From one-size-fits-all to phenotype-based pharmacotherapy: How far are we in obesity management?

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

New Medications for the Treatment of Diabetes

An Albumin-Exendin-4 Conjugate Engages Central and Peripheral Circuits Regulating Murine Energy and Glucose Homeostasis

ASGE EndoVators Summit: Defining the role and value of endoscopic therapies in obesity management

New Glucose-Lowering Agents for Diabetic Kidney Disease.

Diabetes mellitus, defined as a fasting plasma glucose of ≥126 mg/dL or a glycosylated hemoglobin A1c level (HbA1c) of ≥6.5%, afflicts ≈12.9% of adults in the United States and nearly 285 million adults worldwide.1,2 Diabetes mellitus is a major risk factor for the development of cardiovascular disease, independently conferring a 2-fold excess risk of coronary heart disease and stroke.3 Macrovascular events in diabetes mellitus remain the leading cause of mortality, and the burden of cardiovascular disease attributable to diabetes mellitus has increased over the past decade.4 An increase in the prevalence of obesity has contributed to the rise in diabetes mellitus. Additionally, obesity independently increases the risk of cardiovascular disease in patients with diabetes mellitus.5 Although strict glycemic control unequivocally reduces the microvascular complications of diabetes mellitus, the macrovascular benefits of intensive therapy have been difficult to establish, with conflicting results from large clinical trials.6–9 Multifactorial strategies are recommended to reduce cardiovascular risk in diabetes mellitus through enhanced glycemic control, blood pressure reduction, lipid management, weight loss, and physical activity.10 Unfortunately, despite aggressive interventions for hyperglycemia, <50% of patients achieve standard HbA1c targets with conventional therapy.11 Polypharmacy is required to achieve glycemic control in the majority of patients within 3 years of diagnosis.12 Although combinations of drug classes can synergistically target multiple pathophysiological defects, novel therapies are required to manage diabetes mellitus and mitigate cardiovascular risks. Dipeptidyl-peptidase IV (DPP-IV) inhibitor and glucagon-like peptide-1 (GLP-1) receptor agonist incretin therapies were developed to complement conventional treatment options for diabetes mellitus. Despite promising initial reports of cardioprotective effects, DPP-IV inhibitors have failed to demonstrate improved cardiovascular outcomes in large clinical trials.13–15 Randomized studies to evaluate cardiovascular outcomes associated with GLP-1 receptor agonists are currently underway. This review presents …

Preoperative considerations of new long-acting glucagon-like peptide-1 receptor agonists in diabetes mellitus

Background: Opioid use disorder (OUD) is a global health crisis, contributing to significant public health challenges and economic loss. Although existing treatments are available, there is a critical need for novel therapeutic strategies. This review examined the potential of glucagon-like peptide-1 (GLP-1) receptor agonists, primarily used in diabetes management, as a repurposed treatment for OUD.Methods: We explored preclinical studies that demonstrate how GLP-1 receptor agonists can modulate neurobiological pathways involved in opioid addiction, particularly dopaminergic signaling. We also reviewed initial human clinical trials examining the impact of GLP-1 receptor agonists on opioid self-administration, relapse behavior, and cravings.Findings: Preclinical data suggest that GLP-1 receptor agonists can reduce opioid self-administration and relapse behavior in animal models. Early human clinical trials indicate promising results, showing a potential role for GLP-1 receptor agonists in reducing opioid cravings and improving treatment outcomes.Conclusion: Although early findings are encouraging, further research is needed to confirm these results, optimize dosing regimens, and clarify the underlying mechanisms of action. Given the interplay between metabolic and neuropsychiatric factors in OUD, GLP-1 receptor agonists offer a unique therapeutic advantage. Large-scale clinical trials are essential to determine their long-term efficacy, safety, and integration into comprehensive OUD treatment plans.

Insulin and glucagon are well-known peptide hormones that keep glucose levels within a healthy range in the body. But they are only part of a complex network that controls concentrations of this ubiquitous sugar in blood and tissues. Other molecules regulate glucose by controlling insulin secretion from the pancreas or protecting pancreatic β cells against stresses that lead to cellular dysfunction or cell death (1). One of these protective regulators is glucagon-like peptide 1 (GLP-1), a 30-amino-acid-long peptide produced in specialized epithelial cells of the intestine, called L cells, and also in the brain and other organs and tissues (2). GLP-1 belongs to a group of peptides that mediate the “incretin effect,” an endocrine response to glucose arising from food digestion in the intestines (2, 3). This response helps regulate food intake and the fate of dietary glucose. Specifically, GLP-1 is released from the intestinal cells when food is ingested and then binds to and activates the GLP-1 receptor (GLP-1R), a G protein–coupled receptor on many cell types, including β cells in which GLP-1R signaling stimulates insulin synthesis and secretion (3). Notably, the incretin effect stimulates insulin secretion from pancreatic β cells more strongly than exposure to glucose alone. An article published in the Journal of Biological Chemistry (4), recognized as a Classic here, added to our understanding of the incretin effect by showing that GLP-1R signaling protects β cells from cell death (Fig. 1). This finding was significant for preventing or managing type 2 diabetes, in which β-cell apoptosis occurs (5) and may contribute to insufficient pancreatic insulin production (6). Open in a separate window Figure 1. Li et al. (4) have shown that binding of the receptor agonist exendin-4 to GLP-1R on pancreatic β cells protects the cells from cellular injury and cytokine-induced apoptosis and thereby preserves glucose homeostasis in mice. Binding of GLP-1 to its cognate receptor on pancreatic β cells up-regulates intracellular cAMP levels, in turn reducing streptozotocin-induced β-cell death. Images of exendin-4 and GLP-1R (with GLP-1 bound) are from Ref. 7; image of cAMP is from Wikimedia, used under Creative Commons.

INTRODUCTION Obesity is a chronic disease associated with significant metabolic and cardiovascular complications. Bariatric surgery remains the most effective treatment for severe obesity, achieving substantial and sustained weight loss while improving glycemic control and reducing cardiovascular risk. Glucagon-like peptide-1 (GLP-1) receptor agonists have emerged as a pharmacological alternative, offering weight reduction and metabolic benefits with a lower risk of immediate complications. However, differences in long-term efficacy, safety, and adherence raise questions about their potential to replace metabolic surgery. OBJETIVE This study aims to compare the effectiveness, safety, and long-term outcomes of GLP-1 receptor agonists and bariatric surgery in obesity management. The analysis includes weight loss results, metabolic improvements, treatment adherence, complication rates, and cost-effectiveness. Additionally, the study explores whether a combined approach could enhance obesity treatment outcomes. METHODS A narrative review was conducted using articles published in the last five years from PubMed, Cochrane, Medline, Embase, and SciELO databases. The descriptors used included “Obesity treatment” OR “Bariatric surgery” OR “GLP-1 receptor agonists” OR “Pharmacological weight loss” OR “Metabolic surgery.” Studies comparing pharmacological and surgical interventions in terms of weight loss, metabolic effects, cardiovascular outcomes, and patient adherence were analyzed. RESULTS AND DISCUSSION Bariatric surgery resulted in greater long-term weight loss and higher rates of type 2 diabetes remission compared to GLP-1 receptor agonists. While pharmacotherapy provided significant metabolic improvements, its efficacy depended on continuous use, with weight regain frequently occurring after discontinuation. GLP-1 receptor agonists demonstrated cardiovascular benefits, but adherence was limited due to gastrointestinal side effects and financial burden. In contrast, surgery carried higher initial risks but produced sustained metabolic benefits and reduced long-term medication dependence. CONCLUSION Bariatric surgery remains the superior intervention for obesity management, particularly in patients with severe obesity and metabolic syndrome. GLP-1 receptor agonists offer a viable non-surgical alternative but require continuous therapy for sustained effects. A personalized approach, integrating pharmacological and surgical strategies, may optimize outcomes in select patients. Future research should focus on refining combined treatment models to maximize long-term success.

Obesity is a chronic disease associated with increased risk of obesity-related complications and mortality. Our better understanding of the weight regulation mechanisms and the role of gut-brain axis on appetite has led to the development of safe and effective entero-pancreatic hormone-based treatments for obesity such as glucagon-like peptide-1 (GLP-1) receptor agonists (RA). Semaglutide 2.4 mg once weekly, a subcutaneously administered GLP-1 RA approved for obesity treatment in 2021, results in 15–17% mean weight loss (WL) with evidence of cardioprotection. Oral GLP-1 RA are also under development and early data shows similar WL efficacy to semaglutide 2.4 mg. Looking to the next generation of obesity treatments, combinations of GLP-1 with other entero-pancreatic hormones with complementary actions and/or synergistic potential (such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, and amylin) are under investigation to enhance the WL and cardiometabolic benefits of GLP-1 RA. Tirzepatide, a dual GLP-1/GIP receptor agonist has been approved for glycaemic control in type 2 diabetes as well as for obesity management leading in up to 22.5% WL in phase 3 obesity trials. Other combinations of entero-pancreatic hormones including cagrisema (GLP-1/amylin RA) and the triple agonist retatrutide (GLP-1/GIP/glucagon RA) have also progressed to phase 3 trials as obesity treatments and early data suggests that may lead to even greater WL than tirzepatide. Additionally, agents with different mechanisms of action to entero-pancreatic hormones (e.g. bimagrumab) may improve the body composition during WL and are in early phase clinical trials. We are in a new era for obesity pharmacotherapy where combinations of entero-pancreatic hormones approach the WL achieved with bariatric surgery. In this review, we present the efficacy and safety data for the pipeline of obesity pharmacotherapies with a focus on entero-pancreatic hormone-based treatments and we consider the clinical implications and challenges that the new era in obesity management may bring.

Obesity is a global public health challenge. Pharmacological interventions, such as glucagon-like peptide-1 (GLP-1) receptor agonists (eg, semaglutide) and dual GLP-1/gastric inhibitory polypeptide receptor agonists (eg, tirzepatide), have led to significant weight loss among users. Digital health platforms offering behavioral support may enhance the effectiveness of these medications. This retrospective service evaluation investigated the impact of engagement with an app-based digital weight loss program on weight loss outcomes among individuals using GLP-1 receptor agonists (semaglutide) and dual GLP-1/gastric inhibitory polypeptide receptor agonists (tirzepatide) in the United Kingdom over 5 months. Data were collected from the Voy weight loss digital health platform between February 2023 and August 2024. Participants were adults aged 18-75 years with a BMI ≥30 or ≥27.5 kg/m2 with the presence of obesity-related comorbidities who initiated a weight management program involving semaglutide or tirzepatide. Engagement was defined based on attendance at coaching sessions, frequency of app use, and regular weight tracking. Participants were categorized as "engaged" or "nonengaged" accordingly. Weight loss outcomes were assessed over a period of up to 5 months. Statistical analyses included chi-square tests, independent t tests, Kaplan-Meier survival analysis, and calculations of Cohen d for effect sizes. A total of 57,975 participants were included in the analysis, with 31,407 (54.2%) classified as engaged and 26,568 (45.8%) as nonengaged. Engaged participants achieved significantly greater weight loss at each time point. At month 3, engaged participants had a mean weight loss of 9% (95% CI 9% to 9.1%) compared with 5.9% (95% CI 5.9% to 6%) in nonengaged participants (P<.001), representing a mean difference of 3.1 percentage points (95% CI 3.1% to 3.1%). A Cohen d effect size of 0.89 indicated a large effect. At month 5, engaged participants had a mean weight loss of 11.53% (95% CI 11.5% to 11.6%) compared with 8% (95% CI 7.9% to 8%) in the nonengaged participants (P<.001). A Cohen d effect size of 0.56 indicated a moderate effect. Participants using tirzepatide achieved more significant weight loss than those using semaglutide at month 5 (13.9%, 95% CI 13.5% to 14.3% vs 9.5%, 95% CI 9.2% to 9.7%; P<.001). The proportion of engaged participants achieving ≥5%, ≥10%, and ≥15% weight loss was significantly higher than the nonengaged group at corresponding time points from months 3 to 5 respectively (P<.001). Engagement with a digital weight management platform significantly enhances weight loss outcomes among individuals using GLP-1 receptor agonists. The combination of pharmacotherapy and digital behavioral support offers a promising strategy to promote the supported self-care journey of individuals seeking clinically effective obesity management interventions.

Introduction Glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) have changed the landscape of type 2 diabetes (T2D) management due to their cardio-renal benefits, their glucose-lowering efficacy and weight loss (WL) maintenance. However, the response to GLP-1 RA monotherapy is heterogeneous. Additionally, the majority of GLP-1 RAs are injectable treatments. Oral GLP-1 RAs and injectable combinations of GLP-1 with other entero-pancreatic hormones (glucose-dependent insulinotropic polypeptide (GIP), glucagon and amylin) are under development for T2D and obesity management. Areas covered Herein, we review the data on (i) oral GLP-1 RAs (oral semaglutide 25/50 mg and orforglipron) and (ii) dual/triple agonists (tirzepatide, cagrilintide 2.4 mg/semaglutide 2.4 mg, survodutide, mazdutide, retatrutide) that have recently completed phase 3 trials for T2D or are currently in phase 3 clinical trials. Tirzepatide is the first approved dual agonist (GLP-1/GIP) for T2D and obesity management. Expert opinion We are in a new era in T2D management where entero-pancreatic hormone-based treatments can result in ≥15% WL and euglycemia for many people with T2D. Multiple molecules with different mechanisms of action are under development for T2D, obesity and other metabolic complications. Data on their cardio-renal benefits, long-term efficacy and safety as well as their cost-effectiveness will better inform their position in treatment algorithms.

nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum ranging from simple steatosis to steatohepatitis (NASH), increasing fibrosis and eventually, cirrhosis ([22][1]). Importantly, NASH accompanied by fibrosis and severe inflammation is the most relevant predictor for disease progression

Gut hormones are peptide hormones produced by the digestive tract that regulate digestion, nutrient absorption and metabolism eg. GLP-1, GIP, Glucagon, Amylin. The earliest gut hormone-based therapy for diabetes is the DPP-4 inhibitors eg. Vildagliptin, Sitagliptin, Linagliptin, which inhibit the DPP-4 enzyme that breaks down the incretin hormones (GLP-1 and GIP). The increase in circulating GLP-1 and GIP results in improved glycemia. The next class is the GLP-1 receptor agonist (GLP-1RA), which is based either on the exendin molecule (eg. Exenatide, Lixisenatide) or the human GLP-1 molecule (eg. Liraglutide, Dulaglutide, Semaglutide). The advantage of these GLP-1RAs is the benefit of weight reduction in addition to glucose lowering, and Liraglutide and Semaglutide have also been approved as obesity management medications in people with obesity without diabetes. GLP-1RAs (Liraglutide, Dulaglutide, Semaglutide) have also been shown to reduce the risk of major CV events in people with diabetes and more recently, Semaglutide has also been shown to reduce the risk of major CV events in people with obesity without diabetes. The newest class of gut hormone-based therapy is the dual incretin (GLP-1 and GIP) receptor agonist, Tirzepatide, which can result in more glucose lowering and weight reduction. This agent has also been approved as an obesity management medication in people with obesity without diabetes. There are now a number of agents being developed for the treatment of diabetes and obesity. Glucagon receptor (GCGR) agonism has been shown to increase energy expenditure. Hence, the development of GLP-1RA and GCGR agonists is expected to provide superior body weight reduction versus GLP-1RA alone. Mazdutide and Survodutide are two such agents being developed. Triple receptor agonist (GLP-1/GIP/GCGR agonist), Retatrutide, has been developed and shown to result in more glucose and body weight reduction. Other agents being studied are GLP-1 and Amylin receptor agonist (CagriSema, Amycretin) and GLP-1RA and GIP-R inhibitor (MariTide). In the oral formulation, small molecule GLP-1RA, Orforglipron and oral Amycretin are in development. In summary, gut hormone-based therapy has shown remarkable success not only for diabetes but also for obesity management. It also has the potential to reduce long-term diabetes and obesity complications, such as CV and CKD events. [J Assoc Clin Endocrinol Diabetol Bangladesh, 2025;4(Suppl 1): S6]