A method for comparing multiple imputation techniques: A case study on the U.S. national COVID cohort collaborative.

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 multiple imputation techniques. We demonstrate the feasibility of our approach on a large cohort of type-2 diabetes patients provided by the National COVID Cohort Collaborative (N3C) Enclave, where we explored the influence of various patient characteristics on outcomes related to COVID-19. Our analysis included classic multiple imputation techniques as well as simple complete-case Inverse Probability Weighted models. Extensive experiments show that our approach can effectively highlight the most promising and performant missing-data handling strategy for our case study. Moreover, our methodology allowed a better understanding of the behavior of the different models and of how it changed as we modified their parameters. Our method is general and can be applied to different research fields and on datasets containing heterogeneous types.

Binge size and loss of control as correlates of eating behavior and psychopathology among individuals with binge eating disorder and higher weight.

Studies comparing individuals with loss of control (LOC) eating who do and do not have objectively large binge episodes have found that degree of LOC is more important than binge size to psychological and behavioral outcomes. However, the relative importance of these characteristics has not been investigated in a population with binge eating disorder (BED), who by definition all have objectively large binge episodes. Persons with BED and higher weight (N = 34) were enrolled in a BED treatment trial and completed the Loss of Control Over Eating Scale, the Eating Disorder Examination, and measures of eating behavior, mood, and quality of life. Body mass index (BMI) was calculated from measured height and weight. The size of the largest binge episode (measured in kilocalories) and degree of LOC were entered into multiple regression equations to determine their relationships with disordered eating symptoms, depression, quality of life, and BMI in this pilot study. Greater LOC had a stronger independent association than binge size with higher total eating psychopathology, shape dissatisfaction, hunger, food cravings and food addiction symptoms. Larger binge size had a stronger independent association than LOC with higher weight concern and lower general and social quality of life. Both characteristics were associated with higher eating concern and neither were associated with depression or BMI. Both binge size and degree of LOC are associated with important psychosocial treatment targets in patients with BED. Future research should validate the largest binge episode measurement method and replicate the present findings in a larger sample.

Effects of liraglutide on appetite, food preoccupation, and food liking: results of a randomized controlled trial.

BACKGROUND: Some weight loss medications, including liraglutide 3.0 mg, are thought to facilitate weight loss by improving appetite control. However, no studies have evaluated their long-term appetitive effects. SUBJECTS/METHODS: This study examined changes in appetite in a subsample of 113 adults with obesity (76.1% female, 55.8% white, BMI = 38.8 ± 4.8 kg/m2) who participated in a 52-week trial. Participants were randomized to intensive behavioral therapy alone (IBT-alone), IBT with liraglutide 3.0 mg/day (IBT-liraglutide), or IBT-liraglutide combined with a 12-week meal replacement diet (Multi-component). Participants rated their hunger, fullness after meals, liking of meals, and food preoccupation (all as experienced over the past week) using visual analogue scales (0-100 mm). Ratings were completed at baseline and eight subsequent visits over the year. RESULTS: At week 52, participants treated by IBT-alone lost 6.2 ± 1.6% of baseline weight, compared with 11.8 ± 1.6% and 12.1 ± 1.5% in the IBT-liraglutide and Multi-component groups, respectively. Compared to IBT-alone, IBT-liraglutide participants reported larger reductions at week 6 in hunger (-0.3 ± 4.2 vs -16.8 ± 4.0 mm, p = .005) and food preoccupation (+0.2 ± 3.7 vs -16.3 ± 3.6 mm, p = .002) and larger increases in fullness (-5.1 ± 3.2 vs +9.8 ± 3.0 mm, p = .001). These significant differences persisted at all assessments through week 24. There were no differences between IBT-alone and IBT-liraglutide in meal liking. IBT-alone and Multi-component participants differed in hunger at week 6, and in food preoccupation at all assessments through week 24. Multi-component participants reported reduced liking of meals relative to the IBT-alone and IBT-liraglutide groups through weeks 40 and 52, respectively. There were no other differences among any groups at week 52. CONCLUSIONS: Consistent with short-term studies, IBT-liraglutide participants reported greater improvements in hunger, fullness, and food preoccupation than those assigned to IBT-alone. Differences in appetite persisted for 24 weeks but were not maintained at week 52, despite the relatively greater weight losses in the liraglutide-treated participants at the trial's end.

Associations between causal attributions for obesity and long-term weight loss.

Obesity is a complex disease caused by a wide array of behavioral, biological, and environmental factors. However, obesity is often attributed to oversimplified and stigmatizing causal factors such as laziness, lack of willpower, and failure to take personal responsibility for one's health. Understanding of the causal factors that contribute to obesity among people with obesity may affect their weight management efforts. The current study explored associations between causal attributions for obesity and long-term weight loss, as well as examined potential changes in attributions with weight reduction. The 16-item Causal Attributions for Obesity scale (rated 1-7) was administered to 178 patients seeking behavioral/pharmacological weight-loss treatment. Causal attributions and weight were assessed at baseline, after 14 weeks of a low-calorie diet, and again at weeks 24 and 52 of a subsequent randomized trial (i.e., 66 weeks total). Logistic and linear regression examined effects of baseline causal attribution ratings on weight loss. Higher baseline ratings of personal responsibility attributions predicted 38% reduced odds of achieving ≥10% weight loss at week 52 (p = 0.02). Causal attribution ratings did not change over time or correlate continuously with weight change. Thus, attributing obesity to a failure of personal responsibility may impair long-term weight management efforts for individuals seeking ≥10% weight loss. Targeted techniques are needed to reduce patients' stigmatizing beliefs about the causes of obesity.

Early Weight Loss in Behavioral Treatment Predicts Later Rate of Weight Loss and Response to Pharmacotherapy.

BACKGROUND: Early weight loss (EWL) in the first 1-2 months of behavioral treatment is a strong predictor of later total weight loss. It is not clear whether participants with lower early losses lose less in ongoing treatment or simply fail to overcome the smaller initial loss. Furthermore, no study has tested whether EWL in behavioral treatment predicts response to a different treatment modality, such as pharmacotherapy. METHODS: Data were from 170 participants with obesity (baseline BMI = 40.8 ± 5.8 kg/m2, 87.6% female; 71.3% Black) enrolled in a two-phase trial. Data from the weight loss phase, which provided weekly lifestyle counseling and a meal replacement diet, were used to examine the relationship between 4-week EWL and subsequent rate of weight loss in behavioral treatment. Data from the maintenance phase, in which 137 participants who had lost ≥5% of initial weight were randomized to 52 weeks of maintenance counseling with lorcaserin or placebo, were used to determine whether EWL with behavioral treatment affects the benefit of pharmacotherapy. RESULTS: EWL in the first 4 weeks of behavioral treatment (3.6 ± 1.7%) predicted greater total losses at Week 14 (r2 = 0.61, p < .001) and a faster rate of weight loss in the subsequent 9 weeks of the program (p < .001). During the maintenance phase, lower EWL in behavioral treatment predicted a greater benefit of lorcaserin, in comparison with placebo, for the maintenance of a ≥5% loss at Weeks 24 and 52. CONCLUSIONS: These findings support recommendations to modify treatment for individuals with low EWL.

Weight Bias Internalization and Long-Term Weight Loss in Patients With Obesity.

BACKGROUND: The relationship between weight bias internalization (WBI) and long-term weight loss is largely unknown. PURPOSE: To determine the effects of weight loss on WBI and assess whether WBI impairs long-term weight loss. METHODS: One hundred thirty-three adults with obesity completed the Weight Bias Internalization Scale (WBIS) at baseline, after a 14-week lifestyle intervention in which they lost ≥5 per cent of initial weight, and at weeks 24 and 52 of a subsequent randomized controlled trial (RCT) for weight-loss maintenance (66 weeks total). Linear mixed models were used to examine the effects of weight loss on WBIS scores and the effects of baseline WBIS scores on weight change over time. Logistic regression was used to determine the effects of baseline WBIS scores on achieving ≥5 and ≥10 per cent weight loss. RESULTS: Changes in weight did not predict changes in WBIS scores. Baseline WBIS scores predicted reduced odds of achieving ≥5 and ≥10 per cent weight loss at week 24 of the RCT (p values < .05). At week 52, the interaction between participant race and WBIS scores predicted weight loss (p = .046) such that nonblack (but not black) participants with higher baseline WBIS scores had lower odds of achieving ≥10 per cent weight loss (OR = 0.38, p = .01). Baseline WBIS scores did not significantly predict rate of weight change over time. CONCLUSIONS: Among participants in a weight loss maintenance trial, WBI did not change in relation to changes in weight. More research is needed to clarify the effects of WBI on long-term weight loss and maintenance across race/ethnicity. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov identifier NCT02388568.

Perceptions of a large amount of food based on binge-eating disorder diagnosis.

OBJECTIVE: This study examined what adults with binge-eating disorder (BED) and obesity perceived as the threshold for a large amount of food and how their evaluations compared to ratings by participants with obesity but without BED. METHOD: This was a cross-sectional study of 150 participants with obesity. BED was assessed using the Questionnaire on Eating and Weight Patterns and confirmed via interview. Participants completed the Eating Patterns Questionnaire and Eating Inventory. RESULTS: Participants with BED had significantly higher thresholds for a large amount of food relative to those without BED. Compared to participants without BED, those with BED had significantly higher thresholds on 13 of the 22 food items. In the overall sample, being male and having higher hunger scores were associated with greater thresholds. DISCUSSION: Individuals with obesity and BED had larger portion standards than participants without BED. Individuals with BED may benefit from interventions targeted toward decreasing perceptions of portion sizes.

Effects of addictive-like eating behaviors on weight loss with behavioral obesity treatment.

To examine the relationship between food cravings and food addiction as defined by the Yale Food Addiction Scale (YFAS) and to assess the effects of these variables on weight loss during a 14-week group lifestyle modification program. Data were from 178 participants who were prescribed a 1000-1200 kcal/day portion-controlled diet and provided with weekly group lifestyle modification sessions. Participants completed the Food Craving Inventory and YFAS pre- and post-treatment. Weight was measured weekly. Participants with YFAS-defined food addiction (6.7%) reported more frequent overall food cravings relative to those without food addiction. More frequent food cravings at baseline were associated with less weight loss over the 14 weeks. Analyzed categorically, participants in the highest tertile of baseline food cravings lost 7.6 ± 0.5% of initial weight, which was significantly less compared to those in the lowest tertile who lost 9.1 ± 0.5%. Percent weight loss did not differ significantly between participants with YFAS-defined food addiction (6.5 ± 1.2%) and those who did not meet criteria (8.6 ± 0.3%). Addictive-like eating behaviors significantly declined from pre- to post-treatment. Participants with frequent food cravings lost less weight than their peers. Targeted interventions for food cravings could improve weight loss in these individuals. Few participants met YFAS-defined criteria for food addiction. Addictive-like eating behaviors tended to decline during behavioral weight loss, but neither baseline nor change in YFAS scores predicted weight loss.

Identification of Binge Eating Disorder Criteria: Results of a National Survey of Healthcare Providers.

PURPOSE: To determine whether general healthcare providers and adult psychiatrists recognized binge eating disorder (BED) symptoms and features. The aims were to examine how they delineated the core criteria of BED-eating a large amount of food and sense of loss of control over eating-and how their evaluations compared to ratings by BED experts. DESIGN: This is a cross-sectional study of a nationwide U.S. sample of healthcare providers and a convenience sample of BED experts. METHODS: Providers were mailed surveys that asked respondents about their perceptions of a large amount of food and whether they thought case vignettes met thresholds for loss of control. Participants were also asked to select BED diagnostic criteria from a symptom list. Results were analyzed using one-way analyses of variance with post-hoc comparisons and chi-squared tests. FINDINGS: The survey was completed by 405 healthcare providers (response rate of 28.4%). Ratings of a large amount of food did not differ between BED experts and general healthcare providers (p = .10) or psychiatrists (p = .90). Provider groups did not differ significantly on whether five of the six vignettes met thresholds for loss of control (p > .05). Of the respondents, 93.0% of general healthcare providers and 88.6% of psychiatrists could not correctly identify the diagnostic criteria for BED. CONCLUSIONS: Across provider groups, demarcation of a large amount of food and loss of control over eating were relatively consistent. However, general healthcare providers and psychiatrists were not able to correctly identify BED symptoms. CLINICAL RELEVANCE: Training and education are greatly needed to improve knowledge of the diagnostic criteria for BED.

A pilot study of acceptance-based behavioural weight loss for adolescents with obesity.

BACKGROUND: Acceptance and commitment therapy (ACT) is a psychological treatment that has been found to increase weight loss in adults when combined with lifestyle modification, compared with the latter treatment alone. However, an ACT-based treatment for weight loss has never been tested in adolescents. METHODS: The present pilot study assessed the feasibility and acceptability of a 16-week, group ACT-based lifestyle modification treatment for adolescents and their parents/guardians. The co-primary outcomes were: (1) mean acceptability scores from up to 8 biweekly ratings; and (2) the percentage reduction in body mass index (BMI) from baseline to week 16. The effect size for changes in cardiometabolic and psychosocial outcomes from baseline to week 16 also was examined. RESULTS: Seven families enrolled and six completed treatment (14.3% attrition). The mean acceptability score was 8.8 for adolescents and 9.0 for parents (on a 1-10 scale), indicating high acceptability. The six adolescents who completed treatment experienced a 1.3% reduction in BMI (SD = 2.3, d = 0.54). They reported a medium increase in cognitive restraint, a small reduction in hunger, and a small increase in physical activity. They experienced small improvements in most quality of life domains and a large reduction in depression. CONCLUSIONS: These preliminary findings indicate that ACT plus lifestyle modification was a highly acceptable treatment that improved weight, cognitive restraint, hunger, physical activity, and psychosocial outcomes in adolescents with obesity.

Sex Differences in Obesity and Mental Health.

PURPOSE OF REVIEW: The purposes of this study were to examine the relationships between obesity and a wide range of mental health issues and to identify where sex differences exist and may vary across disorders. RECENT FINDINGS: Research on sex differences in the relationship between obesity and psychiatric disorders is more abundant in some areas, such as depression and eating disorders, than others, such as anxiety, trauma, and substance use. However, for most of the disorders, their relationships with obesity and sex are complex and are usually moderated by additional variables. Thus, studies that find stronger relationships for women between depression and obesity cross-sectionally do not tell the whole story, as longitudinal studies suggest that this relationship may also be present among men, particularly when confounders are considered. For those with eating disorders, men and women with obesity are fairly equally affected, and weight and shape concerns may play a role in maintaining these behaviors for both sexes. Weight stigma, though, seems to have worse consequences for women than men with obesity. Sex differences exist in relation to the associations between mental health and obesity. However, these differences vary by disorder, with disorder-specific moderators playing a role, such as age for depressive disorders, comorbid depression for anxiety disorders, and weight and shape concerns for eating disorders. More work is needed to understand if sex differences play a role in the relationship between obesity and anxiety, trauma, and substance use disorders.

Semaglutide for the treatment of obesity.

Semaglutide is a glucagon-like peptide-1 receptor agonist that was recently approved by the US Food and Drug Administration for chronic weight management. This paper reviews data on the mechanism of action, weight-loss and cardiometabolic efficacy, and safety of semaglutide 2.4 mg/week for obesity. Semaglutide has demonstrated the largest weight loss of any obesity medication to date with reductions of approximately 15% of initial weight at 68 weeks, accompanied by improvements in cardiovascular risks factors and physical functioning. The approval of this medication provides patients with greater options for weight management.

The Role of Lifestyle Modification with Second-Generation Anti-obesity Medications: Comparisons, Questions, and Clinical Opportunities.

PURPOSE OF REVIEW: This review examines lifestyle modification for obesity management with the goal of identifying treatment components that could support the use of a new generation of anti-obesity medications (AOMs). RECENT FINDINGS: Semaglutide reliably reduces baseline body weight by approximately 15% at 68 weeks, in contrast to 5-10% for lifestyle modification. Tirzepatide induces mean losses as great as 20.9%. Both medications reduce energy intake by markedly enhancing satiation and decreasing hunger, and they appear to lessen the need for traditional cognitive and behavioral strategies (e.g., monitoring food intake) to achieve calorie restriction. Little, however, is known about whether patients who lose weight with these AOMs adopt healthy diet and activity patterns needed to optimize body composition, cardiometabolic health, and quality of life. When used with the new AOMs, the focus of lifestyle modification is likely to change from inducing weight loss (through calorie restriction) to facilitating patients' adoption of dietary and activity patterns that will promote optimal changes in body composition and overall health.

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection? A population-level view in the EHR-based RECOVER program.

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.

A pilot randomized controlled trial of liraglutide 3.0 mg for binge eating disorder.

Objective: To assess the efficacy of liraglutide 3.0 mg, a glucagon-like peptide-1 (GLP-1) receptor agonist, for binge eating disorder (BED). Methods: Adults with a body mass index (BMI) ≥ 27 kg/m2 enrolled in a pilot, 17-week double-blind, randomized controlled trial of liraglutide 3.0 mg/day for BED. The primary outcome was number of objective binge episodes (OBEs)/week. Binge remission, weight change, and psychosocial variables were secondary outcomes. Mixed effect models were used for continuous variables, and generalized estimating equations were used for remission rates. Results: Participants (n = 27) were 44.2 ± 10.6 years; BMI = 37.9 ± 11.8 kg/m2; 63% women; and 59% White and 41% Black. At baseline, the liraglutide group (n = 13) reported 4.7 ± 0.7 OBEs/week, compared with 3.0 ± 0.7 OBEs/week for the placebo group, p = 0.07. At week 17, OBEs/week decreased by 4.0 ± 0.6 in liraglutide participants and by 2.5 ± 0.5 in placebo participants (p = 0.37, mean difference = 1.2, 95% confidence interval 1.3, 2.0). BED remission rates of 44% and 36%, respectively, did not differ. Percent weight loss was significantly greater in the liraglutide versus the placebo group (5.2 ± 1.0% vs. 0.9 ± 0.7%, p = 0.005). Conclusion: Participants in both groups reported reductions in OBEs, with the liraglutide group showing clinically meaningful weight loss. A pharmacy medication dispensing error was a significant limitation of this study. Further research on liraglutide and other GLP-1 agonists for BED is warranted.

Clinical Insight on Semaglutide for Chronic Weight Management in Adults: Patient Selection and Special Considerations.

Losses of 5-10% or more of initial body weight are associated with improvements in obesity-related comorbidities. However, attaining and sustaining this level of weight loss is challenging. The novel anti-obesity medication semaglutide 2.4 mg injected subcutaneously once weekly as an adjunct to a reduced-calorie diet and physical activity helps patients achieve average losses of 9.6-17.4% of initial body weight at week 68, as well as improvements in cardiometabolic and psychosocial indices. Despite these average benefits, prescribers should carefully assess the suitability of patients for this medication. In this paper, we discuss considerations for the selection of individuals who are candidates for semaglutide and special considerations related to the use of this medication. These include its efficacy and safety, as well as its contraindications, potential adverse effects, management of comorbidities and drug interactions, insurance coverage and cost, and patient preferences.

Binge eating disorder and eating self-efficacy in adults seeking bariatric surgery.

This study assessed the relationships between binge eating disorder (BED) and eating self-efficacy in a sample of patients prior to bariatric surgery. The study also examined the extent that BED status accounted for variance in self-efficacy after controlling for demographic factors (age, sex and race), physical variables (comorbidities and body mass index [BMI]) and depressive symptoms. This was a cross-sectional study of pre-surgical data from patients seeking bariatric surgery at a university-based healthcare system (N = 98; mean ± SD age of 46.2 ± 12.5 years; BMI of 45.4 ± 7.2 kg/m2 ; 86.7% female; and 60.2% of patients self-identified as White). Patients completed the Weight and Lifestyle Inventory (WALI), Beck Depression Inventory-II (BDI-II) and Weight Efficacy Lifestyle Questionnaire. Of the total sample, 15.3% met criteria for BED, 33.7% had subthreshold BED and 51.0% were free of this disorder. In adjusted analyses, total self-efficacy was significantly lower in patients with subthreshold BED (B ± SE = -15.88 ± 7.23, p = .03) and individuals with BED (B ± SE = -35.07 ± 10.23, p = .001) than in those without BED. Patients with BED, compared to those without, had significantly worse scores (in adjusted analyses) on the self-efficacy subscales of negative emotions (p = .003), availability of food (p < .001), social pressure (p = .004) and positive activities (p = .03). In patients seeking bariatric surgery, total self-efficacy scores were significantly lower in patients with BED and subthreshold BED than those without BED. The results suggest that eating self-efficacy may be an important factor to target in patients with BED who seek bariatric surgery.

Glycemic Control and Clinical Outcomes in U.S. Patients With COVID-19: Data From the National COVID Cohort Collaborative (N3C) Database.

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 hospitalized. RESULTS: The study included 39,616 patients (50.9% female, 55.4% White, 26.4% Black or African American, and 16.1% Hispanic or Latino, with mean ± SD age 62.1 ± 13.9 years and mean ± SD HbA1c 7.6% ± 2.0). There was an increasing risk of hospitalization with incrementally higher HbA1c levels, but risk of death plateaued at HbA1c >8%, and risk of invasive ventilation or ECMO plateaued >9%. There was no significant difference in LOS across HbA1c levels. CONCLUSIONS: In a large, multicenter cohort of patients in the U.S. with T2D and COVID-19 infection, risk of hospitalization increased with incrementally higher HbA1c levels. Risk of death and invasive ventilation also increased but plateaued at different levels of glycemic control.

Are fewer cases of diabetes mellitus diagnosed in the months after SARS-CoV-2 infection?

Long-term sequelae of severe acute respiratory coronavirus-2 (SARS-CoV-2) infection may include an increased incidence of diabetes. Our objective was to describe the temporal relationship between new diagnoses of diabetes mellitus and SARS-CoV-2 infection in a nationally representative database. There appears to be a sharp increase in diabetes diagnoses in the 30 days surrounding SARS-CoV-2 infection, followed by a decrease in new diagnoses in the post-acute period, up to 360 days after infection. These results underscore the need for further investigation, as understanding the timing of new diabetes onset after COVID-19 has implications regarding potential etiology and screening and treatment strategies.

Diabetes medications and associations with Covid-19 outcomes in the N3C database: A national retrospective cohort study.

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 (RR 0.68, 0.32-1.44), and mortality (RR 0.82, 0.41-1.64). Compared to SU, metformin was associated with a lower risk of ventilation (RR 0.5, 95% CI 0.28-0.98, p = 0.044) and mortality (RR 0.56, 95%CI 0.33-0.97, p = 0.037). There was no difference in unadjusted or adjusted results of the negative control. CONCLUSIONS: There were clinically significant associations between metformin use and less severe COVID-19 compared to SU, but not compared to DPP4i. New-user studies and randomized trials are needed to assess early outpatient treatment and post-exposure prophylaxis with therapeutics that are safe in adults, children, pregnancy and available worldwide.