GIP

Clinical Advances in Heart Failure with Preserved Ejection Fraction: A Systematic Review of Therapeutic and Mechanistic Evidence.

Razieh Parizad, Juniali Hatwal, Mohammadreza Taban Sadeghi +4 more

Heart failure with preserved ejection fraction (HFpEF) has emerged as the predominant of heart failure (HF), particularly among aging populations and individuals with a high burden of comorbidities. Its underlying pathophysiological mechanisms are complex, multifactorial and, heterogeneous.

Tirzepatide-induced ketoacidosis with hyperglycemia in a patient without diabetes.

Mendel Shloush, Vania Rodriguez, Victor Guillen +1 more

Tirzepatide,a dual GLP-1 and GIP receptor agonist, is increasingly used for weight management in both patients with diabetes and patients without diabetes. While gastrointestinal side effects such as nausea are common, severe metabolic complications like ketoacidosis are rare and often overlooked. We report the case of a 38-year-old woman with congenital heart disease who developed acute ketoacidosis with hyperglycemia following five months of tirzepatide therapy. Laboratory findings confirmed high anion gap metabolic acidosis, elevated ketones, and significant hyperglycemia. With supportive care, including intravenous fluids, insulin infusion, and electrolyte replacement, she recovered fully. This represents a rare case of tirzepatide-induced hyperglycemic ketoacidosis in a patient without diabetes. In contrast, the two previously reported cases by Singh and cols. and Iqbal and cols. involved patients without diabetes who developed euglycemic ketoacidosis with normal glucose levels while on tirzepatide. This case underscores the importance of vigilant monitoring for metabolic complications, including hyperglycemia and ketoacidosis, in patients without diabetes, particularly those with comorbidities.

Emerging Role of Dual Glucagon-Like Peptide-1 (GLP-1)/Glucose-Dependent Insulinotropic Polypeptide (GIP) Receptor Agonists in Cardiovascular Prevention.

Nicolle Contreras Figueroa, Maynor Jose Lopez Mendoza, Asdrubal Ulloa +3 more

Dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonists have emerged as a novel therapeutic class with potential relevance for cardiovascular prevention, particularly in the context of obesity and type 2 diabetes mellitus. Incretin physiology provides the biological foundation for this approach, as GLP-1 and GIP exert complementary metabolic and vascular effects. While GLP-1 receptor agonists have demonstrated well-established reductions in major adverse cardiovascular events, GIP has regained interest due to evidence suggesting preserved vascular and anti-atherosclerotic actions despite reduced insulinotropic efficacy in diabetes.  Dual receptor agonism integrates these pathways, leading to substantial improvements in cardiometabolic risk factors. Agents such as tirzepatide induce marked and sustained weight loss, with significant reductions in visceral adiposity, a key driver of cardiovascular disease. These effects are accompanied by robust improvements in glycemic control and insulin sensitivity, resulting in attenuation of glucotoxicity and lipotoxicity, both of which contribute to endothelial dysfunction and myocardial injury. Additional benefits include reductions in blood pressure, favorable modulation of lipid profiles, and suppression of systemic inflammatory markers, alongside improvements in endothelial function and vascular stiffness. Pharmacologically, dual GLP-1/GIP receptor agonists are engineered to provide balanced receptor activation, allowing superior metabolic efficacy compared with single GLP-1 receptor agonists. Clinical trial data indicate cardiovascular safety and improvements in surrogate cardiovascular endpoints, with reductions in major cardiometabolic risk factors comparable to those achieved with established incretin therapies. However, definitive evidence of incremental cardiovascular outcome benefits remains limited.

Tirzepatide and metformin effects on hunger and BMI in an adolescent with hyperphagia and severe obesity due to MC4R Deficiency: a case report.

Eline E P L van der Walle, Mariëtte R Boon, Elisabeth F C van Rossum +1 more

Tirzepatide, a dual GLP-1/GIP receptor agonist, is recently approved for the treatment of type 2 diabetes and obesity in adults. Melanocortin-4-receptor (MC4R) deficiency is the most common monogenic cause of obesity and presents with hyperphagia and early onset obesity. While tirzepatide seems to be effective in inducing weight loss in adults with MC4R deficiency, its effects on hyperphagia and weight loss in pediatric patients are unexplored.

Novel GLP-1-based Medications for Type 2 Diabetes and Obesity.

Jang Won Son, Carel W le Roux, Matthias Blüher +2 more

The approvals of semaglutide and tirzepatide have set new benchmarks in the treatment of type 2 diabetes and obesity. Building on their success, novel glucagon-like peptide-1 (GLP-1)-based therapeutics are rapidly advancing. These next-generation agents engage not only GLP-1 receptors but also those for other gastro-entero-pancreatic hormones such as glucose-dependent insulinotropic polypeptide (GIP), glucagon, amylin, and peptide YY to enhance energy uptake, storage, and expenditure through synergistic mechanisms. Both GIP receptor agonism and antagonism, particularly in combination with GLP-1 receptor agonism, have shown promise. Maridebart cafraglutide, combining GLP-1 receptor agonism with GIP receptor antagonism, exemplifies this innovative approach. Glucagon coagonists like survodutide and mazdutide have demonstrated significant weight loss and improved glycemic control. Amylin-based agents, including CagriSema (cagrilintide + semaglutide) and amycretin, enhance satiety and glycemic outcomes through complementary actions. Further innovation is seen in triple agonists such as retatrutide, which targets GIP, GLP-1, and glucagon receptors to amplify metabolic effects. Meanwhile, the emergence of orally active small-molecule GLP-1 receptor agonists like danuglipron and orforglipron, which are resistant to enzymatic degradation, marks a major advance in patient-friendly drug delivery. This review explores the mechanisms, clinical development, and therapeutic potential of these novel agents, excluding already approved drugs like liraglutide, semaglutide, and tirzepatide. We highlight how multireceptor agonists and oral GLP-1-based therapies may reshape the future landscape of obesity and type 2 diabetes treatment by offering more effective and better-tolerated options.

[Obesity: novel pharmacological treatments].

Jochen Seufert

Obesity is currently considered as adiposity based chronic disease with BMI as therapeutic target for prevention of obesity associated complications. For treatment of obesity, a stepwise approach is recommended including multifactorial basal therapy with nutrition counseling, exercise training and behavior modification. Further steps comprise adjuvant pharmacological treatment and bariatric surgery. With the development of incretin based medications that activate GLP-1 and GIP receptors for increase in satiety, an impressive improvement in effectivity of obesity medications is observed. Licensed substances in Germany include the GLP-1 receptor agonists liraglutide and semaglutide, and the GLP-1/GIP receptor coagonist tirzepatide. Trial data reveal weight losses of on average 7.5 kg after 160 weeks for liraglutide, up to 17.4 kg after 68 weeks for semaglutide, and up to 22.5 kg after 72 weeks for tirzepatide. In addition, semaglutide demonstrated positive results in cardiovascular outcome trials. The weight reducing effects of incretin based substances are close to those achieved by bariatric interventions, therefore closing the gap between lifestyle intervention and bariatric surgery.

A DYRK inhibitor ameliorates glucose homeostasis and increases incretin-producing cells in diabetic mice.

Michishige Terasaki, Qiao Zhou, Olov Andersson +1 more

Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have been shown to improve hyperglycemia in patients with type 2 diabetes, suggesting that an enhanced capacity of GIP and GLP-1 production could be beneficial in type 2 diabetes. We have recently found that dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) inhibitors reduce glucose levels and increase the number of intestinal gip-expressing K-cells and glp-1-expressing L-cells in zebrafish. However, their effects on mammals require exploration in greater detail. In this study, we examined whether oral administration of a DYRK inhibitor, ID-8, to diabetic db/db mice affects glucose homeostasis, plasma levels of insulin, incretins, number of intestinal K-cells and L-cells and pancreatic cell volume in vivo. ID-8-treated mice showed a significant reduction in HbA1c levels and decreased blood glucose levels after oral glucose tolerance test along with enhanced plasma levels of insulin, total-GIP and total-GLP-1. The number of K-cells and L-cells in the intestines of ID-8-treated mice was increased, and a subset of these cells were co-stained with a DYRK-regulated transcriptional factor, nuclear factor of activated T cells 4 (NFATc4), but not co-localized with the proliferation marker EdU. There were no significant differences of pancreatic β- and α-cell mass between the ID-8- and vehicle-treated mice. Moreover, mRNA levels of incretins were significantly increased in ID-8-treated human intestinal organoids. Our present study demonstrated that ID-8 improved hyperglycemia in association with enhanced plasma levels of insulin and incretins as well as an increased number of K-cells and L-cells in diabetic mice; therefore, it may be a novel therapeutic agent for diabetes.

Probable Tirzepatide-Induced Rhabdomyolysis in an HIV-Positive Patient.

Drew A Wells, Kaulin Duncan, Sami Sakaan

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, has gained widespread use for the treatment of type 2 diabetes mellitus, obesity, and obstructive sleep apnea. This report presents the first probable case of tirzepatide-associated rhabdomyolysis in a human immunodeficiency virus (HIV)-positive patient.

Cardio-Obesity and Therapeutic Advances: Intersections Between Excess Adiposity, Cardiovascular Risk, and Pharmacologic Interventions.

Diana De Oliveira-Gomes, Alfonso Martinez de Majo, Angie Ardila-Delgado +4 more

This review examines the mechanistic pathways linking obesity and cardiovascular disease, with particular emphasis on recent advancements in pharmacologic therapies. It evaluates the cardiovascular effects of novel anti-obesity medications and their integration into current treatment paradigms. Additionally, these pharmacologic strategies are contextualized alongside lifestyle interventions and metabolic bariatric surgery.

Role of endogenous incretin hormones, GLP-1 and GIP, in cardiovascular physiology.

Khushali Trivedi, Vernon W Dolinsky

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.

Tirzepatide reduces alcohol drinking and relapse-like behaviours in rodents.

Christian E Edvardsson, Louise Adermark, Sam Gottlieb +11 more

Alcohol use disorder (AUD) remains a major public health problem, with few effective medications currently available. However, peptides of the gut-brain axis appear to offer promising therapeutic targets for AUD as they influence the mesolimbic reward circuitry.

Glucose-dependent insulinotropic polypeptide reduces postprandial glucose excursions but does not protect from hypoglycaemia in persons with type 1 diabetes-A randomised placebo-controlled study.

Bjørn Hoe, Sebastian M N Heimbürger, Lærke S Gasbjerg +13 more

In type 1 diabetes, glucose-dependent insulinotropic polypeptide (GIP) increases glucagon secretion during low plasma glucose and improves time in the glycaemic range during daytime. To explore the glucose-stabilising potential of GIP in type 1 diabetes, we evaluated the effects of exogenous and endogenous GIP on plasma glucose excursions in a setting of excess prandial insulin and physical activity after meal ingestion.

Hormonal Modulation of Fat Mass Induced Insulin Resistance.

Humam Emad Rajha, Ahmed Arabi, Dima Nasrallah +12 more

This study examines the impact of body mass index (BMI) on homeostatic model assessment for insulin sensitivity (HOMA-S) and homeostatic model assessment for pancreatic β-cell function (HOMA-B) in adults with obesity but without diabetes. Additionally, the association of key hormones, leptin and gastric inhibitory peptide (GIP), with HOMA indices and BMI has been investigated.

Long-acting GIPR agonist LY3537021 reduces body weight and fasting blood glucose in patients with T2D: Preclinical development and phase 1 randomized ascending dose studies.

William Roell, Jorge Alsina-Fernandez, Hongchang Qu +13 more

Tirzepatide, a single-molecule dual glucose-dependent insulinotropic polypeptide (GIP)/glucagon-like peptide-1 (GLP-1) receptor (R) agonist, has shown superiority in the reduction of blood glucose and body weight, above selective GLP-1R agonists, but the contribution of GIP to these effects remains incompletely understood.

A metabolic comparison of GIPR agonism versus GIPR antagonism in male mice.

Iona Davies, Alexandra Turland, Hanh Duyen Tran +9 more

Targeting the glucose dependent insulinotropic polypeptide receptor (GIPR) is of growing interest for treating type 2 diabetes and obesity, though the optimal approach remains unclear. Both GIPR agonism and antagonism, respectively, incorporated into drugs like tirzepatide and maridebart cafraglutide, have paradoxically both shown significant weight loss effects in humans.

The Roles of Incretin Hormones GIP and GLP-1 in Metabolic and Cardiovascular Health: A Comprehensive Review.

Dai Yamanouchi

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) play central roles in metabolic and cardiovascular regulation. GLP-1 receptor agonists (GLP-1RAs) are established therapies for type 2 diabetes mellitus (T2DM) and obesity because of their insulinotropic effects, weight reduction, and proven cardiovascular benefit in trial level. In contrast, GIP was historically overlooked due to reduced β-cell responsiveness in T2DM. The development of dual GIP/GLP-1 receptor agonists has reshaped this view. Tirzepatide, the first-in-class co-agonist, an antidiabetic medication to treat type 2 diabetes and for weight loss, provides superior glycemic control and weight loss compared with selective GLP-1RAs in clinical trials, demonstrating synergistic actions between the two incretin pathways. This review summarizes key physiology, pathophysiology, and therapeutic evidence in incretin biology. We describe secretion patterns, receptor distributions, and distinct actions of GIP and GLP-1, as well as alterations in incretin signaling in T2DM and obesity. Cardiovascular protective mechanisms are outlined, including improvements in lipid metabolism, reductions in blood pressure, enhanced endothelial nitric oxide activity, suppression of macrophage inflammation, decreased foam-cell formation, and stabilization of atherosclerotic plaques. At the therapeutic level, emerging directions-such as dual and triple agonists-and unresolved questions regarding long-term vascular effects of GIP and the potential for genotype-guided incretin therapy are also discussed. Collectively, these findings highlight an emerging shift toward integrated incretin-axis modulation as a therapeutic strategy for metabolic and cardiovascular disease.

A narrative review on tirzepatide's therapeutic potential in glycemic control and cardioprotection.

Mrudula Thiriveedi, Francis Sto Domingo, Hannah Yates +4 more

Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, represents a new class of incretin-based therapy for type 2 diabetes mellitus (T2DM), obesity, and related comorbidities. This narrative review synthesizes evidence from the SURPASS, SURMOUNT, and SUMMIT clinical trial programs. Across studies, tirzepatide reduced glycated hemoglobin (HbA1c) by up to 2.5% and body weight by more than 20%. It also improved cardiovascular risk factors (blood pressure, lipids, inflammation) and has demonstrated benefits in patients with heart failure with preserved ejection fraction (HFpEF) and obstructive sleep apnea (OSA), with reductions in the apnea-hypopnea index (AHI) and heart failure hospitalizations. Its safety profile is consistent with that of GLP-1 receptor agonists (GLP-1 RAs), although gastrointestinal side effects, gallbladder events, and thyroid cancer signals warrant monitoring. Ethical concerns related to off-label use, weight regain after discontinuation, and barriers to real-world access remain active issues. Ongoing outcome trials and real-world data will clarify its long-term role and potential integration into future clinical guidelines.

An Online Prescription for Hospitalisation: Euglycaemic Ketoacidosis Caused by an Online Tirzepatide Prescription.

Thibagaran Sathambihai, Kushagra Mathur, Seshnag Siddavaram

Obesity affects a significant proportion of the UK population, and tirzepatide, a dual glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP) receptor agonist, is increasingly being prescribed by online services as well as primary care for weight loss in both diabetic and non-diabetic patients. We present the case of a 61-year-old woman with no past medical history, who developed euglycaemic ketoacidosis following six weeks of tirzepatide (Mounjaro®) therapy, which was initiated via an online consultation for weight loss. Despite normal blood glucose levels, she exhibited significant ketonaemia and metabolic acidosis, which resolved with intravenous fluid resuscitation and replacement. This case brings to light the importance of treating clinicians being aware of the potential adverse side effects of euglycaemic ketoacidosis in patients using tirzepatide, and highlights the risk when these medications are prescribed via novel care pathways, which have less rigid monitoring paradigms than traditional prescribing models. Early recognition of, and prompt management, are important to ensure the mitigation of morbidity associated with this under-recognised adverse effect.

Positron emission tomography to assess drug occupancy at peripheral and central incretin receptors.

Amina Khalil, Irina Velikyan, Mengfei Xiong +3 more

Incretin mimetics, especially dual/triple agonists, are effective for type 2 diabetes and obesity, though mechanisms remain unclear. This study applied PET using [68Ga]Ga-DO3A-Exendin-4 and [68Ga]S02-GIP-T4 to assess GLP-1R and GIPR occupancy of SAR441255 (a GLP-1R, GIPR, and GCGR agonist) and tirzepatide in pig pancreas and CNS.

GLP-1 receptor agonists on WHO-EML 2025 list: major breakthrough bounded by persistent challenge.

Kanimozhi Mani

The World Health Organisation (WHO) periodically updates its Model List of Essential Medicines (EML) and Essential Medicines for Children (EMLc) to address evolving global health priorities. The 24th EML and 10th EMLc, released on 5th September 2025, mark a major milestone by expanding access to twenty new medicines for diabetes, cancer, cystic fibrosis, haemophilia, psoriasis, and blood disorders. Notably, the inclusion of glucagon-like peptide-1 (GLP-1) receptor agonists-semaglutide, liraglutide, dulaglutide-and the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, tirzepatide, represents a paradigm shift in the management of type 2 diabetes mellitus (T2DM) and obesity. These agents have demonstrated significant benefits in lowering blood glucose levels, reducing cardiovascular and renal complications, and promoting weight loss in T2DM patients with established cardiovascular disease (CVD), chronic kidney disease (CKD), or obesity. This move aims to bridge the longstanding treatment gap in low- and middle-income countries (LMICs), where high drug costs have limited access to such therapies. Their recognition as essential medicines enables prioritisation of limited resources, facilitates equitable pricing, and supports the development of generics and biosimilars post-patent expiry. This inclusion aligns with Sustainable Development Goal 3.4, which aims to reduce premature mortality from non-communicable diseases (NCDs) by 1/3 by 2030. However, challenges persist, including financial constraints, limited healthcare infrastructure, and risks of irrational use, particularly for obesity alone. Effective implementation through national policies, training, and rational prescribing frameworks is essential to translating this global milestone into tangible public health benefits and to reducing the growing burden of diabetes and obesity worldwide.

Insulinoma Unmasked By Tirzepatide: A Rare Case of Postprandial Hypoglycemia In a Nondiabetic Patient.

Michael Polisky, Dina Kamel, Jeong-Hee Ku

A 63-year-old woman with obesity presented with severe postprandial hypoglycemia that worsened after starting tirzepatide for weight loss. Further evaluation led to the diagnosis of insulinoma. This case suggests that the use of tirzepatide can provoke severe hypoglycemia episodes in patients with insulinoma and highlights the importance of including insulinoma as a differential diagnosis for hypoglycemia in patients taking incretin-based therapy.

Effect of Weight-Neutral Treatment With Semaglutide or Tirzepatide on β-Cell Identity in db/db Mice.

Zhaobin Deng, Dongxu Zheng, Jinsook Son +4 more

Insulin resistance and pancreatic β-cell failure are key characteristics of type 2 diabetes (T2D). Impaired β-cell function is associated with loss of β-cell identity, resulting in β-cell dedifferentiation or trans-differentiation to other endocrine cells. We have shown that β-cell dedifferentiation can be reversed, restoring insulin secretion. The aim of this study was to investigate whether semaglutide or tirzepatide treatment can reverse early stages of β-cell dedifferentiation in db/db mice independent of their effect on body weight.

An Open-Label, Single-Center Proof of Concept Study Evaluating the Efficacy and Safety of Tirzepatide for Moderate to Severe Hidradenitis Suppurativa.

Ana Sofia Acosta-Madiedo, Marcela Gutierrez, Martha Gutierrez +2 more

Hidradenitis suppurativa (HS) is a chronic inflammatory disease associated with obesity and metabolic dysregulation. Current therapies yield variable benefits and do not target metabolic drivers. Tirzepatide, a dual GLP-1/GIP receptor agonist, induces weight loss and exerts anti-inflammatory effects, offering a potential novel approach for the treatment of HS.

GLP1 and GIP Receptor Agonists: Effects on the Gastrointestinal Tract and Management Strategies for Primary Care Physicians.

Bibek Saha, Vijayvardhan Kamalumpundi, Don C Codipilly

Type 2 diabetes and obesity drive significant morbidity, mortality, and health care costs in the United States. Clinicians increasingly prescribe glucagon-like peptide 1 (GLP1) receptor agonists (GLP1-RAs) and dual GLP1 and glucose-dependent insulinotropic polypeptide receptor agonists to treat these and other conditions. However, 40% to 70% of patients experience gastrointestinal adverse effects, such as nausea, vomiting, diarrhea, constipation, delayed gastric emptying, and biliary disease. High-quality studies have not yet confirmed an increased risk of pancreatitis. Management of gastrointestinal symptoms should start with dietary modifications-smaller, more frequent meals; adequate hydration; and avoidance of high-fat or high-sugar foods. If symptoms persist, patients can trial several medications for symptom relief. For patients undergoing elective endoscopy, clinicians should engage in shared decision-making to weigh the risks of continuing vs temporarily discontinuing incretin-based therapies. For endoscopy, GLP1-RA use is associated with a higher incidence of retained gastric contents but not with increased aspiration risk. Long-acting formulations (eg, semaglutide, dulaglutide, and tirzepatide, among others), high doses, procedures during dose escalation, and gastrointestinal comorbidities that delay gastric emptying raise risk of retained gastric contents. In most cases, clinicians can continue GLP1-RAs periprocedurally, although a 24-hour liquid diet may benefit high-risk patients. For colonoscopy, withholding GLP1-RAs may reduce the risk of inadequate bowel preparation, but further research should clarify the magnitude of this risk.

The Clinical Application of GLP-1RAs and GLP-1/GIP Dual Receptor Agonists Based on Pharmacological Mechanisms: A Review.

Zhao Liu, Shanshan Yu, Xinyan Jin +5 more

This review provides a comprehensive examination of the clinical pharmacological mechanisms and broad therapeutic applications of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and dual receptor agonists targeting both glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptors. GLP-1RAs exert their effects by stimulating insulin secretion, suppressing glucagon release, delaying gastric emptying, and reducing appetite through the activation of the GLP-1 receptor. These agents have demonstrated significant efficacy in the management of type 2 diabetes mellitus (T2DM) and obesity. Moreover, emerging evidence suggests that GLP-1RAs may confer cardiovascular protection, neuroprotective benefits, and positive effects on mental health. Dual GLP-1/GIP receptor agonists, such as tirzepatide, simultaneously activate both receptors, thereby potentiating glycemic control, promoting weight loss, and ameliorating metabolic dysfunction. This review also addresses recent advances in the development of other dual and triple receptor agonists. Distinct from prior reviews that predominantly focus on a single drug class or limited clinical indications, this article systematically contrasts the mechanistic pathways, therapeutic efficacy, and safety profiles of GLP-1RAs versus GLP-1/GIP dual receptor agonists. Notably, it integrates the most current evidence pertaining to novel domains, such as perioperative management, neuropsychiatric outcomes, and the innovation of multi-receptor agonists. This synthesis offers a timely and practical resource to inform clinical precision medicine and to guide future investigative efforts.

Intestinal fructose metabolism triggers a glucagon-like peptide-1-β-cell axis to prevent post-fructose hyperglycaemia.

Naoya Murao, Yusuke Seino, Risa Morikawa +10 more

Fructose ingestion increases circulating glucagon-like peptide-1 (GLP-1) and insulin, yet the specific contributions of these hormonal responses to glycaemic control remain incompletely defined. We hypothesised that fructose metabolism in intestinal L-cells triggers GLP-1 secretion, which then potentiates insulin secretion and counteracts fructose-induced hyperglycaemia. To test this hypothesis, we systematically characterised metabolic responses across multiple mouse strains after 24 h ad libitum fructose ingestion. In both lean (NSY.B6-a/a) and obese diabetic (NSY.B6-Ay/a) mice, fructose elevated plasma insulin, GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). The insulin response was preserved in GIP receptor-deficient mice (Gipr-/-) but was abolished in proglucagon-deficient mice (Gcg-/-) by pharmacological GLP-1 receptor antagonism, indicating a requirement for GLP-1, but not GIP. Across strains, fructose-induced insulin response correlated with attenuation of post-fructose glycaemia, consistent with insulin being essential for suppressing fructose-induced hyperglycaemia. To explore the mechanism underlying fructose-induced GLP-1 secretion, we combined ATP-sensitive potassium channel-deficient mice (Kcnj11-/-), the GLUTag L-cell line, and metabolic tracing of 13C-labelled fructose in freshly isolated intestinal crypts. These complementary approaches support a model in which fructolysis increases the ATP/ADP ratio in L-cells, closes KATP channels and stimulates GLP-1 secretion. In obese diabetic mice, increased fructolytic flux and a higher ATP/ADP ratio were associated with elevated GLP-1 levels, further corroborating this model. Collectively, our findings indicate that intestinal fructose metabolism drives GLP-1 secretion required to potentiate insulin secretion, thereby establishing a gut-pancreas axis that counter-regulates fructose-induced hyperglycaemia. KEY POINTS: Fructose ingestion acutely increases plasma insulin levels, but the underlying mechanisms and physiological significance remain elusive. Our study demonstrates that short-term (24 h) fructose ingestion in mice elevates both insulin and glucagon-like peptide 1 (GLP-1) levels in the blood, with the plasma insulin response being GLP-1-dependent. We found that fructose metabolism in intestinal L-cells triggered GLP-1 secretion by increasing the ATP/ADP ratio and closing ATP-sensitive K+ (KATP) channels. This intestinal fructose metabolism-GLP-1-β-cell axis plays a crucial role in preventing fructose-induced hyperglycaemia, an effect that is compromised in obese diabetic mice. These insights highlight the previously unclear metabolic responses following short-term fructose ingestion and their importance in glucose homeostasis.

[Progress on tirzepatide, a GIP/GLP-1 receptor agonist, for the treatment of obesity-related obstructive sleep apnea].

L X Wang, Y Xiao

Obstructive sleep apnea (OSA) is a common sleep-disordered breathing. Obesity is one of the primary risk factors for OSA, while OSA itself may promote weight gain by impairing metabolism and increasing insulin resistance, thereby creating a vicious cycle. Together, these conditions pose a persistent public health challenge. In recent years, tirzepatide, a dual glucose-dependent insulinotropic polypeptide/glucagon-like peptide 1 (GIP/GLP-1) receptor agonist, has demonstrated therapeutic potential beyond weight loss in the management of obesity, encompassing various mechanisms. The recent SURMOUNT-OSA study showed that tirzepatide significantly reduced the apnea hypopnea index (AHI) in OSA patients and improved oxygen desaturation, blood pressure, and cardiovascular disease (CVD)-related risk factors. These effects are thought to be mediated not only by weight reduction, but also by modulation of fat distribution, inflammatory status, and autonomic nervous system function. This highlights the potential advantages of tirzepatide in obese patients with OSA. This review summarizes recent advances in tirzepatide research in this population, exploring its mechanisms of action, efficacy, and safety, with the aim of providing a theoretical basis for precision treatment strategies for OSA.

Psychological and behavioral effects of GLP-1 and GIP agonists in weight loss: a comprehensive review.

Fatima Ameer, Nicole Yañez Villacres, Daniel Bustos +9 more

Obesity remains a major global health challenge, severely affecting metabolic and cardiovascular health. Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) receptor agonists mark a significant breakthrough in diabetes and obesity management, significantly aiding in weight loss and glycemic control. Tirzepatide, a dual agonist for GLP-1 and GIP receptors, effectively promotes weight loss and improves metabolic parameters by influencing insulin secretion, appetite regulation, and gastric emptying.

Preservation of lean soft tissue during weight loss induced by GLP-1 and GLP-1/GIP receptor agonists: A case series.

Grant M Tinsley, Spencer Nadolsky

GLP-1 receptor agonists (e.g., semaglutide) and dual GLP-1/GIP receptor agonists (e.g., tirzepatide) are effective for reducing body weight and fat mass, though lean soft tissue loss comprised 26%-40% of weight loss in recent trials. This case series describes three patients (two female, one male; body mass index: 32.9-51.9 kg m-2) who prioritized lean soft tissue preservation strategies during treatment with semaglutide or tirzepatide. Patients engaged in intentional exercise or structured physical activity 4-7 days·week-1, including resistance training 3-5 days·week-1. Typical protein intakes were 0.7-1.7 g·kg-1·day-1 relative to body mass and 1.6-2.3 g·kg-1·day-1 relative to fat-free mass. Changes in weight, fat mass, and lean soft tissue were: -33.0%, -53.4%, and -6.9% (case 1); -26.8%, -61.6%, and +2.5% (case 2); and -13.2%, -46.9%, and +5.8% (case 3). Accordingly, one patient lost 8.7% of weight as lean soft tissue, while two increased lean soft tissue. These findings highlight the potential for some individuals to preserve or even increase lean soft tissue during treatment with semaglutide or tirzepatide alongside supportive lifestyle strategies.

Tirzepatide, a dual GLP-1 and GIP receptor agonist, promotes bone loss in obese mice via gut microbial-related metabolites.

Ning Chen, Mengdan Zhang, Baohong Shi +10 more

As a novel dual glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) receptor agonist, Tirzepatide (TZP) is a recently approved medication for treating type 2 diabetes mellitus (T2DM) and obesity; however, the effect of TZP in bone remodeling remains unclear.