Glucose-dependent Insulinotropic Polypeptide Receptor Agonist Research Articles

Role of incretins and glucagon receptor agonists in metabolic dysfunction-associated steatotic liver disease: Opportunities and challenges

Metabolic dysfunction-associated steatotic liver disease (MASLD) has become the most common chronic liver disease worldwide, paralleling the rising pandemic of obesity and type 2 diabetes. Due to the growing global health burden and complex pathogenesis of MASLD, a multifaceted and innovative therapeutic approach is needed. Incretin receptor agonists, which were initially developed for diabetes management, have emerged as promising candidates for MASLD treatment. This review describes the pathophysiological mechanisms and action sites of three major classes of incretin/glucagon receptor agonists: glucagon-like peptide-1 receptor agonists, glucose-dependent insulinotropic polypeptide receptor agonists, and glucagon receptor agonists. Incretins and glucagon directly or indirectly impact various organs, including the liver, brain, pancreas, gastrointestinal tract, and adipose tissue. Thus, these agents significantly improve glycemic control and weight management and mitigate MASLD pathogenesis. Importantly, this study provides a summary of clinical trials analyzing the effectiveness and safety of incretin receptor agonists in MASLD management and provides an in-depth analysis highlighting their beneficial effects on improving liver function, hepatic steatosis, and intrahepatic inflammation. There are emerging challenges associated with the use of these medications in the real world, particularly adverse events, drug-drug interactions, and barriers to access, which are discussed in detail. Additionally, this review highlights the evolving role of incretin receptor agonists in MASLD management and suggests future research directions.

Healthcare professionals' perceptions and management of obesity & knowledge of glucagon, GLP-1, GIP receptor agonists, and dual agonists.

Anti-obesity medications (AOMs) have historically had limited weight-loss efficacy. However, newer glucagon-like peptide-1 receptor agonist (GLP-1 RA)-based therapies seem to be more effective, including dual agonists of GLP-1R and the glucagon receptor (GCGR) or glucose-dependent insulinotropic polypeptide receptor. To explore healthcare professionals' (HCPs) experience in obesity treatment and their understanding of agonists of GCGR, glucose-dependent insulinotropic polypeptide (GIP) RA, and GLP-1 RA. This cross-sectional online survey of HCPs prescribing AOMs was conducted in the United States in 2023 with a questionnaire designed to evaluate prescribing behavior and understanding of GCGR, GIP RA, and GLP-1 RA. The 785 respondents (251 primary-care physicians [PCPs], 263 endocrinologists, and 271 advanced practice providers [APPs]) reported 55% of their patients had obesity (body mass index ≥30kg/m2 or ≥27 with weight-related complications) and recommended AOMs to 49% overall, significantly more endocrinologists (57% of patients, p<0.0005) than PCPs (43%) or APPs (46%). The greatest barriers to treatment were medication cost/lack of insurance (mean 4.2 on 1-5 scale [no barrier-extreme barrier]), low patient engagement/adherence (3.3), and inadequate time/staff (3.1). Metformin was the type 2 diabetes (T2D) medication most commonly prescribed to treat obesity in T2D patients (92.5% of respondents). Most HCPs (65%) were very/extremely familiar with GLP-1 RA, but only 30% with GIP RA and 16% with GCGR. Most HCPs expected dual GCGR/GLP-1 RA to benefit many obesity-related conditions; however, only a minority of HCPs perceived that they would benefit non-cardiometabolic complications of obesity. Among HCPs prescribing AOMs, gaps exist in the management of people living with obesity as <50% are prescribed AOMs. Barriers to treatment indicate a need to improve access to AOMs. HCPs were less familiar with GCGR or GIP RA than GLP-1 RA but expect dual GCGR/GLP-1 RA may offer additional benefits, potentially addressing treatment barriers and access. Thus, there is a need for greater education among HCPs regarding the mechanism of action and therapeutic effects of GCGR agonists, and dual GCGR/GLP-1 RA, so that the full range of obesity-related complications can be effectively treated.

Customizable Click Biochemistry Strategy for the Design and Preparation of Glucagon-like Peptide-1 Conjugates and Coagonists.

The development of oligomeric glucagon-like peptide-1 (GLP-1) and GLP-1-containing coagonists holds promise for enhancing the therapeutic potential of the GLP-1-based drugs for treating type 2 diabetes mellitus (T2DM). Here, we report a facile, efficient, and customizable strategy based on genetically encoded SpyCatcher-SpyTag chemistry and an inducible, cleavable self-aggregating tag (icSAT) scheme. icSAT-tagged SpyTag-fused GLP-1 and the dimeric or trimeric SpyCatcher scaffold were designed for dimeric or trimeric GLP-1, while icSAT-tagged SpyCatcher-fused GLP-1 and the icSAT-tagged SpyTag-fused GIP were designed for dual GLP-1/GIP (glucose-dependent insulinotropic polypeptide) receptor agonist. These SpyCatcher- and SpyTag-fused protein pairs were spontaneously ligated directly from the cell lysates. The subsequent icSAT scheme, coupled with a two-step standard column purification, resulted in target proteins with authentic N-termini, with yields ranging from 35 to 65 mg/L and purities exceeding 99%. In vitro assays revealed 3.0- to 4.1-fold increased activities for dimeric and trimeric GLP-1 compared to mono-GLP-1. The dual GLP-1/GIP receptor agonist exhibited balanced activity toward the GLP-1 receptor or the GIP receptor. All the proteins exhibited 1.8- to 3.0-fold prolonged half-lives in human serum compared to mono-GLP-1 or GIP. This study provides a generally applicable click biochemistry strategy for developing oligomeric or dual peptide/protein-based drug candidates.

Evaluating the efficacy of GIPR agonists on non-alcoholic fatty liver disease: A Mediation Mendelian Randomization Study

ObjectiveNon-alcoholic fatty liver disease (NAFLD) is becoming the most common chronic liver disease worldwide while still lacks drugs for treatment or prevention. We aimed to investigate the causal role of glucose-dependent insulinotropic polypeptide receptor agonists (GIPRAs) on NAFLD and identify the mediated risk factors by which GIPRAs exert their therapeutic effects. MethodsGenetic proxies of GIPRAs were identified as cis-SNPs of GIPR associated with both the gene expression level and HbA1c and analyses including colocalization and linkage disequilibrium (LD) were performed for validation. We then performed two-sample two-step mendelian randomization to determine the causal effect of GIPRAs on NAFLD. ResultsThe MR analysis suggested genetic proxies of GIPRAs were causally associated with reduced risk of NAFLD (Odds ratio (OR): 0.46, 95 % confidence interval (95 % CI): 0.24–0.88, P = 0.02) and T2DM (OR: 0.10, 95 % CI: 0.07–0.13, P < 0.01). In addition, Mediation analysis showed evidence of indirect effect of GIPRAs on NAFLD via TRIG (0.88, [0.85–0.92], P < 0.01) and HDL-C (0.85, [0.80–0.90], P < 0.01). ConclusionsOur study provided strong evidence to support the causal role of GIPRAs on reducing the risk of NAFLD probably through improving lipid metabolism, especially TG and HDL-C, providing guidance for future clinical trials.

DR10627, a Novel Dual Glucagon‑like Peptide‑1 and Gastric Inhibitory Polypeptide Receptor Agonist for the Treatment of Obesity and Type 2 Diabetes Mellitus.

Diabetes and obesity are momentous risk factors threatening people's lives and health. Currently available incretin analogue glucagon-like peptide 1 (GLP-1) possesses huge hypoglycemic effect with the unsatisfactory effect of weight loss. Co-agonists targeting GLP-1R plus glucagon receptor (GCGR) or gastric inhibitory polypeptide receptor (GIPR) show synergistic benefits in glycaemic control and weight loss. Here, we describe a novel dual GIP and GLP-1 receptor agonist, DR10627, and performed a preclinical assessment of it. The agonistic ability of DR10627 was indirectly assessed by inducing cAMP accumulation in Chinese hamster ovary (CHO) cells transfected with GLP-1R or GIPR in vitro. The plasma pharmacokinetics of DR10627 were analysed in cynomolgus monkeys. The OGTTs were performed in Sprague‑Dawley (SD) rats. The glucose lowering effects were evaluated by repeated administration of DR10627 in diabetic (db/db) mice for 4 weeks. The effects of anti-obesity and improving metabolism of DR10627 were evaluated by repeated administration of DR10627 in diet-induced obesity (DIO) mice for 57 days. DR10627 had the capacity to activate both GLP-1R and GIPR in vitro. The terminal half-life of DR10627 was found to be approximately 4.19-5.8 h in cynomolgus monkeys. DR10627 had a great improvement in oral glucose tolerance in SD rats. Moreover, DR10627 had a potent glucose-lowering effect in db/db mice, and the hypoglycemic effect of 18 nmol/kg DR10627 was better than that of 50 nmol/kg liraglutide. In addition, 10 and 30 nmol/kg DR10627 possessed the ability of potentiating the weight-loss, lipid-lowing efficacy and improving metabolism to a greater extent than 80 nmol/kg liraglutide. Preclinical assessment demonstrated that administration of DR10627 resulted in glucose lowering in SD rats and db/db mice, and substantial body weight reduction and metabolism improvement in DIO mice. DR10627 is a promising agent deserving further investigation for the treatment of type 2 diabetes and obesity.

Immunomodulation and inflammation: Role of GLP-1R and GIPR expressing cells within the gut

Glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are peptide hormones produced by enteroendocrine cells in the small intestine. Despite being produced in the gut, the leveraging of their role in potentiating glucose-stimulated insulin secretion, also known as the incretin effect, has distracted from discernment of direct intestinal signaling circuits. Both preclinical and clinical evidence have highlighted a role for the incretins in inflammation. In this review, we highlight the discoveries of GLP-1 receptor (GLP-1R)+ natural (TCRαβ and TCRγδ) and induced (TCRαβ+CD4+ cells and TCRαβ+CD8αβ+) intraepithelial lymphocytes. Both endogenous signaling and pharmacological activation of GLP-1R impact local and systemic inflammation, the gut microbiota, whole-body metabolism, as well as the control of GLP-1 bioavailability. While GIPR signaling has been documented to impact hematopoiesis, the impact of these bone marrow-derived cells in gut immunology is not well understood. We uncover gaps in the literature of the evaluation of the impact of sex in these GLP-1R and GIP receptor (GIPR) signaling circuits and provide speculations of the maintenance roles these hormones play within the gut in the fasting-refeeding cycles. GLP-1R agonists and GLP-1R/GIPR agonists are widely used as treatments for diabetes and weight loss, respectively; however, their impact on gut homeostasis has not been fully explored. Advancing our understanding of the roles of GLP-1R and GIPR signaling within the gut at homeostasis as well as metabolic and inflammatory diseases may provide targets to improve disease management.

Abstract 2188: Tirzepatide treatment restores antitumor immunity in a model of obesity-driven cancer

Abstract Obesity is a widely and increasingly prevalent disease and a risk factor for several cancers. Recent work has shown that weight loss following bariatric surgery is potently protective against obesity-associated cancers. However, little is known about the potential anticancer effects of weight loss achieved through incretin-based therapies. We therefore interrogated the effects of the dual glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide receptor agonist tirzepatide (TZP) on body weight and tumor progression in a mouse model of obesity and transplanted colon cancer cells. Moreover, we tested whether TZP-mediated weight loss can reverse obesity-associated suppression of CD8+ T cell immunity. Male C57BL/6J mice were fed either 60 kcal% fat diet (D12492) or a sucrose-matched 10 kcal% fat diet (D12450J) for ≥15 weeks to generate diet induced obese (DIO) or control mice, respectively. Once DIO mice reached a body weight of 47 g they were randomized to begin TZP treatment or receive a vehicle control every other day for 3 weeks (when stable body weights were reached for TZP mice). All mice then received subcutaneous injections with 2.5 × 105 MC38 cells and continued to receive TZP or vehicle. To determine the role of CD8+ T cell mediated tumor control in driving the effects of TZP treatment, mice received either CD8-depleting antibodies or an isotype control at days -2, 0, 2 relative to tumor cell injection and subsequently every 4 days. Tumor mass was determined by digital scale. Fasting blood glucose, body weight loss, and body composition were monitored to determine the metabolic effects of TZP. Immune cell populations were measured by full spectrum flow cytometry. We found TZP reduced body weight, fasting blood glucose, and adiposity relative to DIO mice, as was expected. These metabolic improvements were accompanied by reduction of tumor mass in TZP mice relative to DIO mice. DIO mice had increased levels of exhausted T cells which were normalized by TZP treatment. Depletion of CD8+ cells did not alter the tumor mass of DIO mice, indicating negligible CD8+ T cell-mediated tumor control. In contrast, CD8+ cell depletion in control and TZP mice increased in tumor masses to the levels comparable to those of DIO mice. These results demonstrate that TZP can mitigate obesity-associated acceleration of tumor growth and restore markers of effective antitumor T cell immunity. Critically, we find that restoration of CD8+ T cell function is essential for TZP’s ability to limit tumor growth in DIO mice. Taken together, these results demonstrate that the metabolic improvements achieved by TZP treatment are accompanied by mitigation of obesity-driven immunosuppression. These findings shed important light on the potential for TZP and other incretin-based therapies to limit obesity-associated cancer progression, and are especially timely given the growing population of patients utilizing incretin-based therapies. Citation Format: Michael F. Coleman, Elaine M. Glenny, Tori L. McFarlane, Hannah M. Malian, Claire E. Gates, Fangxin Chen, Alyssa N. Ho, Violet A. Kiesel, Stephen D. Hursting. Tirzepatide treatment restores antitumor immunity in a model of obesity-driven cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2188.

Tirzepatide-Induced Ketoacidosis in Non-Diabetic Patients.

Tirzepatide is a novel glucagon-like peptide 1/glucose-dependent insulinotropic peptide (GLP-1/GIP) receptor agonist. It was recently approved for diabetes control and weight reduction in non-diabetic patients. We report the first case of ketoacidosis after the use of tirzepatide in an obese non-diabetic patient, secondary to the possibility of starvation ketoacidosis and insulin resistance. The dual-acting GLP-1 and GIP receptor agonists, tirzepatide, can induce ketoacidosis in obese non-diabetic patients. The dual-acting GLP-1 and GIP receptor agonists can cause ketoacidosis in obese non-diabetic patients.Ketoacidosis induced by tirzepatide is serious, and physicians should be aware of this complication and be alert to early symptoms, check serum and urine ketone levels, and stop medication.

A scalable application of Artificial Intelligence-Driven Insulin Titration Program to transform Type 2 Diabetes Management.

Despite new pharmacotherapy, most patients with long-term Type 2 Diabetes are still hyperglycemic. This could have been solved by insulin with its unlimited potential efficacy, but its dynamic physiology demands frequent titrations which are overdemanding. This report provides a real-life account for a scalable transformation of diabetes care in a community-based endocrinology center by harnessing AI-based autonomous insulin titration. The center embedded the d-Nav® technology and its dedicated clinical support. Reported outcomes include treatment efficacy/safety in the first 600 patients and use of cardiorenal-risk reduction pharmacotherapy. Patients used d-Nav for 8.2±3.0 months with 82% retention. Age was 67.1±11.5 years and duration of diabetes was 19.8±11.0 years. During the last 3 years before d-Nav, HbA1c had been overall higher than 8% and at the beginning of the program it was as high as 8.6%±2.1% with 29.3% of the patients with HbA1c>9%. With d-Nav, HbA1c decreased to 7.3%±1.2% with 5.7% of patients with HbA1c>9%. During the first 3 months, d-Nav reduced total daily dose of insulin in 1 of every 5 patients due to relatively low glucose levels to minimize the risk of hypoglycemia. GLP-1 or dual GLP-1 and GIP receptor agonists were prescribed in about a half of the patients and SGLT2 inhibitor in a third. The frequency of hypoglycemia (<54mg/dl) was 0.4±0.6/month and severe hypoglycemia 1.7/100-patient-years. The use of d-Nav allowed for improvement in overall diabetes management with appropriate use of both insulin and non-insulin pharmacologic agents in a scalable way.

The preclinical discovery and clinical evaluation of tirzepatide for the treatment of type 2 diabetes

ABSTRACT Introduction Despite numerous antidiabetic medications available for the treatment of type 2 diabetes, a substantial percentage of patients fail to achieve optimal glycemic control. Furthermore, the escalating obesity pandemic underscores the urgent need for effective relevant pharmacotherapies. Tirzepatide, a novel dual GIP and GLP-1 receptor agonist, offers a promising therapeutic option. Areas covered This review describes the discovery and clinical development of tirzepatide. Based on data from pivotal in vivo and in vitro studies, the authors present the pharmacodynamic profile of tirzepatide. Furthermore, they summarize data from the clinical trial programs that assessed the efficacy and safety of tirzepatide for the treatment of type 2 diabetes or obesity in a broad spectrum of patients, and discuss its therapeutic potential. Expert opinion Tirzepatide effectively reduces glucose levels and body weight in patients with type 2 diabetes and/or obesity, with a generally safe profile. Based on data from phase 3 clinical trials, several agencies have approved its use for the treatment of type 2 diabetes and obesity. Clinicians should be aware of possible adverse events, mainly mild-to-moderate gastrointestinal side effects. Overall, tirzepatide represents a promising treatment option for the treatment of type 2 diabetes.

Worth Their Weight? An Update on New and Emerging Pharmacologic Agents for Obesity and Their Potential Role for Persons with Cardiac Conditions.

Obesity is associated with cardiovascular (CV) conditions, including but not limited to atherosclerotic disease, heart failure, and atrial fibrillation. Despite this, the impact of intentional weight loss on CV outcomes for persons with obesity and established CV conditions remains poorly studied. New and emerging pharmacologic therapies for weight loss primarily targeting the incretin/nutrient sensing axes induce substantial and sustained weight loss. The glucagon-like-peptide 1 receptor agonists (GLP-1 RA) liraglutide and semaglutide have US FDA approval for the treatment of obesity, and the application for an obesity indication for the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide is presently under FDA review. Extensive phase II and IIIa randomized controlled trials are underway evaluating permutations of combined GLP-1 RA, GIP receptor agonist, GIP receptor antagonist, and glucagon receptor agonists. Clinical outcome trials of these therapies in persons with obesity at high risk of established CV conditions should make it possible to estimate the role of intentional weight loss in managing CV risk via these medications. High-dose once weekly injectable semaglutide (2.4mg/week) use among persons with obesity and heart failure with preserved ejection fraction was effective at both reducing weight and improving health status; exercise capacity was also improved. Ongoing CV outcome trials of oral semaglutide and once weekly injectable tirzepatide will help to establish the role of these therapies among persons with other CV conditions. In addition to these two therapies targeting a CV claim or indication, many other new therapeutics for weight loss, as reviewed, are currently in development. The impact of pharmacologic-induced weight loss on CV conditions for persons with obesity and established CV conditions is currently under investigation for multiple agents. These therapies may offer new avenues to manage CV risk in persons with obesity and with established or at high risk for CV disease.

IDF23-0254 A Phase 1, Dose-Escalation Study of a Novel dual GIP and GLP-1 receptor agonist (HS-20094) in Healthy Chinese Subjects

IDF23-0254 A Phase 1, Dose-Escalation Study of a Novel dual GIP and GLP-1 receptor agonist (HS-20094) in Healthy Chinese Subjects

Investigating incretins: a review of the use of GLP-1 and GIP receptor agonists for weight loss

Until recently, medicinal treatment for weight loss contributed only modestly to weight loss, with no particular medicine working notably better than the others, and all having side effects

What is the pipeline for future medications for obesity?

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

Tirzepatide prevents neurodegeneration through multiple molecular pathways

BackgroundSeveral evidence demonstrated that glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce the risk of dementia in type 2 diabetes patients by improving memory, learning, and overcoming cognitive impairment. In this study, we elucidated the molecular processes underlying the protective effect of Tirzepatide (TIR), a dual glucose-dependent insulinotropic polypeptide receptor agonist (GIP-RA)/ GLP-1RA, against learning and memory disorders.MethodsWe investigated the effects of TIR on markers of neuronal growth (CREB and BDNF), apoptosis (BAX/Bcl2 ratio) differentiation (pAkt, MAP2, GAP43, and AGBL4), and insulin resistance (GLUT1, GLUT4, GLUT3 and SORBS1) in a neuroblastoma cell line (SHSY5Y) exposed to normal and high glucose concentration. The potential role on DNA methylation of genes involved in neuroprotection and epigenetic modulators of neuronal growth (miRNA 34a), apoptosis (miRNA 212), and differentiation (miRNA 29c) was also investigated. The cell proliferation was detected by measuring Ki-67 through flow cytometry. The data were analysed by SPSS IBM Version 23 or GraphPad Prism 7.0 software and expressed as the means ± SEM. Differences between the mean values were considered significant at a p-value of < 0.05. GraphPad Prism software was used for drawing figures.ResultsFor the first time, it was highlighted: (a) the role of TIR in the activation of the pAkt/CREB/BDNF pathway and the downstream signaling cascade; (b) TIR efficacy in neuroprotection; (c) TIR counteracting of hyperglycemia and insulin resistance-related effects at the neuronal level.ConclusionsWe demonstrated that TIR can ameliorate high glucose-induced neurodegeneration and overcome neuronal insulin resistance. Thus, this study provides new insight into the potential role of TIR in improving diabetes-related neuropathy.Graphical

Incretin Therapies for Patients with Type 2 Diabetes and Chronic Kidney Disease.

Since the early 2000s, an influx of novel glucose-lowering agents has changed the therapeutic landscape for treatment of diabetes and diabetes-related complications. Glucagon-like peptide-1 (GLP-1) receptor agonists represent an important therapeutic class for the management of type 2 diabetes (T2D), demonstrating benefits beyond glycemic control, including lowering of blood pressure and body weight, and importantly, decreased risk of development of new or worsening chronic kidney disease (CKD) and reduced rates of atherosclerotic cardiovascular events. Plausible non-glycemic mechanisms that benefit the heart and kidneys with GLP-1 receptor agonists include anti-inflammatory and antioxidant effects. Further supporting their use in CKD, the glycemic benefits of GLP-1 receptor agonists are preserved in moderate-to-severe CKD. Considering current evidence, major guideline-forming organizations recommend the use of GLP-1 receptor agonists in cases of T2D and CKD, especially in those with obesity and/or in those with high cardiovascular risk or established heart disease. Evidence continues to build that supports benefits to the heart and kidneys of the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide. Ongoing outcome and mechanistic studies will continue to inform our understanding of the role of GLP-1 and dual GLP-1/GIP receptor agonists in diverse patient populations with kidney disease.

Glucose-dependent insulinotropic polypeptide receptor systems in the hypothalamus and the brainstem regulate feeding and weight through distinct pathways.

The report by Adriaenssens et al. in JCI Insight 22 May 2023 explored the role and property of the neurons that express glucose-dependent insulinotropic polypeptide receptor (GIPR) in the brainstem and hypothalamus. The chemogenetic activation of the brainstem GIPR neurons and that of the hypothalamic GIPR neurons showed different feeding and behavior responses. The brainstem GIPR neurons projected to the paraventricular hypothalamus and lateral parabrachial nucleus. Fluorescent-labeled, stabilized peptide GIPR agonist (GIPRA), peripherally injected, localized to the area postrema, nucleus tractus solitarius, median eminence and arcuate hypothalamus. This report showed the role of brainstem GIPR neurons in receiving GIPRA to drive the neural circuit to reduce feeding and bodyweight. In this commentary, distinct and possible cooperative roles of the hypothalamic and the brainstem GIPR pathways will also be discussed.

Glucose-dependent insulinotropic polypeptide regulates body weight and food intake via GABAergic neurons in mice

The development of single-molecule co-agonists for the glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) and glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) is considered a breakthrough in the treatment of obesity and type 2 diabetes. But although GIPR–GLP-1R co-agonism decreases body weight with superior efficacy relative to GLP-1R agonism alone in preclinical1–3 and clinical studies4,5, the role of GIP in regulating energy metabolism remains enigmatic. Increasing evidence suggests that long-acting GIPR agonists act in the brain to decrease body weight through the inhibition of food intake3,6–8; however, the mechanisms and neuronal populations through which GIP affects metabolism remain to be identified. Here, we report that long-acting GIPR agonists and GIPR–GLP-1R co-agonists decrease body weight and food intake via inhibitory GABAergic neurons. We show that acyl-GIP decreases body weight and food intake in male diet-induced obese wild-type mice, but not in mice with deletion of Gipr in Vgat(also known as Slc32a1)-expressing GABAergic neurons (Vgat-Gipr knockout). Whereas the GIPR–GLP-1R co-agonist MAR709 leads, in male diet-induced obese wild-type mice, to greater weight loss and further inhibition of food intake relative to a pharmacokinetically matched acyl-GLP-1 control, this superiority over GLP-1 vanishes in Vgat-Gipr knockout mice. Our data demonstrate that long-acting GIPR agonists crucially depend on GIPR signaling in inhibitory GABAergic neurons to decrease body weight and food intake.

Abstract 14462: Baseline Characteristics of Tirzepatide-Treated Participants Who Shifted to a Normal Body Mass Index (&lt;25 kg/m 2 ): A Post Hoc Analysis From SURMOUNT-1

Introduction: Tirzepatide is a once weekly GIP and GLP-1 receptor agonist approved for the treatment of type 2 diabetes and under investigation for chronic weight management. In SURMOUNT-1, tirzepatide treatment resulted in substantial body weight reductions in people with obesity (body mass index (BMI) ≥30 kg/m 2 ) or overweight (BMI ≥27 kg/m 2 ). Hypothesis: This post hoc analysis assessed the baseline characteristics of tirzepatide-treated participants who reached normal BMI, defined by &lt;25 kg/m 2 . Methods: Participants (N=1834) from SURMOUNT-1 with at least one post-baseline BMI measurements and adherent to tirzepatide (≥75% of doses received) were included in this analysis. The proportion of participants who shifted to a normal BMI was assessed during the study period. Baseline demographics and clinical characteristics were compared between participants who shifted to a normal BMI vs those who did not reach a normal BMI by week 72. Results: A total of 380 participants shifted to a normal BMI during the study period. Participants who shifted to a normal BMI were slightly older, more likely to be female, with shorter duration of obesity and lower baseline BMI (in particular a BMI ≥27 to &lt;30 kg/m 2 or ≥30 to &lt;35 kg/m 2 ), HbA1c, fasting glucose, fasting insulin, systolic blood pressure, ALT and eGFR vs those who did not reach a normal BMI (Table). Additionally, fewer had prediabetes and hypertension, and a greater proportion of participants had dyslipidemia in those who reached the normal BMI vs those who did not. Conclusions: In this post hoc analysis from SURMOUNT-1, approximately one in five participants with overweight or obesity receiving tirzepatide treatment reached the normal BMI (&lt;25 kg/m 2 ) by week 72. Participants who reached the normal BMI were older, more likely to be female and had several favorable characteristics at baseline including lower baseline BMI, HbA1c, blood pressure, ALT and eGFR compared to those who did not reach the normal BMI.

Abstract 16589: Predicting Cardiovascular Risk in Participants Treated With Tirzepatide in the SURPASS 1-5 Trials

Predicting atherosclerotic cardiovascular disease (ASCVD) risk considers factors that individually influence the likelihood of experiencing a major cardiovascular (CV) event. Tirzepatide (TZP) is a GIP and GLP-1 receptor agonist that improved risk factors such as lipid profile and systolic blood pressure across the Phase 3 SURPASS T2D program. We compared the effect of TZP versus the comparator on calculated ASCVD risk from baseline to endpoint in each of the 5 SURPASS (S) studies. We assessed the ASCVD risk in T2D participants without CVD history from S 1-5 studies using an American College of Cardiology/American Heart Association risk engine. The risk engine considers the factors: sex, age, race, total cholesterol, high density lipoprotein, systolic blood pressure, antihypertensive medication use, smoking and diabetes status. Risk scores and categories are summarized by treatment group. The baseline characteristics vary between studies (female sex ranges from 44.9% to 54.6%, mean age in years ranges from 53.6 to 64.3) but were similar among treatment groups within each study. The median baseline risk score across the TZP dose range were 6.5-11.5 for S-1, 9.3-10.8 for S-2, 12.4-15.4 for S-3, 22.9-26.0 for S-4, and 14.8-19.1 for S5. At the primary endpoint (40 or 52 Weeks), the ASCVD risk category for 10.9-21.4% of TZP-treated participants improved versus 2.9-12.7% for placebo/comparator (Table). Also, the risk category for 1.2-9.4% of TZP-treated participants worsened versus 6.3-14.9% for placebo/comparator. The median CV risk score was decreased in all TZP treatment groups while the median CV risk score was increased in the placebo/basal insulin groups. In SURPASS-2, the decreases in CV risk score were qualitatively greater in the TZP groups compared to the semaglutide group. TZP treatment lowers CV risk and significantly more participants shift to a lower CV risk category when compared to placebo, basal insulins, and semaglutide.