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Introduction Type 2 diabetes mellitus (T2DM) is a powerful risk factor for cardiovascular disease (CVD), conferring a greater relative risk in women than men. We sought to examine sex differences in cardiometabolic risk factors and management in the contemporary cohort represented by the Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE).Research design and methods GRADE enrolled 5047 participants (1837 women, 3210 men) with T2DM on metformin monotherapy at baseline. The current report is a cross-sectional analysis of baseline data collected July 2013 to August 2017.Results Compared with men, women had a higher mean body mass index (BMI), greater prevalence of severe obesity (BMI≥40 kg/m2), higher mean LDL cholesterol, greater prevalence of low HDL cholesterol, and were less likely to receive statin treatment and achieve target LDL, with a generally greater prevalence of these risk factors in younger women. Women with hypertension were equally likely to achieve blood pressure targets as men; however, women were less likely to receive ACE inhibitors or angiotensin receptor blockers. Women were more likely to be divorced, separated or widowed, and had fewer years of education and lower incomes.Conclusions This contemporary cohort demonstrates that women with T2DM continue to have a greater burden of cardiometabolic and socioeconomic risk factors than men, particularly younger women. Attention to these persisting disparities is needed to reduce the burden of CVD in women.Trial registration number ClinicalTrials.gov (NCT01794143)

Context: β-Cell response to glucose is compromised in individuals with type 2 diabetes (T2D), possibly due in part to excessive carbohydrate consumption., Objective: This study was conducted to determine if a eucaloric carbohydrate-restricted (CR) diet (∼9% energy from carbohydrate, 65% energy from fat), compared to a eucaloric higher carbohydrate (HC) diet (∼55% energy from carbohydrate, 20% energy from fat), would improve β-cell response to glucose in participants with T2D., Methods: Participants were 57 African American and European American adults with T2D not using insulin. Medications were discontinued 1 to 2 weeks prior to baseline testing. A hyperglycemic clamp was used to assess the acute (first-phase) and maximal (arginine-stimulated) C-peptide response to glucose at baseline and after 12 weeks of controlled diet therapy (all food provided). An oral glucose tolerance test (OGTT) was used to assess the disposition index (DI)., Results: At 12 weeks, a statistically significant effect of diet was observed on acute C-peptide response (2-fold greater with the CR diet; P < .01). For maximal C-peptide, a significant effect of diet was observed (22% greater with the CR diet; P < .05), as was a significant diet-by-race interaction (P < .05), indicating that the diet effect was specific to European Americans (48% greater with the CR diet; P < .01). OGTT results showed a significant effect of diet on DI at 12 weeks (32% greater with the CR diet; P < .05)., Conclusion: These results suggest that a eucaloric CR diet has beneficial effects on β-cell function in patients with mild T2D., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

The spectrum of cardiorenal and metabolic diseases comprises many disorders, including obesity, type 2 diabetes (T2D), chronic kidney disease (CKD), atherosclerotic cardiovascular disease (ASCVD), heart failure (HF), dyslipidemias, hypertension, and associated comorbidities such as pulmonary diseases and metabolism dysfunction-associated steatotic liver disease and metabolism dysfunction-associated steatohepatitis (MASLD and MASH, respectively, formerly known as nonalcoholic fatty liver disease and nonalcoholic steatohepatitis [NAFLD and NASH]). Because cardiorenal and metabolic diseases share pathophysiologic pathways, two or more are often present in the same individual. Findings from recent outcome trials have demonstrated benefits of various treatments across a range of conditions, suggesting a need for practice recommendations that will guide clinicians to better manage complex conditions involving diabetes, cardiorenal, and/or metabolic (DCRM) diseases. To meet this need, we formed an international volunteer task force comprising leading cardiologists, nephrologists, endocrinologists, and primary care physicians to develop the DCRM 2.0 Practice Recommendations, an updated and expanded revision of a previously published multispecialty consensus on the comprehensive management of persons living with DCRM. The recommendations are presented as 22 separate graphics covering the essentials of management to improve general health, control cardiorenal risk factors, and manage cardiorenal and metabolic comorbidities, leading to improved patient outcomes., Competing Interests: Declaration of competing interest None of the Task Force members received monetary renumeration for their contributions to the creation or writing of this consensus document. See the Supplementary Appendix for full declarations of competing interests for each author., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Stress is associated with physiological and behavioral adaptations that increase the risk for obesity and related diseases in adults and children. Mechanisms linking stress to chronic disease are diverse and not fully elucidated, but research suggests stress may impact eating behaviors and increase food intake and thereby, risk for obesity., Objective: The purpose of this study was to test the hypotheses that women's perceived stress and household disorder are associated with more uncontrolled and emotional eating among women, more food responsiveness and emotional overeating among their children, and greater adiposity in both women and their children., Methods: Women (n = 86) completed the Perceived Stress Scale, Confusion, Hubbub and Order Scale, Three Factor Eating Questionnaire, and Child Eating Behavior Questionnaire. Total body fat (%) was measured via dual-energy X-ray absorptiometry. Linear regression models evaluated associations of perceived stress and household disorder with eating behaviors and adiposity of women and their children (4-10 years old)., Results: In a sample of predominantly non-Hispanic Black women (84.9%, n = 73), more perceived stress and household disorder were associated with more uncontrolled and emotional eating (p < 0.05). Women's perceived stress was not associated with their children's eating behaviors; however, household disorder was positively associated with children's food responsiveness and emotional overeating (p < 0.05). Perceived stress and household disorder were not associated with adiposity of women or their children., Conclusions: These findings suggest household disorder may be a factor for home-based interventions to consider when addressing eating behaviors among families with children., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: W. Timothy Garvey has served as a consultant on advisory boards for Boehringer-Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, Zealand, Allurion, Merck and the Milken Foundation, and a site principal investigator for multi-centered clinical trials sponsored by their university and funded by Novo Nordisk, Eli Lilly, Epitomee, Neruovalens and Pfizer. W. Timothy Garvey has served as a board member for the American Association of Clinical Endocrinology, and as a member of Data Monitoring Committees for phase 3 clinical trials conducted by Boehringer-Ingelheim and Eli Lilly. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Purpose of Review: This review aims to discuss strengths and limitations of body mass index (BMI) in diagnosing obesity, the use of alternative anthropometric measurements, and potential new technology that may change the future of obesity diagnosis and management., Recent Findings: The diagnosis of obesity requires the anthropometric assessment of adiposity. In clinical settings, this should include BMI with confirmation that elevated BMI represents excess adiposity and a measure of fat distribution (i.e., waist circumference (WC), waist to height ratio (WHtR), or WC divided by height 0.5 (WHR.5R). Digital anthropometry and bioelectric impedance (BIA) can estimate fat distribution and be feasibly employed in the clinic. In addition, the diagnosis should include a clinical component assessing the presence and severity of weight-related complications. As anthropometric measures used in the diagnosis of obesity, BMI is generally sufficient if confirmed to represent excess adiposity, and there are advantages to the use of WHtR over WC to assess fat distribution. BIA and digital anthropometry have the potential to provide accurate measures of fat mass and distribution in clinical settings. There should also be a clinical evaluation for the presence and severity of obesity complications that can be used to stage the disease., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Anti-obesity medications (AOMs) have historically had limited weight-loss efficacy. However, newer glucagon-like peptide-1 receptor agonist (GLP-1 RA)-based therapies seem to be more effective, including dual agonists of GLP-1R and the glucagon receptor (GCGR) or glucose-dependent insulinotropic polypeptide receptor., Objective: To explore healthcare professionals' (HCPs) experience in obesity treatment and their understanding of agonists of GCGR, glucose-dependent insulinotropic polypeptide (GIP) RA, and GLP-1 RA., Methods: This cross-sectional online survey of HCPs prescribing AOMs was conducted in the United States in 2023 with a questionnaire designed to evaluate prescribing behavior and understanding of GCGR, GIP RA, and GLP-1 RA., Results: The 785 respondents (251 primary-care physicians [PCPs], 263 endocrinologists, and 271 advanced practice providers [APPs]) reported 55% of their patients had obesity (body mass index ≥30 kg/m 2 or ≥27 with weight-related complications) and recommended AOMs to 49% overall, significantly more endocrinologists (57% of patients, p <  0.0005) than PCPs (43%) or APPs (46%). The greatest barriers to treatment were medication cost/lack of insurance (mean 4.2 on 1-5 scale [no barrier-extreme barrier]), low patient engagement/adherence (3.3), and inadequate time/staff (3.1). Metformin was the type 2 diabetes (T2D) medication most commonly prescribed to treat obesity in T2D patients (92.5% of respondents). Most HCPs (65%) were very/extremely familiar with GLP-1 RA, but only 30% with GIP RA and 16% with GCGR. Most HCPs expected dual GCGR/GLP-1 RA to benefit many obesity-related conditions; however, only a minority of HCPs perceived that they would benefit non-cardiometabolic complications of obesity., Conclusions: Among HCPs prescribing AOMs, gaps exist in the management of people living with obesity as <50% are prescribed AOMs. Barriers to treatment indicate a need to improve access to AOMs. HCPs were less familiar with GCGR or GIP RA than GLP-1 RA but expect dual GCGR/GLP-1 RA may offer additional benefits, potentially addressing treatment barriers and access. Thus, there is a need for greater education among HCPs regarding the mechanism of action and therapeutic effects of GCGR agonists, and dual GCGR/GLP-1 RA, so that the full range of obesity-related complications can be effectively treated., Competing Interests: W. Timothy Garvey, MD, has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck, and as a site principal investigator for multi‐centered clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly, Epitomee, Neurovalens, and Pfizer. Cathy D. Mahle, PhD, is an employee of Boehringer Ingelheim, which is developing a dual glucagon receptor/GLP‐1 receptor agonist. Robert F. Kushner, MD, serves on scientific advisory boards for Novo Nordisk and WW and serves as a consultant for Altimmune, Pfizer, Boehringer Ingelheim and Eli Lilly. Trevor Bell, PhD, is employed by dQ&A, a market research firm whose clients include several pharmaceutical and device companies in the diabetes field., (© 2024 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Objective: To describe the individual and joint associations of baseline factors with glycemia, and also with differential effectiveness of medications added to metformin., Research Design and Methods: Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) participants (with type 2 diabetes diagnosed for <10 years, on metformin, and with HbA1c 6.8-8.5%; N = 5,047) were randomly assigned to a basal insulin (glargine), sulfonylurea (glimepiride), glucagon-like peptide 1 agonist (liraglutide), or dipeptidyl peptidase 4 inhibitor (sitagliptin). The glycemic outcome was HbA1c ≥7.0%, subsequently confirmed. Univariate and multivariate regression and classification and regression tree (CART) analyses were used to assess the association of baseline factors with the glycemic outcome at years 1 and 4., Results: In univariate analyses at baseline, younger age (<58 years), Hispanic ethnicity, higher HbA1c, fasting glucose, and triglyceride levels, lower insulin secretion, and relatively greater insulin resistance were associated with the glycemic outcome at years 1 and/or 4. No factors were associated with differential effectiveness of the medications by year 4. In multivariate analyses, treatment group, younger age, and higher baseline HbA1c and fasting glucose were jointly associated with the glycemic outcome by year 4. The superiority of glargine and liraglutide at year 4 persisted after multiple baseline factors were controlled for. CART analyses indicated that failure to maintain HbA1c <7% by year 4 was more likely for younger participants and those with baseline HbA1c ≥7.4%., Conclusions: Several baseline factors were associated with the glycemic outcome but not with differential effectiveness of the four medications. Failure to maintain HbA1c <7% was largely driven by younger age and higher HbA1c at baseline. Factors that predict earlier glycemic deterioration could help in targeting patients for more aggressive management., (© 2024 by the American Diabetes Association.)

Background: Cardiometabolic risk prediction models that incorporate metabolic syndrome traits to predict cardiovascular outcomes may help identify high-risk populations early in the progression of cardiometabolic disease., Objectives: The purpose of this study was to examine whether a modified cardiometabolic disease staging (CMDS) system, a validated diabetes prediction model, predicts major adverse cardiovascular events (MACE)., Methods: We developed a predictive model using data accessible in clinical practice [fasting glucose, blood pressure, body mass index, cholesterol, triglycerides, smoking status, diabetes status, hypertension medication use] from the REGARDS (REasons for Geographic And Racial Differences in Stroke) study to predict MACE [cardiovascular death, nonfatal myocardial infarction, and/or nonfatal stroke]. Predictive performance was assessed using receiver operating characteristic curves, mean squared errors, misclassification, and area under the curve (AUC) statistics., Results: Among 20,234 REGARDS participants with no history of stroke or myocardial infarction (mean age 64 ± 9.3 years, 58% female, 41% non-Hispanic Black, and 18% diabetes), 2,695 developed incident MACE (13.3%) during a median 10-year follow-up. The CMDS development model in REGARDS for MACE had an AUC of 0.721. Our CMDS model performed similarly to both the ACC/AHA 10-year risk estimate (AUC 0.721 vs 0.716) and the Framingham risk score (AUC 0.673)., Conclusions: The CMDS predicted the onset of MACE with good predictive ability and performed similarly or better than 2 commonly known cardiovascular disease prediction risk tools. These data underscore the importance of insulin resistance as a cardiovascular disease risk factor and that CMDS can be used to identify individuals at high risk for progression to cardiovascular disease.

Objective: In Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study (GRADE) (5,047 participants, mean follow-up 5.0 years), differences in glycemic control were demonstrated over time among four randomized therapies added to metformin. Weight gain and hypoglycemia are also important outcomes for people with type 2 diabetes. We compared the effects of the four randomized GRADE medications on a composite outcome incorporating glycemic deterioration, weight gain, and hypoglycemia., Research Design and Methods: The composite outcome was time to first occurrence of any of the following: HbA1c >7.5%, confirmed; ≥5% weight gain; or severe or recurrent nonsevere hypoglycemia. Secondary analyses included examination of individual components of the composite outcome, subgroup effects and potential mediators, and treatment satisfaction. Cumulative incidence was estimated with the Kaplan-Meier estimator. Cox proportional hazards models were used to assess pairwise group differences in risk of an outcome., Results: Risk of reaching the composite outcome (events per 100 participants per treatment year [PTYs]) was lowest with liraglutide (19 per 100 PTYs) followed by sitagliptin (26 per 100 PTYs), glargine (29 per 100 PTYs), and glimepiride (40 per 100 PTYs); all pairwise comparisons were statistically significant. The order was the same for risk of weight gain and hypoglycemia, but risk of glycemic deterioration was lowest with glargine, followed by liraglutide, glimepiride, and sitagliptin. No significant heterogeneity in risk of composite outcome was detected across prespecified covariates. Participants who reached the composite outcome had modestly but significantly lower treatment satisfaction., Conclusions: Among participants treated with common second-line drug classes for type 2 diabetes, the liraglutide group had the lowest and glimepiride the highest risk of reaching a composite outcome encompassing glycemic deterioration, weight gain, and hypoglycemia. These findings may inform decision-making regarding type 2 diabetes therapy., (© 2024 by the American Diabetes Association.)

Aim: To assess the effect of tirzepatide on long-term risk of atherosclerotic cardiovascular disease (ASCVD) among people with obesity or overweight without diabetes from SURMOUNT-1., Materials and Methods: SURMOUNT-1, a phase 3 trial, evaluated the efficacy and safety of tirzepatide in adults with body mass index ≥30 or ≥27 kg/m 2 and at least one weight-related complication, excluding diabetes. Participants were randomly assigned to tirzepatide (5/10/15 mg) or placebo. Changes from baseline in cardiometabolic variables were assessed. The predicted 10-year ASCVD risk scores were calculated (American College of Cardiology/American Heart Association risk engine) at baseline, week 24, and week 72 in SURMOUNT-1 participants without a history of ASCVD. Percent change in risk scores from baseline to weeks 24 and 72 was compared between tirzepatide and placebo using mixed model for repeated measures analysis. Analyses were also conducted in participants with intermediate to high risk at baseline., Results: Tirzepatide-treated groups demonstrated reductions in cardiometabolic variables over 72 weeks. In participants without a history of ASCVD (N = 2461), the baseline median risk score was low and did not differ across groups (1.5%-1.6%). Relative change in risk from baseline to week 72 was greater for tirzepatide (-23.5% to -16.4%) than placebo (12.7%; P < 0.001). Relative change among participants with intermediate-to-high baseline risk was significantly greater for tirzepatide (P < 0.05). Intermediate-to-high-risk participants demonstrated similar relative change but greater absolute risk reduction compared to the overall population., Conclusion: Tirzepatide treatment significantly reduced the 10-year predicted risk of ASCVD versus placebo in patients with obesity or overweight without diabetes., (© 2023 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aim: We assessed the impact of tirzepatide on 10-year predicted risk of developing type 2 diabetes (T2D) among participants in the SURMOUNT-1 trial., Materials and Methods: In this post hoc analysis of SURMOUNT-1, the Cardiometabolic Disease Staging risk engine was used to calculate the 10-year predicted risk of T2D at baseline, week 24 and week 72 among participants randomized to receive 5, 10, or 15 mg tirzepatide or placebo. Mean changes in risk scores from baseline to weeks 24 and 72 were compared between tirzepatide and placebo groups. Subgroup analyses were conducted based on participants' glycaemic status and body mass index at baseline., Results: Mean baseline T2D predicted risk scores did not differ between tirzepatide and placebo groups (range: 22.9%-24.3%). At week 72, mean absolute T2D predicted risk score reductions were significantly greater in tirzepatide groups (5 mg, 12.4%; 10 mg, 14.4%; 15 mg, 14.7%) versus placebo (0.7%). At week 72, median relative predicted risk reductions following tirzepatide treatment ranged from 60.3% to 69.0%. For participants with and without prediabetes, risk reductions were significantly greater in tirzepatide groups versus placebo. At week 72, participants with prediabetes (range: 16.0%-20.3%) had greater mean risk score reductions from baseline versus those without prediabetes (range: 10.1%-11.3%). Across body mass index subgroups, mean reductions from baseline were significantly greater in tirzepatide groups versus placebo., Conclusion: Tirzepatide treatment significantly reduced the 10-year predicted risk of developing T2D compared with placebo in participants with obesity or overweight, regardless of baseline glycaemic status., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Objective: The primary purpose of the current study was to test the hypothesis that the proinsulin-to-C-peptide (PI-to-CP) ratio, as an index of proinsulin secretion, would be higher and associated with indices of β-cell function in African American adults relative to European American adults without type 2 diabetes., Research Design and Methods: Participants were 114 African American and European American adult men and women. A 2-h oral glucose tolerance test was conducted to measure glucose, insulin, C-peptide, and proinsulin and derive indices of β-cell response to glucose. The Matsuda index was calculated as a measure of insulin sensitivity. The disposition index (DI), the product of insulin sensitivity and β-cell response, was calculated for each phase of β-cell responsivity. Pearson correlations were used to investigate the relationship of the PI-to-CP ratio with each phase of β-cell response (basal, Φb; dynamic, Φd; static, Φs; total, Φtot), disposition indices (DId, DIs, DItot), and insulin sensitivity. Multiple linear regression analysis was used to evaluate independent contributions of race, BMI, and glucose tolerance status on PI-to-CP levels before and after adjustment for insulin sensitivity., Results: African American participants had higher fasting and 2-h PI-to-CP ratios. The fasting PI-to-CP ratio was positively associated with Φb, and the fasting PI-to-CP ratio and 2-h PI-to-CP ratio were inversely associated with DId and insulin sensitivity only in African American participants., Conclusions: The PI-to-CP ratio could be useful in identifying African American individuals at highest risk for β-cell dysfunction and ultimately type 2 diabetes., (© 2023 by the American Diabetes Association.)

Background: Leptin resistance occurs with obesity, but it is unknown if individuals at risk for obesity develop leptin resistance prior to obesity., Objective: Investigate whether leptin resistance is independent of weight status in children at risk for obesity due to intrauterine exposure to maternal obesity or gestational diabetes mellitus (GDM)., Methods: Mother-child dyads (N = 179) were grouped by maternal pregnancy weight and GDM status: (1) normal weight, no GDM; (2) overweight/obesity, no GDM; (3) overweight/obesity with GDM. Children (4-10 years) were further stratified by current body mass index (BMI) <85th or ≥85th percentile. Leptin resistance of children and mothers was calculated as fasting leptin/fat mass index. Two-way ANOVA was used to assess whether leptin concentrations and leptin resistance differed by current weight status or in utero exposure group, after adjusting for race, sex and Tanner stage., Results: Children with a BMI ≥85th percentile had more leptin resistance than those with a BMI <85th percentile (p < 0.001), but leptin resistance did not differ by in utero exposure. Similarly, leptin resistance in women was associated with weight status and not prior GDM., Conclusions: Results suggest that leptin concentrations are associated with obesity but not risk for obesity based on in utero exposure to maternal obesity or GDM., (© 2023 World Obesity Federation.)

Objective: In the Semaglutide Treatment Effect in People with obesity (STEP) trials, once-weekly subcutaneous semaglutide 2.4 mg plus lifestyle intervention reduced body weight and improved cardiometabolic parameters in adults with obesity (or overweight with weight-related comorbidities). Effects on the risk of developing type 2 diabetes (T2D) require investigation., Methods: STEP 1 (68 weeks) and 5 (104 weeks) randomized participants to semaglutide 2.4 mg or placebo. STEP 4 included a 20-week semaglutide run-in followed by randomization to 48 weeks of continued semaglutide or withdrawal (placebo). Ten-year T2D risk scores were calculated post hoc using Cardiometabolic Disease Staging., Results: In STEP 1 (N = 1583), relative risk score reductions were greater with semaglutide versus placebo (semaglutide: -61.1%; placebo: -12.9%; p < 0.0001). These reductions were maintained to week 104 in STEP 5 (N = 295; semaglutide: -60.0%; placebo: 3.5%; p < 0.0001). Risk scores during the STEP 4 run-in period (N = 776) were reduced from 20.6% to 11.1% and further to 7.7% at week 68 with continued semaglutide, increasing to 15.4% with withdrawal (relative risk score change: semaglutide: -32.1%; placebo: +40.6%; p < 0.0001). Risk score reductions mirrored weight loss., Conclusions: Cardiometabolic Disease Staging risk assessment suggests that once-weekly semaglutide 2.4 mg may substantially lower 10-year T2D risk in people with overweight or obesity., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

Background: We assessed the efficacy and safety of the oral glucagon-like peptide-1 analogue, semaglutide 50 mg, taken once per day versus placebo for the treatment of overweight or obesity in adults without type 2 diabetes., Methods: This randomised, double-blind, placebo-controlled, phase 3, superiority trial enrolled adults with a BMI of at least 30 kg/m 2 , or at least 27 kg/m 2 with bodyweight-related complications and comorbidities, without type 2 diabetes. The trial was done at 50 outpatient clinics in nine countries across Asia, Europe, and North America. Participants were randomly allocated (1:1) via an interactive web-response system to oral semaglutide escalated to 50 mg, or visually matching placebo, once per day for 68 weeks, plus lifestyle intervention. Group assignment was masked for participants, investigators, and those assessing outcomes. Coprimary endpoints were the percentage change in bodyweight and whether participants reached a bodyweight reduction of at least 5% at week 68 for oral semaglutide 50 mg versus placebo, assessed regardless of treatment discontinuation or use of other bodyweight-lowering therapies (an intention-to-treat analysis). Safety was assessed in participants who received at least one dose of trial drug. This trial, registered with ClinicalTrials.gov (NCT05035095), is now complete., Findings: From Sept 13 to Nov 22, 2021, 709 participants were screened, of whom 667 were randomly assigned to oral semaglutide 50 mg (n=334) or placebo (n=333). The estimated mean bodyweight change from baseline to week 68 was -15·1% (SE 0·5) with oral semaglutide 50 mg versus -2·4% (0·5) with placebo (estimated treatment difference -12·7 percentage points, 95% CI -14·2 to -11·3; p<0·0001). More participants reached bodyweight reductions of at least 5% (269 [85%] of 317 vs 76 [26%] of 295; odds ratio [OR] 12·6, 95% CI 8·5 to 18·7; p<0·0001), 10% (220 [69%] vs 35 [12%]; OR 14·7, 9·6 to 22·6), 15% (170 [54%] vs 17 [6%]; OR 17·9, 10·4 to 30·7), and 20% (107 [34%] vs 8 [3%]; OR 18·5, 8·8 to 38·9) at week 68 with oral semaglutide 50 mg versus placebo. Adverse events were more frequent with oral semaglutide 50 mg (307 [92%] of 334) than with placebo (285 [86%] of 333). Gastrointestinal adverse events (mostly mild to moderate) were reported in 268 (80%) participants with oral semaglutide 50 mg and 154 (46%) with placebo., Interpretation: In adults with overweight or obesity without type 2 diabetes, oral semaglutide 50 mg once per day led to a superior and clinically meaningful decrease in bodyweight compared with placebo., Funding: Novo Nordisk., Competing Interests: Declaration of interests FKK has consulted for 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; received research grants from Chr Hansen, Novo Nordisk, and Zealand Pharma; received honoraria for lectures, presentations, and educational events from 89bio, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Pharmacosmos, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; received support for attendance at scientific meetings from Bayer, Boehringer Ingelheim, and Novo Nordisk; has participated in data safety monitoring boards or advisory boards for 89bio, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi, Structure Therapeutics, Zealand Pharma, and Zucara; and has received study drugs for clinical trials from Boehringer Ingelheim, Chr Hansen, Eli Lilly, Novo Nordisk, and Sanofi. FKK is a minority shareholder in Antag Therapeutics, a co-owner of the weight loss clinic Medicinsk Vægttabsbehandling ApS, and holds a patent for GIP peptide analogues (assignee University of Copenhagen; patent EP3189072B1, European Patent Office). VRA has received medical writing support from Novo Nordisk; consultancy fees from Applied Therapeutics, Fractyl, Novo Nordisk, Pfizer, and Sanofi; research grant support (to institution) from Applied Therapeutics, Eli Lilly, Fractyl, Novo Nordisk, and Sanofi; and support for attendance at investigator meetings and scientific conferences for related presentations from Eli Lilly, Fractyl, and Novo Nordisk. VRA's spouse is an employee of Janssen. RDdV and TH-H are employees of, and shareholders in, Novo Nordisk. PNL is an employee of Novo Nordisk. JR has received grants or research support from Applied Therapeutics, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi, Merck, Oramed, Novartis, Novo Nordisk, Pfizer, and Sanofi; has served on scientific advisory boards and received honorarium or consulting fees from Applied Therapeutics, Boehringer Ingelheim, Eli Lilly, Hanmi, Novo Nordisk, Oramed, Sanofi, Structure Therapeutics, Terns Pharma, and Zealand Pharma; and has received honoraria for lectures from Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Sanofi. DMR has received medical writing support from Novo Nordisk; has been a clinical investigator for AstraZeneca, Boehringer Ingelheim, and Novo Nordisk; has received consulting fees from Boehringer Ingelheim, Kayentis, and Novo Nordisk; has acted as an unpaid consultant for Eli Lilly; has received honoraria as a speaker from Boehringer Ingelheim and Novo Nordisk; has received personal fees from the American Diabetes Association, the Endocrine Society, Medscape, PeerView, and Prime Therapeutics for the development of continuing medical education materials; has received support for attendance at scientific congresses by the American Diabetes Association, the Endocrine Society, Medscape, Novo Nordisk, PeerView, and Prime Therapeutics; has participated in scientific advisory boards for Boehringer Ingelheim and Novo Nordisk; and is a shareholder in Eli Lilly. WTG has received medical writing support from Novo Nordisk; has served as a site principal investigator for multicentred clinical trials sponsored by his university and funded by Eli Lilly, Epitomee, Neurovalens, Novo Nordisk, and Pfizer; has served as a consultant on advisory boards for Alnylam Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Fractyl Health, Inogen, Merck, Novo Nordisk, and Pfizer; and has served on the executive committee of the American Association of Clinical Endocrinology (term expired May, 2021)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Weight reduction is essential for improving health outcomes in people with obesity and type 2 diabetes. We assessed the efficacy and safety of tirzepatide, a glucose-dependent insulinotropic polypeptide and glucagon-like peptide-1 receptor agonist, versus placebo, for weight management in people living with obesity and type 2 diabetes., Methods: This phase 3, double-blind, randomised, placebo-controlled trial was conducted in seven countries. Adults (aged ≥18 years) with a body-mass index (BMI) of 27 kg/m 2 or higher and glycated haemoglobin (HbA 1c ) of 7-10% (53-86 mmol/mol) were randomly assigned (1:1:1), using a computer-generated random sequence via a validated interactive web-response system, to receive either once-weekly, subcutaneous tirzepatide (10 mg or 15 mg) or placebo for 72 weeks. All participants, investigators, and the sponsor were masked to treatment assignment. Coprimary endpoints were the percent change in bodyweight from baseline and bodyweight reduction of 5% or higher. The treatment-regimen estimand assessed effects regardless of treatment discontinuation or initiation of antihyperglycaemic rescue therapy. Efficacy and safety endpoints were analysed with data from all randomly assigned participants (intention-to-treat population). This trial is registered with ClinicalTrials.gov, NCT04657003., Findings: Between March 29, 2021, and April 10, 2023, of 1514 adults assessed for eligibility, 938 (mean age 54·2 years [SD 10·6], 476 [51%] were female, 710 [76%] were White, and 561 [60%] were Hispanic or Latino) were randomly assigned and received at least one dose of tirzepatide 10 mg (n=312), tirzepatide 15 mg (n=311), or placebo (n=315). Baseline mean bodyweight was 100·7 kg (SD 21·1), BMI 36·1 kg/m 2 (SD 6·6), and HbA 1c 8·02% (SD 0·89; 64·1 mmol/mol [SD 9·7]). Least-squares mean change in bodyweight at week 72 with tirzepatide 10 mg and 15 mg was -12·8% (SE 0·6) and -14·7% (0·5), respectively, and -3·2% (0·5) with placebo, resulting in estimated treatment differences versus placebo of -9·6% percentage points (95% CI -11·1 to -8·1) with tirzepatide 10 mg and -11·6% percentage points (-13·0 to -10·1) with tirzepatide 15 mg (all p<0·0001). More participants treated with tirzepatide versus placebo met bodyweight reduction thresholds of 5% or higher (79-83% vs 32%). The most frequent adverse events with tirzepatide were gastrointestinal-related, including nausea, diarrhoea, and vomiting and were mostly mild to moderate in severity, with few events leading to treatment discontinuation (<5%). Serious adverse events were reported by 68 (7%) participants overall and two deaths occurred in the tirzepatide 10 mg group, but deaths were not considered to be related to the study treatment by the investigator., Interpretation: In this 72-week trial in adults living with obesity and type 2 diabetes, once-weekly tirzepatide 10 mg and 15 mg provided substantial and clinically meaningful reduction in bodyweight, with a safety profile that was similar to other incretin-based therapies for weight management., Funding: Eli Lilly and Company., Competing Interests: Declaration of interests WTG has served as a consultant on advisory boards for Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, Pfizer, Fractyl Health, Alnylam Pharmaceuticals, Inogen, and Merck, and as a site principal investigator for multicentred clinical trials sponsored by his university and funded by Novo Nordisk, Eli Lilly and Company, Epitomee, Neurovalens, and Pfizer. JPF has received research funding (paid to his institution) from Akero, AstraZeneca, Boehringer Ingelheim, 89bio, Eli Lilly and Company, Intercept, IONIS, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, and Sanofi; has received consulting fees from Akero, Altimmune, Boehringer Ingelheim, Carmot Therapeutics, Echosens, 89bio, Eli Lilly and Company, Merck, Novo Nordisk, Pfizer, and Sanofi; has received speaker bureau honoraria from Eli Lilly and Company and travel support for attending meetings from Eli Lilly and Company, Novo Nordisk, Pfizer, and Sanofi; has served on advisory boards for Altimmune, Becton Dickenson, Boehringer Ingelheim, Carmot Therapeutics, Eli Lilly and Company, Gilead, Intercept, Merck, Novo Nordisk, Pfizer, and Sanofi; and has served on the board of directors for T1D Exchange. AMJ reports grants or contracts (through her institution) from Novo Nordisk, Eli Lilly and Company, Rhythm Pharmaceutical, and National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases; consults for Amgen and Scholar Rock; has received honoraria or travel support from Eli Lilly and Company, Novo Nordisk, and WeightWatchers, and stock options from Intellihealth; and serves on advisory boards for AstraZeneca, Boehringer Ingelheim, Biohaven, Eli Lilly and Company, Intellihealth, Novo Nordisk, Rhythm Pharmaceuticals, Structure Therapeutics, Terns Pharmaceutics, and WeightWatchers. CWlR reports grants from the Irish Research Council, Science Foundation Ireland, Anabio, and the Health Research Board. He serves on advisory boards and speakers’ panels of Novo Nordisk, Herbalife, GI Dynamics, Eli Lilly and Company, Johnson & Johnson, Glia, Irish Life Health, and Boehringer Ingelheim; is a member of the Irish Society for Nutrition and Metabolism outside the area of work commented on here; was the chief medical officer and director of the Medical Device Division of Keyron in 2021 (both unremunerated positions); is a previous investor in Keyron; was gifted stock holdings and divested all stock holdings in Keyron in September, 2021; continues to provide scientific advice to Keyron for no remuneration; and provides obesity clinical care in the Beyond BMI clinic and is a shareholder. NS has received grants and personal fees from AstraZeneca, Boehringer Ingelheim, and Novartis; a grant from Roche Diagnostics; and personal fees from Abbott Laboratories, Afimmune, Amgen, Eli Lilly and Company, Hanmi Pharmaceuticals, Janssen, Merck Sharp & Dohme, Novartis, Novo Nordisk, Pfizer, and Sanofi, outside of the submitted work. SZ, HM, NNA, MCB, IB, and XMZ are employees and shareholders of Eli Lilly and Company., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To focus on the intersection of perception, diagnosis, stigma, and weight bias in the management of obesity and obtain consensus on actionable steps to improve care provided for persons with obesity., Methods: The American Association of Clinical Endocrinology (AACE) convened a consensus conference of interdisciplinary health care professionals to discuss the interplay between the diagnosis of obesity using adiposity-based chronic disease (ABCD) nomenclature and staging, weight stigma, and internalized weight bias (IWB) with development of actionable guidance to aid clinicians in mitigating IWB and stigma in that context., Results: The following affirmed and emergent concepts were proposed: (1) obesity is ABCD, and these terms can be used in differing ways to communicate; (2) classification categories of obesity should have improved nomenclature across the spectrum of body mass index (BMI) using ethnic-specific BMI ranges and waist circumference (WC); (3) staging the clinical severity of obesity based on the presence and severity of ABCD complications may reduce weight-centric contribution to weight stigma and IWB; (4) weight stigma and internalized bias are both drivers and complications of ABCD and can impair quality of life, predispose to psychological disorders, and compromise the effectiveness of therapeutic interventions; (5) the presence and of stigmatization and IWB should be assessed in all patients and be incorporated into the staging of ABCD severity; and (6) optimal care will necessitate increased awareness and the development of educational and interventional tools for health care professionals that address IWB and stigma., Conclusions: The consensus panel has proposed an approach for integrating bias and stigmatization, psychological health, and social determinants of health in a staging system for ABCD severity as an aid to patient management. To effectively address stigma and IWB within a chronic care model for patients with obesity, there is a need for health care systems that are prepared to provide evidence-based, person-centered treatments; patients who understand that obesity is a chronic disease and are empowered to seek care and participate in behavioral therapy; and societies that promote policies and infrastructure for bias-free compassionate care, access to evidence-based interventions, and disease prevention., Competing Interests: Disclosures The Task Force was empaneled in accordance with AACE Conflict of Interest (COI) Policy and approved by the AACE COI Subcommittee. All members of the expert Task Force completed AACE’s disclosure form regarding any multiplicities of interests related to commercial and direct financial relationships within the preceding 12 months with companies that develop products connected with endocrine disorders. Categories for disclosure include employment, stock or other ownership, direct financial relationships (eg, speaker or consultant), research funding, authorship or panel involvement on a guidance document related to an overlapping topic, or other situations related to a perceived COI. The AACE COI Subcommittee reviewed these disclosures against an AACE-approved list of ineligible companies for this consensus statement and reached consensus regarding members who could serve on the Task Force in the nonconflicted majority, those who could serve in the conflicted minority with management strategy, and those who were disqualified from serving on the Task Force. The AACE CPG Oversight Committee reviewed and approved the AACE COI Subcommittee’s decisions regarding manageable COI and empanelment. Members of this Task Force were reminded to update potential disclosures if new potential conflicts arose during their appointments and to verify currency of disclosures. AACE made every effort to minimize the potential for conflicts of interest that could influence the recommendations of this CPG. Disclosures related to obesity are provided below; however, none were deemed as conflicts of interest as there were no discussions of treatment or management options in the development of the consensus statement. B.A. serves on speakers’ bureaus for Astra Zeneca, Corcept, Eli Lilly, and Novo Nordisk. J.A. serves on advisory boards for Eli Lilly and Novo Nordisk. W.G. serves as a volunteer consultant on advisory boards for Jazz Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer without financial compensation, serves on advisory boards for Alnylam Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Fractyl Health, and Novo Nordisk with financial compensation, and receives research support as a site principal investigator for clinical trials sponsored by his institution and funded by Eli Lilly, Novo Nordisk, Epitomee, and Pfizer. T.K. is the owner of Ted Kyle Consulting, LLC and a consultant for Gelesis, Johnson & Johnson, Novo Nordisk, and Nutrisystem. K.N., M.A., M.B., and M.C. have nothing to disclose., (Copyright © 2023 AACE. Published by Elsevier Inc. All rights reserved.)

Objective: This study evaluated the effect of once-weekly semaglutide 2.4 mg on 2-year control of eating., Methods: In STEP 5, adults with overweight/obesity were randomized 1:1 to semaglutide 2.4 mg or placebo, plus lifestyle modification, for 104 weeks. A 19-item Control of Eating Questionnaire was administered at weeks 0, 20, 52, and 104 in a subgroup of participants. P values were not controlled for multiplicity., Results: In participants completing the Control of Eating Questionnaire (semaglutide, n = 88; placebo, n = 86), mean body weight changes were -14.8% (semaglutide) and -2.4% (placebo). Scores significantly improved with semaglutide versus placebo for Craving Control and Craving for Savory domains at weeks 20, 52, and 104 (p < 0.01); for Positive Mood and Craving for Sweet domains at weeks 20 and 52 (p < 0.05); and for hunger and fullness at week 20 (p < 0.001). Improvements in craving domain scores were positively correlated with reductions in body weight from baseline to week 104 with semaglutide. At 104 weeks, scores for desire to eat salty and spicy food, cravings for dairy and starchy foods, difficulty in resisting cravings, and control of eating were significantly reduced with semaglutide versus placebo (all p < 0.05)., Conclusions: In adults with overweight/obesity, semaglutide 2.4 mg improved short- and longer-term control of eating associated with substantial weight loss., (© 2023 The Authors. Obesity published by Wiley Periodicals LLC on behalf of The Obesity Society.)

High blood pressure (BP) is the leading risk factor for cardiovascular disease (CVD). Although factors outside the home, such as crime and noise, have been associated with high BP in women and children, it is unknown if disorder within the home (household disorder) influences BP. We tested the hypothesis that women and children with more household disorder would have higher BP, independent of age, race, sodium intake, and body mass index (BMI). This study was a secondary analysis of data from mother-child dyads ( n = 216). Mothers were 87% African American, 34 ± 5 years old, with BMI 33.59 ± 9.43 kg/m². Children were 7 ± 2 (range: 4-10) years of age with BMI z score 0.60 ± 2.07. Household disorder was measured by the Confusion Hubbub and Order Scale. Mother-child dyads were assessed for weight, height, BP (adults), BP percentile (children), energy intake, and sodium intake. The relationship between household disorder and BP was evaluated using Pearson's partial correlation coefficients. In fully adjusted models, household disorder was positively associated with systolic BP for mothers ( r = 0.15, p < .05) and tended to be positively associated with diastolic BP ( r = 0.11, p = .10). For the children, household disorder was not associated with systolic or diastolic BP percentile. This study's results suggest that household disorder is positively associated with higher BP in adult women, but not their children. Nevertheless, these data suggest that interventions to address household disorder could benefit maternal BP and potentially improve long-term CVD outcomes. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Aims: Evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on cardiometabolic risk factors in people with overweight/obesity without diabetes in the STEP 1 and 4 trials., Materials and Methods: STEP 1 and 4 were phase III, 68-week, placebo-controlled trials of once-weekly semaglutide 2.4 mg combined with lifestyle intervention; STEP 4 had a 20-week semaglutide run-in and 48-week randomized withdrawal period. Participants had a body mass index ≥30 kg/m 2 or ≥27 kg/m 2 with one or more weight-related comorbidity, without diabetes. Pre-specified endpoints were changes in waist circumference, systolic/diastolic blood pressure (SBP/DBP), lipids, fasting plasma glucose (FPG), fasting serum insulin and antihypertensive/lipid-lowering medication use. Post-hoc assessments included non-high-density lipoprotein (HDL) cholesterol, homeostatic model assessment of insulin resistance (HOMA-IR; STEP 1 only), atherosclerotic cardiovascular disease (ASCVD) risk (American College of Cardiology/American Heart Association algorithm; STEP 1 only) and cardiometabolic risk factors by weight loss achieved (<5%, 5% to <10%, 10% to <15%, or ≥15%) (STEP 1 only)., Results: Of the 1961 participants in STEP 1 and 803 in STEP 4, most had one or more complication/comorbidity at baseline, with dyslipidaemia and hypertension most prevalent. In STEP 1, reductions in waist circumference, SBP, DBP, FPG, fasting serum insulin, lipids and HOMA-IR were greater with semaglutide versus placebo (p ≤ .001). Reductions in SBP, non-HDL cholesterol, low-density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight-loss categories. Non-significant ASCVD risk reductions were observed with semaglutide versus placebo (p > .05). In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run-in (week 0-20) were maintained over week 20-68 with continued semaglutide, but deteriorated following the switch to placebo (p < .001 [week 20-68]). Net reductions in antihypertensive/lipid-lowering medication use occurred with semaglutide versus placebo (both trials)., Conclusions: Semaglutide may improve cardiometabolic risk factors and reduce antihypertensive/lipid-lowering medication use versus placebo in adults with overweight/obesity without diabetes. These potential benefits were not maintained after treatment discontinuation., Gov Numbers: STEP 1 NCT03548935, STEP 4 NCT03548987., (© 2022 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Abstract This study investigated the clinical and economic impact of anti-obesity medications (AOMs; orlistat, liraglutide, phentermine/topiramate extended-release [ER], naltrexone ER/bupropion ER) among United States Veterans with obesity participating in Motivating Overweight/Obese Veterans Everywhere! (MOVE!), a government-initiated weight management program. The study population was identified from electronic medical records of the Veterans Health Administration (2010-2020). Clinical indices of obesity and health care resource utilization and costs were evaluated at 6, 12, and 24 months after the initial dispensing of an AOM in the AOM+MOVE! cohort ( N  = 3732, mean age 57 years, 79% male) or on the corresponding date of an inpatient or outpatient encounter in the MOVE! cohort ( N  = 7883, mean age 58 years, 81% male). At 6 months postindex, the AOM+MOVE! cohort had better cardiometabolic indices (eg, systolic blood pressure, diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, hemoglobin A1c) than the MOVE! cohort, with the trends persisting at 12 and 24 months. The AOM+MOVE! cohort was significantly more likely than the MOVE! cohort to have weight decreases of 5%-10%, 10%-15%, and >15% and lower body mass index at 6, 12, and 24 months. The AOM+MOVE! cohort also had fewer inpatient and emergency department visits than the MOVE! cohort, which was associated with lower mean total medical costs including inpatient costs. These results suggest that combining AOM treatment with the MOVE! program could yield long-term cost savings for the Veterans Affairs network and meaningful clinical improvements for Veterans with obesity.

Background: SARS-CoV-2 (COVID-19) continues to be a major public health issue. Obesity is a major risk factor for disease severity and mortality associated with COVID-19., Objective: This study sought to estimate the healthcare resource use and cost outcomes in patients hospitalized with COVID-19 in the United States (US) according to body mass index (BMI) class., Methods: Retrospective cross-sectional study analyzing data from the Premier Healthcare COVID-19 database for hospital length-of-stay (LOS), intensive care unit (ICU) admission, ICU LOS, invasive mechanical ventilator use, invasive mechanical ventilator use duration, in-hospital mortality, and total hospital costs from hospital charge data., Results: After adjustment for patient age, gender, and race, patients with COVID-19 and overweight or obesity had longer durations for mean hospital LOS (normal BMI = 7.4 days, class 3 obesity = 9.4 days, p  < .0001) and ICU LOS (normal BMI = 6.1 days, class 3 obesity = 9.5 days, p  < .0001) than patients with normal weight. Patients with normal BMI had fewer days on invasive mechanical ventilation compared to patients with overweight and obesity classes 1-3 (6.7 days vs. 7.8, 10.1, 11.5, and 12.4, respectively, p  < .0001). The predicted probability of in-hospital mortality was nearly twice that of patients with class 3 obesity compared to patients with normal BMI (15.0 vs 8.1%, p  < .0001). Mean (standard deviation) total hospital costs for a patient with class 3 obesity is estimated at $26,545 ($24,433-$28,839), 1.5 times greater than the mean for a patient with a normal BMI at $17,588 ($16,298-$18,981)., Conclusions: Increasing levels of BMI class, from overweight to obesity class 3, are significantly associated with higher levels of healthcare resource utilization and costs in adult patients hospitalized with COVID-19 in the US. Effective treatment of overweight and obesity are needed to reduce the burden of illness associated with COVID-19.

Purpose: Investigate whether obesity risk and current weight status are independently associated with physical activity (PA) and whether PA is associated with adiposity and insulin resistance (homeostatic model assessment of insulin resistance) among children with high versus low obesity risk based on in utero exposure to maternal overweight/obesity with gestational diabetes mellitus (GDM; high risk) or without GDM (overweight/obesity; high risk) or maternal normal weight without GDM (low risk)., Method: Secondary analysis of data from children born to women with overweight/obesity and GDM, overweight/obesity without GDM, or normal weight without GDM. PA was assessed with accelerometry, percentage of body fat derived from anthropometrics, and homeostatic model assessment of insulin resistance calculated from glucose and insulin., Results: Among 4- to 10-year-old children (N = 163), analyses of covariance showed that children with a current BMI ≥85th percentile had less vigorous PA than those with BMI <85th percentile, but in utero exposure was not an independent predictor of PA. In linear regression modeling, moderate to vigorous PA was inversely associated with percentage of body fat and homeostatic model assessment of insulin resistance independent of age, Tanner stage, and accelerometer wear time, with stronger associations in high-risk groups., Conclusions: Children's PA is related to current weight status but not underlying risk for obesity but may be especially important to reduce obesity and insulin resistance in high-risk children.

A known association exists between exposure to gestational diabetes mellitus (GDM) and epigenetic age acceleration (EAA) in GDM-exposed offspring compared to those without GDM exposure. This association has not been assessed previously in mothers with pregnancies complicated by GDM. A total of 137 mother-child dyads with an index pregnancy 4−10 years before study enrollment were included. Clinical data and whole blood samples were collected and quantified to obtain DNA methylation (DNAm) estimates using the Illumina MethylEPIC 850K array in mothers and offspring. DNAm age and age acceleration were evaluated using the Horvath and Hannum clocks. Multivariable linear regression models were performed to determine the association between EAA and leptin, high-density lipoprotein cholesterol (HDL-C), fasting glucose, fasting insulin, and HOMA-IR. Mothers with a GDM and non-GDM pregnancy had strong correlations between chronological age and DNAm age (r > 0.70). Offspring of GDM mothers had moderate to strong correlations, whereas offspring of non-GDM mothers had moderate correlations between chronological age and DNAm age. Association analyses revealed a significant association between EAA and fasting insulin in offspring (FDR < 0.05), while HDL-C was the only metabolic marker significantly associated with EAA in mothers (FDR < 0.05). Mothers in the GDM group had a higher predicted epigenetic age and age acceleration than mothers in the non-GDM group. The association between EAA with elevated fasting insulin in offspring and elevated HDL-C in mothers suggests possible biomarkers that can better elucidate the effects of exposure to a GDM pregnancy and future cardiometabolic outcomes.

Background: Inflammation is a key driver of atherosclerotic cardiovascular disease. C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity., Methods: STEP 1, 2, and 3 were 68-week, placebo-controlled trials of semaglutide for weight management in participants with overweight/obesity, with (STEP 2) or without (STEP 1 and 3) type 2 diabetes. Change in serum CRP from baseline to week 68 was assessed as a prespecified secondary endpoint for semaglutide 2.4 mg versus placebo (STEP 1, 2, and 3) and versus semaglutide 1.0 mg (STEP 2). Post hoc assessments included change in CRP by baseline characteristics (bodyweight, body mass index [BMI], glycaemic status, CRP concentration); change in CRP-defined cardiovascular risk category (<1 [low], 1-3 [intermediate], and >3 mg/L [high]); and correlation between change in CRP and change in bodyweight, waist circumference, fasting serum insulin (STEP 1 and 3), fasting plasma glucose, and homeostatic model assessment of insulin resistance (HOMA-IR)., Findings: The trials took place from June through November 2018 (STEP 1 and 2) and from August 2018 to April 2020 (STEP 3). In all trials, semaglutide 2.4 mg reduced CRP at week 68 versus placebo (estimated treatment difference [ETD; 95% CI] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, and -48% [-55 to -39] in STEP 3; all p < 0.05). In STEP 2, CRP reductions were greater with semaglutide 2.4 mg (-49%) than with 1.0 mg (-42%) but the difference did not reach statistical significance (ETD [95% CI] -12% [-23 to 1]; p = 0.06). Reductions in CRP occurred in parallel with bodyweight loss and were consistent regardless of baseline BMI/bodyweight/glycaemic status. More semaglutide-treated participants had reductions in CRP-defined cardiovascular risk versus those on placebo. Reductions in CRP were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, fasting serum insulin, and HOMA-IR (data not shown)., Interpretation: In people with overweight/obesity, once-weekly semaglutide 2.4 mg and 1.0 mg reduced CRP concentration irrespective of baseline BMI/bodyweight/glycaemic status compared with placebo. These data suggest a potential anti-inflammatory role of semaglutide in obesity., Funding: Novo Nordisk., Competing Interests: Dr Bhatta is an employee of Novo Nordisk A/S. Professor Davies reported receiving research funding from AstraZeneca, Boehringer Ingelheim, Janssen, 10.13039/501100004191Novo Nordisk, and Sanofi-Aventis; has acted as consultant, advisory board member, and speaker for Boehringer Ingelheim, Eli Lilly, Novo Nordisk, Sanofi-Aventis; advisory board member and speaker for AstraZeneca; advisory board member for Gilead Sciences Ltd, Janssen, and Lexicon; and speaker for Napp Pharmaceuticals and Takeda Pharmaceuticals International Inc. She is co-funded by the NIHR Leicester Biomedical Research Centre. Dr. Deanfield reports personal fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, Bayer, grants from BHF, MRC(UK), NIHR, Public Health England, MSD, Pfizer, Cancer Research UK, Alzheimer’s Research UK, other from Novo Nordisk, outside the submitted work. Dr. Garvey reports grants from 10.13039/501100004191Novo Nordisk, during the conduct of the study; grants from Novo Nordisk, grants from Eli Lilly, grants from Epitomee, grants from Pfizer, personal fees from Boehringer Ingelheim, personal fees from Novo Nordisk, personal fees from Fractyl Health, personal fees from Alnylam Pharmaceuticals, personal fees from Merck, personal fees from Eli Lilly, outside the submitted work. Camilla Jensen is an employee of Novo Nordisk A/S. Dr Kandler is an employee of Novo Nordisk A/S. Dr. Kosiborod reports grants, personal fees and other from AstraZeneca, personal fees from Alnylam, personal fees from Amgen, personal fees from Applied Therapeutics, personal fees from Bayer, grants and personal fees from Boehringer Ingelheim, personal fees from Cytokinetics, personal fees from Eli Lilly, personal fees from Esperion Therapeutics, personal fees from Janssen, personal fees from Lexicon, personal fees from Merck (Diabetes and Cardiovascular), personal fees from Novo Nordisk, personal fees from Pharmacosmos, personal fees from Sanofi, personal fees from Vifor Pharma, outside the submitted work. Dr. Kushner reports personal fees from Novo Nordisk, personal fees from Eli Lilly, outside the submitted work. Dr. Rubino reports other from Novo Nordisk, during the conduct of the study; personal fees and other from Novo Nordisk, personal fees and other from Boehringer Ingelheim, personal fees from Endocrine Society, PeerView, WebMD, outside the submitted work. Dr. Verma reports grants and personal fees from Amarin, grants and personal fees from Amgen, grants and personal fees from Bayer, grants and personal fees from Boehringer Ingelheim, personal fees from Canadian Medical and Surgical Knowledge Translation Research Group, grants and personal fees from Eli Lilly, personal fees from EOCI, grants and personal fees from HLS Therapeutics, personal fees from Janssen, personal fees from Novartis, grants and personal fees from Novo Nordisk, personal fees from Otsuka, grants and personal fees from Pfizer, grants and personal fees from PhaseBio, personal fees from Sanofi, personal fees from Sun Pharma, personal fees from TKTWG, outside the submitted work., (© 2022 The Authors.)

BACKGROUND: Obesity prevalence exceeds 40% in the US adult population, posing a substantial burden on the health care system. Antiobesity medication (AOM) is recommended for obesity management. However, little evidence exists estimating the economic impact of AOMs on health care costs over time. OBJECTIVE: To estimate the impact of AOMs indicated for long-term therapy on shortterm direct medical costs, by obesity class, in a commercially insured population. METHODS: For this retrospective cohort study, we used the IBM MarketScan Commercial Claims and Encounters Database to capture health care utilization between January 1, 2015, and December 31, 2019. Adults aged 18-63 years with a body mass index greater than or equal to 30 kg/m2 were categorized into 2 cohorts based on new AOM usage at cohort entry. New AOM users were taking 1 of 4 AOMs currently approved by the US Food and Drug Administration for long-term therapy, with greater than 112 days supply of medicine within 12 months after treatment initiation. AOM nonusers were those not taking an AOM indicated for long-term therapy during the baseline or follow-up period. We used difference-in-differences estimation to calculate the change in average annual total health care costs and cost of medications (excluding AOMs) over a 2-year follow-up period using inverse probability of treatment-weighted estimates. RESULTS: The study population included 219,971 patients, 1,405 AOM users and 218,566 AOM nonusers. Over 2 years, patients on treatment were more than twice as likely to be classified into a lower obesity class than AOM nonusers. Although the average yearly direct cost of care increased for both treatment groups in the first year of follow-up, by year 2, costs for untreated patients continued to rise while costs for patients on therapy remained stable or declined. The difference-in-differences of medication cost (excluding AOMs) and total health care cost (excluding AOMs) across all 3 obesity classes in year 2 ranged from $1,321 to $1,952 and $1,323 to $2,766, respectively, indicating a cost savings. Total cost of care, inclusive of AOMs, followed a similar trend. CONCLUSIONS: Use of AOMs is associated with the odds of moving to a lower obesity class and a general stabilization or reduction in health care costs in year 2 of follow-up. When considering change in health care costs over time, use of AOMs may be an effective strategy to mitigate the rising health care costs associated with obesity. DISCLOSURES: Dr Toliver is an employee of Novo Nordisk, Inc. Dr Watkins, Dr Kim, and Ms Whitmire were employees of Novo Nordisk at the time the study was conducted. Dr Garvey has served as a volunteer consultant on advisory committees for Jazz Pharmaceuticals, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, and Pfizer; in each instance, he received no financial compensation, nor was there a financial relationship. He also has served as site principal investigator for clinical trials sponsored by his university and funded by Eli Lilly, Novo Nordisk, Epitomee, and Pfizer. Novo Nordisk funded the study and had a role in the study design, data collection, analysis, and interpretation of data, as well as writing support of the manuscript.

The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg (n = 152) or placebo (n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m -2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was -15.2% in the semaglutide group (n = 152) versus -2.6% with placebo (n = 152), for an estimated treatment difference of -12.6 %-points (95% confidence interval, -15.3 to -9.8; P < 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P < 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430., (© 2022. The Author(s).)

Objective: The objective of this clinical practice guideline is to provide updated and new evidence-based recommendations for the comprehensive care of persons with diabetes mellitus to clinicians, diabetes-care teams, other health care professionals and stakeholders, and individuals with diabetes and their caregivers., Methods: The American Association of Clinical Endocrinology selected a task force of medical experts and staff who updated and assessed clinical questions and recommendations from the prior 2015 version of this guideline and conducted literature searches for relevant scientific papers published from January 1, 2015, through May 15, 2022. Selected studies from results of literature searches composed the evidence base to update 2015 recommendations as well as to develop new recommendations based on review of clinical evidence, current practice, expertise, and consensus, according to established American Association of Clinical Endocrinology protocol for guideline development., Results: This guideline includes 170 updated and new evidence-based clinical practice recommendations for the comprehensive care of persons with diabetes. Recommendations are divided into four sections: (1) screening, diagnosis, glycemic targets, and glycemic monitoring; (2) comorbidities and complications, including obesity and management with lifestyle, nutrition, and bariatric surgery, hypertension, dyslipidemia, retinopathy, neuropathy, diabetic kidney disease, and cardiovascular disease; (3) management of prediabetes, type 2 diabetes with antihyperglycemic pharmacotherapy and glycemic targets, type 1 diabetes with insulin therapy, hypoglycemia, hospitalized persons, and women with diabetes in pregnancy; (4) education and new topics regarding diabetes and infertility, nutritional supplements, secondary diabetes, social determinants of health, and virtual care, as well as updated recommendations on cancer risk, nonpharmacologic components of pediatric care plans, depression, education and team approach, occupational risk, role of sleep medicine, and vaccinations in persons with diabetes., Conclusions: This updated clinical practice guideline provides evidence-based recommendations to assist with person-centered, team-based clinical decision-making to improve the care of persons with diabetes mellitus., (Copyright © 2022 AACE. Published by Elsevier Inc. All rights reserved.)

The obesity epidemic has been linked to the worsening diabetes epidemic. Despite this, weight reduction for individuals with obesity is seen as a secondary, or even tertiary, consideration in the treatment of type 2 diabetes (T2D). The aim of this review is to examine the benefits of weight management in individuals with T2D. A literature review of current available published data on the benefits of weight reduction in individuals with T2D was conducted. In individuals with T2D who have obesity or overweight, modest and sustained weight reduction results in improvement in glycaemic control and decreased utilization of glucose-lowering medication. A total body weight loss of 5% or higher reduces HbA1c levels and contributes to mitigating risk factors of cardiovascular disease, such as hyperlipidaemia and hypertension, as well as other disease-related complications of obesity. Progressive improvements in glycaemic control and cardiometabolic risk factors can occur when the total body weight loss increases to 10% or more. In the approach to treating patients with T2D and obesity, prioritizing weight management and the use of therapeutics that offer glycaemic control as well as the additional weight loss should be emphasized given their potential to attenuate the progression and severity of T2D., (© 2022 Eli Lilly and Company. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: Including race as a biological construct in risk prediction models may guide clinical decisions in ways that cause harm and widen racial disparities. This study reports on using race versus social determinants of health (SDoH) in predicting the associations between cardiometabolic disease severity (assessed using cardiometabolic disease staging) and COVID-19 hospitalization., Methods: Electronic medical record data on patients with a positive COVID-19 polymerase chain reaction test in 2020 and a previous encounter in the electronic medical record where cardiometabolic disease staging clinical data (BMI, blood glucose, blood pressure, high-density lipoprotein cholesterol, and triglycerides) were available from 2017 to 2020, were analyzed in 2021. Associations between cardiometabolic disease staging and COVID-19 hospitalization adding race and SDoH (individual and neighborhood level [e.g., Social Vulnerability Index]) in different models were examined. Area under the curve was used to assess predictive performance., Results: A total of 2,745 patients were included (mean age of 58 years, 59% female, 47% Black). In the cardiometabolic disease staging model, area under the curve was 0.767 vs 0.777 when race was included. Adding SDoH to the cardiometabolic model improved the area under the curve to 0.809 (p<0.001), whereas the addition of SDoH and race increased the area under the curve to 0.811. In race-stratified models, the area under the curve for non-Hispanic Blacks was 0.781, whereas the model for non-Hispanic Whites performed better with an area under the curve of 0.821., Conclusions: Cardiometabolic disease staging was predictive of hospitalization after a positive COVID-19 test. Adding race did not markedly increase the predictive ability; however, adding SDoH to the model improved the area under the curve to ≥0.80. Future research should include SDoH with biological variables in prediction modeling to capture social experience of race., (Copyright © 2022 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: This study aimed to determine the ability of retrospective cardiometabolic disease staging (CMDS) and social determinants of health (SDoH) to predict COVID-19 outcomes., Methods: Individual and neighborhood SDoH and CMDS clinical parameters (BMI, glucose, blood pressure, high-density lipoprotein, triglycerides), collected up to 3 years prior to a positive COVID-19 test, were extracted from the electronic medical record. Bayesian logistic regression was used to model CMDS and SDoH to predict subsequent hospitalization, intensive care unit (ICU) admission, and mortality, and whether adding SDoH to the CMDS model improved prediction was investigated. Models were cross validated, and areas under the curve (AUC) were compared., Results: A total of 2,873 patients were identified (mean age: 58 years [SD 13.2], 59% were female, 45% were Black). CMDS, insurance status, male sex, and higher glucose values were associated with increased odds of all outcomes; area-level social vulnerability was associated with increased odds of hospitalization (odds ratio: 1.84, 95% CI: 1.38-2.45) and ICU admission (odds ratio 1.98, 95% CI: 1.45-2.85). The AUCs improved when SDoH were added to CMDS (p < 0.001): hospitalization (AUC 0.78 vs. 0.82), ICU admission (AUC 0.77 vs. 0.81), and mortality (AUC 0.77 vs. 0.83)., Conclusions: Retrospective clinical markers of cardiometabolic disease and SDoH were independently predictive of COVID-19 outcomes in the population., (© 2022 The Obesity Society.)

Background: Epidemiologic observations suggest increased potato consumption correlates with weight gain, adiposity, and diabetes risk, whereas nut consumption is associated with weight control and metabolic health. Randomized controlled trial (RCT) data indicate humans respond to changes in energy intake in single dietary components and compensate for extra energy consumed., Objectives: We completed an RCT testing whether increased daily potato consumption influences energy balance [specifically, fat mass (FM)] compared with calorie-matched almond consumption., Methods: A 30-d RCT of 180 adults prescribed calorie-matched (300 kcal/d, n = 60 participants/group) than consumed 1 of the following: 1) almonds (almond group), 2) French fries (potato group), or 3) French fries with herb/spices mix (potato + herb/spices group). Baseline and 30-d FM were measured by DXA (primary outcome), with secondary outcomes including body weight and carbohydrate metabolism markers [glycated hemoglobin (HbA1c), fasting blood glucose and insulin, HOMA-IR)]. A subset of 5 participants/group participated in a postprandial meal-based tolerance test., Results: A total of 180 participants were randomly assigned [gender: 67.8% female; mean ± SD age: 30.4 ± 8.7 y; BMI (in kg/m2): 26.1 ± 4.2; and weight: 75.6 ± 15.4 kg], with 12 dropouts and 3 terminations. No significantly different FM changes were observed between almond and potato consumption [combined ± herb/spices; mean ± SE almond: 230.87 ± 114.01 g; potato: 123.73 ± 86.09 g; P = 0.443], fasting glucose (P = 0.985), insulin (P = 0.082), HOMA-IR (P = 0.080), or HbA1c (P = 0.269). Body weight change was not significantly different in the potato groups combined compared with the almond group (P = 0.116), but was significantly different among the 3 groups (P = 0.014; almond: 0.49 ± 0.20 kg; potato: -0.24 ± 0.20 kg; potato + herb/spices: 0.47 ± 0.21 kg). In meal tests, significantly lower post-prandial glucose and insulin responses to almonds compared with potatoes were observed (P = 0.046, P = 0.006, respectively), with potato + herb/spices having intermediate effects., Conclusion: There were no significant differences in FM or in glucoregulatory biomarkers after 30 d of potato consumption compared with almonds. Results do not support a causal relation between increased French fried potato consumption and the negative health outcomes studied. This trial was registered at clinicaltrials.gov as NCT03518515., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.)

In treating obesity as a chronic disease, the essential goal of weight loss therapy is not the quantity of weight loss as an end unto itself but rather the prevention and treatment of complications to enhance health and mitigate morbidity and mortality. This perspective on obesity care is consistent with the complications-centric American Association of Clinical Endocrinology (AACE) obesity guidelines and the diagnostic term of adiposity-based chronic disease (ABCD). Many complications require 10% to 20% weight loss to achieve therapeutic goals; however, existing obesity medications fail to produce ≥10% weight loss in the majority of patients. In June, 2021, semaglutide 2.4 mg/week was approved for chronic weight management. Phase 3 clinical trials demonstrated that this medication produced > 10% placebo-subtracted weight loss, more than half of patents lost ≥15%, and over one third lost ≥20% of baseline weight. This essentially doubles effectiveness over existing obesity medications, provides sufficient weight loss to ameliorate a broad range of complications, and qualifies as the first member of a second-generation class of obesity medications. The advent of second-generation medications fully enables a treat-to-target approach for management of ABCD as a chronic disease. Specifically, with this degree of efficacy, second-generation medications permit active management of body weight as a biomarker to targets associated with effective treatment and prevention of specific complications. ABCD can now be managed similar to other chronic diseases such as type 2 diabetes, hypertension, and atherosclerosis, which are treated to biomarker targets that can be modified based on the clinical status of individual patients [ie, hemoglobin A1c (HbA1c), blood pressure, and low-density lipoprotein cholesterol (LDL-c)] to prevent the respective complications of these diseases., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society.)

Objective: Obesity in pregnancy and gestational diabetes (GDM) increase cardiometabolic disease risk but are difficult to disentangle. This study aimed to test the hypothesis that 4-10 years after a pregnancy complicated by overweight/obesity and GDM (OB-GDM), women and children would have greater adiposity and poorer cardiometabolic health than those with overweight/obesity (OB) or normal weight (NW) and no GDM during the index pregnancy., Methods: In this cross-sectional study, mother-child dyads were stratified into three groups based on maternal health status during pregnancy (OB-GDM = 67; OB = 76; NW = 76). Weight, height, waist and hip circumferences, and blood pressure were measured, along with fasting glucose, insulin, HbA1c, lipids, adipokines, and cytokines., Results: Women in the OB and OB-GDM groups had greater current adiposity and poorer cardiometabolic health outcomes than those in the NW group ( p  < 0.05). After adjusting for current adiposity, women in the OB-GDM group had higher HbA1c, glucose, HOMA-IR and triglycerides than NW and OB groups ( p  < 0.05). Among children, adiposity was greater in the OB-GDM versus NW group ( p  < 0.05), but other indices of cardiometabolic health did not differ., Conclusions: Poor cardiometabolic health in women with prior GDM is independent of current adiposity. Although greater adiposity among children exposed to GDM is evident at 4-10 years, differences in cardiometabolic health may not emerge until later., Competing Interests: Stella Aslibekyan discloses employment and equity in 23andMe, Inc. She was involved in the design and initiation of this project prior to leaving UAB to join 23andMe, Inc. The other authors and the institution have received grants supporting their work on this project, as described in “Funding”. Additional grants and contracts and participation on advisory boards during the last 36 months for work unrelated to this project have been disclosed in the combined COI. All authors report no financial conflicts of interest pertaining to work on this project., (© 2022 The Authors. Obesity Science & Practice published by World Obesity and The Obesity Society and John Wiley & Sons Ltd.)

Adiposity-based chronic disease (ABCD) requires life-long treatment and follow up. Obesity protects obesity through altered regulation of caloric intake and set point mechanisms, which help maintain a high equilibrium body weight. Lifestyle interventions and obesity medications do not permanently alter the set point, which often makes weight loss achieved using lifestyle changes short-lived and operates to drive weight regain once medications are discontinued. Bariatric surgery procedures can alter appetite and lower the "set point" for the equilibrium body weight via unknown mechanisms. However, few patients attain an ideal body weight following surgery, many regain weight, and all require long-term follow up for the disease. The excess adiposity associated with ABCD gives rise to complications that impair health and confer morbidity and mortality; however, the genetic risks and potential interactions between genes and the environment that give rise to complications cannot be eliminated. The equilibrium body weight around which set point mechanisms operate can be modified by the environment, which underscores the importance of a less obesogenic environment for the prevention and treatment of ABCD on a population basis. Whether ABCD will eventually be curable will depend on a clear understanding of the molecular mechanisms that determine the set point regulation of body weight and the ability to permanently modulate the set point to oscillate around a lean body mass. However, the conceptualization of ABCD as a chronic disease does present us with opportunities for primary, secondary, and tertiary prevention to avert disease progression. For tertiary care, the advent of new, more effective second-generation obesity medications will allow clinicians to treat to target via active management of body weight into a target range that will ameliorate specific complications., (Copyright © 2021 AACE. Published by Elsevier Inc. All rights reserved.)

Importance: Phase 3 trials have not compared semaglutide and liraglutide, glucagon-like peptide-1 analogues available for weight management., Objective: To compare the efficacy and adverse event profiles of once-weekly subcutaneous semaglutide, 2.4 mg, vs once-daily subcutaneous liraglutide, 3.0 mg (both with diet and physical activity), in people with overweight or obesity., Design, Setting, and Participants: Randomized, open-label, 68-week, phase 3b trial conducted at 19 US sites from September 2019 (enrollment: September 11-November 26) to May 2021 (end of follow-up: May 11) in adults with body mass index of 30 or greater or 27 or greater with 1 or more weight-related comorbidities, without diabetes (N = 338)., Interventions: Participants were randomized (3:1:3:1) to receive once-weekly subcutaneous semaglutide, 2.4 mg (16-week escalation; n = 126), or matching placebo, or once-daily subcutaneous liraglutide, 3.0 mg (4-week escalation; n = 127), or matching placebo, plus diet and physical activity. Participants unable to tolerate 2.4 mg of semaglutide could receive 1.7 mg; participants unable to tolerate 3.0 mg of liraglutide discontinued treatment and could restart the 4-week titration. Placebo groups were pooled (n = 85)., Main Outcomes and Measures: The primary end point was percentage change in body weight, and confirmatory secondary end points were achievement of 10% or more, 15% or more, and 20% or more weight loss, assessed for semaglutide vs liraglutide at week 68. Semaglutide vs liraglutide comparisons were open-label, with active treatment groups double-blinded against matched placebo groups. Comparisons of active treatments vs pooled placebo were supportive secondary end points., Results: Of 338 randomized participants (mean [SD] age, 49 [13] years; 265 women [78.4%]; mean [SD] body weight, 104.5 [23.8] kg; mean [SD] body mass index, 37.5 [6.8]), 319 (94.4%) completed the trial, and 271 (80.2%) completed treatment. The mean weight change from baseline was -15.8% with semaglutide vs -6.4% with liraglutide (difference, -9.4 percentage points [95% CI, -12.0 to -6.8]; P < .001); weight change with pooled placebo was -1.9%. Participants had significantly greater odds of achieving 10% or more, 15% or more, and 20% or more weight loss with semaglutide vs liraglutide (70.9% of participants vs 25.6% [odds ratio, 6.3 {95% CI, 3.5 to 11.2}], 55.6% vs 12.0% [odds ratio, 7.9 {95% CI, 4.1 to 15.4}], and 38.5% vs 6.0% [odds ratio, 8.2 {95% CI, 3.5 to 19.1}], respectively; all P < .001). Proportions of participants discontinuing treatment for any reason were 13.5% with semaglutide and 27.6% with liraglutide. Gastrointestinal adverse events were reported by 84.1% with semaglutide and 82.7% with liraglutide., Conclusions and Relevance: Among adults with overweight or obesity without diabetes, once-weekly subcutaneous semaglutide compared with once-daily subcutaneous liraglutide, added to counseling for diet and physical activity, resulted in significantly greater weight loss at 68 weeks., Trial Registration: ClinicalTrials.gov Identifier: NCT04074161.

The worldwide increase in the prevalence of obesity and adiposity-related comorbidities has required a novel approach to cardiometabolic risk mitigation focused on the key mechanistic drivers of disease. The current manuscript presents the case of a 74-year-old male with obesity complicated by coronary artery disease, hypertriglyceridemia, hypertension, nonalcoholic fatty liver disease, obstructive sleep apnea, and type 2 diabetes. Expert panelists discuss optimal diagnostic and treatment strategies focused on lifestyle modifications including dietary interventions such as the Mediterranean dietary pattern, medications that target multiple drivers of disease, as well as procedural options., (© 2021 American Society for Parenteral and Enteral Nutrition.)

Objective: Insulin sensitivity is lower in African American (AA) versus Caucasian American (CA). We tested the hypothesis that lower insulin sensitivity in AA could be explained by mitochondrial respiratory rates, coupling efficiency, myofiber composition, or H 2 O 2 emission. A secondary aim was to determine whether sex affected the results., Methods: AA and CA men and women, 19-45 years, BMI 17-43 kg m 2 , were assessed for insulin sensitivity (SI Clamp ) using a euglycemic clamp at 120 mU/m 2 /min, muscle mitochondrial function using high-resolution respirometry, H 2 O 2 emission using amplex red, and % myofiber composition., Results: SI Clamp was greater in CA (p < 0.01) and women (p < 0.01). Proportion of type I myofibers was lower in AA (p < 0.01). Mitochondrial respiratory rates, coupling efficiency, and H 2 O 2 production did not differ with race. Mitochondrial function was positively associated with insulin sensitivity in women but not men. Statistical adjustment for mitochondrial function, H 2 O 2 production, or fiber composition did not eliminate the race difference in SI Clamp ., Conclusion: Neither mitochondrial respiratory rates, coupling efficiency, myofiber composition, nor mitochondrial reactive oxygen species production explained lower SI Clamp in AA compared to CA. The source of lower insulin sensitivity in AA may be due to other aspects of skeletal muscle that have yet to be identified., (© 2021 The Authors. Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Although several obesity clinical practice guidelines are available and relevant for primary care, a practical and effective medical model for treating obesity is necessary. The aim of this study was to develop and implement a holistic population health-based framework with components to support primary care-based obesity management in US health care organizations. The Obesity Care Model Collaborative (OCMC) was conducted with guidance and expertise of an advisory committee, which selected participating health care organizations based on prespecified criteria. A committee comprising obesity and quality improvement specialists and representatives from each organization developed and refined the obesity care framework for testing and implementing guideline-based practical interventions targeting obesity. These interventions were tracked over time, from an established baseline to 18 months post implementation. Ten geographically diverse organizations, treating patients with diverse demographics, insurance coverage, and health status, participated in the collaborative. The key interventions identified for managing obesity in primary care were applicable across the 4 OCMC framework domains: community, health care organization, care team, and patient/family. Care model components were developed within each domain to guide the primary care of obesity based on each organization's structure, resources, and culture. Key interventions included development of quality monitoring systems, training of leadership and staff, identifying clinical champions, patient education, electronic health record best practice alerts, and establishment of community partnerships, including the identification of external resources. This article describes the interventions developed based on the framework, with a focus on implementation of the model and lessons learned.