Pharmacotherapy For Obesity Research Articles

Advances in obesity pharmacotherapy; learning from metabolic surgery and beyond

Currently, metabolic surgery (MS) constitutes the most effective means for durable weight loss of clinically meaningful magnitude, type 2 diabetes remission and resolution of non-alcoholic steatohepatitis, as well as other obesity-related comorbidities. Accumulating evidence on the mechanisms through which MS exerts its actions has highlighted the altered secretion of hormonally active peptides of intestinal origin with biological actions crucial to energy metabolism as key drivers of MS clinical effects. The initial success of glucagon-like peptide-1 (GLP-1) receptor agonists regarding weight loss and metabolic amelioration have been followed by the development of unimolecular dual and triple polyagonists, additionally exploiting the effects of glucagon and/or glucose-dependent insulinotropic polypeptide (GIP) which achieves a magnitude of weight loss approximating that of common MS operations. Through the implementation of such therapies, the feasibility of a “medical bypass”, namely the replication of the clinical effects of MS through non-surgical interventions may be foreseeable in the near future. Apart from weight loss, this approach ought to be put to the test also regarding other clinical outcomes, such as liver steatosis and steatohepatitis, cardiovascular disease, and overall prognosis, on which MS has a robustly demonstrated impact. Besides, a medical bypass as an alternative, salvage, or combination strategy to MS may promote precision medicine in obesity therapeutics.

Milestones in the journey towards addressing obesity; Past trials and triumphs, recent breakthroughs, and an exciting future in the era of emerging effective medical therapies and integration of effective medical therapies with metabolic surgery.

The 21st century is characterized by an increasing incidence and prevalence of obesity and the burden of its associated comorbidities, especially cardiometabolic diseases, which are reaching pandemic proportions. In the late '90s, the "black box" of adipose tissue and energy homeostasis was opened with the discovery of leptin, transforming the adipose tissue from an "inert fat-storage organ" to the largest human endocrine organ and creating the basis on which more intensified research efforts to elucidate the pathogenesis of obesity and develop novel treatments were based upon. Even though leptin was eventually not proven to be the "standalone magic bullet" for the treatment of common/polygenic obesity, it has been successful in the treatment of monogenic obesity syndromes. Additionally, it shifted the paradigm of treating obesity from a condition due to "lack of willpower" to a disease due to distinct underlying biological mechanisms for which specific pharmacotherapies would be needed in addition to lifestyle modification. Subsequently, the melanocortin pathway proved to be an equally valuable pathway for the pharmacotherapy of obesity. Melanocortin receptor agonists have recently been approved for treating certain types of syndromic obesity. Other molecules- such as incretins, implicated in energy and glucose homeostasis- are secreted by the gastrointestinal tract. Glucagon-like peptide 1 (GLP-1) is the most prominent one, with GLP-1 analogs approved for common/polygenic obesity. Unimolecular combinations with other incretins, e.g., GLP-1 with gastric inhibitory polypeptide and/or glucagon, are expected to be approved soon as more effective pharmacotherapies for obesity and its comorbidities. Unimolecular combinations with other compounds and small molecules activating the receptors of these molecules are currently under investigation as promising future pharmacotherapies. Moreover, metabolic and bariatric surgery has also demonstrated impressive results, especially in the case of morbid obesity. Consequently, this broadening therapeutic armamentarium calls for a well-thought-after and well-coordinated multidisciplinary approach, for instance, through cardiometabolic expertise centers, that would ideally address effectively and cost-effectively obesity and its comorbidities, providing tangible benefits to large segments of the population.

FRI017 Precision-engineered Activin And GDF Ligand Trap HS235: A Novel Lean Mass-preserving Treatment for Obesity

Abstract Disclosure: G. Schang: Employee; Self; 35Pharma Inc. M. Poujol de Molliens: Employee; Self; 35Pharma Inc. E. Brûlé: Employee; Self; 35Pharma Inc. C. Chauvet: Employee; Self; 35Pharma Inc. J. Denis: Employee; Self; 35Pharma Inc. A. Sours: Employee; Self; 35Pharma Inc. V. Ganesh: Employee; Self; 35Pharma Inc. G. Tremblay: Employee; Self; 35Pharma Inc. J. Schoelermann: Employee; Self; 35Pharma Inc. M. O'Connor-McCourt: Employee; Self; 35Pharma Inc. Introduction: Novel anti-obesity medications including incretin mimetics have revolutionized the pharmacotherapy of obesity and type 2 diabetes, leading to unprecedented weight loss and clinically meaningful improvement of glucose metabolism and cardiometabolic health. However, this loss of fat mass is accompanied by undesirable loss of lean body mass (LBM) which can account for 15 - 40% of overall weight loss. Loss of LBM by incretin-based therapies negatively impacts resting metabolic rate, leading to a weight loss plateau and often unsustainable results. The preservation, or even increase, of LBM is therefore a desirable treatment goal for obesity pharmacotherapy and improvement of overall health. Activins and growth differentiation factors (GDFs), which are members of the TGF-beta superfamily, are validated targets controlling body composition and metabolism. Specifically, blockade of activins and GDFs has anabolic effects in metabolically active tissues such as skeletal muscle and brown adipose tissue, while reducing white adipose tissue mass. Therefore, specific and selective blockade of activins and GDFs represents a novel anti-obesity treatment strategy which can act orthogonally to current anti-obesity medications. Aims and objectives: HS235 is an activin receptor ectodomain-based (ActR) Fc-fusion protein that has been rationally designed to attain optimal inhibition of ligands controlling body composition in obesity. Methods: A structure-assisted rational molecular engineering approach coupled with cell-based potency screening was employed to design HS235. In vivo target engagement and pharmacodynamic response to HS235 were assessed in mice by quantifying metabolic biomarkers including muscle hypertrophy, muscle and fat gene expression, as well as plasma metabolites. To further validate the anti-obesogenic potential of HS235, diet-induced obese (DIO) mice were injected with HS235, an incretin mimetic, or a combination of both. Fat mass, LBM, glucose metabolism, exercise tolerance, and biomarker readouts were assessed at the end of study. Results: In cell-based assays, HS235 potently and selectively neutralized activins and GDFs implicated in body composition. This translated to complete in vivo target engagement and pharmacodynamic response. In a DIO mouse model, both HS235 and the incretin mimetic significantly improved metabolic parameters and decreased fat mass, but only HS235 increased LBM, while incretin-based treatment led to LBM loss. Importantly, the addition of HS235 to the incretin mimetic prevented this loss of LBM. Conclusion: Potent and selective inhibition of activins and GDFs by HS235 represents a novel LBM preserving weight loss strategy. Collectively, these data support the development of HS235 as a novel anti-obesity agent that may also complement currently approved incretin-based medications. Presentation: Friday, June 16, 2023

FRI066 Treatment History And Comorbidities Reported By Patients With Hypothalamic Obesity Treated With Setmelanotide In A Phase 2 Trial

Abstract Disclosure: C.L. Roth: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. A.H. Shoemaker: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc., Saniona. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. M. Gottschalk: Advisory Board Member; Self; Rhythm Pharmaceuticals, Inc. Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. J. Miller: Other; Self; Study funding from Rhythm Pharmaceuticals, Inc. G. Yuan: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. S. Malhotra: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. C. Scimia: Employee; Self; Rhythm Pharmaceuticals, Inc. Stock Owner; Self; Rhythm Pharmaceuticals, Inc. M.J. Abuzzahab: Consulting Fee; Self; Pfizer, Inc., Consynance, Rhythm Pharmaceuticals, Inc., Endo Pharmaceuticals. Background: Hypothalamic obesity (HO) is an acquired form of severe obesity that can occur following surgical resection or radiotherapy of brain tumors. Multiple factors associated with the development of HO—including degree of hypothalamic damage from tumor treatment, comorbidities (eg, pituitary deficiencies), polypharmacy used to treat comorbidities, and unique pathophysiology—confer treatment challenges; HO is often unresponsive to lifestyle modifications and traditional obesity pharmacotherapies. In a Phase 2, 16-week trial of setmelanotide in patients with HO, 16 of 18 patients (88.9% [90% confidence interval, 69.0%-98.0%]; P<0.0001) achieved ≥5% body mass index (BMI) reduction from baseline, with a mean percent BMI change of −15.4% in patients adhering to treatment (n=17). We assessed patient histories (ie, tumor treatments, prior attempts to lose weight, and comorbidities) reported in the trial to further characterize this patient population. Methods: Patients aged ≥6 to ≤40 years with documented evidence of HO were enrolled in an open-label Phase 2 trial (NCT04725240) and received setmelanotide once daily for 16 weeks. The primary endpoint was the proportion of patients with ≥5% BMI reduction from baseline at Week 16. Tumor treatments, prior attempts to lose weight, and comorbidities are summarized narratively. Results: Eighteen patients with HO (age range, 6-24 years) were treated with setmelanotide. HO was diagnosed in patients following treatment of craniopharyngioma (n=14), hamartoma (n=3), or juvenile pilocytic astrocytoma (n=1). Six patients (33.3%) had tumor recurrence and/or multiple tumor treatments. Thirteen patients (72.2%) reported prior lifestyle modifications (ie, calorie restriction [n=4], low-carbohydrate diet [n=6], dietary tracking/modification [n=4], food access restriction [n=1], personal training [n=1]) and/or pharmacotherapy use (ie, exenatide [n=3], semaglutide [n=1], liraglutide [n=2], metformin [n=2], methylphenidate [n=2], dextroamphetamine [n=1], lisdexamfetamine [n=2], naltrexone [n=3], oxytocin [n=3], phentermine [n=1]) without substantial benefit. Comorbidities occurring in ≥25% of patients were diabetes insipidus (n=14), hypothyroidism (n=14), growth hormone deficiency (n=11), adrenal insufficiency (n=10), hypogonadism (n=8), pan/hypopituitarism (n=8), psychiatric disorders (n=8), vision problems (n=6), gastrointestinal symptoms (n=6), obstructive sleep apnea (n=5), and hypothalamic-pituitary disorder (n=3). All patients adhering to treatment (n=17, including those with pituitary deficiencies and common comorbidities)) experienced BMI reductions with setmelanotide. Conclusions: Despite complex medical histories, hypothalamic damage, and various prior failed interventions, setmelanotide reduced BMI in patients with HO in a Phase 2 trial. Presentation: Friday, June 16, 2023

The Therapeutic Aspects of Obesity

The prevalence of obesity has increased worldwide, reaching pandemic levels. More than half of the world’s population will be overweight or obese by 2035 without significant action, according to a report of the World Obesity Federation’s. The World Health Organization defines overweight as body mass index (BMI) >25 kg/m2 and obesity >30 kg/m2 and describes these conditions as abnormal or excessive fat accumulation that is associated with increased health risk. Epidemiologic studies have revealed an association between high BMI and an extensive range of chronic diseases such as non alcoholic fatty liver disease, cardiovascular diseases, diabetes mellitus, several malignancies, musculoskeletal diseases, chronic kidney disease, and mental disorders, which consequently, affect negatively subjects’ quality of life and raise healthcare costs. Obesity as a chronic and progressive lifelong disease requires an active approach to treatment. For obese persons, it is recommended that a diet with an energy deficit of 500 kcal/day and a low energy density should be instituted for the purpose of weight loss and stabilization of a lower weight. More physical exercise in everyday life promotes weight loss and improves risk factors and obesity-associated diseases. Behavior modification and behavioral therapy support changes in nutrition and exercise in everyday life. Pharmacotherapy for obesity can be considered if patients have a BMI of 30 kg/m2 or greater or BMI of 27 kg/m2 or greater with weight-related comorbidities. The choice of the anti-obesity medication needs to take into consideration the patient’s clinical and biochemical profile, co-morbidities, and drug contra-indications, as well as expected degree of weight loss and improvements in cardio-renal and metabolic risk. Successful therapy for obesity depends on tailoring treatment to patients’ behaviors and comorbidities and monitoring of efficacy, safety, and tolerability.

The locus coeruleus contributes to the anorectic, nausea, and autonomic physiological effects of glucagon-like peptide-1.

Increasing the therapeutic potential and reducing the side effects of U.S. Food and Drug Administration-approved glucagon-like peptide-1 receptor (GLP-1R) agonists used to treat obesity require complete characterization of the central mechanisms that mediate both the food intake-suppressive and illness-like effects of GLP-1R signaling. Our studies, in the rat, demonstrate that GLP-1Rs in the locus coeruleus (LC) are pharmacologically and physiologically relevant for food intake control. Furthermore, agonism of LC GLP-1Rs induces illness-like behaviors, and antagonism of LC GLP-1Rs can attenuate GLP-1R-mediated nausea. Electrophysiological and behavioral pharmacology data support a role for LC GLP-1Rs expressed on presynaptic glutamatergic terminals in the control of feeding and malaise. Collectively, our work establishes the LC as a site of action for GLP-1 signaling and extends our understanding of the GLP-1 signaling mechanism necessary for the development of improved obesity pharmacotherapies.

Pharmacotherapy of Obesity: An Updated Overview

Obesity is an emerging epidemic in Canada that poses a threat to public health. Pharmaceutical weight management is an option for managing excess weight. In this review, we briefly discuss the pathophysiology of obesity and present the current pharmacotherapy for its treatment, focusing on orlistat, naltrexone/bupropion, liraglutide, and semaglutide. In addition, we briefly discuss upcoming pharmacotherapies for the management of obesity.

Available therapies for the treatment of obesity. Are lifestyle modifications and pharmacotherapy enough to reduce weight? - review of the literature

Introduction: The World Health Organization (WHO) defines obesity as "abnormal or excessive accumulation of adipose tissue that poses a health risk". It results from the interdependencies between genetic, cultural, and socio-economic factors. The choice of therapy in the treatment of overweight and obesity depends on body mass index (BMI), individual predispositions, comorbidities and weight history. Among the treatment methods stand out, dietary modification, lifestyle changes, pharmacotherapy, and bariatric surgery. Each of these treatments can be used individually or as a combination treatment using knowledge of physiology. The aim of the study is to assess the effectiveness of overweight and obesity treatment using pharmacotherapy and lifestyle modification. Material and Methods: The research material was collected by searching databases with scientific articles about obesity, pharmacotherapy in obesity, the impact of lifestyle modifications, behavioral behavior, and physical activity on the reduction of body fat. The scientific database Pubmed and Web of Science were used. Research articles, systematic reviews and meta-analyses were included. Summary Obesity is an epidemic of the 21st century, bringing with it several negative consequences. Prevention of the disease, quick diagnosis, and implementation of appropriate treatment to reduce unnecessary fat and excess weight are extremely important. Lifestyle change including dietary modification, physical activity and pharmacotherapy are promising treatments for overweight and obesity.

A Narrative Review: Phentermine and Topiramate for the Treatment of Pediatric Obesity.

The prevalence of pediatric obesity has increased exponentially over the past four decades. The American Academy of Pediatrics recently released updated clinical practice guidelines highlighting the importance of identifying pediatric obesity as a chronic disease. The guidelines support consideration of concurrent treatment with intensive lifestyle interventions, obesity pharmacotherapy, and bariatric surgery. The dramatic rise in pediatric obesity has spurred interest in utilizing obesity pharmacotherapy to support sustained weight reduction in pediatric cohorts, in the hopes of preventing the emergence of later-appearing, significant co-morbidities. Despite the enormous demand, the obstacles posed by performance of needed clinical trials in the pediatric population markedly limits available pharmacotherapy for the treatment of obesity in pediatrics. Currently, there are five medications approved by the Food and Drug Administration for use in youth with obesity. In 2022, the phentermine/topiramate (PHEN/TPM), once-daily, controlled-release, combination product received FDA approval, for the indication of chronic weight management, in youth with obesity, ages 12 years and older. The objectives of this narrative review are to: (1) Review the mechanism of action of phentermine and topiramate, (2) Summarize the safety and efficacy data of topiramate and phentermine use as both monotherapies and in combination, and (3) Discuss clinical practice guidelines and clinical implications, for the use of these agents in youths with obesity.

Future therapies for obesity

Obesity is a chronic disease associated with increased morbidity and mortality. Bariatric surgery can lead to sustained long-term weight loss (WL) and improvement in multiple obesity-related complications, but it is not scalable at the population level. Over the past few years, gut hormone-based pharmacotherapies for obesity and type 2 diabetes mellitus (T2DM) have rapidly evolved, and combinations of glucagon-like peptide 1 (GLP1) with other gut hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) as dual or triple agonists are under investigation to enhance and complement the effects of GLP1 on WL and obesity-related complications. Tirzepatide, a dual agonist of GLP1 and GIP receptors, marks a new era in obesity pharmacotherapy in which a combination of gut hormones could approach the WL achieved with bariatric surgery. In this review, we discuss emerging obesity treatments with a focus on gut hormone combinations and the concept of a multimodal approach for obesity management.

When diet is not enough - obesity treatment options

Introduction: Obesity and overweight are common diseases affecting both children and adults. They cause a number of health consequences, both physical and mental. The diseases underlying obesity include hypertension, type II diabetes and selected cancers. The etiology is multifactorial, resulting from environmental, behavioral and genetic factors. Aim of the study: The aim of our study is to summarize the therapeutic options available to overweight and obese people. We paid special attention to the available pharmacology and surgical treatment. We compared these methods in terms of effectiveness, possible complications and side effects. Materials and methods: The literature available in the PubMed and Google Scholar databases was reviewed, using the following keywords: "obesity treatment", "obesity pharmacotherapy", "bariatric surgery". Conclusions: There are many treatment options for people who have not improved with diet and increased physical activity alone. The availability of both pharmacotherapy and bariatric surgery enables effective treatment of obesity and overweight tailored to the needs of patients.

Current and future pharmacotherapies for obesity in children and adolescents.

Obesity is a common chronic disease in children and adolescents and its prevalence is increasing worldwide. The causes are multifactorial but involve biological predisposition towards a specific body-weight set point and defended adipose tissue mass converging with an obesogenic environment. Comprehensive treatment of paediatric obesity includes lifestyle modification therapy, anti-obesity medications (AOMs) and/or metabolic surgery. Lifestyle modification therapy used alone produces fairly modest weight loss for most youth with obesity. The emergence of new AOMs has changed the landscape of paediatric weight management, improving the outlook for youth with obesity. This Review briefly highlights obesity development pathways in youth and the role that pharmacotherapy can play in counteracting these pathophysiological forces. Here, results from adolescent AOM clinical trials published since 2020 are reviewed, including the safety, efficacy and tolerability of the newest treatments (glucagon-like peptide 1 receptor agonists and phentermine-topiramate). The importance of a comprehensive and chronic care model, including both lifestyle modification and ongoing pharmacotherapy, will be discussed in the context of maximizing long-term health outcomes. Finally, insight will be provided into the emerging pipeline of AOMs (for example, incretin receptor co-agonists and tri-agonists) and how future therapies might fundamentally change the prognosis for youth with obesity.

A long-acting GDF15 analog causes robust, sustained weight loss and reduction of food intake in an obese nonhuman primate model.

Growth Differentiation Factor-15 (GDF15) is a circulating polypeptide linked to cellular stress and metabolic adaptation. GDF15's half-life is ~3 h and activates the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL) receptor expressed in the area postrema. To characterize sustained GFRAL agonism on food intake (FI) and body weight (BW), we tested a half-life extended analog of GDF15 (Compound H [CpdH]) suitable for reduced dosing frequency in obese cynomolgus monkeys. Animals were chronically treated once weekly (q.w.) with CpdH or long-acting GLP-1 analog dulaglutide. Mechanism-based longitudinal exposure-response modeling characterized effects of CpdH and dulaglutide on FI and BW. The novel model accounts for both acute, exposure-dependent effects reducing FI and compensatory changes in energy expenditure (EE) and FI occurring over time with weight loss. CpdH had linear, dose-proportional pharmacokinetics (terminal half-life ~8 days) and treatment caused exposure-dependent reductions in FI and BW. The 1.6 mg/kg CpdH reduced mean FI by 57.5% at 1 week and sustained FI reductions of 31.5% from weeks 9-12, resulting in peak reduction in BW of 16 ± 5%. Dulaglutide had more modest effects on FI and peak BW loss was 3.8 ± 4.0%. Longitudinal modeling of both the FI and BW profiles suggested reductions in BW observed with both CpdH and dulaglutide were fully explained by exposure-dependent reductions in FI without increase in EE. Upon verification of the pharmacokinetic/pharmacodynamic relationship established in monkeys and humans for dulaglutide, we predicted that CpdH could reach double digit BW loss in humans. In summary, a long-acting GDF15 analog led to sustained reductions in FI in overweight monkeys and holds potential for effective clinical obesity pharmacotherapy.

A Survey of Obesity Education and Training in United States Pharmacy Schools

ObjectiveTo assess how obesity is addressed in Doctor of Pharmacy (PharmD) schools and colleges, identify the extent to which core obesity competencies are covered in the curricula, and identify opportunities for expanding obesity management training. MethodsAn online survey was conducted with PharmD program leaders in the United States. Respondents answered questions regarding obesity education in their pharmacy school curricula. Data were analyzed in aggregate, using descriptive statistics. ResultsWe collected responses from 75 of 150 (50%) PharmD programs. One-third (32%) of respondents thought their graduating students were very prepared to discuss obesity pharmacotherapy (anti-obesity medication) options with patients. A total of 45% reported obesity pharmacological treatment was covered to a great extent. Few respondents (19%) were very familiar with anti-obesity medications; 21% thought their students were similarly familiar. No programs covered weight stigma and discrimination to a great extent. Most respondents (88%) believed obesity education was fairly/very important to include in PharmD curricula, and 96% thought it was similarly appropriate to include. But 72% indicated that expanding obesity education was not a priority/low priority. Lack of room in the curricula was cited as the greatest barrier, with 60% of PharmD programs reporting this to be a large barrier. ConclusionPharmacists, as medication experts, are key members of the care team. However, obesity management/pharmacotherapy is not emphasized in most pharmacy schools. Therefore, pharmacists are not well-prepared to provide counseling on medications for obesity. Leveraging guidance on core obesity competencies and available resources could help expand obesity education in pharmacy schools.

Metabolic and bariatric surgery and obesity pharmacotherapy for cancer prevention: current status and future possibilities.

Obesity is a chronic, relapsing, progressive disease of excess adiposity that increases the risk of developing at least 13 types of cancer. This report provides a concise review of the current state of the science regarding metabolic and bariatric surgery and obesity pharmacotherapy related to cancer risk. Meta-analyses of cohort studies report that metabolic and bariatric surgery is independently associated with a lower risk of incident cancer than nonsurgical obesity care. Less is known regarding the cancer-preventive effects of obesity pharmacotherapy. The recent approval and promising pipeline of obesity drugs will provide the opportunity to understand the potential for obesity therapy to emerge as an evidence-based cancer prevention strategy. There are myriad research opportunities to advance our understanding of how metabolic and bariatric surgery and obesity pharmacotherapy may be used for cancer prevention.

Tirzepatide - a novel dual GLP-1 and GIP receptor agonist used in pharmacotherapy of obesity: A literature review

Background: Obesity is a chronic disease, which along with its complications, poses a huge threat to both our health as individuals and our healthcare as a community.
 Objective: The aim of this work is to review efficacy and safety of Tirzepatide, a novel dual GIP/GLP-1 receptor agonist in the treatment of obesity
 Method: A literature review was conducted on databases such as PubMed and Google Scholar using terms “obesity”, “obesity treatment”, “glucagon-like peptide 1”, “Glucose-dependent insulinotropic polypeptide”, “Tirzepatide” as keywords. The review was performed in accordance with the PRISMA guidelines.
 Results: Administration of tirzepatide once weekly provides a substantial and sustained reduction in bodyweight with little side effects.
 Conclusions: Clinical trials showed both high efficacy and safety of Tirzepatide in management of obesity. Due to its novel, broadened mechanism of action it seems to be the most effective drug for reducing bodyweight available on the market. Tirzepatide could be our answer to tackling the problem of world-wide obesity epidemic.

GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy

ABSTRACT Introduction Obesity is recognized as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist, recently approved for management of type 2 diabetes mellitus. Areas covered Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarizes experimental, preclinical, and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritizing clinical research published within the last 10 years where possible. Expert Opinion GLP-1R mimetics are often discontinued within 24 months meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.

Current and emerging medications for the management of obesity in adults.

Current and emerging medications for the management of obesity in adults.

Pharmacotherapy of obesity—Competition to bariatric surgery or a meaningful supplement?

Obesity is acomplex chronic disease and requires along-term multimodal approach. The current treatment algorithm for treatment of obesity mainly consists of astepwise approach, which starts with alifestyle intervention followed by or combined with medication treatment, whereas bariatric surgery is often reserved for the last option. This article provides an overview of the currently available conservative medicinal treatment regimens and the currently approved medications as well as medications currently undergoing approval studies with respect to the efficacy and possible side effects. Special attention is paid to the importance of combination treatment of pharmacotherapy and surgery in the sense of amultimodal treatment. The data so far show that using amultimodal approach an improvement in the long-term weight loss and metabolic benefits can be achieved for the patients.

Long-term complications of significant weight loss: lessons learned from bariatric surgery

The increasing prevalence of worldwide obesity calls for a comprehensive understanding of available treatment options. Bariatric surgery remains a very effective obesity treatment, showing substantial effects on obesity-related complications, including type 2 diabetes mellitus and cardiovascular disease, mainly related to significant long-term weight loss. Besides the benefits, weight loss can lead to some deleterious consequences, such as gallstones, constipation, muscle mass loss, bone fractures, vitamin deficiencies, peripheral neural palsy, suicide, eating disorders, alcohol dependency syndrome, and increased divorce. Those consequences may also be seen after long-term effective pharmacotherapy for obesity. Understanding these risks will lead to improved awareness and successful treatment with both surgical and nonsurgical treatments.