Glucose-dependent Insulinotropic Polypeptide Receptor Research Articles

75-LB: CT-388, a Novel Once-Weekly Dual GLP-1 and GIP Receptor Modulator, Is Safe, Well-Tolerated, and Produces More than 8% Weight Loss in Four Weeks in Overweight and Obese Adults

GLP-1 and GIP can deliver complementary pharmacology when combined. CT-388 is a biased dual GLP-1 and GIP receptor modulator that exhibits no to minimal β-arrestin coupling at either receptor, designed for once-weekly subcutaneous dosing. A Phase 1, randomized, placebo-controlled, double-blind study was conducted where single ascending doses (0.5-7.5 mg) and multiple ascending doses (MAD; doses 5-12 mg via titration in 3 cohorts) for 4 weeks were administered to overweight/obese adults. Primary objective was to investigate safety and tolerability of CT-388. Total of 64 participants (men/women: 28/36; median age/BMI: 34 years/33 kg/m2) received at least 1 dose of CT-388 or placebo. PK profile was investigated over a wide dose range (0.5-12 mg) and supports once-weekly administration. Percent change in body weight from baseline at Day 29 was dose responsive and significantly greater in CT-388 treated participants versus placebo (p <0.0001) across the 3 MAD cohorts with Least Square Mean difference [95% CI] of -4.8% [-6.3, -3.3], -6.4% [-7.8, -5.0], and -8.5% [-10.4, -6.7]. Mean percent decrease from baseline at Day 23 in fasting glucose (↓8-10%), insulin (↓20-26%), HOMA-IR (↓26-33%), AUC0-120min glucose (↓26-28%) and AUC0-120min insulin (↓33-58%) during oGTT were seen in cohorts dosed up to 12 mg CT-388, suggestive of improved insulin sensitivity. Over the 4-week treatment period, CT-388 was generally well tolerated with no treatment-related discontinuations. The most frequent side effects reported were gastrointestinal (decreased appetite, nausea, vomiting, diarrhea), which were mostly mild in severity. In summary, CT-388 delivers clinically meaningful weight loss and metabolic control with a favorable tolerability profile. These data warrant further clinical evaluation of CT-388, possibly with minimal to no titration, for the treatment of obesity, T2DM, and other weight-related comorbidities. Disclosure M. Chakravarthy: Employee; Carmot Therapeutics, Inc. F. A. Argüelles-Tello: Research Support; Carmot Therapeutics, Inc. A. A. Sun: None. M. Elliott: Employee; Carmot Therapeutics, Inc. L. Acosta: None. J. E. Rankin: None. S. K. Hansen: Board Member; Carmot Therapeutics, Inc.

774-P: Weight-Independent Effects of CT-868, a Signaling Biased Dual GLP-1/GIP Receptor Modulator, on Glucose Homeostasis in Overweight and Obese Adults with Type 2 Diabetes

GLP-1 and GIP can deliver complementary pharmacology when combined. CT-868 (CT) is a biased dual GLP-1 and GIP receptor modulator that exhibits no arrestin coupling or receptor internalization at either receptor. Its effects on insulin (INS) secretion via graded glucose infusion (GGI), glucose (GLUC) homeostasis in response to a mixed meal tolerance test (MMTT), gastric emptying (GE), and food intake (FI) were investigated in a randomized, double-blind crossover study in 20 overweight and obese adults with T2D split into 2 groups: CT vs placebo (PL), n=7 and CT vs PL vs liraglutide (LI), n = 13, the latter as a fixed 3rd period. Mean age and BMI were 52.2 years and 32.7 kg/m2 with 55% males. Treatments were administered for 4 days to minimize weight loss with 14 days washout between periods. GGI data showed robust INS secretion for CT-868 vs PL [change in ISR/GLUC at GIRmax (pmol/kg/min): CT 1.1 (0.1), PL 0.1 (0.2), LI 1.0 (0.3)]. MMTT based GLUC iAUC0-240 was significantly reduced for CT vs PL [72(46) vs 392(48)mmol/L*min] and numerically lower vs. LI [187(55) mmol/L*min] accompanied by significantly decreased INS iAUC0-240 vs both PL and LI: CT 1178(846), PL 5833(873), LI 4613(1253) mU/L*min. As both CT and LI had similar delayed GE vs PL, the reduced GLUC and INS excursion seen with CT suggests improved INS sensitivity or enhanced INS independent GLUC disposal. CT demonstrated minimal suppression of glucagon during MMTT vs LI that showed glucagon lowering. FI was lower for CT vs PL accompanied by reduction in hunger and appetite as assessed by VAS. There were no significant body weight changes in any treatment period. GI side effects were mostly mild and transient. This data supports a robust weight-independent effect of CT-868 (vs unbiased liraglutide) on glucose disposal with minimal suppression of glucagon. Further delineation of CT-868's longer term effects in overweight and obese patients with both T2D and T1D is underway. Disclosure M.Chakravarthy: Employee; Carmot Therapeutics, Inc. M.Hernandez: None. M.Elliott: Employee; Carmot Therapeutics, Inc. A.Macias: None. S.K.Hansen: Board Member; Carmot Therapeutics, Inc. M.Hompesch: Board Member; ProSciento, Consultant; Wiley-Blackwell, Employee; ProSciento, Stock/Shareholder; ProSciento.

1649-P: Biased GLP-1 Improves Weight Loss with Additional Benefits on Glucose Homeostasis via Biased GIP in Diabetic Rodent Models

GLP-1 and GIP when combined can deliver complementary pharmacology. CT-868 (CT) and CT-859 are biased dual GLP-1 and GIP receptor modulators with no β-arrestin coupling on either receptor. Effect of both compounds on weight loss (WL) and glucose (GLUC) homeostasis were assessed in relevant rodent models. At non-GIPR engaging doses in ob/ob mice, 30 nmol/kg CT achieved greater WL vs 200 nmol/kg Liraglutide (LI), an unbiased GLP-1RA (19.8% vs 11.5%, p=0.002), indicating biased GLP-1 improves WL vs unbiased GLP-1. GLUC tolerance test (GTT) in GIPR-/- mice showed similar reduction in AUCGLUC with LI and CT-859 at 20 nmol/kg 4h after dosing (53% vs 62%, p=NS), but only CT-859 maintained significant reduction after 24h and 48h, indicating biased GLP-1 induces a sustained GLUC lowering effect. After 14d of dosing in Akita mice with non-GIPR engaging doses of CT 20 nmol/kg, blood glucose (BG) decreased 30% vs LI 20 nmol/kg (p=0.01) indicating superior effect of biased GLP-1 on glycemic control. At GIPR engaging doses, CT 200 nmol/kg on background of insulin (INS) significantly lowered BG vs LI 200nmol/kg in Akita (↓35%, p=0.009) and DIO-STZ (↓32%, p<0.0001) mice. Akita mice treated for 14d with CT 300 nmol/kg + low INS normalized BG to same extent as vehicle + high INS, but with 68% lower INS levels (p < 0.0001). In GLP-1R-/- mice, CT 300 nmol/kg lowered AUCGLUC 38% vs vehicle (p<0.0001) without concomitant INS excursion, showing that GIP enhances INS independent GLUC disposal or INS sensitivity. In response to pyruvate challenge, CT 100 nmol/kg suppressed AUCGLUC 36% (p<0.05) and 14% (p=0.006) on a background of INS treatment in Akita and GLP-1R-/- mice, respectively, suggesting GIPR activation may contribute to suppression of endogenous GLUC production. Together, these data demonstrate that CT provides improved WL via biased GLP-1 with enhanced GLUC homeostasis via biased GIP relative to unbiased GLP-1 (LI). These findings have translated to T2D patients treated with CT-868. Disclosure R.Rodriguez: Employee; Carmot Therapeutics, Inc. T.Tracy: Employee; Carmot Therapeutics, Inc. M.Morales: None. A.Hergarden: Employee; Carmot Therapeutics, Inc. D.Lam: Employee; Carmot Therapeutics, Inc. S.Krishnan: Employee; Carmot Therapeutics, Inc. S.K.Hansen: Board Member; Carmot Therapeutics, Inc. M.Chakravarthy: Employee; Carmot Therapeutics, Inc.

763-P: Safety, Tolerability, Pharmacokinetics (PK), and Pharmacodynamics (PD) of a Dual GLP-1/GIP Receptor Agonist (HRS9531) in Healthy Subjects—A Phase 1, Randomized, Double-Blind, Placebo-Controlled, Single and Multiple Ascending Dose (SAD and MAD) Study

Background: Accumulating evidences suggest that dual GLP-1/GIP receptor agonist can achieve prominent glycemic control and body weight loss. Here we report the results of a phase 1 SAD and MAD study of HRS9531 in healthy subjects (NCT05152277). Methods: In the SAD, healthy subjects were randomized (4:1) to receive subcutaneous injection of HRS9531 (0.1, 0.3, 0.9, 2.7, 5.4, and 8.1 mg) or placebo. In the MAD, healthy subjects were randomized (4:1) to receive HRS9531 (0.9, 2.7, and 5.4 mg [2.7/2.7/4.0/5.4 mg titration]) or placebo once a week for 4 wks. The primary endpoints for both parts were safety and tolerability. Results: Sixty and 30 subjects were recruited into SAD and MAD respectively. The most common adverse events were abdominal distension and nausea in SAD, and urine ketone body present and nausea in MAD; all considered mild to moderate in severity (mostly mild). No severe hypoglycemia or serious events occurred. Drug exposure were proportional to dose from 0.9-8.1 mg. The median Tmax and mean t1/2 were 48-72 h and 156-182 h in SAD, and 48-72 h and 169-192 h after the fourth dosing in MAD, respectively. Fasting plasma glucose (FPG) levels decreased dose-dependently after single and multiple dosing. The 0 to 2 h glucose AUC during oral glucose tolerance test (OGTT) on D23 decreased dose-dependently relative to placebo in MAD. In SAD, body weight loss was dose-dependent and the maximal mean loss on D8 was 3.8 kg (4.9%) in 8.1 mg group. In MAD, the mean weight loss on D29 (after 4 wks treatment) ranged 4.3-7.7 kg (6.7%-9.3%) across 0.9-5.4 mg groups, and maximal loss (8.0 kg, 10.0%) occurred on D36 in 5.4 mg group. Conclusions: HRS9531 was well tolerated, had favorable PK, and led to evident glucose decrease and body weight loss. These data support further clinical development of HRS9531 for metabolism-related disorders such as T2DM and obesity. Disclosure K.He: None. F.Wei: None. H.Chen: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Y.Zhang: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Z.Sheng: Employee; Jiangsu Hengrui Pharmaceuticals Co., Ltd. Q.Wen: None. Funding Jiangsu Hengrui Pharmaceuticals Co., Ltd.

1755-P: EndoC-ßH5 Is a Storable and Ready-to-Use Human Pancreatic Beta Cell That Can Model Type 1 and 2 Diabetes

EndoC-βH5 is a newly developed human pancreatic beta cell model and an optimized version among the EndoC-βH (EndoC-βH1/2/3) family. EndoC-βH5 cells are storable and ready-to-use and they robustly and reproducibly secrete insulin in response to glucose and incretins across experiments and laboratories. Specifically, they dose dependently respond to physiological concentrations of glucose. In addition, their response to GLP-1 and GIP receptor agonists is also highly reproducible and dose-dependent. Given the continuously increasing number of diabetes patients worldwide, the need for physiologically relevant human cellular models is greater than ever and EndoC-βH5 cells represent a novel human pancreatic beta cell solution that can help developing human diabetes models and drug screening and validation assays. In this study, we are developing pathological and drug screening models. EndoC-βH5 cells are sensitive to palmitate/high glucose as well as cytokine induced cell loss, recapitulating hallmarks of T2D. In addition, we evaluated impairment of insulin secretion and ER stress in these contexts in order to assess the mechanistic relevance of the models. We then addressed T1D modeling. We generated HLA-A2 expressing EndoC-βH5 cells and evaluated HLA-A2 alloreactive T lymphocyte activation and diabetogenic T lymphocyte induced cytotoxicity. Finally, we determined that EndoC-βH5 cells express functional glucagon (GCG) receptor, which contributes to the modulation of glucose induced insulin secretion, highlighting the potential of EndoC-βH5 as a model to study dual and triple GLP-1/GIP/GCG receptor agonists in a reproducible human cellular model. Overall, EndoC-βH5 cells appear to be a powerful tool to develop Type 1/2 diabetes and drug discovery models. Disclosure H.Olleik: None. B.Blanchi: Employee; Human Cell Design.

The incretin co-agonist tirzepatide requires GIPR for hormone secretion from human islets

The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance1. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity2, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity3,4. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control5. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.

0567 Tirzepatide for the Treatment of OSA: Rationale and Design of the SURMOUNT-OSA Phase 3 Trial

Abstract Introduction Weight reduction is a standard recommended component of OSA treatment in people with obesity or overweight; however, the challenge to achieve and maintain weight reduction has limited its clinical application outside of the benefit established after bariatric surgery. Currently no FDA-approved anti-obesity medication (AOM) has demonstrated clinically meaningful improvement in OSA severity and symptomology. Methods Tirzepatide is a single molecule GIP and GLP-1 receptor agonist. In SURMOUNT-1, a 72-week phase 3 clinical trial in participants with obesity or overweight, tirzepatide 15mg provided average reductions in body weight of 22.5% which occurred with beneficial effects on blood pressure, lipids, and physical functioning. In a linear meta regression model, we estimated that tirzepatide treatment would provide clinically meaningful apnea-hypopnea index decrease compared to placebo-treated participants with obesity and OSA. SURMOUNT-OSA, a placebo controlled 52-week, phase 3 trial, will investigate efficacy and safety of tirzepatide for the treatment of moderate to severe OSA (defined as AHI ≥15) in participants with obesity. SURMOUNT-OSA utilizes an umbrella master protocol and 2 Intervention-Specific Appendices (ISAs): ISA 1 includes participants with no current OSA treatment and ISA 2 includes participants using positive airway pressure therapy. Approximately 412 participants will be randomly assigned to placebo or tirzepatide across the entire master protocol, with approximately 206 participants in each ISA. While participants will receive tirzepatide or placebo based on a 1:1 randomization ratio, all participants will receive background lifestyle intervention for weight reduction. Results The primary endpoint for the individual ISAs is the difference in AHI response measured by polysomnography between tirzepatide and placebo arms at week 52. Secondary endpoints include hypoxic burden, functional outcomes and cardiometabolic biomarkers. The trial is utilizing a unique hierarchical functional outcomes endpoint based on Functional Outcomes of Sleep Questionnaire methodology. The trial employs wearables, such as home sleep testing and accelerometry to capture time to improvement as exploratory outcomes. Conclusion SURMOUNT-OSA aims to explore whether tirzepatide provides clinically meaningful improvement in obesity-related OSA by targeting an underlying etiology. Support (if any) Eli Lilly

GIP receptor agonism blocks chemotherapy-induced nausea and vomiting

Nausea and vomiting remain life-threatening obstacles to successful treatment of chronic diseases, despite a cadre of available antiemetic medications. Our inability to effectively control chemotherapy-induced nausea and vomiting (CINV) highlights the need to anatomically, molecularly, and functionally characterize novel neural substrates that block CINV. Behavioral pharmacology assays of nausea and emesis in 3 different mammalian species were combined with histological and unbiased transcriptomic analyses to investigate the beneficial effects of glucose-dependent insulinotropic polypeptide receptor (GIPR) agonism on CINV. Single-nuclei transcriptomics and histological approaches in rats revealed a topographical, molecularly distinct, GABA-ergic neuronal population in the dorsal vagal complex (DVC) that is modulated by chemotherapy but rescued by GIPR agonism. Activation of DVCGIPR neurons substantially decreased behaviors indicative of malaise in cisplatin-treated rats. Strikingly, GIPR agonism blocks cisplatin-induced emesis in both ferrets and shrews. Our multispecies study defines a peptidergic system that represents a novel therapeutic target for the management of CINV, and potentially other drivers of nausea/emesis.

The Methylation Analysis of the Glucose-Dependent Insulinotropic Polypeptide Receptor (GIPR) Locus in GH-Secreting Pituitary Adenomas.

The glucose-dependent insulinotropic polypeptide receptor (GIPR) is aberrantly expressed in about one-third of GH-secreting pituitary adenomas (GH-PAs) and has been associated with a paradoxical increase of GH after a glucose load. The reason for such an overexpression has not yet been clarified. In this work, we aimed to evaluate whether locus-specific changes in DNA methylation patterns could contribute to this phenomenon. By cloning bisulfite-sequencing PCR, we compared the methylation pattern of the GIPR locus in GIPR-positive (GIPR+) and GIPR-negative (GIPR-) GH-PAs. Then, to assess the correlation between Gipr expression and locus methylation, we induced global DNA methylation changes by treating the lactosomatotroph GH3 cells with 5-aza-2'-deoxycytidine. Differences in methylation levels were observed between GIPR+ and GIPR- GH-PAs, both within the promoter (31.9% vs. 68.2%, p < 0.05) and at two gene body regions (GB_1 20.7% vs. 9.1%; GB_2 51.2% vs. 65.8%, p < 0.05). GH3 cells treated with 5-aza-2'-deoxycytidine showed a ~75% reduction in Gipr steady-state level, possibly associated with the observed decrease in CpGs methylation. These results indicate that epigenetic regulation affects GIPR expression in GH-PAs, even though this possibly represents only a part of a much more complex regulatory mechanism.

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

Central glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) signaling is critical in GIP-based therapeutics' ability to lower body weight, but pathways leveraged by GIPR pharmacology in the brain remain incompletely understood. We explored the role of Gipr neurons in the hypothalamus and dorsal vagal complex (DVC) - brain regions critical to the control of energy balance. Hypothalamic Gipr expression was not necessary for the synergistic effect of GIPR/GLP-1R coagonism on body weight. While chemogenetic stimulation of both hypothalamic and DVC Gipr neurons suppressed food intake, activation of DVC Gipr neurons reduced ambulatory activity and induced conditioned taste avoidance, while there was no effect of a short-acting GIPR agonist (GIPRA). Within the DVC, Gipr neurons of the nucleus tractus solitarius (NTS), but not the area postrema (AP), projected to distal brain regions and were transcriptomically distinct. Peripherally dosed fluorescent GIPRAs revealed that access was restricted to circumventricular organs in the CNS. These data demonstrate that Gipr neurons in the hypothalamus, AP, and NTS differ in their connectivity, transcriptomic profile, peripheral accessibility, and appetite-controlling mechanisms. These results highlight the heterogeneity of the central GIPR signaling axis and suggest that studies into the effects of GIP pharmacology on feeding behavior should consider the interplay of multiple regulatory pathways.

Tirzepatide attenuates lipopolysaccharide-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway

BackgroundsSepsis-induced cardiac dysfunction is a leading cause of mortality in intensive care units. Tirzepatide, a dual glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor agonist, possess cardio-protective, their effects on sepsis-induced cardiomyopathy remain unknown. MethodsC57BL/6 mice received subcutaneous injections of tirzepatide once a day for 14 days before subjected to LPS challenge for 12 h. LPS-induced cardiac dysfunction and its potential mechanisms were estimated by pathological analysis, echocardiographic measurement, electrocardiography, langendorff-perfused heart and molecular analysis. ResultsPretreatment with tirzepatide attenuates LPS-induced cardiac dysfunction. tirzepatide remarkably reduces LPS-mediated inflammatory responses by inhibiting the cardiac protein levels of TNF-α, IL-6, and IL-1B in mice. Interestingly, tirzepatide administration also improves cardiomyocytes apoptosis caused by LPS treatment. Furthermore, the protective roles of irzepatide against LPS-mediated increased inflammatory responses and decreased cardiomyocytes apoptosis are partially blunted by inhibiting TLR4/NF-kB/NLRP3 inflammation signaling. In addition, tirzepatide reduce the susceptibility ventricular arrhythmia in LPS-treated mice. ConclusionIn brief, tirzepatide attenuates LPS-induced left ventricular remodeling and dysfunction by inhibiting the TLR4/NF-kB/NLRP3 pathway.

Genetically proxied impaired GIPR signaling and risk of 6 cancers

Preclinical and genetic studies suggest that impaired glucose-dependent insulinotropic polypeptide receptor (GIPR) signaling worsens glycemic control. The relationship between GIPR signaling and the risk of cancers influenced by impaired glucose homeostasis is unclear. We examined the association of a variant in GIPR, rs1800437 (E354Q), shown to impair long-term GIPR signaling and lower circulating glucose-dependent insulinotropic peptide concentrations, with risk of 6 cancers influenced by impaired glucose homeostasis (breast, colorectal, endometrial, lung, pancreatic, and renal) in up to 235,698 cases and 333,932 controls. Each copy of E354Q was associated with a higher risk of overall and luminal A-like breast cancer and this association was consistent in replication and colocalization analyses. E354Q was also associated with higher postprandial glucose concentrations but diminished insulin secretion and lower testosterone concentrations. Our human genetics analysis suggests an adverse effect of the GIPR E354Q variant on breast cancer risk, supporting further evaluation of GIPR signaling in breast cancer prevention.

Abstract #1394102: Orlistat for Weight Loss: Remembering All the Tools of the Trade

New medications like the gastric inhibitory polypeptide (GIP) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) have been making headlines as more effective weight loss medications. However, in the light of recent manufacturing delays, cost and side effects, older weight loss medications should still be considered. A 58-year-old female with history of metabolic syndrome and depression presented to endocrinology clinic to discuss weight loss medications. On presentation, she was at her maximum weight of 205 pounds (BMI 37.5). She previously enrolled in the Veterans Affairs Hospital ‘MOVE’ program and started metformin 1000mg twice a day with minimal weight loss. Her insurance did not cover GLP-1 RAs and both bupropion-naltrexone and phentermine-topiramate were contraindicated since she was already taking bupropion and had a history of kidney stones. The patient was started on orlistat 120mg three times a day, which she tolerated, and in 2 months had a 4% weight loss to 197 pounds (BMI 36). Over the next 7 months she lost an additional 16 pounds (BMI 32.9) and no longer qualified for bariatric surgery. After 2.5 years, the patient has lost 57 pounds (BMI 27.1, 28% weight loss), her A1c has decreased from 6.8% to 6.1%, her total cholesterol has decreased from 202 to 127, and her LDL from 101 to 58 (atorvastatin 10mg was added at the same time as orlistat). She now self titrates orlistat based on her meals and averages taking the medication one to two times a day. Orlistat functions by inhibiting gastrointestinal lipases, resulting in decreased absorption of fat by 30%. It has been shown to promote and maintain weight loss of an average of 3.8%, as well as reduce the risk of developing type 2 diabetes and lower cholesterol. While other weight loss medications, such as bupropion-naltrexone, phentermine-topiramate, and GLP-1 RAs have contraindications in patients with significant cardiac history, hyperthyroidism, seizures, and pancreatitis, orlistat has no contraindications. This medication is ideal in patients who eat a high fat diet or do not want to administer injections and is cost effective with minimal contraindications. The limiting factor is gastrointestinal side effects such as fatty stool and fecal incontinence, which occur in approximately 25% of patients. These side effects decrease in frequency with long-term use and are reduced when given with psyllium. In summary, this case highlights orlistat as an effective weight loss medication in the appropriate patient.

GIPR expression is induced by thiazolidinediones in a PPARγ-independent manner and repressed by obesogenic stimuli

Adipose tissue (AT) dysfunctions are associated with the onset of insulin resistance (IR) and type 2 diabetes mellitus (T2DM). Targeting glucose-dependent insulinotropic peptide receptor (GIPR) is a valid option to increase the efficacy of glucagon-like peptide 1 (GLP-1) receptor agonists in T2DM treatment. Nevertheless, the therapeutic potential of targeting the GIP/GIPR axis and its effect on the AT are controversial. In this work, we explored the expression and regulation of GIPR in precursor cells and mature adipocytes, investigating if and how obesogenic stimuli and thiazolidinediones perturb GIPR expression. Using publicly available gene expression datasets, we assessed that, among white adipose tissue (WAT) cells, adipocytes express lower levels of GIPR compared to cells of mesothelial origin, pericytes, dendritic and NK/T cells. However, we report that GIPR levels markedly increase during the in vitro differentiation of both murine and human adipocytes, from 3T3-L1 and human mesenchymal precursor cells (MSCs), respectively. Notably, we demonstrated that thiazolidinediones – ie. synthetic PPARγ agonists widely used as anti-diabetic drugs and contained in the adipogenic mix – markedly induce GIPR expression. Moreover, using multiple in vitro systems, we assessed that thiazolidinediones induce GIPR in a PPARγ-independent manner. Our results support the hypothesis that PPARγ synthetic agonists may be used to increase GIPR levels in AT, potentially affecting in turn the targeting of GIP system in patients with metabolic dysfunctions. Furthermore, we demonstrate in vitro and in vivo that proinflammatory stimuli, and especially the TNFα, represses GIPR both in human and murine adipocytes, even though discordant results were obtained between human and murine cellular systems for other cytokines. Finally, we demonstrated that GIPR is negatively affected also by the excessive lipid engulfment. Overall, we report that obesogenic stimuli - ie. pro-inflammatory cytokines and the increased lipid accumulation – and PPARγ synthetic ligands oppositely modulate GIPR expression, possibly influencing the effectiveness of GIP agonists.

Is retatrutide (LY3437943), a GLP-1, GIP, and glucagon receptor agonist a step forward in the treatment of diabetes and obesity?

ABSTRACT Introduction Despite there being a wide range of medicines available for the treatment of type 2 diabetes, the high rate of mortality suggests treatment needs to be improved. Only a few medicines have shown long-term effectiveness in obesity, and new medicines are urgently needed. Areas covered A multiple-ascending dose phase 1b clinical trial of a new drug retatrutide (LY3437943), which in addition to stimulating Glucagon-like peptide 1 (GLP-1) and Glucose-dependent insulinotropic polypeptide (GIP) receptors, stimulates glucagon receptors, in subjects with type 2 diabetes. Retatrutide was relatively safe and pharmacokinetics support once-weekly dosing. Expert opinion The role of stimulating glucagon receptors in the treatment of type 2 diabetes and/or obesity is poorly defined and needs to be clarified. Although retatrutide may be superior to the GLP-1 receptor agonist dulaglutide in reducing plasma glucose and body weight, this is not a meaningful comparison, as another GLP-1 receptor agonist (semaglutide) is more potent than dulaglutide at this and may have similar efficacy to retatrutide. Retatrutide also needs to be compared to another Eli Lilly and Company drug, the combined GLP-1 and GIP receptor agonist, tirzepatide. The safety of retatrutide needs to be determined in larger and longer trials.

Special Report: Potential Strategies for Addressing GLP-1 and Dual GLP-1/GIP Receptor Agonist Shortages.

Unexpected drug shortages of the long-acting glucagon-like peptide-1 (GLP-1) receptor agonists dulaglutide and semaglutide and the dual GLP-1/glucose-dependent insulinotropic polypeptide (GIP) receptor agonist tirzepatide emerged in late 2022 and have persisted through the first quarter of 2023 (1). The drug shortage has not affected product doses equally; some doses are more widely available than others (2). For the purposes of this article, we will consider the dual GLP-1/GIP receptor agonist tirzepatide to be included when referring to GLP-1 receptor agonist product shortages. These shortages predominately occurred because of an unexpected increase in demand for GLP-1 receptor agonists without adequate adjustment in production (3). The inadequate supply has created new access barriers for patients previously using or wishing to initiate these products for glycemic management, weight loss, and/or cardiovascular risk reduction. Thus, strategies to mitigate this disruption to patient care are needed.

Tirzepatide - a novel dual GLP-1 and GIP receptor agonist used in pharmacotherapy of obesity: A literature review

Background: Obesity is a chronic disease, which along with its complications, poses a huge threat to both our health as individuals and our healthcare as a community.&#x0D; Objective: The aim of this work is to review efficacy and safety of Tirzepatide, a novel dual GIP/GLP-1 receptor agonist in the treatment of obesity&#x0D; Method: A literature review was conducted on databases such as PubMed and Google Scholar using terms “obesity”, “obesity treatment”, “glucagon-like peptide 1”, “Glucose-dependent insulinotropic polypeptide”, “Tirzepatide” as keywords. The review was performed in accordance with the PRISMA guidelines.&#x0D; Results: Administration of tirzepatide once weekly provides a substantial and sustained reduction in bodyweight with little side effects.&#x0D; Conclusions: Clinical trials showed both high efficacy and safety of Tirzepatide in management of obesity. Due to its novel, broadened mechanism of action it seems to be the most effective drug for reducing bodyweight available on the market. Tirzepatide could be our answer to tackling the problem of world-wide obesity epidemic.&#x0D;

The relative importance of Endogenously Secreted incretin hormones, GLP‐1 and GIP for Postprandial Glucose Tolerance and β‐Cell Function After Roux‐en‐Y Gastric Bypass and Sleeve Gastrectomy Surgery

Bariatric surgery procedures, namely Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) is increasingly used worldwide, have been shown to be the most effective strategy to induce and maintain weight loss as well as inducing long-term remission from type 2 diabetes among people with significant obesity. The mechanism for diabetes remission remains unclear and multi-factorial, although increased secretion of endogenous glucagon-like peptide 1 (GLP-1) hormones to improve postprandial β-cell function is widely considered to be the main mechanism for diabetes remission following RYGB. However, recent studies have shown that rate of remission between the two types of bariatric surgery procedures are similar but yet, the mechanism for remission above and beyond weight loss per se following SG is less clear. Beyond GLP-1, the role of the other major incretin hormone, glucose-dependent insulinotropic polypeptide (GIP), is relatively unexplored after bariatric surgery. A study published in Diabetes Care have therefore studied the effects of separate and combined GLP-1 receptor (GLP-1R) and GIP receptor (GIPR) blockade during mixed-meal tests in un-operated (CON), SG-operated, and RYGB-operated people with no history of diabetes. The investigator found that, as expected, postprandial GLP-1 concentrations were highest after RYGB but also higher after SG compared with CON. In contrast, postprandial GIP concentrations were lowest after RYGB. Interestingly, blockage of GLP-1R reduced β-cell glucose sensitivity and increased postprandial glucose responses in both surgical groups but had no effect in CON. Blockage of GIPR however reduced β-cell glucose sensitivity and increased postprandial glucose responses in the CON and SG groups but had no effect in the RYGB group. This study showed that while GLP-1 is the most important mediator of improved beta cell function after RYGB, both GLP-1 and GIP are equally important after SG. The combine benefits of GLP-1 and GIP following SG is interesting, given the recent emergence of the dual GLP-1 and GIP agonist for the treatment of diabetes and obesity. It would be interesting also to explore the relative role of Glucagon on beta cell function following both procedures.

Combined glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonism attenuates atherosclerosis severity in APOE*3-Leiden.CETP mice

Background and aimsCombined agonism of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP1R) is superior to single GLP1R agonism in terms of glycemic control and lowering body weight in individuals with obesity and with or without type 2 diabetes mellitus. As both GIPR and GLP1R signaling have also been implicated in improving inflammatory responses and lipid handling, two crucial players in atherosclerosis development, here we aimed to investigate the effects of combined GIPR/GLP1R agonism in APOE*3-Leiden.CETP mice, a well-established mouse model for human-like lipoprotein metabolism and atherosclerosis development. MethodsFemale APOE*3-Leiden.CETP mice were fed a Western-type diet (containing 16% fat and 0.15% cholesterol) to induce dyslipidemia, and received subcutaneous injections with either vehicle, a GIPR agonist (GIPFA-085), a GLP1R agonist (GLP-140) or both agonists. In the aortic root area, atherosclerosis development was assessed. ResultsCombined GIPR/GLP1R agonism attenuated the development of severe atherosclerotic lesions, while single treatments only showed non-significant improvements. Mechanistically, combined GIPR/GLP1R agonism decreased markers of systemic low-grade inflammation. In addition, combined GIPR/GLP1R agonism markedly lowered plasma triglyceride (TG) levels as explained by reduced hepatic very-low-density lipoprotein (VLDL)-TG production as well as increased TG-derived fatty acid uptake by brown and white adipose tissue which was coupled to enhanced hepatic uptake of core VLDL remnants. ConclusionsCombined GIPR/GLP1R agonism attenuates atherosclerosis severity by diminishing inflammation and increasing VLDL turnover. We anticipate that combined GIPR/GLP1R agonism is a promising strategy to lower cardiometabolic risk in humans.

GLP-1/GIP analogs: potential impact in the landscape of obesity pharmacotherapy

ABSTRACT Introduction Obesity is recognized as a major healthcare challenge. Following years of slow progress in discovery of safe, effective therapies for weight management, recent approval of the glucagon-like peptide 1 receptor (GLP-1R) mimetics, liraglutide and semaglutide, for obesity has generated considerable excitement. It is anticipated these agents will pave the way for application of tirzepatide, a highly effective glucose-dependent insulinotropic polypeptide receptor (GIPR), GLP-1R co-agonist, recently approved for management of type 2 diabetes mellitus. Areas covered Following promising weight loss in obese individuals in Phase III clinical trials, liraglutide and semaglutide were approved for weight management without diabetes. Tirzepatide has attained Fast Track designation for obesity management by the US Food and Drug Association. This narrative review summarizes experimental, preclinical, and clinical data for these agents and related GLP-1R/GIPR co-agonists, prioritizing clinical research published within the last 10 years where possible. Expert Opinion GLP-1R mimetics are often discontinued within 24 months meaning long-term application of these agents in obesity is questioned. Combined GIPR/GLP-1R agonism appears to induce fewer side effects, indicating GLP-1R/GIPR co-agonists may be more suitable for enduring obesity management. After years of debate, this GIPR-biased GLP-1R/GIPR co-agonist highlights the therapeutic promise of including GIPR modulation for diabetes and obesity therapy.