Prevalence and predictors of female sexual dysfunction among sexually active women in the diabetes prevention program outcomes study.

OBJECTIVE: To determine the burden and identify correlates of female sexual dysfunction (FSD) among women with prediabetes (PreD) and type 2 diabetes (T2D) enrolled in the Diabetes Prevention Program (DPP) Outcomes Study (DPPOS). METHODS: The DPPOS visit included the Female Sexual Function Index (FSFI) to determine sexual function. Of 1464 participants, 1320 (90%) completed the (FSFI) and 426 were sexually active. A backward selection multivariable logistic regression model estimated the odds of FSD for sociodemographic, clinical, and diabetes-related covariates. RESULTS: One hundred and eighty-five (43%) had a score of ≤26.55 and met the criteria for FSD. After adjustment for DPP treatment and age, urinary incontinence (UI) (odds ratio [OR] = 1.91, 95% confidence interval [CI] = 1.15-3.17) and hysterectomy (OR = 1.89, 95% CI = 1.01-3.53) were associated with increased odds of FSD. Increased body mass index was protective for FSD (OR = 0.93 per kg/m2, 95% CI = 0.89-0.96). Michigan Neuropathy Screening Instrument-based peripheral neuropathy (mean±SD scores 1.1±1.3 vs. 0.9±1.1, p < 0.0001) and Electrocardiogram (ECG)-based autonomic dysfunction measures (mean ± SD heart rate levels 64.3 ± 6.8 vs. 65.6 ± 10.2, p = 0.008) were associated with FSD. There were no differences in diabetes rates between women who did (66.5%) and did not (66%) have (p = 0.7). CONCLUSIONS: FSD is prevalent in women with PreD and T2D. Our findings suggest that FSD is associated with neuropathic complications commonly observed in PreD and T2D.

Effects of Long-term Metformin and Lifestyle Interventions on Cardiovascular Events in the Diabetes Prevention Program and Its Outcome Study.

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).

COMETS Analytics: An Online Tool for Analyzing and Meta-Analyzing Metabolomics Data in Large Research Consortia.

Consortium-based research is crucial for producing reliable, high-quality findings, but existing tools for consortium studies have important drawbacks with respect to data protection, ease of deployment, and analytical rigor. To address these concerns, we developed COnsortium of METabolomics Studies (COMETS) Analytics to support and streamline consortium-based analyses of metabolomics and other -omics data. The application requires no specialized expertise and can be run locally to guarantee data protection or through a Web-based server for convenience and speed. Unlike other Web-based tools, COMETS Analytics enables standardized analyses to be run across all cohorts, using an algorithmic, reproducible approach to diagnose, document, and fix model issues. This eliminates the time-consuming and potentially error-prone step of manually customizing models by cohort, helping to accelerate consortium-based projects and enhancing analytical reproducibility. We demonstrated that the application scales well by performing 2 data analyses in 45 cohort studies that together comprised measurements of 4,647 metabolites in up to 134,742 participants. COMETS Analytics performed well in this test, as judged by the minimal errors that analysts had in preparing data inputs and the successful execution of all models attempted. As metabolomics gathers momentum among biomedical and epidemiologic researchers, COMETS Analytics may be a useful tool for facilitating large-scale consortium-based research.

Risk of Severe COVID-19 Disease and the Pandemic's Impact on Service Utilization Among a Longitudinal Cohort of Persons with HIV-Washington, DC.

People with HIV (PWH) have a high burden of medical comorbidities, potentially putting them at increased risk for severe COVID-19. Additionally, during the COVID-19 pandemic, HIV care delivery has been restructured and the impact on HIV outcomes is unknown. The objectives of this study were first, to examine the risk of severe COVID-19 among PWH, using a definition incorporating clinical risk factors, and second, to examine the pandemic's impact on HIV care. We used data from the DC Cohort, a large cohort of people receiving HIV care in Washington, DC. We found that a high proportion of participants across all age groups qualified as increased (58%) or high risk (34%) for severe COVID-19. Between 2019 and 2020, encounters increased (17.7%, increasing to 23.5% of active DC Cohort participants had an encounter) while laboratory utilization decreased (14.4%, decreasing to 11.4% of active DC Cohort participants had an HIV RNA test performed). Implications of our work include the importance of protecting vulnerable people with HIV from acquiring COVID-19 and potentially manifesting severe complications through strategies including vaccination. Additionally, acknowledging that HIV service delivery will likely be changed long-term by the pandemic, adaptation is required to ensure continued progress towards 90-90-90 goals.

Non-traditional biomarkers and incident diabetes in the Diabetes Prevention Program: comparative effects of lifestyle and metformin interventions.

AIMS/HYPOTHESIS: We compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker-incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes. METHODS: The Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these. RESULTS: E-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]). CONCLUSIONS/INTERPRETATION: These findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.

Does diabetes prevention translate into reduced long-term vascular complications of diabetes?

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.

The Consortium of Metabolomics Studies (COMETS): Metabolomics in 47 Prospective Cohort Studies.

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).

Effect of Long-Term Metformin and Lifestyle in the Diabetes Prevention Program and Its Outcome Study on Coronary Artery Calcium.

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.

Metformin for diabetes prevention: insights gained from the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study.

The largest and longest clinical trial of metformin for the prevention of diabetes is the Diabetes Prevention Program/Diabetes Prevention Program Outcomes Study (DPP/DPPOS). In this review, we summarise data from the DPP/DPPOS, focusing on metformin for diabetes prevention, as well as its long-term glycaemic and cardiometabolic effects and safety in people at high-risk of developing diabetes. The DPP (1996-2001) was a RCT of 3234 adults who, at baseline, were at high-risk of developing diabetes. Participants were assigned to masked placebo (n = 1082) or metformin (n = 1073) 850 mg twice daily, or intensive lifestyle intervention (n = 1079). The masked metformin/placebo intervention phase ended approximately 1 year ahead of schedule because of demonstrated efficacy. Primary outcome was reported at 2.8 years. At the end of the DPP, all participants were offered lifestyle education and 88% (n = 2776) of the surviving DPP cohort continued follow-up in the DPPOS. Participants originally assigned to metformin continued to receive metformin, unmasked. The DPP/DPPOS cohort has now been followed for over 15 years with prospective assessment of glycaemic, cardiometabolic, health economic and safety outcomes. After an average follow-up of 2.8 years, metformin reduced the incidence of diabetes by 31% compared with placebo, with a greater effect in those who were more obese, had a higher fasting glucose or a history of gestational diabetes. The DPPOS addressed the longer-term effects of metformin, showing a risk reduction of 18% over 10 and 15 years post-randomisation. Metformin treatment for diabetes prevention was estimated to be cost-saving. At 15 years, lack of progression to diabetes was associated with a 28% lower risk of microvascular complications across treatment arms, a reduction that was no different among treatment groups. Recent findings suggest metformin may reduce atherosclerosis development in men. Originally used for the treatment of type 2 diabetes, metformin, now proven to prevent or delay diabetes, may serve as an important tool in battling the growing diabetes epidemic. Long-term follow-up, currently underway in the DPP/DPPOS, is now evaluating metformin's potential role, when started early in the spectrum of dysglycaemia, on later-stage comorbidities, including cardiovascular disease and cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00038727 and NCT00004992.

A High-Carbohydrate, High-Fiber, Low-Fat Diet Results in Weight Loss among Adults at High Risk of Type 2 Diabetes.

Background: Weight loss is a key factor in reducing diabetes risk. The Diabetes Prevention Program (DPP) is a completed clinical trial that randomly assigned individuals at high risk of diabetes to a placebo (PLBO), metformin (MET), or intensive lifestyle intervention (ILS) group, which included physical activity (PA) and reduced dietary fat intake.Objective: We aimed to evaluate the associations between diet and weight at baseline and to identify specific dietary factors that predicted weight loss among DPP participants.Methods: Diet was assessed by a food frequency questionnaire. The associations between intakes of macronutrients and various food groups and body weight among DPP participants at baseline were assessed by linear regression, adjusted for race/ethnicity, age, sex, calorie intake, and PA. Models that predicted weight loss at year 1 were adjusted for baseline weight, change in calorie intake, and change in PA and stratified by treatment allocation (MET, ILS, and PLBO). All results are presented as estimates ± SEs.Results: A total of 3234 participants were enrolled in the DPP; 2924 had completed dietary data (67.5% women; mean age: 50.6 ± 10.7 y). Adjusted for calorie intake, baseline weight was negatively associated with carbohydrate intake (-1.14 ± 0.18 kg body weight/100 kcal carbohydrate, P < 0.0001) and, specifically, dietary fiber (-1.26 ± 0.28 kg/5 g fiber, P < 0.0001). Baseline weight was positively associated with total fat (1.25 ± 0.21 kg/100 kcal, P < 0.0001), saturated fat (1.96 ± 0.46 kg/100 kcal, P < 0.0001), and protein (0.21 ± 0.05 kg/100 kcal, P < 0.0001). For all groups, weight loss after 1 y was associated with increases in carbohydrate intake, specifically dietary fiber, and decreases in total fat and saturated fat intake.Conclusions: Higher carbohydrate consumption among DPP participants, specifically high-fiber carbohydrates, and lower total and saturated fat intake best predicted weight loss when adjusted for changes in calorie intake. Our results support the benefits of a high-carbohydrate, high-fiber, low-fat diet in the context of overall calorie reduction leading to weight loss, which may prevent diabetes in high-risk individuals. This trial was registered at clinicaltrials.gov as NCT00004992.