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IntroductionTo investigate long-term metformin adherence in the Diabetes Prevention Program Outcomes Study (DPPOS) by examining: (1) predictors of long-term adherence to study metformin and (2) whether metformin adherence was associated with incident type 2 diabetes.Research design and methodsDPPOS was an open-label continuation of the randomized clinical trial (Diabetes Prevention Program (DPP)) in which eligible participants randomized to the metformin group were offered study metformin and followed over 11 years. A brief structured adherence interview was administered semiannually. Metformin adherence was assessed by pill counts. Predictors of metformin adherence were examined in multivariate regression models. Incident diabetes associated with metformin adherence and other variables was assessed in Cox proportional hazards models.ResultsOf 868 participants eligible to continue taking study metformin, 664 (76%) took at least some metformin over 11 years, with 478 of them reporting problems with adherence. DPPOS cumulative adherence showed significant associations of higher adherence (≥80%) with early adherence at 3 months in DPP (p<0.001) and lower depression scores during DPPOS (p<0.001); significant differences were also seen by race/ethnicity (p<0.004). Predicting adherence by multivariate modeling showed odds of adherence significantly lower for Black participants and for participants reporting more than one barrier. Odds for adherence were significantly higher for those adherent early in DPP and those reporting at least one planned strategy to improve adherence. Higher metformin adherence was significantly associated with a lower diabetes risk (p=0.04), even after adjustment for demographic variables, depression, and anxiety scores.ConclusionsIn this long-term diabetes prevention study, early metformin adherence and planned strategies to promote adherence improved long-term adherence over 11 years; higher adherence to metformin was related to lower diabetes incidence. Incorporating strategies to promote adherence when initially prescribing metformin and counseling to support adherence over time are warranted.

Abstract Context There is little information about fatty liver in prediabetes as it transitions to early diabetes. Objective This study is aimed at evaluating the prevalence and determinants of fatty liver in the Diabetes Prevention Program (DPP). Methods We measured liver fat as liver attenuation (LA) in Hounsfield units (HU) in 1876 participants at ~14 years following randomization into the DPP, which tested the effects of lifestyle or metformin interventions versus standard care to prevent diabetes. LA was compared among intervention groups and in those with versus without diabetes, and associations with baseline and follow-up measurements of anthropometric and metabolic covariates were assessed. Results There were no differences in liver fat between treatment groups at 14 years of follow-up. Participants with diabetes had lower LA (mean ± SD: 46 ± 16 vs 51 ± 14 HU; P < 0.001) and a greater prevalence of fatty liver (LA < 40 HU) (34% vs 17%; P < 0.001). Severity of metabolic abnormalities at the time of LA evaluation was associated with lower LA categories in a graded manner and more strongly in those with diabetes. Averaged annual fasting insulin (an index of insulin resistance [OR, 95% CI 1.76, 1.41-2.20]) waist circumference (1.63, 1.17-2.26), and triglyceride (1.42, 1.13-1.78), but not glucose, were independently associated with LA < 40 HU prevalence. Conclusion Fatty liver is common in the early phases of diabetes development. The association of LA with insulin resistance, waist circumference, and triglyceride levels emphasizes the importance of these markers for hepatic steatosis in this population and that assessment of hepatic fat in early diabetes development is warranted.

Objective Glycemic control deteriorates more rapidly in youth vs adults. We compared model‐derived measures of β‐cell function between youth and adults with either impaired glucose tolerance (IGT) or type 2 diabetes to determine if a β‐cell defect differentiates these age groups. Methods This is a cross‐sectional analysis of baseline data from the Restoring Insulin Secretion (RISE) Study. Youth (54 Y‐IGT, 33 Y‐D) and adults (250 A‐IGT, 104 A‐D) underwent 3‐hour oral glucose tolerance tests for modeling of insulin secretion rates (ISRs), glucose sensitivity, and rate sensitivity. Insulin sensitivity was quantified as the glucose infusion rate/insulin (M/I) from a hyperglycemic clamp. Results Youth had lower insulin sensitivity despite similar body mass index. Analyses were adjusted for insulin sensitivity. Youth had higher basal ISRs (Y‐IGT 200 ± 161 vs A‐IGT 152 ± 74, P < .001; Y‐D 245 ± 2.5 vs A‐D 168 ± 115 pmol/min/m2, P = .007) and total ISRs (Y‐IGT 124 ± 86 vs A‐IGT 98 ± 39, P < .001; Y‐D 116 ± 110 vs A‐D 97 ± 62 nmol/m2, P = .002). Within IGT, glucose sensitivity (Y‐IGT 140 ± 153 vs A‐IGT 112 ± 70 pmol/min/m2/mM, P = .004) and rate sensitivity (median[interquartile range]:Y‐IGT 2271[1611, 3222] vs A‐IGT 1164[685, 1565] pmol/m2/mM, P < .001) were higher in youth, but not different by age group within diabetes. Conclusions Model‐derived measures of β‐cell function provide additional insight into the pathophysiology of type 2 diabetes in youth with higher ISRs and β‐cell secretion more responsive to glucose in youth relative to adults even after adjusting for differences in insulin sensitivity. It is unknown whether these findings in youth reflect β‐cells that are healthier or whether this is a defect that contributes to more rapid loss of function.

The presence of islet autoantibodies and islet reactive T cells (T+) in adults with established type 2 diabetes (T2D) have been shown to identify those patients with more severe β-cell dysfunction. However, at what stage in the progression toward clinical T2D does islet autoimmunity emerge as an important component influencing β-cell dysfunction? In this ancillary study to the Restoring Insulin SEcretion (RISE) Study, we investigated the prevalence of and association with β-cell dysfunction of T+ and autoantibodies to the 65 kDa glutamic acid decarboxylase antigen (GADA) in obese pre-diabetes adults with impaired glucose tolerance (IGT) and recently diagnosed treatment naïve (Ndx) T2D. We further investigated the effect of 12 months of RISE interventions (metformin or liraglutide plus metformin, or with 3 months of insulin glargine followed by 9 months of metformin or placebo) on islet autoimmune reactivity. We observed GADA(+) in 1.6% of NdxT2D and 4.6% of IGT at baseline, and in 1.6% of NdxT2D and 5.3% of IGT at 12 months, but no significant associations between GADA(+) and β-cell function. T(+) was observed in 50% of NdxT2D and 60.4% of IGT at baseline, and in 68.4% of NdxT2D and 83.9% of IGT at 12 months. T(+) NdxT2D were observed to have significantly higher fasting glucose ( p = 0.004), and 2 h glucose ( p = 0.0032), but significantly lower steady state C-peptide (sscpep, p = 0.007) compared to T(−) NdxT2D. T(+) IGT participants demonstrated lower but not significant ( p = 0.025) acute (first phase) C-peptide response to glucose (ACPRg) compared to T(−) IGT. With metformin treatment, T(+) participants were observed to have a significantly lower Hemoglobin A1c (HbA1c, p = 0.002) and fasting C-peptide ( p = 0.002) compared to T(−), whereas T(+) treated with liraglutide + metformin had significantly lower sscpep ( p = 0.010) compared to T(−) participants. In the placebo group, T(+) participants demonstrated significantly lower ACPRg ( p = 0.001) compared to T(−) participants. In summary, T(+) were found in a large percentage of obese pre-diabetes adults with IGT and in recently diagnosed T2D. Moreover, T(+) were significantly correlated with treatment effects and β-cell dysfunction. Our results demonstrate that T(+) are an important component in T2D.

IntroductionDiabetes mellitus is associated with endothelial dysfunction. However, there is little information on the relationships of fasting blood glucose (FBG), including high normal blood glucose and impaired fasting glucose (IFG) with endothelial function. The purpose of this study was to evaluate the relationship between FBG level and flow-mediated vasodilation (FMD) using a large sample size.Research design and methodsThis study was a cross-sectional study. We measured FMD in 7265 subjects at 31 general hospitals. The subjects were divided into four groups based on FBG levels: <100, 100–109, 110–125, and ≥126 mg/dL or known diabetes. The subjects were also divided into six groups based on FBG levels: <90, 90–94, 95–99, 100–109, 110–125, and ≥126 mg/dL or known diabetes.ResultsFMD decreased in relation to increase in FBG level. There was a significant difference in FMD between the FBG of <100 mg/dL group and the other three groups (6.7±3.1% vs 5.9±2.8%, 5.7±3.1%, and 5.1±2.6%, respectively; p<0.001). After adjustment for confounding factors, the odds of having the lowest quartile of FMD were significantly higher in the FBG of 95–99, 100–104, 105–109, 110–125, and ≥126 mg/dL or known diabetes groups than in the FBG of the <90 mg/dL group.ConclusionsThese findings suggest that FBG of 100–109 mg/dL and FBG of 110–125 mg/dL are similarly associated with endothelial dysfunction and that a pre-IFG state (FBG of 95–99 mg/dL) is also a risk for endothelial dysfunction compared with FBG of <90 mg/dL.Trial registration numberUMIN000012950, UMIN000012951, UMIN000012952, and UMIN000003409.

In a secondary analysis comparing the effect of insulin glargine, glimepiride, liraglutide, and sitagliptin, added to metformin, on the incidences of microvascular complications and death, no material between-group differences were seen.

We analyzed the incidence of kidney disease in the Diabetes Prevention Program Outcomes Study (DPPOS) by originally randomized treatment group assignment: Intensive Lifestyle (ILS), Metformin (MET) or Placebo (PLB). The current analyses used a time-to-event approach in which the primary outcome was kidney disease, ascertained as urine albumin-to-creatinine ratio (ACR) ≥ 3.39 mg/mmol (30 mg/g) or eGFR <45 mL/min/1.73m2, with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD). At a median of 21 years following randomization in DPP, diabetes development was reduced in both the ILS (HR 0.73 [95%CI = 0.62, 0.85]) and MET groups (HR 0.85 [0.73, 0.99]) compared to the PLB group. Although risk for developing the primary kidney disease outcome was higher among those with incident diabetes compared to those without (HR 1.81 [1.43, 2.30]), it did not differ by intervention groups (ILS vs. PLB 1.02 (0.81, 1.29); MET vs. PLB 1.08 (0.86, 1.35). There was a non-significant metformin by age interaction (p = 0.057), with metformin being beneficial for kidney disease in the younger but potentially harmful in the older participants. Development of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment. Diabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992 DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727 •What is already known about this subject?•Glycemic control is able to prevent/delay the onset and delay the progression of diabetic kidney disease.•What is the study question?•Do interventions that prevent or delay the onset of type 2 diabetes influence the development of later kidney disease?•What are the new findings?•Development of kidney disease was increased in subjects who developed diabetes in the DPPOS.•The development of kidney disease did not differ among treatment groups possibly due to their limited glycemic separation.•How might this impact on clinical practice in the foreseeable future?•Lifestyle and Metformin interventions reduce the development of diabetes in high-risk individuals.•These interventions may need to be given for many years before an effect on the long-term complications of diabetes is seen.

Background The RISE Pediatric Medication Study compared strategies for preserving β‐cell function, including a 9‐month follow‐up after treatment withdrawal to test treatment effect durability. Objective Evaluate OGTT measures of glucose and β‐cell response through 12 months of intervention and 9 months of medication washout. Participants Youth (n = 91) aged 10 to 19 years with BMI ≥85th percentile and impaired glucose tolerance (IGT) or recently diagnosed type 2 diabetes (T2D). Methods A multicenter randomized clinical trial comparing insulin glargine for 3 months followed by metformin for 9 months (G→Met) or metformin alone (Met) for 12 months. We report within‐group changes from baseline to end of medication intervention (M12), baseline to 9 months post‐medication withdrawal (M21), and end of medication (M12) to M21. OGTT C‐peptide index [CPI] paired with 1/fasting insulin evaluated β‐cell response. Results At M12, both treatments were associated with stable fasting glucose (G→Met baseline 6.0 ± 0.1 vs M12 5.9 ± 0.2 mmol/L, P = .62; Met baseline 6.1 ± 0.2 vs M12 6.0 ± 0.2 mmol/L, P = .73) and 2‐hour glucose (G→Met baseline 10.2 ± 0.4 vs M12 9.3 ± 0.5 mmol/L, P = .03; Met baseline 10.2 ± 0.4 vs M12 10.6 ± 0.6 mmol/L, P = .88). Following medication withdrawal, fasting glucose worsened (G→Met M21 8.6 ± 1.8, P = .004; Met M21 7.8 ± 0.7 mmol/L, P = .003), as did 2‐hour glucose (G→Met M21 13.2 ± 1.4, P = .002; Met M21 13.1 ± 1.2 mmol/L, P = .006), associated with declines in β‐cell response. Conclusions G→Met and Met were associated with stable glucose measures during 12 months of treatment in youth with IGT or recently diagnosed T2D. Glucose and β‐cell response worsened post‐medication withdrawal, suggesting treatment must be long‐term or alternative treatments pursued.

The metabolic syndrome is a cluster of clinical characteristics thought to be associated with increased coronary risk. This analysis evaluates angiographic progression of coronary disease in women who are postmenopausal with and without the metabolic syndrome enrolled in the Women’s Angiographic Vitamin & Estrogen (WAVE) trial, a randomized, controlled trial of hormone therapy and antioxidant vitamins. A total of 425 women who are postmenopausal and have angiographic coronary disease were enrolled at 7 clinics between July 1997 and August 1999. Women were categorized as having the metabolic syndrome when they met the National Cholesterol Education Program Adult Treatment Panel III definition. Coronary angiograms were performed at baseline and after 2.8 ± 0.9 years (mean ± SD). Quantitative coronary angiographic analysis was performed at a core laboratory. Women with the metabolic syndrome (177/294, 60%) were more likely to be taking cholesterol-lowering medication (65% vs 51%, P = .01) and had higher body mass index (33 ± 6 vs 28 ± 6 kg/m 2, P <.001). The mean reduction in minimum lumen diameter was greater (−0.041 ± 0.151 vs −0.023 ± 0.148 mm/year, P = .33) and new lesions were more frequent (34% vs 23%, P = .054) in women with the metabolic syndrome. In multivariate analysis, the metabolic syndrome was not an independent predictor of angiographic disease progression. However, clinical events (myocardial infarction, stroke, or coronary death) were more frequent among women with the metabolic syndrome ( P = .02). The metabolic syndrome was prevalent among postmenopausal women with coronary disease enrolled in the WAVE trial. Having the metabolic syndrome was not independently associated with changes in minimum lumen diameter or the development of new or progressing coronary lesions, but did confer an increased risk of clinical cardiovascular events.

The Effect of Vitamin Therapy on the Progression of Coronary Artery Atherosclerosis Varies by Haptoglobin Type in Postmenopausal Women Andrew P. Levy , MD, PHD 1 , Paula Friedenberg , MS 2 , Rachel Lotan , PHD 1 , Pamela Ouyang , MD 3 , Mark Tripputi , MS 2 , Lyall Higginson , MD 4 , Frederick R. Cobb , MD 5 , Jean-Claude Tardif , MD 6 , Vera Bittner , MD 7 and Barbara V. Howard , PHD 8 1 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel 2 George Washington University Biostatistics Center, Washington, DC 3 Division of Cardiology, Johns Hopkins Bayview Medical Center, Baltimore, Maryland 4 University of Ottawa Heart Institute, Ottawa, Ontario, Canada 5 Duke Center for Living, Duke University, Durham, North Carolina 6 Montreal Heart Institute, Montreal, Quebec, Canada 7 Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, Alabama 8 Department of Cardiology, Medstar Research Institute, Washington, DC Address correspondence and reprint requests to Dr. Andrew P. Levy, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. E-mail: alevy{at}tx.technion.ac.il Abstract OBJECTIVE —Antioxidant trials have not demonstrated efficacy in slowing cardiovascular disease but could not rule out benefit for specific patient subgroups. Antioxidant therapy reduces LDL oxidizability in haptoglobin 1 allele homozygotes (Hp 1-1), but not in individuals with the haptoglobin 2 allele (Hp 2-1 or Hp 2-2). We therefore hypothesized that haptoglobin type would be predictive of the effect of vitamin therapy on coronary atherosclerosis as assessed by angiography. RESEARCH DESIGN AND METHODS —We tested this hypothesis in the Women’s Angiographic Vitamin and Estrogen (WAVE) trial, a prospective angiographic study of vitamins C and E with or without hormone replacement therapy (HRT) in postmenopausal women. Haptoglobin type was determined in 299 women who underwent baseline and follow-up angiography. The annualized change in the minimum luminal diameter (MLD) was examined in analyses stratified by vitamin use, haptoglobin type, and diabetes status. RESULTS —We found a significant benefit on the change in MLD with vitamin therapy as compared with placebo in Hp 1-1 subjects (0.079 ± 0.040 mm, P = 0.049). This benefit was more marked in diabetic subjects (0.149 ± 0.064 mm, P = 0.021). On the other hand, there was a trend toward a more rapid decrease in MLD with vitamin therapy in Hp 2-2 subjects, which was more marked in diabetic subjects (0.128 ± 0.057 mm, P = 0.027). HRT had no effect on these outcomes. CONCLUSIONS —The relative benefit or harm of vitamin therapy on the progression of coronary artery stenoses in women in the WAVE study was dependent on haptoglobin type. This influence of haptoglobin type seemed to be stronger in women with diabetes. HRT, hormone replacement therapy MLD, minimum luminal diameter WAVE, Women’s Angiographic Vitamin and Estrogen Footnotes A.P.L. is the author of a patent that claims to predict diabetic vascular complications based on the haptoglobin phenotype. He has received no financial compensation from this patent. Accepted January 6, 2004. Received November 3, 2003. DIABETES CARE