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Background Our aim was to investigate the association of coronary artery calcium (CAC) with cognitive function in adults with impaired glucose tolerance or type 2 diabetes. Methods and Results The Diabetes Prevention Program was a randomized controlled trial comparing an intensive lifestyle intervention, metformin, or placebo for prevention of type 2 diabetes among patients with prediabetes. After 3 years, intensive lifestyle intervention and placebo were stopped, the metformin arm was unmasked, and participants continued in the DPPOS (Diabetes Prevention Program Outcomes Study). Approximately 14 years after randomization (Y14), CAC (Agatston score) was assessed with computed tomography, and cognitive performance was assessed with the Spanish English Verbal Learning Test (SEVLT) and Digit Symbol Substitution Test. SEVLT and Digit Symbol Substitution Test were reassessed 5 years later (Y19) along with the Modified Mini-Mental State Exam. We examined cross-sectional and longitudinal associations between CAC and cognition among 1931 participants using linear and logistic regression. In unadjusted analyses, compared with no calcification, CAC score >300 was associated with decreased performance on all cognitive tests at Y14 in both sexes. Additionally, CAC >300 was associated with a greater 5-year decline in SEVLT Immediate Recall in both sexes and SEVLT Delayed Recall in women. After adjustment for demographic, genetic, metabolic, vascular, and behavioral covariates, CAC score >300 remained associated with greater decline in only SEVLT Delayed Recall in women. Conclusions In women with prediabetes or diabetes, CAC >300, compared with no calcification, was independently associated with greater decline in verbal memory. Registration information clinicaltrials.gov. Identifier: NCT00038727.

Aims: 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)., Methods: 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/1.73m 2 , with confirmation required at the next visit, or adjudicated end-stage kidney disease (ESKD)., Results: 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., Conclusions: Development of kidney disease was increased in participants who developed diabetes but did not differ by original treatment group assignment., Clinical Trial Registrations: Diabetes Prevention Program (DPP) Clinical trial reg. no. NCT00004992 DPP Outcomes Study (DPPOS) Clinical trial reg. no. NCT0038727., Competing Interests: Declaration of competing interest MEM, MTr, ASL, JPC, DD, WHH, WCK, TJO, EBS, PS, MTe, NHW and DMN report no Conflicts of Interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: DNA methylation (DNAme) has been cross-sectionally associated with type 2 diabetes and hemoglobin A1c (HbA1c) in the general population. However, longitudinal data and data in type 1 diabetes are currently very limited. Thus, we performed an epigenome-wide association study (EWAS) in an observational type 1 diabetes cohort to identify loci with DNAme associated with concurrent and future HbA1cs, as well as other clinical risk factors, over 28 years., Research Design and Methods: Whole blood DNAme in 683 597 CpGs was analyzed in the Pittsburgh Epidemiology of Diabetes Complications study of childhood onset (<17 years) type 1 diabetes (n=411). An EWAS of DNAme beta values and concurrent HbA1c was performed using linear models adjusted for diabetes duration, sex, pack years of smoking, estimated cell type composition variables, and technical/batch covariates. A longitudinal EWAS of subsequent repeated HbA1c measures was performed using mixed models. We further identified methylation quantitative trait loci (meQTLs) for significant CpGs and conducted a Mendelian randomization., Results: DNAme at cg19693031 (Chr 1, Thioredoxin-Interacting Protein ( TXNIP )) and cg21534330 (Chr 17, Casein Kinase 1 Isoform Delta ) was significantly inversely associated with concurrent HbA1c. In longitudinal analyses, hypomethylation of cg19693031 was associated with consistently higher HbA1c over 28 years, and with higher triglycerides, pulse rate, and albumin:creatinine ratio (ACR) independently of HbA1c. We further identified 34 meQTLs in SLC2A1/SLC2A1-AS1 significantly associated with cg19693031 DNAme., Conclusions: Our results extend prior findings that TXNIP hypomethylation relates to worse glycemic control in type 1 diabetes by demonstrating the association persists over the long term. Additionally, the associations with triglycerides, pulse rate, and ACR suggest TXNIP DNAme could play a role in vascular damage independent of HbA1c. These findings strengthen potential for interventions targeting TXNIP to improve glycemic control in type 1 diabetes through its role in SLC2A1 /glucose transporter 1-mediated glucose regulation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Lifestyle intervention and metformin have been shown to prevent diabetes; however, their efficacy in preventing cardiovascular disease associated with the development of diabetes is unclear. We examined whether these interventions reduced the incidence of major cardiovascular events over a 21-year median follow-up of participants in the DPP trial (Diabetes Prevention Program) and DPPOS (Diabetes Prevention Program Outcomes Study)., Methods: During DPP, 3234 participants with impaired glucose tolerance were randomly assigned to metformin 850 mg twice daily, intensive lifestyle or placebo, and followed for 3 years. During the next 18-year average follow-up in DPPOS, all participants were offered a less intensive group lifestyle intervention, and unmasked metformin was continued in the metformin group. The primary outcome was the first occurrence of nonfatal myocardial infarction, stroke, or cardiovascular death adjudicated by standard criteria. An extended cardiovascular outcome included the primary outcome or hospitalization for heart failure or unstable angina, coronary or peripheral revascularization, coronary heart disease diagnosed by angiography, or silent myocardial infarction by ECG. ECGs and cardiovascular risk factors were measured annually., Results: Neither metformin nor lifestyle intervention reduced the primary outcome: metformin versus placebo hazard ratio 1.03 (95% CI, 0.78-1.37; P = 0.81) and lifestyle versus placebo hazard ratio 1.14 (95% CI, 0.87-1.50; P = 0.34). Risk factor adjustment did not change these results. No effect of either intervention was seen on the extended cardiovascular outcome., Conclusions: Neither metformin nor lifestyle reduced major cardiovascular events in DPPOS over 21 years despite long-term prevention of diabetes. Provision of group lifestyle intervention to all, extensive out-of-study use of statin and antihypertensive agents, and reduction in the use of study metformin together with out-of-study metformin use over time may have diluted the effects of the interventions., Registration: URL: https://www., Clinicaltrials: gov; Unique identifiers: DPP (NCT00004992) and DPPOS (NCT00038727).

Competing Interests: I report grant review honorarium from Nova Nordisk.

Objectives: Patients with type 1 diabetes (T1D) exhibit modest lipid abnormalities as measured by traditional metrics. This study aimed to identify lipidomic predictors of rapid decline of kidney function in T1D., Research Design and Methods: In a case-control study, 817 patients with T1D from three large cohorts were randomly split into training and validation subsets. Case was defined as >3 mL/min/1.73 m 2 per year decline in estimated glomerular filtration rate (eGFR), while control was defined as <1 mL/min/1.73 m 2 per year decline over a minimum 4-year follow-up. Lipids were quantified in baseline serum samples using a targeted mass spectrometry lipidomic platform., Results: At individual lipids, free fatty acid (FFA)20:2 was directly and phosphatidylcholine (PC)16:0/22:6 was inversely and independently associated with rapid eGFR decline. When examined by lipid class, rapid eGFR decline was characterized by higher abundance of unsaturated FFAs, phosphatidylethanolamine (PE)-Ps, and PCs with an unsaturated acyl chain at the sn1 carbon, and by lower abundance of saturated FFAs, longer triacylglycerols, and PCs, PEs, PE-Ps, and PE-Os with an unsaturated acyl chain at the sn1 carbon at eGFR ≥90 mL/min/1.73 m 2 . A multilipid panel consisting of unsaturated FFAs and saturated PE-Ps predicted rapid eGFR decline better than individual lipids (C-statistic, 0.71) and improved the C-statistic of the clinical model from 0.816 to 0.841 ( P = 0.039). Observations were confirmed in the validation subset., Conclusions: Distinct from previously reported predictors of GFR decline in type 2 diabetes, these findings suggest differential incorporation of FFAs at the sn1 carbon of the phospholipids' glycerol backbone as an independent predictor of rapid GFR decline in T1D., (© 2021 by the American Diabetes Association.)

The global epidemic of type 2 diabetes has prompted numerous studies and public health efforts to reduce its development. A variety of interventions, including lifestyle modifications and pharmacological agents directed at ameliorating the major risk factors for type 2 diabetes, are of proven efficacy in reducing the development of type 2 diabetes in people with impaired glucose tolerance. While prevention of the hyperglycaemia characteristic of diabetes is arguably an important, clinically relevant outcome, a more compelling outcome with greater clinical significance is the prevention or reduction of the relatively diabetes-specific microvascular and less-specific cardiovascular disease (CVD) complications associated with diabetes. These complications cause the majority of morbidity and excess mortality associated with diabetes. Any reduction in diabetes should, logically, also reduce the occurrence of its long-term complications; however, most diabetes prevention trials have not been of sufficient duration to allow such an evaluation. The limited long-term data, largely from the Da Qing Diabetes Prevention Study (DQDPS) and the Diabetes Prevention Program (DPP) and their respective follow-up studies (DQDPOS and DPPOS), suggest a reduction in microvascular complications and amelioration of CVD risk factors. Only the DQDPOS and Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (STOP-NIDDM) studies have shown a reduction in CVD events and only DQDPOS has demonstrated a decrease in CVD and overall mortality. While these limited data are promising, whether diabetes prevention directly reduces complication-related morbidity and mortality remains unclear. Longer follow-up of prevention studies is needed to supplement the limited current clinical trial data, to help differentiate the effects of diabetes prevention itself from the means used to reduce diabetes development and to understand the balance among benefits, risks and costs of prevention.

Background: Diabetic medications can cause hypoglycemia, which may lead to myocardial damage., Objectives: This study sought to determine whether hypoglycemia is associated with higher levels of high-sensitivity cardiac troponin T (hsTnT)., Methods: The BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) trial randomized patients with type 2 diabetes mellitus and stable coronary artery disease, and closely followed them for hypoglycemia over the first year. Hypoglycemia was classified by maximum severity and frequency. hsTnT was measured at baseline and 1 year, and analyzed using multivariable regression., Results: Of 1,984 patients, follow-up hypoglycemia was absent in 1,026 (52%) patients, mild in 875 (44%), and severe in 83 (4%), and occurred less than weekly in 561 (28%) and greater than or equal to weekly in 397 (20%). hsTnT levels were associated with hypoglycemia: a median of 11.4 ng/l (interquartile range [IQR]: 8.1 to 17.3 ng/l) for none, 12.5 ng/l (IQR: 8.3 to 19.3 ng/l) for mild, and 13.7 ng/l (IQR: 9.9 to 24.9 ng/l) for severe hypoglycemia (p = 0.0001); and 12.5 ng/l (IQR: 8.3 to 18.1 ng/l) for less than weekly and 13.0 ng/l (IQR: 8.8 to 21.1 ng/l) for greater than or equal to weekly hypoglycemia (p = 0.0013). Severe hypoglycemia was associated with 34% higher 1-year hsTnT levels (p < 0.0001) in unadjusted analysis, 17% higher (p = 0.006) after adjustment for baseline factors unrelated to diabetes, and 6% higher (p = 0.23) after further adjustment for the duration and severity of diabetes. Hypoglycemia greater than or equal to weekly was associated with 14% higher hsTnT (p = 0.0003) in unadjusted analysis, 12% higher (p = 0.0002) after adjustment for baseline factors unrelated to diabetes, and 4% higher (p = 0.16) after adjustment for diabetes related factors., Conclusions: Hypoglycemia was associated with elevated hsTnT levels, but this may be due to more severe diabetes in patients who developed hypoglycemia, rather than the direct result of hypoglycemia. (Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes [BARI2D]; NCT00006305)., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: The implementation of the Chronic Care Model (CCM) improves health care quality. We examined the sustained effectiveness of multicomponent integrated care in type 2 diabetes., Research Design and Methods: We searched PubMed and Ovid MEDLINE (January 2000-August 2016) and identified randomized controlled trials comprising two or more quality improvement strategies from two or more domains (health system, health care providers, or patients) lasting ≥12 months with one or more clinical outcomes. Two reviewers extracted data and appraised the reporting quality., Results: In a meta-analysis of 181 trials ( N = 135,112), random-effects modeling revealed pooled mean differences in HbA 1c of -0.28% (95% CI -0.35 to -0.21) (-3.1 mmol/mol [-3.9 to -2.3]), in systolic blood pressure (SBP) of -2.3 mmHg (-3.1 to -1.4), in diastolic blood pressure (DBP) of -1.1 mmHg (-1.5 to -0.6), and in LDL cholesterol (LDL-C) of -0.14 mmol/L (-0.21 to -0.07), with greater effects in patients with LDL-C ≥3.4 mmol/L (-0.31 vs. -0.10 mmol/L for <3.4 mmol/L; P difference = 0.013), studies from Asia (HbA 1c -0.51% vs. -0.23% for North America [-5.5 vs. -2.5 mmol/mol]; P difference = 0.046), and studies lasting >12 months (SBP -3.4 vs. -1.4 mmHg, P difference = 0.034; DBP -1.7 vs. -0.7 mmHg, P difference = 0.047; LDL-C -0.21 vs. -0.07 mmol/L for 12-month studies, P difference = 0.049). Patients with median age <60 years had greater HbA 1c reduction (-0.35% vs. -0.18% for ≥60 years [-3.8 vs. -2.0 mmol/mol]; P difference = 0.029). Team change, patient education/self-management, and improved patient-provider communication had the largest effect sizes (0.28-0.36% [3.0-3.9 mmol/mol])., Conclusions: Despite the small effect size of multicomponent integrated care (in part attenuated by good background care), team-based care with better information flow may improve patient-provider communication and self-management in patients who are young, with suboptimal control, and in low-resource settings., (© 2018 by the American Diabetes Association.)

Currently 23 million U.S. adults have been diagnosed with diabetes (1). The two most common forms of diabetes are type 1 and type 2. Type 1 diabetes results from the autoimmune destruction of the pancreas's beta cells, which produce insulin. Persons with type 1 diabetes require insulin for survival; insulin may be given as a daily shot or continuously with an insulin pump (2). Type 2 diabetes is mainly caused by a combination of insulin resistance and relative insulin deficiency (3). A small proportion of diabetes cases might be types other than type 1 or type 2, such as maturity-onset diabetes of the young or latent autoimmune diabetes in adults (3). Although the majority of prevalent cases of type 1 and type 2 diabetes are in adults, national data on the prevalence of type 1 and type 2 in the U.S. adult population are sparse, in part because of the previous difficulty in classifying diabetes by type in surveys (2,4,5). In 2016, supplemental questions to help distinguish diabetes type were added to the National Health Interview Survey (NHIS) (6). This study used NHIS data from 2016 to estimate the prevalence of diagnosed diabetes among adults by primary type. Overall, based on self-reported type and current insulin use, 0.55% of U.S. adults had diagnosed type 1 diabetes, representing 1.3 million adults; 8.6% had diagnosed type 2 diabetes, representing 21.0 million adults. Of all diagnosed cases, 5.8% were type 1 diabetes, and 90.9% were type 2 diabetes; the remaining 3.3% of cases were other types of diabetes. Understanding the prevalence of diagnosed diabetes by type is important for monitoring trends, planning public health responses, assessing the burden of disease for education and management programs, and prioritizing national plans for future type-specific health services., Competing Interests: No conflicts of interest were reported.

Background: Despite the reduced incidence of coronary heart disease with intensive risk factor management, people with diabetes mellitus and prediabetes remain at increased coronary heart disease risk. Diabetes prevention interventions may be needed to reduce coronary heart disease risk. This approach was examined in the DPP (Diabetes Prevention Program) and the DPPOS (Diabetes Prevention Program Outcome Study), a long-term intervention study in 3234 subjects with prediabetes (mean±SD age, 64±10 years) that showed reduced diabetes risk with lifestyle and metformin compared with placebo over 3.2 years., Methods: The DPPOS offered periodic group lifestyle sessions to all participants and continued metformin in the originally randomized metformin group. Subclinical atherosclerosis was assessed in 2029 participants with coronary artery calcium (CAC) measurements after an average of 14 years of follow-up. The CAC scores were analyzed continuously as CAC severity and categorically as CAC presence (CAC score >0) and reported separately in men and women., Results: There were no CAC differences between lifestyle and placebo intervention groups in either sex. CAC severity and presence were significantly lower among men in the metformin versus the placebo group (age-adjusted mean CAC severity, 39.5 versus 66.9 Agatston units, P =0.04; CAC presence, 75% versus 84%, P =0.02), but no metformin effect was seen in women. In multivariate analysis, the metformin effect in men was not influenced by demographic, anthropometric, or metabolic factors; by the development of diabetes mellitus; or by use/nonuse of statin therapy., Conclusions: Metformin may protect against coronary atherosclerosis in prediabetes and early diabetes mellitus among men., Clinical Trial Registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00038727., (© 2017 American Heart Association, Inc.)

Background: In Phase 2/3 studies of basal insulin peglispro (BIL) compared to insulin glargine, patients with type 1 or type 2 diabetes previously treated with insulin and randomized to BIL had an increase in serum triglycerides (TGs). To further understand lipoprotein changes, a lipid substudy which included liver fat content was designed to assess relationships among the measured variables for each diabetes cohort and compare the hepato-preferential insulin BIL to glargine., Methods: In three cohorts of patients with diabetes (type 1, type 2 insulin naïve, and type 2 previously on insulin; n = 652), liver fat content (LFC) was determined by magnetic resonance imaging (MRI) and blood lipids were analyzed by nuclear magnetic resonance (NMR) spectroscopy at baseline, 26 and 52 weeks of treatment. Apolipoproteins, adiponectin, and other lipid parameters were also measured. Descriptive statistics were done, as well as correlation analyses to look for relationships among LFC and lipoproteins or other lipid measures., Results: In patients with type 1 diabetes treated with BIL, but not glargine, small LDL and medium and large VLDL subclass concentrations increased from baseline. In patients with type 2 diabetes previously on insulin and treated with BIL, large VLDL concentration increased from baseline. In insulin naïve patients with type 2 diabetes treated with BIL, there were very few changes, while in those treated with glargine, small LDL and large VLDL decreased from baseline. Baseline LFC correlated significantly in one or more cohorts with baseline large VLDL, small LDL, VLDL size, and Apo C3. Changes in LFC by treatment showed generally weak correlations with lipoprotein changes, except for positive correlations with large VLDL and VLDL size. Adiponectin was higher in patients with type 1 diabetes compared to patients with type 2 diabetes, but decreased with treatment with both BIL and glargine., Conclusions: The lipoprotein changes were in line with the observed changes in serum TGs; i.e., the cohorts experiencing increased TGs and LFC with BIL treatment had decreased LDL size and increased VLDL size. These data and analyses add to the currently available information on the metabolic effects of insulins in a very carefully characterized cohort of patients with diabetes. Clinicaltrials.gov registration numbers and dates NCT01481779 (2011), NCT01435616 (2011), NCT01454284 (2011), NCT01582451 (2012).

Aims/hypothesis: Haptoglobin(Hp) 2-2 genotype has been shown to increase coronary artery disease (CAD) risk in numerous type 2 diabetes studies but in only one type 1 diabetes cohort. We assessed the association of Hp2-2 with incident CAD over 26years of follow-up in 1303 Caucasian participants of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study., Methods: DCCT randomized volunteers with type 1 diabetes to intensive versus conventional therapy within two cohorts: 'primary prevention' with 1-5years diabetes duration and 'secondary intervention' with 1-15years diabetes duration and early retinopathy, with or without albuminuria, but no advanced complications. CAD was defined as myocardial infarction (MI) or death judged to be from CAD, silent MI, angina, coronary revascularization, or congestive heart failure due to CAD., Results: In the entire DCCTcohort, Hp2-2 was not significantly associated with incident CAD or MI. However, in pre-specified exploratory subgroup analyses, an increased MI risk was suggested in the secondary cohort for those with Hp2-2., Conclusions/interpretation: The analysis does not statistically confirm an overall association between Hp 2-2 and incident CAD, however, some suggestions of associations were observed in secondary analyses., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Context: Vitamin B12 deficiency may occur with metformin treatment, but few studies have assessed risk with long-term use., Objective: To assess the risk of B12 deficiency with metformin use in the Diabetes Prevention Program (DPP)/DPP Outcomes Study (DPPOS)., Design: Secondary analysis from the DPP/DPPOS. Participants were assigned to the placebo group (PLA) (n = 1082) or the metformin group (MET) (n = 1073) for 3.2 years; subjects in the metformin group received open-label metformin for an additional 9 years., Setting: Twenty-seven study centers in the United States., Patients: DPP eligibility criteria were: elevated fasting glucose, impaired glucose tolerance, and overweight/obesity. The analytic population comprised participants with available stored samples. B12 levels were assessed at 5 years (n = 857, n = 858) and 13 years (n = 756, n = 764) in PLA and MET, respectively., Intervention: Metformin 850 mg twice daily vs placebo (DPP), and open-label metformin in the metformin group (DPPOS)., Main Outcome Measures: B12 deficiency, anemia, and peripheral neuropathy., Results: Low B12 (≤ 203 pg/mL) occurred more often in MET than PLA at 5 years (4.3 vs 2.3%; P = .02) but not at 13 years (7.4 vs 5.4%; P = .12). Combined low and borderline-low B12 (≤ 298 pg/mL) was more common in MET at 5 years (19.1 vs 9.5%; P < .01) and 13 years (20.3 vs 15.6%; P = .02). Years of metformin use were associated with increased risk of B12 deficiency (odds ratio, B12 deficiency/year metformin use, 1.13; 95% confidence interval, 1.06–1.20). Anemia prevalence was higher in MET, but did not differ by B12 status. Neuropathy prevalence was higher in MET with low B12 levels., Conclusions: Long-term use of metformin in DPPOS was associated with biochemical B12 deficiency and anemia. Routine testing of vitamin B12 levels in metformin-treated patients should be considered.

Objective: Restoration of normal glucose regulation (NGR) in people with prediabetes significantly decreases the risk of future diabetes. We sought to examine whether regression to NGR is also associated with a long-term decrease in cardiovascular disease (CVD) risk., Research Design and Methods: The Framingham (2008) score (as an estimate of the global 10-year CVD risk) and individual CVD risk factors were calculated annually for the Diabetes Prevention Program Outcomes Study years 1-10 among those patients who returned to NGR at least once during the Diabetes Prevention Program (DPP) compared with those who remained with prediabetes or those in whom diabetes developed during DPP (N = 2,775)., Results: The Framingham scores by glycemic exposure did not differ among the treatment groups; therefore, pooled estimates were stratified by glycemic status and were adjusted for differences in risk factors at DPP baseline and in the treatment arm. During 10 years of follow-up, the mean Framingham 10-year CVD risk scores were highest in the prediabetes group (16.2%), intermediate in the NGR group (15.5%), and 14.4% in people with diabetes (all pairwise comparisons P < 0.05), but scores decreased over time for those people with prediabetes (18.6% in year 1 vs. 15.9% in year 10, P < 0.01). The lower score in the diabetes group versus other groups, a declining score in the prediabetes group, and favorable changes in each individual risk factor in all groups were explained, in part, by higher or increasing medication use for lipids and blood pressure., Conclusions: Prediabetes represents a high-risk state for CVD. Restoration of NGR and/or medical treatment of CVD risk factors can significantly reduce the estimated CVD risk in people with prediabetes., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: We evaluate whether lifestyle and metformin interventions used to prevent diabetes have durable effects on markers of inflammation and coagulation and whether the effects are influenced by the development of diabetes., Research Design and Methods: The Diabetes Prevention Program was a controlled clinical trial of 3,234 subjects at high risk for diabetes who were randomized to lifestyle, metformin, or placebo interventions for 3.4 years. Diabetes was diagnosed semiannually by fasting glucose and annually by oral glucose tolerance testing. In addition to baseline testing, anthropometry was performed every 6 months; fasting insulin yearly; and hs-CRP, tissue plasminogen activator (tPA), and fibrinogen at 1 year and end of study (EOS)., Results: CRP and tPA levels were unchanged in the placebo group but fell in the lifestyle and metformin groups at 1 year and remained lower at EOS. These reductions were not seen in those who developed diabetes over the course of the study despite intervention. Fibrinogen was lower at 1 year in the lifestyle group. Differences in weight and weight change explained most of the influence of diabetes on the CRP response in the lifestyle group, but only partly in the placebo and metformin groups. Weight, insulin sensitivity, and hyperglycemia differences each accounted for the influence of diabetes on the tPA response., Conclusions: Lifestyle and metformin interventions have durable effects to lower hs-CRP and tPA. Incident diabetes prevented these improvements, and this was accounted for by differences in weight, insulin resistance, and glucose levels., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Aims: To determine the association of metabolic syndrome (MetS) and its components with diabetes risk in participants with impaired glucose tolerance (IGT), and whether intervention-related changes in MetS lead to differences in diabetes incidence., Methods: We used the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III) revised MetS definition at baseline and intervention-related changes of its components to predict incident diabetes using Cox models in 3234 Diabetes Prevention Program (DPP) participants with IGT over an average follow-up of 3.2 years., Results: In an intention-to-treat analysis, the demographic-adjusted hazard ratios (95% confidence interval) for diabetes in those with MetS (vs. no MetS) at baseline were 1.7 (1.3-2.3), 1.7 (1.2-2.3) and 2.0 (1.3-3.0) for placebo, metformin and lifestyle groups, respectively. Higher levels of fasting plasma glucose and triglycerides at baseline were independently associated with increased risk of diabetes. Greater waist circumference (WC) was associated with higher risk in placebo and lifestyle groups, but not in the metformin group. In a multivariate model, favourable changes in WC (placebo and lifestyle) and high-density lipoprotein cholesterol (placebo and metformin) contributed to reduced diabetes risk., Conclusions: MetS and some of its components are associated with increased diabetes incidence in persons with IGT in a manner that differed according to DPP intervention. After hyperglycaemia, the most predictive factors for diabetes were baseline hypertriglyceridaemia and both baseline and lifestyle-associated changes in WC. Targeting these cardiometabolic risk factors may help to assess the benefits of interventions that reduce diabetes incidence., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Objective: To report the annual incidence of type 1 and type 2 diabetes among youth and to describe characteristics of youth diagnosed with diabetes in the U.S. Virgin Islands (USVI)., Research Design and Methods: All residents ≤19 years of age diagnosed with diabetes between January 2001 and December 2010 were identified from review of medical records of all hospitals and confirmed by physician query., Results: A total of 82 eligible patients were identified and the registry ascertainment was estimated to be 98.7% complete. The overall age-adjusted annual incidence rates (per 100, 000) of type 1 and type 2 diabetes for the study period were 15.3 (95% CI: 11.3-20.1) and 9.6 (95% CI: 6.8-13.5), respectively. The incidence of type 1 diabetes increased significantly over the study period, with an epidemic-like threefold increase occurring from 2005 (8.7/100, 000) to 2006 (26.4/100, 000; p = 0.05). The incidence of type 1 diabetes was highest in the 10-19 age group in girls (25.6/100, 000), but no age difference was seen in boys, resulting from the lack of a pubertal peak in non-Hispanic Black boys. The incidence of type 2 diabetes rose significantly between 2001 (5.3/100, 000) and 2010 (12.5/100, 000; p = 0.03)., Conclusions: The incidence of type 1 and type 2 diabetes in youth is increasing in the USVI, similar to global patterns. Further studies are needed to explore the missing pubertal rise in type 1 diabetes incidence in non-Hispanic Black boys and factors associated with the epidemic-like increases observed over the decade., (© 2012 John Wiley & Sons A/S.)

This pilot project evaluated the Group Lifestyle Balance program (GLB), an adaptation of the DPP lifestyle intervention, delivered via DVD with remote participant support provided by the University of Pittsburgh Diabetes Prevention Support Center. Results suggest that GLB-DVD with remote support may provide an effective alternative for GLB delivery., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Introduction: We assessed the cost-effectiveness of a community-based, modified Diabetes Prevention Program (DPP) designed to reduce risk factors for type 2 diabetes and cardiovascular disease., Methods: We developed a Markov decision model to compare costs and effectiveness of a modified DPP intervention with usual care during a 3-year period. Input parameters included costs and outcomes from 2 projects that implemented a community-based modified DPP for participants with metabolic syndrome, and from other sources. The model discounted future costs and benefits by 3% annually., Results: At 12 months, usual care reduced relative risk of metabolic syndrome by 12.1%. A modified DPP intervention reduced relative risk by 16.2% and yielded life expectancy gains of 0.01 quality-adjusted life-years (3.67 days) at an incremental cost of $34.50 ($3,420 per quality-adjusted life-year gained). In 1-way sensitivity analyses, results were sensitive to probabilities that risk factors would be reduced with or without a modified DPP and that patients would enroll in an intervention, undergo testing, and acquire diabetes with or without an intervention if they were risk-factor-positive. Results were also sensitive to utilities for risk-factor-positive patients. In probabilistic sensitivity analysis, the intervention cost less than $20,000 per quality-adjusted life-year gained in approximately 78% of model iterations., Conclusion: We consider the modified DPP delivered in community and primary care settings a sound investment.

In order to examine lipids, a major treatment parameter in those with diabetes and heart disease, the authors analyzed baseline data from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. The study consisted of 2368 participants with type 2 diabetes and coronary artery disease from 49 sites in 6 countries (2295 provided lipid measurements). Fifty-nine percent of participants had a low-density lipoprotein (LDL) cholesterol level < 100 mg/dL. Levels of total, LDL, and non-high-density lipoprotein (HDL) cholesterol and triglycerides differed by age group (younger than 55, 55-64, and 65 years and older); they were lowest in those aged 65 years. Women had higher total, LDL, and non-HDL cholesterol values. Education was associated with lower total, LDL, and non-HDL cholesterol levels. LDL cholesterol and triglyceride values were lower in the United States and Canada. Adjustment for age, sex, education level, randomization year, and medication did not eliminate these differences. Geographic variation was seen and was not fully accounted for by demographic or treatment characteristics (all P values < .05).

Background: The Diabetes Prevention Program (DPP) demonstrated that lifestyle intervention reduces risk for type 2 diabetes and the metabolic syndrome. A universal framework for translation of multiple aspects of the DPP intervention, including training, support, and evaluation is needed to enhance treatment fidelity in a variety of settings., Purpose: This study aims to develop a comprehensive model for diabetes prevention translation using a modified DPP lifestyle intervention., Methods: The DPP lifestyle intervention was adapted to a 12-session group-based program called Group Lifestyle Balance for implementation in the community setting. A model for training and support mirroring that of the DPP was developed for prevention professionals administering the program. The process of training/support and program implementation was evaluated for feasibility and effectiveness using a nonrandomized prospective design in two phases (N=51, Phase 1: 2005-2006; N=42, Phase 2: 2007-2009; data analysis completed 2008-2009). A total of 93 nondiabetic individuals with BMI >or=25 kg/m(2) and the metabolic syndrome or prediabetes participated. Measures were collected at baseline and post-intervention for all and 6 and 12 months post-intervention for Phase 2., Results: Significant decreases in weight, waist circumference, and BMI were noted in both phases from baseline. Participants in Phase 2 also demonstrated decreases in total cholesterol, non-HDL cholesterol, and systolic and diastolic blood pressure that were maintained at 12 months. Average combined weight loss for both groups over the course of the 3-month intervention was 7.4 pounds (3.5% relative loss, p<0.001); 23.8% and 52.2% of those who completed the program reached 7% and 5% weight loss, respectively. More than 80% of those achieving 7% weight loss in the Phase-2 group maintained their weight loss at 6 months., Conclusions: A comprehensive diabetes prevention model for training, intervention delivery, and support was shown to be successful and was effective in reducing diabetes and cardiovascular disease risk factors in this group of high-risk individuals.

Background: Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established., Methods: We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention., Results: At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003)., Conclusions: Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.), (2009 Massachusetts Medical Society)

Objective: Although subjects with diabetes have increased risk for cardiovascular disease (CVD), the evolution of this increased risk as pre-diabetic individuals progress to diabetes is not understood. This study examines the longitudinal relationship between selected CVD risk factors (blood pressure, triglycerides, HDL and LDL cholesterol, and LDL peak particle density [PPD]) and glycemia in the three treatment groups of the Diabetes Prevention Program., Research Design and Methods: A total of 3,234 participants with impaired glucose tolerance (IGT) were followed for a mean of 3.2 years after randomization to intensive lifestyle intervention (ILS), metformin, or placebo. Using repeated-measures models, adjusted mean levels of risk factors were estimated for an annual change in glycemic status. Tests were also conducted to assess the risk factor trends with improvement or worsening of glycemic status., Results: CVD risk factor values and changes from baseline became more unfavorable as glucose tolerance status deteriorated but improved with reversion to normal glucose tolerance (NGT), especially in the ILS intervention group (trend test P < 0.001 for all risk factors except for LDL PPD [P = 0.02] in ILS and HDL cholesterol [P = 0.02] in placebo). Although there were few significant differences in the transition from IGT to diabetes, there were strong relationships between risk factors and continuous measures of glycemia., Conclusions: Progression from IGT to diabetes is associated with mild deterioration, whereas reversion to NGT is associated with improvement in risk factors. Early intervention with ILS, but less so with metformin, in participants at high risk for diabetes improves the cardiovascular risk and glucose tolerance profile simultaneously.

Background: Given the high prevalence of polycystic ovarian syndrome (PCOS) in the population, the increased risk for the development of type 2 diabetes in these women, and the role of type 2 diabetes in mediating adverse long-term sequelae, the objective of this analysis was to quantify the contribution of this early-life exposure (e.g., PCOS) to the burden of type 2 diabetes in the total population of middle-aged women., Methods: The cumulative incidence and relative risk (RR) of type 2 diabetes were examined in a group of women with PCOS (n = 149) and unaffected women (n = 166), aged 35-64, who were part of an ongoing investigation of cardiovascular risk factors in women with PCOS. The population attributable risk percent (PAR%) was calculated using Levin's formula to estimate the percentage of type 2 diabetes in the total population among middle-aged women that can be attributed to the presence of PCOS at young adulthood., Results: When the RR of type 2 diabetes among women with PCOS observed in our current study and others (4.0-6.0) was applied to an estimated 6%-10% prevalence of PCOS in the female population, 15.0%-35.6% of all incident cases of type 2 diabetes in white women were estimated to be attributable to PCOS. Moreover, other investigators have noted this proportion of undiagnosed PCOS in populations of women with type 2 diabetes., Conclusions: These results support the recommendation that all women with PCOS should be periodically rescreened for diabetes and underscores the importance of the early identification of young women with PCOS and the need for early lifestyle intervention.

Objective: Diabetes is associated with increased urinary incontinence risk. Weight loss improves incontinence, but exercise may worsen this condition. We examined whether an intensive lifestyle intervention or metformin therapy among overweight pre-diabetic women was associated with a lower prevalence of incontinence., Research Design and Methods: We analyzed data from the Diabetes Prevention Program, a randomized controlled trial in 27 U.S. centers. Of the 1,957 women included in this analysis, 660 (34%) were randomized to intensive lifestyle therapy, 636 (32%) to metformin, and 661 (34%) to placebo with standard lifestyle advice. The main outcome measure was incontinence symptoms by frequency and type by a validated questionnaire completed at the end-of-trial visit (mean 2.9 years)., Results: The prevalence of total (stress or urge) weekly incontinence was lower among women in the intensive lifestyle group (38.3%) than those randomized to metformin (48.1%) or placebo (45.7%). This difference was most apparent among women with stress incontinence (31.3% for intensive lifestyle group vs. 39.7% for metformin vs. 36.7% for placebo, P = 0.006). Changes in weight accounted for most of the protective effect of the intensive lifestyle intervention on stress incontinence., Conclusions: Less-frequent urinary incontinence may be a powerful motivator for women to choose lifestyle modification to prevent diabetes.

Objective: To examine whether a potential marker for type 2 diabetes (family history) is related to CAD in type 1 diabetic subjects. The two major types of primary diabetes, type 1 and type 2, are both associated with an increased risk of developing coronary artery disease (CAD). However, the etiology and associated risk factors may differ by type of diabetes. In type 2 diabetes, CAD is likely to be linked with the insulin resistance associated with the type 2 "process," while CAD in type 1 diabetes has, so far, been more closely linked to renal disease. Because the etiologies of type 1 and type 2 diabetes are different, it is possible that some CAD in type 1 diabetes may be related to the coexistence of type 2 diabetes susceptibility (i.e., insulin resistance)., Research Design and Methods: We evaluated the interrelationships between family history of type 2 diabetes (age at onset > 30 years, no insulin for 1st year) and presence of CAD in a cohort of childhood-onset type 1 diabetic subjects using the Pittsburgh Epidemiology of Diabetes Complications study (n = 658)., Results: A first-degree family history of type 2 diabetes was reported in 112 subjects, and CAD was present in 119 subjects. Those subjects reporting a family history of type 2 diabetes were significantly older, had a longer duration of type 1 diabetes, had higher triglyceride and LDL cholesterol levels, and had a borderline significantly increased Beck depression inventory. Sex differences in CAD risk factors were also noted. Using logistic regression analysis, the odds ratio (95% CI) for the presence of CAD in association with a family history of NIDDM was 1.89 (1.27-2.84). The odds ratio (95% CI) after adjusting for disease duration, triglycerides, hypertension, Beck depression, and nephropathy status was 1.45 (0.87-2.28)., Conclusions: We conclude that a family history of type 2 diabetes is a risk factor for CAD in type 1 diabetic subjects. This supports the concept that insulin resistance may contribute to development of CAD in type 1 diabetes.

While it is generally accepted that non-insulin-dependent diabetes mellitus (NIDDM) increases atherosclerotic risk, controversy remains as to whether this effect is greater for women than men (thus reducing the usual gender differential). Furthermore, it is unclear to what extent changes in general risk factors may account for this increased risk. The literature was reviewed with meta-analyses. Gender specific overall relative risks with 95% confidence intervals for coronary heart disease (CHD) mortality (ICD codes 410-414) were calculated. Similarly, overall gender specific odds ratios for prevalent myocardial infarction (MI) are presented. Data are generated from both fixed effects and random effects models. Frequency counts of studies showing specific cardiovascular disease (CVD) risk factor effects in diabetes are given as is the number of studies showing diabetes to be an independent risk factor. The overall relative risk (the ratio of men to women) for CHD mortality in diabetes was 1.46 (1.21-1.75) and 2.29 (2.05-2.55) in nondiabetes suggesting that the gender differential is reduced in diabetes. However, heterogeneity was high (P < 0.001). Exclusion of studies that were exclusively in elderly subjects eliminated heterogeneity (P > 0.05), but retained a separation of the confidence intervals. Overall odds ratios (men:women) show no suggestion of a diabetes effect on the gender difference for prevalent MI, 1.77 (diabetes) and 1.79 (no diabetes). The effects of six general CVD risk factors were unclear, although the largest study showed a clear effect of cholesterol, smoking, and blood pressure. All 10 studies in women report diabetes to be an independent risk factor as do 8 out of 12 studies in men. NIDDM reduces the gender differential in CHD mortality, but not for prevalent MI (or other end points). Although the effect of specific CVD risk factors is inconsistent across studies, this is likely to reflect limited sample size and power. The major three risk factors, cholesterol, blood pressure, and smoking, probably operate in NIDDM but do not fully explain the increased risk of CVD in NIDDM.

Relatives of patients with insulin-dependent diabetes mellitus (IDDM) carry an increased risk of developing IDDM. A number of studies that focus on the development of IDDM in such relatives, and the metabolic, immunologic, and viral factors involved are reviewed. These studies indicate that the destructive process in the beta-cells goes on for varying and often extended periods before the development of clinical disease. Thus, the events surrounding the time of clinical diagnosis may be of importance only as triggering mechanisms. Future studies may, therefore, be better directed toward long-term surveillance of the metabolic, viral, and immunologic status of first-degree relatives of IDDM subjects and the associations of these factors with genetic influences such as HLA-DR types or subtypes.