John B Buse

BackgroundTirzepatide, a once weekly GIP/GLP-1 receptor agonist, reduces blood glucose and body weight in people with type 2 diabetes. The cardiovascular (CV) safety and efficacy of tirzepatide have not been definitively assessed in a cardiovascular outcomes trial.MethodsTirzepatide is being studied in a randomized, double-blind, active-controlled CV outcomes trial. People with type 2 diabetes aged ≥40 years, with established atherosclerotic CV disease, HbA1c ≥7% to ≤10.5%, and body mass index ≥25 kg/m2 were randomized 1:1 to once weekly subcutaneous injection of either tirzepatide up to 15 mg or dulaglutide 1.5 mg. The primary outcome is time to first occurrence of any major adverse cardiovascular event (MACE), defined as CV death, myocardial infarction, or stroke. The trial is event-driven and planned to continue until ≥1,615 participants experience an adjudication-confirmed component of …

OBJECTIVE We report mortality outcomes in GRADE among people with type 2 diabetes diagnosed within 10 years and no recent history of cardiovascular events or cancer. RESEARCH DESIGN AND METHODS Overall mortality rates and major causes of death were assessed over an average of 5 years of follow-up. Cause of death was adjudicated centrally by a committee masked to treatment assignment. We examined baseline covariates and the 10-year Framingham Risk Score for associations. RESULTS Mortality rate was low (0.59 per 100 participant-years). Participants who died during follow-up were likely to be older, male, have a history of hypertension, smoking, and have moderate albuminuria. The two most common underlying causes of death were “cardiovascular-cause” (a composite of underlying causes) (38.6%) and cancer (26.8%). There were …

ConclusionLes auteurs de l’étude COVID-OUT, d’excellente qualité méthodologique, concluent à l’efficacité de l’usage préventif de la metformine chez les adultes obèses ou en surpoids atteints de covid-19 en vue d’éviter l’apparition d’un covid long. De sérieuses réserves concernant l’analyse des résultats et leur interprétation mettent en doute cette conclusion ou la rendent prématurée. Il est nécessaire de mener une nouvelle étude portant sur la survenue d’un covid long comme critère de jugement principal, utilisant une définition précise et standardisée du covid long.

Background Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. Methods COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative …

A year has passed since we were given the responsibility of leading Diabetes Care. In 2023, perhaps the most momentous highlight for all of us from a health perspective has been the sense that we are on the better side of recovery from the coronavirus disease 2019 (COVID-19) pandemic. This realization is in part due to the rapid application of technology that allowed for the development of mRNA vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These vaccines have saved many lives and appropriately resulted in the awarding of the 2023 Nobel Prize in

MethodsUtilizing observational data from the National COVID Cohort Collaborative through September 2022, we compared outcomes in 78,806 individuals with a prescription of GLP-1RA and SGLT-2i versus a prescription of dipeptidyl peptidase 4 inhibitors (DPP-4i) within 24 months of a positive SARS-CoV-2 PCR test. We also compared concomitant GLP-1RA/SGLT-2i therapy to GLP-1RA and SGLT-2i monotherapy. The primary outcome was 60-day mortality, measured from the positive test date. Secondary outcomes included emergency room (ER) visits, hospitalization, and mechanical ventilation within 14 days. Using a super learner approach and accounting for baseline characteristics, associations were quantified with odds ratios (OR) estimated with targeted maximum likelihood estimation (TMLE).ResultsUse of GLP-1RA (OR 0.64, 95% confidence interval [CI] 0.56–0.72) and SGLT-2i (OR 0.62, 95% CI 0.57 …

BackgroundHypercoagulable state contributing to thrombotic complications worsens COVID-19 severity and outcomes, whereas anticoagulation improves outcomes by alleviating hypercoagulability.ObjectivesTo examine whether hemophilia, an inherent hypocoagulable condition, offers protection against COVID-19 severity and reduces venous thromboembolism (VTE) risk in persons with hemophilia (PwH).MethodsA 1:3 propensity score–matched retrospective cohort study used national COVID-19 registry data (January 2020 through January 2022) to compare outcomes between 300 male PwH and 900 matched controls without hemophilia.ResultsAnalyses of PwH demonstrated that known risk factors (older age, heart failure, hypertension, cancer/malignancy, dementia, and renal and liver disease) contributed to severe COVID-19 and/or 30-day all-cause mortality. Non–central nervous system bleeding was an …

OBJECTIVE We evaluated whether adding basal insulin to metformin in adults with early type 2 diabetes mellitus (T2DM) would increase emotional distress relative to other treatments. RESEARCH DESIGN AND METHODS The Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) of adults with T2DM of <10 years’ duration, HbA1c 6.8–8.5%, and taking metformin monotherapy randomly assigned participants to add insulin glargine U-100, sulfonylurea glimepiride, the glucagon-like peptide-1 receptor agonist liraglutide, or the dipeptidyl peptidase 4 inhibitor sitagliptin. The Emotional Distress Substudy enrolled 1,739 GRADE participants (mean [SD] age 58.0 [10.2] years, 32% female, 56% non-Hispanic White, 18% non-Hispanic Black, 17% Hispanic) and assessed diabetes distress and depressive symptoms every 6 months. Analyses examined …

The prevalence of hypercortisolism in persons with difficult-to-control type 2 diabetes (T2D) may be higher than currently appreciated, particularly in persons who require a greater number of antihyperglycemic agents and/or have more comorbidities. To better understand the prevalence and whether treatment of hypercortisolism may result in better control of diabetes and other hypercortisolism-associated comorbidities, we have designed CATALYST, a prospective phase 4 study in adults with difficult-to-control T2D (HbA1c 7.5–11.5%) despite receiving multiple antihyperglycemic agents. CATALYST is being conducted at about 30 sites in the United States. In Part 1, about 1000 persons with difficult-to-control T2D will be screened with a 1-mg dexamethasone suppression test (cutoff: serum cortisol >1.8 µg/dL; dexamethasone ≥140 ng/dL). Patients with ACTH-dependent hypercortisolism will be referred out of the …

AimsType 2 diabetes (T2D) is a risk factor for cardiovascular and non-cardiovascular mortality. However, global distribution of cause-specific deaths in T2D is poorly understood. We characterized cause-specific deaths by geographic region among individuals with T2D at risk for cardiovascular disease (CVD).Methods and ResultsThe international EXSCEL trial included 14,752 participants with T2D (73% with established CVD). We identified the proportion of deaths over 5-year follow-up attributed to cardiovascular and non-cardiovascular causes, and associated risk factors. During median 3.2-year follow-up, 1,091 (7.4%) participants died. Adjudicated causes of death were 723 cardiovascular (66.3% of deaths), including 252 unknown, and 368 non-cardiovascular (33.7%). Most deaths occurred in North America (N=356/9.6% across region) and Eastern Europe (N=326/8.1%), with fewest in Asia/Pacific (N=68/4.4 …

Our sample includes beneficiaries with diabetes who were using insulin between 1 December 2017 and 31 December 2020. To be included, member–index date combinations had to 1) have four or more adjudicated claims for insulin and one or more medical claims with a diabetes diagnostic code in the 365 days before index, 2) be eligible for $10 months throughout the preperiod, 3) not turn 65 years old before the end of the postperiod, and 4) have one or more health care charges in the pre-or postperiod. We implemented a pre-post nonequivalent groups design via differencesin-differences (DiD) with administrative claims data, and we used generalized estimating equations with a negative binomial distribution, log link, and exchangeable correlation structure to model all-cause ED visits per 1,000 members. The intervention date (among the treated individuals) was the first date of a filled prescription for any …

IntroductionIncreasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: (1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), (2) a single RCT, and (3) a hybrid randomized-external data study.MethodsThe hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of …

Clinical trial processes are unnecessarily inefficient and costly, slowing the translation of medical discoveries into treatments for people living with disease. To reduce redundancies and inefficiencies, a group of clinical trial experts developed a framework for clinical trial site readiness based on existing trial site qualifications from sponsors. The site readiness practices are encompassed within six domains: research team, infrastructure, study management, data collection and management, quality oversight, and ethics and safety. Implementation of this framework for clinical trial sites would reduce inefficiencies in trial conduct and help prepare new sites to enter the clinical trials enterprise, with the potential to improve the reach of clinical trials to underserved communities. Moreover, the framework holds benefits for trial sponsors, contract research organizations, trade associations, trial participants, and the public. For …

Background/AimsWe present and describe recruitment strategies implemented from 2013 to 2017 across 45 clinical sites in the United States, participating in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study, an unmasked, randomized controlled trial evaluating four glucose-lowering medications added to metformin in individuals with type 2 diabetes mellitus (duration of diabetes <10 years). We examined the yield of participants recruited through Electronic Health Records systems compared to traditional recruitment methods to leverage access to type 2 diabetes patients in primary care.MethodsSite selection criteria included availability of the study population, geographic representation, the ability to recruit and retain a diverse pool of participants including traditionally underrepresented groups, and prior site research experience in diabetes clinical trials. Recruitment initiatives …

Background Previous studies suggested GLP‐1 receptor agonists (GLP1RA) may improve cognitive function and liraglutide’s effect on Alzheimer’s disease is being evaluated by the ELAD (Evaluating Liraglutide in Alzheimer’s Disease) clinical trial. Method To examine whether liraglutide decrease Alzheimer’s disease and related dementia (ADRD) risk compared with other antidiabetics, we implemented an active comparator, new user cohort design identifying initiators of liraglutide, DPP‐4 inhibitors (DPP4i), respectively, using a US nationwide 20% random sample of fee‐for‐service Medicare beneficiaries aged 70+ with parts A, B, and D coverage from 2007‐2019. We required patients to have 2nd prescription of the same drug class and be free of ADRD in the 3‐year window (during which requiring 3‐year continuous enrollment of parts A, B) prior to drug initiation. The ADRD outcome was defined as 1) ³1 …

Objective:To examine, using data from the National COVID Cohort Collaborative (N3C), whether patients with pre-existing autoimmune disease (AID) diagnosis and/or immunosuppressant (IS) exposure are at a higher risk of developing severe COVID-19 outcomes.

Time spent in glycemic target range (time in range [TIR]; plasma glucose 70–180 mg/dL [3.9–10.0 mmol/L]) as a surrogate endpoint for long-term diabetes-related outcomes requires validation. This post hoc analysis investigated the association between TIR, derived from 8-point glucose profiles (derived TIR [dTIR]) at 12 months, and time to cardiovascular or severe hypoglycemic episodes in people with type 2 diabetes in the DEVOTE trial. At 12 months, dTIR was significantly negatively associated with time to first major adverse cardiovascular event (P = 0.0087), severe hypoglycemic episode (P < 0.0001), or microvascular event (P = 0.024). A nonsignificant trend was seen toward association between 12-month hemoglobin A1c (HbA1c) and these outcomes, but this was no longer seen after addition of dTIR to the model. The results support targeting TIR >70% and suggest dTIR could be used in addition to …

OBJECTIVES/GOALS: Chronic or new symptoms after infection with severe-acute-respiratory-coronavirus-2 (SARS-CoV-2) has been termed post-acute sequelae of Covid-19 (PASC) or Long Covid. Our objective is to present results from COVID-OUT, a phase 3 double-blind, randomized controlled trial of early outpatient treatment of Covid-19 with repurposed medications. METHODS/STUDY POPULATION: COVID-OUT enrolled adults age 30 to 85 with overweight or obesity who had proof of SARS-CoV-2 infection and fewer than 7 days of symptoms. In this 2 by 3 factorial design trial of metformin, ivermectin, fluvoxamine, or exact-matching placebo of each medication, participants were randomized 1:1:1:1:1:1 to the 6 treatment allocations. This abstract focuses on whether early treatment with metformin prevented Long Covid. Immediate release metformin was titrated to 1500mg daily over the first 6 days. We …

Previous studies suggested GLP-1 receptor agonists (GLP1RA) may improve cognitive function and liraglutide’s effect on Alzheimer’s disease is being evaluated by the ELAD (Evaluating Liraglutide in Alzheimer's Disease) clinical trial. To examine whether liraglutide decrease Alzheimer’s disease and related dementia (ADRD) risk compared with other antidiabetics, we implemented an active comparator, new user cohort design identifying initiators of liraglutide, DPP-4 inhibitors (DPP4i), respectively, using a US nationwide 20% random sample of fee-for-service Medicare beneficiaries aged 70+ with parts A, B, and D coverage from 2007-2019. We required patients to have 2nd prescription of the same drug class and be free of ADRD in the 3-year window (during which requiring 3-year continuous enrollment of parts A, B) prior to drug initiation. The ADRD outcome was defined as 1)≥ 1 ADRD claims in 1 year AND …

ObjectivesThe overarching goal was to assess the impact of 3 different SMBG testing approaches on patient-centered outcomes in patients with non–insulin-treated T2DM within the real-world clinic setting. OBJECTIVE 1: Assess SMBG effectiveness on 2 primary patient-centered outcomes, glycemic control (A1c) and health-related quality of life (HRQOL), over 1 year in 450 participants with non–insulin-treated diabetes mellitus (DM) in the following 3 groups:(1) no SMBG testing,(2) once-daily SMBG testing with standard patient feedback consisting of glucose values immediately reported to the patient through the glucometer, and (3) once-daily SMBG testing with enhanced patient feedback consisting of glucose values immediately reported to the patient plus automated, tailored messaging also delivered via the glucometer. OBJECTIVE 2: Evaluate the impact of SMBG on secondary patient-centered outcomes including (1) DM-related quality of life,(2) DM self-care,(3) DM treatment satisfaction,(4) DM self-efficacy,(5) patient–provider communication,(6) hypoglycemia frequency, and (7) health care utilization. OBJECTIVE 3: Conduct qualitative assessments of the patient participant and provider experience for all 3 intervention groups. This objective supports efficient translation of study findings to real-world clinic settings by exploring such issues as patient–provider communications, use of the glucometer and accompanying reports, utility of the treatment algorithm given to providers, and practice burden.MethodsUsing a stakeholder engagement approach, we developed and implemented a pragmatic trial. We randomly assigned 450 patients with …

The Hazard Ratio (HR) is a well-established treatment effect measure in randomized trials involving right-censored time-to-events, and the Cardiovascular Outcome Trials (CVOTs) conducted since the FDA’s 2008 guidance have indeed largely evaluated excess risk by estimating a Cox HR. On the other hand, the limitations of the Cox model and of the HR as a causal estimand are well known, and the FDA’s updated 2020 CVOT guidance invites us to reassess this default approach to survival analyses. We highlight the shortcomings of Cox HR-based analyses and present an alternative following the causal roadmap—moving in a principled way from a counterfactual causal question to identifying a statistical estimand, and finally to targeted estimation in a large statistical model. We show in simulations the robustness of Targeted Maximum Likelihood Estimation (TMLE) to informative censoring and model …

Increasing emphasis on the use of real-world evidence (RWE) to support clinical policy and regulatory decision-making has led to a proliferation of guidance, advice, and frameworks from regulatory agencies, academia, professional societies, and industry. A broad spectrum of studies use real-world data (RWD) to produce RWE, ranging from randomized trials with outcomes assessed using RWD to fully observational studies. Yet, many proposals for generating RWE lack sufficient detail, and many analyses of RWD suffer from implausible assumptions, other methodological flaws, or inappropriate interpretations. The Causal Roadmap is an explicit, itemized, iterative process that guides investigators to prespecify study design and analysis plans; it addresses a wide range of guidance within a single framework. By supporting the transparent evaluation of causal assumptions and facilitating objective comparisons of …

IntroductionDiabetes mellitus in underrepresented racial and ethnic groups (URG) is rapidly increasing in incidence and has worse outcomes than diabetes in non-Hispanic White individuals. Rare and Atypical Diabetes Network (RADIANT) established recruitment targets based on the racial and ethnic distribution of the USA to enroll a diverse study population. We examined participation of URG across RADIANT study stages and described strategies to enhance recruitment and retention of URG.Materials and MethodsRADIANT is a multicenter NIH-funded study of people with uncharacterized forms of atypical diabetes. RADIANT participants consent online and progress through three sequential study stages, as eligible.ResultsWe enrolled 601 participants with mean age 44 ± 16.8 years, 64.4% female. At Stage 1, 80.6% were White, 7.2% African American (AA), 12.2% other/more than one race, and 8.4% Hispanic …

Metabolic mechanisms underlying the heterogeneity of major adverse cardiovascular (CV) event (MACE) risk in individuals with type 2 diabetes mellitus (T2D) remain unclear. We hypothesized that circulating metabolites reflecting mitochondrial dysfunction predict incident MACE in T2D. Targeted mass-spectrometry profiling of 60 metabolites was performed on baseline plasma samples from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS; discovery cohort) and Exenatide Study of Cardiovascular Event Lowering (EXSCEL; validation cohort) biomarker substudy cohorts. A principal components analysis metabolite factor comprising medium-chain acylcarnitines (MCACs) was associated with MACE in TECOS and validated in EXSCEL, with higher levels associated with higher MACE risk. Meta-analysis showed that long-chain acylcarnitines (LCACs) and dicarboxylacylcarnitines were also …

Precisely and efficiently identifying subgroups with heterogeneous treatment effects (HTEs) in real-world evidence studies remains a challenge. Based on the causal forest (CF) method, we developed an iterative CF (iCF) algorithm to identify HTEs in subgroups defined by important variables. Our method iteratively grows different depths of the CF with important effect modifiers, performs plurality votes to obtain decision trees (subgroup decisions) for a family of CFs with different depths, then finds the cross-validated subgroup decision that best predicts the treatment effect as a final subgroup decision. We simulated 12 different scenarios and showed that the iCF outperformed other machine learning methods for interaction/subgroup identification in the majority of scenarios assessed. Using a 20% random sample of fee-for-service Medicare beneficiaries initiating sodium-glucose cotransporter-2 inhibitors …

An introduction is presented in which author discusses articles on topics including focuses on original art created by a person with diabetes or a person whose life has been affected by this disease, including family members, friends and health care professionals.

The potential for bias, be it based on gender, socioeconomics, or race/ethnicity, is a concern in nearly every aspect of life. Reduction in all forms of inequity is critically important generally, and certainly in the field of academic medicine. An extensive and growing body of literature suggests continued prejudice against women and early-career investigators in science and academic medicine, including appointment to leadership positions in health science fields (academic or industry), promotion, award recognition, and funding (1). Fairness in peer review is critical for academic publishing and its many downstream effects. Recently, issues related to publication have come under additional scrutiny, with the hope that additional exposure will lead to further change.A recent report by Liu et al.(2) presented the results of an analysis of more than 1,100 academic journals published by Elsevier and the more than 100,000 …

Introduction Increasing interest in real-world evidence has fueled the development of study designs incorporating real-world data (RWD). Using the Causal Roadmap, we specify three designs to evaluate the difference in risk of major adverse cardiovascular events (MACE) with oral semaglutide versus standard-of-care: 1) the actual sequence of non-inferiority and superiority randomized controlled trials (RCTs), 2) a single RCT, and 3) a hybrid randomized-external data study. Methods The hybrid design considers integration of the PIONEER 6 RCT with RWD controls using the experiment-selector cross-validated targeted maximum likelihood estimator. We evaluate 95% confidence interval coverage, power, and average patient-time during which participants would be precluded from receiving a glucagon-like peptide-1 receptor agonist (GLP1-RA) for each design using simulations. Finally, we estimate the effect of oral semaglutide on MACE for the hybrid PIONEER 6-RWD analysis. Results In simulations, Designs 1 and 2 performed similarly. The tradeoff between decreased coverage and patient-time without the possibility of a GLP1-RA for Designs 1 and 3 depended on the simulated bias. In real data analysis using Design 3, external controls were integrated in 84% of cross-validation folds, resulting in an estimated risk difference of -1.53%-points (95% CI -2.75%-points to -0.30%-points). Conclusions The Causal Roadmap helps investigators to minimize potential bias in studies using RWD and to quantify tradeoffs between study designs. The simulation results help to interpret the level of evidence provided by the real data analysis in support of …

NEHA REDDY, STEVE JOHNSON, RICHARD A. MOFFITT, MICHAEL EVANS, HSIN-CHIEH YEH, JANE EB REUSCH, RACHEL WONG, JOHN B. BUSE, CAROLYN BRAMANTE, JEREMY HARPER; 192-LB: Temporal Relationship of New Pediatric Diabetes Diagnoses and COVID-19. Diabetes 20 June 2023; 72 (Supplement_1): 192–LB. https://doi. org/10.2337/db23-192-LB

Background Many older adults with cancer have ≥2 impairments on geriatric assessment which impacts present and future frailty status, treatment tolerability, and outcomes. Our objective was to identify and describe distinct geriatric assessment impairment classes using latent class analysis (LCA) in older patients with gastrointestinal malignancies and assess 1-year mortality. Methods We used the Cancer & Aging Resilience Evaluation (CARE) Study, a registry of older adults (≥60 years) at University of Alabama at Birmingham. The analytic cohort included patients with gastrointestinal malignancies who completed a self-administered geriatric assessment (CARE tool) before chemotherapy and had ≥1 geriatric assessment impairment. Thirteen geriatric assessment impairments were used as indicators in LCA. Resultant classes were described, mortality was estimated, and …

Exogenous estrogen is associated with reduced coronavirus disease (COVID) mortality in nonimmunosuppressed/immunocompromised (non-ISC) postmenopausal females. Here, we examined the association of estrogen or testosterone hormone replacement therapy (HRT) with COVID outcomes in solid organ transplant recipients (SOTRs) compared to non-ISC individuals, given known differences in sex-based risk in these populations. SOTRs ≥45 years old with COVID-19 between April 1, 2020 and July 31, 2022 were identified using the National COVID Cohort Collaborative. The association of HRT use in the last 24 months (exogenous systemic estrogens for females; testosterone for males) with major adverse renal or cardiac events in the 90 days post-COVID diagnosis and other secondary outcomes were examined using multivariable Cox proportional hazards models and logistic regression. We repeated …

It has been widely recognized that site-specific attributes such as infrastructure, personnel, and participant recruitment-related factors are critical to effective and successful conduct of clinical trials [Reference Mehta, Goyal and Singh 1–Reference Dombernowsky, Haedersdal, Lassen and Thomsen 4]. Industry, federal, and foundation sponsors consider these factors in their assessment of site readiness when selecting sites to execute clinical trial protocols. While site selection factors vary somewhat depending on sponsor and trial type,“A Framework for Assessing for Clinical Trial Site Readiness” has identified a core set of site readiness practices that are recommended for all sites interested in initiating and executing clinical trials [Reference Buse, Austin and Johnston 5]. The site readiness practices include factors spanning domains of research team, infrastructure, study management, data collection and …

A symphony of emotions could be heard on 24 June 2023 as we concluded the American Diabetes Association (ADA) Scientific Sessions’ Diabetes Care Symposium on social determinants of health. Hundreds of conference attendees listened to her masterful presentation, which was recorded the week before her passing, and stood captivated by her unmatched ability to cover topics about the social and political systems and structures that must be transformed to truly care for people living with diabetes. Her talk reflected her own personal experience of being diagnosed with type 1 diabetes at the age of 9, having difficulty accessing medical care because of her race, and being underinsured and not able to afford diabetes supplies. Her outstanding work and unyielding commitment to it can be attributed to her knowledge that the challenges she faced as a young adult were not unique and the toil of such challenges …

BackgroundFood insecurity is associated with worse glycemic management for individuals with type 2 diabetes mellitus (T2DM), but whether medically tailored meals (MTM), a food insecurity intervention, can improve glycemic management is unclear.ObjectiveTo describe the protocol for a trial assessing whether an MTM plus lifestyle intervention improves hemoglobin A1c (HbA1c) and participant-reported outcomes, relative to a food subsidy (money that can be spent on foods participants choose), for adults with both T2DM and food insecurity.MethodsThe Food as Medicine for Diabetes (FAME-D) randomized clinical trial (goal n = 200) is a pragmatic trial with an active comparator. Participants, who will have T2DM and report food insecurity, will be randomly assigned to a 6-month MTM plus telephone-delivered lifestyle change intervention, or a 6-month food subsidy ($40/month). The primary outcome is HbA1c at 6 …

Introduction Inflammation is a pathophysiological process associated with increased cardiovascular (CV) risk, with high-sensitivity C-reactive protein (hsCRP) used as a biomarker to predict CV risk. However, the prevalence of systemic inflammation (defined as hsCRP ≥ 2 mg/L) in contemporary cohorts with high CV risk, including CV disease (CVD), chronic kidney disease (CKD), obesity and/or type 2 diabetes (T2D), is not well characterized. Purpose To evaluate the proportion of individuals with systemic inflammation and the characteristics of individuals with and without systemic inflammation among groups at high risk of CV events, using baseline data from three ongoing randomized, placebo-controlled, phase 3 trials investigating the efficacy of semaglutide versus placebo in high CV risk populations (SELECT, SOUL and FLOW). Methods SELECT …

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear. Methods Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series …

Background: Post-acute sequelae of COVID, termed “Long COVID”, is an emerging chronic illness potentially affecting~ 10% of those with COVID-19. We sought to determine if outpatient treatment with metformin, ivermectin, or fluvoxamine could prevent Long COVID.Methods: COVID-OUT (NCT04510194) was a decentralized, multi-site trial in the United States testing three medications (metformin, ivermectin, fluvoxamine) using a 2x3 parallel treatment factorial randomized assignment to efficiently share placebo controls. Participants, investigators, care providers, and outcomes assessors were masked to randomized treatment assignment. Inclusion criteria included: age 30 to 85 years with overweight or obesity, symptoms< 7 days, enrolled within<= 3 days of documented SARS-CoV-2 infection. Long COVID diagnosis from a medical provider was a pre-specified secondary outcome assessed by monthly surveys through 300 days after randomization and confirmed in medical records.Findings: Of 1323 randomized trial participants, 1125 consented for long-term follow up, and 95.1% completed> 9 months of follow up. The median age was 45 years (IQR, 37 to 54), and 56% were female (7% pregnant). The median BMI was 30 kg/m2 (IQR, 27 to 34). Overall, 8.4% reported a medical provider diagnosed them with Long COVID; cumulative incidence: 6.3% with metformin and 10.6% with matched placebo. The hazard ratio (HR) for metformin preventing Long COVID was 0.58 (95% CI, 0.38 to 0.88; P= 0· 009) versus placebo. The metformin effect was consistent across subgroups, including viral variants. When metformin was started within< 4 days of …

CATALYST: A Phase 4 Study of Hypercortisolism in Patients with Difficult-to-Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies Assessing Prevalence and Treatment with Mifepristone

SEPRA, a 2-year, ongoing, open-label, randomized, pragmatic study (NCT03596450) compares the effects of once-weekly SC semaglutide (sema) with physician's choice SOC when added to≤ 2 oral antidiabetic medications for treatment intensification in US health-insured adults with T2D. The objective is to generate real-world evidence to support routine clinical decision making and complement clinical trial data. The primary endpoint is the proportion of patients who achieve HbA 1c< 7% at 1 year. Patients (N= 1278) were randomized to receive sema according to label (n= 644) or SOC excluding sema (n= 634). All other treatment was per routine clinical care. Baseline characteristics were comparable (Table 1). Most common SOC medications were other GLP-1RAs (71.3%) and SGLT2is (15.5%). Sema dosing at 1 year was 26.6% at 0.25 mg, 30.4% at 0.5 mg and 24.4% at 1 mg (10.6% ended study and 7.6 …

Glucose-responsive formulations of insulin can increase its therapeutic index and reduce the burden of its administration. However, it has been difficult to develop single-dosage formulations that can release insulin in both a sustained and glucose-responsive manner. Here we report the development of a subcutaneously injected glucose-responsive formulation that nearly does not trigger the formation of a fibrous capsule and that leads to week-long normoglycaemia and negligible hypoglycaemia in mice and minipigs with type 1 diabetes. The formulation consists of gluconic acid-modified recombinant human insulin binding tightly to poly-l-lysine modified by 4-carboxy-3-fluorophenylboronic acid via glucose-responsive phenylboronic acid–diol complexation and electrostatic attraction. When the insulin complex is exposed to high glucose concentrations, the phenylboronic acid moieties of the polymers bind rapidly …

BACKGROUND Observational and preclinical data suggest metformin may prevent severe coronavirus disease 2019 (COVID-19) outcomes. PURPOSE We conducted a systematic review of randomized, placebo-controlled clinical trials of metformin treatment for COVID-19 to determine whether metformin affects clinical or laboratory outcomes in individuals infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and present a structured summary of preclinical data. STUDY SELECTION Two independent reviewers searched PubMed, Scopus, Cochrane COVID-19 Study Register, and ClinicalTrials.gov on 1 February 2023 with no date restrictions for trials where investigators randomized adults with COVID-19 to metformin versus control and assessed clinical and/or laboratory outcomes of interest. The Cochrane Risk of Bias 2 tool was used …

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include increased incidence of diabetes. Here we describe the temporal relationship between new type 2 diabetes and SARS-CoV-2 infection in a nationwide database. We found that while the proportion of newly diagnosed type 2 diabetes increased during the acute period of SARS-CoV-2 infection, the mean proportion of new diabetes cases in the 6 months post-infection was about 83% lower than the 6 months preinfection. These results underscore the need for further investigation to understand the timing of new diabetes after COVID-19, etiology, screening, and treatment strategies.

adult; aged; antiviral activity; calibration; clinical trial; conference abstract; contraindication; controlled study; coronavirus disease 2019; droplet digital polymerase chain reaction; drug therapy; factorial design; female; follow up; gene amplification; hospitalization; human; limit of detection; long COVID; major clinical study; male; nonhuman; nose smear; outpatient; phase 3 clinical trial; randomized controlled trial; regression model; Severe acute respiratory syndrome coronavirus 2; single blind procedure; titrimetry; vaccination; virus load; endogenous compound; fluvoxamine; ivermectin; metformin; nirmatrelvir; nucleocapsid protein; placebo

BackgroundDespite previous research findings on higher risks of stillbirth among pregnant individuals with SARS-CoV-2 infection, it is unclear whether the gestational timing of viral infection modulates this risk.ObjectiveThis study aimed to examine the association between timing of SARS-CoV-2 infection during pregnancy and risk of stillbirth.Study DesignThis retrospective cohort study used multilevel logistic regression analyses of nationwide electronic health records in the United States. Data were from 75 healthcare systems and institutes across 50 states. A total of 191,403 pregnancies of 190,738 individuals of reproductive age (15–49 years) who had childbirth between March 1, 2020 and May 31, 2021 were identified and included. The main outcome was stillbirth at ≥20 weeks of gestation. Exposures were the timing of SARS-CoV-2 infection: early pregnancy (<20 weeks), midpregnancy (21–27 weeks), the …

BackgroundPost-COVID-19 condition (also known as long COVID) is an emerging chronic illness potentially affecting millions of people. We aimed to evaluate whether outpatient COVID-19 treatment with metformin, ivermectin, or fluvoxamine soon after SARS-CoV-2 infection could reduce the risk of long COVID.MethodsWe conducted a decentralised, randomised, quadruple-blind, parallel-group, phase 3 trial (COVID-OUT) at six sites in the USA. We included adults aged 30–85 years with overweight or obesity who had COVID-19 symptoms for fewer than 7 days and a documented SARS-CoV-2 positive PCR or antigen test within 3 days before enrolment. Participants were randomly assigned via 2 × 3 parallel factorial randomisation (1:1:1:1:1:1) to receive metformin plus ivermectin, metformin plus fluvoxamine, metformin plus placebo, ivermectin plus placebo, fluvoxamine plus placebo, or placebo plus placebo …

The epidemic of diabetes continues to exert great burden and cost on affected people, their families, and society. Current estimates of the burden of prediabetes and diabetes in youth and adults for the US are made available through the Centers for Disease Control and Prevention (CDC)(https://www. cdc. gov/diabetes/data/statistics-report/index. html and https://gis. cdc. gov/grasp/diabetes/DiabetesAtlas. html) and for regions of the world by the International Diabetes Federation (https://diabetesatlas. org/2022-reports/). These data are typically updated every year or two. CDC’s estimates for the prevalence of both diagnosed and undiagnosed diabetes, prevalence of prediabetes among adults, incidence of newly diagnosed diabetes, risk factors for diabetes-related complications, and burden of coexisting conditions and complications provide valuable information, but many questions are not addressed in these …

Every five years or so, the editorial team leading Diabetes Care turns over with the appointment of new leadership. This issue of volume 46 represents the first of a new editorial team, making it the tenth group to be responsible for the scientific content of the journal. Starting in 1978 with Jay Skyler as its first editor, Diabetes Care has gone from strength to strength with new initiatives and a steady increase in its influence. This impact has been in line with the charge given at the journal’s founding by the then president of the American Diabetes Association Norbert Freinkel when he wrote,“The new journal is designed to promote better patient care by serving the expanded needs of all health professionals committed to the care of patients with diabetes.” For the past five years, Matthew Riddle and his erudite team have overseen the activities of the journal, bringing the latest information to the readership to enhance the …

Background: Despite increased use of continuous glucose monitoring (CGM) systems, studies to quantify patterns of CGM use are limited. In December 2018, a policy change by a commercial insurer expanded coverage of CGM through the pharmacy benefit, creating an opportunity to evaluate the impact of this change on CGM utilization. Research Design and Methods: Pharmacy and medical claims from 2016 to 2020 were used to estimate the prevalence of CGM use among insulin users with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) before and after the policy change. Change in CGM use was assessed using an interrupted time series design. Results: At the beginning of the study period, 18.8% of T1DM patients and 1.2% of T2DM patients used CGM. Use rose to 30.5% and 6.6% in the quarter before the policy change. The policy resulted in an immediate 9.5% (P < 0.0001) and 2.8 …

ImportanceSARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termedpostacute sequelae of SARS-CoV-2 infection(PASC), also known aslong COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.ObjectiveTo develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.Design, Setting, and ParticipantsProspective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after …

IntroductionOnce-weekly subcutaneous semaglutide, a glucagon-like peptide-1 analog, is approved in the USA as an adjunct to diet and exercise for adults with inadequately controlled type 2 diabetes (T2D) to improve glycemic control and reduce the risk of major adverse cardiovascular events in people with T2D and established cardiovascular disease. The Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) phase III clinical trial program demonstrated the efficacy and safety of once-weekly subcutaneous semaglutide; however, determining its effectiveness in a real-world setting could support decision-making by clinicians, payers and policy makers in routine clinical practice.Research design and methodsSEmaglutide PRAgmatic (SEPRA) is an ongoing open-label, randomized, pragmatic clinical trial designed to compare the effects of once-weekly subcutaneous semaglutide versus …

ImportanceType 2 diabetes (T2D) is the leading cause of kidney disease in the US. It is not known whether glucose-lowering medications differentially affect kidney function.ObjectiveTo evaluate kidney outcomes in the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness (GRADE) trial comparing 4 classes of glucose-lowering medications added to metformin for glycemic management in individuals with T2D.Design, Setting, and ParticipantsA randomized clinical trial was conducted at 36 sites across the US. Participants included adults with T2D for less than 10 years, a hemoglobin A1clevel between 6.8% and 8.5%, and estimated glomerular filtration rate (eGFR) greater than or equal to 60 mL/min/1.73 m2who were receiving metformin treatment. A total of 5047 participants were enrolled between July 8, 2013, and August 11, 2017, and followed up for a mean of 5.0 years (range, 0-7.6 years …

BackgroundOnce-daily oral semaglutide is an effective type 2 diabetes treatment. We aimed to investigate a new formulation of oral semaglutide at higher investigational doses versus the approved 14 mg dose in adults with inadequately controlled type 2 diabetes.MethodsThis global, multicentre, randomised, double-blind, phase 3b trial, carried out at 177 sites in 14 countries, enrolled adults with type 2 diabetes, glycated haemoglobin (HbA1c) 8·0−10·5% (64−91 mmol/mol), a BMI of 25·0 kg/m2 or greater, receiving stable daily doses of one to three oral glucose-lowering drugs. Participants were randomly assigned (1:1:1), by means of an interactive web response system, to once-daily oral semaglutide 14 mg, 25 mg, or 50 mg for 68 weeks. Investigators, site personnel, trial participants, and trial sponsor staff were masked to dose assignment throughout the trial. The primary endpoint was change in HbA1c from …

Of N=1199 EXSCEL participants with prevalent HF, 284 (24%), 704 (59%) and 211 (18%) had HFpEF, HFmrEF and HFrEF, respectively. Eight PCA protein factors and 221 individual proteins within these factors differed significantly across the three EF groups. Levels of the majority of proteins (83%) demonstrated concordance between HFmrEF and HFpEF, but higher levels in HFrEF, predominated by the domain of extracellular matrix regulation, e.g. COL28A1 and tenascin C [TNC]; p<0.0001. Concordance between HFmrEF and HFrEF was observed in a minority of proteins (1%) including MMP-9 (p<0.0001). Biologic pathways of epithelial-mesenchymal transition, ECM receptor interaction, complement and coagulation cascades, and cytokine receptor interaction demonstrated enrichment among proteins with the dominant pattern, i.e. HFmrEF-HFpEF concordance. Baseline levels of 208 (94%) of the 221 proteins were associated with time-to-incident HF hospitalization including domains of extracellular matrix (COL28A1, TNC), angiogenesis (ANG2, VEGFa, VEGFd), myocyte stretch (NT-proBNP), and renal function (cystatin-C). Change in levels of 10 of the 221 proteins from baseline to 12 months (including increase in TNC) predicted incident HF hospitalization (p<0.05). Levels of 30 of the 221 significant proteins (including TNC, NT-proBNP, ANG2) were reduced differentially by EQW compared with placebo (interaction p<0.0001).

Disclosure: J.P. Frias: Advisory Board Member; Self; Corcept Therapeutics. Consulting Fee; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.J. Auchus: Consulting Fee; Self; Corcept Therapeutics. Grant Recipient; Self; Corcept Therapeutics. Speaker; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. I. Bancos: None. L. Blonde: Advisory Board Member; Self; Corcept Therapeutics. Other; Self; Corcept Therapeutics. R.S. Busch: Consulting Fee; Self; Corcept Therapeutics. Speaker; Self; Bayer, Inc., Novo Nordisk, Amgen Inc, Eli Lilly & Company, AstraZeneca. J.B. Buse: Advisory Board Member; Self; AstraZeneca, Bayer, Inc., Boehringer Ingelheim, Eli Lilly & Company, Jansen Pharmaceuticals, Mannkind Corporation, Sanofi, Alkahest, Altimmune, Anji, Biomea Fusion Inc, CeQur, Cirius Therapeutics Inc, GentiBio, Glycadia, Glyscend, Mellitus Health, Moderna, Pendulum …

The COVID-19 pandemic accelerated the development of decentralized clinical trials (DCT). DCT’s are an important and pragmatic method for assessing health outcomes yet comprise only a minority of clinical trials, and few published methodologies exist. In this report, we detail the operational components of COVID-OUT, a decentralized, multicenter, quadruple-blinded, randomized trial that rapidly delivered study drugs nation-wide. The trial examined three medications (metformin, ivermectin, and fluvoxamine) as outpatient treatment of SARS-CoV-2 for their effectiveness in preventing severe or long COVID-19. Decentralized strategies included HIPAA-compliant electronic screening and consenting, prepacking investigational product to accelerate delivery after randomization, and remotely confirming participant-reported outcomes. Of the 1417 individuals with the intention-to-treat sample, the remote nature of the …

Study Objective To estimate the prevalence of potential moderate to severe drug–drug interactions (DDIs) involving nirmatrelvir/ritonavir, identify interacting medications, and evaluate risk factors associated with potential DDIs. Design Cross‐sectional study. Data Source Electronic health records from the National COVID Cohort Collaborative Enclave, one of the largest COVID‐19 data resources in the United States. Patients Outpatients aged ≥18 years and started nirmatrelvir/ritonavir between December 23, 2021 and March 31, 2022. Intervention Nirmatrelvir/ritonavir. Measurements The outcome is potential moderate to severe DDIs, defined as starting interacting medications reported by National Institutes of Health 30 days before or 10 days after starting nirmatrelvir/ritonavir. Main Results Of 3214 outpatients who started nirmatrelvir/ritonavir, the mean age was 56.8 ± 17.1 years, 39.5% were male …

Healthcare datasets obtained from Electronic Health Records have proven to be extremely useful for assessing associations between patients’ predictors and outcomes of interest. However, these datasets often suffer from missing values in a high proportion of cases, whose removal may introduce severe bias. Several multiple imputation algorithms have been proposed to attempt to recover the missing information under an assumed missingness mechanism. Each algorithm presents strengths and weaknesses, and there is currently no consensus on which multiple imputation algorithm works best in a given scenario. Furthermore, the selection of each algorithm’s parameters and data-related modeling choices are also both crucial and challenging.In this paper we propose a novel framework to numerically evaluate strategies for handling missing data in the context of statistical analysis, with a particular focus on …

Current antiviral treatment options for SARS-CoV-2 infections are not available globally, cannot be used with many medications, and are limited to virus-specific targets. 1–3 Biophysical modeling of SARS-CoV-2 replication predicted that protein translation is an especially attractive target for antiviral therapy. 4 Literature review identified metformin, widely known as a treatment for diabetes, as a potential suppressor of protein translation via targeting of the host mTor pathway. 5 In vitro, metformin has antiviral activity against RNA viruses including SARS-CoV-2. 6, 7 In the COVID-OUT phase 3, randomized, placebo-controlled trial of outpatient treatment of COVID-19, metformin had a 42% reduction in ER visits/hospitalizations/death through 14 days; a 58% reduction in hospitalizations/death through 28 days, and a 42% reduction in Long COVID through 10 months. 8, 9 Here we show viral load analysis of specimens …

OBJECTIVEEnvironmental exposures may have greater predictive power for type 2 diabetes than polygenic scores (PGS). Studies examining environmental risk factors, however, have included only individuals with European ancestry, limiting the applicability of results. We conducted an exposome-wide association study in the multiancestry Personalized Environment and Genes Study to assess the effects of environmental factors on type 2 diabetes.RESEARCH DESIGN AND METHODSUsing logistic regression for single-exposure analysis, we identified exposures associated with type 2 diabetes, adjusting for age, BMI, household income, and self-reported sex and race. To compare cumulative genetic and environmental effects, we computed an overall clinical score (OCS) as a weighted sum of BMI and prediabetes, hypertension, and high cholesterol status and a polyexposure score (PXS) as a weighted sum of …

Aim To describe the design of the SOUL trial (Semaglutide cardiOvascular oUtcomes triaL) and the baseline clinical data of its participants. Materials and methods In SOUL, the effects of oral semaglutide, the first oral glucagon‐like peptide‐1 receptor agonist, on the risk of cardiovascular (CV) events in individuals with type 2 diabetes and established atherosclerotic CV disease (ASCVD) and/or chronic kidney disease (CKD) will be assessed. SOUL is a randomized, double‐blind, parallel‐group, placebo‐controlled CV outcomes trial comparing oral semaglutide (14 mg once daily) with placebo, both in addition to standard of care, in individuals aged ≥50 years with type 2 diabetes and evidence of ASCVD (coronary artery disease [CAD], cerebrovascular disease, symptomatic peripheral arterial disease [PAD]) and/or CKD (estimated glomerular filtration rate <60 mL/min/1.73 m2). The primary outcome is time …

Background Data conflict on whether vaccination decreases severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load. The objective of this analysis was to compare baseline viral load and symptoms between vaccinated and unvaccinated adults enrolled in a randomized trial of outpatient coronavirus disease 2019 (COVID-19) treatment. Methods Baseline data from the first 433 sequential participants enrolling into the COVID-OUT trial were analyzed. Adults aged 30–85 with a body mass index (BMI) ≥25 kg/m2 were eligible within 3 days of a positive SARS-CoV-2 test and <7 days of symptoms. Log10 polymerase chain reaction viral loads were normalized to human RNase P by vaccination status, by time from vaccination, and by symptoms. Results Two hundred seventy-four participants with known vaccination status contributed optional …

BackgroundThe use of hydroxychloroquine or chloroquine (HCQ/CQ) as monotherapy or combined with azithromycin for the treatment of coronavirus disease 2019 (COVID-19) may increase the risk of serious cardiovascular adverse events (SCAEs).ObjectiveOur objective was to describe and evaluate the risk of SCAEs with HCQ/CQ as monotherapy or combined with azithromycin compared with that for therapeutic alternatives.MethodsWe performed a disproportionality analysis and descriptive case series using the US FDA Adverse Event Reporting System.ResultsCompared with remdesivir, HCQ/CQ was associated with increased reporting of SCAEs (reporting odds ratio [ROR] 2.1; 95% confidence interval [CI] 1.8–2.5), torsade de pointes (TdP)/QTc prolongation (ROR 35.4; 95% CI 19.4–64.5), and ventricular arrhythmia (ROR 2.5; 95% CI 1.6–3.9); similar results were found in comparison with other therapeutic …

MUSTAFA TOSUR, LAURA GANDOLFO, ASHOK BALASUBRAMANYAM, ROCHELLE N. NAYLOR, TONI I. POLLIN, NEDA RASOULI, JOHN B. BUSE, MARIA J. REDONDO, RADIANT STUDY GROUP; 1116-P: Enrollment of Racial/Ethnic Minorities in the Rare and Atypical Diabetes Network (RADIANT). Diabetes 1 June 2022; 71 (Supplement_1): 1116–P. https://doi. org/10.2337/db22-1116-P

Objective. The concentrations of endogenous metabolites in saliva can be altered based on the systemic condition of the hosts and may, in theory, serve as a reflection of systemic disease progression. Hemoglobin A1C is used clinically to measure long-term average glycemic control. The aim of the study was to demonstrate if there were differences in the salivary metabolic profiles between well and poorly controlled type 1 and type 2 subjects with diabetes. Subjects and Methods. Subjects with type 1 and type 2 diabetes were enrolled (n = 40). The subjects were assigned to phenotypic groups based on their current level of A1C: <7 = well-controlled and >7 = poorly controlled. Demographic data, age, gender, and ethnicity, were used to match the two phenotypic groups. Whole saliva samples were collected and immediately stored at −80°C. Samples were spiked using an isotopically labeled internal standard and analyzed by UPLC-TOF-MS using a Waters SYNAPT G2-Si mass spectrometer. Results. Unsupervised principal components analysis (PCA) and orthogonal partial least squares regression discrimination analysis (OPLS-DA) were used to define unique metabolomic profiles associated with well and poorly controlled diabetes based on A1C levels. Conclusion. OPLS-DA demonstrates good separation of well and poorly controlled in both type 1 and type 2 diabetes. This provides evidence for developing saliva-based monitoring tools for diabetes.

Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors are now seen as an integral part of therapy in type 2 diabetes to control not only blood glucose but to improve cardiovascular and kidney outcomes. Diabetic ketoacidosis (DKA) is an uncommon but serious complication of type 2 diabetes, which has a high case fatality rate. The absolute risk of DKA in large, prospective randomized clinical trials in people with type 2 diabetes using SGLT2 inhibitors has been low, although the relative risk is higher in those assigned to SGLT2 inhibitors compared with placebo. In those without diabetes but prescribed SGLT2 inhibitors for heart failure or chronic kidney disease, the risk of DKA is similar to placebo. Over the course of the COVID‐19 pandemic, cases of DKA have also been reported in cases of COVID‐19 hospitalizations. Consensus guidelines have recommended that SGLT2 inhibitors should be avoided in cases of …

Background While vaccination is the most important way to combat the SARS-CoV-2 pandemic, there may still be a need for early outpatient treatment that is safe, inexpensive, and currently widely available in parts of the world that do not have access to the vaccine. There are in-silico, in-vitro, and in-tissue data suggesting that metformin inhibits the viral life cycle, as well as observational data suggesting that metformin use before infection with SARS-CoV2 is associated with less severe COVID-19. Previous observational analyses from single-center cohorts have been limited by size. Methods Conducted a retrospective cohort analysis in adults with type 2 diabetes (T2DM) for associations between metformin use and COVID-19 outcomes with an active comparator design of prevalent users of therapeutically equivalent diabetes monotherapy: metformin versus dipeptidyl-peptidase-4-inhibitors (DPP4i) and sulfonylureas (SU). This took place in the National COVID Cohort Collaborative (N3C) longitudinal U.S. cohort of adults with +SARS-CoV-2 result between January 1 2020 to June 1 2021. Findings included hospitalization or ventilation or mortality from COVID-19. Back pain was assessed as a negative control outcome. Results 6,626 adults with T2DM and +SARS-CoV-2 from 36 sites. Mean age was 60.7 +/- 12.0 years; 48.7% male; 56.7% White, 21.9% Black, 3.5% Asian, and 16.7% Latinx. Mean BMI was 34.1 +/- 7.8kg/m2. Overall 14.5% of the sample was hospitalized; 1.5% received mechanical ventilation; and 1.8% died. In adjusted outcomes, compared to DPP4i, metformin had non-significant associations with reduced need for ventilation …

Background: There is a need to validate time-in-range (TIR; percentage of time with plasma glucose between 70 and 180 mg/dL (3.9-10.0 mmol/L) as a surrogate endpoint for long-term clinical outcomes.Methods: We used data from patients with 8-point glucose profiles (8pp) from the double-blind cardiovascular outcomes trial, DEVOTE (NCT01959529). In total, 7637 patients with T2D and either established CVD or at high risk for CVD were included in the trial. The primary endpoint in DEVOTE was time to first MACE. The 8pp were collected at 1 year, 2 years and end-of-trial. Median length of follow-up was 2 years. For 5644 patients, 8pps with at least 7 points existed. Among the 681 major adverse cardiovascular events (MACEs) in DEVOTE, 360 were among patients with 8pps. Individual TIR was derived as the proportion of the 8pp within range. A Cox model was used to estimate the association between derived …

Methods:Double-blind crossover study of 8 IPAA patients with refractory high BF treated with daily administration of the GLP-1 receptor agonist (GLP-1-RA) liraglutide or placebo.Results:Liraglutide, but not placebo, reduced daily BF by more than 35%(P< 0.03).Discussion:Larger randomized controlled studies are warranted to delineate the treatment potential of GLP-1RA's in IPAA patients suffering from non-inflammatory high BF.

Background Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. Methods In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs — metformin, ivermectin, and fluvoxamine — in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had …

Augmenting the control arm of a randomized controlled trial (RCT) with external data may increase power at the risk of introducing bias. Existing data fusion estimators generally rely on stringent assumptions or may have decreased coverage or power in the presence of bias. Framing the problem as one of data-adaptive experiment selection, potential experiments include the RCT only or the RCT combined with different candidate real-world datasets. To select and analyze the experiment with the optimal bias-variance tradeoff, we develop a novel experiment-selector cross-validated targeted maximum likelihood estimator (ES-CVTMLE). The ES-CVTMLE uses two bias estimates: 1) a function of the difference in conditional mean outcome under control between the RCT and combined experiments and 2) an estimate of the average treatment effect on a negative control outcome (NCO). We define the asymptotic distribution of the ES-CVTMLE under varying magnitudes of bias and construct confidence intervals by Monte Carlo simulation. In simulations involving violations of identification assumptions, the ES-CVTMLE had better coverage than test-then-pool approaches and an NCO-based bias adjustment approach and higher power than one implementation of a Bayesian dynamic borrowing approach. We further demonstrate the ability of the ES-CVTMLE to distinguish biased from unbiased external controls through a re-analysis of the effect of liraglutide on glycemic control from the LEADER trial. The ES-CVTMLE has the potential to improve power while providing relatively robust inference for future hybrid RCT-RWD studies.

The hemoglobin glycation index (HGI) is the difference between observed HbA1c and predicted HbA1c from FPG using linear regression. HGI is an important biomarker of clinical management/drug treatment outcomes and can identify individuals at high risk for multiple adverse events and outcomes before the appearance of clinical symptoms. Here, we sought to test if variation in HGI has genetic determinants in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) clinical trial using a genome-wide association approach (N= 7913). We subsequently replicated the top hits (P< 1e-5) in the Atherosclerosis Risk in Communities Study (ARIC; N= 3741). An intergenic SNP rs73407935 (7q11. 22) was associated with HGI (P= 5.8 e-10) with the locus replicating in ARIC. Further, multiple variants at suggestive genome-wide significance in discovery (P< 5e-6) replicated in ARIC including variants near or in …

Background: Ejection fraction (EF) is a key component of heart failure (HF) categorization, including the newly-proposed HF with mildly reduced EF (HFmrEF) category. The biologic basis of HFmrEF, as an entity distinct from HF with preserved EF (HFpEF) and reduced EF (HFrEF), has not been substantiated. Methods: The EXSCEL trial randomized participants with type 2 diabetes to once-weekly exenatide (EQW) vs. placebo. In participants with prevalent HF, we profiled ~5000 serum proteins. Principal component analysis (PCA) and ANOVA (FDR p<0.1) were used to determine differences in factors and individual proteins between three EF groups, as documented in EXSCEL (EF>55% [HFpEF], EF 40-55% [HFmrEF], EF<40% [HFrEF]). Cox proportional hazards was used to assess relationships between baseline proteins and changes in protein level with incident HF hospitalization. Results: Of 1199 EXSCEL …

Once-weekly subcutaneous semaglutide 2.0 mg showed superior efficacy with similar safety vs. 1.0 mg in 961 participants with type 2 diabetes (HbA 8.0-10.0%) after 40 weeks in SUSTAIN FORTE. We assessed the effect of semaglutide 2.0 mg vs. 1.0 mg on HbA and body weight (BW) in prespecified baseline (BL) HbA (< 9.0%,≥ 9.0%) and BMI (< 35,≥ 35 kg/m) subgroups.Mean BL HbA was 8.9% and BMI 34.6 kg/m. For HbA and BW, estimated treatment differences favored semaglutide 2.0 mg vs. 1.0 mg across all BL HbA and BMI subgroups. Treatment-by-subgroup interactions were nonsignificant (HbA, p= 0.55 and p= 0.41; BW, p= 0.40 and p= 0.13;). Greater mean HbA reductions were observed for both doses in the higher vs. lower BL HbA subgroup. Conversely, greater mean BW reductions were observed for both doses in the lower vs. higher BL HbA subgroup. Similar mean HbA reductions were observed …

AIMS To determine the effect of TTP399, a hepatoselective glucokinase activator, on the risk of ketoacidosis during insulin withdrawal in individuals with type 1 diabetes (T1D). MATERIALS AND METHODS Twenty-three participants with T1D using insulin pump therapy were randomized to 800 mg TTP399 (n = 12) or placebo (n = 11) for 7 to 10 days. After the treatment period, an insulin withdrawal test (IWT) was performed, during which insulin pumps were removed to induce ketogenesis. The IWT was stopped after 10 hours or if blood glucose reached >399 mg/dL [22.1 mmol/L], if beta-hydroxybutyrate (BHB) was >3.0 mmol/L, or for patient discomfort. The primary endpoint was the proportion of participants who reached BHB concentrations of 1 mmol/L or greater. RESULTS During the 7- to 10-day treatment period, mean fasting plasma glucose was significantly reduced ( -27.6 vs. -4.4 mg/dL [-1.5 vs. -0.2 mmol/L]; P = 0.03) and there were fewer adverse events, including hypoglycaemia, in the TTP399-treated arm. During the IWT, no differences were observed between TTP399 and placebo in mean serum BHB concentration, mean duration of IWT, or BHB at termination of IWT. However, serum bicarbonate was numerically higher and urine acetoacetate was quantitatively lower in the TTP399-treated participants. As a result of higher bicarbonate values, none of the TTP399-treated participants met the prespecified criteria for diabetic ketoacidosis (DKA), defined as BHB >3 mmol/L and serum bicarbonate <18 mEq/L, compared to 42% of placebo-treated participants. CONCLUSIONS When used as an adjunctive therapy to insulin, TTP399 …

Background: At least two-thirds of people with hemodialysis-dependent kidney failure have comorbid diabetes which associates with higher mortality. Some GLP-1 receptor agonists (RA) do not require renal dosing and could uniquely benefit dialysis patients, individuals with tremendous cardiovascular disease burden.Methods: Using data from a national surveillance system for kidney failure in the US that includes Medicare Part D prescription drug claims, we: 1) calculated the quarterly prevalence of antihyperglycemic use among diabetic hemodialysis patients from 2012 to 2017 and 2) characterized antihyperglycemic users in October 2017.Results: Among the 129,865 hemodialysis patients with comorbid diabetes, insulin was the most prescribed agent (33%), followed by sulfonylureas (SU, 7%) and DPP4 inhibitors (DPP4i, 5%) in October 2017. SU use fell, and DPP4i use rose from 2012 to 2017. Less than 5 …

Background: SARS-CoV-2 vaccination has decreasing protection from acquiring any infection with 2 emergence of new variants; however, vaccination continues to protect against progression to severe COVID-3

Introduction: Impaired fatty acid oxidation is common to both kidney and CV complications of diabetes mellitus (DM). We compared metabolic profiles of different cardiorenal trajectories to identify common pathways and unique signatures which may inform disease mechanisms. Methods The EXSCEL trial randomized patients with type 2 DM to exenatide vs placebo. For this study, we performed targeted metabolomics of 60 metabolites (45 acylcarnitines [ACs], 15 amino acids, ketone bodies, and nonesterified fatty acids) in 978 EXSCEL participants. Principal components analysis (PCA) was used for dimensionality reduction and multivariable logistic regression to examine the association of each PCA factor with four cardiorenal outcomes: CV (CV death, MI, or stroke), renal (≥30% eGFR decline, ESKD, or renal death), cardiorenal (both outcomes), or neither. We also evaluated the factors associations with …

The DAWN and SEED trials demonstrate the potential of glucokinase activators for the treatment of type 2 diabetes, but how they fit in the overall treatment algorithm remains to be determined.

Identification of adjunctive, oral pharmacotherapies to treat T1D has been limited by risk of DKA. TTP399, an oral hepatoselective GKA, significantly improves glycemia in individuals with T1D compared to placebo. This double-blind, randomized, placebo-controlled, Phase 1 mechanistic study examined whether TTP399 decreases ketogenesis during insulin withdrawal.Individuals with T1D (n= 23) using insulin pump therapy were randomized to TTP399 or placebo for 7-days after which an insulin withdrawal test (IWT) was performed. Insulin pumps were disconnected for up to hours to induce ketogenesis.

OBJECTIVE Differences in type 2 diabetes phenotype by age are described, but it is not known whether these differences are seen in a more uniformly defined adult population at a common early stage of care. We sought to characterize age-related clinical and metabolic characteristics of adults with type 2 diabetes on metformin monotherapy, prior to treatment intensification. RESEARCH DESIGN AND METHODS In the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), participants were enrolled who had type 2 diabetes duration <10 years, had HbA1c 6.8–8.5%, and were on metformin monotherapy. Participants were randomly assigned to one of four additional glucose-lowering medications. We compared baseline clinical and metabolic characteristics across age categories (<45, 45 to <55, 55 to <65, and ≥65 years) using ANOVA and …

Real-time monitoring of muscular oxygenation can enhance post-operative care of muscular wounds and peripheral artery disease. In article number 2200468, Wubin Bai and co-workers report a strategy by integrating microneedle waveguides with a wireless optoelectronic system in a thin, flexible construction to overcome the limitation of sensing depth and enable stable, continuous monitoring of muscular oxygenation without extensive implantation procedures.

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional health care team providing diabetes care in the U.S. and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the health care system, and physical activity behaviors, including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists, including assessment of subgroups …

BackgroundLong Covid is an emerging chronic illness potentially affecting millions, sometimes preventing the ability to work or participate in normal daily activities. COVID-OUT was an investigator-initiated, multi-site, phase 3, randomized, quadruple-blinded placebo-controlled clinical trial (NCT04510194

OBJECTIVE The purpose of the study is to evaluate the relationship between HbA1c and severity of coronavirus disease 2019 (COVID-19) outcomes in patients with type 2 diabetes (T2D) with acute COVID-19 infection. RESEARCH DESIGN AND METHODS We conducted a retrospective study using observational data from the National COVID Cohort Collaborative (N3C), a longitudinal, multicenter U.S. cohort of patients with COVID-19 infection. Patients were ≥18 years old with T2D and confirmed COVID-19 infection by laboratory testing or diagnosis code. The primary outcome was 30-day mortality following the date of COVID-19 diagnosis. Secondary outcomes included need for invasive ventilation or extracorporeal membrane oxygenation (ECMO), hospitalization within 7 days before or 30 days after COVID-19 diagnosis, and length of stay (LOS) for patients who were …

SEPRA (NCT03596450) is a 2-yr, multicenter, open-label, randomized pragmatic clinical trial comparing the long-term effects of once-weekly subcutaneous semaglutide vs. standard of care (both added to≤ 2 oral antidiabetic medications) in US health-insured adults with T2D and physician-determined inadequate glycemic control. SEPRA will assess glycemic control, weight loss, healthcare utilization, and patient-reported outcomes by collecting individual-level data from routine clinical practice and health insurance claims. The primary endpoint is the proportion of patients achieving HbA 1c< 7.0% at yr 1. The study design was evaluated using the Pragmatic Explanatory Continuum Indicator Summary (PRECIS)-2 assessment; it scored 4-5 in all 9 domains, suggesting a highly pragmatic study. Of 1,278 patients enrolled, 54% were male with mean (±SD) age 57.4±11.1 yrs, BMI 35.7±8.0 kg/m 2, diabetes duration 7.4 …

The 558,000 individuals in the US receiving maintenance dialysis experience tremendous mortality, with a median survival of∼ 48 months (1). Comorbid diabetes is present in> 60% of incident cases of dialysis-dependent kidney failure and is associated with higher mortality rates, primarily driven by cardiovascular causes (1, 2). Renal impairment limits the use of many antihyperglycemic agents, rendering insulin the mainstay diabetes treatment for most patients receiving dialysis. However, insulin-induced hypoglycemia is common due to autonomic neuropathy, hypoglycemia unawareness, and impaired renal gluconeogenesis (3). Management of glycemia is therefore challenging, and frequent oscillations between hyper-and hypoglycemia contribute to poor cardiovascular outcomes in patients with dialysis-dependent kidney failure (2, 4).Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) improve glycemic …

RESEARCH DESIGN AND METHODSIn the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE), participants were enrolled who had type 2 diabetes duration< 10 years, had HbA1c 6.8–8.5%, and were on metformin monotherapy. Participants were randomly assigned to one of four additional glucose-lowering medications. We compared baseline clinical and metabolic characteristics across age categories (< 45, 45 to< 55, 55 to< 65, and‡ 65 years) using ANOVA and Pearson v2 tests.

OBJECTIVE To evaluate the association of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severity of infection with longer-term glycemic control and weight in people with type 2 diabetes (T2D) in the U.S. RESEARCH DESIGN AND METHODS We conducted a retrospective cohort study using longitudinal electronic health record data of patients with SARS-CoV-2 infection from the National COVID Cohort Collaborative (N3C). Patients were ≥18 years old with an ICD-10 diagnosis of T2D and at least one HbA1c and weight measurement prior to and after an index date of their first coronavirus disease 2019 (COVID-19) diagnosis or negative SARS-CoV-2 test. We used propensity scores to identify a matched cohort balanced on demographic characteristics, comorbidities, and medications used to treat diabetes. The primary outcome was the postindex …

The American Diabetes Association and the European Association for the Study of Diabetes convened a panel to update the previous consensus statements on the management of hyperglycaemia in type 2 diabetes in adults, published since 2006 and last updated in 2019. The target audience is the full spectrum of the professional healthcare team providing diabetes care in the USA and Europe. A systematic examination of publications since 2018 informed new recommendations. These include additional focus on social determinants of health, the healthcare system and physical activity behaviours including sleep. There is a greater emphasis on weight management as part of the holistic approach to diabetes management. The results of cardiovascular and kidney outcomes trials involving sodium–glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, including assessment of subgroups …