Mitigating loss of lean muscle in GLP-1 and dual GLP-1/GIP agonists: Pipeline opportunities and limitations.

Obesity, type 2 diabetes (T2D), and cardiovascular disease are closely related conditions contributing to the global rise in cardiometabolic disease. Incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have emerged as critical regulators of glucose metabolism, pancreatic function, and cardiovascular physiology. However, despite increasing clinical use of GLP-1 receptor agonists and dual GLP-1/GIP agonists, the precise mechanisms by which endogenous incretins influence cardiovascular tissues remain incompletely understood, particularly in the context of obesity and T2D. This review explores the signalling mechanisms and physiological actions of natural endogenous GLP-1 and GIP, with a focus on cardiovascular physiology. Endogenous GLP-1 promotes insulin secretion, β-cell survival, and appetite suppression, and exerts protective effects on the endothelium. GLP-1 also reduces inflammation, enhances nitric oxide production, and improves myocardial glucose utilization during ischemia. Endogenous GIP is involved in insulin secretion, β-cell survival, and adipogenesis. In obesity and T2D, incretin secretion and insulinotropic effects are altered. The therapeutic potential of GLP-1 receptor agonists and emerging dual GLP-1/GIP agonists has been shown to aid in managing metabolic dysfunction and, more recently, in preventing cardiovascular complications.

Glucagon-like peptide-1 (GLP-1) receptor agonists and dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) agonists, such as tirzepatide, have transformed the management of type 2 diabetes and obesity through durable glycemic control, weight reduction, and cardiovascular protection. However, their widespread use has revealed a high incidence of gastrointestinal adverse events, particularly dyspepsia and gastroparesis-like symptoms. While most effects are transient, a significant subset of patients develop persistent intolerance, often leading to misdiagnosis, unnecessary investigations, or premature treatment discontinuation. Current therapeutic options remain limited, with guidelines offering little direction for managing symptoms, in this subset of dyspeptic patients. This growing clinical challenge highlights the urgent need for structured strategies, including risk stratification, tailored dose titration, and multidisciplinary care, to balance metabolic efficacy with gastrointestinal tolerability.

Effects on pancreatic Beta and other Islet cells of the glucose-dependent insulinotropic polypeptide

Alcohol Use Disorder (AUD) contributes significantly to global mortality. GLP-1 (Glucagon-like peptide-1) and GLP-1/GIP (Glucose-dependent Insulinotropic Polypeptide) agonists, FDA-approved for managing type 2 diabetes and obesity, where the former has shown to effectively reduce the consumption of alcohol in animal models but no reports exist on the latter. In this report, we conducted two studies. In the first study, we conducted an analysis of abundant social media texts. Specifically, a machine-learning based attribution mapping of ~ 68,250 posts related to GLP-1 or GLP-1/GIP agonists on the Reddit platform. Secondly, we recruited participants (n = 153; current alcohol drinkers; BMI ≥ 30) who self-reported either taking Semaglutide (GLP-1 agonist), Tirzepatide (the GLP-1/GIP combination) for ≥ 30 days or, as a control group; no medication to manage diabetes or weight loss for a within and between subject remote study. In the social media study, we report 8 major themes including effects of medications (30%); diabetes (21%); and Weight loss and obesity (19%). Among the alcohol-related posts (n = 1580), 71% were identified as craving reduction, decreased desire to drink, and other negative effects. In the remote study, we observe a significantly lower self-reported intake of alcohol, drinks per drinking episode, binge drinking odds, Alcohol Use Disorders Identification Test (AUDIT) scores, and stimulating, and sedative effects in the Semaglutide or Tirzepatide group when compared to prior to starting medication timepoint (within-subjects) and the control group (between-subjects). In summary, we provide initial real-world evidence of reduced alcohol consumption in people with obesity taking Semaglutide or Tirzepatide medications, suggesting potential efficacy for treatment in AUD comorbid with obesity.

Individuals with obesity often exhibit low muscle quality and are at risk of reduced muscle mass and diminished cardiorespiratory fitness (CRF). Glucagon-like peptide 1 (GLP-1) receptor agonists (GLP-1RA) and dual GLP-1 and glucose-dependent insulinotropic polypeptide receptor agonist (GLP-1/GIPRA) promote significant loss in adipose tissue but are also associated with notable reductions in fat-free mass (FFM). It is not yet understood how these drugs affect CRF, which is an independent predictor of all-cause and cardiovascular mortality. People with obesity frequently have low CRF, which is defined by the Fick principle-the product of cardiac output and peripheral oxygen extraction. Cardiovascular dysfunction and reduced muscle quality, due to lipid infiltration, relatively low muscle mass, and dysfunctional microvasculature, work in concert to affect the determinants of the Fick equation and cause low CRF in this population. Weight loss interventions, including GLP-1RAs and dual GLP-1/GIPRA, may improve these measures. However, recent trials show GLP-1RAs and dual GLP-1/GIPRA therapy accelerates FFM loss. Evidence indicates that approximately 25% to 40% of weight loss attributed to GLP-1RAs and dual GLP-1/GIPRA comes from FFM loss, a rate far exceeding the annual age-related decline of FFM in adults. While these therapies have revolutionized obesity and glycemic management by inducing significant weight loss, reducing blood glucose levels, and demonstrating cardiovascular benefits in individuals with or without type 2 diabetes, clinical studies have failed to show improvements in CRF, a critical determinant of long-term cardiovascular health, and the long-term implications of FFM loss in these individuals remain unknown. GLP-1RAs and dual GLP-1/GIPRA significantly reduce body weight and adiposity, along with a substantial FFM loss but with no clear evidence of CRF enhancement. Further research is needed to elucidate the complex interplay among GLP-1 and dual GLP-1/GIP receptor agonism, FFM, direct cardiovascular measures, and determinants of CRF to optimize clinical outcomes in obesity and type 2 diabetes.

Beneficial metabolic actions of a stable GIP agonist following pre-treatment with a SGLT2 inhibitor in high fat fed diabetic mice

Incretin hormones include glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Due to their promising action on insulinotropic secretion and improving insulin resistance (IR), incretin-based therapies have become a new class of antidiabetic agents for the treatment of type 2 diabetes mellitus (T2DM). Recently, the links between neurodegenerative diseases and T2DM have been identified in a number of studies, which suggested that shared mechanisms, such as insulin dysregulation or IR, may underlie these conditions. Therefore, the effects of incretins in neurodegenerative diseases have been extensively investigated. Protease-resistant long-lasting GLP-1 mimetics such as lixisenatide, liraglutide, and exenatide not only have demonstrated promising effects for treating neurodegenerative diseases in preclinical studies but also have shown first positive results in Alzheimer's disease (AD) and Parkinson's disease (PD) patients in clinical trials. Furthermore, the effects of other related incretin-based therapies such as GIP agonists, dipeptidyl peptidase-IV (DPP-IV) inhibitors, oxyntomodulin (OXM), dual GLP-1/GIP, and triple GLP-1/GIP/glucagon receptor agonists on neurodegenerative diseases have been tested in preclinical studies. Incretin-based therapies are a promising approach for treating neurodegenerative diseases.

Introduction The long‐acting glucagon‐like peptide‐1 (GLP‐1) agonist semaglutide and the GLP‐1/glucose‐dependent insulinotropic polypeptide (GIP) agonist tirzepatide have demonstrated efficacy in reducing cardiometabolic risk factors in individuals with diabetes and obesity. Popularity of these agents has led to increased demand, even among patients with cardiometabolic risk factors beyond type 2 diabetes mellitus (T2DM). The growing demand and supply chain disruptions have resulted in a shortage of therapies. As a direct consequence, patients are exploring alternative options including compounded GLP‐1 ± GIP formulations. Objective This study reports real‐world observations on the safety and efficacy of compounded semaglutide and tirzepatide within a clinical pharmacist‐managed cardiometabolic clinic. Methods This retrospective cohort included 50 patients with cardiometabolic risk who had received a prescription for compounded GLP‐1 ± GIP therapy between July 2022 and July 2023. Observations were reported for this cohort with changes from baseline to 12 weeks and out to 24 weeks. Primary outcomes were changes in weight/body mass index (BMI) and hemoglobin A1c (HbA1c). Secondary outcomes included changes in waist circumference, blood pressure, triglyceride levels, inflammatory markers, medication adherence, and the incidence of adverse events and/or dropout rates. Results Fifty patients (18 males and 32 females) completed the 12‐week follow‐up, with an additional subset of patients ( n = 40) continuing to 24 weeks of therapy. The average weight loss observed at 12 weeks was 16.06 ± 7.6 pounds ( p = 0.001) and 38.82 ± 11.4 pounds at 24 weeks. HbA1c decreased on average from 5.5 ± 0.3 at baseline to 5.3 ± 0.3 at 12 weeks ( p < 0.0001) and to 5.2 ± 0.027 ( p < 0.001) at 24 weeks. All secondary cardiometabolic outcomes improved significantly throughout the study. Conclusion This study demonstrates a significant positive impact on cardiometabolic outcomes from utilizing compounded GLP‐1 ± GIP agonists when branded products could not be obtained. These observations also support the use of compounded GLP‐1 ± GIP agonists under pharmacist supervision as an alternative during drug shortages.

Obesity is a chronic condition demanding effective treatment strategies, among which pharmacotherapy plays a critical role. As glucagon-like peptide-1 (GLP-1) agonist approved by the Food and Drug Administration (FDA) for long-term weight management in adults with obesity, liraglutide and semaglutide have great weight loss effect through reducing food intake and delaying gastric emptying. The emergence of unimolecular polypharmacology, which utilizes single molecules to simultaneously target multiple receptors or pathways, marked a revolutionary improvement in GLP-1-based obesity pharmacotherapy. The dual agonist tirzepatide activates both GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) receptors and has shown enhanced potency for weight loss compared to conventional GLP-1 mono agonist. Furthermore, emerging data suggests that unimolecular GLP-1/glucagon (GCG) dual agonist, as well as GLP-1/GIP/GCG triple agonist, may offer superior weight loss efficacy over GLP-1 agonist. This review summarizes the comprehensive mechanisms underlying the pronounced advantages of GLP-1/GIP dual agonist, GLP-1/GCG dual agonist and GLP-1/GIP/GCG triple agonist over GLP-1 mono agonist in weight reduction in obese adults without type 2 diabetes. A deeper understanding of these unimolecular multitargeting GLP-1-based agonists will provide insights for their clinical application and guide the development of new drugs for obesity treatment.

Strong associations exist between obstructive sleep apnea (OSA) and obesity. Prior studies have demonstrated that weight reduction in people with OSA and obesity improves severity of OSA. Until recently, there were no approved pharmacotherapies for OSA. We aim to review recent literature on GLP-1 receptor agonists and GIP agonists and their potential role in the management of OSA. Novel pharmacotherapies developed to target obesity include glucagon-like peptide-1 (GLP-1) receptor agonists and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. These therapies have proven to be helpful in many comorbid conditions, with published studies suggesting a benefit in OSA. GLP-1 receptor agonists and GIP agonists are emerging potential therapies for OSA and associated cardiometabolic risk.

Incretin hormones are peptides released in the intestine in response to the presence of nutrients in its lumen. The main incretins are glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 stimulates insulin secretion, inhibits glucagon secretion at pancreatic α cells and has also extrapancreatic influences as slowing of gastric emptying which increases the feeling of satiety. GIP is the main incretin hormone in healthy people, causative of most the incretin effects, but the insulin response after GIP secretion in type 2 diabetes mellitus (T2DM) is strongly reduced. Therefore, in the past GIP has been considered an unappealing therapeutic target for T2DM. This conception has been changing during recent years, since it has been reported that resistance to GIP can be reversed and its effectiveness restored by improving glycemic control. This fact paved the way for the development of a GIP receptor agonist-based therapy for T2DM, looking also for the possibility of finding a combined GLP-1/GIP receptor agonist. In this framework, the novel dual GIP and GLP-1 receptor agonist tirzepatide seems to be not just a new antidiabetic medication. Administered as a subcutaneous weekly injection, it is a manifold single pharmacological agent that has the ability to significantly lower glucose levels, as well as improve insulin sensitivity, reduce weight and amend dyslipidemia favorably modifying the lipid profile. Tirzepatide and additional dual GLP-1/GIP receptor agonists that could eventually be developed in the future seem to be a promising furthest advance for the management of several cardiometabolic settings. Obviously, it is too early to be overly hopeful since it is still necessary to determine the long-term effects of these compounds and properly verify the potential cardiovascular benefits. Anyway, we are currently facing a novel and very appealing therapeutic option.

Background/Objectives: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) effectively manage type 2 diabetes mellitus (T2DM) but may impair gastrointestinal motility, increasing the risk of small intestinal bacterial overgrowth (SIBO). Diagnostic evaluation of SIBO commonly involves breath testing and clinical assessment. This study aimed to assess the association between GLP-1 RAs or dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) RAs are associated with incident SIBO. Methods: We conducted a retrospective cohort study using the TriNetX global database, identifying adult T2DM patients initiating GLP-1 RA or dual GLP-1/GIP RA therapy versus other second-line T2DM agents (OSLT2DM) from 1 January 2006 to 2 December 2024. Patients with major abdominal surgery, connective tissue disorders, gastroparesis, or other high-risk conditions for SIBO were excluded. 1:1 Propensity score matching was applied. Short-term (<1 year) and long-term (up to 5 years) risks were evaluated with Kaplan–Meier curves and univariable Cox models. Results: After matching, 216,173 patients per cohort were analyzed. Short-term analysis demonstrated a higher incidence of diagnostically confirmed SIBO in patients treated with GLP-1 RA/GIP (0.177 per 1000 patient-years) compared to OSLT2DM (0.083 per 1000 patient-years; HR 2.14, 95% CI 1.13–4.07; p = 0.0491). Long-term analysis indicated a non-significant trend toward increased risk in the GLP-1 RA/GIP group (HR 2.02, 95% CI 0.98–4.12), though Kaplan–Meier analysis revealed a sustained divergence (p = 0.017). Conclusions: GLP-1 RA and dual GLP-1/GIP RA therapy are associated with increased short-term SIBO risk. Symptom-driven SIBO breath-test evaluation may be warranted in patients initiating these agents.

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

&lt;p dir="ltr"&gt;&lt;a href="" target="_blank"&gt;This narrative review highlights the degree to which new anti-obesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. &lt;/a&gt;Glucagon-like peptide-1 receptor agonists (GLP-1ra) induce substantial weight loss in randomised trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Therapies such as liraglutide and semaglutide (GLP-1ra), tirzepatide (GLP-1 and GIP receptor dual agonist) and retatrutide (GLP-1, GIP, and glucagon-receptor triple agonist), are peptides with incretin agonist activity that induce up to ~15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. &lt;a href="" target="_blank"&gt;However, these agents also cause rapid and significant loss of lean mass (~10%, ~6 kg), comparable to a decade of ageing. &lt;/a&gt;Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration over 10 weeks can elicit large increases in lean mass (~3 kg) and strength (~25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared to either alone. Retaining lean mass during incretin therapy could potentially blunt body weight (and fat) re-gain on cessation of weight loss pharmacotherapy. &lt;a href="" target="_blank"&gt;We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy, to optimise changes in body composition by preserving lean mass while achieving fat loss.&lt;/a&gt;&lt;/p&gt;

&lt;p dir="ltr"&gt;&lt;a href="" target="_blank"&gt;This narrative review highlights the degree to which new anti-obesity medications based on gut-derived nutrient-stimulated hormones (incretins) cause loss of lean mass, and the importance of resistance exercise to preserve muscle. &lt;/a&gt;Glucagon-like peptide-1 receptor agonists (GLP-1ra) induce substantial weight loss in randomised trials, effects that may be enhanced in combination with glucose-dependent insulinotropic polypeptide (GIP) receptor agonists. Therapies such as liraglutide and semaglutide (GLP-1ra), tirzepatide (GLP-1 and GIP receptor dual agonist) and retatrutide (GLP-1, GIP, and glucagon-receptor triple agonist), are peptides with incretin agonist activity that induce up to ~15-24% weight loss in adults with overweight and obesity, alongside beneficial impacts on blood pressure, cholesterol, blood glucose, and insulin. &lt;a href="" target="_blank"&gt;However, these agents also cause rapid and significant loss of lean mass (~10%, ~6 kg), comparable to a decade of ageing. &lt;/a&gt;Maintaining muscle mass and function as humans age is crucial to avoiding sarcopenia and frailty, which are strongly linked to morbidity and mortality. Studies indicate that supervised resistance exercise training interventions with a duration over 10 weeks can elicit large increases in lean mass (~3 kg) and strength (~25%) in men and women. After a low-calorie diet, combining aerobic exercise with liraglutide improved weight loss maintenance compared to either alone. Retaining lean mass during incretin therapy could potentially blunt body weight (and fat) re-gain on cessation of weight loss pharmacotherapy. &lt;a href="" target="_blank"&gt;We propose that tailored resistance exercise training be recommended as an adjunct to incretin therapy, to optimise changes in body composition by preserving lean mass while achieving fat loss.&lt;/a&gt;&lt;/p&gt;