To evaluate shifts in waist-to-height ratio (WHtR) categories among adults with obesity or overweight, with or without prediabetes, treated with tirzepatide in the SURMOUNT-1 study. This post hoc analysis included 2,538 participants from the SURMOUNT-1 Phase 3, double-blind, randomized, placebo-controlled trial. Adults with BMI ≥ 30 or ≥ 27 kg/m² and at least one obesity-related complication (ORC), excluding diabetes, were randomized to receive once-weekly tirzepatide (5, 10, or 15 mg) or placebo, alongside a reduced-calorie diet and increased physical activity. Participants were grouped by baseline WHtR (≤ 0.49, > 0.49 to ≤ 0.59, > 0.59) according to the National Institute for Health and Care Excellence (NICE) framework. Participants with prediabetes at baseline had additional follow-up data beyond week 72, and shifts in their WHtR categories at week 176 were also included. Change from baseline in WHtR was analyzed using a mixed model for repeated measures (MMRM). Shift tables were used to summarize changes from baseline to post-baseline WHtR category levels. At baseline, 89.8

While nutrient-stimulated hormone (NuSH) therapies (e.g., glucagon-like pepide-1 receptor agonists and dual/triple agonists) have transformed the landscape of obesity pharmacotherapy, the next generation of medications may target body composition optimization or other cardiovascular benefits. This review examines novel obesity mechanisms outside of the NuSH class. Unique mechanisms for obesity treatment include peripherally restricted cannabinoid-1 receptor antagonism, myostatin/activin inhibitors, selective androgen receptor modulators, melanocortin-4 receptor agonism, mitochondrial modulation, thyroid receptor agonists, and fibroblast growth factor analogues. By targeting fat distribution, muscle preservation, inflammatory/oxidative stress pathways, lipid metabolism, and energy expenditure, these agents may improve both the magnitude and quality of weight loss. Early evidence suggests complementary roles alongside NuSH-based therapies for induction, augmentation, and maintenance strategies. Several non-NuSH agents have demonstrated potential in preclinical and early clinical studies to optimize body composition, but additional studies are required to prove large-scale, long-term safety and efficacy.

Obesity is a chronic, multifactorial disease associated with more than 200 complications including type 2 diabetes, cardiovascular disease, obstructive sleep apnea, dyslipidemia, hypertension, premature mortality, and numerous other adverse effects spanning multiple organ systems. In addition to these health complications, obesity also contributes to weight stigma and bias, which negatively affect access to care, treatment outcomes, and quality of life. Together, these complications and social consequences drive high morbidity, premature mortality, and increasing healthcare costs. Early diagnosis of obesity and systematic screening for related conditions are essential to improving health outcomes. Clinicians must treat obesity in addition to managing its complications, offering individualized strategies that may include lifestyle modification, pharmacotherapy, and bariatric surgery. Because obesity is a chronic and relapsing disease, effective management requires long-term follow-up and coordinated care through a multidisciplinary team. The effective treatment of obesity and its comorbidities can improve individual health outcomes, reduce healthcare costs, and reduce the global burden of chronic disease.

BACKGROUND:The burden of obesity-related health conditions remains incompletely explored. Previous studies have been underpowered to study severe obesity, focused on a limited set of health outcomes, and lacked diversity in study populations. METHODS:We studied 270,657 participants from the All of Us research program with linked electronic health records and body mass index (the weight in kilograms divided by the square of the height in meters) greater than or equal to 18.5. We investigated the prevalence and incidence of 16 a priori-identified outcomes covering cardiovascular-kidney-metabolic syndrome and others: hypertension, type 2 diabetes mellitus, hyperlipidemia/dyslipidemia, heart failure, atrial fibrillation, atherosclerotic cardiovascular disease, chronic kidney disease, pulmonary embolism, deep vein thrombosis, gout, metabolic dysfunction-associated steatotic liver disease, biliary calculus, obstructive sleep apnea, asthma, gastroesophageal reflux disease, and osteoarthritis. Adjusted hazard ratios were calculated for each BMI category and compared with normal weight. The population-attributable fraction was calculated for different obesity classifications. RESULTS:The included population was 62.0% women and 22.0% Black. Class I, II, and III obesity was observed in 21.2%, 11.3%, and 9.8% of participants, respectively. Obesity was strongly associated with all incident outcomes, with graded associations across higher classes of obesity. Class III obesity was most strongly associated with obstructive sleep apnea, type 2 diabetes mellitus, and metabolic dysfunction-associated steatotic liver disease (hazard ratio [95% confidence interval {CI}], 10.94 [9.97 to 12.00], 7.74 [7.03 to 8.53], and 6.72 [6.01 to 7.50], respectively), with weaker associations for asthma, osteoarthritis, and atherosclerotic cardiovascular disease (hazard ratio [95% CI], 2.14 [1.95 to 2.35], 2.06 [1.94 to 2.19], and 1.96 [1.70 to 2.25], respectively). Associations were consistent across sex and race. The obesity-related population-attributed fraction ranged from 14.0% (osteoarthritis) to 51.5% (obstructive sleep apnea) in this population. CONCLUSIONS:Obesity, particularly severe obesity, was strongly associated with the incidence of 16 common health outcomes.

OBJECTIVE:Increases in adiposity and adverse changes in adipose distribution commonly occur in women during midlife and with the onset of menopause. This post hoc analysis assessed body weight changes with tirzepatide by reproductive stage. METHODS:Women participants from SURMOUNT-1, -3, and -4 randomized to tirzepatide (15 mg or maximum tolerated dose) or placebo were retrospectively categorized as being in the pre-, peri-, or post-menopause stages. Body weight and waist circumference changes, the proportion of participants achieving body weight-reduction thresholds, and waist to height ratio (WHtR) category shift among those with baseline BMI < 35 kg/m2 were assessed at end of study treatment. RESULTS:In SURMOUNT-1, significantly greater body weight reductions from baseline were observed with tirzepatide versus placebo in women in the premenopause (26% vs. 2%), perimenopause (23% vs. 3%), and postmenopause stages (23% vs. 3%; p < 0.001). Greater waist circumference reductions were also observed with tirzepatide across the subgroups (22 vs. 4 cm, 20 vs. 5 cm, and 20 vs. 4 cm, respectively; p < 0.001). Across the reproductive stage subgroups, 97% to 98% of participants achieved body weight reductions that were ≥5% with tirzepatide versus 29% to 33% with placebo. Furthermore, 30% to 52% of women among the reproductive stage subgroups who had baseline BMI < 35 kg/m2 reached WHtR ≤ 0.49 (low central adiposity) with tirzepatide. Similar results were observed in SURMOUNT-3 and -4. CONCLUSIONS:In this post hoc analysis, tirzepatide treatment was associated with significant body weight, waist circumference, and WHtR reductions versus placebo in women living with obesity or overweight and without type 2 diabetes, irrespective of reproductive stage.

BACKGROUND:Population-level adverse effects of obesity beyond commonly considered chronic conditions need to be characterized to understand its overall burden. OBJECTIVE:To assess the cross-sectional associations between obesity and self-reported status of overall health, quality of life, pain, fatigue, ability of physical activity, and the risks of developing chronic pain syndrome, chronic fatigue syndrome, fibromyalgia, and insomnia. METHODS:Using data from the All of Us Research Program (the United States), we included participants with a body mass index (BMI) ≥18.5 kg/m2 and available Overall Health Survey or electronic health records. Cross-sectional analyses of self-reported variables were conducted using multivariable logistic and linear regression models. Cox proportional-hazard models were used to assess risks for incident outcomes. RESULTS:Among 323,640 participants (60.3% were female, mean age: 51.3 years), 20.7%, 11.0%, and 9.5% were with Classes I, II, and III obesity, respectively. Higher BMI categories were correlated with worse health metrics, with Class III obesity exhibiting the greatest disparities. Among those with Class III obesity, 9.6% (vs. 3.2% for normal weight) reported poor overall health, 28.3% (vs. 13.2%) reported severe pain, and 11.8% (vs. 8.4%) had prevalent insomnia. Graded associations were observed across high BMI categories, with Class III obesity showing the strongest effects. Compared with normal weight, in Class III obesity, the odds ratio (95% CI) was 3.82 (3.69-3.96) for fair/poor overall health, 3.93 (3.71-4.17) for severe pain, and 3.13 (2.98-3.29) for severely limited physical activity; the hazard ratio (95% CI) was 2.83 (2.36-3.40) for fibromyalgia and 1.53 (1.41-1.65) for insomnia. CONCLUSION:Obesity imposes a substantial burden on broad aspects of well-being in the US population.

This Viewpoint introduces and provides a definition for the term primordial care and discusses how it relates to primary care use in the US.

ObjectiveThe objective of this study was to assess antihypertensive and lipid-lowering treatment changes in participants receiving semaglutide 2.4 mg versus placebo across pooled populations from five Semaglutide Treatment Effect in People with Obesity (STEP) trials.MethodsEfficacy and safety of semaglutide 2.4 mg were evaluated in the STEP clinical trials. In this post hoc analysis, STEP 1, 3, 6, and 8 (which included people with overweight or obesity) and, separately, STEP 2 and 6 (which included people with overweight or obesity and type 2 diabetes) were pooled for analysis. Changes in antihypertensive or lipid-lowering treatment intensity from randomization to end of treatment were evaluated.ResultsIn both pooled samples, a higher proportion of participants in the semaglutide 2.4 mg group versus placebo underwent antihypertensive or lipid-lowering treatment intensity reduction by end of treatment. A smaller proportion underwent antihypertensive or lipid-lowering treatment intensification by end of treatment in the semaglutide 2.4 mg group of both samples versus placebo. In participants receiving antihypertensive or lipid-lowering medications in both samples, greater numeric reductions in body weight were observed in the semaglutide 2.4 mg group versus placebo.ConclusionsThese results support a relationship between semaglutide 2.4 mg treatment of overweight and obesity and reduced need for antihypertensive and lipid-lowering treatment, facilitating treatment intensity reduction/discontinuation and abating treatment intensification. imageConclusionsThese results support a relationship between semaglutide 2.4 mg treatment of overweight and obesity and reduced need for antihypertensive and lipid-lowering treatment, facilitating treatment intensity reduction/discontinuation and abating treatment intensification. image

PurposeRising obesity and type 2 diabetes mellitus (T2DM) rates can be mitigated by various strategies, with a 10% total body weight loss (TBWL) threshold often required for T2DM remission. T2DM remission rates after bariatric surgery like Roux-en-Y gastric bypass (RYGB) are well established; endoscopic sleeve gastroplasty (ESG) is a less invasive option that averages 15% TBWL and allows for T2DM remission. This study explores the DiaRem (Diabetes Remission post-RYGB) score's ability to predict T2DM remission 1-year post-ESG.Materials and MethodsWe conducted a retrospective cohort study on 39 individuals with T2DM who underwent ESG. Age, utilization of diabetes medications, insulin administration, and hemoglobin A1c levels were used to calculate the DiaRem score. The area under the receiver operating characteristic curve (AUC) was employed to evaluate the discriminative ability of DiaRem in distinguishing diabetes remission.ResultsAmong the 39 patients with a median hemoglobin A1c of 6.7, 12.8% required insulin, and 43.6% used diabetes medication. At 1-year post-ESG, 69.2% of patients experienced diabetes remission with a median %TWBL of 12.7. The DiaRem score's ability to detect diabetes resolution for ESG patients had a sensitivity of 100% and a specificity of 58.3%, at the optimal cutoff value of 10. The AUC was 0.779 (95% CI 0.546-0.959).ConclusionOur study demonstrated the DiaRem score's predictive value for T2DM remission post-ESG, highlighting its utility in clinical decision-making for ESG-related outcomes. Further investigation is needed to identify alternative indicators that may enhance predictive accuracy, thus refining personalized decision-making for this patient group.

Osteoporosis is a metabolic bone disorder for which treatment options include antiresorptive therapies (e.g., bisphosphonates, denosumab); anabolics (e.g., teriparatide, abaloparatide); and dual mechanisms (e.g., romosozumab). Management of osteoporosis with concurrent antiresorptive and anabolic agents may be superior to monotherapy, as demonstrated in the DATA trial with the combination of denosumab and teriparatide. However, there is limited experience with the combination of denosumab and romosozumab, which may be an alternative antiresorptive/anabolic regimen for individuals who are not candidates for PTH receptor agonists. In this case, we present a young man with glucocorticoid-induced osteoporosis who could not tolerate a daily injectable anabolic and who experienced improvement in bone mineral density with concurrent denosumab and off-label romosozumab administration.

Waist-to-height ratio (WHtR) is a practical estimate of central adiposity and can be a better predictor of cardiometabolic disease than body mass index (BMI). Tirzepatide (TZP) is a once weekly GIP/GLP-1 receptor agonist approved in the US for treatment of type 2 diabetes and obesity. The objectives of this post hoc analyses of SURMOUNT-1 (SM-1) and SURMOUNT-2 (SM-2) were to assess change from baseline (BL) to Week 72 in WHtR and to assess shift from BL to Week 72 in WHtR risk categories as defined by recent NICE guidelines for individuals with BMI < 35 kg/m2: "healthy" (WHtR ≤0.49), "increased" (WHtR >0.49 to ≤0.59), and "high" (WHtR >0.59).

Background:Obesity in pediatric patients is strongly associated with increased vascular and metabolic risk. Prediabetes is present in up to 1 in 5 adolescents, aged 12-18 years-old, though is thought to remit spontaneously in a significant portion. Pediatric patients with type 2 diabetes mellitus (T2D) have a more rapid decline of beta-cell function and progression to treatment failure than adult T2D patients. Thus, there is a strong interest in better understanding the natural history of prediabetes in these youth. We aimed to evaluate the real-world rate of progression of prediabetes to T2D in adolescent patients. Methods:This is a retrospective study of 9,275 adolescent subjects aged 12-21 years-old with at least 3 years of de-identified commercial claims data and a new diagnosis of prediabetes during the observation period. Enrollees with a T2D diagnosis and/or diabetes medication use in the 1 year prior to prediabetes diagnosis or a T2D diagnosis in the 1 month following prediabetes diagnosis were excluded. Enrollees with diagnoses of type 1 diabetes (T1D) or polycystic ovarian syndrome over the 3 years were also excluded. Progression to T2D was defined by claims data of two T2D diagnoses at least 7 days apart, HbA1c ≥ 6.5%, and/or prescription of insulin without known T1D. Enrollees were followed for 2 years after prediabetes diagnosis. Results:Overall, 232 subjects (2.5%) progressed from prediabetes to T2D. There were no differences found in T2D progression based on sex or age. Progression to T2D occurred at a median of 302 days after prediabetes diagnosis (IQR 123 to 518 days). This study was limited by the lack of laboratory/anthropometric data in administrative claims, as well as the exclusion of 23,825 enrollees for lack of continuous commercial claims data over 3 years. Conclusion:In the largest sample to date on adolescent prediabetes, we found a 2.5% progression of prediabetes to T2D over a median duration of about one year.

The aim of this article is to review the current pharmacologic treatment options available for the treatment of obesity. The efficacy of each medication and its effect on cardiometabolic profile is highlighted. The use of off-label medications is discussed, along with medications currently under development. Achieving and maintaining long-term clinically significant weight loss is likely to require the use of two or more anti-obesity medications. While the current evidence for combination therapies is limited, polypharmacotherapy is an area of active research, and emerging therapies are anticipated to be multi-target agents. Promising medications in the pipeline include dual GLP-1/GIP receptor agonists, combination GLP-1 receptor agonists and amylin analogues, dual GLP-1/glucagon receptor agonists, and tripeptides. This review aims to summarize the current pharmacologic treatment options available for the treatment of obesity. Medication regimens should be individualized to the patient to optimize benefits versus risks. Consider combinations of anti-obesity medications with different mechanisms to overcome the biological compensatory mechanisms that drive weight regain. Off-label prescribing may be necessary to overcome barriers to care and should be informed by current evidence.