Use of GLP-1 receptor agonists alone or in combination with other gastrointestinal hormones that delay gastric emptying for treatment of postbariatric hypoglycemia

Abstract

Compositions, methods, and kits are described herein for management of postbariatric hypoglycemia or other hypoglycemic disorders characterized by rapid gastric emptying. In certain aspects, such compositions, methods, and kits can effectively slow gastric emptying in a subject in need thereof.

Description

PATENT Attorney Docket No.079445-014710PC-1498864 Client Ref. No. S24-056 USE OF GLP-1 RECEPTOR AGONISTS ALONE OR IN COMBINATION WITH OTHER GASTROINTESTINAL HORMONES THAT DELAY GASTRIC EMPTYING FOR TREATMENT OF POSTBARIATRIC HYPOGLYCEMIA CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] The present application claims priority to U.S. Provisional Application No. 63 / 645,810 filed May 10, 2024, the full disclosure of which is incorporated by reference in its entirety for all purposes. TECHNICAL FIELD

[0002] The present technology generally relates to treatments for postbariatric hypoglycemia, and in particular, to compositions and methods for delivery of one or more postbariatric hypoglycemia agents to treat postbariatric hypoglycemia, e.g., by slowing gastric emptying. Examples of such agents include GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying. The provided technology further relates to treatments for other hypoglycemic disorders characterized by rapid gastric emptying, where these other disorders can be related to surgical or nonsurgical complications. BACKGROUND

[0003] Postbariatric hypoglycemia (PBH) complications occur following up to 38% of Roux-en-Y Gastric Bypass (RYBG) surgeries and up to 17% of vertical sleeve gastrectomies. About 11% and 4.8% of these cases, respectively, are severe enough to seek medical attentionat inpatient or outpatient facilities. This condition, which causes frequent neuroglycopenic symptoms, places patients at high risk for disability and death due to impaired cognitive and physical functioning. Long term medical complications are likely, with data supporting increased risk of arrhythmias, dementia, and anxiety.

[0004] There are currently no approved medical therapies for PBH that can relieve the burden of this serious and unwanted complication. A need therefore exists for new methods to treat PBH and / or reduce gastric emptying. The present disclosure addresses this need, thereby providing associated advantages as well as other benefits. BRIEF SUMMARY

[0005] This summary provides a high-level overview of various aspects of the disclosure and introduces some of the concepts that are described and illustrated in the present document and the accompanying figures. The summary is not intended to identify key or essential features of the claimed subject matter, nor is it intended to be used in isolation to determine the scope of the claimed subject matter. Covered embodiments of the disclosure are defined by the claims, not this summary. The subject matter should be understood by reference to appropriate portions of the entire specification, any or all figures, and each claim. Some of the exemplary embodiments of the present disclosure are discussed below.

[0006] Compositions, methods, and kits are described herein for management of postbariatric hypoglycemia. In certain aspects, such compositions, methods, and kits can effectively slow gastric emptying in a subject in need thereof. Also described herein are methods of treatment for postbariatric hypoglycemia comprising administration of such compositions and methods for delivery of agents to treat postbariatric hypoglycemia (referred to herein as “postbariatric treatment agents” or “postbariatric hypoglycemia agents”), in particular, by slowing gastric emptying, are also described herein. Examples of such agents include GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists (e.g., AMG 133 (Amgen)), GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof. Also provided are methods of treatment for conditions other than or in addition to postbariatric hypoglycemia, where these alternative or additional conditions are also hypoglycemic disorders characterized by rapid gastricemptying, and where the methods involve administering one or more agents (e.g., “postbariatric treatment agents” or “postbariatric hypoglycemia agents”) from the provided postbariatric hypoglycemia treatment methods.

[0007] In some embodiments, for example, a method of treating a disease or condition includes administering to a subject a composition comprising a postbariatric hypoglycemia agent, in particular, by slowing gastric emptying. Examples of such agents include GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP- glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof. In some embodiments, the GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment can be administered in an effective amount to reduce gastric emptying in a subject compared to a baseline of the subject without a composition as described herein. In some embodiments, the subject can be a subject that has previously had a bariatric surgery. BRIEF DESCRIPTION OF THE DRAWINGS

[0008] Many aspects of the present disclosure can be better understood with reference to the following drawings. The components in the drawings are not necessarily to scale. Instead, emphasis is placed on illustrating clearly the principles of the present disclosure.

[0009] FIG. 1 presents a graph plotting data for the gastric emptying rate during a standardized scintigraphy test (gold standard test for quantifying gastric emptying) performed after an overnight fast in patients with PBH (n=15) as compared to age and body mass index (BMI)-matched Roux-en-Y Gastric Bypass (RYGB) surgical controls who do not have PBH (n=10), and for reference, age and BMI-matched nonsurgical controls (n=12). The data shown in FIG. 1 demonstrate that the 1-hour residual volume is 67% lower in RYGB patients with PBH as compared to RYGB patients without PBH (p=0.024). These data indicate for the first time that faster gastric emptying may explain why some but not all individuals develop PBH following RYGB. The rate of gastric emptying is therefore a potential novel treatment target.

[0010] FIGS.2-4 present graphs plotting data for gastric emptying in three subjects following administration of the GLP-1 receptor agonist semaglutide. The data demonstrate slowing of gastric emptying, indicated by higher residual volume at 60 min after consuming a standardized test meal with a radioactive tracer, with semaglutide treatment (0.5 mg / wk for at least five weeks) in three patients with PBH and severe postprandial hypoglycemia.

[0011] FIGS.5-7 present data from continuous glucose monitoring (CGM) performed during standardized low-carb meal administration for the study of FIGS. 2-4. No increase in hypoglycemia was observed for the three subjects, supporting the safety of giving a GLP-1 analog (semaglutide) to patients who already have very high GLP-1, which stimulates insulin and lowers glucose.

[0012] FIG.8 presents a bar graph plotting insulin resistance in nonsurgical controls (NSC), surgical (RYGB) controls (SC), and patients with postbariatric hypoglycemia (PBH). The SSPG value, indicating the degree of insulin resistance, is not significantly different in PBH vs SC, indicating that enhanced insulin sensitivity does not contribute to development of PBH. DETAILED DESCRIPTION I. INTRODUCTION

[0013] The inventors have previously shown that altered nutrient transit is largely responsible for PBH, with hypersecretion of GLP-1 as a result of fast nutrient transit to the hindgut, where GLP-1 is secreted. The inventors have also previously demonstrated that blocking the GLP-1 receptor with a GLP-1 receptor antagonist (e.g., avexitide) represents an effective therapy for treatment of PBH. However, GLP-1 receptor antagonists are still under development for treatment of PBH, and there are currently no approved medical therapies for PBH.

[0014] More recently, the inventors conducted experiments involving post-RYGB patients with PBH and without PBH to investigate what features differed between the two cohorts. Specifically, they tested the hypothesis that those with more rapid gastric emptying (leading to faster nutrient transit and more hindgut stimulation) would be at higher risk for PBH. Their data in FIG. 1 and Table 2 showed a statistically significant increase in gastric emptying rate among those affected by PBH compared to matched surgical (RYGB) controls, providingsupport for this hypothesis. It was concluded that treatments aimed at slowing gastric emptying might represent an effective therapy for this disorder.

[0015] GLP1 RAs, among other pharmaceutical agents and small molecules (e.g., gastrointestinal hormones / analogs such as GIP, glucagon, PYY, amylin, and non- gastrointestinal hormones such as proton-pump inhibitors), are known to slow gastric emptying in non-RYGB individuals (e.g., patients with diabetes or obesity). Treatment of PBH with exogenous administration of a GLP-1 RA, for example, is counter intuitive since the mechanism of hypoglycemia in PBH is largely due to very high levels of endogenous GLP-1 (resulting from rapid nutrient transit to the hindgut), which in turn stimulates insulin secretion and lowers glucose, leading to hypoglycemia. Despite how counterintuitive it may be, as described herein, the inventors conducted a pilot study to determine whether treatment with semaglutide, a GLP-1 RA, slows gastric emptying in RYGB patients with PBH. The inventors hypothesized that further elevations of GLP-1 from agonist treatment do not further increase insulin secretion, which is already extremely high, but have a significant impact on gastric slowing, the benefit of which overrides the potential drawback of increased GLP-1 on insulin stimulation. This is possible particularly because the synthetic analogues are not identical to the endogenous hormones and are injected subcutaneously rather than secreted by the gut with more direct access to pancreatic beta cells. Results, shown in FIGS. 2A and B (and Table 3), demonstrate significant slowing of the baseline very rapid transit, without any increase in hypoglycemia, indicating potential therapeutic benefit.

[0016] This class of medications causes weight loss which is well known to enhance sensitivity to insulin (i.e., insulin sensitivity) and consequent reductions in ambient glucose concentrations. For these reasons, weight loss of any kind, including use of GLP-1 RAs, can lower hyperglycemia in patients with T2D. However, weight loss in normoglycemic individuals has not been shown to cause hypoglycemia. Furthermore, the inventors have tested the hypothesis that greater insulin sensitivity might be present in individuals with PBH vs surgical controls – data clearly showed that this was not the case (FIG. 8) and thus inducing greater insulin sensitivity via weight loss that might result from long-term use of a GLP-1-RA alone or in combination with other compounds / drugs that slow gastric emptying (and promote weight loss) as described herein is not expected to worsen hypoglycemia. As described herein, treating patients with PBH with GLP-1 RAs alone or in combination with other gastrointestinal analogs or small molecules that promote slowing of gastric emptying may improve hypoglycemia and glycemic variability in patients with PBH.

[0017] Furthermore, in some examples the GLP-1 RA drugs characteristics most beneficial for treating postbariatric hypoglycemia are those least effective for treating obesity, i.e., a current primary clinical and commercial application for such drugs. In particular, GLP-1 RA drugs that are shorter acting and / or that promote less weight loss have been shown to be more effective in slowing gastric emptying as compared to the longer-acting agents that are more effective in promoting weight loss. As used herein in the context of drugs or other agents, the terms “short-acting” and the like refer to bioactive compounds for which the plasma concentration in a subject returns to a near-zero concentration within 24 h of administration (e.g., subcutaneous administration), and / or for which the intended type and degree of pharmacological effects substantially or essentially end within 24 h of such administration. Accordingly, a short-acting drug (e.g., a short-acting GLP-1 RA drug) can be one that requires dosage frequencies at least as often as once daily. Additionally, a drug or agent referred to as promoting less weight loss can be, for example, one that results in a subject’s weight loss that is less than 20% of the weight of the subject prior to use of the drug or agent in a treatment, e.g., less than 16%, less than 13%, less than 10%, less than 8%, less than 6.5%, less than 5%, less than 4%, less than 3%, less than 2.5%, or less than 2% of the weight of the subject prior to the treatment. The present disclosure therefore provides a significant benefit by identifying an unappreciated utility for drugs that may otherwise have been considered to be insufficiently effective. Further, because in many cases these drugs may already have established production processes, safety profiles and / or regulatory clearances, they may be more readily available for use with the methods provided herein.

[0018] To address challenges related to treatment of PBH, the present technology provides composition and methods for delivery of agents that treat postbariatric hypoglycemia, in particular, by slowing gastric emptying. Examples of such agents include GLP-1 RAs, GLP-1- GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof. In some embodiments, for example, a method of treating a disease or condition (e.g., PBH) includes administering a composition to a subject. In some embodiments, methods of treatment as described herein use GLP-1 RAs or GLP-1 / GIP dual agonists given as directed (weekly subcutaneously or orally) in patients with diagnosed postbariatric hypoglycemia for the indication of treating hypoglycemia. The provided methods can also be useful for treating otherhypoglycemic disorders characterized by rapid gastric emptying. Examples related to surgical complications include those associated with Nissen fundoplication, gastric peroral endoscopic myotomy (G-POEM), gastrectomy, esophagectomy, pyloroplasty, and gastrojejunostomy. Nonsurgical examples include postural orthostatic tachycardia syndrome (POTS), familial dysautonomia, and idiopathic dumping syndrome.

[0019] Compositions and methods as described herein are further advantageous over existing methods as they target proven pathophysiology (rapid gastric emptying) and effectively slow it; extensive safety data from large clinical trials including individuals without hyperglycemia (no risk of hypoglycemia) exist; delivery devices (pens) are already established; and no approved therapies exist – they are in phase 2 trials but will take years to get approved. Compositions, methods, and kits as described herein can further be advantageous as they can enjoy a much faster road to approval based on at least the above.

[0020] Embodiments of the present disclosure will be described more fully hereinafter with reference to the accompanying drawings in which like numerals represent like elements throughout the several figures, and in which example embodiments are shown. Embodiments of the claims may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. The examples set forth herein are non-limiting examples and are merely examples among other possible examples.

[0021] The headings provided herein are for convenience only and do not interpret the scope or meaning of the claimed present technology. Embodiments under any one heading may be used in conjunction with embodiments under any other heading. II. DEFINITIONS

[0022] Unless specifically indicated otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by those of ordinary skill in the art to which this disclosure belongs. In addition, any method or material similar or equivalent to a method or material described herein can be used in the practice of the present disclosure. For purposes of the present disclosure, the following terms are defined.

[0023] As used herein, the singular forms “a,” “an,” and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a phospholipid” optionally includes a combination of two or more phospholipids, and the like.

[0024] As used herein, the terms “generally,” and similar terms are used as terms of approximation and not as terms of degree, and are intended to account for the inherent variations in measured or calculated values that would be recognized by those of ordinary skill in the art.

[0025] The terms “about” and “approximately” as used herein shall generally mean an acceptable degree of error for the quantity measured given the nature or precision of the measurements. Exemplary degrees of error are within 20%; preferably, within 10%; and more preferably, within 5% of a given value or range of values. Any reference to “about X” or “approximately X” specifically indicates at least the values X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, and 1.05X. Thus, expressions “about X” or “approximately X” are intended to teach and provide written support for a claim limitation of, for example, “0.98X.” Numerical quantities given herein are approximate unless stated otherwise, meaning that the term “about” or “approximately” can be inferred when not expressly stated. When “about” is applied to the beginning of a numerical range, it applies to both ends of the range.

[0026] Moreover, unless the word “or” is expressly limited to mean only a single item exclusive from the other items in reference to a list of two or more items, then the use of “or” in such a list is to be interpreted as including (a) any single item in the list, (b) all of the items in the list, or (c) any combination of the items in the list. As used herein, the phrase “and / or” as in “A and / or B” refers to A alone, B alone, and A and B.

[0027] As used herein, the terms “including,” “comprising,” “having,” “containing,” and variations thereof, are inclusive and open-ended and do not exclude additional, unrecited elements or method steps beyond those explicitly recited. As used herein, the phrase “consisting of” is closed and excludes any element, step, or ingredient not explicitly specified. As used herein, the transitional phrase “consisting essentially of” (and grammatical variants) is to be interpreted as encompassing the recited materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the present disclosure or features of the claims. See, for example, In re Herz, 537 F.2d 549, 551-52, 190 U.S.P.Q.461, 463 (CCPA 1976) (emphasis in the original); see also MPEP §2111.03. Thus, the term “consisting essentially of” as used herein should not be interpreted as equivalent to “comprising.”

[0028] The terms “first,” “second,” “third,” and the like when used herein with reference to elements or properties, are simply to more clearly distinguish or identify multiple elements orproperties, and are not intended to indicate an order or other serial or numerical limitation, or to require that each of the multiple elements or properties are present.

[0029] The terms “subject,” “patient,” and “individual” are used herein interchangeably to include a human or animal. For example, the animal subject may be a mammal, a primate (e.g., a monkey), a livestock animal (e.g., a horse, a cow, a sheep, a pig, or a goat), a companion animal (e.g., a dog, a cat), a laboratory test animal (e.g., a mouse, a rat, a guinea pig, a bird), an animal of veterinary significance, or an animal of economic significance.

[0030] As used herein, the term percent “identity,” in the context of two or more nucleic acid or polypeptide sequences, may refer to two or more sequences or subsequences that have a specified percentage of nucleotides or amino acid residues that are the same, when compared and aligned for maximum correspondence, as measured using one of the sequence comparison algorithms described below (e.g., BLASTP and BLASTN or other algorithms available to persons of skill) or by visual inspection. Depending on the application, the percent “identity” can exist over a region of the sequence being compared, e.g., over a functional domain, or, alternatively, exist over the full length of the two sequences to be compared. For sequence comparison, typically one sequence acts as a reference sequence to which test sequences are compared. When using a sequence comparison algorithm, test and reference sequences are input into a computer, subsequence coordinates are designated, if necessary, and sequence algorithm program parameters are designated. The sequence comparison algorithm then calculates the percent sequence identity for the test sequence(s) relative to the reference sequence, based on the designated program parameters. For purposes herein, percent identity and sequence similarity may be performed using the BLAST algorithm, which is described in Altschul et al. (J. Mol. Biol. 215:403 (1990)). Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information.

[0031] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limits of that range is also specifically disclosed. Each smaller range between any stated value or intervening value in a stated range and any other stated or intervening value in that stated range is encompassed by the disclosure. The upper and lower limits of these smaller ranges may independently be included or excluded in the range, and each range where either, neither or both limits are included in the smaller ranges is also encompassed by the disclosure, subject to any specifically excluded limit in the stated range.Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.

[0032] As used herein the term “activate” is used in reference to a receptor or receptor complex to reflect a biological effect, directly and / or by participation in a multicomponent signaling cascade, arising from the binding of an agonist ligand to a receptor responsive to the binding of the ligand.

[0033] As used herein, the term “activity” is used with respect to a molecule to describe a property of the molecule with respect to a test system (e.g. an assay) or biological or chemical property (e.g., the degree of binding of the molecule to another molecule) or of a physical property of a material or cell (e.g., modification of cell membrane potential). Examples of such biological functions include but are not limited to catalytic activity of a biological agent, the ability to stimulate intracellular signaling, gene expression, cell proliferation, the ability to modulate immunological activity such as inflammatory response. “Activity” is typically expressed as a level of a biological activity per unit of agent tested such as [catalytic activity] / [mg protein], [immunological activity] / [mg protein], international units (IU) of activity, [STAT5 phosphorylation] / [mg protein], [T cell proliferation] / [mg protein], plaque forming units (pfu), etc.

[0034] The terms “administration” and “administer” are used interchangeably herein to refer the act of contacting a subject, including contacting a cell, tissue, organ, or biological fluid of the subject in vitro, in vivo or ex vivo with a therapeutic agent (e.g. a glucagon-like peptide-1 (GLP-1) receptor agonist, a GLP1-GIP dual agonist, or a pharmaceutical formulation comprising one or more of the foregoing). Administration of a therapeutic agent may be achieved through any of a variety of art recognized methods including but not limited to the topical administration, intravascular injection (including intravenous or intraarterial infusion), intradermal injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, inhalation and the like. The term “administration” includes contact of an agent to the cell, tissue or organ as well as the contact of an agent to a fluid, where the fluid is in contact with the cell, tissue or organ. In embodiments, a glucagon-like peptide-1 (GLP-1) receptor agonist, a GLP1-GIP dual agonist, or a pharmaceutical formulation comprising one or more of the foregoing can be administered weekly subcutaneously or orally.

[0035] As used herein the term “affinity” refers to the degree of specific binding of a first molecule (e.g., a ligand) to a second molecule (e.g., a receptor) and is measured by theequilibrium dissociation constant (KD), a ratio of the dissociation rate constant between the molecule and its target (Koff) and the association rate constant between the molecule and its target (Kon).

[0036] As used herein, the term “agonist” refers a first agent that specifically binds a second agent (“target”) and interacts with the target to cause or promote an increase in the activation of the target. In some instances, agonists are activators of receptor proteins that modulate cell activation, enhance activation, sensitize cells to activation by a second agent, or up-regulate the expression of one or more genes, proteins, ligands, receptors, biological pathways, that may result in cell proliferation or pathways that result in cell cycle arrest or cell death such as by apoptosis. In some embodiments, an agonist is an agent that binds to a receptor and alters the receptor state, resulting in a biological response. The response mimics the effect of the endogenous activator of the receptor. The term “agonist” includes partial agonists, full agonists and superagonists. An agonist may be described as a “full agonist” when such agonist which leads to a substantially full biological response (i.e., the response associated with the naturally occurring ligand / receptor binding interaction) induced by receptor under study, or a partial agonist. In contrast to agonists, antagonists may specifically bind to a receptor but do not result in the signal cascade typically initiated by the receptor and may act to modify the actions of an agonist at that receptor. Inverse agonists are agents that produce a pharmacological response that is opposite in direction to that of an agonist. A “super agonist” or “superagonist” is a type of agonist that is capable of producing a maximal response greater than the endogenous agonist for the target receptor, and thus has an activity of more than 100% of the native ligand. A super agonist is typically a synthetic molecule that exhibits greater than 110%, alternatively greater than 120%, alternatively greater than 130%, alternatively greater than 140%, alternatively greater than 150%, alternatively greater than 160%, or alternatively greater than 170% of the response in an evaluable quantitative or qualitative parameter of the naturally occurring form of the molecule when evaluated at similar concentrations in a comparable assay.

[0037] As used herein, the term “comparable” is used to describe the degree of difference in two measurements of an evaluable quantitative or qualitative parameter. For example, where a first measurement of an evaluable quantitative parameter and a second measurement of the evaluable parameter do not deviate beyond a range that the skilled artisan would recognize as not producing a statistically significant difference in effect between the two results in the circumstances, the two measurements would be considered “comparable.” In some instances, measurements may be considered “comparable” if one measurement deviates from another byless than 30%, alternatively by less than 25%, alternatively by less than 20%, alternatively by less than 15%, alternatively by less than 10%, alternatively by less than 7%, alternatively by less than 5%, alternatively by less than 4%, alternatively by less than 3%, alternatively by less than 2%, or by less than 1%. In particular embodiments, one measurement is comparable to a reference standard if it deviates by less than 15%, alternatively by less than 10%, or alternatively by less than 5% from the reference standard.

[0038] As used herein, the term “downstream signaling” refers to the cellular signaling process that is caused by the interaction of two or more cell surface receptors that are brought into proximity of each other.

[0039] As used herein, the terms “effective concentration” or its abbreviation “EC” are used interchangeably to refer to the concentration of an agent in an amount sufficient to effect a change in a given parameter in a test system. The abbreviation “E” refers to the magnitude of a given biological effect observed in a test system when that test system is exposed to a test agent. When the magnitude of the response is expressed as a factor of the concentration (“C”) of the test agent, the abbreviation “EC” is used. In the context of biological systems, the term Emax refers to the maximal magnitude of a given biological effect observed in response to a saturating concentration of an activating test agent. When the abbreviation EC is provided with a subscript (e.g., EC40,EC50, etc.) the subscript refers to the percentage of the Emax of the biological observed at that concentration. For example, the concentration of a test agent sufficient to result in the induction of a measurable biological parameter in a test system that is 30% of the maximal level of such measurable biological parameter in response to such test agent, this is referred to as the “EC30” of the test agent with respect to such biological parameter. Similarly, the term “EC100” is used to denote the effective concentration of an agent that results the maximal (100%) response of a measurable parameter in response to such agent. Similarly, the term EC50 (which is commonly used in the field of pharmacodynamics) refers to the concentration of an agent sufficient to results in the half-maximal (50%) change in themeasurable parameter. The term “saturating concentration” refers to the maximum possiblequantity of a test agent that can dissolve in a standard volume of a specific solvent (e.g., water) under standard conditions of temperature and pressure. In pharmacodynamics, a saturating concentration of a drug is typically used to denote the concentration sufficient of the drug such that all available receptors are occupied by the drug, and EC50is the drug concentration to give the half-maximal effect. The EC of a particular effective concentration of a test agent may be abbreviated with respect to the with respect to particular parameter and test system.

[0040] As used herein, the term “ligand” refers to a molecule that exhibits specific bindingto a receptor and results in a change in the biological activity of the receptor so as to effect a change in the activity of the receptor to which it binds. In one embodiment, the term “ligand” refers to a molecule, or complex thereof, that can act as an agonist or antagonist of a receptor. As used herein, the term “ligand” encompasses natural and synthetic ligands. “Ligand” also encompasses small molecules, e.g., peptide mimetics of cytokines and peptide mimetics of antibodies. The complex of a ligand and receptor is termed a “ligand-receptor complex.”

[0041] As used herein, the terms “modulate,” “modulation,” and the like refer to the ability of a test agent to affect a response, either positive or negative or directly or indirectly, in a system, including a biological system or biochemical pathway.

[0042] As used herein the terms “polypeptide,” “peptide,” and “protein,” used interchangeably herein, refer to a polymeric form of amino acids of any length, which can include genetically coded and non-genetically coded amino acids, chemically or biochemically modified or derivatized amino acids, and polypeptides having modified polypeptide backbones. The terms include fusion proteins, including, but not limited to, fusion proteins with a heterologous amino acid sequence; fusion proteins with heterologous and homologous leader sequences; fusion proteins with or without N-terminus methionine residues; fusion proteins with immunologically tagged proteins; fusion proteins of immunologically active proteins (e.g. antigenic diphtheria or tetanus toxin fragments) and the like.

[0043] As used herein the terms “prevent,” “preventing,” “prevention,” and the like refer to a course of action initiated with respect to a subject prior to the onset of a disease, disorder, condition or symptom thereof so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject’s risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed due to genetic, experiential or environmental factors to having a particular disease, disorder or condition. In certain instances, the terms “prevent,” “preventing,” and “prevention” are also used to refer to the slowing of the progression of a disease, disorder or condition from a present its state to a more deleterious state.

[0044] As used herein, the term “receptor” refers to a polypeptide having a domain that specifically binds a ligand that binding of the ligand results in a change to at least one biological property of the polypeptide. In some embodiments, the receptor is a “soluble” receptor that isnot associated with a cell surface. In some embodiments, the receptor is a cell surface receptor that comprises an extracellular domain (ECD) and a membrane associated domain which serves to anchor the ECD to the cell surface. In some embodiments of cell surface receptors, the receptor is a membrane spanning polypeptide comprising an intracellular domain (ICD) and extracellular domain (ECD) linked by a membrane spanning domain typically referred to as a transmembrane domain (TM). The binding of the ligand to the receptor results in a conformational change in the receptor resulting in a measurable biological effect. In some instances, where the receptor is a membrane spanning polypeptide comprising an ECD, TM, and ICD, the binding of the ligand to the ECD results in a measurable intracellular biological effect mediated by one or more domains of the ICD in response to the binding of the ligand to the ECD. In some embodiments, a receptor is a component of a multi-component complex to facilitate intracellular signaling. For example, the ligand may bind a cell surface molecule that not associated with any intracellular signaling when alone, but that upon ligand binding facilitates the formation of a multimeric complex that results in intracellular signaling.

[0045] As used herein, the term “recombinant” is used as an adjective to refer to a polypeptide, nucleic acid, or cell that was modified using recombinant DNA technology. A recombinant protein is a protein produced using recombinant DNA technology and may be designated as such using the abbreviation of a lower case “r” to denote the method by which the protein was produced. Similarly, a cell is referred to as a “recombinant cell” if the cell has been modified by the incorporation (e.g., transfection, transduction, infection) of exogenous nucleic acids (e.g., ssDNA, dsDNA, ssRNA, dsRNA, mRNA, viral or non-viral vectors, plasmids, cosmids, and the like) using recombinant DNA technology. The techniques and protocols for recombinant DNA technology are well known in the art such as those can be found in Sambrook et al. (1989) Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Plainview, N.Y.) and other standard molecular biology laboratory manuals.

[0046] The term “response,” for example, of a cell, tissue, organ, or organism, encompasses a quantitative or qualitative change in a evaluable biochemical or physiological parameter, (e.g., concentration, density, adhesion, proliferation, activation, phosphorylation, migration, enzymatic activity, level of gene expression, rate of gene expression, rate of energy consumption, level of or state of differentiation, where the change is correlated with activation, stimulation, or treatment, or with internal mechanisms such as genetic programming. In certain contexts, the terms “activation,” “stimulation,” and the like refer to cell activation as regulatedby internal mechanisms, as well as by external or environmental factors. In contrast, the terms “inhibition,” “down-regulation,” and the like refer to the opposite effects.

[0047] As used herein, the term “specifically bind” refers to the degree of selectivity or affinity for which one molecule binds to another. In the context of binding pairs (e.g., a binding molecule described herein / receptor, a ligand / receptor, antibody / antigen, antibody / ligand, antibody / receptor binding pairs), a first molecule of a binding pair is said to specifically bind to a second molecule of a binding pair when the first molecule of the binding pair does not bind in a significant amount to other components present in the sample. A first molecule of a binding pair is said to specifically bind to a second molecule of a binding pair when the affinity of the first molecule for the second molecule is at least two-fold greater, alternatively at least five times greater, alternatively at least ten times greater, alternatively at least 20 times greater, or alternatively at least 100 times greater than the affinity of the first molecule for other components present in the sample.

[0048] As used herein, the term “substantially” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that is 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or higher of a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. In some embodiments, “substantially the same” refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that produces an effect, e.g., a physiological effect, that is approximately the same as a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length.

[0049] As used herein, the term “suffering from” refers to a determination made by a physician with respect to a subject based on the available information accepted in the field for the identification of a disease, disorder or condition including but not limited to X-ray, CT- scans, conventional laboratory diagnostic tests (e.g., blood count), genomic data, protein expression data, and / or immunohistochemistry, that the subject requires or will benefit from treatment. The term suffering from is typically used in conjunction with a particular disease state. For example, “suffering from a neoplastic disease” refers to a subject diagnosed with the presence of a neoplasm.

[0050] As used herein, the term “therapeutically effective amount” is used in reference to the administration of an agent to a subject, either alone or as part of a pharmaceutical composition or treatment regimen, in a single dose or as part of a series of doses, in an amount capable ofhaving any detectable, positive effect on any symptom, aspect, or characteristic of a disease, disorder or condition when administered to the subject. The therapeutically effective amount can be ascertained by measuring relevant physiological effects, and it may be adjusted in connection with a dosing regimen and in response to diagnostic analysis of the subject’s condition, and the like. The parameters for evaluation to determine a therapeutically effective amount of an agent are determined by the physician using art accepted diagnostic criteria including but not limited to indicia such as age, weight, sex, general health, ECOG score, observable physiological parameters, blood levels, blood pressure, electrocardiogram, computerized tomography, X-ray, and the like. Alternatively, or in addition, other parameters commonly assessed in the clinical setting may be monitored to determine if a therapeutically effective amount of an agent has been administered to the subject such as body temperature, heart rate, normalization of blood chemistry, normalization of blood pressure, normalization of cholesterol levels, or any symptom, aspect, or characteristic of the disease, disorder or condition, modification of biomarker levels, increase in duration of survival, extended duration of progression free survival, extension of the time to progression, increased time to treatment failure, extended duration of event free survival, extension of time to next treatment, improvement objective response rate, improvement in the duration of response, and the like that that are relied upon by clinicians in the field for the assessment of an improvement in the condition of the subject in response to administration of an agent.

[0051] The terms “treat,” “treating,” treatment,” and the like refer to a course of action (such as administering an agent described herein, or a pharmaceutical composition comprising same) initiated with respect to a subject after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, or the like in the subject so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of such disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with such disease, disorder, or condition. The treatment includes a course of action taken with respect to a subject suffering from a disease where the course of action results in the inhibition (e.g., arrests the development of the disease, disorder or condition or ameliorates one or more symptoms associated therewith) of the disease in the subject.

[0052] The term “pharmaceutical composition” refers to a composition that is physiologically acceptable and pharmacologically acceptable. In some instances, the composition includes an agent for buffering and preservation in storage, and can include buffers and carriers for appropriate delivery, depending on the route of administration.

[0053] The term “pharmaceutical acceptable carrier” refers to a substance that aids the administration of an agent (e.g., GLP-1 RA, GLP-1 dual agonist, etc.) to a cell, an organism, or a subject. “Pharmaceutically acceptable carrier” refers to a carrier or excipient that can be included in a composition or formulation and that causes no significant adverse toxicological effect on the patient. Non-limiting examples of pharmaceutically acceptable carrier include water, NaCl, normal saline solutions, lactated Ringer’s, normal sucrose, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavors and colors, and the like. One of skill in the art will recognize that other pharmaceutical carriers are useful in the present disclosure. III. COMPOSITIONS COMPRISING AND FOR DELIVERY OF AGENTS THAT TREAT POSTBARIATRIC HYPOGLYCEMIA

[0054] Described herein are compositions comprising agents for treatment of postbariatric hypoglycemia, in particular, by slowing gastric emptying. Examples of such agents include GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP- glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof. In some embodiments, the present technology provides compositions for delivery of glucagon-like peptide-1 (GLP-1) receptor agonists (also known as and / or referred to herein as GLP-1 RAs, incretin mimetics, or GLP-1 analogs), GLP-1 / GIP dual agonists, GLP1RA / glucagon agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogues, and GLP1-GIP-glucagon triple agonists (e.g., retatrutide), for treating a disease or condition in a subject. GLP-1 is an incretin hormone that contributes to the regulation of glucose homeostasis within the body through its interaction with the GLP- 1 receptor. GLP-1 is secreted from intestinal L-cells in response to nutrients and lowers blood glucose by stimulating insulin and suppressing glucagon secretion in a glucose-dependent manner, reducing the risk of hypoglycemia. Metabolic effects of GLP-1 include glucose- dependent stimulation of insulin secretion, inhibition of glucagon secretion, inhibition of food intake, decrease of gastric emptying, and increase of natriuresis and diuresis. GLP-1 has also been shown to influence learning, memory, reward behavior, and palatability, as well as exhibit neuroprotective, cardioprotective, and anti-inflammatory effects. However, the therapeutic applicability of native GLP-1 is limited by its short half-life in vivo (approximately 2 to 3 minutes) and inactivation by the enzyme dipeptidyl peptidase 4 (DPP-4).

[0055] GLP-1 RAs are a class of drugs that interact with the GLP-1 receptor and display structural similarities to native GLP-1, but with modifications to extend the in vivo half-life and thus provide improved bioavailability. GLP-1 RAs can be categorized as either short-acting or long-acting compounds. Short-acting GLP-1 RAs have been rendered resistant to cleavage by DPP-4 by altering the amino acids at the second and third N-terminal positions, but are still subject to renal elimination and thus generally have a half-life from approximately 2 to 5 hours. Examples of short-acting GLP-1 RAs include exenatide and lixisenatide. Long-acting GLP-1 RAs implement mechanisms to reduce renal elimination, such as acylation with fatty acids to facilitate binding to serum albumin or conjugation to a larger molecule / component, and thus can have a half-life from 12 hours to several days. Examples of long-acting GLP-1 RAs include liraglutide (acylation with C16 fatty monoacid), semaglutide (acylation with C18 fatty diacid), tirzepatide (acylation with C20 fatty diacid), retatrutide (acylation with C20 fatty diacid), albiglutide (conjugation to albumin), dulaglutide (conjugation to Fc fragment of IgG), exenatide-LAR (long-acting release) (coupled to biodegradable polymer microspheres), and amylin. Other compounds can be utilized as well, for example, proton pump inhibitors.

[0056] In some embodiments, the present technology provides a composition comprising at least one GLP-1 RA. The GLP-1 RA can include a peptide that binds to the GLP-1 receptor. The peptide can be an analogue of a native GLP-1 peptide, such as the endogenous human GLP-1 peptide (e.g., GLP-1 (7-36) or GLP-1 (7-37)). For example, the peptide can include a sequence having at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 97%, 99%, or 100% sequence identity to any one of SEQ ID NO: 1 or SEQ ID NO: 2. The peptide can be produced in suitable host cells via recombinant DNA technology, can be produced in a cell-free system, or can be produced synthetically via solid phase synthesis. Table 1: GLP-1 Peptides

[0057] In some embodiments, the GLP-1 RA is a mono-receptor agonist that binds exclusively to the GLP-1 receptor. For example, in certain embodiments, the GLP-1 RA is a small molecule or non-peptide GLP-1 agonist, for example, those currently under development by Crinetics Bio. Examples of GLP-1 mono-receptor agonists include exenatide, exenatide- LAR, lixisenatide, liraglutide, semaglutide, albiglutide, dulaglutide, efpeglenatide, and ecnoglutide. The peptide of the GLP-1 mono-receptor agonist can be an analogue of a native GLP-1 peptide, as previously described.

[0058] In some embodiments, the GLP-1 RA is a dual-receptor agonist that binds to the GLP- 1 receptor and an additional receptor. For instance, the GLP-1 RA can be a dual GLP- 1 / glucagon receptor agonist that binds to the GLP-1 receptor and the glucagon receptor. Examples of dual GLP-1 / glucagon receptor agonists include efinopegdutide, cotadutide, mazdutide, and BI 45690. In such embodiments, the peptide of the dual GLP-1 / glucagon receptor agonist can be an analogue of oxyntomodulin, which is a gut hormone that activates both the GLP-1 receptor and the glucagon receptor. As another example, the GLP-1 RA can be a dual GLP-1 / GIP receptor agonist that binds to the GLP-1 receptor and the GIP receptor. Examples of dual GLP-1 / GIP receptor agonists include tirzepatide, LY3493269, VK2735, CT- 868, and AMG133. In such embodiments, the peptide of the dual GLP-1 / GIP receptor agonist can be an analogue of GIP, which has high sequence similarity to GLP-1 in the N-terminal part of the peptide.

[0059] In some embodiments, the GLP-1 RA is a triple-receptor agonist that binds to the GLP-1 receptor and two additional receptors. For example, the GLP-1RA can be a triple GLP- 1 / glucagon / GIP receptor agonist that binds to the GLP-1 receptor, the glucagon receptor, and the GIP receptor. Examples of triple GLP-1 / glucagon / GIP receptor agonists include retatrutide.

[0060] In some embodiments, the GLP-1 RA is used in combination with amylin or an amylin analog (agonist) that is short acting (e.g., pramlintide) or long acting (e.g., cagrilintide and / or davalintide) and that binds to the amylin receptor. Other suitable agents that include or consist of amylin or an amylin analog include, for example, CagriSema (a combination of cagrilintide and semaglutide), petrelinitide, amycretin (a dual GLP-1 and amylin receptor agonist), NN1213, and dual amylin and calcitonin receptor agonists (e.g., KPB-042 and KPB- 066A). In some embodiments, amylin alone may be used. In other embodiments, tirzepatide alone may be used. In some embodiments, a GLP-1 RA can be used in combination with amylinand / or tirzepatide. GLP-1 RA / glucagon dual agonists and GLP-1 RA / GIP agonists / antagonists can also be used alone or in combination with other agents as described herein.

[0061] The peptide or peptides of the compositions described above and herein, for example, a GLP-1 RA or GLP-1 / GIP dual agonist, can be attached to at least one substituent (also referred to herein as a “side chain”). The substituent can prolong the half-life of the peptide in vivo, such as by binding of the substituent to serum albumin. For example, the substituent can be a lipophilic substituent having a plurality of carbon atoms, such as at least 10, 15, 20, 25, 30, 35, or 40 carbon atoms. In some embodiments, the lipophilic substituent is an acyl group of a fatty acid, such as a straight chain fatty acid or a branched fatty acid. The fatty acid can be a fatty monoacid, e.g., an aliphatic monocarboxylic acid having 4 to 38 carbon atoms, which may be saturated or unsaturated. The fatty acid can be a fatty diacid, e.g., an aliphatic dicarboxylic acid having 4 to 38 carbon atoms, which may be saturated or unsaturated. The fatty acid can be a C4 to C38 fatty acid, such as a C4 fatty acid, a C6 fatty acid, a C8 fatty acid, a C10 fatty acid, a C12 fatty acid, a C14 fatty acid, a C15 fatty acid, a C16 fatty acid, a C17 fatty acid, a C18 fatty acid, a C20 fatty acid, a C22 fatty acid, a C24 fatty acid, a C26 fatty acid, a C28 fatty acid, a C30 fatty acid, a C32 fatty acid, a C34 fatty acid, a C36 fatty acid, or a C38 fatty acid.

[0062] In some embodiments, the lipophilic substituent is an acyl group having the formula CH3(CH2)nCO–, where n is an integer from 4 to 38, or from 4 to 24, such as CH3(CH2)4CO–, CH3(CH2)6CO–, CH3(CH2)8CO–, CH3(CH2)10CO–, CH3(CH2)12CO–, CH3(CH2)14CO–, CH3(CH2)16CO–, CH3(CH2)18CO–, CH3(CH2)20CO–, CH3(CH2)22CO–, or CH3(CH2)24CO–.

[0063] In some embodiments, the lipophilic substituent is an acyl group having the formula HOOC(CH2)nCO–, where n is an integer from 4 to 38, or from 4 to 24, such as HOOC(CH2)14CO–, HOOC(CH2)16CO–, HOOC(CH2)18CO–, HOOC(CH2)20CO–, or HOOC(CH2)22CO–.

[0064] In some embodiments, the lipophilic substituent is an acyl group of a straight-chainor branched alkane , -dicarboxylic acid.

[0065] In some embodiments, the lipophilic substituent is an acyl group having the formula CH3(CH2)nCO–NHCH(COOH)(CH2)2CO–, where n is an integer from 10 to 24.

[0066] In some embodiments, the lipophilic substituent is an acyl group having the formula CH3(CH2)nCO–NHCH((CH2)2COOH)CO–, where n is an integer from 8 to 24.

[0067] In some embodiments, the lipophilic substituent is an acyl group having the formula COOH(CH2)nCO–, where n is an integer from 8 to 24.

[0068] In some embodiments, the lipophilic substituent is an acyl group having the formula –NHCH(COOH)(CH2)4NH–CO(CH2)nCH3, where n is an integer from 8 to 18.

[0069] The substituent can be attached to the peptide or peptides of the compositions described above and herein via any suitable mechanism, such as acylation, alkylation, ester formation, amide formation, coupling to a cysteine residue, and / or other conjugation chemistries known to those of skill in the art. For example, the substituent can be covalently attached to the peptide via an amide bond between a carboxyl group of the substituent and an amino group of the peptide. The amino group of the peptide can be the N-terminal amino group of the peptide or can be a side chain amino group of an amino acid residue of the peptide (e.g., an amino group of a lysine residue of the peptide). The substituent can be attached to the peptide directly, or can be attached to the peptide via a linker, which may also be referred to herein as a spacer. For instance, the substituent can be attached to the peptide via an amide bond between a carboxyl group of the linker and an amino group of an amino acid residue of the peptide. The linker can be any suitable linker known to those of skill in the art, such as a peptide linker (e.g., a -glutamate linker), a hydrophilic spacer (e.g., 8-amino-3,6-dioxaoctanoic acid), a hydrophobic spacer, or a combination thereof.

[0070] In some embodiments, the GLP-1 RA is exenatide, exenatide-LAR, lixisenatide, liraglutide, semaglutide, albiglutide, dulaglutide, efpeglenatide, ecnoglutide, efinopegdutide, cotadutide, mazdutide, BI 45690, tirzepatide, LY3493269, VK2735, CT-868, AMG133, or retatrutide. In some embodiments, the GLP-1 RA is liraglutide, semaglutide, ecnoglutide, cotadutide, mazdutide, tirzepatide, or retatrutide. Additional examples of GLP-1 RAs are provided in International Patent Application Publication Nos. WO 2005 / 027978 and WO 2014 / 005858, the disclosures of each of which are incorporated by reference herein in their entirety. Optionally, the composition can include a combination of two or more different GLP- 1 RAs, such as two or more of any of the GLP-1 RAs disclosed herein.

[0071] In certain embodiments according to the present disclosure, GLP1 RAs can be used alone. In certain embodiments, a GLP-1 receptor against can be used in combination with GIP and glucagon agonists or antagonists. In certain embodiments, GLP-1 RAs can be used in combination with amylin analogs alone or with amylin analogs in combination with the other hormones. In some embodiments, GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagondual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment can be used alone or in any combination with any of the other gastric emptying- slowing agents described herein.

[0072] The composition can include any suitable amount of the postbariatric treatment agent (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1- GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) for providing the desired therapeutic effect. For example, the composition can include at least 0.05 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.3 mg, 0.35 mg, 0.40 mg, 0.45 mg, 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, or 400 mg of the postbariatric treatment agent. Alternatively or in combination, the composition can include no more than 500 mg, 400 mg, 300 mg, 275 mg, 250 mg, 225 mg, 200 mg, 175 mg, 150 mg, 125 mg, 100 mg, 90 mg, 80 mg, 70 mg, 60 mg, 50 mg, 45 mg, 40 mg, 35 mg, 30 mg, 25 mg, 20 mg, 15 mg, 10 mg, 5 mg, 2 mg, 1 mg, 0.5 mg, 0.45 mg, 0.40 mg, 0.35 mg, 0.30 mg, 0.25 mg, 0.20 mg, 0.15 mg, 0.10 mg, or 0.05 mg of the postbariatric treatment agent. The amount of the postbariatric treatment agent in the composition can be within a range from about 0.05 mg to 500 mg, 0.1 mg to 500 mg, 0.15 mg to 500 mg, 0.2 mg to 500 mg, 0.25 mg to 500 mg, 0.3 mg to 500 mg, 0.35 mg to 500 mg, 0.40 mg to 500 mg, 0.45 mg to 500 mg, 0.5 mg to 500 mg, 0.5 mg to 250 mg, about 0.5 mg to 150 mg, 0.5 mg to 100 mg, 0.5 mg to 50 mg, 0.5 mg to 40 mg, 0.5 mg to 30 mg, 0.5 mg to 20 mg, 0.5 mg to 10 mg, 1 mg to 500 mg, 1 mg to 250 mg, 1 mg to 150 mg, 1 mg to 100 mg, 1 mg to 50 mg, 1 mg to 40 mg, 1 mg to 30 mg, 1 mg to 20 mg, 1 mg to 10 mg, 10 mg to 500 mg, 10 mg to 250 mg, 10 mg to 150 mg, 10 mg to 100 mg, 10 mg to 50 mg, 10 mg to 40 mg, 10 mg to 30 mg, 10 mg to 20 mg, 20 mg to 500 mg, 20 mg to 250 mg, 20 mg to 150 mg, 20 mg to 100 mg, 20 mg to 50 mg, 20 mg to 40 mg, 20 mg to 30 mg, 30 mg to 500 mg, 30 mg to 250 mg, 30 mg to 150 mg, 30 mg to 100 mg, 30 mg to 50 mg, 30 mg to 40 mg, 40 mg to 500 mg, 40 mg to 250 mg, 40 mg to 150 mg, 40 mg to 100 mg, 40 mg to 50 mg, 50 mg to 500 mg, 50 mg to 250 mg, 50 mg to 150 mg, 50 mg to 100 mg, 100 mg to 500 mg, 100 mg to 250 mg, 100 mg to 150 mg, 150 mg to 500 mg, 150 mg to 250 mg, or 250 mg to 500 mg. The amount of thepostbariatric treatment agent in the composition can be approximately 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 400 mg or 500 mg.

[0073] In some embodiments, the postbariatric treatment agent (e.g., GLP-1 RAs, GLP-1- GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) is present in the composition at a concentration of at least 0.05 mg / mL, 0.1 mg / mL, 0.15 mg / mL, 0.2 mg / mL, 0.25 mg / mL, 0.3 mg / mL, 0.35 mg / mL, 0.40 mg / mL, 0.45 mg / mL, 0.5 mg / mL, 1 mg / mL, 1.5 mg / mL, 2 mg / mL, 5 mg / mL, 10 mg / mL, 20 mg / mL, 50 mg / mL, 100 mg / mL, 120 mg / mL, or 150 mg / mL. Alternatively or in combination, the concentration of the postbariatric treatment agent in the composition is no more than 200 mg / mL, 150 mg / mL, 120 mg / mL, 100 mg / mL, 50 mg / mL, 20 mg / mL, 10 mg / mL, 5 mg / mL, 2 mg / mL, 1.5 mg / mL, 1 mg / mL, or 0.5 mg / mL. The concentration of the postbariatric treatment agent in the composition can be within a range from 0.05 mg / mL to 200 mg / mL, 0.05 mg / mL to 150 mg / mL, 0.05 mg / mL to 120 mg / mL, 0.05 mg / mL to 100 mg / mL, 0.05 mg / mL to 50 mg / mL, 0.05 mg / mL to 20 mg / mL, 0.05 mg / mL to 10 mg / mL, 0.05 mg / mL to 5 mg / mL, 0.05 mg / mL to 2 mg / mL, 0.05 mg / mL to 1.5 mg / mL, 0.05 mg / mL to 1 mg / mL, 0.5 mg / mL to 200 mg / mL, 0.5 mg / mL to 150 mg / mL, 0.5 mg / mL to 120 mg / mL, 0.5 mg / mL to 100 mg / mL, 0.5 mg / mL to 50 mg / mL, 0.5 mg / mL to 20 mg / mL, 0.5 mg / mL to 10 mg / mL, 0.5 mg / mL to 5 mg / mL, 0.5 mg / mL to 2 mg / mL, 0.5 mg / mL to 1.5 mg / mL, 0.5 mg / mL to 1 mg / mL, 1 mg / mL to 200 mg / mL, 1 mg / mL to 150 mg / mL, 1 mg / mL to 120 mg / mL, 1 mg / mL to 100 mg / mL, 1 mg / mL to 50 mg / mL, 1 mg / mL to 20 mg / mL, 1 mg / mL to 10 mg / mL, 1 mg / mL to 5 mg / mL, 1 mg / mL to 2 mg / mL, 1 mg / mL to 1.5 mg / mL, 1.5 mg / mL to 200 mg / mL, 1.5 mg / mL to 150 mg / mL, 1.5 mg / mL to 120 mg / mL, 1.5 mg / mL to 100 mg / mL, 1.5 mg / mL to 50 mg / mL, 1.5 mg / mL to 20 mg / mL, 1.5 mg / mL to 10 mg / mL, 1.5 mg / mL to 5 mg / mL, 1.5 mg / mL to 2 mg / mL, 2 mg / mL to 200 mg / mL, 2 mg / mL to 150 mg / mL, 2 mg / mL to 120 mg / mL, 2 mg / mL to 100 mg / mL, 2 mg / mL to 50 mg / mL, 2 mg / mL to 20 mg / mL, 2 mg / mL to 10 mg / mL, 2 mg / mL to 5 mg / mL, 5 mg / mL to 200 mg / mL, 5 mg / mL to 150 mg / mL, 5 mg / mL to 120 mg / mL, 5 mg / mL to 100 mg / mL, 5 mg / mL to 50 mg / mL, 5 mg / mL to 20 mg / mL, 5 mg / mL to 10 mg / mL, 10 mg / mL to 200 mg / mL, 10 mg / mL to 150 mg / mL, 10 mg / mL to 120 mg / mL, 10 mg / mL to 100 mg / mL, 10 mg / mL to 50 mg / mL,10 mg / mL to 20 mg / mL, 20 mg / mL to 200 mg / mL, 20 mg / mL to 150 mg / mL, 20 mg / mL to 120 mg / mL, 20 mg / mL to 100 mg / mL, 20 mg / mL to 50 mg / mL, 50 mg / mL to 200 mg / mL, 50 mg / mL to 150 mg / mL, 50 mg / mL to 120 mg / mL, 50 mg / mL to 100 mg / mL, or 100 mg / mL to 200 mg / mL.

[0074] Optionally, the compositions herein can include other therapeutic compositions, in addition to the postbariatric treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof). The other therapeutic cargo can include one or more therapeutic agents that produce a desired therapeutic effect, such as small molecule drugs, peptides, proteins, polysaccharides, nucleic acids, cells, or combinations thereof. In some embodiments, the therapeutic agent(s) act in concert with the GLP-1 RA or GLP-1 / GIP dual agonist to augment gastric emptying or prevent postprandial hypoglycemia. These include SGLT1 inhibitors, SGLT2 inhibitors, combined SGLT1 / SGLT2 inhibitors, and acarbose and miglitol. Optionally, the therapeutic agent(s) can be administered to the subject separately from the composition via any suitable administration route (e.g., parenteral or non- parenteral administration).

[0075] In certain embodiments GLP-1 RA and all other injectable peptide hormones and non-peptide (e.g., small molecule) combinations described above may be administered as oral peptides (semaglutide) or oral nonpeptide or small molecule formulations, such as orforglipron, lotiglipron, danuglipron, and cinchonine, which are nonpeptide GLP-1 RA, and others under development that will effectively stimulate GLP-1, GIP, glucagon, or a combination of these receptors. IV. ADMINISTRATION AND DOSAGE OF POSTBARIATRIC HYPOGLYCEMIA TREATMENT AGENTS

[0076] The compositions herein comprising one or more postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) can be administered to the subject via anysuitable route, such as a parenteral route. For example, in some embodiments, the composition is administered to the subject via injection (e.g., subcutaneous injection or intramuscular injection). Injection of the composition can be performed using any suitable device having a lumen configured for delivery of the composition, such as needles (e.g., hypodermic needles, surgical needles, infusion needles), injector pens, catheters, trocars, cannulas, tubing, etc. The composition can be injected into any suitable site in the subject’s body, such as an arm, thigh, abdomen, or buttock. The composition can be formulated to have a volume that is sufficiently small for injection, such as a volume less than or equal to 2 mL, 1.75 mL, 1.5 mL, 1.25 mL, 1 mL, 0.75 mL, 0.5 mL, 0.25 mL, 0.20 mL, 0.15 mL, 0.10 mL, 0.09 mL, 0.08 mL, 0.07 mL, 0.06 mL, 0.05 mL, 400 μL, 300 μL, 200 μL, 100 μL, 90 μL, 80 μL, 70 μL, 60 μL, 50 μL, 40 μL, 30 μL, 20 μL, or 10 μL. Lower doses or volumes can be administered more frequently (e.g., pre-prandial dosing) than larger doses and volumes. In some embodiments, the composition is administered as a single injection at a single injection site, while in other embodiments, the composition can be administered as multiple injections at the same or different injection sites. The composition can be administered to the subject at any suitable frequency, such as once per day, more than once per day (in advance of meals for shorter-acting formulations), once per week,, multiple times per week, once per 2 weeks, once per 4 weeks, once per month, once per 2 months, once per 3 months, once per 4 months, once per 5 months, once per 6 months, once 9 months, or once per year. For example, exenatide can be administered in an amount of 5-10 micrograms twice or three times daily.

[0077] The compositions herein can be configured to deliver a therapeutically effective amount of the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) over a desired treatment period, which can be an amount that is effective to ameliorate or prevent a symptom of a disease or condition in a subject. For example, the treatment period can be at least 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 28 days, 35 days, 40 days, 50 days, 60 days, 70 days, 80 days, 90 days, 100 days, 110 days, 120 days, 150 days, 180 days, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 1 year, or longer, for example, for subjects having chronic disease that may need treatment for the remainder of the subject’s lifetime. The treatment period can beapproximately 2 weeks, 4 weeks, 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, or longer for individuals that may need chronic treatment.

[0078] During the treatment period, in certain embodiments, the composition can deliver the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) at a rate of approximately 0.05 mg / week, 0.1 mg / week, 0.25 mg / week, 0.5 mg / week, 1 mg / week, 1.5 mg / week, 2 mg / week, 2.5 mg / week, 3 mg / week, 4 mg / week, 5 mg / week, 6 mg / week, 7 mg / week, 8 mg / week, 9 mg / week, 10 mg / week, 11 mg / week, 12 mg / week, 15 mg / week, 20 mg / week, or 25 mg / week. The delivery rate can be within a range from 0.1 mg / week to 25 mg / week, 0.25 mg / week to 25 mg / week, 0.5 mg / week to 20 mg / week, 0.5 mg / week to 2 mg / week, 0.5 mg / week to 1.5 mg / week, 1 mg / week to 2 mg / week, 2 mg / week to 5 mg / week, 5 mg / week to 15 mg / week, 5 mg / week to 10 mg / week, 10 mg / week to 20 mg / week, 10 mg / week to 15 mg / week, 12 mg / week to 25 mg / week, 12 mg / week to 15 mg / week, 15 mg / week to 25 mg / week, 15 mg / week to 20 mg / week, or 20 mg / week to 25 mg / week.

[0079] During the treatment period, in certain embodiments, the composition can deliver the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment) at a rate of approximately 0.05 mg / day, 0.1 mg / day, 0.25 mg / day, 0.5 mg / day, 1 mg / day, 1.5 mg / day, 2 mg / day, 2.5 mg / day, 3 mg / day, 4 mg / day, 5 mg / day, 6 mg / day, 7 mg / day, 8 mg / day, 9 mg / day, 10 mg / day, 11 mg / day, 12 mg / day, 15 mg / day, 20 mg / day, or 25 mg / day. The delivery rate can be within a range from 0.05 mg / day to 25 mg / day, 0.1 mg / day to 25 mg / day, 0.25 mg / day to 25 mg / day, 0.5 mg / day to 20 mg / day, 0.5 mg / day to 2 mg / day, 0.5 mg / day to 1.5 mg / day, 1 mg / day to 2 mg / day, 2 mg / day to 5 mg / day, 5 mg / day to 15 mg / day, 5 mg / day to 10 mg / day, 10 mg / day to 20 mg / day, 10 mg / day to 15 mg / day, 12 mg / day to 25 mg / day, 12 mg / day to 15 mg / day, 15 mg / day to 25 mg / day, 15 mg / day to 20 mg / day, or 20 mg / day to 25 mg / day.

[0080] During the treatment period, in certain embodiments, the composition can deliver the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment) at a rate of approximately 0.05 mg / dose, 0.1 mg / dose, 0.25 mg / dose, 0.5 mg / dose, 1 mg / dose, 1.5 mg / dose, 2 mg / dose, 2.5 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 11 mg / dose, 12 mg / dose, 15 mg / dose, 20 mg / dose, or 25 mg / dose. The delivery rate can be within a range from 0.05 mg / dose to 25 mg / dose, 0.1 mg / dose to 25 mg / dose, 0.25 mg / dose to 25 mg / dose, 0.5 mg / dose to 20 mg / dose, 0.5 mg / dose to 2 mg / dose, 0.5 mg / dose to 1.5 mg / dose, 1 mg / dose to 2 mg / dose, 2 mg / dose to 5 mg / dose, 5 mg / dose to 15 mg / dose, 5 mg / dose to 10 mg / dose, 10 mg / dose to 20 mg / dose, 10 mg / dose to 15 mg / dose, 12 mg / dose to 25 mg / dose, 12 mg / dose to 15 mg / dose, 15 mg / dose to 25 mg / dose, 15 mg / dose to 20 mg / dose, or 20 mg / dose to 25 mg / dose.

[0081] During the treatment period, in certain embodiments, the composition can deliver the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) at a rate of approximately 0.05 μg / day, 0.1 μg / day, 0.25 μg / day, 0.5 μg / day, 1 μg / day, 1.5 μg / day, 2 μg / day, 2.5 μg / day, 3 μg / day, 4 μg / day, 5 μg / day, 6 μg / day, 7 μg / day, 8 μg / day, 9 μg / day, 10 μg / day, 11 μg / day, 12 μg / day, 15 μg / day, 20 μg / day, or 25 μg / day. The delivery rate can be within a range from 0.05 μg / day to 25 μg / day, 0.1 μg / day to 25 μg / day, 0.25 μg / day to 25 μg / day, 0.5 μg / day to 20 μg / day, 0.5 μg / day to 2 μg / day, 0.5 μg / day to 1.5 μg / day, 1 μg / day to 2 μg / day, 2 μg / day to 5 μg / day, 5 μg / day to 15 μg / day, 5 μg / day to 10 μg / day, 10 μg / day to 20 μg / day, 10 μg / day to 15 μg / day, 12 μg / day to 25 μg / day, 12 μg / day to 15 μg / day, 15 μg / day to 25 μg / day, 15 μg / day to 20 μg / day, or 20 μg / day to 25 μg / day.

[0082] During the treatment period, in certain embodiments, the composition can deliver the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastricemptying for PBH treatment, alone or in any combination thereof) at a rate of approximately 0.05 μg / dose, 0.1 μg / dose, 0.25 μg / dose, 0.5 μg / dose, 1 μg / dose, 1.5 μg / dose, 2 μg / dose, 2.5 μg / dose, 3 μg / dose, 4 μg / dose, 5 μg / dose, 6 μg / dose, 7 μg / dose, 8 μg / dose, 9 μg / dose, 10 μg / dose, 11 μg / dose, 12 μg / dose, 15 μg / dose, 20 μg / dose, or 25 μg / dose. The delivery rate can be within a range from 0.05 μg / dose to 25 μg / dose, 0.1 μg / dose to 25 μg / dose, 0.25 μg / dose to 25 μg / dose, 0.5 μg / dose to 20 μg / dose, 0.5 μg / dose to 2 μg / dose, 0.5 μg / dose to 1.5 μg / dose, 1 μg / dose to 2 μg / dose, 2 μg / dose to 5 μg / dose, 5 μg / dose to 15 μg / dose, 5 μg / dose to 10 μg / dose, 10 μg / dose to 20 μg / dose, 10 μg / dose to 15 μg / dose, 12 μg / dose to 25 μg / dose, 12 μg / dose to 15 μg / dose, 15 μg / dose to 25 μg / dose, 15 μg / dose to 20 μg / dose, or 20 μg / dose to 25 μg / dose.

[0083] Alternatively or in combination, the composition can deliver the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment) at a rate of approximately 0.5 wt% / day, 0.6 wt% / day, 0.7 wt% / day, 0.8 wt% / day, 0.9 wt% / day, 1 wt% / day, 1.25 wt% / day, 1.5 wt% / day, 1.75 wt% / day, 2 wt% / day, 2.5 wt% / day, 3 wt% / day, 4 wt% / day, or 5 wt% / day (the wt% of the postbariatric treatment agent can be measured relative to the total amount of the GLP-1 RA initially present in the composition). V. METHODS OF TREATMENT UTILIZING POSTBARIATRIC HYPOGLYCEMIA AGENTS

[0084] In some embodiments, the present technology provides methods for treating a subject by administering a composition as described herein (e.g., compositions comprising postbariatric hypoglycemic treatment agents, for example, GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) . The composition can treat a disease or condition of the subject by producing a desired therapeutic effect in the subject, such as alleviation of symptoms, a reduction in the severity of the disease or condition, inhibiting an underlying cause of the disease or condition, steadying the disease or conditionin a non-advanced state, delaying the progress of a disease or condition, and / or improvement or alleviation of the disease or condition.

[0085] Methods of treatment as described herein can comprise treating postbariatric hypoglycemia (PBH) in a subject utilizing a composition comprising one or more postbariatric treatment agents as described herein. In certain aspects, the subject can be a subject that has undergone bariatric surgery, for example, a Roux-en-Y Gastric Bypass (RYBG), a vertical sleeve gastrectomy, or a duodenal switch.

[0086] Methods of treatment as described herein can comprising reducing gastric emptying in a subject. In certain aspects, the subject can be a subject that has undergone bariatric surgery, for example, a Roux-en-Y Gastric Bypass (RYBG), a vertical sleeve gastrectomy, or a duodenal switch. The reduction in gastric emptying can be measured by techniques known in the art, for example, scintigraphy. According to methods as described herein, gastric emptying can be reduced in a subject that has been administered a composition as described herein compared to gastric emptying in the same subject but without administration of the composition.

[0087] Examples of other diseases and conditions that may be treated using the compositions described herein include diabetes and / or related conditions (e.g., prediabetes, type 1 diabetes, type 2 diabetes, hyperglycemia, impaired glucose tolerance), obesity or excessive body weight, eating disorders (e.g., bulimia nervosa, binge eating disorder), cardiovascular disease (e.g., hypertension, atherosclerosis, myocardial infarction, coronary heart diseases), liver disease (e.g., non-alcoholic fatty liver disease), neurological and / or neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, peripheral neuropathy, ischemia, stroke, multiple sclerosis), inflammatory diseases (e.g., asthma, psoriasis, inflammatory bowel disease), renal diseases, bone diseases (e.g., bone fragility, osteoporosis), and hormonal diseases (e.g., polycystic ovary syndrome). In certain embodiments, diseases and conditions that can be treated according to the present disclosure include other upper GI surgeries that lead to rapid transit and are associated with postprandial hypoglycemia including Nissen fundoplication, total gastrectomy, esophagectomy, other related upper GI surgeries, OAGB and SADI.

[0088] In some embodiments, a method of treating PBH and / or reducing gastric emptying includes administering a composition of the present disclosure to a subject in need thereof. The composition can be administered to the subject via a single injection (e.g., a subcutaneous orintramuscular injection). The composition can include a therapeutically effective amount of the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) for treating PBH and / or reducing gastric emptying. For example, the therapeutically effective amount can be an amount of the agent that results in the sustained reduction and / or regulation of the subject’s blood glucose levels over the treatment period. The therapeutically effective amount can be an amount of the agent that results in reduced gastric emptying compared to without treatment over the treatment period. In certain embodiments, non-peptide compositions can be administered to the subject via oral administration.

[0089] The therapeutically effective amount can be within a range from 0.1 mg / week to 25 mg / week, 0.1 mg / week to 5 mg / week, 0.5 mg / week to 20 mg / week, 0.5 mg / week to 2 mg / week, 0.75 mg / week to 1.5 mg / week, 1 mg / week to 2 mg / week, 5 mg / week to 10 mg / week, 10 mg / week to 20 mg / week, or 10 mg / week to 15 mg / week. The therapeutically effective amount may vary depending on the type of agent, for example, and without intending to be limiting, the therapeutically effectively amount may be approximately 1 mg / week for semaglutide; approximately 12.6 mg / week (1.8 mg / day) for liraglutide; approximately 2.5 mg / week, 5 mg / week, 7.5 mg / week, 10 mg / week, 12.5 mg / week, or 15 mg / week for tirzepatide; and approximately 1 mg / week, 4 mg / week, 8 mg / week or 12 mg / week for retatrutide. For example, the treatment period can be at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, or 12 months.

[0090] In some embodiments, a method of treating PBH and / or reducing gastric emptying includes administering a composition of the present disclosure to a subject in need thereof. The composition can be administered to the subject via a single injection (e.g., a subcutaneous or intramuscular injection). The composition can be administered in a therapeutically effective amount of one or more postbariatric treatment agents. For example, the therapeutically effective amount can be an amount of the one or more postbariatric treatment agents that results in maintenance of blood sugar within a desired range. For example, the therapeutically effective amount can be an amount of the postbariatric treatment agent that reduces the level or rate gastric emptying after food intake in a subject compared to the level or rate of gastric emptying in a subject after food intake without the composition. The therapeutically effective amountcan be within a range from 0.05 mg / week to 25 mg / week, 0.1 mg / week to 25 mg / week, 0.1 mg / week to 5 mg / week, 0.5 mg / week to 20 mg / week, 0.5 mg / week to 2 mg / week, 0.75 mg / week to 1.5 mg / week, 1 mg / week to 2 mg / week, 5 mg / week to 10 mg / week, 10 mg / week to 20 mg / week, or 10 mg / week to 15 mg / week. The therapeutically effective amount may vary depending on the type of the postbariatric treatment agent e.g., the therapeutically effectively amount may be, for example and without intending to be limiting, approximately 1 mg / week for semaglutide; approximately 12.6 mg / week (1.8 mg / day) for liraglutide; approximately 2.5 mg / week, 5 mg / week, 7.5 mg / week, 10 mg / week, 12.5 mg / week, or 15 mg / week for tirzepatide; and approximately 1 mg / week, 4 mg / week, 8 mg / week or 12 mg / week for retatrutide. In certain aspects, compositions as described herein can be administered during a treatment period, and the treatment period can be at least 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 9 months, 12 months, or indefinitely for subjects having chronic issues. VI. KITS COMPRISING POSTBARIATRIC TREATMENT AGENTS

[0091] In some embodiments, the present disclosure provides kits for preparing a composition as described herein. The kit can include a solution containing the postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) and one or more solutions containing the components of a pharmaceutical solution (e.g., a pharmaceutically acceptable carrier or vehicle). Optionally, the kit can include an additional therapeutic agent. The kit can include a postbariatric hypoglycemic treatment agents (e.g., GLP-1 RAs, GLP-1-GIP dual agonists, GLP-1 RA / glucagon dual agonists, GLP-1 RA / GIP agonists / antagonists, GLP-1 RA / amylin dual agonists, amylin, amylin analogs, GLP1-GIP-glucagon triple agonists (e.g., retatrutide), and other gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH treatment, alone or in any combination thereof) in a dosage unit formulation, for example, in a single unit dose form suitable for a single administration.

[0092] The solutions can be provided in tubes, bottles, ampoules, syringes, or any other suitable storage container. In some embodiments, the solutions each independently include a suitable pharmaceutically acceptable diluent. The pharmaceutically acceptable diluent can beany diluent that does not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject. Examples of pharmaceutically acceptable diluents include, but are not limited to, saline, Ringer’s solution, dextrose solution, phosphate buffered saline, water, or a combination thereof. The pharmaceutically acceptable diluent can include an isotonicity imparting agent, such as mannitol, sodium chloride, potassium chloride, or monosodium phosphate. The pharmaceutically acceptable diluent can include a buffer, such as an acetate buffer, bicarbonate, TRIS, HEPES, MOPS, CHES, CHAPS, or phosphate buffered saline. The pharmaceutically acceptable diluent can include stabilizers and / or preservatives, as appropriate. Additional examples and details of pharmaceutically acceptable diluents can be found, for example, in Martin, Remington’s Pharmaceutical Sciences, 21st Ed., Mack Publ. Co., Easton, Pa. (2005), which is incorporated herein by reference in its entirety. VII. EXEMPLARY EMBODIMENTS

[0093] The following embodiments are contemplated. All combinations of features and embodiments are contemplated.

[0094] Embodiment 1: A method of treating postbariatric hypoglycemia, the method comprising: administering a composition to a subject in need thereof, wherein the composition comprises a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA), a GLP1-glucose- dependent insulinotropic polypeptide (GLP1-GIP) dual agonist, a GLP-1 RA / glucagon dual agonist, a GLP-1 RA / GIP agonist / antagonist, a GLP-1RA / amylin dual agonist, amylin, one or more amylin analogs, a GLP1-GIP-glucagon triple agonist (e.g., retatrutide), or gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH, alone or in any combination thereof.

[0095] Embodiment 2: An embodiment of embodiment 1, wherein the subject in need thereof has undergone a bariatric surgery.

[0096] Embodiment 3: An embodiment of embodiment 2, wherein the bariatric surgery is a Roux-en-Y Gastric Bypass (RYBG), a vertical sleeve gastrectomy, a one-anastomosis gastric bypass (OAGB), a single-anastomosis duodeno-ileal bypass (SADI), or a biliopancreatic diversion with duodenal switch (BPD-DS).

[0097] Embodiment 4: An embodiment of any one of embodiments 1 to 3, wherein the subject in need thereof has undergone a non-bariatric upper-gastrointestinal surgery.

[0098] Embodiment 5: An embodiment of embodiment 4, wherein the non-bariatric upper- gastrointestinal surgery is an esophagectomy, gastrectomy, or a Nissen fundoplication.

[0099] Embodiment 6: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises a GLP-1 receptor agonist.

[0100] Embodiment 7: An embodiment of embodiment 6, wherein the GLP-1 receptor agonist comprises semaglutide, lixisenatide, exenatide, or a combination thereof.

[0101] Embodiment 8: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises a GLP1-GIP dual agonist.

[0102] Embodiment 9: An embodiment of embodiment 8, wherein the GLP1-GIP dual agonist comprises tirzepatide.

[0103] Embodiment 10: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises amylin or an analog thereof.

[0104] Embodiment 11: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises a GLP-1RA / amylin dual agonists.

[0105] Embodiment 12: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises a GLP1-GIP-glucagon triple agonist.

[0106] Embodiment 13: An embodiment of embodiment 12, wherein the GLP1-GIP- glucagon triple agonist comprises retatrutide.

[0107] Embodiment 14: An embodiment of any one of embodiments 1 to 13, wherein the composition is administered in an effective amount of to reduce gastric emptying in the subject compared to without administration of the composition.

[0108] Embodiment 15: An embodiment of embodiment 14, wherein the effective amount is about 0.05 mg to about 500 mg.

[0109] Embodiment 16: An embodiment of any one of embodiments 1 to 15, wherein the composition further comprises a pharmaceutically-acceptable carrier.

[0110] Embodiment 17: A method of reducing gastric emptying, the method comprising: administering the composition of any one of embodiments 1 to 16 to a subject in need thereof.

[0111] Embodiment 18: An embodiment of embodiment 17, wherein the subject in need thereof has undergone a bariatric surgery.

[0112] Embodiment 19: An embodiment of embodiment 18, wherein the bariatric surgery is a Roux-en-Y Gastric Bypass (RYBG), a vertical sleeve gastrectomy, or a duodenal switch.

[0113] Embodiment 20: An embodiment of any one of embodiments 17 to 19, wherein the subject in need thereof has undergone a non-bariatric upper-gastrointestinal surgery.

[0114] Embodiment 21: An embodiment of embodiment 20, wherein the non-bariatric surgery is an esophagectomy or a Nissen fundoplication.

[0115] Embodiment 22: A kit, comprising the composition of any one of embodiments 1 to 16; and instructions for use.

[0116] Embodiment 23: An embodiment of embodiment 22, wherein the composition is present in a dosage formulation suitable for one or more administrations to the subject.

[0117] Embodiment 24: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises a GLP-1 RA / GIP agonist / antagonist.

[0118] Embodiment 25: An embodiment of any one of embodiments 1 to 5, wherein the composition comprises a GLP-1 RA / glucagon dual agonist. EXAMPLES

[0119] The following examples are offered for illustrative purposes only, and are not intended to limit the disclosure in any manner. Example 1. Enhanced Gastric Emptying in PBH Patients

[0120] This example was designed to test the hypothesis that, while gastric emptying is expected to be faster in Roux-en-Y gastric bypass (RYGB) vs nonsurgical controls, those RYGB patients who develop post-bariatric hypoglycemia (PBH) have more rapid emptying than those who do not develop PBH. This hypothesis follows on work performed by the inventors showing that, in patients with RYBG, altered nutrient transit, in which a greater nutrient load is delivered to the hindgut (distal small and large intestine), leads to an immediate glucose spike, associated with insulin and GLP-1 hypersecretion, followed by hypoglycemia (McLaughlin T, Peck MC, Holst J & Deacon C, J. Clin. Endocrinol. Metab. (2010) 95:1851; Craig CM & McLaughlin T, AACE Clin. Case Rep. (2014) 1:e84). In two case reports, the inventors showed that this is a consequence of altered nutrient transit rather than anotherconsequence of surgery or underlying physiology (e.g., generally overactive B-cells), by demonstrating that hyperinsulinemic hypoglycemia as well as the GLP-1 surge following a standardized oral liquid meal could be completely reversed by delivering the same meal through a gastrostomy tube into the remnant stomach, in which nutrients follow the original route of transit through the gut (stomach to duodenum and jejunum and then to ileum and large intestine) (McLaughlin T, Peck MC, Holst J & Deacon C, J. Clin. Endocrinol. Metab. (2010) 95:1851; Craig CM & McLaughlin T, AACE Clin. Case Rep. (2014) 1:e84). The inventors further showed that the mediator of hypoglycemia in response to altered nutrient transit was overstimulation of GLP-1, which is secreted by enteroendocrine cells in the hindgut in proportion to nutrient load. When GLP-1 was blocked by a competitive antagonist, exendin 9- 39, the hyperinsulinemic hypoglycemia was reversed (Craig CM, Liu LF, Deacon CF, Holst JJ & McLaughlin TL, Diabetologia (2017) 60:531).

[0121] As shown by the data of FIG.1 and Table 2, the 1 hour residual volume is 67% lower in RYGB patients with PBH as compared to RYGB patients without PBY (p < 0.024), and also lower than nonsurgical controls, with lower values indicating more rapid emptying. This data demonstrates that rapid transit from gastric pouch may explain why a subset (up to 38%) of RYGB patients develop PBH. The data further points to gastric pouch emptying rate as a treatment target. Table 2: Scintigraphy raw data of FIG.1 Cohort Residual 0 h Residual 0.5 h Residual 1 h Residual 2 h Residual 3 h Residual 4 hp-value PBH and 0.373 0.187 0.024** 0.241 0.195 0.235 SC p-value PBH and 2.30×10-112.50×10-89.80×10-70.001 0.007 0.001 NSCExample 2. Effect of GLP-1 RA Administration on Gastric Emptying in PBH Patients

[0122] FIGS.2-7 show data testing the hypothesis that administration of a drug (semaglutide) known to slow gastric emptying in healthy non-bypassed patients may represent a therapeutic approach to PBH by addressing the rapid gastric emptying given the above results of Example 1 implicating rapid gastric emptying as a potential cause of PBH. Semaglutide is a GLP-1 analog that is used to treat type 2 diabetes and promote weight loss. Because this drug augments postprandial insulin secretion and lowers postprandial glucose, the very disturbances sought to be reversed in PBH, the notion that this drug might prevent hyperinsulinemic hypoglycemia is highly counterintuitive. Interestingly, endogenously secreted GLP-1, in addition to stimulating insulin and lowering glucose, also slows gastric emptying in non-bypassed patients with or without diabetes. Given anecdotal reports from the inventors’ patients that these drugs helped to “stabilize” glucose, the inventors hypothesized that this class of drugs may benefit PBH patients by slowing gastric emptying, which based on the above data in FIG. 1, was recently shown to represent a therapeutic target. Based on the known glucose lowering effect of GLP- 1 analogs, which can also be co-administered with GIP analogs, glucagon analogs, GIP antagonists, and / or amylin, in both peptide and nonpeptide formulations, none of these would be expected to prevent hyperinsulinemic hypoglycemia in PBH patients. However, if the GLP- 1 effect on slowing gastric emptying were greater than the effect on insulin secretion, one might see a benefit based on the data shown in FIG.1.

[0123] GLP1, glucagon, and amylin, but not GIP, have been shown to slow gastric emptying in rodents and / or humans (Holst JJ, Metabolism (2019) 96:46; Nauck MA, Quast DR, Wefers J & Pfeiffer AFH, Diabetes Obes. Metab. (2021) 23:5; Murthy SN & Ganiban G, Peptides 1988; 9(3): 583-588.; Kreel L, Br. J. Radiol. (1975) 48:691). That these compounds would slow gastric emptying in patients who have had RYGB is counterintuitive given that endogenous GLP-1 concentrations are already extremely high due to the physiology described above, and the addition of a synthetic analog therefore might not further slow gastric emptying. Additionally, the altered anatomy, in which there is only a small gastric pouch, might not respond to GLP-1 with slowing of emptying rate as has been shown in healthy controls and patients with type 2 diabetes. The investigators thus undertook a pilot study to see if the GLP- 1 analog, semaglutide, could slow gastric emptying in patients with RYGB and prevent postprandial hypoglycemia.

[0124] Four patients consented to undergo standardized gastric emptying by scintigraphy while wearing a continuous glucose monitor at baseline and again following at least five weeks of semaglutide, titrated up to a dose of 0.5 mg weekly. FIGS.2-7 and Table 3 below show data for the three patients who had finished the testing by the time results were reported. The data clearly show that semaglutide decreased gastric emptying by 2- to 5-fold at the 1-hour time point which is the primary measure used. This result had not been shown before and supports the hypothesis that these drugs could be repurposed to treat PBH given the data presented in Figure 1 pointing to more rapid gastric emptying as a differentiating feature between RYGB patients who develop PBH versus those who do not (surgical controls).

[0125] This test was not sufficient to measure a treatment-related reduction in hypoglycemia because, for patient safety, the meal administered for the gastric emptying test was very low in carbohydrate (FIGS.5-7). Continuous glucose monitoring (CGM) was conducted to determine if the treatment prevented postprandial hypoglycemia or possibly aggravated it, since GLP1 analogs are widely known to lower glucose in patients with type 2 diabetes (T2D). The CGM tracings of FIGS. 5-7 show no hyperglycemia or hypoglycemia following the standardized meal, due to the fact that a very low carbohydrate meal was used (for patient safety in the nuclear medicine scanner), which did not trigger the expected glucose spike followed by hypoglycemia that is typical in these patients. However, a reduction in fasting or post-meal glucose as a result of semaglutide treatment was not seen, which provides a notable signal of the safety of the treatment, since semaglutide is used for glucose lowering in patients with T2D.

[0126] This class of drugs is “antihyperglycemic” but not “hypoglycemic” like insulin and sulfonylureas and glinides, which are drugs that lower glucose when high but do not lower glucose levels when in the normal range and thus can be used safely in individuals without hyperglycemia (and is widely used for weight loss in normoglycemic individuals). Semaglutide, however, has not been studied in patients with hypoglycemic disorders. Furthermore, while semaglutide is known to delay gastric emptying in nonsurgical individuals, it has not been studied in patients who have undergone bariatric surgery and who have only a small pouch rather than a full stomach. As such, the effects on gastric emptying and glucose profiles have not been evaluated in patients with PBH prior to the data presented here. The data in FIG. 1 implicating rapid transit as a cause of PBH, and the data in FIGS.2-7, showing that semaglutide slows gastric emptying substantially in post RYGB patients with PBH, without increasing the risk of hypoglycemia, together demonstrate that this class of drugs, and other gastrointestinal hormone analogs, provide a significant new treatment approach for PBH.Table 3: Gastric emptying scintigraphy (gastric emptying expressed as residual volume) in three patients before and after semaglutide 0.5 mg weekly Patient ID: 52254-080 Residual VolumeT+0 T+30 T+60 T+120 T+180 T+240Baseline 65.1% 22.9% 8.6% 1.3% 0.00% 0.00% Semaglutide 0.5 mg / wk81.06% 65.1% 47.9% 22.7% 15% 5.3%Patient ID: 52254-006 Residual T+0 T+30 T+60 T+120 T+180 T+240 Baseline 37.90% 9.72% 11.66% 0.31% 0.00% 0.00% Semaglutide 0.5 mg / wk34.04% 27.49% 29.98% 9.09% 0.00% 0.00%Patient ID: 52254-082 Residual T+0 T+30 T+60 T+120 T+180 T+240 Baseline 45.3% 4.68% 4.43% 0.97% 0.00% 0.00% Semaglutide 0.5 mg / wk33.98% 23.0% 13.4% 0.11% 0.00% 0.00%Example 3. Additional GLP-1 RA Agents Suitable for Slowing Gastric Emptying in PBH Patients

[0127] As described herein, GLP-1 RA drugs that are particularly suitable for treating postbariatric hypoglycemia surprisingly include those that are shorter acting, which have also failed as weight loss drugs and thus are no longer in clinical use given the abundance of newer same-class agents that promote more weight loss. Examples of drug compounds exhibiting such unexpectedly advantageous characteristics can be found in published literature descriptions (Jalleh et al., J. Clin. Endocrinol. Metabol.110 (2025): 1; Jalleh et al., Endocrinol. 166 (2025): bqae155; Rayner et al., Diabetes Care 43 (2020): 1813), where the references with these descriptions failed to appreciate or consider the positive implications of their presented data for the methods provided by this disclosure. In these references no mention was made regarding use for PBH or other hypoglycemic disorders related to rapid gastric emptying. The interest in slowed gastric emptying in these studies was as a means to reduce glucose peak after eating or as a potential safety issue.

[0128] For example, Jalleh et al. (J. Clin. Endocrinol. Metabol.110 (2025): 1) describes an investigation of GLP-1 receptor agonists therapeutics used for type 2 diabetes and obesity, where the investigation aimed to identify areas needing further study to increase patient safety. The data presented in Figures 1 and 2 of this article show that short-acting GLP-1 receptor agonists (e.g., lixisenatide and exenatide) are more effective than long-acting GLP-1 receptor agonists (e.g., liraglutide, semaglutide, and efpeglenatide) in terms of delaying gastric emptying. Additionally, Jalleh et al. (Endocrinol.166 (2025): bqae155) reviews physiological effects of GLP-1 receptor agonists, and provides data in Figure 3 further demonstrating that gastric retention is increased following 8 weeks of administration of short-acting lixisenatide. And Figure 1 of Rayner et al. (Diabetes Care 43 (2020): 1813) also presents data showing delayed gastric emptying following 8 weeks of lixisenatide treatment, while Figures 2A and 2B of this publication present graphs showing flattened glucose curves in patients having Type 2 diabetes who have been administered lixisenatide, where the flattened glucose curves exhibit no dip below baseline after sustained treatment. These journal articles are incorporated herein by reference in their entireties for all purposes. Notably, the short-acting drugs studied by these references have substantially no value for treating obesity and only minimal value for treating diabetes in view of significantly more effective long-acting drugs such as semaglutide and tirzepatide. The short-acting drugs are, however, suitable for effective use with the PBH treatment methods provided herein due to the high performance of these drugs in delaying gastric emptying.

[0129] Although many of the embodiments are described above with respect to compositions and methods for treatment of postbariatric hypoglycemia, in particular resulting as a complication of bariatric surgery, the technology is applicable to other applications and / or other approaches, such as treatment of other diseases or conditions such as obesity or type 2 diabetes. Moreover, other embodiments in addition to those described herein are within the scope of the technology. Additionally, several other embodiments of the technology can have different configurations, components, or procedures than those described herein. A person of ordinary skill in the art, therefore, will understand that the technology can have other embodiments with additional elements, or the technology can have other embodiments without several of the features shown and described above with reference to the figures.

[0130] The descriptions of embodiments of the technology are not intended to be exhaustive or to limit the technology to the precise form disclosed above. Where the context permits, singular or plural terms may also include the plural or singular term, respectively. Althoughspecific embodiments of, and examples for, the technology are described above for illustrative purposes, various equivalent modifications are possible within the scope of the technology, as those skilled in the relevant art will recognize. For example, while steps are presented in a given order, alternative embodiments may perform steps in a different order. The various embodiments described herein may also be combined to provide further embodiments.

[0131] To the extent any materials incorporated herein by reference conflict with the present disclosure, the present disclosure controls.

[0132] It will also be appreciated that specific embodiments have been described herein for purposes of illustration, but that various modifications may be made without deviating from the technology. Further, while advantages associated with certain embodiments of the technology have been described in the context of those embodiments, other embodiments may also exhibit such advantages, and not all embodiments need necessarily exhibit such advantages to fall within the scope of the technology. Accordingly, the disclosure and associated technology can encompass other embodiments not expressly shown or described herein.

Claims

WHAT IS CLAIMED IS:

1. A method of treating postbariatric hypoglycemia, the method comprising: administering a composition to a subject in need thereof, wherein the composition comprises a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1 RA), a GLP1-glucose- dependent insulinotropic polypeptide (GLP1-GIP) dual agonist, a GLP-1 RA / glucagon dual agonist, a GLP-1 RA / GIP agonist / antagonist, a GLP-1RA / amylin dual agonist, amylin, one or more amylin analogs, a GLP1-GIP-glucagon triple agonist (e.g., retatrutide), or gastrointestinal hormone analogs that are known to promote slowing of gastric emptying for PBH, alone or in any combination thereof.

2. The method of claim 1, wherein the subject in need thereof has undergone a bariatric surgery.

3. The method of claim 2, wherein the bariatric surgery is a Roux-en-Y Gastric Bypass (RYBG), a vertical sleeve gastrectomy, a one-anastomosis gastric bypass (OAGB), a single-anastomosis duodeno-ileal bypass (SADI), or a biliopancreatic diversion with duodenal switch (BPD-DS).

4. The method of claim 1, wherein the subject in need thereof has undergone a non-bariatric upper-gastrointestinal surgery.

5. The method of claim 4, wherein the non-bariatric upper-gastrointestinal surgery is an esophagectomy, gastrectomy, or a Nissen fundoplication.

6. The method of claim 1, wherein the composition comprises a GLP-1 receptor agonist.

7. The method of claim 6, wherein the GLP-1 receptor agonist comprises semaglutide, lixisenatide, exenatide, or a combination thereof.

8. The method of claim 1, wherein the composition comprises a GLP1-GIP dual agonist.

9. The method of claim 8, wherein the GLP1-GIP dual agonist comprises tirzepatide.

10. The method of claim 1, wherein the composition comprises amylin or an analogthereof.

11. The method of claim 1, wherein the composition comprises a GLP-1RA / amylin dual agonists.

12. The method of claim 1, wherein the composition comprises a GLP1-GIP- glucagon triple agonist.

13. The method of claim 12, wherein the GLP1-GIP-glucagon triple agonist comprises retatrutide.

14. The method of claim 1, wherein the composition is administered in an effective amount of to reduce gastric emptying in the subject compared to without administration of the composition.

15. The method of claim 14, wherein the effective amount is about 0.05 mg to about 500 mg.

16. The method of claim 1, wherein the composition further comprises a pharmaceutically-acceptable carrier.

17. A method of reducing gastric emptying, the method comprising: administering the composition of claim 1 to a subject in need thereof.

18. The method of claim 17, wherein the subject in need thereof has undergone a bariatric surgery.

19. The method of claim 18, wherein the bariatric surgery is a Roux-en-Y Gastric Bypass (RYBG), a vertical sleeve gastrectomy, or a duodenal switch.

20. The method of claim 17, wherein the subject in need thereof has undergone a non-bariatric upper-gastrointestinal surgery.

21. The method of claim 20, wherein the non-bariatric surgery is an esophagectomy or a Nissen fundoplication.

22. A kit, comprising the composition of claim 1; and instructions for use.

23. The kit of claim 22, wherein the composition is present in a dosage formulation suitable for one or more administrations to the subject.

24. The method of claim 1, wherein the composition comprises a GLP-1 RA / GIP agonist / antagonist.

25. The method of claim 1, wherein the composition comprises a GLP-1 RA / glucagon dual agonist.

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