Empowering the Participant Voice (EPV): Design and implementation of collaborative infrastructure to collect research participant experience feedback at scale.

Empowering the Participant Voice (EPV) is an NCATS-funded six-CTSA collaboration to develop, demonstrate, and disseminate a low-cost infrastructure for collecting timely feedback from research participants, fostering trust, and providing data for improving clinical translational research. EPV leverages the validated Research Participant Perception Survey (RPPS) and the popular REDCap electronic data-capture platform. This report describes the development of infrastructure designed to overcome identified institutional barriers to routinely collecting participant feedback using RPPS and demonstration use cases. Sites engaged local stakeholders iteratively, incorporating feedback about anticipated value and potential concerns into project design. The team defined common standards and operations, developed software, and produced a detailed planning and implementation Guide. By May 2023, 2,575 participants diverse in age, race, ethnicity, and sex had responded to approximately 13,850 survey invitations (18.6%); 29% of responses included free-text comments. EPV infrastructure enabled sites to routinely access local and multi-site research participant experience data on an interactive analytics dashboard. The EPV learning collaborative continues to test initiatives to improve survey reach and optimize infrastructure and process. Broad uptake of EPV will expand the evidence base, enable hypothesis generation, and drive research-on-research locally and nationally to enhance the clinical research enterprise.

Racial differences in measures of glycemia in the Vitamin D and Type 2 Diabetes (D2d) Study: a secondary analysis of a randomized trial.

INTRODUCTION: Understanding how race may influence the association between A1c and glycemia can improve diabetes screening. We sought to determine whether, for a given A1c level, glucose levels during an oral glucose tolerance test (OGTT) differed by race. RESEARCH DESIGN AND METHODS: From data collected at 22 US clinical sites, we conducted a cross-sectional study of concurrently measured A1c and OGTT and observational longitudinal follow-up of the subset with high-risk pre-diabetes. Numerical integration methods were used to calculate area under the glycemic curve (AUCglu) during OGTT and least squares regression model to estimate A1c for a given AUCglu by race, controlling for potential confounders. RESULTS: 1016 black, 2658 white, and 193 Asian persons at risk of diabetes were included in cross-sectional analysis. Of these, 2154 with high-risk pre-diabetes were followed for 2.5 years. For a given A1c level, AUCglu was lower in black versus white participants. After adjustment for potential confounders, A1c levels for a given AUCglu quintile were 0.15-0.20 and 0.02-0.19 percentage points higher in black and Asian compared with white participants, respectively (p<0.05). In longitudinal analyses, black participants were more likely to be diagnosed with diabetes by A1c than white participants (28% vs 10%, respectively; p<0.01). Black and Asian participants were less likely to be diagnosed by fasting glucose than white participants (16% vs 15% vs 37%, respectively; p<0.05). Black participants with A1c levels in the lower-level quintiles had greater increase in A1c over time compared with white participants. CONCLUSIONS: Use of additional testing beyond A1c to screen for diabetes may better stratify diabetes risk in the diverse US population.

Feasibility of tracking invasive Escherichia coli disease among older adults in a community setting: A prospective observational study.

PURPOSE: Invasive Escherichia coli disease (IED) encompasses a diverse range of sterile site infections. This study evaluated the feasibility of capturing IED among community-dwelling older adults to inform the implementation of a phase 3 efficacy trial of a novel vaccine against IED (NCT04899336). METHODS: EXPECT-1 (NCT04087681) was a prospective, multinational, observational study conducted in medically stable participants aged ≥ 60 years. At least 50% of participants were selected based on a history of urinary tract infection (UTI) in the previous 10 years. The main outcomes were the incidence of IED and the number of hospitalisations reported by the site vs participant. The length of follow-up was 12 months. In a US-based substudy, a smartphone-based geofencing was evaluated to track hospital entries. RESULTS: In total, 4470 participants were enrolled (median age, 70.0 years); 59.5% (2657/4469) of participants had a history of UTI in the previous 10 years. Four IED events were captured through deployment of different tracking methods: a self-report, a general practitioner (GP) report, and a follow-up call. The incidence rate of IED was 98.6 events per 100,000 person-years. The number of reported hospitalisations was 2529/4470 (56.6%) by the site and 2177/4470 (48.7%) by participants; 13.8% of hospitalisations would have been missed if utilising only site reports. Geofencing detected 72 hospital entries. CONCLUSION: Deployment of multiple tracking methods can optimise detection of IED among community-dwelling older adults. Older adults with a history of UTI could be feasibly targeted for a phase 3 vaccine efficacy trial through a network of GPs.

Describing current use, barriers, and facilitators of patient portal messaging for research recruitment: Perspectives from study teams and patients at one institution.

Introduction: The electronic health record (EHR) and patient portal are used increasingly for clinical research, including patient portal recruitment messaging (PPRM). Use of PPRM has grown rapidly; however, best practices are still developing. In this study, we examined the use of PPRM at our institution and conducted qualitative interviews among study teams and patients to understand experiences and preferences for PPRM. Methods: We identified study teams that sent PPRMs and patients that received PPRMs in a 60-day period. We characterized these studies and patients, in addition to the patients' interactions with the PPRMs (e.g., viewed, responded). From these groups, we recruited study team members and patients for semi-structured interviews. A pragmatic qualitative inquiry framework was used by interviewers. Interviews were audio-recorded and analyzed using a rapid qualitative analysis exploratory approach. Results: Across ten studies, 35,037 PPRMs were sent, 33% were viewed, and 17% were responded to. Interaction rates varied across demographic groups. Six study team members completed interviews and described PPRM as an efficient and helpful recruitment method. Twenty-eight patients completed interviews. They were supportive of receiving PPRMs, particularly when the PPRM was relevant to their health. Patients indicated that providing more information in the PPRM would be helpful, in addition to options to set personalized preferences. Conclusions: PPRM is an efficient recruitment method for study teams and is acceptable to patients. Engagement with PPRMs varies across demographic groups, which should be considered during recruitment planning. Additional research is needed to evaluate and implement recommended changes by study teams and patients.

Clinical and Echocardiographic Diversity Associated With Physical Fitness in the Project Baseline Health Study: Implications for Heart Failure Staging.

BACKGROUND: Clinical and echocardiographic features may carry diverse information about the development of heart failure (HF). Therefore, we determined heterogeneity in clinical and echocardiographic phenotypes and its association with exercise capacity. METHODS: In 2036 community-dwelling individuals, we defined echocardiographic profiles of left and right heart remodeling and dysfunction. We subdivided the cohort based on presence (+) or absence (-) of HF risk factors (RFs) and echocardiographic abnormalities (RF-/Echo-, RF-/Echo+, RF+/Echo-, RF+/Echo+). Multivariable-adjusted associations between subgroups and physical performance metrics from 6-minute walk and treadmill exercise testing were assessed. RESULTS: The prevalence was 35.3% for RF-/Echo-, 4.7% for RF-/Echo+, 39.3% for RF+/Echo-, and 20.6% for RF+/Echo+. We observed large diversity in echocardiographic profiles in the Echo+ group. Participants with RF-/Echo+ (18.6% of Echo+) had predominantly echocardiographic abnormalities other than left ventricular (LV) diastolic dysfunction, hypertrophy and reduced ejection fraction, whereas their physical performance was similar to RF-/Echo-. In contrast, participants with RF+/Echo+ presented primarily with LV hypertrophy or dysfunction, features that related to lower 6-minute walking distance and lower exercise capacity. CONCLUSIONS: Subclinical echocardiographic abnormalities suggest HF pathogenesis, but the presence of HF risk factors and type of echo abnormality should be considered so as to distinguish adverse from benign adaptation and to stratify HF risk.

Accelerated Epigenetic Aging Is Associated With Multiple Cardiometabolic, Hematologic, and Renal Abnormalities: A Project Baseline Health Substudy.

BACKGROUND: Epigenetic clocks estimate chronologic age using methylation levels at specific loci. We tested the hypothesis that accelerated epigenetic aging is associated with abnormal values in a range of clinical, imaging, and laboratory characteristics. METHODS: The Project Baseline Health Study recruited 2502 participants, including 1661 with epigenetic age estimates from the Horvath pan-tissue clock. We classified individuals with extreme values as having epigenetic age acceleration (EAA) or epigenetic age deceleration. A subset of participants with longitudinal methylation profiling was categorized as accelerated versus nonaccelerated. Using principal components analysis, we created phenoclusters using 122 phenotypic variables and compared individuals with EAA versus epigenetic age deceleration, and at one year of follow-up, using logistic regression models adjusted for sex (false discovery rate [Q] <0.10); in secondary exploratory analyses, we tested individual clinical variables. RESULTS: The EAA (n=188) and epigenetic age deceleration (n=195) groups were identified as having EAA estimates ≥5 years or ≤-5 years, respectively. In primary analyses, individuals with EAA had higher values for phenoclusters summarizing lung function and lipids, and lower values for a phenocluster representing physical function. In secondary analyses of individual variables, neutrophils, body mass index, and waist circumference were significantly higher in individuals with EAA (Q<0.10). No phenoclusters were significantly different between participants with accelerated (n=148) versus nonaccelerated (n=112) longitudinal aging. CONCLUSIONS: We report multiple cardiometabolic, hematologic, and physical function features characterizing individuals with EAA. These highlight factors that may mediate the adverse effects of aging and identify potential targets for study of mitigation of these effects. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03154346.

Pragmatic evaluation of events and benefits of lipid lowering in older adults (PREVENTABLE): Trial design and rationale.

Whether initiation of statins could increase survival free of dementia and disability in adults aged ≥75 years is unknown. PREVENTABLE, a double-blind, placebo-controlled randomized pragmatic clinical trial, will compare high-intensity statin therapy (atorvastatin 40 mg) with placebo in 20,000 community-dwelling adults aged ≥75 years without cardiovascular disease, disability, or dementia at baseline. Exclusion criteria include statin use in the prior year or for >5 years and inability to take a statin. Potential participants are identified using computable phenotypes derived from the electronic health record and local referrals from the community. Participants will undergo baseline cognitive testing, with physical testing and a blinded lipid panel if feasible. Cognitive testing and disability screening will be conducted annually. Multiple data sources will be queried for cardiovascular events, dementia, and disability; survival is site-reported and supplemented by a National Death Index search. The primary outcome is survival free of new dementia or persisting disability. Co-secondary outcomes are a composite of cardiovascular death, hospitalization for unstable angina or myocardial infarction, heart failure, stroke, or coronary revascularization; and a composite of mild cognitive impairment or dementia. Ancillary studies will offer mechanistic insights into the effects of statins on key outcomes. Biorepository samples are obtained and stored for future study. These results will inform the benefit of statins for increasing survival free of dementia and disability among older adults. This is a pioneering pragmatic study testing important questions with low participant burden to align with the needs of the growing population of older adults.

Effect of intratrial mean 25(OH)D concentration on diabetes risk, by race and weight: an ancillary analysis in the D2d study.

BACKGROUND: Higher serum 25-hydroxyvitamin D [25(OH)D] is associated with lower type 2 diabetes risk. 25(OH)D varies due to skin pigmentation and weight. OBJECTIVES: This analysis aims to determine whether the effect of vitamin D differs among people of color and those with overweight/obesity (who have higher diabetes risk) compared with individuals who are White or have normal weight. METHODS: The D2d study is a randomized clinical trial in people with prediabetes that tested the effects of daily vitamin D3 4000 IU vs. placebo on diabetes risk (median followup 2.5 y). We compared baseline and intratrial mean 25(OH)D concentrations, defined as the mean of all available annual 25(OH)D values, among groups defined by self-reported race and body mass index (BMI). We used Cox proportional hazards models to assess the associations between intratrial mean 25(OH)D and diabetes risk by race- and BMI-based groups. RESULTS: Asian (n=130), Black (n=616), and White (n=1616) participants were included. Both baseline and intratrial mean 25(OH)D concentrations differed significantly by race groups (both P < 0.001) and were lower in Asian and Black vs. White participants, and in those with higher vs. lower BMI adjusted for race (both P < 0.001). Compared with those with lower concentrations, Black and White participants with intratrial mean 25(OH)D ≥ 40 ng/mL had significantly reduced diabetes risk [HR (95% CI): Black: 0.51 (0.29, 0.92); White: 0.42 (0.30, 0.60)] and with a similar reduction in diabetes risk among Asian participants: 0.39 (0.14, 1.11). Compared with those with lower concentrations, participants with baseline BMI < 40 kg/m2 who achieved intratrial mean 25(OH)D concentrations ≥ 40 ng/mL had a significantly reduced diabetes risk. There was no statistically significant interaction between intratrial 25(OH)D and race or between intratrial 25(OH)D and BMI on diabetes risk. CONCLUSIONS: Among people with prediabetes, particularly for Black and White race groups and those with BMI < 40 kg/m2, the optimal 25(OH)D concentration may be ≥ 40 ng/mL to optimize diabetes-prevention efforts. This trial was registered at clinicaltrials.gov as NCT01942694.

Multi-dimensional characterization of prediabetes in the Project Baseline Health Study.

BACKGROUND: We examined multi-dimensional clinical and laboratory data in participants with normoglycemia, prediabetes, and diabetes to identify characteristics of prediabetes and predictors of progression from prediabetes to diabetes or reversion to no diabetes. METHODS: The Project Baseline Health Study (PBHS) is a multi-site prospective cohort study of 2502 adults that conducted deep clinical phenotyping through imaging, laboratory tests, clinical assessments, medical history, personal devices, and surveys. Participants were classified by diabetes status (diabetes [DM], prediabetes [preDM], or no diabetes [noDM]) at each visit based on glucose, HbA1c, medications, and self-report. Principal component analysis (PCA) was performed to create factors that were compared across groups cross-sectionally using linear models. Logistic regression was used to identify factors associated with progression from preDM to DM and for reversion from preDM to noDM. RESULTS: At enrollment, 1605 participants had noDM; 544 had preDM; and 352 had DM. Over 4 years of follow-up, 52 participants with preDM developed DM and 153 participants reverted to noDM. PCA identified 33 factors composed of clusters of clinical variables; these were tested along with eight individual variables identified a priori as being of interest. Six PCA factors and six a priori variables significantly differed between noDM and both preDM and DM after false discovery rate adjustment for multiple comparisons (q < 0.05). Of these, two factors (one comprising glucose measures and one of anthropometry and physical function) demonstrated monotonic/graded relationships across the groups, as did three a priori variables: ASCVD risk, coronary artery calcium, and triglycerides (q < 10-21 for all). Four factors were significantly different between preDM and noDM, but concordant or similar between DM and preDM: red blood cell indices (q = 8 × 10-10), lung function (q = 2 × 10-6), risks of chronic diseases (q = 7 × 10-4), and cardiac function (q = 0.001), along with a priori variables of diastolic function (q = 1 × 10-10), sleep efficiency (q = 9 × 10-6) and sleep time (q = 6 × 10-5). Two factors were associated with progression from prediabetes to DM: anthropometry and physical function (OR [95% CI]: 0.6 [0.5, 0.9], q = 0.04), and heart failure and c-reactive protein (OR [95% CI]: 1.4 [1.1, 1.7], q = 0.02). The anthropometry and physical function factor was also associated with reversion from prediabetes to noDM: (OR [95% CI]: 1.9 [1.4, 2.7], q = 0.02) along with a factor of white blood cell indices (OR [95% CI]: 0.6 [0.4, 0.8], q = 0.02), and the a priori variables ASCVD risk score (OR [95% CI]: 0.7 [0.6, 0.9] for each 0.1 increase in ASCVD score, q = 0.02) and triglycerides (OR [95% CI]: 0.9 [0.8, 1.0] for each 25 mg/dl increase, q = 0.05). CONCLUSIONS: PBHS participants with preDM demonstrated pathophysiologic changes in cardiac, pulmonary, and hematology measures and declines in physical function and sleep measures that precede DM; some changes predicted an increased risk of progression to DM. A factor with measures of anthropometry and physical function was the most important factor associated with progression to DM and reversion to noDM. Future studies may determine whether these changes elucidate pathways of progression to DM and related complications and whether they can be used to identify individuals at higher risk of progression to DM for targeted preventive interventions. Trial registration ClinicalTrials.gov NCT03154346.

Practice Patterns of Fundoscopic Examination for Diabetic Retinopathy Screening in Primary Care.

Importance: Primary care professionals (PCPs) have a central role in screening for diabetic retinopathy (DR), especially in settings where access to specialty eye care is limited. Data on current DR screening practice patterns in primary care are needed to inform screening strategies. Objectives: To assess the practice patterns of fundoscopic examination for DR screening in a large primary care network and to evaluate the sensitivity and accuracy of PCP fundoscopy for detecting DR. Design, Setting, and Participants: A retrospective cohort study was performed using random sampling and manual review of electronic health records of PCP fundoscopic examination documentation compared with documentation of an examination performed by an eye care professional (ophthalmologist or optometrist) within 2 years before or after primary care encounters. From a single-institution primary care network of 28 clinics, 7449 adult patients with diabetes seen at least once in the primary care network in 2019 were eligible for this study. Data from 2001 encounters were abstracted from the electronic health record for a random sample of 767 patients. Data analysis was performed from January 2021 to May 2022. Exposure: Fundoscopic examination by PCPs. Main Outcomes and Measures: The frequency of PCPs performing fundoscopy at least once in the calendar year for patients with diabetes. Univariate and multivariable logistic regression analyses were performed to identify patient, clinician, and clinic factors associated with PCPs performing fundoscopy at least once in the calendar year. The PCP examination results were compared with diagnoses made by eye care professionals to assess the sensitivity and accuracy of the findings from PCP examinations. Results: Among the 767 adult patients with diabetes included in the analysis, 387 (50.5%) were female, and the median age was 64 years (IQR, 54-71 years). Primary care professionals documented a fundoscopic examination for 93 patients (12.1%); all results were documented as normal. When eye care professional examination results were used as the reference standard, the accuracy of PCP fundoscopic examination was 62.7% (95% CI, 50.0%-73.9%) and sensitivity for detecting disease was 0.0% (95% CI, 0.0%-14.9%). No patient demographic or clinical characteristics were associated with PCPs performing fundoscopy. In multivariable logistic regression, the number of PCP years in practice was associated with greater odds of patients receiving fundoscopy at least once in the year (adjusted odds ratio per 10 years in practice, 1.26; 95% CI, 1.01-1.59; P = .04); having nurse practitioner credentials was associated with lower odds of receiving fundoscopy (adjusted odds ratio, 0.23; 95% CI, 0.04-0.79; P = .049; compared with having physician credentials); after adjusting for rural clinic location, clinic location in a primary care shortage area, and documentation of an up-to-date eye care professional examination by a PCP in the study year. Conclusions and Relevance: In this cohort study, fundoscopic examination was rarely performed and was not sensitive for detecting DR in primary care practice. Because the rate of DR screening by eye care professionals remains low, research to explore and break down barriers to the implementation of effective primary care-based DR screening strategies, such as teleretinal imaging, is needed to prevent vision loss from undiagnosed DR.

The effect of vitamin D supplementation on cardiovascular risk in patients with prediabetes: A secondary analysis of the D2d study.

AIMS: Low blood 25(OH)D level is associated with increased cardiovascular disease (CVD) risk. Additionally, individuals with prediabetes are at higher risk for CVD than individuals with normoglycemia. We investigated the effects of vitamin D supplementation on CVD outcomes in the vitamin D and type 2 diabetes (D2d) study, a large trial among adults with prediabetes. METHODS: 2423 participants were randomized to 4000 IU/day of vitamin D3 or placebo and followed for median 3.0 years for new-onset diabetes. In pre-specified secondary analyses, we examined the effect of vitamin D supplementation on composite Major Adverse Cardiovascular Events (MACE); expanded MACE (MACE + revascularization); atherosclerotic CVD (ASCVD) risk score; and individual CVD risk factors (blood pressure, lipids, high-sensitivity C-reactive protein). Cox models compared hazard ratios (HR) between the two groups on MACE and expanded MACE. RESULTS: Mean age was 60 years, 45 % were women, 13 % had history of CVD. Twenty-one participants assigned to vitamin D and 12 participants assigned to placebo met the MACE outcome (HR 1.81, 95%CI 0.89 to 3.69). There were 27 expanded MACE outcomes in each group (HR 1.02, 95%CI, 0.59 to 1.76). There were no significant differences between vitamin D and placebo in individual CVD risk factors, but change in ASCVD risk score favored the vitamin D group (-0.45 %, 95%CI -0.75 to -0.15). CONCLUSIONS: In people with prediabetes not selected for vitamin D insufficiency and with intermediate CVD risk, vitamin D supplementation did not decrease MACE but had a small favorable effect on ASCVD risk score. TRIAL REGISTRATION: D2d ClinicalTrials.gov number, NCT01942694, prospectively registered September 16, 2013.

Safety and tolerability of high-dose daily vitamin D3 supplementation in the vitamin D and type 2 diabetes (D2d) study-a randomized trial in persons with prediabetes.

BACKGROUND/OBJECTIVES: Routine use of vitamin D supplements has increased substantially in the United States. However, the safety and tolerability of long-term use of high-dose vitamin D are not known. We assessed the safety and tolerability of high-dose, daily vitamin D3 in the vitamin D and type 2 diabetes (D2d) study. SUBJECTS/METHODS: In total, 2423 overweight/obese persons with prediabetes were randomized in a double-blind manner to either 4000 IU of vitamin D3 (the tolerable upper intake level for adults by the National Academy of Medicine) taken daily or matching placebo. All participants were included in this analysis. Incident adverse events (AE) were ascertained 4 times a year at in-person visits (twice a year) and interim remote encounters (twice a year) and were defined as untoward or unfavorable medical occurrences. Serious adverse events (SAE) included death, life-threatening events, and hospitalizations. RESULTS: A total of 8304 AEs occurred during 3 years of follow-up and were less frequent in the vitamin D group compared to placebo (Incidence Rate Ratio [IRR] = 0.94; 95% Confidence Interval (CI) 0.90, 0.98). The overall frequency of protocol-specified AEs of interest, which included nephrolithiasis, hypercalcemia, hypercalciuria, or low estimated glomerular filtration rate, was low and did not differ by group. There were no significant between-group differences in total SAEs (IRR = 0.96 (0.81, 1.14)). CONCLUSION: Vitamin D3 supplementation at 4000 IU per day was safe and well tolerated among overweight/obese participants at high risk for diabetes who were appropriately monitored for safety. In this population, this dose of vitamin D3 did not increase risk of AEs or SAEs, including those previously associated with vitamin D such as hypercalcemia, hypercalciuria, or nephrolithiasis. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01942694, prospectively registered September 16, 2013.

Effects of Vitamin D Supplementation on Insulin Sensitivity and Secretion in Prediabetes.

CONTEXT: Vitamin D regulates glucose homeostasis pathways, but effects of vitamin D supplementation on ß-cell function remain unclear. OBJECTIVE: To investigate the effects of vitamin D3 supplementation on insulin sensitivity and ß-cell function. METHODS: This is a prespecified secondary analysis of the Vitamin D and Type 2 Diabetes study. Overweight/obese adults at high risk for type 2 diabetes (prediabetes) were randomly treated with vitamin D3 4000 IU or matching placebo daily for 24 months. MAIN OUTCOME: Disposition index (DI), as an estimate of ß-cell function, was calculated as the product of Homeostasis Model Assessment 2 indices derived from C-peptide values (HOMA2%Scpep) and C-peptide response during the first 30 minutes of a 75-g oral glucose tolerance test (OGTT). RESULTS: Mean age was 60.5 ± 9.8 years and body mass index was 31.9 ± 4.4 kg/m2. Mean serum 25(OH)D level increased from 27.9 ± 10.3 ng/mL at baseline to 54.9 ng/mL at 2 years in the vitamin D group and was unchanged (28.5 ± 10.0 ng/mL) in the placebo group. The baseline DI predicted incident diabetes independent of the intervention. In the entire cohort, there were no significant differences in changes in DI, HOMA2%Scpep, or C-peptide response between the 2 groups. Among participants with baseline 25(OH)D level <12 ng/mL, the mean percent differences for DI between the vitamin D and placebo groups was 8.5 (95% CI, 0.2-16.8). CONCLUSIONS: Supplementation with vitamin D3 for 24 months did not improve an OGTT-derived index of ß-cell function in people with prediabetes not selected based on baseline vitamin D status; however, there was benefit among those with very low baseline vitamin D status.

Effect of Vitamin D Supplementation on Kidney Function in Adults with Prediabetes: A Secondary Analysis of a Randomized Trial.

BACKGROUND AND OBJECTIVES: Low serum 25-hydroxyvitamin D (25[OH]D) concentration has been associated with higher levels of proteinuria and lower levels of eGFR in observational studies. In the Vitamin D and Type 2 Diabetes (D2d) study, we investigated the effect of vitamin D supplementation on kidney outcomes in a population with prediabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Overweight/obese adults with high risk for type 2 diabetes (defined by meeting two of three glycemic criteria for prediabetes) were randomized to vitamin D3 4000 IU per day versus placebo. Median duration of treatment was 2.9 years (interquartile range 2.0-3.5 years). Kidney outcomes included (1) worsening in Kidney Disease: Improving Global Outcomes (KDIGO ) risk score (low, moderate, high, very high) on two consecutive follow-up visits after the baseline visit and (2) mean changes in eGFR and urine albumin-to-creatinine ratio (UACR). RESULTS: Among 2166 participants (mean age 60 years, body mass index 32 kg/m2, serum 25(OH)D 28 ng/ml, eGFR 87 ml/min per 1.73 m2, UACR 11 mg/g, 79% with hypertension), 10% had moderate, high, or very high KDIGO risk score. Over a median follow-up of 2.9 years, there were 28 cases of KDIGO worsening in the vitamin D group and 30 in the placebo group (hazard ratio, 0.89; 95% confidence interval [95% CI], 0.52 to 1.52]). Mean difference in eGFR from baseline was -1.0 ml/min per 1.73 m2 (95% CI, -1.3 to -0.7) in the vitamin D group and -0.1 ml/min per 1.73 m2 (95% CI, -0.4 to 0.2) in the placebo group; between-group difference was -1.0 ml/min per 1.73 m2 (95% CI, -1.4 to -0.6). Mean difference in UACR was 2.7 mg/g (95% CI, 1.2 to 4.3) in the vitamin D group and 2.0 (95% CI, 0.5 to 3.6) in the placebo group; between-group difference was 0.7 mg/g (95% CI, -1.5 to 2.9). CONCLUSIONS: Among persons with prediabetes, who were not preselected on the basis of serum 25(OH)D concentration, vitamin D supplementation did not affect progression of KDIGO risk scores and did not have a meaningful effect on change in UACR or eGFR.

Vitamin D Supplementation for Prevention of Cancer: The D2d Cancer Outcomes (D2dCA) Ancillary Study.

CONTEXT: Observational studies suggest that low vitamin D status may be a risk factor for cancer. OBJECTIVE: In a population with prediabetes and overweight/obesity that is at higher risk of cancer than the general population, we sought to determine if vitamin D supplementation lowers the risk of cancer and precancers. METHODS: The Vitamin D and type 2 diabetes (D2d) cancer outcomes study (D2dCA) is an ancillary study to the D2d study, which was conducted at 22 academic medical centers in the United States. Participants had prediabetes and overweight/obesity and were free of cancer for the previous 5 years. Participants were randomized to receive vitamin D3 4000 IU daily or placebo. At scheduled study visits (4 times/year), cancer and precancer events were identified by questionnaires. Clinical data were collected and adjudicated for all reported events. Cox proportional hazard models compared the hazard ratio (HR) of incident cancers and precancers between groups. RESULTS: Over a median follow-up period of 2.9 years, among 2385 participants (mean age 60 years and 25-hydroxyvitamin D 28 ng/mL), there were 89 cases of cancer. The HR of incident cancer for vitamin D vs placebo was 1.07 (95% CI 0.70, 1.62). Of 241 participants with incident precancers, 239 had colorectal adenomatous polyps. The HR for colorectal polyps for vitamin D vs placebo was 0.83 (95% CI 0.64, 1.07). CONCLUSION: In the D2d population of participants with prediabetes and overweight/obesity, not selected for vitamin D insufficiency, vitamin D supplementation did not have a significant effect on risk of incident cancer or colorectal polyps.

Reproducibility of a prediabetes classification in a contemporary population.

AIMS: To assess whether meeting both fasting plasma glucose (FPG) and HbA1c criteria for prediabetes in people at high risk indicates with near certainty the presence of dysglycemia on repeat testing. METHODS: Observational study using data from Vitamin D and Type 2 Diabetes (D2d) study. HbA1c, FPG were measured at screening visit 1; FPG, HbA1c and 2 h plasma glucose (2hPG) measured at screening visit 2 (a median of 21 days later); participants classified as having normal glucose regulation (all 3 tests in normal range), prediabetes or diabetes (at least 1 of 3 tests in diabetes range). A predictive model was developed to estimate the probability of confirming dysglycemia and for detecting diabetes at screening visit 2 based on values of FPG and HbA1c at screening visit 1. RESULTS: Of 1271 participants who met both FPG and HbA1c criteria for prediabetes at screening visit 1, 98.6% exhibited dysglycemia (defined as prediabetes or diabetes) on repeat testing (84.5% were classified as having prediabetes, 14.1% were reclassified as having diabetes). Of those with diabetes, 62.6% were identified by 2hPG alone. CONCLUSIONS: Combined measurement of FPG and HbA1c is a reliable and reproducible measure to identify presence of dysglycemia among people at high risk. A prediction model is provided to help clinicians decide whether an oral glucose tolerance test will provide value in detecting diabetes based on the 2hPG criterion.

Preliminary evidence of effects of potassium chloride on a metabolomic path to diabetes and cardiovascular disease.

INTRODUCTION: Low potassium intake can affect cardiovascular disease (CVD) risk and cardiometabolic risk factors. OBJECTIVE: We hypothesize that potassium chloride (KCl) supplementation can improve cardiovascular risk metabolomic profile. METHODS: In this secondary analysis of a pilot randomized clinical trial (RCT) of 26 participants with prediabetes randomized to KCl or placebo, we performed targeted mass-spectrometry-based metabolomic profiling on baseline and 12-week (end-of-study) plasma samples. Principal component analysis (PCA) was used to reduce the many correlated metabolites into fewer, independent factors that retain most of the information in the original data. RESULTS: Those taking KCl had significant reductions (corresponding to lower cardiovascular risk) in the branched-chain amino acids (BCAA) factor (P = 0.004) and in valine levels (P = 0.02); and non-significant reductions in short-chain acylcarnitines (SCA) factor (P = 0.11). CONCLUSIONS: KCl supplementation may improve circulating BCAA levels, which may reflect improvements in overall cardiometabolic risk profile. CLINICAL TRIALS REGISTRY: Clinicaltrials.gov identifier: NCT02236598; https://clinicaltrials.gov/ct2/show/NCT02236598.

Vitamin D Supplementation and Prevention of Type 2 Diabetes.

BACKGROUND: Observational studies support an association between a low blood 25-hydroxyvitamin D level and the risk of type 2 diabetes. However, whether vitamin D supplementation lowers the risk of diabetes is unknown. METHODS: We randomly assigned adults who met at least two of three glycemic criteria for prediabetes (fasting plasma glucose level, 100 to 125 mg per deciliter; plasma glucose level 2 hours after a 75-g oral glucose load, 140 to 199 mg per deciliter; and glycated hemoglobin level, 5.7 to 6.4%) and no diagnostic criteria for diabetes to receive 4000 IU per day of vitamin D3 or placebo, regardless of the baseline serum 25-hydroxyvitamin D level. The primary outcome in this time-to-event analysis was new-onset diabetes, and the trial design was event-driven, with a target number of diabetes events of 508. RESULTS: A total of 2423 participants underwent randomization (1211 to the vitamin D group and 1212 to the placebo group). By month 24, the mean serum 25-hydroxyvitamin D level in the vitamin D group was 54.3 ng per milliliter (from 27.7 ng per milliliter at baseline), as compared with 28.8 ng per milliliter in the placebo group (from 28.2 ng per milliliter at baseline). After a median follow-up of 2.5 years, the primary outcome of diabetes occurred in 293 participants in the vitamin D group and 323 in the placebo group (9.39 and 10.66 events per 100 person-years, respectively). The hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75 to 1.04; P = 0.12). The incidence of adverse events did not differ significantly between the two groups. CONCLUSIONS: Among persons at high risk for type 2 diabetes not selected for vitamin D insufficiency, vitamin D3 supplementation at a dose of 4000 IU per day did not result in a significantly lower risk of diabetes than placebo. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; D2d ClinicalTrials.gov number, NCT01942694.).