Highway to the danger zone? A cautionary account that GLP-1 receptor agonists may be too effective for unmonitored weight loss.

Glucagon-like peptide 1 (GLP-1) receptor agonists are revolutionizing obesity and type 2 diabetes treatment, delivering remarkable weight loss outcomes. These medications, leveraging the effects of the insulin-regulating hormone GLP-1 via actions on peripheral and central nervous system targets, have raised hopes with their bariatric surgery-rivaling results. However, questions remain about their long-term safety and efficacy. Drawing from our expertise in obesity medicine and psychiatry, we reflect upon our experiences with the clinical use of these medications and delve into the nuanced challenges and risks they pose, particularly for those prone to disordered eating or those diagnosed with rare genetic diseases of obesity. We contend that effectively managing weight loss within this "danger zone" necessitates (1) proactive screening and continuous monitoring for disordered eating, (2) vigilant monitoring for appetite-related maladaptive responses, including food aversion and dehydration, and (3) ongoing assessment for broader health impacts. A multifaceted, interdisciplinary approach that melds medical, psychological, dietary, and behavioral strategies is crucial to delivering tailored and thorough care to each patient.

Successful treatment of binge eating disorder with the GLP-1 agonist semaglutide: A retrospective cohort study.

Objective: Binge eating disorder (BED) is the most common eating disorder, and yet only one pharmacotherapy (lisdexamfetamine), which has known abuse-potential, is FDA-approved. Topiramate is also commonly prescribed off-label for binge eating but has many contraindications. In contrast, the glucagon-like peptide-1 (GLP1) analog semaglutide has profound effects on central satiety signaling leading to reduced food intake, and has been approved for the treatment of obesity based on its efficacy and safety profile. Semaglutide would thus seem to be a potential candidate for the treatment of BED. Methods: This open-label study examined the effects of semaglutide on Binge Eating Scale (BES) scores in individuals with BED. Patients were divided into three groups: those prescribed semaglutide, those prescribed either lisdexamphetamine or topiramate, and those prescribed a combination of semaglutide with lisdexamphetamine or topiramate. Results: Patients receiving semaglutide only exhibited greater reductions in BES scores compared to the other groups. Combined pharmacotherapy with both semaglutide and the other anti-obesity medications did not result in greater reductions in BES scores compared to the semaglutide-only group. Findings were similar in patients with moderate/severe BED, as well as the full sample. Conclusion: The therapeutic effects of semaglutide in binge eating disorder warrant further investigation.

Case report of PLXNA4 variant associated with hyper-response to phentermine/topiramate pharmacotherapy: Potential genetic basis for superior weight loss response?

Background: Once thought to be primarily a result of lifestyle, it is now known that obesity has significant genetic components. Dozens of genes have been linked to obesity, and office-based genetic testing for obesity-associated genes is now readily available. As both pharmacotherapy and genetic testing for obesity become more accessible, pharmacogenetic personalization is becoming a reality. In this case report, a patient with a PLXNA4 polymorphism had a superior weight loss response to phentermine/topiramate therapy than has previously been reported in the literature. Thus, variants in PLXNA4 may provide a genetic basis for this patient's superior response to weight loss pharmacotherapy and cardiovascular risk factor reduction. Methods: In this case study, office-based genetic testing was utilized to identify the presence of variants in nearly 80 genes that have been linked to obesity in a patient who had hyper-responsive weight loss results on phentermine/topiramate pharmacotherapy. Results: A variant of the PLXNA4 gene, which has known pathogenic variants linked to genetic obesity syndromes, was identified in this patient who had a superior weight loss response to phentermine/topiramate pharmacotherapy. Conclusion: Due to overlapping molecular pathways, it is possible that PLXNA4 variants convey a superior weight-loss response and therefore superior cardiovascular risk factor reduction phentermine/topiramate therapy. Further studies are needed to examine the relationship between PLXNA4 variants and weight loss with phentermine/topiramate pharmacotherapy.

Significant Decrease in Alcohol Use Disorder Symptoms Secondary to Semaglutide Therapy for Weight Loss: A Case Series.

Objective: Despite being a major cause of preventable death worldwide, alcohol use disorder (AUD) currently has only 3 FDA-approved pharmacotherapies. The glucagon-like peptide-1 receptor agonist (GLP-1RA) semaglutide has shown promise in preclinical studies for reducing alcohol consumption, but there are currently no randomized clinical trials that associate a decline in AUD symptoms with semaglutide use. This case series presents 6 patients with positive AUD screenings who were treated with semaglutide for weight loss. All subsequently exhibited significant improvement in AUD symptoms.Methods: Retrospective chart review was utilized to identify patients treated with semaglutide for weight loss who also had positive screenings for AUD on the Alcohol Use Disorder Identification Test (AUDIT; score > 8 considered positive) prior to initiation of semaglutide therapy. Six patients were identified who met these criteria. A paired t test was utilized to compare initial AUDIT scores with AUDIT scores after initiation of semaglutide therapy.Results: All 6 identified patients (100%) had significant reduction in AUD symptomatology based on AUDIT score improvement following treatment with semaglutide (mean decrease of 9.5 points, P < .001).Conclusions: This case series is consistent with preclinical data and suggests that GLP-1RAs have strong potential in the treatment of AUD. Additional randomized, placebo-controlled clinical studies are needed to fully assess the efficacy of semaglutide in treating AUD.

Use of GLP-1 agonists in high risk patients prior to bariatric surgery: a cohort study.

INTRODUCTION: Body mass index (BMI) > 50 kg/m2 is associated with relatively increased morbidity and mortality with bariatric surgery (BS). There is reluctance to consider these patients operative candidates without preoperative weight loss. Glucagon-like peptide-1 (GLP-1) agonists have demonstrated effective weight loss in the post-BS setting. This study aims to determine the safety and efficacy of GLP-1 agonists in the pre-habilitation of patients with BMI > 50 kg/m2. METHODS: This is a retrospective review of bariatric surgery patients with BMI > 50 kg/m2 from a single bariatric center. Patients were compared by preoperative GLP-1 therapy status. All patients received medical, surgical, psychiatric, and nutritional evaluation and counseling. Preoperative BMI, change in weight from program intake until surgery, time to surgery, and perioperative complications were evaluated. RESULTS: 31 patients were included in the analysis. 18 (58%) received a GLP-1 agonist preoperatively. GLP-1 agonist use was associated with a 5.5 ± 3.2-point reduction in BMI compared to 2.9 ± 2.4 amongst controls (p = 0.026). There was no difference in the mean length of time in the bariatric program prior to surgery between groups (p = 0.332). There were no reported complications related to GLP-1 use in the preoperative setting and no difference in perioperative complications between groups (p = 0.245). DISCUSSION: GLP-1 agonist use in patients with a BMI > 50 kg/m2 results in significantly more weight loss prior to bariatric surgery, without increased time to surgery or complication rate. Further study is required to evaluate the long-term impact of preoperative GLP-1 agonist use prior to bariatric surgery. This therapy may improve perioperative and long-term outcomes in the very high-risk BMI population.

Obesity Pillars roundtable: Excessive weight reduction with highly effective anti-obesity medications (heAOMs).

Background: Historically, many anti-obesity medications (AOMs) were withdrawn from development and/or the market due to safety concerns. Another challenge was that, with some exceptions, most of these AOMs had limited weight reducing efficacy. Approved AOMs often did not meet the weight reduction expectations of either clinicians, or their patients. Currently, newer approved and investigational AOMs achieve greater weight reduction than older AOMs. This has prompted an emerging new challenge of "too much weight loss" with some of these highly effective anti-obesity medications (heAOM) - something many did not think possible prior to year 2020. Methods: This roundtable review includes perspectives from 3 obesity specialists with experience in the clinical use of AOMs. The intent is to provide perspectives and guidance in managing patients with obesity who experience "too much weight loss" with heAOM. Results: The panelists generally agreed that before treatment with heAOMs, patients with obesity are best informed about the importance of healthful nutrition, adequate hydration, routine physical activity, behavior modification techniques, goals of treatment, and anticipated changes not only from a medical standpoint, but also from a psychosocial standpoint. Clinicians might best recognize that the definition of "excessive weight reduction" may have both objective and subjective considerations, with body composition analyses often essential to accurately assess adiposity. Conclusions: The consensus of the panelists is reflected in a proposed structured and algorithmic approach to the patient with excessive weight reduction. Once properly evaluated, if the excessive weight reduction is determined most likely due to the heAOM hyper-responders, then this should prompt the clinician to educate the patient (and possibly family and friends) on the health and psychosocial aspects of weight reduction, and engage in a shared decision-making process that determines if the heAOM is best kept at the same dose, decreased in dose, temporarily held, or rare cases, best discontinued.

Life vs Loans: Does Debt Affect Career Satisfaction in Osteopathic Graduates?

BACKGROUND: The cost of undergraduate osteopathic medical education continues to grow. It is important to understand how the rising cost of matriculation negatively affects training and career satisfaction of entering students. OBJECTIVE: To better understand any association between level of educational debt and satisfaction with osteopathic medical education, career choice, and financial services. METHODS: Responses were analyzed from the American Association of Colleges of Osteopathic Medicine survey of pending medical school graduates from 2007 through 2016 regarding indebtedness and specialty selection. RESULTS: From 2007 to 2016, the mean educational debt level at graduation rose consistently among osteopathic graduates (from $155,698 to $240,331, respectively). In all years, there was no significant effect of debt quartile on satisfaction with choice of osteopathic medicine as a career. Quartile variable with debt did not show a significant effect on satisfaction with education experience in 2010, 2013, and 2016. Top quartile debt was associated with higher satisfaction with financial service departments in all years. CONCLUSION: Although debt has consistently increased for osteopathic medical graduates, it does not affect their satisfaction with either their educational experience or their choice of osteopathic medicine as a career.

How Trainees Finance Their Medical Education: Implications of Higher Education Act Reform.

CONTEXT: The Public Service Loan Forgiveness (PSLF) program is among several repayment programs currently available for recipients of federal student loans. Medical education debt has continued to expand at a rapid pace in the decade since PSLF was created. Proposed changes to the Higher Education Act would substantially transform how future medical trainees finance and repay medical education debt. OBJECTIVE: To better understand relationships between debt and personal stress, as well as between repayment- and forgiveness-program use, in the context of competing legislation. METHODS: Surveys were sent to all Accreditation Council for Graduate Medical Education-accredited internal medicine residency programs (osteopathic and allopathic). RESULTS: From a potential pool of 579 residents, data were obtained from 403 unique respondents (response rate, 69.6%) at 12 residency programs, for a program response rate of 2.2%. Of these respondents, 290 (71.9%) completed the demographic portion of the survey. Median education debt was $225,000. Residents with the top quartile of debt burden were more likely to use PSLF (odds ratio [OR], 3.27; P=.02), more likely to enter loan forbearance (OR, 2.14; P=.03), and indicated a higher level of stress (OR, 5.94; P<.001) compared with those in the second and third quartiles. CONCLUSION: Proposed legislative changes to the Higher Education Act would scale back loan repayment options and also eliminate PSLF for future borrowers. Our data suggest that higher debt burdens are associated with increased debt-related stress. Given program popularity and growing use, along with growing concerns of physician burnout, policy makers should weigh the potential downstream effects of policy change on prospective future physicians.

Choosing Primary Care: Factors Influencing Graduating Osteopathic Medical Students.

CONTEXT: Access to primary care (PC) improves health outcomes and decreases health care costs. The shortage of PC physicians and shifting physician workforce makes this an ongoing concern. Osteopathic medical schools are making strides to fill this void. Considering the critical need for PC physicians in the United States, this study aims to identify factors related to choosing a PC specialty. OBJECTIVE: To understand possible motivations of osteopathic medical students pursuing a career in PC specialties by examining the role of sex and the influence of 5 key factors in this decision. METHODS: Responses from the annual American Association of Colleges of Osteopathic Medicine graduate survey (2007-2016) were analyzed. Self-reported practice decision considerations of 5 key factors, including (1) intellectual and technical content, (2) debt level, (3) lifestyle, (4) prestige/income level, and (5) personal experience and abilities were summarized, and their subjective value was contrasted between osteopathic medicine graduates pursuing PC specialties vs those pursuing non-PC specialties. RESULTS: The mean percentage of graduates pursuing PC and non-PC specialties from 2007 to 2016 was 31.3% and 68.7%, respectively. Women were 1.75 times more likely to choose PC than men (95% CI, 1.62-1.89). Regardless of specialty choice, lifestyle was the most important factor each year (1027 for PC [75.3%] vs 320 for non-PC [63.3%] in 2016; P<.0001). Students entering PC were more likely to report prestige and income level to be "no or minor influence" compared with students entering non-PC specialties (P<.0001). Debt level was more likely to be a "major influence" to students choosing to enter non-PC specialties than to those entering PC (P<.0001), and the percentage of non-PC students has grown from 383 in 2007 (22.9%) to 833 in 2016 (30.6%). CONCLUSION: Sex was found to significantly influence a graduate's choice of specialty, and female graduates were more likely to enter practice in PC. Each of the 5 survey factors analyzed was significantly different between students entering PC and students entering non-PC specialties. Lifestyle was deemed a major influencing factor, and responses suggested that debt level is a strong influencing factor among students pursuing non-PC specialties.

Role of Debt and Loan Forgiveness/Repayment Programs in Osteopathic Medical Graduates' Plans to Enter Primary Care.

CONTEXT: Osteopathic medicine emphasizes partnering with patients to help them attain or maintain health. This philosophy encourages physicians to practice primary care and a mission of improving community health. However, there is currently a shortage of primary care physicians in many areas of the United States. OBJECTIVE: To determine whether intended practice patterns of recent graduates of colleges of osteopathic medicine favor primary care and whether practice patterns correlate with medical education debt. METHODS: Responses were analyzed from the American Association of Colleges of Osteopathic Medicine survey of pending medical school graduates from 2007 through 2016 regarding indebtedness and specialty selection. RESULTS: The percentage of graduating osteopathic medical students who chose a primary care specialty increased from 28.1% (676 students) in 2007 to 33.2% (1377 students) in 2016. Among graduates, those above the 75th percentile of debt had a general move toward more non-primary care positions, with a value of 74.4% in 2007 and 79.9% in 2016. Graduates below the 25th percentile had a gradual increase in primary care representation, moving from 24.6% in 2007 to 29.4% in 2016. In 2007, graduates with a loan forgiveness/repayment program were more likely to choose primary care over graduates without such a program (OR, 0.681 [95% CI, 0.505-0.920]; P=.02). Analysis of subsequent years showed a declining OR with increasing significance. CONCLUSIONS: Results of this analysis indicated that increased educational debt loan directly influenced physician practice choice. Graduates with high debt burden were more likely to enter primary care fields and use loan forgiveness/repayment programs. Graduates with high debt burden who did not use loan forgiveness/repayment programs were more likely to enter non-primary care specialty fields, with this trend increasing as mean medical school debt increased. This association has implications for policies that could affect choice of primary care. However, further research is needed to fully understand the primary care choice by graduates of colleges of osteopathic medicine.

Practice Area Intentions of Graduates of Colleges of Osteopathic Medicine: What Role Does Debt Play?

CONTEXT: Enrollment in colleges of osteopathic medicine continues to increase, as does the need for physicians practicing in underserved areas. The cost of osteopathic medical education is substantial, with students often incurring debt of $200,000 or more. It is unclear whether practice patterns of new graduates will be affected by debt-to-income ratios. OBJECTIVE: To determine whether the intended practice location of graduates of colleges of osteopathic medicine is associated with medical education debt. METHODS: Using data from the American Association of Colleges of Osteopathic Medicine's annual survey to graduates of colleges of osteopathic medicine, the authors focused on graduates' intention to practice in an underserved area, the amount of debt incurred, and plans to enter a loan-repayment program. Survey data from 2007, 2010, 2013, and 2016 were analyzed. RESULTS: From 2007 to 2016, the percentage of graduates who intended to practice in underserved areas increased (27.5% to 35.3%, respectively). Graduates with the most debt intended to practice in underserved areas at a higher percentage than those with the least amount of debt, and they also planned on using loan-repayment programs at a higher rate. CONCLUSION: There is a strong association among the intention to practice in an underserved area, high debt load, and intention to use a loan-repayment program. Therefore, the osteopathic medical community should support increased access to loan-repayment programs to help its graduates surmount economic and social barriers to providing care in underserved areas.

Heterogeneity assessment in gastroenterology systematic reviews: an analysis of current practices.

AIM: In systematic reviews and meta-analyses, variation (heterogeneity) in the primary studies is often a concern resulting from factors such as study design, data analysis methods, study quality, settings and interventions and/or patient characteristics. After determining the extent of heterogeneity, authors examine the causes of heterogeneity via sensitivity analysis, subgroup analysis and/or meta-regression analysis. There is no assessment of heterogeneity practices in gastroenterological literature; thus, we present this assessment. METHODS: We performed a PubMed search to identify systematic reviews published from 2011 to 2016 in the top 10 gastroenterology journals, as well as gastrointestinal topics in general medical journals and the PROSPERO trial registry. The first and second authors independently abstracted data elements, such as levels of inconsistency, sensitivity analysis, subgroup analysis and meta-regression analysis. RESULTS: The search identified 3154 studies; of these, 337 were eligible for inclusion. Included studies consisted of 306 from the gastroenterology literature, 19 studies from PROSPERO and 12 studies from the general internal medicine journals. A significant number of reviews in gastroenterology journals (31.05%, 95/306), internal medicine journals (16.67%, 2/12) and PROSPERO (52.63%, 10/19) conducted a meta-analysis despite having fewer than 10 primary studies. Most of the reviews in gastroenterology journals (81.05%, 248/306), general internal medicine journals (75%, 9/12) and PROSPERO results (73.68%, 14/19) used a combination of methods to assess heterogeneity. There were 20 various definitions of levels of inconsistency (I) throughout all the results. Random effects was the most common model choice in gastroenterology journals reviews (57.84%; 177/306), internal medicine journals (75%, 9/12) and for PROSPERO results (41.11%, 8/19). The majority of reviews did not discuss the impact of heterogeneity on results in the gastroenterology journals (62.09%, 190/306), only one study in the general internal medicine journals and only one study in the PROSPERO results. CONCLUSION: In gastroenterology journals and other journals printing gastrointestinal topic systematic reviews, most conducted statistical tests for heterogeneity; however, the statistical methods could be more robust and the impact of heterogeneity discussed more often in the article.

Pain Management in Abdominal Wall Reconstruction.

BACKGROUND: In abdominal wall reconstruction, adequate pain control and minimization of narcotic consumption are essential to improving patient outcomes and satisfaction. Previous studies have examined the role of individual strategies, such as neuraxial analgesia and multimodal analgesia. However, there has not been a study that examined all potential determinants of postoperative narcotic requirements, including intraoperative strategies. METHODS: Consecutive patients who underwent abdominal wall reconstruction were reviewed. Preoperative factors (chronic preoperative narcotic usage, indication for abdominal wall reconstruction, administration of neuraxial analgesia), intraoperative factors (intraoperative narcotics administered, method of mesh fixation), and postoperative factors (multimodal analgesia, complications) were collected. The main outcomes were daily amount of opioids used and length of hospital stay. RESULTS: Ninety-three patients were included in the study. Patients who had an epidural required lower doses of opioids postoperatively, while those on chronic preoperative opioids, those whose mesh was fixated using transfascial sutures, and those who received large doses of opioids intraoperatively required higher doses of postoperative opioids. Hospital length of stay was longer in patients who received transfascially sutured mesh and those on chronic opioids preoperatively. CONCLUSIONS: This study provides potential strategies to improve pain control and minimize narcotic consumption postoperatively in patients undergoing abdominal wall reconstruction. Intraoperative administration of opioids should be minimized to avoid the development of tolerance. Epidural analgesia reduces postoperative narcotic requirement and may be especially beneficial in patients at highest risk for postoperative pain, including those on chronic opioids, and those in whom transfascial sutures are used for mesh fixation.