First Case Report: A Case of Severe Cholestatic Hepatitis Induced by a Novel Dual Agonist of GLP- 1 and GIP Receptors

First Case Report: A Case of Severe Cholestatic Hepatitis Induced by a Novel Dual Agonist of GLP- 1 and GIP Receptors | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report First Case Report: A Case of Severe Cholestatic Hepatitis Induced by a Novel Dual Agonist of GLP- 1 and GIP Receptors Junmin Jiang，, Minling Cao This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4807780/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract GLP-1 and GIP receptor agonists are increasingly used in the management of T2DM and obesity due to their ability to stimulate insulin secretion, delay gastric emptying, and suppress appetite. The combination of GLP-1 and GIP agonism offers enhanced glycemic control and weight loss. Nevertheless, the advent of these novel therapies has also brought forth safety concerns, including cases of cholestatic hepatitis. The patient with obesity was prescribed a GLP-1/GIP dual receptor agonist as part of their treatment regimen. Shortly after 4 dose of therapy, the patient developed symptoms of severe cholestatic hepatitis, marked by jaundice and elevated liver enzymes. While hospitalized, no causes other than the medication were identified, and a liver biopsy conclusively diagnosed drug-induced cholestatic hepatitis. This represents the first documented case, and it is intended to draw global attention. GLP-1 Receptor GIP Receptor Cholestatic Hepatitis obesity Figures Figure 1 Figure 2 Figure 3 1. INTRODUCTION In recent years, the global obesity epidemic has fueled the relentless pursuit of effective weight management strategies. Among these, the emergence of glucagon-like peptide-1 (GLP-1) receptor agonists and their combination with glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists, collectively known as GLP-1/GIP dual agonists, has garnered significant attention as a promising therapeutic avenue for obesity and related comorbidities. These novel drugs, by virtue of their dual mechanism of action targeting appetite regulation and energy expenditure, have catapulted into the spotlight as the "stars" of the weight loss arena. However, the narrative of unbridled success is not without its shadows, as evidenced by a recently case of severe cholestatic hepatitis associated with this class of medications. A proprietary dual agonist of GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Polypeptide) receptors developed by Borui Pharmaceuticals(༈BGM0504, CTR20230120), potently activates their downstream pathways, yielding biological effects encompassing glycemic control, weight reduction, and therapeutic potential for non-alcoholic steatohepatitis (NASH), thereby demonstrating its extensive therapeutic potential across metabolic disorders. Representing an advancement over existing agents such as semaglutide and liraglutide. However, clinical trials revealed that this new dual agonist drug induced a severe case of cholestatic hepatitis. A 52-year-old male patient started exhibiting symptoms three weeks after the fourth dose of BGM0504 injection. While hospitalized, no causes other than the medication were identified, and a liver biopsy conclusively diagnosed drug-induced cholestatic hepatitis. The following is a detailed description of the case. 2. CASE PRESENTATION A 52 y.o. male presented with sudden onset of jaundice in his conjunctiva and skin. Upon hospital admission for liver function tests, he was found to have significantly elevated bilirubin levels. During his hospitalization, a review of his medical history revealed a previous diagnosis of obesity and no history of alcohol consumption. Notably, three weeks prior to his illness, he had completed his fourth injection of a weight-loss medication (BGM0504, administered every other week, with doses of 2.5mg, 2.5mg, 5mg and 5mg, respectively). This medication, similar to the novel drug Tirzepatide, is a dual agonist targeting both GLP-1 and GIP receptors. Prior to his symptoms, he had experienced influenza-like symptoms such as headaches and muscle aches. Admission labs: ALT 327, AST 129, Total Bilirubin 123.8 umol/L, INR 0.88 and MELD score of 15.09. Upon comprehensive screening, all tests for hepatitis A, B, C, D, and E viruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV), influenza virus, and common respiratory viruses yielded negative results. Furthermore, no abnormalities were detected in immunoglobulin levels or autoantibody profiles. Ceruloplasmin, Coombs and G6PD were all negative. Upon admission, the patient's predominant symptoms were jaundice, fatigue, and weakness, without fever or abdominal pain. Abdominal ultrasonography and MRI did not reveal any signs of biliary obstruction or gallstones. Liver biopsy pathology revealed punctate necrosis of hepatocytes accompanied by inflammatory cell infiltration, cholestatic pigment granules, capillary bile duct dilation, and bile plug formation, predominantly in zones 3 and 2 of the hepatic acinus. Viral, Autoimmune and Genetic liver worked up unremarkable. Based on a RUCAM score of 9, a clinical diagnosis of drug-induced liver injury was established. During the fifth week post-administration of BGM0504, the jaundice reached its peak, with bilirubin levels exceeding 311 umol/L. Consequently, our center initiated four sessions of artificial liver bilirubin adsorption therapy in conjunction with hormonal treatment. Following these aggressive interventions, the patient's condition began to plateau in the sixth week post-BGM0504 administration and bilirubin levels commenced a decline from the seventh week onwards. Table 1 ༎Patient laboratory findings before and after medication Test Before medication First injection 3 weeks after medication 4weeks after medication 5weeks after medication 6 weeks after medication Normal Range Body mass index(BMI) 33.02 32.53 28.7 28.7 28.6 28.4 18.5–24 kg/m 2 Fasting blood glucose (FBG) 5.10 7.61 6.22 5.45 4.88 3.94 3.9–6.1 mmol/L White blood cells (WBC) 6.64 6.84 3.82 6.94 6.27 10.94 3.5–9.5*10 9 /L Hemoglobin (HGB) 156 145 141 136 134 128 130–175 g/L Platelet (PLT) 162 127 159 208 150 173 125–350*10 9 /L Alanine aminotransferase (ALT) 24 53 327 93 33 44 9–50 U/L Aspartate aminotransferase (AST) 16 37 129 28 32 40 15–40 U/L Alkaline phosphatase(ALP) 80 84 379 278 150 117 45–125 U/L γ-Glutamyl transferase (γ-GGT) 68 97 637 340 107 98 10–60 U/L Total Bilirubin(TB) 9.9 6.8 123.8 180.7 311.9 248.7 0–23 umol/L Conjugated bilirubin (CB) 3.8 3.4 102.5 157.0 261.5 209.8 0–8 umol/L INR 0.96 0.94 0.88 0.91 0.98 0.90 0.8–1.2 3. DISCUSSION In the dawn of the 21st century's third decade, the global epidemic of obesity continues to pose a significant health challenge, with profound implications for individual well-being, healthcare systems, and economies worldwide. By 2024, projections based on current trends and epidemiological studies suggest that the prevalence of obesity, defined as a body mass index (BMI) of 30 or above, will reach unprecedented levels. According to the World Health Organization (WHO) and recent meta-analyses incorporating data from multiple international sources, the global obesity rate is anticipated to surpass 20% of the adult population, with some regions experiencing even higher rates, driven by factors such as sedentary lifestyles, unhealthy diets, and reduced physical activity.[ 1 ] This alarming surge in obesity rates underscores the urgent need for effective and safe interventions. Among the various strategies employed to combat obesity, anti-obesity injections have emerged as a promising therapeutic option, particularly for individuals with clinically severe obesity or those who have failed to achieve significant weight loss through lifestyle modifications alone. These medications offer a targeted approach to weight management, often targeting specific physiological pathways associated with appetite regulation, energy expenditure, or fat metabolism. Anti-obesity injections can be broadly classified into several categories based on their mechanisms of action. One of the most widely studied and increasingly prescribed classes is glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is a naturally occurring hormone produced by the intestine that stimulates insulin secretion, inhibits glucagon release, and promotes satiety by influencing central appetite centers in the brain. GLP-1 receptor agonists mimic the effects of native GLP-1, enhancing its action and durability, thereby reducing food intake and promoting weight loss.[ 2 ] Examples of GLP-1 receptor agonist injections include liraglutide (Saxenda®), semaglutide (Ozempic® for diabetes, Wegovy® for obesity), and dulaglutide (Trulicity® primarily for diabetes but with potential off-label use for obesity). Other classes of anti-obesity injections include those that target the melanocortin-4 receptor (MC4R), such as setmelanotide, which is primarily indicated for rare genetic forms of obesity related to MC4R deficiency. In recent years, the development of weight loss drugs has evolved from focusing on a single target to a combination of multiple targets, with effectively addressing the issues of unsatisfactory weight loss effects and significant adverse reactions with single target interventions. Although the use of GLP-1 receptor agonists alone has achieved satisfactory results in weight loss, but recently, global pharmaceutical companies have been competing to develop another type of dual agonist called Tirzepatide. In this article, BGM0504 featured is akin to Tirzepatide, a dual agonist that concurrently activates not only the GLP-1 receptor but also another metabolism-related target, the glucose-dependent insulinotropic polypeptide receptor (GIPR). This dual activation ultimately leads to a remarkable 22.5% reduction in body weight. Moreover, activating the GIP receptor can alleviate gastrointestinal adverse reactions caused by GLP-1 receptor activation. GLP-1/GIP dual agonists represent a major breakthrough in this regard, harnessing the physiological roles of GLP-1 in enhancing insulin secretion, suppressing glucagon release, reducing appetite, and increasing energy expenditure, along with GIP antagonism to further modulate fat metabolism. These dual properties have sparked a surge in popularity among healthcare professionals and individuals seeking to manage their weight. Initial studies painted a relatively favorable with fewer gastrointestinal side effects than some traditional weight loss medications. Administered through injection, GLP-1/GIP dual agonists offer a more convenient alternative to daily pill-taking, appealing to patients seeking a more streamlined treatment regimen. However, the focus of this discussion remains on those more commonly prescribed for general obesity management, with GLP-1 receptor agonists being the forefront. While anti-obesity injections have demonstrated efficacy in promoting weight loss and improving metabolic parameters, their use is not without potential adverse effects. Among the most notable concerns is the potential for hepatic toxicity, given the liver's central role in drug metabolism and elimination. Recent literature has reported a range of hepatic adverse events associated with GLP-1 receptor agonists, though the overall incidence is considered low and mostly mild to moderate in severity. A meta-analysis by Xie et al. reviewing the safety profiles of GLP-1 receptor(semaglutide) agonists across multiple trials found that elevations in liver enzymes (aspartate aminotransferase, alanine aminotransferase) were among the most common adverse events, occurring in approximately 5–10% of patients.[ 3 ] However, these elevations were generally transient, asymptomatic, and resolved with continued treatment or discontinuation in most cases. More severe hepatic adverse events, such as acute liver injury or hepatitis, have been reported but are rare. For instance, a case report by Kern et al. described a patient who developed autoimmune hepatitis-like symptoms after initiating liraglutide therapy, highlighting the need for close monitoring and prompt intervention in such cases.[ 4 ] Overall, the benefit-risk profile of anti-obesity injections, particularly GLP-1 receptor agonists, remains favorable for many patients with obesity. Nevertheless, healthcare providers must be vigilant in assessing patients' individual risk factors, monitoring for adverse events, and adjusting treatment plans accordingly to ensure safe and effective weight management. In our meticulous review of the existing literature, we have identified potential molecular mechanisms that may underlie the development of severe cholestatic hepatitis induced by GLP-1 and GIP dual receptor agonists. We conducted a literature review and discovered potential causative pathways as follows: 1) Impaired Bile Acid Transport: GLP-1 and GIP receptor agonists may interfere with the complex mechanisms involved in bile acid transport within the liver. Studies suggest that these drugs may alter the expression or function of transporters such as multidrug resistance protein 3 (MDR3/MDR2), which is crucial for the secretion of phosphatidylcholine into bile, a necessary component for bile salt solubilization[ 5 ]. Inhibition of MDR3 could lead to bile salt precipitation, causing intrahepatic cholestasis. 2) Alterations in Hepatocyte Function: The dual receptor agonist may directly or indirectly affect hepatocyte function, disrupting bile formation and secretion. GLP-1 agonists have been shown to modulate intracellular signaling pathways that regulate cholesterol and bile acid metabolism [ 6 ]. Disruptions in these pathways could lead to impaired bile acid synthesis or secretion, resulting in bile stasis. 3) Inflammatory and Immune Responses: The onset of cholestatic hepatitis may also be mediated by inflammatory and immune-mediated mechanisms. GLP-1/GIP agonists may trigger an immune response within the liver, leading to hepatocyte damage and subsequent bile duct obstruction. This is supported by evidence of increased levels of inflammatory markers and infiltrating immune cells in the liver tissue of affected patients [ 7 ]. 4)Genetic Susceptibility: Individual genetic variations may play a role in the development of severe adverse reactions to GLP-1/GIP agonists. Polymorphisms in genes encoding bile acid transporters or those involved in drug metabolism and elimination may predispose certain individuals to bile stasis upon exposure to these drugs[ 8 ]. 4. Conclusion The soaring popularity of weight loss injections, particularly GLP-1/GIP dual agonists, reflects the pressing need for effective obesity management strategies and the significant strides made in pharmaceutical innovation. However, the reported case of severe cholestatic hepatitis underscores the importance of maintaining a critical eye towards emerging therapies and underscores the need for ongoing safety surveillance. As the field of obesity medicine continues to evolve, it is crucial to strike a delicate balance between harnessing the potential of novel drugs and ensuring the safety and well-being of those who rely on them. Declarations ETHICS APPROVAL AND CONSENT TO PARTICIPATE Not applicable. HUMAN AND ANIMAL RIGHTS Not applicable. CONSENT FOR PUBLICATION Informed consent was obtained prior. STANDARDS OF REPORTING CARE guidelines were followed. AVAILABILITY OF DATA AND MATERIALS Access to data is permitted with the author's permission. CONFLICT OF INTEREST The author declares no conflict of interest. FUNDING This research received no specific funding from any public,commercial, or not-for-profit funding agency. ACKNOWLEDGEMENTS Declared none. References World Health Organization. Obesity and Overweight:Report of WHO Scientific Group[R].Geneva:WHO,2022. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes[J]. Lancet. 2006;368(9548):1696–705. Xie P, Abildlund MT, Bakdal TA, et al. A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects[J]. DIABETES OBES METAB. 2024;26(8):3068–77. Kern E, VanWagner LB, Yang GY, et al. Liraglutide-induced autoimmune hepatitis[J]. JAMA INTERN MED. 2014;174(6):984–7. Marso SP, Holst AG, Vilsboll T. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes[J]. NEW ENGL J MED. 2017;376(9):891–2. Tuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial[J]. LANCET DIABETES ENDO. 2018;6(8):605–17. Zhou Y, Chen M, Liu L, et al. Difference in Gastrointestinal Risk Associated with Use of GLP-1 Receptor Agonists: A Real-World Pharmacovigilance Study[J]. Diabetes Metab Syndr Obes. 2022;15:155–63. Bai Y. Genetic polymorphisms and adverse drug reactions to GLP-1 receptor agonists: A review of current evidence[J]. Pharmacogenomics Personalized Med. 2022;15:23–35. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4807780","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":336947682,"identity":"a1f13916-82f0-404e-92c5-0c820986da47","order_by":0,"name":"Junmin Jiang，","email":"","orcid":"","institution":"University of Chinese Medicine","correspondingAuthor":false,"prefix":"","firstName":"Junmin","middleName":"","lastName":"Jiang，","suffix":""},{"id":336947683,"identity":"8898e488-f077-4fc7-90f7-5b2265069058","order_by":1,"name":"Minling Cao","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAzUlEQVRIie3PMQqDMBiG4YRAXH73iMUzRATpIHiQLpFCJjt1dRAcugiuFnoJb2AR6uIBHAvOhZygrdClm3ErNO/8PcOHkMn0g+GC9ErBy4v7XJOQE5W43pAADa0msSoICUQkyUehSeyCyglSGuDz1Iwoi3aLxJm/+JcBPOLK4xbd5CFfIn5BBXuULKBuGjKcd8sk7oAz+8mT0hk0CS4gdABEUjPQJnTv19AGHOYvQucLrrrrXUHrcatrRpVFy+Q7zsSa+YesFSaTyfQfvQFoajzM06TNKAAAAABJRU5ErkJggg==","orcid":"","institution":"University of Chinese Medicine","correspondingAuthor":true,"prefix":"","firstName":"Minling","middleName":"","lastName":"Cao","suffix":""}],"badges":[],"createdAt":"2024-07-26 11:48:05","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4807780/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4807780/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":63830872,"identity":"caa5983a-be42-46de-aa34-51618244f2f8","added_by":"auto","created_at":"2024-09-02 19:01:42","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":112935,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal ultrasound findings\u003c/p\u003e\n\u003cp\u003e(a)There is no abnormality in the portal vein, and the blood flow into the liver is unobstructed.\u003c/p\u003e\n\u003cp\u003e(b) Spleen size is basically normal.\u003c/p\u003e\n\u003cp\u003e(c)The liver parenchyma has dense echogenicity. The gallbladder has a small volume.\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4807780/v1/2254cf2df5bd38926e594325.jpg"},{"id":63830870,"identity":"536630ff-7d81-414d-900e-2c19c33bdb02","added_by":"auto","created_at":"2024-09-02 19:01:42","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":242783,"visible":true,"origin":"","legend":"\u003cp\u003eAbdominal MRI + MRCP examination\u003c/p\u003e\n\u003cp\u003e(a) The liver was normal in size and shape.\u003c/p\u003e\n\u003cp\u003e(b) MR Enhanced scan showed no enhancement, no focal signal abnormalities.\u003c/p\u003e\n\u003cp\u003e(c) Spleen size is normal, no abnormal signal. There was no thickening of the gallbladder wall and no abnormal signal shadow in the cavity.\u003c/p\u003e\n\u003cp\u003e(d) MRCP showed normal intrahepatic duct movement, no obvious dilatation, good development of common bile duct and left and right hepatic duct, and normal duct diameter.\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4807780/v1/c050683fcf573799a40fb24d.jpg"},{"id":63830871,"identity":"11c676e6-73b8-47be-853e-61705432c2e8","added_by":"auto","created_at":"2024-09-02 19:01:42","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":139416,"visible":true,"origin":"","legend":"\u003cp\u003eLiver biopsy - Electron microscopy, immunohistochemistry and special staining\u003c/p\u003e\n\u003cp\u003e(A) Toluine blue staining showed that the lobular structure of the liver tissue was preserved, including 1 portal area and 1 central vein. There was no obvious swelling of the liver cells, slight expansion of the rough endoplasmic reticulum, and no expansion of the smooth endoplasmic reticulum. Mitochondria were swollen, irregular or huge in shape, and crystal formation was observed.\u003c/p\u003e\n\u003cp\u003e(B) Under electron microscope, there was no swelling of hepatic sinusoidal endothelial cells, lymphocytes, Kupffer cells and stellate cells. Fascicular collagen fiber deposition was observed between hepatocytes and the Disse space.\u003c/p\u003e\n\u003cp\u003e(C) The space of hepatocytes widened obviously, and there were different kinds of cholestatic pigment granules in hepatocytes. Dense collagen fiber deposition with lymphocyte infiltration in the sink area.\u003c/p\u003e\n\u003cp\u003e(D) Lipid droplets were found in some hepatocytes. Increased capillary bile duct, high dilatation, cholestasis, coelomal microvilli reduced and missing.\u003c/p\u003e\n\u003cp\u003e(E) \u0026nbsp;Some of the portal areas were slightly enlarged, a few lymphocytes, neutrophils, plasma cells infiltrated, slight local interfacial inflammation, small bile duct injury.\u003c/p\u003e\n\u003cp\u003e(F) Hepatocytes were mildly edema, hepatocyte steatosis (\u0026lt;5%), spot-like necrosis with inflammatory cell infiltration, cholestatic pigment granules, capillary bile duct dilatation, bile thrombi, mainly in acinar area 3 and 2.\u003c/p\u003e\n\u003cp\u003e(G) Immunohistochemistry indicated CD68 showed regionally activated Kupffer cells.\u003c/p\u003e\n\u003cp\u003e(H) Immunohistochemistry indicated CK7, CK19 bile duct epithelium +.\u003c/p\u003e\n\u003cp\u003e(I) Immunohistochemistry indicated α-SMA slightly activated hepatic stellate cells. MUM1 A few plasma cells +; IgG-, IgG4-.\u003c/p\u003e\n\u003cp\u003e(J) D-PAS shows many intracellular waxy samples of Kupffer cells, Prussian blue(-), copper stain(-).\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-4807780/v1/7d4590ad291acc8c855e0141.jpg"},{"id":78099573,"identity":"fe1b7357-c377-4b35-9ffe-9afd78a45040","added_by":"auto","created_at":"2025-03-10 01:08:36","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":913998,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4807780/v1/377448a6-1fc0-432a-9eca-3c510aab670c.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"First Case Report: A Case of Severe Cholestatic Hepatitis Induced by a Novel Dual Agonist of GLP- 1 and GIP Receptors","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eIn recent years, the global obesity epidemic has fueled the relentless pursuit of effective weight management strategies. Among these, the emergence of glucagon-like peptide-1 (GLP-1) receptor agonists and their combination with glucose-dependent insulinotropic polypeptide (GIP) receptor antagonists, collectively known as GLP-1/GIP dual agonists, has garnered significant attention as a promising therapeutic avenue for obesity and related comorbidities. These novel drugs, by virtue of their dual mechanism of action targeting appetite regulation and energy expenditure, have catapulted into the spotlight as the \"stars\" of the weight loss arena. However, the narrative of unbridled success is not without its shadows, as evidenced by a recently case of severe cholestatic hepatitis associated with this class of medications.\u003c/p\u003e \u003cp\u003eA proprietary dual agonist of GLP-1 (Glucagon-Like Peptide-1) and GIP (Glucose-Dependent Insulinotropic Polypeptide) receptors developed by Borui Pharmaceuticals(༈BGM0504, CTR20230120), potently activates their downstream pathways, yielding biological effects encompassing glycemic control, weight reduction, and therapeutic potential for non-alcoholic steatohepatitis (NASH), thereby demonstrating its extensive therapeutic potential across metabolic disorders. Representing an advancement over existing agents such as semaglutide and liraglutide. However, clinical trials revealed that this new dual agonist drug induced a severe case of cholestatic hepatitis. A 52-year-old male patient started exhibiting symptoms three weeks after the fourth dose of BGM0504 injection. While hospitalized, no causes other than the medication were identified, and a liver biopsy conclusively diagnosed drug-induced cholestatic hepatitis. The following is a detailed description of the case.\u003c/p\u003e"},{"header":"2. CASE PRESENTATION","content":"\u003cp\u003eA 52 y.o. male presented with sudden onset of jaundice in his conjunctiva and skin. Upon hospital admission for liver function tests, he was found to have significantly elevated bilirubin levels. During his hospitalization, a review of his medical history revealed a previous diagnosis of obesity and no history of alcohol consumption. Notably, three weeks prior to his illness, he had completed his fourth injection of a weight-loss medication (BGM0504, administered every other week, with doses of 2.5mg, 2.5mg, 5mg and 5mg, respectively). This medication, similar to the novel drug Tirzepatide, is a dual agonist targeting both GLP-1 and GIP receptors. Prior to his symptoms, he had experienced influenza-like symptoms such as headaches and muscle aches.\u003c/p\u003e \u003cp\u003eAdmission labs: ALT 327, AST 129, Total Bilirubin 123.8 umol/L, INR 0.88 and MELD score of 15.09. Upon comprehensive screening, all tests for hepatitis A, B, C, D, and E viruses, Epstein-Barr virus (EBV), cytomegalovirus (CMV), influenza virus, and common respiratory viruses yielded negative results. Furthermore, no abnormalities were detected in immunoglobulin levels or autoantibody profiles.\u003c/p\u003e \u003cp\u003eCeruloplasmin, Coombs and G6PD were all negative. Upon admission, the patient's predominant symptoms were jaundice, fatigue, and weakness, without fever or abdominal pain. Abdominal ultrasonography and MRI did not reveal any signs of biliary obstruction or gallstones. Liver biopsy pathology revealed punctate necrosis of hepatocytes accompanied by inflammatory cell infiltration, cholestatic pigment granules, capillary bile duct dilation, and bile plug formation, predominantly in zones 3 and 2 of the hepatic acinus. Viral, Autoimmune and Genetic liver worked up unremarkable. Based on a RUCAM score of 9, a clinical diagnosis of drug-induced liver injury was established.\u003c/p\u003e \u003cp\u003eDuring the fifth week post-administration of BGM0504, the jaundice reached its peak, with bilirubin levels exceeding 311 umol/L. Consequently, our center initiated four sessions of artificial liver bilirubin adsorption therapy in conjunction with hormonal treatment. Following these aggressive interventions, the patient's condition began to plateau in the sixth week post-BGM0504 administration and bilirubin levels commenced a decline from the seventh week onwards.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e༎Patient laboratory findings before and after medication\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"8\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTest\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBefore medication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eFirst injection\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3 weeks after medication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4weeks after medication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e5weeks after medication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e6 weeks after medication\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eNormal Range\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody mass index(BMI)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e33.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e32.53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e28.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e28.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e18.5\u0026ndash;24 kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFasting blood glucose (FBG)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5.10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.61\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e5.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e4.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e3.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.9\u0026ndash;6.1 mmol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWhite blood cells (WBC)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e3.82\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e6.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e6.27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e3.5\u0026ndash;9.5*10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHemoglobin (HGB)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e156\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e141\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e134\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e128\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e130\u0026ndash;175 g/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePlatelet (PLT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e162\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e127\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e159\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e173\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e125\u0026ndash;350*10\u003csup\u003e9\u003c/sup\u003e/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlanine aminotransferase (ALT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e327\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e9\u0026ndash;50 U/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAspartate aminotransferase (AST)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e129\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e15\u0026ndash;40 U/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAlkaline phosphatase(ALP)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e80\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e84\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e379\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e278\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e150\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e45\u0026ndash;125 U/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eγ-Glutamyl transferase (γ-GGT)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e340\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e10\u0026ndash;60 U/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal Bilirubin(TB)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e123.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e180.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e311.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e248.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u0026ndash;23 umol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eConjugated bilirubin (CB)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e102.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e157.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e261.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e209.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0\u0026ndash;8 umol/L\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.96\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.88\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0.98\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0.8\u0026ndash;1.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e "},{"header":"3. DISCUSSION","content":"\u003cp\u003eIn the dawn of the 21st century's third decade, the global epidemic of obesity continues to pose a significant health challenge, with profound implications for individual well-being, healthcare systems, and economies worldwide. By 2024, projections based on current trends and epidemiological studies suggest that the prevalence of obesity, defined as a body mass index (BMI) of 30 or above, will reach unprecedented levels. According to the World Health Organization (WHO) and recent meta-analyses incorporating data from multiple international sources, the global obesity rate is anticipated to surpass 20% of the adult population, with some regions experiencing even higher rates, driven by factors such as sedentary lifestyles, unhealthy diets, and reduced physical activity.[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e] This alarming surge in obesity rates underscores the urgent need for effective and safe interventions. Among the various strategies employed to combat obesity, anti-obesity injections have emerged as a promising therapeutic option, particularly for individuals with clinically severe obesity or those who have failed to achieve significant weight loss through lifestyle modifications alone. These medications offer a targeted approach to weight management, often targeting specific physiological pathways associated with appetite regulation, energy expenditure, or fat metabolism.\u003c/p\u003e \u003cp\u003eAnti-obesity injections can be broadly classified into several categories based on their mechanisms of action. One of the most widely studied and increasingly prescribed classes is glucagon-like peptide-1 (GLP-1) receptor agonists. GLP-1 is a naturally occurring hormone produced by the intestine that stimulates insulin secretion, inhibits glucagon release, and promotes satiety by influencing central appetite centers in the brain. GLP-1 receptor agonists mimic the effects of native GLP-1, enhancing its action and durability, thereby reducing food intake and promoting weight loss.[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] Examples of GLP-1 receptor agonist injections include liraglutide (Saxenda\u0026reg;), semaglutide (Ozempic\u0026reg; for diabetes, Wegovy\u0026reg; for obesity), and dulaglutide (Trulicity\u0026reg; primarily for diabetes but with potential off-label use for obesity). Other classes of anti-obesity injections include those that target the melanocortin-4 receptor (MC4R), such as setmelanotide, which is primarily indicated for rare genetic forms of obesity related to MC4R deficiency.\u003c/p\u003e \u003cp\u003eIn recent years, the development of weight loss drugs has evolved from focusing on a single target to a combination of multiple targets, with effectively addressing the issues of unsatisfactory weight loss effects and significant adverse reactions with single target interventions. Although the use of GLP-1 receptor agonists alone has achieved satisfactory results in weight loss, but recently, global pharmaceutical companies have been competing to develop another type of dual agonist called Tirzepatide. In this article, BGM0504 featured is akin to Tirzepatide, a dual agonist that concurrently activates not only the GLP-1 receptor but also another metabolism-related target, the glucose-dependent insulinotropic polypeptide receptor (GIPR). This dual activation ultimately leads to a remarkable 22.5% reduction in body weight. Moreover, activating the GIP receptor can alleviate gastrointestinal adverse reactions caused by GLP-1 receptor activation.\u003c/p\u003e \u003cp\u003eGLP-1/GIP dual agonists represent a major breakthrough in this regard, harnessing the physiological roles of GLP-1 in enhancing insulin secretion, suppressing glucagon release, reducing appetite, and increasing energy expenditure, along with GIP antagonism to further modulate fat metabolism. These dual properties have sparked a surge in popularity among healthcare professionals and individuals seeking to manage their weight. Initial studies painted a relatively favorable with fewer gastrointestinal side effects than some traditional weight loss medications. Administered through injection, GLP-1/GIP dual agonists offer a more convenient alternative to daily pill-taking, appealing to patients seeking a more streamlined treatment regimen.\u003c/p\u003e \u003cp\u003eHowever, the focus of this discussion remains on those more commonly prescribed for general obesity management, with GLP-1 receptor agonists being the forefront. While anti-obesity injections have demonstrated efficacy in promoting weight loss and improving metabolic parameters, their use is not without potential adverse effects. Among the most notable concerns is the potential for hepatic toxicity, given the liver's central role in drug metabolism and elimination. Recent literature has reported a range of hepatic adverse events associated with GLP-1 receptor agonists, though the overall incidence is considered low and mostly mild to moderate in severity. A meta-analysis by Xie et al. reviewing the safety profiles of GLP-1 receptor(semaglutide) agonists across multiple trials found that elevations in liver enzymes (aspartate aminotransferase, alanine aminotransferase) were among the most common adverse events, occurring in approximately 5\u0026ndash;10% of patients.[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e] However, these elevations were generally transient, asymptomatic, and resolved with continued treatment or discontinuation in most cases. More severe hepatic adverse events, such as acute liver injury or hepatitis, have been reported but are rare. For instance, a case report by Kern et al. described a patient who developed autoimmune hepatitis-like symptoms after initiating liraglutide therapy, highlighting the need for close monitoring and prompt intervention in such cases.[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e] Overall, the benefit-risk profile of anti-obesity injections, particularly GLP-1 receptor agonists, remains favorable for many patients with obesity. Nevertheless, healthcare providers must be vigilant in assessing patients' individual risk factors, monitoring for adverse events, and adjusting treatment plans accordingly to ensure safe and effective weight management.\u003c/p\u003e \u003cp\u003eIn our meticulous review of the existing literature, we have identified potential molecular mechanisms that may underlie the development of severe cholestatic hepatitis induced by GLP-1 and GIP dual receptor agonists. We conducted a literature review and discovered potential causative pathways as follows: 1) Impaired Bile Acid Transport: GLP-1 and GIP receptor agonists may interfere with the complex mechanisms involved in bile acid transport within the liver. Studies suggest that these drugs may alter the expression or function of transporters such as multidrug resistance protein 3 (MDR3/MDR2), which is crucial for the secretion of phosphatidylcholine into bile, a necessary component for bile salt solubilization[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Inhibition of MDR3 could lead to bile salt precipitation, causing intrahepatic cholestasis. 2) Alterations in Hepatocyte Function: The dual receptor agonist may directly or indirectly affect hepatocyte function, disrupting bile formation and secretion. GLP-1 agonists have been shown to modulate intracellular signaling pathways that regulate cholesterol and bile acid metabolism [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Disruptions in these pathways could lead to impaired bile acid synthesis or secretion, resulting in bile stasis. 3) Inflammatory and Immune Responses: The onset of cholestatic hepatitis may also be mediated by inflammatory and immune-mediated mechanisms. GLP-1/GIP agonists may trigger an immune response within the liver, leading to hepatocyte damage and subsequent bile duct obstruction. This is supported by evidence of increased levels of inflammatory markers and infiltrating immune cells in the liver tissue of affected patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. 4)Genetic Susceptibility: Individual genetic variations may play a role in the development of severe adverse reactions to GLP-1/GIP agonists. Polymorphisms in genes encoding bile acid transporters or those involved in drug metabolism and elimination may predispose certain individuals to bile stasis upon exposure to these drugs[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e"},{"header":"4. Conclusion","content":"\u003cp\u003eThe soaring popularity of weight loss injections, particularly GLP-1/GIP dual agonists, reflects the pressing need for effective obesity management strategies and the significant strides made in pharmaceutical innovation. However, the reported case of severe cholestatic hepatitis underscores the importance of maintaining a critical eye towards emerging therapies and underscores the need for ongoing safety surveillance. As the field of obesity medicine continues to evolve, it is crucial to strike a delicate balance between harnessing the potential of novel drugs and ensuring the safety and well-being of those who rely on them.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eETHICS APPROVAL AND CONSENT TO PARTICIPATE\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHUMAN AND ANIMAL RIGHTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONSENT FOR PUBLICATION\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Informed consent was obtained prior.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSTANDARDS OF REPORTING\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;CARE guidelines were followed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAVAILABILITY OF DATA AND MATERIALS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Access to data is permitted with the author's permission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;The author declares no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFUNDING\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;This research received no specific funding from any public,commercial, or not-for-profit funding agency.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGEMENTS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Declared none.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eWorld Health Organization. Obesity and Overweight:Report of WHO Scientific Group[R].Geneva:WHO,2022.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDrucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes[J]. Lancet. 2006;368(9548):1696\u0026ndash;705.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXie P, Abildlund MT, Bakdal TA, et al. A phase 1, randomized, double-blind, placebo-controlled trial investigating the pharmacokinetics, pharmacodynamics, safety and tolerability of oral semaglutide in healthy Chinese subjects[J]. DIABETES OBES METAB. 2024;26(8):3068\u0026ndash;77.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKern E, VanWagner LB, Yang GY, et al. Liraglutide-induced autoimmune hepatitis[J]. JAMA INTERN MED. 2014;174(6):984\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarso SP, Holst AG, Vilsboll T. Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes[J]. NEW ENGL J MED. 2017;376(9):891\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuttle KR, Lakshmanan MC, Rayner B, et al. Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial[J]. LANCET DIABETES ENDO. 2018;6(8):605\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhou Y, Chen M, Liu L, et al. Difference in Gastrointestinal Risk Associated with Use of GLP-1 Receptor Agonists: A Real-World Pharmacovigilance Study[J]. Diabetes Metab Syndr Obes. 2022;15:155\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBai Y. Genetic polymorphisms and adverse drug reactions to GLP-1 receptor agonists: A review of current evidence[J]. Pharmacogenomics Personalized Med. 2022;15:23\u0026ndash;35.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"GLP-1 Receptor, GIP Receptor, Cholestatic Hepatitis, obesity","lastPublishedDoi":"10.21203/rs.3.rs-4807780/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4807780/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGLP-1 and GIP receptor agonists are increasingly used in the management of T2DM and obesity due to their ability to stimulate insulin secretion, delay gastric emptying, and suppress appetite. The combination of GLP-1 and GIP agonism offers enhanced glycemic control and weight loss. Nevertheless, the advent of these novel therapies has also brought forth safety concerns, including cases of cholestatic hepatitis. The patient with obesity was prescribed a GLP-1/GIP dual receptor agonist as part of their treatment regimen. Shortly after 4 dose of therapy, the patient developed symptoms of severe cholestatic hepatitis, marked by jaundice and elevated liver enzymes. While hospitalized, no causes other than the medication were identified, and a liver biopsy conclusively diagnosed drug-induced cholestatic hepatitis. This represents the first documented case, and it is intended to draw global attention.\u003c/p\u003e","manuscriptTitle":"First Case Report: A Case of Severe Cholestatic Hepatitis Induced by a Novel Dual Agonist of GLP- 1 and GIP Receptors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-09-02 19:01:37","doi":"10.21203/rs.3.rs-4807780/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7b15f87d-df83-457a-9bc7-aeb0016e9223","owner":[],"postedDate":"September 2nd, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-03-10T01:08:18+00:00","versionOfRecord":[],"versionCreatedAt":"2024-09-02 19:01:37","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4807780","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4807780","identity":"rs-4807780","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}