, and the 3-year cumulative incidences of diabetes were 55.0%, 39.3%, 40.5% and 39.5% in Groups 1–4, respectively. The relative risk reduction was 28.5% with LSM (95% CI 20.5–37.3, p=0.018), 26.4% with MET (95% CI 19.1–35.1, p=0.029) and 28.2% with LSM + MET (95% CI 20.3–37.0, p=0.022), as compared with the control group. The number needed to treat to prevent one incident case of diabetes was 6.4 for LSM, 6.9 for MET and 6.5 for LSM + MET. Conclusions/interpretation Progression of IGT to diabetes is high in native Asian Indians. Both LSM and MET significantly reduced the incidence of diabetes in Asian Indians with IGT; there was no added benefit from combining them. Electronic Supplementary Material Supplementary material is available for this article at     

Diabetes and impaired glucose tolerance in an Asian community in Tanzania

The prevalence of diabetes and impaired glucose tolerance has been determined in an Asian Muslim community in Dar-es-Salaam, Tanzania. Two-h oral glucose (75 g) tolerance tests were performed on 1049 subjects over 14 years old, who were fasting, from a random sample of families. The overall age and sex-adjusted prevalence of diabetes was 7.1% (4.4% known, 2.7% previously undiagnosed) with a steady increase from 0.8% at 15-24 years and 3.0% at 25-34 years, to 24.9% for 65 years and over. Impaired glucose tolerance (IGT) rates ranged from 11.4% (15-24 years) to 22.3% (over 64 years). The overall age-adjusted prevalence of IGT was 21.5%. The mean body indices (BMIs) were 24.3 and 26.4 for males and females, respectively, but age-adjusted diabetes rates were similar in the two sexes (7.0% and 7.6%, respectively). Diabetes and IGT were commoner in those with BMI greater than 25 only in the older age groups. Diabetes and IGT were commoner in those with a family history of diabetes. Increasing parity was also associated with a higher diabetes prevalence. Diabetes and IGT are thus common in Asians in Tanzania, in contrast to the indigenous community. Rates are indeed higher than in most other immigrant Asian communities.     

Metabolic effects of metformin in patients with impaired glucose tolerance.

AIMS: To assess the effect of metformin on insulin sensitivity, glucose tolerance and components of the metabolic syndrome in patients with impaired glucose tolerance (IGT). METHODS: Forty first-degree relatives of patients with Type 2 diabetes fulfilling WHO criteria for IGT and participating in the Botnia study in Finland were randomized to treatment with either metformin 500 mg b.i.d. or placebo for 6 months. An oral glucose tolerance test (OGTT) and a euglycaemic hyperinsulinaemic clamp in combination with indirect calorimetry was performed at 0 and 6 months. The patients were followed after stopping treatment for another 6 months in an open trial and a repeat OGTT was performed at 12 months. RESULTS: Metformin treatment resulted in a 20% improvement in insulin-stimulated glucose metabolism (from 28.7 +/- 13 to 34.4 +/- 10.7 micromol/kg fat-free mass (FFM)/min) compared with placebo (P = 0.01), which was primarily due to an increase in glucose oxidation (from 16.6 +/- 3.6 to 19.1 +/- 4.4 micromol/kg FFM; P = 0.03) These changes were associated with a minimal improvement in glucose tolerance, which was maintained after 12 months. CONCLUSIONS: Metformin improves insulin sensitivity in subjects with IGT primarily by reversal of the glucose fatty acid cycle. Obviously large multicentre studies are needed to establish whether these effects are sufficient to prevent progression to manifest Type 2 diabetes and associated cardiovascular morbidity and mortality. Diabet. Med. 18, 578-583 (2001)     

Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance.

AIMS: This study was initiated to test the hypothesis that metformin treatment leads to enhanced glucose disposal at ambient insulin concentrations. METHODS: Nineteen obese patients with impaired glucose tolerance (IGT) were treated with either metformin or placebo in a randomized, double-blind, placebo-controlled, cross-over study. Insulin secretion and insulin resistance were quantified using the homeostasis model assessment (HOMA) and insulin-stimulated glucose disposal were measured by determining the steady-state plasma glucose (SSPG). RESULTS: The average benefit of metformin was 0.6 mmol/l for glucose (95% confidence interval (CI) 0.2-0.9 P = 0.002), 2.8 pmol/l for insulin (95% CI 0.2-5.4, P = 0.019). Insulin resistance, as quantified by HOMA, was improved by 1.1 (95% CI 0.2-2.0, P = 0.004), without any change in insulin secretion. Basal and insulin-stimulated glucose oxidation were comparable in the placebo and metformin-treated groups at the end of each treatment period, as was the SSPG concentration. However, both systolic and diastolic blood pressures fell significantly following metformin administration as compared to treatment with placebo. CONCLUSIONS: These results indicate that metformin administration to patients with IGT is associated with enhanced glucose disposal at baseline insulin concentrations and a fall in blood pressure. In contrast, neither glucose oxidation nor glucose disposal were increased in association with metformin treatment under conditions of physiological hyperinsulinaemia.     

Incidence of diabetes mellitus in women following impaired glucose tolerance in pregnancy is lower than following impaired glucose tolerance in the non-pregnant state

Summary Impaired glucose tolerance (IGT), which is asymptomatic and requires a glucose tolerance test for detection, is a well-known risk factor for diabetes mellitus. Outside the research setting it is rarely identified in people who lack specific risk factors for diabetes except during pregnancy, at which time screening with an oral glucose challenge is a routine procedure. A 75-g oral glucose tolerance test was performed during the latter part of pregnancy or during a routine epidemiology survey in 15–39-year-old Pima Indian women with no history of abnormal glucose tolerance. Those with IGT by World Health Organization criteria were included in this study. Diabetes incidence in women was compared between those whose IGT was first detected during pregnancy and those who were not pregnant when IGT was first recognized. Seventeen of 73 pregnant women and 114 of 244 non-pregnant women developed diabetes within 10 years. When controlled for plasma glucose concentration, age, body mass index, parity and duration of follow-up, those who were not pregnant were at higher risk of developing diabetes than those who were pregnant (hazard rate ratio = 1.71, 95 % confidence interval = 1.01–2.91). Previous studies had reported that women with IGT during pregnancy are at higher risk of diabetes than women with normal glucose tolerance. This study suggests that women with IGT during pregnancy are at lower risk than non-pregnant women with a similar plasma glucose concentration who, in the clinical setting, are likely to remain unrecognized. [Diabetologia (1996) 39: 1334–1337] Received: 15 February 1996 and in revised form: 8 May 1996