Obesity is a pandemic problem that correlates with a cluster of metabolic factors leading to poor cardiovascular outcomes, morbidity, and an increased risk of overall mortality. It is necessary to approach obesity with a comprehensive treatment plan, which may involve lifestyle modifications (diet, exercise, and behavioral therapy) and pharmacological interventions. This article provides an overview of the mechanisms of action, efficacy, and safety of available long-term anti-obesity drugs and introduces other potential agents under investigation.

Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.

Incretin mimetics, including glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide agonists, have become first-line treatment options for the treatment of type 2 diabetes and obesity. Their therapeutic status is attributed to their high level of efficacy as well as positive impact on related comorbidities, such as sleep apnea and heart failure. Multiple incretin mimetics are currently available with different durations of drug action, dosing frequencies, and delivery devices. Patients may benefit from education on the proper drug administration, anticipated adverse effects, and nutrition considerations with treatment. Practitioners must monitor progress and support the patient to achieve maintenance doses for optimal weight reduction and diabetes-related outcomes. This review aims to present the current literature supporting US Food and Drug Administration-approved indications of incretin mimetics, equip healthcare professionals to optimize care for patients who are prescribed these agents, and provide insights into potential future applications, which may include dual- or triple-mechanism agents that are injected or administered orally. Additional studies are anticipated with existing and future incretin mimetics for the treatment of type 2 diabetes, obesity, and related comorbidities in a rapidly developing therapeutic pipeline.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) have emerged as a leading pharmacologic for managing weight gain across most populations, including peri and postmenopausal women who frequently suffer from weight gain. There is a paucity of data about this specific population and how they respond to these medications. This review aims to discuss the data available about the use and effects of GLP-1 RAs in the peri and postmenopausal populations.

GLP-1 RAs are consistently the most effective pharmacologic for weight loss and can be a valuable tool for use in peri and postmenopausal women.

Additional research is needed to determine the risks and benefits and ideal use of GLP-1 RAs in peri and postmenopausal women.

The increasing prevalence of obesity represents a significant and growing challenge in orthopaedic surgery. This is particularly true for patients with morbid obesity, who have a significantly increased risk of postoperative complications. The newer incretin-based therapies (such as semaglutide and tirzepatide), these so-called "weight loss injections", offer promising potential for preoperative weight reduction and minimisation of peri- and postoperative complications.

However, the evidence regarding their influence on postoperative outcomes is inconsistent. Retrospective studies suggest that rapid weight loss immediately prior to orthopaedic surgery may increase the risk of complications, including septic shock and revision surgery. Meta-analyses, on the other hand, indicate potential protective effects in surgical outcomes with prior long-term weight reduction.

There are currently no sufficiently qualitative studies on the safety and efficacy of these new drugs in the orthopaedic surgery sector. An individualised and multidisciplinary approach, therefore, remains relevant in order to achieve an optimal surgical outcome for the individual patient.

Kidney transplantation (KT) is the best treatment for patients with kidney failure, associated with improved survival and quality of life compared with maintenance dialysis. However, despite constant improvements in the assessment and management of the alloimmune response, KT patients frequently demonstrate a reduced estimated glomerular filtration rate. Therefore, the usual complications of chronic kidney disease (CKD), such as anemia, hypertension, metabolic acidosis, hyperkalemia, or persistent secondary hyperparathyroidism, are highly prevalent after KT. However, their underlying mechanisms are different in the transplant setting (compared with the nontransplanted CKD population), and management recommendations are based on relatively poor-quality data. In recent years, new therapies have emerged, significantly improving kidney and cardiovascular outcomes of non-KT patients with CKD. Whether those new drugs could improve the outcomes of KT patients has largely been under investigated so far. In this review, we will address the challenges of the management of a KT patient with a reduced estimated glomerular filtration rate, cover the published evidence, and highlight the critical knowledge gaps.

Novel antidiabetic drugs, particularly sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, have significantly transformed the management landscape for type 2 diabetes mellitus, cardiovascular diseases, and chronic kidney diseases, owing to their well-established cardiorenal protective effects. Given the shared risk factors and comorbidities, it is relevant to consider the potential risk of venous thromboembolism (VTE) in individuals prescribed these novel antidiabetic medications. This literature review aims to summarize currently available evidence on VTE risk associated with novel antidiabetic drugs, including GLP-1 receptor agonists, dipeptidyl-peptidase IV (DPP-4) inhibitors, and SGLT2 inhibitors. Following a comprehensive search on PubMed using relevant keywords and backward reference searching, we identified 25 publications that directly reported on associations between these medications and VTE risk. Findings from these studies, including seven meta-analyses, reveal inconsistent results: some studies suggest that GLP-1 receptor agonists or DPP-4 inhibitors may be associated with increased risk of VTE, whereas SGLT2 inhibitors do not appear to be associated with VTE and may even be a protective factor. A notable limitation of the existing studies is the significant challenge posed by confounding in observational studies, while the randomized controlled trials (RCTs) often concluded with a limited number of VTE events, if it was studied. Furthermore, all identified studies focused on the risk of primary VTE, leaving an important knowledge gap regarding whether these novel antidiabetic drugs may influence the efficacy or safety of anticoagulants used for preventing VTE recurrence. Addressing these gaps presents an important avenue for future research.

Obesity is prevalent among patients with adult congenital heart disease (ACHD) and contributes to adverse cardiovascular outcomes. There is a paucity of data regarding glucagon-like peptide-1 receptor agonists (GLP-1 RA) for weight loss in patients with ACHD.

The purpose of this study was to assess the effect, safety, and outcomes of GLP-1 RA among patients with ACHD.

This is a retrospective cohort study of patients with ACHD at Mayo Clinic (01/2013-01/2024) who were prescribed semaglutide or liraglutide. The primary endpoint was weight loss. Secondary endpoints were changes in New York Heart Association class, hemoglobin A1c, estimated glomerular filtration rate, and safety endpoints of renal adverse event, hypoglycemia, hospitalization/drug discontinuation due to side effects.

Seventy patients received GLP-1 RA over a mean duration of 21 ± 20 months. Majority (85.7%) had moderate/severe complexity congenital heart disease. Weight loss >5% was achieved in 30 (42.9%) patients. Patients with body mass index ≥35 kg/m2 were more likely to achieve weight loss >5% [66.7% vs 40%, P = 0.027]. Younger age resulted in improved weight loss of 0.17 kg per 1-year age difference (P = 0.014). Hemoglobin A1c lowered by a mean of 0.6% (P = 0.054). There were no significant changes in New York Heart Association class or estimated glomerular filtration rate. One-third of patients experienced side effects, mostly from gastrointestinal intolerance (20%); 11.4% discontinued the medication due to side effects.

GLP-1 RAs are safe and effective for weight loss in patients with ACHD with beneficial effects on glycemic control.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are a newer class of glucose-lowering drugs with established cardiovascular benefit. However, their impact on bowel preparation quality remains controversial.

This article aimed to assess the association between GLP-1 RA use and colonoscopy quality indicators.

Electronic searches of PubMed and Embase were conducted up to January 2025. Clinical trials comparing colonoscopy quality indicators between GLP-1 RA users and controls were included. Non-English literature, meeting abstracts, and unpublished data were excluded. The primary outcome was the rate of inadequate bowel preparation; secondary outcomes included BBPS scores and adenoma/polyp detection rate (ADR/PDR).

Six trials were included, involving 8778 GLP-1 RA users and 8290 controls. GLP-1 RA users had a higher rate of inadequate bowel preparation (risk difference = 0.06, 95 % CI 0.05-0.08, p < 0.001, I² = 39 %). Total BBPS scores were lower among GLP-1 RA users (mean difference = -0.31, 95 % CI -0.39--0.23, p < 0.001, I² = 0 %). Two studies reported increased ADR/PDR in GLP-1 RA users; one showed a neutral result.

GLP-1 RA is associated with inadequate bowel preparation. Further research is needed to establish the optimal GLP-1 RA washout period before colonoscopy.

Amylin, a pancreatic peptide, has a well-established role in feeding behavior control. Amylin analogues are clinically utilized in patients with diabetes and are under investigation as potential anti-obesity pharmacotherapies. The neural circuits underlying actions of amylin on behavior are not well understood. While amylin was found to bind to the central amygdala (CeA) of rodents and primates and we found that all components of amylin receptors are present in the CeA, their potential role in physiology or behavior remains unknown. Here, we investigated the impact of this potential pancreas - CeA amylin-mediated communication - on ingestive and motivated behaviors. Activation of CeA amylin receptors resulted in a robust hypophagia, reduced food-motivated behavior, and altered macronutrient preference in male and female rats. Clinically used amylin analogue, pramlintide, reduced meal size and frequency by acting on the CeA. Disruption of CeA amylin signaling led to hyperphagia and body weight gain in a sex divergent manner. Importantly, CeA amylin signaling was required for appetite suppression induced by peripherally applied amylin, highlighting translational relevance of this brain site. Our data indicate the CeA is a critical neural substrate for amylin signaling.

Bariatric surgery, once the criterion standard in obesity treatment, has a small but concerning association with increased suicidality. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs), originally developed to treat diabetes, now provide substantial efficacy in the treatment of obesity. However, concerns of risk of suicidality with these medicines have been raised.

To evaluate the risk of suicidality and self-harm in randomized, placebo-controlled trials of GLP-1 RAs in adults with diabetes or obesity.

MEDLINE, Embase, ClinicalTrials.gov, and Cochrane databases were systematically searched from inception to August 29, 2023.

Reports of randomized clinical trials (RCTs) lasting 6 or more months comparing GLP-1 RAs with placebo for the treatment of diabetes or obesity published in peer-reviewed journals were identified. Two independent reviewers screened all search-identified studies for inclusion. Records of outcomes were queried from primary papers, ClinicalTrials.gov entries, and corresponding authors.

Two independent researchers abstracted data and assessed data quality and validity using PRISMA guidelines. Data were pooled using random-effects models.

Pooled incidence of completed or attempted suicide, occurrences of suicidal ideation, or self-harm.

A total of 27 of 144 RCTs meeting inclusion criteria systematically recorded suicide and/or self-harm-related events and included 32 357 individuals receiving GLP-1 RAs and 27 046 treated with placebo, over 74 740 and 68 095 person-years of follow-up, respectively. Event incidence was very low in the GLP-1 RA (0.044 per 100 person-years) and placebo (0.040 per 100 person-years) groups, with no statistically significant difference (rate ratio [RR], 0.76; 95% CI, 0.48-1.21; P = .24). Subgroup analyses did not suggest differences in outcomes based on diabetes status or GLP-1 RA used. Five studies were considered at risk of bias due to the loss of more than 5% of participants to follow-up. Otherwise, studies were not found to be heterogeneous nor at high risk of bias.

There is unlikely to be an increase in the very low incidence of suicide-related adverse events among individuals receiving GLP-1 RAs within the context of RCTs. While these findings may further ease concerns about these adverse effects, continued monitoring is warranted to identify particular patients who may be at risk as extended use of GLP-1 RAs expands.

Researchers and clinicians have increasingly recognized the importance of investigating and considering sex differences in obesity treatment. In this narrative review, we first summarized sex differences in select obesity-related conditions that have been the focus of studies of second-generation anti-obesity medications (i.e., semaglutide and tirzepatide) including type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure. We next described sex differences related to obesity treatments with a focus on the second-generation anti-obesity medications, semaglutide and tirzepatide.

Type 2 diabetes, obstructive sleep apnea, knee osteoarthritis, and heart failure demonstrated sex-specific pathways influenced by factors such as hormones and body composition. Lifestyle modification, on average, resulted in larger weight losses in males. In contrast, second-generation AOMs produced higher mean weight losses among females. Females reported more adverse events (e.g., nausea, vomiting) with second-generation anti-obesity medications. The few studies that have performed analyses of changes in obesity-related comorbidities stratified by sex have shown consistent improvements between males and females in heart failure and cardiovascular outcomes. Studies are needed to evaluate the effect of sex on the efficacy of anti-obesity medications including on mental health, investigate the mechanisms underlying these effects, and develop interventions to improve the availability and access of these medications.

Healthy "environment-sleep-emotion-exercise-diet" intervention [E(e)SEEDi] lifestyle can improve the quality of life, prolong aging and promote longevity due to improvement of human immunity and prevention of cardiovascular diseases (CVD). Here, the author reviewed the associations between these core elements with CVD and cardiovascular aging, and developed a new scoring system based on the healthy E(e)SEEDi lifestyle for prediction and evaluation of life expectancy. These core factors are assigned 20 points each (120 points in total), and a higher score predicts healthier aging and longevity. The E(e)SEEDi represents "a tree of life" bearing the fruits of longevity as well as "a rocket of anti-ageing" carrying people around the world on a journey of longevity. In conclusion, the E(e)SEEDi can delay aging and increase the life expectancy due to the role of a series of cellular and molecular "mechanisms-hallmarks-biomarkers". It's believed that the novel scoring system has a huge potential and beautiful prospects.

Worldwide, nearly 40% of adults are overweight and 13% are obese. Health consequences of excess weight include cardiovascular diseases, type 2 diabetes, dyslipidemia, and increased mortality. Treating obesity is challenging and calorie restriction often leads to rebound weight gain. Treatments such as bariatric surgery create hesitancy among patients due to their invasiveness. GLP-1 medications have revolutionized weight loss and can reduce body weight in obese patients by between 15% and 25% on average after about 1 year. Their mode of action is to mimic the endogenous GLP-1, an intestinal hormone that regulates glucose metabolism and satiety. However, GLP-1 drugs carry known risks and, since their use for weight loss is recent, may carry unforeseen risks as well. They carry a boxed warning for people with a personal or family history of medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2. Gastrointestinal adverse events (nausea, vomiting, diarrhea) are fairly common while pancreatitis and intestinal obstruction are rarer. There may be a loss of lean body mass as well as premature facial aging. A significant disadvantage of using these medications is the high rate of weight regain when they are discontinued. Achieving success with pharmacologic treatment and then weaning to avoid future negative effects would be ideal.

Glucagon-like peptide 1 (GLP-1) agonists are an effective medication for glycemic control and weight loss. These effects may reduce complications in diabetic patients undergoing total hip arthroplasty (THA). However, there remains a paucity of data on the impact of GLP-1 medications in nondiabetic patients using the medication solely for weight reduction. There is concern that rapid weight loss associated with GLP-1 agonists may lead to malnutrition and increase the risk of postoperative complications in patients undergoing THA.

A retrospective query was performed from January 1, 2010, to January 1, 2022, using an insurance claims database to identify patients undergoing primary THA on GLP-1 agonists (n = 839,715). Patients on GLP-1 therapy (n = 5,345) at the time of surgery were propensity score-matched 1:1 to controls who were not on GLP-1 agonists (n = 5,345) based on age, sex, the Elixhauser Comorbidity Index, and its components. Patients who had diabetes mellitus were excluded. The 90-day outcomes were evaluated, including medical complications, readmission, and reoperation rates. We also examined the incidence of all-cause revision and implant-related complications at a 2-year follow-up. Odds ratios (ORs) were generated using logistic regression analyses.

Patients who were on GLP-1 agonist medications were less likely to develop acute blood loss anemia (OR: 0.57; 95% confidence interval [CI]: 0.34 to 0.96) and require postoperative transfusion (OR: 0.53; 95% CI: 0.36 to 0.78) or visit the emergency department within 90 days of surgery (OR: 0.81; 95% CI: 0.69 to 0.92) when compared to patients who did not have GLP-1 therapy. Patients were at comparable risk of deep venous thrombosis, pulmonary embolism, mortality, stroke, myocardial infarction, acute kidney injury, and sepsis regardless of GLP-1 status (P > 0.05). Notably, the rate of aspiration pneumonia was similar between groups (OR: 1.17; 95% CI: 0.62 to 2.19). Also, GLP-1 therapy did not put patients at higher risk of surgical complications, including periprosthetic joint infection, instability, fracture, loosening, or all-cause revision, at 90 days and two years (P > 0.05).

Use of a GLP-1 agonist does not appear to increase the odds of postoperative medical and surgical complications after THA in nondiabetic patients taking GLP-1 medications for weight loss alone.

Fabry disease (FD) is an X-linked lysosomal storage disorder characterized by deficiency of α-galactosidase A (α-GalA), leading to the accumulation of glycosphingolipids and multi-organ dysfunction, particularly affecting the cardiovascular and renal systems. Disease-modifying treatments such as enzyme replacement therapy (ERT) and oral chaperone therapy (OCT) have limited efficacy, particularly in advanced disease, prompting a need for innovative therapeutic approaches targeting underlying molecular mechanisms beyond glycosphingolipid storage alone. Recent insights into the pathophysiology of FD highlights chronic inflammation and mitochondrial, lysosomal, and endothelial dysfunction as key mediators of disease progression. Adjunctive therapies such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, glucagon-like peptide-1 (GLP-1) agonists, and mineralocorticoid receptor antagonists (MRAs) demonstrate significant cardiovascular and renal benefits in conditions including heart failure and chronic kidney disease. These drugs also modulate pathways involved in the pathophysiology of FD, such as autophagy, oxidative stress, and pro-inflammatory cytokine signaling. While theoretical foundations support their utility, dedicated trials are necessary to confirm efficacy in the FD-specific population. This narrative review highlights the importance of expanding therapeutic strategies in FD, advocating for a multi-faceted approach involving evidence-based adjunctive treatments to improve outcomes. Tailored research focusing on diverse FD phenotypes, including females and non-classical variants of disease, will be critical to advancing care and improving outcomes in this complex disorder.

Cigarette smoking cessation reduces cardiovascular risk via various mechanisms. Thereby, the role of blood pressure remains unclear, with studies reporting both decreased and increase blood pressure values after cessation, potentially influenced by weight change. We previously showed that the glucagon like peptide-1 analogue dulaglutide mitigates weight gain after smoking cessation. This secondary analysis investigates the effect of smoking cessation on blood pressure changes in dulaglutide- vs. placebo-treated individuals. We hypothesized a beneficial effect of smoking cessation on blood pressure, particularly in dulaglutide-treated participants.

This is a predefined secondary analysis of a randomized, double-blind, placebo-controlled trial. Participants (n = 255) underwent a 12-week smoking cessation programme including standard of care (behavioural counselling and varenicline) with weekly injections of dulaglutide 1.5 mg or placebo, followed by a follow-up of 52 weeks. The primary outcome was change in systolic blood pressure after 52 weeks in abstinent vs. smoking individuals. Further outcomes included blood pressure and body weight changes at Week 12 and 52 according to smoking status and treatment arms. A path analysis was performed to estimate direct and indirect effect of different variables on systolic blood pressure changes. Two hundred and eighteen out of 255 participants with complete blood pressure readings were included in the analyses. Across the entire study population, systolic blood pressure was stable over the period of 52 weeks after smoking cessation despite a weight gain of +3 kg (0, 5.4) at Week 52. Blood pressure reductions were seen in the subgroups of participants with minimal weight gain ≤3 kg [-4.6 mmHg (-9, 3)] and in individuals with hypertensive blood pressure values at baseline [-16 mmHg (-22, 2)]. Dulaglutide treatment reduced body weight and blood pressure initially, followed by a weight rebound and a blood pressure increase of +7.5 mmHg (-1, 15) at Week 52. The path analysis identified weight as an important factor influencing blood pressure during smoking cessation.

Our analysis suggests that smoking cessation may have a beneficial effect on blood pressure- especially in hypertensive individuals-, counteracting the expected blood pressure increase caused by post-cessation weight gain. However, it also underlines the importance of weight control after smoking cessation as a crucial factor in smoking cessation.

ClinicalTrials.gov: NCT03204396.

Emerging data on cardiovascular outcomes, specifically major adverse cardiovascular events (MACE), are being reported from various trials involving incretin mimetics, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and glucose-dependent insulinotropic polypeptide (GIP), especially among patients with obesity and diabetes. Our aim was to evaluate this matter, while also involving various traditional cardiovascular risk factors [e.g., several body weight (BW) parameters, blood pressure (BP), lipid profile].

A search of PubMed, Europe PMC, ScienceDirect, Cochrane, and ClinicalTrials.gov up to September 2024 was performed to identify GLP-1 RA and GIP trials in MACE risk reduction as a primary endpoint. Our secondary endpoints included a reduction in BW, waist circumference (WC), body mass index (BMI), BP changes, and lipid modifying effects, while also yielding safety concerns surrounding the use of these pharmaceutical agents. Mean differences (MD) and risk ratios (RR) were summarized using random-effects model.

A total of 11 eligible randomized controlled trials (RCTs) comprising 8 GLP-1 RA trials and 3 dual GLP-1 RA/GIP (tirzepatide) trials were included. Compared with control groups, GLP-1 RA significantly reduced the MACE risk by 32% [RR 0.68 (95% CI 0.53-0.87); P = 0.002; I2 = 73%, P-heterogeneity < 0.001] and 59% for tirzepatide [RR 0.41 (95% CI 0.18-0.92); P = 0.03; I2 = 0%, P-heterogeneity = 0.96]. Incretin mimetics also substantially reduced BW, BP, and improved lipid panel measures. However, there was an increased risk of adverse events, specifically gastrointestinal disorders within the incretin mimetics subset.

Incretin mimetics have shown promise in reducing MACE risk while also enhancing cardiovascular risk factors, including blood pressure and lipid profile, in adults with obesity without diabetes.

As the prevalence of obesity increases worldwide, and lifestyle modification or pharmaceutical treatment yields insufficient results for patients with severe obesity, an increasing number of patients opt for metabolic bariatric surgery as an effective and durable treatment of this disease. Seeing as 80% of these patients are women, many of whom are of reproductive age, pregnancies after metabolic bariatric surgery become increasingly common. Metabolic bariatric surgery has many benefits for overall health and pregnancy outcomes, but certain risks are also reported. This leads to the rise of a new population of patients with their own specific needs regarding follow-up. This review discusses the various benefits and risks of these types of surgery for pregnancy. We provide an overview of the current state of the evidence and look into future research goals.

Hidradenitis suppurativa (HS) is an inflammatory skin disorder presenting with painful and draining nodules in intertriginous areas that may progress to sinus tracts. There is an increased prevalence of obesity in HS, and obesity may predispose patients to HS. Weight loss has been associated with improvement of HS symptoms. However, weight loss through diet modification, exercise or bariatric surgery has mixed results. Recently, glucagon-like peptide-1 (GLP-1) receptor agonists have been investigated for weight loss in HS. These drugs are effective for weight loss and reduce weight-related comorbidities, with few significant side effects. Early studies of liraglutide and semaglutide in HS have demonstrated improvement in disease severity and quality of life. GLP-1 receptor agonists are a promising therapy for patients with HS and may improve symptoms through decreased mechanical stress and moderation of inflammation.

Successful treatment of obesity requires a multidisciplinary approach including dietary strategy, physical activity, and behavioral modification. The seven FDA-approved anti-obesity medications are phentermine, orlistat, phentermine/topiramate ER, naltrexone SR/bupropion SR, liraglutide 3.0 mg, semaglutide 2.4 mg, and tirzepatide. Obesity is a chronic disease and these medications should be prescribed with the intention of long-term use. In this article, we summarize data from phase 3 clinical trials which led to drug approval, and we review the clinical indications, mechanism of action, dosing/administration, side effects, drug interactions and contraindications for each medication.

The objective of this study was to investigate the efficacy and safety of the Epitomee capsule versus placebo as an adjunct to high-intensity lifestyle intervention in participants with overweight or obesity.

The Randomized Evaluation of Efficacy and Safety of the Epitomee Capsule Trial (RESET) was a prospective, double-blind, placebo-controlled pivotal trial in adults with baseline BMI of 27.0 to 40.0 kg/m2. The co-primary endpoints at week 24 were percentage change from baseline in body weight for the Epitomee and placebo groups and proportion of Epitomee-treated patients achieving ≥5% weight loss compared with a 35% threshold. The primary safety endpoint was the incidence of device-related serious adverse events.

A total of 138 participants received Epitomee and 141 received placebo. Mean (SD) change in body weight from baseline was -6.6% (6.5%) with Epitomee and -4.6% ( 4.7%) with placebo; least-squares means were -6.1% (0.6%) and -4.2% (0.6%), respectively (p = 0.0054). Fifty-six percent of Epitomee-treated participants attained ≥5% weight loss from baseline, which was significantly greater than the 35% predefined threshold (p < 0.0001). Twenty-seven percent of Epitomee-treated and eleven percent of placebo-treated participants achieved ≥10% weight loss. Adverse event rates were similar between the groups. No device-related serious adverse events occurred.

The Epitomee capsule is a safe and efficacious nonpharmacological option for weight management with potential broad application in participants with overweight or obesity.

Transoral outlet reduction endoscopy (TORe) and glucagon-like peptide-1 agonist, liraglutide, have individually shown promise in managing weight regain after Roux-en-Y gastric bypass. However, combined effects of adjunctive liraglutide to TORe remain unexplored. A cross-over design was utilized to evaluate the efficacy of liraglutide treatment when initiated immediately post-TORe or 1 year post-TORe.

Data was analyzed from a double-blinded randomized controlled trial conducted at three outpatient clinics in São Paulo, Brazil, from January 2019 to December 2021. Two cohorts were established: group placebo then liraglutide (group PL) received subcutaneous saline dosed daily for 12 months after TORe then liraglutide for the subsequent 12 months, while group liraglutide then placebo (group LP) started subcutaneous liraglutide followed by subcutaneous saline in a similar fashion. Each participant received placebo and liraglutide for equal duration over the 24-month treatment phase. The primary outcomes were percent total body weight loss (%TBWL) at 12 and 24 months.

The study comprised 58 participants in group PL and 51 participants in group LP, with no significant difference in mean baseline BMI between groups. Group LP showed significantly higher %TBWL than group PL at 6, 9, and 12 months. Surprisingly, at 21 and 24 months, group LP continued to exhibit greater %TBWL than group PL, even after discontinuing liraglutide.

Immediate post-procedure administration of liraglutide appears to be more effective than placebo in reversing weight regain in patients undergoing TORe. Results indicate that the timing of post-TORe liraglutide initiation may enhance the therapeutic benefits of the procedure.

Obesity is a chronic condition that causes significant morbidity and mortality in people in the United States and around the world. Traditional means of weight loss include diet, exercise, behavioral modifications, and surgery. New weight loss medications, glucagon-like peptide-1 receptor agonists, are revolutionizing the management of weight loss but have implications for fertility and pregnancy. Obesity is associated with infertility and may affect response to ovulation induction medications. In pregnancy, obesity increases the risks of spontaneous abortion, birth defects, gestational diabetes, hypertensive disorders of pregnancy, cesarean delivery, and stillbirth. Lifestyle changes alone for weight loss have not improved outcomes. Glucagon-like peptide-1 receptor agonists and new medications targeting gut hormones can help people achieve their weight loss goals but are contraindicated in pregnancy. Obstetrician-gynecologists should work with patients to manage these medications before they become pregnant, between pregnancies, and after delivery.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs), and dual GLP-1/glucose-dependent insulinotropic peptide (GIP) or glucagon receptor agonists have emerged as promising agents to treat metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH). Although the beneficial effects of GLP-1RAs on glycemic control and weight are well-established, clinicians may be unfamiliar with other potential benefits of this class.

We examined the pleiotropic effects of GLP-1RAs and how they relate to gastroenterologists for MASLD/MASH treatment. Our narrative review of English articles included four GLP-1RAs (subcutaneous semaglutide, liraglutide, dulaglutide, and efpeglenatide), a dual GLP-1/GIP agonist (tirzepatide), a dual GLP-1/glucagon receptor agonist (survodutide), MASLD/MASH, related disorders, clinical management, treatment outcomes and landscape.

In Phase I - III trials, GLP-1RAs are associated with clinically relevant hepatic improvements including MASH resolution, liver fat reduction, and preventing worsening fibrosis. Effects on cardiometabolic parameters align with type 2 diabetes/obesity Phase III data, comprising substantial improvements in glycemic, weight, and cardiovascular outcomes. Promising data also suggest benefits in common comorbidities, including obstructive sleep apnea, polycystic ovary syndrome, chronic kidney disease, and heart failure with preserved ejection fraction.GLP-1RAs represent a valuable pharmacotherapeutic option for gastroenterologists managing individuals with MASLD/MASH and cardiometabolic comorbid conditions.

GLP-1-based therapies have changed the treatment of overweight/obesity. Liraglutide 3.0 mg daily, the first GLP-1 RA approved for treatment of overweight, induced a weight loss of 6-8%, Semaglutide 2.4 mg once weekly improved weight loss to about 12-15%, while the dual GIP/GLP-1 receptor agonist tirzepatide once weekly has induced a weight loss of about 20% in obese people without diabetes.

This review describes results obtained with GLP-1 mono-agonists, GLP-1/GIP dual agonists, GLP-1/glucagon co-agonists, and the triple agonist retatrutide (GIP/GLP-1/glucagon), which have shown beneficial effect both on body weight and steatotic liver disease. A combination of semaglutide (a GLP-1 agonist) and cagrilintide (a long-acting amylin analogue) for weekly administration is currently in phase III development, and so is oral semaglutide and several non-peptide small molecule GLP-1 agonists for oral administration. The adverse events with the GLP-1-based therapies are primarily gastrointestinal and include nausea, vomiting, obstipation, or diarrhea, which often can be mitigated by slow up titration.

The GLP-1-based therapies will change the treatment of obesity and its comorbidities including steatotic liver disease in the future. Outstanding question is maintenance of the weight loss, possibly pharmacological treatment needs to be life-long.

Data on tirzepatide in Asian patients with obesity are limited. This study aimed to gain a better understanding of tirzepatide for treatment of Japanese patients with obesity disease (BMI ≥25 kg/m2 with excessive fat accumulation) as defined by the Japanese Society for the Study of Obesity.

This was a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial of the efficacy and safety of tirzepatide as an adjunct to lifestyle modifications. Japanese adults with obesity disease (BMI ≥27 kg/m2 accompanied by ≥2 obesity-related health disorders or ≥35 kg/m2 accompanied by ≥1 obesity-related health disorders), excluding diabetes, were assigned 1:1:1 via computer-generated random sequence to receive once weekly subcutaneous tirzepatide (10 mg or 15 mg) or placebo. Coprimary endpoints were the mean percent change in bodyweight and the proportion of participants achieving at least 5% bodyweight reduction at week 72, using the efficacy estimand. Efficacy and safety were assessed in the modified intention-to-treat (mITT) population. This study is registered with ClinicalTrials.gov, NCT04844918.

Between May 10, 2021, and June 24, 2023, 413 participants were screened, and 267 were randomly assigned. Due to exclusion of one study site, the mITT population was 225 participants (133 [59%] men and 92 [41%] women, mean age 50·8 [SD 10·7] years), with 73 in the tirzepatide 10 mg group, 77 in the tirzepatide 15 mg group, and 75 in the placebo group, of whom 192 (85%) completed both study and treatment. Estimated treatment differences relative to placebo in change in bodyweight at week 72 were -16·1% (95% CI -18·7 to -13·5; p<0·0001) and -21·1% (95% CI -23·6 to -18·5; p<0·0001) following tirzepatide 10 mg and 15 mg, respectively. At week 72, a higher proportion of participants achieved at least 5% bodyweight reduction with tirzepatide 10 mg (67 [94%] of 71) and 15 mg (73 [96%] of 76) compared with placebo (15 [20%] of 75; both p<0·0001). Cardiometabolic and body composition indices were also improved with tirzepatide. Participants treated with tirzepatide experienced treatment-emergent adverse events more frequently (10 mg: n=61 [84%]; 15 mg: n=66 [86%]) than those who received placebo (52 [69%]), most commonly gastrointestinal symptoms. Study discontinuations due to adverse events were infrequent (placebo: n=3 [4%]; tirzepatide 10 mg: n=1 [1%]; tirzepatide 15 mg: n=0).

In Japanese adults with obesity disease, tirzepatide provided clinically a meaningful reduction in bodyweight compared with placebo over 72 weeks, with a safety profile consistent with that observed in global populations.

Eli Lilly and Company.

For the Japanese translation of the abstract see Supplementary Materials section.

The association between GLP-1 receptor agonists (GLP-1RA) and nonarteritic anterior ischemic optic neuropathy (NAION) remains unclear. Given the debilitating sequelae of NAION and rapid increase of GLP-1RA use, further research is essential to investigate this potential relationship. This study seeks to determine the risk of NAION and ischemic optic neuropathy (ION) in patients prescribed GLP-1RAs.

Retrospective matched cohort study.

TriNetX United States collaborative network.

Patients ≥12 years old with type 2 diabetes (T2DM) and considered overweight or obese (high BMI), with at least one ophthalmology or neurology visit. Among T2DM patients, approximately 120,000 patients with a semaglutide prescription and 220,000 prescribed any GLP-1RA were compared to matched T2DM controls. Among high BMI patients, approximately 58,000 on semaglutide and 66,000 on any GLP-1RA were compared to matched controls.

Patients prescribed semaglutide or any GLP-1RA were compared with those on non-GLP-1RA medications. Populations were propensity matched (1:1) on various demographic and risk factors to balance baseline cohorts.

Cumulative incidence and risk of NAION and ION. Risk ratios (RR) with 95% confidence intervals (CI) were reported, with significance defined as CI <0.9 or > 1.1.

In T2DM patients prescribed semaglutide, the risk of NAION (RR = 0.7, 95% CI: 0.523-0.937) and ION (RR = 0.788, 95% CI: 0.609-1.102) after 5 years was not significantly increased compared to matched T2DM controls. Similarly, T2DM patients on any GLP-1RA demonstrated no significant difference in the risk of NAION (RR = 0.887, 95% CI: 0.735-1.071) or ION (RR = 0.969, 95% CI: 0.813-1.154) compared to controls. Furthermore, no increased risk of either outcome was found in the high BMI groups prescribed semaglutide or any GLP-1RA. The cumulative 5-year risk of NAION and ION in T2DM patients on semaglutide was 0.065% and 0.08%, respectively. In those with high BMI prescribed semaglutide, the risk of NAION and ION after 2 years was 0.038% and 0.404%, respectively.

There was no significant increase in risk of NAION or ION in patients taking semaglutide or GLP-1RAs compared to T2DM or high BMI controls.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have emerged as groundbreaking therapeutic agents in managing a spectrum of metabolic disorders, demonstrating remarkable efficacy across multiple organ systems and disease states. These compounds are not only well-established in the treatment of type 2 diabetes (T2D) and obesity-conditions for which they have received widespread approval-but also exhibit promising potential in addressing cardiovascular disease (CVD) and Metabolic dysfunction-associated steatotic liver disease (MASLD). Recent investigations have begun to illuminate the utility of GLP-1RAs in the management of type 1 diabetes (T1D), as well as neurodegenerative disorders such as Alzheimer's and Parkinson's disease and various behavioral disorders. A plethora of clinical trials have consistently validated the capacity of GLP-1RAs to improve glycemic control, promote weight loss, and mitigate cardiovascular risk factors in individuals with T2D and obesity. While their application in T1D remains limited due to safety concerns-particularly regarding the risks of hypoglycemia and hyperglycemic ketoacidosis-emerging data suggest that GLP-1RAs may offer hepatoprotective benefits, potentially reducing liver fat content and decelerating the progression of MASLD. The neuroprotective attributes of GLP-1 RAs have garnered significant interest, with research indicating their potential to alleviate cognitive decline associated with neurodegenerative diseases. Furthermore, preliminary findings highlight the role of GLP-1 RAs in addressing behavioral disorders, emphasizing their extensive therapeutic promise. This comprehensive review synthesizes the current evidence supporting the diverse therapeutic applications of GLP-1RAs, positioning them as "magic drug" therapies for metabolic and neurological disorders. As ongoing research continues to explore innovative applications and combinations of GLP-1RAs, the landscape of disease management in metabolic and neurological contexts is poised for transformative advancements. This review will also critically assess safety considerations and underscore the need for personalized treatment strategies to optimize patient outcomes in these complex and often comorbid conditions.

In recent years, "metabolic dysfunction-associated steatotic liver disease" (MASLD) has been proposed to better connect liver disease to metabolic dysfunction, which is the most common chronic liver disease worldwide. MASLD affects more than 30% of individuals globally, and it is diagnosed by the combination of hepatic steatosis and obesity, type 2 diabetes, or two metabolic risk factors. MASLD begins with the buildup of extra fat, often greater than 5%, within the liver, causing liver hepatocytes to become stressed. This can proceed to a more severe form, metabolic dysfunction-associated steatohepatitis (MASH), in 20-30% of people, where inflammation in the liver causes tissue fibrosis, which limits blood flow over time. As fibrosis worsens, MASH may lead to cirrhosis, liver failure, or even liver cancer. While the pathophysiology of MASLD is not fully known, the current "multiple-hits" concept proposes that dietary and lifestyle factors, metabolic factors, and genetic or epigenetic factors contribute to elevated oxidative stress and inflammation, causing liver fibrosis. This review article provides an overview of the pathogenesis of MASLD and evaluates existing therapies as well as pharmacological drugs that are currently being studied in clinical trials for MASLD or MASH.

Weight optimization methods in morbidly obese patients with a body mass index (BMI) of ≥40 kg/m 2 undergoing total knee arthroplasty (TKA) have shown mixed results. The purpose of this study was to evaluate the effect of perioperative use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in patients with a BMI of ≥40 kg/m 2 undergoing primary TKA.

Using an administrative claims database, patients with morbid obesity undergoing primary TKA were stratified into GLP-1 RA use for 3 months before and after the surgical procedure (treatment group) and GLP-1 RA non-use (control group), and were matched on the basis of patient age, gender, diagnosis of type-2 diabetes mellitus, and Charlson Comorbidity Index (CCI). In addition, these groups were compared with a contemporaneous cohort of patients undergoing TKA with a BMI of 35.0 to 39.9 kg/m 2 . Outcomes including infection, complications, revision, and readmission were compared between the matched cohorts.

There were significant decreases in the rates of 90-day periprosthetic joint infection (PJI) (1.0% compared with 1.8%; p = 0.037), any medical complications (10.6% compared with 12.7%; p = 0.033), pulmonary embolism (<0.4% compared with 0.6%; p = 0.050), and readmissions (5.3% compared with 8.9%; p < 0.001) in patients with a BMI of ≥40 kg/m 2 who were taking GLP-1 RA versus the control group who were not. There were no differences in the 2-year rates of surgical complications (p > 0.05) between these groups. Compared with obese patients (BMI of 35.0 to 39.9 kg/m 2 ), patients who had a BMI of ≥40 kg/m 2 and were taking a GLP-1 RA did not have increased rates of infection or 90-day or 2-year complications (p > 0.05).

GLP-1 RA administration for at least 90 days prior to and after primary TKA in patients with a BMI of ≥40 kg/m 2 was associated with reductions in the risks of 90-day PJI, any medical complications, and readmission. Additionally, the reduced complication rate that was achieved was similar to that of obese patients with a BMI of 35.0 to 39.9 kg/m 2 undergoing TKA. Randomized clinical trials are needed to define the true effect of these agents on clinical outcomes following TKA.

Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Obesity and overweight have become increasingly significant conditions, affecting more than 70% of the adult population in the United States. These conditions are caused by a combination of factors, including genetic, behavioral, environmental, and medical influences. Obesity is a major risk factor for cardiovascular and metabolic diseases. A comprehensive treatment plan for individuals with obesity must recognize the chronic nature of the condition and offer strategies for weight reduction and long-term cardiometabolic benefits. Over the past several decades, multiple therapeutic options have been implemented to address weight loss, appetite regulation, and caloric expenditure, with the goal of reducing the burden of obesity and improving cardiovascular outcomes. Pharmacological treatment of obesity has focused primarily on the central regulation of appetite and food intake behavior. The introduction of incretin agonists for obesity treatment has ushered in a new era of cardiometabolic health, with a multitargeted mechanism that achieves weight loss, glycemic control, decreased cardiovascular mortality, and other metabolic benefits. This review explores the current pharmacological options and the future of obesity treatment.

The global prevalence of obesity has more than doubled over the past four decades, currently affecting more than a billion individuals. Beyond its recognition as a high-risk condition that is causally linked to many chronic illnesses, obesity has been declared a disease per se that results in impaired quality of life and reduced life expectancy. Notably, two-thirds of obesity-related excess mortality is attributable to cardiovascular disease. Despite the increasingly appreciated link between obesity and a broad range of cardiovascular disease manifestations including atherosclerotic disease, heart failure, thromboembolic disease, arrhythmias, and sudden cardiac death, obesity has been underrecognized and sub-optimally addressed compared with other modifiable cardiovascular risk factors. In the view of major repercussions of the obesity epidemic on public health, attention has focused on population-based and personalized approaches to prevent excess weight gain and maintain a healthy body weight from early childhood and throughout adult life, as well as on comprehensive weight loss interventions for persons with established obesity. This clinical consensus statement by the European Society of Cardiology discusses current evidence on the epidemiology and aetiology of obesity; the interplay between obesity, cardiovascular risk factors and cardiac conditions; the clinical management of patients with cardiac disease and obesity; and weight loss strategies including lifestyle changes, interventional procedures, and anti-obesity medications with particular focus on their impact on cardiometabolic risk and cardiac outcomes. The document aims to raise awareness on obesity as a major risk factor and provide guidance for implementing evidence-based practices for its prevention and optimal management within the context of primary and secondary cardiovascular disease prevention.

This case report is interesting because it highlights a direction for the treatment of comorbid obesity and cocaine use disorder, which is an increasing clinical condition from an epidemiological point of view, and allows us to identify the possibility of a new strategy to address the problem of substance craving, particularly for cocaine.

This case report discusses the efficacy of semaglutide in a 54-year-old Caucasian patient with a history of cocaine abuse and obesity. Subcutaneous semaglutide was administered, as per guidelines, with a progressive weekly increase for a total of 12 weeks. The patient was monitored with respect to clinical parameters, as well as psychodiagnostic ones. The patient demonstrated significant weight loss and a marked reduction in cocaine craving.

The action of semaglutide on the hunger and reward centers offers a new approach to the treatment of patients with obesity and concomitant substance use disorders. By targeting glucagon-like peptide-1 receptors involved in both metabolic regulation and reward processing, semaglutide could potentially reduce both food intake and drug craving, thereby improving outcomes for these patients. The findings suggest that semaglutide may be a promising therapeutic option for the management of substance abuse in patients with comorbid obesity.

Type 2 diabetes is a chronic disease characterized by insulin resistance and often worsened by obesity. Effective management involves the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to assist with glycemic control and weight management. However, these drugs must be administered subcutaneously due to their low oral bioavailability. We developed an oral liraglutide (LRG) formulation by electrostatic complexation of GLP-1 RA with bile acid derivatives and nanomicelle (NM) formation, with non-ionic surfactant n-dodecyl-β-d-maltoside (DDM). The optimized formulation, LDD[1:2:4]-NM, had a mean particle size of 75.9 ± 5.60 nm and a permeability 1347 % higher than that of unformulated LRG when tested in Caco-2/HT29-MTX-E12 cell monolayers. In rats, oral bioavailability was 4.63-fold higher than that of unformulated LRG (1.11 ± 0.20 % vs. 5.14 ± 0.63 %). The absorption mechanism included clathrin-mediated endocytosis, macropinocytosis, and an ASBT-mediated pathway. A 12-week oral treatment consisting of a daily dose of 20 mg LDD[1:2:4]-NM/kg significantly reduced glycohemoglobin levels, a marker of diabetic control, and the HOMA-IR index, a marker of insulin resistance. The weight of epididymal and inguinal white adipose tissue and brown adipose tissue (BAT) was also reduced. Moreover, LDD[1:2:4]-NM had a greater impact on BAT activation, pro-inflammatory gene expression, and lipid metabolism than subcutaneous LRG. This study showed that an oral NM formulation can efficiently deliver LRG. Long-term treatment led to improved hyperglycemic effects, insulin resistance, and modulated lipid metabolism. LDD[1:2:4]-NM is thus a promising oral therapeutic option for the management of type 2 diabetes, potentially transforming treatment paradigms based on the availability of a more convenient administration route.

As reported in the World Obesity Atlas 2024 by the World Obesity Federation, the projections for 2035 suggest that more than 1 [...].

Cardiometabolic diseases represent an escalating global health crisis, slowing or even reversing earlier declines in cardiovascular disease (CVD) mortality. Traditionally, conditions such as obesity, type 2 diabetes mellitus (T2DM), atherosclerotic CVD, heart failure (HF), chronic kidney disease (CKD), and metabolic dysfunction-associated steatotic liver disease (MASLD) were managed in isolation. However, emerging evidence reveals that these disorders share overlapping pathophysiological mechanisms and treatment strategies. In 2023, the American Heart Association proposed the Cardiovascular-Kidney-Metabolic (CKM) syndrome, recognizing the interconnected roles of the heart, kidneys, and metabolic system. Yet, this model omits the liver-a critical organ impacted by metabolic dysfunction. MASLD, which can progress to metabolic dysfunction-associated steatohepatitis (MASH), is closely tied to insulin resistance and obesity, contributing directly to cardiovascular and renal impairment. Notably, MASLD is bidirectionally associated with the development and progression of CKM syndrome. As a result, we introduce an expanded framework-the Cardiovascular-Renal-Hepatic-Metabolic (CRHM) syndrome-to more comprehensively capture the broader inter-organ dynamics. We provide guidance for an integrated diagnostic approach aimed at halting progression to advanced stages and preventing further organ damage. In addition, we highlight advances in medical management that target shared pathophysiological pathways, offering benefits across multiple organ systems. Viewing these conditions as an integrated whole, rather than as discrete entities, and incorporating the liver into this framework fosters a more holistic management strategy and offers a promising path to addressing the cardiometabolic pandemic.

Virtually-delivered obesity care has the potential to increase access to weight loss interventions at scale. While there is ample literature assessing various weight loss interventions, studies specifically demonstrating outcomes of commercial programs offering antiobesity medications in virtual care settings are lacking.

This retrospective cohort study assessed the weight loss outcomes of 66,094 participants in a virtual weight care program that prescribes antiobesity medications alongside a digital behavior change program. Outcomes included the primary endpoint of percent weight loss at 12 months, as well as absolute change in body weight, change in body mass index (BMI), categorical weight loss at three, six, and 12 months, and stratifications by program engagement and medication type (first vs. second generation antiobesity medications).

At program enrollment, members were on average 42.6 years old and 91.5% female, with a BMI of 36.0 kg/m2. At 12 months, the mean percent weight loss was 8.0%, with weight loss increasing over time from 2.9 kg (SD = 3.7, Cohen's d = 0.8) at 3 months, to 5.8 kg (SD = 6.1, Cohen's d = 0.9) at 6 months, to 8.0 kg (SD = 8.7, Cohen's d = 0.9) at 12 months (p < 0.001 for all time points). At 12 months, 64.2% had achieved ≥ 5% weight loss. Weight loss outcomes increased with program engagement. At 12 months, those engaging at least once weekly lost 10.0% of body weight, while those logging weight at least weekly lost 12.0%.

This study provides real-world evidence that users of a virtual commercial weight care clinic who were prescribed antiobesity medications achieved clinically significant weight loss at six and 12 months. These findings support the value of virtual platforms in efficiently scaling access to high-quality weight care.

Given the promising effects of GLP-1/GIP/glucagon receptor triagonists on weight loss in animals and humans, improved understanding of underlying mechanism is required. We investigated a direct lipolytic effect of a specific GLP-1/GIP/glucagon receptor triagonist on human adipose tissue to disentangle central and peripheral effects as potential drivers of weight loss.

Isolated primary adipocytes from subcutaneous adipose tissue biopsies of 22 non-diabetic subjects [63.0 (57.0-69.5) years] were incubated with increasing concentrations of isoprenaline, GLP-1, GIP, glucagon, or a GLP-1/GIP/glucagon receptor triagonist. Glycerol concentration was measured following stimulation to assess lipolysis. mRNA expression of adipose tissue receptors was analyzed in parallel.

Glycerol concentration only increased by isoprenaline, GIP (+13%), and GLP-1/GIP/glucagon receptor triagonist (+28%) but not by GLP-1 or glucagon. This effect was not related to age or body mass index (BMI). Higher adipose tissue GIP receptor mRNA expression was related to elevated glycerol release after GIP and GLP-1/GIP/glucagon receptor triagonist stimulation.

Direct lipolytic effects of GIP seem to exist in human subcutaneous adipose tissue. This might be targetable by multiple receptor agonists, especially with a high GIP receptor affinity. Such a mechanism can potentiate the beneficial effect on weight loss and will therefore represent a promising target of future research.

The trial was registered at German Clinical Trials Register (drks.de) as DRKS00010049.

The escalating obesity epidemic poses serious public health challenges, requiring the development of effective therapeutic strategies. In this study, we aimed to determine if recombinant glycoprotein hormone β5 (GPHB5) protein, particularly in the hybrid form with glycoprotein hormone α2 (GPHA2) (recombinant corticotroph-derived glycoprotein hormone, rCGH), can alleviate obesity in the genetically obese mice, ob/ob. Six-week-old male ob/ob mice were intraperitoneally injected for four weeks with rCGH (10 mg/kg) treatment. Body weight, fat mass and lean mass as well as energy expenditure were evaluated. Blood samples were collected to assess circulating concentrations of triiodothyronine (T3) and thyroxine (T4). Glucose and insulin tolerance tests were also conducted. rCGH significantly decreased body weight and fat mass, stimulated energy expenditure without alterations in food consumption, induced lipolysis and browning of white adipose tissue (WAT) by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling pathway. The treatment with the recombinant protein also led to marked reduction in hepatic steatosis, improved glucose tolerance and insulin sensitivity, and reduced triglycerides (TG), and total cholesterol (T-CHO) levels in ob/ob mice. In conclusion, rCGH attenuated obesity and alleviated metabolic syndromes in ob/ob mice, and it may represent a promising polypeptide-based drug candidate in treating obesity and obesity-related complications without interfering energy intake.

Glucagon-like-peptide-1 receptor agonists (G1RA) have gained popularity as a treatment for weight loss in patients who are overweight or obese, but their utilization patterns and impact on candidates for metabolic and bariatric surgery (MBS) remain understudied.

We aimed to investigate the prevalence, characteristics, and outcomes of patients with a history of G1RA utilization among MBS candidates.

Five high-volume MBS centers in Israel.

Data were collected retrospectively from February 1st, 2023, to September 30th, 2023. Demographic, clinical, and treatment data were analyzed to assess a history of G1RA use, associated factors, adverse events, and treatment outcomes.

Four hundred thirty-four MBS candidates were included in the study. A history of G1RA utilization was obtained in 275 (63%) MBS candidates, with Liraglutide and Semaglutide being the most commonly used agents. Younger age, type 2 diabetes mellitus, dyslipidemia, and no previous MBS history were associated with a higher rate of G1RA utilization. With these medications, median maximal weight loss was 5.38 kg, and mean duration of use was 19 weeks. Patients using G1RA for ≥6 weeks experienced significantly greater weight loss compared to those using it for shorter periods (6.3 ± 6.43 vs 1.65 ± 1.69; P < .001). GI-related adverse events were reported in 57.8% of patients. Over 95% of patients discontinued G1RA due to insufficient weight loss and/or adverse effects. Patients reaching the maximal recommended dose exhibited significantly greater weight loss versus patients who did not reach it for both Liraglutide (5.9 ± 4.98 kg vs. 3.9 ± 5.53 kg; P = .03) and Semaglutide (6.5 ± 7.8 kg vs. 2.5 ± 3.8 kg; P = .016).

Pre-MBS G1RA utilization and failure are prevalent among MBS candidates. Our study underscores the need for further research to understand the role of G1RA therapy in obesity management and the development of guidelines for its appropriate use in MBS candidates.

Weight loss mediated by glucagon-like peptide-1 (GLP-1) analogues is lower in patients with type 2 diabetes versus those without. Type 2 diabetes and obesity are risk factors for metabolic dysfunction-associated steatotic liver disease (MASLD) and associated steatohepatitis (MASH). We evaluated weight changes in adults with MASLD/MASH with or without type 2 diabetes receiving the GLP-1 analogue semaglutide.

This was a post hoc analysis of data from three 48-72-week randomised trials investigating the effect of semaglutide versus placebo in adults with MASLD (NCT03357380) or biopsy-confirmed MASH (NCT02970942 and NCT03987451). Pooled data for semaglutide (0.4 mg once daily and 2.4 mg once weekly [n = 163]) and placebo (n = 137) were analysed at 1 year. Weight changes were analysed by type 2 diabetes status (type 2 diabetes [n = 209], pre-type 2 diabetes [n = 51] and no diabetes [n = 40]) and by other cardiometabolic risk parameters using analysis of covariance and Spearman's rank correlations.

The overall mean weight change was -11.1 kg (-11.7%) and -0.7 kg (-0.6%) with semaglutide and placebo, respectively. While numerically higher for people without type 2 diabetes, estimated treatment differences with semaglutide versus placebo were similar overall for people with type 2 diabetes (-10.2 kg; -10.8%), pre-type 2 diabetes (-9.8 kg; -10.2%) and no diabetes (-11.6 kg; -13.1%). Differences between groups were not statistically significant (p > 0.50 for all). Baseline fasting plasma glucose, glycated haemoglobin, insulin levels, insulin resistance and lipids did not correlate with weight change.

People with MASLD/MASH had similar semaglutide-mediated weight loss regardless of type 2 diabetes status and other cardiometabolic risk parameters.