Anti-obesity Research Articles

Glucagon does not directly stimulate pituitary secretion of ACTH, GH or copeptin

Glucagon is best known for its contribution to glucose regulation through activation of the glucagon receptor (GCGR), primarily located in the liver. However, glucagon’s impact on other organs may also contribute to its potent effects in health and disease. Given that glucagon-based medicine is entering the arena of anti-obesity drugs, elucidating extrahepatic actions of glucagon are of increased importance. It has been reported that glucagon may stimulate secretion of arginine-vasopressin (AVP)/copeptin, growth hormone (GH) and adrenocorticotrophic hormone (ACTH) from the pituitary gland. Nevertheless, the mechanisms and whether GCGR is present in human pituitary are unknown. In this study we found that intravenous administration of 0.2 mg glucagon to 14 healthy subjects was not associated with increases in plasma concentrations of copeptin, GH, ACTH or cortisol over a 120-min period. GCGR immunoreactivity was present in the anterior pituitary but not in cells containing GH or ACTH. Collectively, glucagon may not directly stimulate secretion of GH, ACTH or AVP/copeptin in humans but may instead be involved in yet unidentified pituitary functions.

Systemic Co-Administration of Low-Dose Oxytocin and Glucagon-Like Peptide 1 Additively Decreases Food Intake and Body Weight

Introduction: GLP-1 receptor agonists are the number one drug prescribed for the treatment of obesity and type 2 diabetes. These drugs are not, however, without side effects, and in an effort to maximize therapeutic effect while minimizing adverse effects, gut hormone co-agonists received considerable attention as new drug targets in the fight against obesity. Numerous previous reports identified the neuropeptide oxytocin (OXT) as a promising anti-obesity drug. The aims of this study were to evaluate OXT as a possible co-agonist for GLP-1 and examine the effects of its co-administration on food intake (FI) and body weight (BW) in mice. Methods: FI and c-Fos levels were measured in the feeding centers of the brain in response to an intraperitoneal injection of saline, OXT, GLP-1, or OXT/GLP-1. The action potential frequency and cytosolic Ca2+ ([Ca2+]i) in response to OXT, GLP-1, or OXT/GLP-1 were measured in ex vivo paraventricular nucleus (PVN) neuronal cultures. Finally, FI and BW changes were compared in diet-induced obese mice treated with saline, OXT, GLP-1, or OXT/GLP-1 for 13 days. Results: Single injection of OXT/GLP-1 additively decreased FI and increased c-Fos expression specifically in the PVN and supraoptic nucleus. Seventy percent of GLP-1 receptor-positive neurons in the PVN also expressed OXT receptors, and OXT/GLP-1 co-administration dramatically increased firing and [Ca2+]i in the PVN OXT neurons. The chronic OXT/GLP-1 co-administration decreased BW without changing FI. Conclusion: Chronic OXT/GLP-1 co-administration decreases BW, possibly via the activation of PVN OXT neurons. OXT might be a promising candidate as an incretin co-agonist in obesity treatment.

Drawing attention to previous studies can reduce confidence in a new research finding, even when confidence should increase.

People often learn of new scientific findings from brief news reports, and may discount or ignore prior research, potentially contributing to misunderstanding of findings. In this preregistered study, we investigated how people interpret a brief news report on a new drug for weight loss. Participants read an article that either highlighted the importance of prior research when judging the drug's effectiveness, or made no mention of this issue. For articles describing no prior research, mean confidence in the drug was 62%. For articles that noted prior research was conducted, confidence increased as the proportion of studies with positive findings increased. When prior research was highlighted, confidence decreased by a small amount, even when it should have increased (i.e., even when most of the evidence supported the drug's effectiveness). Thus, people's judgements were more sceptical, but not necessarily more accurate. Judgements were not affected by education level, statistics experience, or personal relevance of the research topic.

Irisin influences the in vitro differentiation of human mesenchymal stromal cells, promoting a tendency towardbeiging adipogenesis.

Mammals exhibit two distinct types of adipose depots: white adipose tissue (WAT)and brown adipose tissue (BAT).While WAT primarily functions as a site for energy storage, BAT serves as a thermogenic tissue that utilizes energy and glucose consumption to regulate core body temperature. Under specific stimuli such as exercise, cold exposure, and drug treatment, white adipocytes possess a remarkable ability to undergo transdifferentiation into brown-like cells known as beige adipocytes. This transformation process, known as the "browning of WAT," leads to the acquisition of new morphological and physiological characteristics by white adipocytes. We investigated the potential role of Irisin, a 12 kDa myokine that is secreted in mice and humans by skeletal muscle after physical activity, in inducing the browning process in mesenchymal stromal cells (MSCs). A subset of the MSCs possesses the remarkable capability to differentiate into different cell types such as adipocytes, osteocytes, and chondrocytes. Consequently, comprehending the effects of Irisin on MSC biology becomes a crucial factor in investigating antiobesity medications. In our study, the primary objective is to evaluate the impact of Irisin on various cell types engaged in distinct stages of the differentiation process, including stem cells, committed precursors, and preadipocytes. By analyzing the effects of Irisin on these specific cell populations, our aim is to gain a comprehensive understanding of its influence throughout the entire differentiation process, rather than solely concentrating on the final differentiated cells. This approach enables us to obtain insights into the broader effects of Irisin on the cellular dynamics and mechanisms involved in adipogenesis.

An Obesity-Centric Approach with and Without Anti-Obesity Medications Compared to the Usual-Care Approach to Management of Patients with Obesity and Type2 Diabetes in an Employer Setting: A Pragmatic Randomized Controlled Trial (EMPOWER-T2D).

This study aimed to compare weight loss and glycated hemoglobin (HbA1c)-reduction effects of two obesity-centric, weight-loss management approaches (with or without anti-obesity medication) versus usual glucose-centric care in patients with obesity and type2 diabetes. Single-center, randomized, open-label, 3-armed, parallel-group, pragmatic, noninferiority trial, July 2020 to August 2022. Adults enrolled in the Cleveland Clinic Employee Health Plan (body mass index [BMI] ≥ 30kg/m2, type2 diabetes diagnosis, HbA1c > 7.5%) were randomized to usual glucose-centric management ("Usual-Care" group) or one of two obesity-centric management strategies: participation in a weight management program plus anti-obesity medication ("WMP + AOM" group), or WMP participation without anti-obesity medication ("WMP-Only" group). Primary endpoints were changes in weight and HbA1c, baseline to month12. Due to enrollment and retention challenges, largely related to COVID-19, only 74/300 planned participants were randomized and the study was terminated early. Participants were predominantly female (59%), median (interquartile range [IQR]) age 53.5 (47, 60) years, 68% white, with baseline median (IQR) BMI and HbA1c of 37.4 (34.2, 42.7) kg/m2 and 8.8% (7.9%, 10.4%), respectively. At month12, mean (90% confidence interval [CI]) percentage weight change in the Usual-Care, WMP-Only, and WMP + AOM groups was - 4.5% (- 6.5%, - 2.5%), - 6.7% (- 8.7%, - 4.7%), and - 8.7% (- 10.7%, - 6.8%), respectively; mean (90%CI) HbA1c change was - 1.7% (- 2.1%, - 1.2%), - 2.2% (- 2.7%, - 1.8%), and - 2.2% (- 2.6%, - 1.7%), respectively. WMP + AOM was superior to Usual-Care for weight change (P = 0.02); both WMP + AOM and WMP-Only were noninferior (P ≤ 0.01) to Usual-Care for change in HbA1c. Including anti-obesity medication was associated with superior weight loss with noninferior HbA1c reductions, warranting further evaluation in larger study populations of obesity-focused approaches to type2 diabetes management. Graphical abstract available for this article. ClinicalTrials.gov NCT03799198.

Medical Weight Management Considerations in Plastic Surgery.

Obesity is one of the largest public health concerns in the US and has reached an epidemic scope over the last few decades. Plastic surgery in patients with obesity has been linked to higher complications both before and after weight loss. This article aims to discuss the evolution and current landscape of anti-obesity medications (AOMs) as they apply to the plastic surgeon. Although bariatric surgery has been effective in long-term treatment, new pharmacologic advances in GLP-1 agonists such as semaglutide have demonstrated promising effectiveness. These medications pose several unique challenges, particularly with regards to perioperative management and risk of weight regain after discontinuation. An understanding of these new pharmacologic agents is crucial for plastic surgeons as we treat those affected by obesity.

Antiobesity Drug Discovery Research: In vitro Models for Shortening the Drug Discovery Pipeline.

Obesity is a growing global health problem, leading to various chronic diseases. Despite standard treatment options, the prevalence of obesity continues to rise, emphasizing the need for new drugs. in vitro methods of drug discovery research provide a time and cost-saving platform to identify new antiobesity drugs. The review covers various aspects of obesity and drug discovery research using in vitro models. Besides discussing causes, diagnosis, prevention, and treatment, the review focuses on the advantages and limitations of in vitro studies and exhaustively covers models based on enzymes and cell lines from different animal species and humans. In contrast to conventional in vivo animal investigations, in vitro preclinical tests using enzyme- and cell line-based assays provide several advantages in development of antiobesity drugs. These methods are quick, affordable, and provide high-throughput screening. They can also yield insightful information about drug-target interactions, modes of action, and toxicity profiles. By shedding light on the factors that lead to obesity, in vitro tests can also present a chance for personalized therapy. Technology will continue to evolve, leading to the creation of more precise and trustworthy in vitro assays, which will become more and more crucial in the search for novel antiobesity medications.

The Global Shortage of Glucagon-Like Peptide-1 Receptor Agonists

The global shortage of glucagon-like peptide-1 (GLP-1) receptor agonists, which are highly sought after as treatments for type 2 diabetes and obesity, is increasing. This deficit is attributed to the unexpected increase in demand for GLP-1 receptor agonists. This has caused significant harm to patients with type 2 diabetes mellitus who are already using GLP-1 receptor agonists for blood sugar management, weight loss, or reduction of cardiovascular risk or those who are looking to start. To address this situation, doctors need to adjust medications considering the patient condition and clinical guidelines and must provide better education on lifestyle modifications such as diet and exercise. Close cooperation between regulatory agencies and manufacturers is needed to mass-produce GLP-1 receptor agonists, as are societal efforts to prevent the trend of GLP-1 receptor agonist use as diet pills.

An obesity medicine curriculum increases the obesity care self-efficacy of internal medicine residents in the primary care setting.

Primary care physicians (PCPs) report insufficient knowledge and training gaps in obesity care. Internal Medicine (IM) residency offers an opportunity to address this educational gap for future PCPs. We designed an innovative, multicomponent curriculum on obesity medicine (OM) in the primary care setting for IM residents. We then conducted a prospective, 6-month, two-arm study within two residency programs in Maryland evaluating feasibility (use, appropriateness for IM training, and satisfaction) of the curriculum as well as changes in self-efficacy within seven obesity care domains, assessed on 4-point scales (1-not at all confident to 4-very confident). One residency program received the curriculum and the other served as the control group. We recruited 35 IM residents to participate (17 intervention, 18 control). Among intervention residents, 42% used all curricular components; appropriateness and satisfaction with the curriculum were high. Compared with controls, intervention residents had statistically significant increases in five obesity care self-efficacy domains: nutrition (intervention 0.8 vs. control 0.2, p = .02), behaviour change (1.2 vs. 0.4, p < .01), weight-gain-promoting medications (0.8 vs. 0.1, p = .01), anti-obesity medications (1.2 vs. 0.5, p = .03), and bariatric surgical counselling (0.9 vs. 0.4, p = .03). There were no significant changes in physical activity or post-bariatric surgical care domains. Our OM curriculum is feasible with IM residents and increases residents' obesity care self-efficacy beyond what is achieved with usual IM training.

Liraglutide-Induced Depression with Suicidality in an Obese Adult: A Case Report

Obesity is a major health issue worldwide. Treating adults with obesity often involves lifestyle and diet changes and sometimes medication. Liraglutide is a drug that is being closely studied for treating obesity. However, the potential side effects of liraglutide, particularly its impact on mood and the development of depression, may be of concern. Given the frequent co-occurrence of obesity and depression, it is important to understand how obesity treatments like liraglutide might affect a person’s mood. A 47-year-old schoolteacher with no personal or family history of mental illness or chronic physical condition sought help for his steadily increasing weight. Despite having a sedentary job and reporting no major stress or substance use, he did not attempt to change his diet or activity level, occasionally experiencing sleep difficulties. He was overweight, with a body mass index of 42. The patient was diagnosed with adult obesity and prescribed liraglutide, diet changes, and exercise. Initially, he lost weight, but he also developed depressive symptoms, including fatigue, loss of interest, sleep disturbances, and suicidal ideation. Following cessation of liraglutide treatment, his depression symptoms got better, but his weight slightly increased. This case sheds light on the possible link between liraglutide and depression in managing obesity. It is crucial for healthcare providers to be aware of potential mental health side effects of obesity drugs like liraglutide. Although the exact reasons behind these mood changes are not fully understood, this case emphasizes the need for careful observation and decision-making in treatment. Understanding these issues can help balance the benefits and risks of liraglutide and ensure better care and treatment options for people with obesity.

Polycystic ovary syndrome and metabolic syndrome: possible ways to correct metabolic disorders

Polycystic ovary syndrome (PCOS) is a common endocrine disease in women of reproductive age. The prevalence of this pathology is approximately 15-20%. PCOS is characterized by hyperandrogenism, hirsutism, menstrual irregularities, and polycystic ovaries. More than half of patients with PCOS have a metabolic syndrome, the main component of which is visceral obesity and insulin resistance, which play an important role in the pathophysiology of PCOS. Insulin resistance is a marker of cardiometabolic risk and can lead to cardiovascular disease and carbohydrate metabolism disorders up to type 2 diabetes mellitus (DM2). Therefore, in the treatment of patients with PCOS, an important aspect is the impact on insulin sensitivity and body weight. This review focuses on various groups of drugs that can potentially have a positive effect on metabolic disorders in PCOS. Among them are metformin, drugs with an incretin effect, as well as drugs for weight loss. Given the similarity of the metabolic and pathological features of PCOS and DM2, as well as the diversity of therapeutic options, there is a potential for expanding the strategy for the treatment of metabolic disorders in PCOS, including through antidiabetic drugs, which, however, requires further study. It should be noted that surgical treatment of obesity also has a beneficial effect and contributes to the normalization of the menstrual cycle and the normalization of the hormonal and metabolic profile in patients with PCOS and severe obesity.

Tirzepatide for the treatment of obstructive sleep apnea: Rationale, design, and sample baseline characteristics of the SURMOUNT -OSA phase 3 trial

BackgroundWeight reduction is a standard recommendation for obstructive sleep apnea (OSA) treatment in people with obesity or overweight; however, weight loss can be challenging to achieve and maintain without bariatric surgery. Currently, no approved anti-obesity medication has demonstrated effectiveness in OSA management. This study is evaluating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA in people with obesity. MethodsSURMOUNT-OSA, a randomized, placebo -controlled, 52-week phase 3 trial, is investigating the efficacy and safety of tirzepatide for treatment of moderate to severe OSA (apnea hypopnea- index ≥15 events/h) in participants with obesity (body mass index ≥30 kg/m2) and an established OSA diagnosis. SURMOUNT-OSA is made of 2 intervention-specific appendices (ISAs): ISA-1 includes participants with no current OSA treatment, and ISA-2 includes participants using positive airway pressure therapy. Overall, 469 participants have been randomized 1:1 to receive tirzepatide or placebo across the master protocol (ISA-1, n = 234; ISA-2, n = 235). All participants are also receiving lifestyle intervention for weight reduction. ResultsThe primary endpoint for the individual ISAs is the difference in apnea hypopnea- index response, as measured by polysomnography, between tirzepatide and placebo arms at week 52. Secondary endpoints include sleep apnea-specific hypoxic burden, functional outcomes, and cardiometabolic biomarkers. The trial employs digital wearables, including home sleep testing to capture time to improvement and accelerometry for daily physical activity assessment, to evaluate exploratory outcomes. ConclusionSURMOUNT-OSA brings a novel design to investigate if tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting the underlying etiology.Trial registration: ClinicalTrials.gov, NCT05412004

Abstract 2189: Tirzepatide mitigates obesity-associated metabolic dysregulation and tumor progression in a mouse model of triple-negative breast cancer

Abstract Obesity is an established risk factor for breast cancer. Dietary and surgical weight loss interventions reduce breast cancer risk but have significant limitations to their widespread use as anticancer strategies. Incretin-based pharmaceuticals safely and effectively promote weight loss, but whether these drugs exert similar protective effects against cancer is unknown. Here we test whether weight loss induced by the glucagon-like peptide 1 (GLP-1)/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide limits tumor growth in an orthotopic mouse model of triple-negative breast cancer. Ten-week-old female C57BL/6NCrl mice were randomized to either a 10 kcal% low-fat diet (control; n=14) or 60 kcal% high-fat diet to promote diet-induced obesity (DIO; n=43). After 18 weeks on diet, DIO mice were randomized by body weight to either i) remain on the high-fat diet (DIO; n=15); ii) lose weight with tirzepatide (TZP; n=13); or iii) lose weight with 30% daily calorie restriction relative to control mice (CR; n=15). All mice were subcutaneously injected with either TZP or vehicle every other day for 13 weeks with the following escalating dosing schedule: 3 nmol/kg TZP in week 1; 10 nmol/kg TZP in weeks 2-3; 20 nmol/kg TZP in weeks 4-7; 30 nmol/kg TZP in weeks 8-11; and 40 nmol/kg TZP in weeks 12-13. Fasting blood glucose and body composition was assessed after 9 weeks of weight loss, and 35,000 E0771 cells were orthotopically transplanted into the 4th mammary fat pad. Tumors growth was monitored for 4 weeks. TZP-treated mice lost on average &amp;gt;20% weight loss by week 4 and remained at or below 20% weight loss for the remainder of the study. Directly prior to E0771 tumor cell injections, TZP-treated mice had lost 23.6±8.9% body weight, versus 39.7±3.6% in CR mice. Relative to DIO mice, blood glucose control was restored in both weight loss groups (DIO: 149.5±18.5 mg/dl; TZP: 124.5±15.5 mg/dl; CR: 107.6±18.8 mg/dl) and &amp;gt;87.5% of the lost weight was attributed to fat mass, rather than lean mass, for TZP-treated and CR mice. Notably, tirzepatide suppressed tumor growth relative to DIO, but the CR group had a greater anticancer effect than TZP. Reduced tumor mass in both weight loss groups was accompanied by a significant reduction in circulating IGF-1, insulin, and leptin relative to DIO mice. These findings are timely and important because i) obesity is a highly prevalent metabolic disease that increases risk and progression of breast cancer and &amp;gt;13 other cancers; ii) incretin therapies, which show promise as highly effective weight loss drugs, are increasingly being prescribed; and iii) the tumor suppressive effects of tirzepatide described herein newly suggest incretin agonism as another propitious option for breaking the obesity-cancer link. Citation Format: Elaine M. Glenny, Alyssa N. Ho, Violet A. Kiesel, Fangxin Chen, Claire E. Gates, Evan M. Paules, Ruihan Xu, C. Alex Holt, Michael F. Coleman, Stephen D. Hursting. Tirzepatide mitigates obesity-associated metabolic dysregulation and tumor progression in a mouse model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2189.

Utilization of Anti-obesity Medications After Bariatric Surgery: Analysis of a Large National Database.

A significant proportion of patients experience insufficient weight loss or weight regain after bariatric surgery. There is a paucity of literature describing anti-obesity medication (AOM) use following bariatric surgery. We sought to identify prevalence and trends of AOM use following bariatric surgery. We utilized the IBM Explorys® database to identify all adults with prior bariatric surgery (Roux-en-Y gastric bypass or sleeve gastrectomy). Those prescribed AOMs (semaglutide, liraglutide, topiramate, phentermine/topiramate, naltrexone/bupropion, orlistat) within 5 years of surgery were further identified. Data was analyzed to characterize AOM utilization among different age, demographic, and comorbid populations. A total of 59,160 adults with prior bariatric surgery were included. Among AOMs studies, prevalence of use was highest for topiramate (8%), followed by liraglutide (2.9%), phentermine/topiramate (1.03%), naltrexone/bupropion (0.95%) semaglutide (0.52%), and orlistat (0.17%). Age distribution varied, with the highest utilization among those age 35-39 years for topiramate, 40-44 years for phentermine/topiramate and naltrexone/bupropion, 45-49 years for semaglutide, and 65-69 years for liraglutide and orlistat. African American race was associated with higher utilization across all AOMs. Among comorbidities, hypertension, hyperlipidemia, and diabetes mellitus were most associated with AOM use. Despite a relatively high incidence of weight regain, AOMs are underutilized following bariatric surgery. It is imperative that barriers to their use be addressed and that AOMs be considered earlier and more frequently in patients with insufficient weight loss or weight regain after bariatric surgery.

Shortage of Weight Loss Drugs Creates Problems for Patients.

Shortage of Weight Loss Drugs Creates Problems for Patients.

Adjuvant and Neo-Adjuvant Anti-Obesity Medications and Bariatric Surgery: A Scoping Review.

To comprehensively summarize the current body of literature on the topic of adjuvant and neoadjuvant pharmacotherapy used in combination with bariatric surgery. Anti-obesity medications (AOMs) have been used since the mid-1900s; however, their use in combination with bariatric surgery is a newer area of research that is rapidly growing. Pharmacotherapy may be used before (neoadjuvant) or after (adjuvant) bariatric surgery. Recent literature suggests that adjuvant AOMs may address weight regain and inadequate weight loss following bariatric surgery. Research on neoadjuvant AOM used to optimize weight loss before bariatric surgery is more limited. A literature review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Thirty-four studies were included after screening and exclusion of irrelevant records. Included studies were as follows: seven prospective studies on adjuvant AOM use, 23 retrospective studies on adjuvant AOM use, one prospective study on adjuvant and neoadjuvant AOM use, one retrospective study on adjuvant or neoadjuvant AOM use, one prospective study on neoadjuvant AOM use, and one case series on neoadjuvant AOM use. In the following scoping review, each of these studies is discussed with the goal of presenting a complete synthesis of the current body of literature on AOM use in combination with bariatric surgery.

Abstract P349: Physical Activity Perceptions and Engagement of Patients Prescribed an Anti-Obesity Medication in a Medical Weight Loss Clinic

Introduction: Physical activity (PA) may elicit important health benefits when coupled with contemporary anti-obesity medications (AOM). However, currently there is little known about perceptions of PA and associated PA engagement of patients receiving these AOM therapies. Hypothesis: We assessed the hypothesis that PA would differ by perceptions of confidence to engage in PA, current and future importance of PA, and PA amount in patients receiving AOM treatment within the context of a medical weight loss clinic. Methods: An electronic survey was distributed to patients in a clinical research registry who were receiving treatment with an AOM at a university medical center-based weight loss clinic. The survey included questions about their perceived confidence to do structured PA or exercise regularly (PA-CONFIDENCE) and perceived importance of structured PA or exercise for management of their body weight currently (PA-IMPORTANCE) or in the future (PA-FUTURE). Participants also reported their current level of PA. Results: Survey responses were received from 96 patients. For these analyses, data were examined for patients currently prescribed a GLP-1 AOM (83 patients). High PA-CONFIDENCE was reported by 44.6% of participants, with 34.9% and 20.5% reporting moderate and low PA-CONFIDENCE, respectively. PA was 154±117 min/wk, 107±105 min/wk, and 76±77 min/wk for high, moderate, and low PA-CONFIDENCE (p=0.033). Participating in ≥150 min/wk of PA was reported by 54.1% with high, 20.7% with moderate, and 11.8% with low PA-CONFIDENCE (p=0.002). Ratings of PA-IMPORTANCE were 63.9% for high, 28.9% for moderate, and 7.2% for low. Participating in ≥150 min/wk of PA was reported by 48.2% with high, 12.5% with moderate, and 0% with low PA-IMPORTANCE (p=0.002). Ratings of PA-FUTURE were 79.5% for high, 18.1% for moderate, and 2.4% for low. Current participation in ≥150 min/wk of PA was reported by 33.7% with high, 12.5% with moderate, and 0% with low PA-FUTURE (p=0.002). Conclusions: Less than one-half of patients prescribed an AOM report confidence to engage in regular structured PA, and of those with high confidence only approximately one-half achieve current public health recommendations for PA. While more than one-half of patients report that PA is important, less than one-half engage in the recommended amount of PA. Strategies are needed to increase perceived confidence to perform and importance of PA in AOM treated patients, and to increase PA participation.

Abstract 50: Factors Associated With Obesity Pharmacotherapy Prescription Among Ambulatory Patients With Excess Weight

Background: Semaglutide, liraglutide (GLP1-RA), and tirzepatide (GLP1/GIP-RA) are potent anti-obesity pharmacotherapies resulting in marked weight loss and improved cardiometabolic outcomes. Limited insurance coverage is a well-understood barrier to these new therapies; thus, we sought to characterize additional clinical and sociodemographic factors associated with the prescription of these medications. Hypothesis: Likelihood of prescription of novel anti-obesity medications will be lower for individuals within racial and ethnic minority and lower SES subgroups. Methods: We identified adults who have obesity (BMI ≥30), existing insurance coverage for anti-obesity medications, and received outpatient care at Johns Hopkins from January 2023 to September 2023. We used multivariable logistic regression to evaluate factors associated with prescription of anti-obesity pharmacotherapies. Results: We included 18,164 patients (mean age 51 years, 64% female, 54% White, 35% Black, 5% Asian, mean BMI 36 kg/m 2 ). About 3% of eligible adults were prescribed anti-obesity medications. The likelihood of prescription was lower among Black adults (OR: 0.76, 95%CI [0.61-0.96]), males (OR: 0.54 [0.42-0.68]), and adults younger and older than 40-50 years of age; and higher for those with higher BMI (per 1-unit higher BMI, OR: 1.06 [1.05-1.07]). Living in a neighborhood with a higher area deprivation index or lower income was not independently associated with the likelihood of prescription. Clinically, those with diabetes (OR: 3.52 [2.78-4.44]) and hypertension (OR: 1.36 [1.08-1.71]) were more likely to be prescribed novel obesity pharmacotherapies. Conclusion: Among those with existing insurance coverage, the likelihood of obesity pharmacotherapy prescription differs by sociodemographic factors and cardiometabolic comorbidities. Understanding the mechanisms of these differences may have key implications for obesity management in diverse populations, and ultimately for cardiometabolic health equity.

Abstract P525: Polygenic Risk Scores for Morning Chronotype and Longer Sleep Duration Are Associated With Weight and Glycemic Outcomes in the Multi-Ethnic Study of Atherosclerosis (MESA)

Introduction: Circadian rhythms regulate key physiological processes, including sleep-wake. Alterations in the circadian rhythm have been associated with greater risk of metabolic diseases. Genome-wide association studies (GWAS) have revealed genes variants associated with sleep phenotypes. Hypothesis: Polygenic risk scores (PRS) for significant SNPs reported in GWAS of chronotype (C), sleep duration (SD), and short sleep (SS, &lt;7/h) are associated with metabolic parameters. Methods: We carried out a longitudinal analysis in 6,814 adults (aged 45-84 y at baseline) from the Multi-Ethnic Study of Atherosclerosis (MESA). Glucose, insulin, insulin resistance (HOMA-IR), body mass index (BMI) and waist circumference (WC) were assessed at baseline (2000-2002) and 16-18 y follow-up (Exam 6, N=3,303). DNA was extracted from whole blood, and genotyping data were obtained by the Affymetrix 6.0 SNP array. PRS for the following phenotypes were constructed as weight sum of genoma-wide significant alleles: 1) chronotype [PRS-C]; 2) continuous SD [PRS-SD]; and 3) SS duration [PRS-SS]. Multivariable linear regression models adjusted by sociodemographic, obesity, smoking, Mediterranean diet, physical activity and antidiabetic drugs were performed to assess associations between PRS and study outcomes (fasting glucose and insulin, HOMA-IR, hemoglobin A1c, BMI, and WC) cross-sectionally and longitudinally. Results: At baseline, none of the PRS were associated with glucose, insulin or HOMA-IR (p&gt;0.05). A significant positive association was detected for PRS-C with BMI and WC: greater genetically determined morningness was associated with lower BMI (β=-20.0±3.0; p&lt;0.001) and smaller WC (β=-44.1±8.0; p&lt;0.001). Similar results were observed with PRS-SD (BMI: β=-0.1±0.0; p=0.005; WC: β=-0.3±0.1; p=0.008) and PRS-SS (BMI: β=9.3±2.8; p&lt;0.001; WC: β=19.8±7.4; p=0.007). In longitudinal analyses, we observed prospective associations between PRS-C with BMI (β=-43.5±12.2; p&lt;0.001), WC (β=-116.0.1±29.1; p&lt;0.001), and glucose (β=-204.7±90.0; p=0.024). PRS-SS was longitudinally associated with HOMA-IR (β=214.1±88.0; p=0.017) and a trend was observed for hemoglobin A1c (β=-6.6±3.4; p=0.053), but not with anthropometrics parameters. No associations were noted for PRS-SD with obesity and glycemic outcomes in longitudinal analyses. Conclusion: In the MESA population, PRS for chronotype, sleep duration, and short sleep are associated with anthropometric but not with glycemic measures in cross-sectional analyses. However, PRS for chronotype and short sleep was associated with anthropometric and glycemic parameters in longitudinal analyses, suggesting the importance of genetic predisposition for morningness and adequate sleep duration for metabolic health.

Association of semaglutide with reduced incidence and relapse of cannabis use disorder in real-world populations: a retrospective cohort study

Cannabis is the most frequently used illicit drug in the United States with more than 45 million users of whom one-third suffer from a cannabis use disorder (CUD). Despite its high prevalence, there are currently no FDA-approved medications for CUD. Patients treated with semaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1RA) approved for treating type 2 diabetes (T2D) and for weight management have reported reduced desire to drink and smoke. Preclinical studies have shown that semaglutide decreased nicotine and alcohol consumption. Preclinical and preliminary clinical evidence of semaglutide’s potential beneficial effects on various substance use disorders led us to evaluate if it pertained to CUD. In this retrospective cohort study of electronic health records (EHRs) from the TriNetX Analytics Network, a global federated health research network of approximately 105.3 million patients from 61 large healthcare organizations in the US, we aimed to assess the associations of semaglutide with both incident and recurrent CUD diagnosis compared to non-GLP-1RA anti-obesity or anti-diabetes medications. Hazard ratio (HR) and 95% confidence intervals (CI) of incident and recurrent CUD were calculated for 12-month follow-up by comparing propensity-score matched patient cohorts. The study population included 85,223 patients with obesity who were prescribed semaglutide or non-GLP-1RA anti-obesity medications, with the findings replicated in 596,045 patients with T2D. In patients with obesity (mean age 51.3 years, 65.6% women), semaglutide compared with non-GLP-1RA anti-obesity medications was associated with lower risk for incident CUD in patients with no prior history CUD (HR: 0.56, 95% CI: 0.42–0.75), and recurrent CUD diagnosis in patients with a prior history CUD (HR: 0.62, 95% CI: 0.46–0.84). Consistent reductions were seen for patients stratified by gender, age group, race and in patients with and without T2D. Similar findings were replicated in the study population with T2D when comparing semaglutide with non-GLP-1RA anti-diabetes medications for incident CUD (HR: 0.40, 95% CI: 0.29–0.56) and recurrent CUD (HR: 0.66, 95% CI: 0.42–1.03). While these findings provide preliminary evidence of the potential benefit of semaglutide in CUD in real-world populations, further preclinical studies are warranted to understand the underlying mechanism and randomized clinical trials are needed to support its use clinically for CUD.