The accelerated approval program for oncology drugs: celebrating more than 250,000 life-years gained and counting.

This commentary explores how 2 recently published studies evaluating the clinical benefit of the FDA's accelerated approval program for oncology drugs came to different conclusions.

Characterization of genetic variants of GIPR reveals a contribution of ß-arrestin to metabolic phenotypes.

Incretin-based therapies are highly successful in combatting obesity and type 2 diabetes1. Yet both activation and inhibition of the glucose-dependent insulinotropic polypeptide (GIP) receptor (GIPR) in combination with glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) activation have resulted in similar clinical outcomes, as demonstrated by the GIPR-GLP-1R co-agonist tirzepatide2 and AMG-133 (ref. 3) combining GIPR antagonism with GLP-1R agonism. This underlines the importance of a better understanding of the GIP system. Here we show the necessity of ß-arrestin recruitment for GIPR function, by combining in vitro pharmacological characterization of 47 GIPR variants with burden testing of clinical phenotypes and in vivo studies. Burden testing of variants with distinct ligand-binding capacity, Gs activation (cyclic adenosine monophosphate production) and ß-arrestin 2 recruitment and internalization shows that unlike variants solely impaired in Gs signalling, variants impaired in both Gs and ß-arrestin 2 recruitment contribute to lower adiposity-related traits. Endosomal Gs-mediated signalling of the variants shows a ß-arrestin dependency and genetic ablation of ß-arrestin 2 impairs cyclic adenosine monophosphate production and decreases GIP efficacy on glucose control in male mice. This study highlights a crucial impact of ß-arrestins in regulating GIPR signalling and overall preservation of biological activity that may facilitate new developments in therapeutic targeting of the GIPR system.

Intra-islet α-cell Gs signaling promotes glucagon release.

Glucagon, a hormone released from pancreatic α-cells, is critical for maintaining euglycemia and plays a key role in the pathophysiology of diabetes. To stimulate the development of new classes of therapeutic agents targeting glucagon release, key α-cell signaling pathways that regulate glucagon secretion need to be identified. Here, we focused on the potential importance of α-cell Gs signaling on modulating α-cell function. Studies with α-cell-specific mouse models showed that activation of α-cell Gs signaling causes a marked increase in glucagon secretion. We also found that intra-islet adenosine plays an unexpected autocrine/paracrine role in promoting glucagon release via activation of α-cell Gs-coupled A2A adenosine receptors. Studies with α-cell-specific Gαs knockout mice showed that α-cell Gs also plays an essential role in stimulating the activity of the Gcg gene, thus ensuring proper islet glucagon content. Our data suggest that α-cell enriched Gs-coupled receptors represent potential targets for modulating α-cell function for therapeutic purposes.

Evaluating glucose-dependent insulinotropic polypeptide and glucagon as key regulators of insulin secretion in the pancreatic islet.

The incretin axis is an essential component of postprandial insulin secretion and glucose homeostasis. There are two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which exert multiple actions throughout the body. A key cellular target for the incretins are pancreatic ß-cells, where they potentiate nutrient-stimulated insulin secretion. This feature of incretins has made this system an attractive target for therapeutic interventions aimed at controlling glycemia. Here, we discuss the role of GIP in both ß-cells and α-cells within the islet, to stimulate insulin and glucagon secretion, respectively. Moreover, we discuss how glucagon secretion from α-cells has important insulinotropic actions in ß-cells through an axis termed α- to ß-cell communication. These recent advances have elevated the potential of GIP and glucagon as a therapeutic targets, coinciding with emerging compounds that pharmacologically leverage the actions of these two peptides in the context of diabetes and obesity.

Development of novel iron(III) crosslinked bioinks comprising carboxymethyl cellulose, xanthan gum, and hyaluronic acid for soft tissue engineering applications.

The advent of three-dimensional (3D) bioprinting offers a feasible approach to construct complex structures for soft tissue regeneration. Carboxymethyl cellulose (CMC) has been emerging as a very promising biomaterial for 3D bioprinting. However, due to the inability to maintain the post-printed stability, CMC needs to be physically blended and/or chemically crosslinked with other polymers. In this context, this study presents the combination of CMC with xanthan gum (XG) and hyaluronic acid (HA) to formulate a multicomponent bioink, leveraging the printability of CMC and XG, as well as the cellular support properties of HA. The ionic crosslinking of printed constructs with iron(III) via the metal-ion coordination between ferric cations and carboxylate groups of the three polymers was introduced to induce improved mechanical strength and long-term stability. Moreover, immortalized human epidermal keratinocytes (HaCaT) and human foreskin fibroblasts (HFF) encapsulated within iron-crosslinked printed hydrogels exhibited excellent cell viability (more than 95%) and preserved morphology. Overall, the presented study highlights that the combination of these three biopolymers and the ionic crosslinking with ferric ions is a valuable strategy to be considered for the development of new and advanced hydrogel-based bioinks for soft tissue engineering applications.

GLP1R and GIPR expression and signaling in pancreatic alpha cells, beta cells and delta cells.

Glucagon-like peptide-1 receptor (GLP1R) and glucose-dependent insulinotropic polypeptide receptor (GIPR) are transmembrane receptors involved in insulin, glucagon and somatostatin secretion from the pancreatic islet. Therapeutic targeting of GLP1R and GIPR restores blood glucose levels in part by influencing beta cell, alpha cell and delta cell function. Despite the importance of the incretin-mimetics for diabetes therapy, our understanding of GLP1R and GIPR expression patterns and signaling within the islet remain incomplete. Here, we present the evidence for GLP1R and GIPR expression in the major islet cell types, before addressing signaling pathway(s) engaged, as well as their influence on cell survival and function. While GLP1R is largely a beta cell-specific marker within the islet, GIPR is expressed in alpha cells, beta cells, and (possibly) delta cells. GLP1R and GIPR engage Gs-coupled pathways in most settings, although the exact outcome on hormone release depends on paracrine communication and promiscuous signaling. Biased agonism away from beta-arrestin is an emerging concept for improving therapeutic efficacy, and is also relevant for GLP1R/GIPR dual agonism. Lastly, dual agonists exert multiple effects on islet function through GIPR > GLP1R imbalance, increased GLP1R surface expression and cAMP signaling, as well as beneficial alpha cell-beta cell-delta cell crosstalk.

GIPR/GLP-1R dual agonist therapies for diabetes and weight loss-chemistry, physiology, and clinical applications.

The incretin system is an essential metabolic axis that regulates postprandial metabolism. The two incretin peptides that enable this effect are the glucose-dependent insulinotropic polypeptide (GIP) and the glucagon-like peptide 1 (GLP-1), which have cognate receptors (GIPR and GLP-1R) on islet ß cells as well as in other tissues. Pharmacologic engagement of the GLP-1R is a proven strategy for treating hyperglycemia in diabetes and reducing body weight. Tirzepatide is the first monomeric peptide with dual activity at both incretin receptors now available for clinical use, and in clinical trials it has shown unprecedented effects to reduce blood glucose and body weight. Here, we discuss the foundational science that led to the development of monomeric multi-incretin receptor agonists, culminating in the development of tirzepatide. We also look to the future of this field and comment on how the concept of multi-receptor agonists will continue to progress for the treatment of metabolic disease.

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.

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.

An injectable PEG-like conjugate forms a subcutaneous depot and enables sustained delivery of a peptide drug.

Many biologics have a short plasma half-life, and their conjugation to polyethylene glycol (PEG) is commonly used to solve this problem. However, the improvement in the plasma half-life of PEGylated drugs' is at an asymptote because the development of branched PEG has only had a modest impact on pharmacokinetics and pharmacodynamics. Here, we developed an injectable PEG-like conjugate that forms a subcutaneous depot for the sustained delivery of biologics. The PEG-like conjugate consists of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) conjugated to exendin, a peptide drug used in the clinic to treat type 2 diabetes. The depot-forming exendin-POEGMA conjugate showed greater efficacy than a PEG conjugate of exendin as well as Bydureon, a clinically approved sustained-release formulation of exendin. The injectable depot-forming exendin-POEGMA conjugate did not elicit an immune response against the polymer, so that it remained effective and safe for long-term management of type 2 diabetes upon chronic administration. In contrast, the PEG conjugate induced an anti-PEG immune response, leading to early clearance and loss of efficacy upon repeat dosing. The exendin-POEGMA depot also showed superior long-term efficacy compared to Bydureon. Collectively, these results suggest that an injectable POEGMA conjugate of biologic drugs that forms a drug depot under the skin, providing favorable pharmacokinetic properties and sustained efficacy while remaining non-immunogenic, offers significant advantages over other commonly used drug delivery technologies.

Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems.

OBJECTIVE: Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials. We sought to develop a long-acting, specific GIPR peptide antagonist as a tool compound suitable for investigating GIPR pharmacology in both rodent and human systems. METHODS: We report a structure-activity relationship of GIPR peptide antagonists based on the human and mouse GIP sequences with fatty acid-based protraction. We assessed these compounds in vitro, in vivo in DIO mice, and ex vivo in islets from human donors. RESULTS: We report the discovery of a GIP(5-31) palmitoylated analogue, [Nα-Ac, L14, R18, E21] hGIP(5-31)-K11 (γE-C16), which potently inhibits in vitro GIP-mediated cAMP generation at both the hGIPR and mGIPR. In vivo, this peptide effectively blocks GIP-mediated reductions in glycemia in response to exogenous and endogenous GIP and displays a circulating pharmacokinetic profile amenable for once-daily dosing in rodents. Co-administration with the GLP-1R agonist semaglutide and this GIPR peptide antagonist potentiates weight loss compared to semaglutide alone. Finally, this antagonist inhibits GIP- but not GLP-1-stimulated insulin secretion in intact human islets. CONCLUSIONS: Our work demonstrates the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice.

GIPR Is Predominantly Localized to Nonadipocyte Cell Types Within White Adipose Tissue.

The incretin hormone glucose-dependent insulinotropic polypeptide (GIP) augments glucose-dependent insulin secretion through its receptor expressed on islet ß-cells. GIP also acts on adipose tissue; yet paradoxically, both enhanced and reduced GIP receptor (GIPR) signaling reduce adipose tissue mass and attenuate weight gain in response to nutrient excess. Moreover, the precise cellular localization of GIPR expression within white adipose tissue (WAT) remains uncertain. We used mouse genetics to target Gipr expression within adipocytes. Surprisingly, targeting Cre expression to adipocytes using the adiponectin (Adipoq) promoter did not produce meaningful reduction of WAT Gipr expression in Adipoq-Cre:Giprflx/flx mice. In contrast, adenoviral expression of Cre under the control of the cytomegalovirus promoter, or transgenic expression of Cre using nonadipocyte-selective promoters (Ap2/Fabp4 and Ubc) markedly attenuated WAT Gipr expression. Analysis of single-nucleus RNA-sequencing, adipose tissue data sets localized Gipr/GIPR expression predominantly to pericytes and mesothelial cells rather than to adipocytes. Together, these observations reveal that adipocytes are not the major GIPR+ cell type within WAT-findings with mechanistic implications for understanding how GIP and GIP-based co-agonists control adipose tissue biology.

The Cost-Effectiveness of Remdesivir for Hospitalized Patients With COVID-19.

OBJECTIVES: This study aimed to estimate the cost-effectiveness of remdesivir, the first novel therapeutic to receive Emergency Use Authorization for the treatment of hospitalized patients with COVID-19, and identify key drivers of value to guide future pricing and reimbursement efforts. METHODS: A Markov model evaluated the cost-effectiveness of remdesivir in patients hospitalized with COVID-19 from a US healthcare sector perspective. A lifetime time horizon captured potential long-term costs and outcomes. Model outcomes included discounted total costs, life-years, and quality-adjusted life-years (QALYs). Remdesivir was modeled as an addition to standard of care and compared with standard of care alone, including dexamethasone for patients requiring respiratory support. COVID-19 hospitalizations were assumed to be reimbursed through a single payment based on the respiratory support received alongside a remdesivir carveout payment in the base case. Sensitivity and scenario analyses identified key drivers. RESULTS: At a unit price of $520 per vial and assuming no survival benefit with remdesivir, the incremental cost-effectiveness was $298 200/QALY for patients with moderate to severe COVID-19 and $1 847 000/QALY for patients with mild COVID-19. Although current data do not support a survival benefit, if one was assumed, the cost-effectiveness estimate was $50 100/QALY for the moderate to severe population and $103 400/QALY for the mild population. Another key driver included the hospitalization payment structure (per diem vs bundled payment). CONCLUSIONS: With the current evidence available, remdesivir's price is too high to align with its expected health gains for hospitalized patients with COVID-19. Results from this study provide a rationale for iterative health technology assessment.

Patient and Payer Preferences for Additional Value Criteria.

Background: Defining the value of healthcare is an elusive target, and depends heavily on the decision context and stakeholders involved. Cost-utility analysis and the quality-adjusted life year (QALY) have become the method and value definition of choice for traditional value judgements in coverage and pricing decisions. Other criteria that may influence value are often not measured and therefore omitted from value assessments, or are only used to qualitatively contextualize assessments. The objective of this study was to engage two key stakeholders; patients and payers to elicit and rank the importance of additional value criteria, potentially assessed in Multiple Criteria Decision Analysis (MCDA). Methods: This study consisted of a focus group with cancer patients (n = 7), including follow-up questions through an electronic survey, and in-depth phone interviews with payers (n = 5). Results: For payers, value equated either with criteria that provided tangible benefits (from their perspective) such as new treatment options that respond to serious unmet need. For patients, population-level value equated to options that would potentially benefit them in the future and the value of hope. However, these criteria were seen by payers as difficult to measure and incorporate into objective decision making. Limitations: The findings from this study are primarily limited due to generalizability. Due to the small sample size, it was outside the scope of this study to calculate a weight for each criterion that could be used as part of a quantitative MCDA. Conclusion: MCDA, with particular attention to qualitative aspects, is an avenue to incorporate these additional criteria into value assessments, as well as provide an opportunity for reflecting the patient's preferences in assessing the value of a treatment.

Comparison of HIV Screening Strategies in the Emergency Department: A Randomized Clinical Trial.

Importance: The National HIV Strategic Plan for the US recommends HIV screening in emergency departments (EDs). The most effective approach to ED-based HIV screening remains unknown. Objective: To compare strategies for HIV screening when integrated into usual ED practice. Design, Setting, and Participants: This randomized clinical trial included patients visiting EDs at 4 US urban hospitals between April 2014 and January 2016. Patients included were ages 16 years or older, not critically ill or mentally altered, not known to have an HIV positive status, and with an anticipated length of stay 30 minutes or longer. Data were analyzed through March 2021. Interventions: Consecutive patients underwent concealed randomization to either nontargeted screening, enhanced targeted screening using a quantitative HIV risk prediction tool, or traditional targeted screening as adapted from the Centers for Disease Control and Prevention. Screening was integrated into clinical practice using opt-out consent and fourth-generation antigen-antibody assays. Main Outcomes and Measures: New HIV diagnoses using intention-to-treat analysis, absolute differences, and risk ratios (RRs). Results: A total of 76 561 patient visits were randomized; median (interquartile range) age was 40 (28-54) years, 34 807 patients (51.2%) were women, and 26 776 (39.4%) were Black, 22 131 (32.6%) non-Hispanic White, and 14 542 (21.4%) Hispanic. A total of 25 469 were randomized to nontargeted screening; 25 453, enhanced targeted screening; and 25 639, traditional targeted screening. Of the nontargeted group, 6744 participants (26.5%) completed testing and 10 (0.15%) were newly diagnosed; of the enhanced targeted group, 13 883 participants (54.5%) met risk criteria, 4488 (32.3%) completed testing, and 7 (0.16%) were newly diagnosed; and of the traditional targeted group, 7099 participants (27.7%) met risk criteria, 3173 (44.7%) completed testing, and 7 (0.22%) were newly diagnosed. When compared with nontargeted screening, targeted strategies were not associated with a higher rate of new diagnoses (enhanced targeted and traditional targeted combined: difference, -0.01%; 95% CI, -0.04% to 0.02%; RR, 0.7; 95% CI, 0.30 to 1.56; P = .38; and enhanced targeted only: difference, -0.01%; 95% CI, -0.04% to 0.02%; RR, 0.70; 95% CI, 0.27 to 1.84; P = .47). Conclusions and Relevance: Targeted HIV screening was not superior to nontargeted HIV screening in the ED. Nontargeted screening resulted in significantly more tests performed, although all strategies identified relatively low numbers of new HIV diagnoses. Trial Registration: ClinicalTrials.gov Identifier: NCT01781949.

Centralized Reminder/Recall for Human Papillomavirus Vaccination: Findings From Two States-A Randomized Clinical Trial.

PURPOSE: Centralized reminder/recall (C-R/R) using Immunization Information Systems has been effective in increasing childhood immunization rates. Previously, C-R/R using autodialer for human papillomavirus (HPV) vaccine did not raise rates. We assessed C-R/R for HPV vaccine using other modalities and focused on younger adolescents. METHODS: We conducted a three-arm pragmatic RCT in randomly sampled primary care practices in Colorado (n = 88) and New York (n = 136), proportionate to where adolescents received care. We randomized, within practices, adolescents aged 11-14 years who had not completed the HPV vaccination series to receive C-R/R using different modalities (Colorado: autodialer, mail, or control; New York: autodialer, text, or control). Up to two reminders were sent in intervention arms for each dose needed between 2/2017 and 12/2018. RESULTS: In Colorado, no significant differences were found for series initiation (31.3% control, 31.1% autodial, 31.8% mail), with slight improvement for series completion in the autodialer arm (29.7% control, 31.1% autodialer, p = .04) but not the mail arm (30.9%, p = .06). No significant differences were found in New York for series initiation (24.1% for all arms) or completion (17.1% control, 16.9% autodial, 17.9% text). Adjusted analyses showed higher completion rates for the autodialer arm in Colorado but not for other arms. In Colorado, C-R/R reduced time to series completion by around 2 months. Cost per adolescent was $1.81 for mail; under $.40 for all other modalities. CONCLUSIONS: C-R/R has less benefit for raising HPV vaccination rates than other studies have noted for childhood immunizations, although it may quicken series completion at little cost.

Insulating Composites Made from Sulfur, Canola Oil, and Wool*.

An insulating composite was made from the sustainable building blocks wool, sulfur, and canola oil. In the first stage of the synthesis, inverse vulcanization was used to make a polysulfide polymer from the canola oil triglyceride and sulfur. This polymerization benefits from complete atom economy. In the second stage, the powdered polymer was mixed with wool, coating the fibers through electrostatic attraction. The polymer and wool mixture were then compressed with mild heating to provoke S-S metathesis in the polymer, which locks the wool in the polymer matrix. The wool fibers imparted tensile strength, insulating properties, and reduced the flammability of the composite. All building blocks are sustainable or derived from waste and the composite is a promising lead on next-generation insulation for energy conservation.

Reductive TCA cycle metabolism fuels glutamine- and glucose-stimulated insulin secretion.

Metabolic fuels regulate insulin secretion by generating second messengers that drive insulin granule exocytosis, but the biochemical pathways involved are incompletely understood. Here we demonstrate that stimulation of rat insulinoma cells or primary rat islets with glucose or glutamine + 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (Gln + BCH) induces reductive, "counter-clockwise" tricarboxylic acid (TCA) cycle flux of glutamine to citrate. Molecular or pharmacologic suppression of isocitrate dehydrogenase-2 (IDH2), which catalyzes reductive carboxylation of 2-ketoglutarate to isocitrate, results in impairment of glucose- and Gln + BCH-stimulated reductive TCA cycle flux, lowering of NADPH levels, and inhibition of insulin secretion. Pharmacologic suppression of IDH2 also inhibits insulin secretion in living mice. Reductive TCA cycle flux has been proposed as a mechanism for generation of biomass in cancer cells. Here we demonstrate that reductive TCA cycle flux also produces stimulus-secretion coupling factors that regulate insulin secretion, including in non-dividing cells.

Targeting the GIPR for obesity: To agonize or antagonize? Potential mechanisms.

BACKGROUND: Glucose-dependent insulinotropic peptide (GIP) is one of two incretin hormones that communicate nutrient intake with systemic metabolism. Although GIP was the first incretin hormone to be discovered, the understanding of GIP's biology was quickly outpaced by research focusing on the other incretin hormone, glucagon-like peptide 1 (GLP-1). Early work on GIP produced the theory that GIP is obesogenic, limiting interest in developing GIPR agonists to treat type 2 diabetes. A resurgence of GIP research has occurred in the last five years, reinvigorating interest in this peptide. Two independent approaches have emerged for treating obesity, one promoting GIPR agonism and the other antagonism. In this report, evidence supporting both cases is discussed and hypotheses are presented to reconcile this apparent paradox. SCOPE OF THE REVIEW: This review presents evidence to support targeting GIPR to reduce obesity. Most of the focus is on the effect of singly targeting the GIPR using both a gain- and loss-of-function approach, with additional sections that discuss co-targeting of the GIPR and GLP-1R. MAJOR CONCLUSIONS: There is substantial evidence to support that GIPR agonism and antagonism can positively impact body weight. The long-standing theory that GIP drives weight gain is exclusively derived from loss-of-function studies, with no evidence to support that GIPR agonisms increases adiposity or body weight. There is insufficient evidence to reconcile the paradoxical observations that both GIPR agonism and antagonism can reduce body weight; however, two independent hypotheses centered on GIPR antagonism are presented based on new data in an effort to address this question. The first discusses the compensatory relationship between incretin receptors and how antagonism of the GIPR may enhance GLP-1R activity. The second discusses how chronic GIPR agonism may produce desensitization and ultimately loss of GIPR activity that mimics antagonism. Overall, it is clear that a deeper understanding of GIP biology is required to understand how modulating this system impacts metabolic homeostasis.

Tirzepatide is an imbalanced and biased dual GIP and GLP-1 receptor agonist.

Tirzepatide (LY3298176) is a dual GIP and GLP-1 receptor agonist under development for the treatment of type 2 diabetes mellitus (T2DM), obesity, and nonalcoholic steatohepatitis. Early phase trials in T2DM indicate that tirzepatide improves clinical outcomes beyond those achieved by a selective GLP-1 receptor agonist. Therefore, we hypothesized that the integrated potency and signaling properties of tirzepatide provide a unique pharmacological profile tailored for improving broad metabolic control. Here, we establish methodology for calculating occupancy of each receptor for clinically efficacious doses of the drug. This analysis reveals a greater degree of engagement of tirzepatide for the GIP receptor than the GLP-1 receptor, corroborating an imbalanced mechanism of action. Pharmacologically, signaling studies demonstrate that tirzepatide mimics the actions of native GIP at the GIP receptor but shows bias at the GLP-1 receptor to favor cAMP generation over ß-arrestin recruitment, coincident with a weaker ability to drive GLP-1 receptor internalization compared with GLP-1. Experiments in primary islets reveal ß-arrestin1 limits the insulin response to GLP-1, but not GIP or tirzepatide, suggesting that the biased agonism of tirzepatide enhances insulin secretion. Imbalance toward GIP receptor, combined with distinct signaling properties at the GLP-1 receptor, together may account for the promising efficacy of this investigational agent.