Sglt1 inhibitor and incretin combinations for treating metabolic disease

Abstract

Methods of treating metabolic disorders are disclosed herein, wherein the methods administer combinations of a sodium / glucose co- transporter 1 (SGLT1) inhibitor with a glucagon-like peptide agonist 1 (GLP 1), a gastric inhibitory peptide- 1 (GIP-1) analog, and / or d) a dual GLP-1-GIP-l receptor agonist.

Description

SGLT1 INHIBITOR AND INCRETIN COMBINATIONS FOR TREATING METABOLIC DISEASECross Reference to Related Applications

[0001] This application claims priority to U.S. Application No. 63 / 506,592, filed on June 6, 2023, the disclosure of which is incorporated by reference.Field of the Invention

[0002] The invention relates to compositions and methods for treating metabolic disease.Background

[0003] Patients with disorders in which lipids are abnormally accumulated in liver, such as non- alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), hypernutritive fatty liver, diabetic fatty liver, alcoholic fatty liver, and toxic fatty liver as well as common fatty liver are increasing year by year. Above all, non-alcoholic steatohepatitis (NASH) is particularly acknowledged as a problem, because it exhibits serious symptoms (see non-Patent Reference 1 or 2 from '976). Moreover, it has been pointed out that abnormal lipid accumulation in liver causes liver inflammation or fibril formation in liver (liver cirrhosis) and makes shifts to serious disorders such as liver cancer (see non-Patent References 1 to 4 from '976), and thus, inhibiting this lipid accumulation is extremely important.

[0004] It is believed that various factors including recent lifestyle changes overlap each other and abnormalities in liver energy metabolism are caused and, consequently, lipid accumulation in liver occurs. Therefore, therapeutic modality is not uniform. Although presently, dietary therapy, exercise therapy, pharmacotherapy and the like are tried as remedies for lipid accumulation in liver, these modalities have difficulties in control orcontinuing implementation. Therefore, therapeutic effects are not always satisfied. As described above, a satisfactory treatment modality for lipid accumulation in liver has not been established, and thus development of more effective drug for lipid accumulation has been desired.

[0005] Various pharmacological approaches are available for treating hyperglycemia and subsequently, Type 2 diabetes mellitus (T2DM) (Hampp, C. et al. Use of Antidiabetic Drugs in the U.S., 2003-2012, Diabetes Care 2014, 37, 1367-1374). These may be grouped into the following classes, each acting through a different primary mechanism: (1) Insulin secretogogues, including sulphonylureas (e.g., glipizide, glimepiride, glyburide); (2) meglitinides (e.g., nateglidine, repaglinide); (3) dipeptidyl peptidase IV (DPP-IV) inhibitors (e.g., sitagliptin, vildagliptin, alogliptin, dutogliptin, linagliptin, saxogliptin); and (4) glucagon-like peptide-l receptor (GLP-IR) agonists (e.g., liraglutide, albiglutide, exenatide, lixisenatide, dulaglutide, semaglutide), which enhance secretion of insulin by acting on the pancreatic beta-cells. Sulphonylureas and meglitinides have limited efficacy and tolerability, cause weight gain and often induce hypoglycemia.DPP-IV inhibitors have limited efficacy. Marketed GLP-IR agonists are peptides administered by subcutaneous injection. Liraglutide is additionally approved for the treatment of obesity.

[0006] Obesity is a chronic disease that is highly prevalent in modem society and is associated with numerous medical problems including hypertension, hypercholesterolemia, and coronary heart disease. It is further highly correlated with T2DM and insulin resistance, the latter of which is generally accompanied by hyperinsulinemia or hyperglycemia, or both. In addition, T2DM is associated with a two to fourfold increased risk of coronary artery disease. Presently, the only treatment that eliminates obesity with high efficacy is bariatric surgery, but this treatment is costly and risky. There is therefore an obvious need for more efficacious pharmacological intervention with fewer side effects and convenient administration.

[0007] Although T2DM is most associated with hyperglycemia and insulin resistance, other diseases associated with T2DM include hepatic insulin resistance, impaired glucose tolerance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, obesity, dyslipidemia, hypertension, hyperinsulinemia and nonalcoholic fatty liver disease (NAFLD).

[0008] NAFLD is the hepatic manifestation of metabolic syndrome, and is a spectrum of hepatic conditions encompassing steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and ultimately hepatocellular carcinoma. NAFLD and NASH are considered the primary fatty liver diseases as they account for the greatest proportion of individuals with elevated hepatic lipids. The severity of NAFLD / NASH is based on the presence of lipids, inflammatory cell infiltrate, hepatocyte ballooning, and the degree of fibrosis. Although not all individuals with steatosis progress to NASH, a substantial portion does.

[0009] Sodium-dependent glucose transporter 1 (SGLT1) is primarily expressed in the small intestine and is responsible for absorption of glucose in the small intestine. U.S. Patent No. 7,635,684 and U.S. Patent No. 7,375,087, herein incorporated by reference in their entirety, describe compounds that show an inhibitory activity in human SGLT1 at the small intestine, for the prevention or treatment of a disease associated with hyperglycemia. U.S. Patent No. 9,200,025, herein incorporated by reference in its entirety, describes inhibitors selective inhibitors for SGLT1, and SGLT1 inhibitors having low systemic exposure, which act locally in the gut for use in treating or managing, inter alia, cardiovascular diseases and disorders, and metabolic diseases and disorders.

[0010] GLP-1 is a 30 amino acid long incretin hormone secreted by the L-cells in the intestine in response to ingestion of food. GLP-1 has been shown to stimulate insulin secretion in a physiological and glucose- dependent manner, decrease glucagon secretion, inhibit gastric emptying, decrease appetite, and stimulate proliferation of beta- cells. In non-clinical experiments GLP-1 promotes continued beta-cell competence by stimulating transcription of genes important for glucose-dependent insulin secretion and by promoting beta-cell neogenesis (Meier et aL Biodrugs. 2003; 17 (2): 93-102).

[0011] In a healthy individual, GLP-1 plays an important role regulating post-prandial blood glucose levels by stimulating glucose-dependent insulin secretion by the pancreas resulting in increased glucose absorption in the periphery. GLP-1 also suppresses glucagon secretion, leading to reduced hepatic glucose output. In addition, GLP-1 delays gastric emptying and slows small bowel motility delaying food absorption. In people with T2DM, the normal post- prandial rise in GLP-1 is absent or reduced (Vilsboll T, et al. Diabetes. 2001. 50; 609-613).

[0012] Holst (Physiol. Rev. 2007, 87, 1409) and Meier (Nat. Rev. Endocrinol. 2012, 8, 728) describe that GLP-1 receptor agonists, such as GLP-1, liraglutide and exendin-4, have 3 major pharmacological activities to improve glycemic control in patients with T2DM by reducing fasting and postprandial glucose (FPG and PPG): (i) increased glucose- dependent insulin secretion (improved first- and second- phase), (ii) glucagon suppressing activity under hyperglycemic conditions, (iii) delay of gastric emptying rate resulting in retarded absorption of meal-derived glucose. There remains a need for an easily administered prevention and / or treatment for cardiometabolic and associated diseases.

[0013] Glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory peptide) is one of two endogenous incretins and is a 42 amino acid peptide hormone released from intestinal K-cells following food intake. GIP and the other incretin, glucagon-like peptide-l (GLP-1), are gut enteroendocrine cell-derived hormones accounting for the incretin effect, which estimated to account for over 70% of the total insulin response to an oral glucose challenge. Due to the incretin effect, the GIP receptor has become an attractive drug target in the treatment of metabolic diseases such as obesity and diabetes, with GIP receptor agonists. GIP itself has a short plasma half-life due to dipeptidyl peptidase-4 (DPP-IV) mediated inactivation, and poor physical stability due to high tendency to form fibrils.

[0014] GLP-1 and GIP-1 dual agonist: An ideal antidiabetic medication should present proven efficacy in lowering elevated glucose levels, promote weight loss, have low risk of hypoglycemia and offer cardiovascular benefits. The idea of simultaneously activating both the GIP and GLP-1 receptors seems appealing for treatment of T2DM since it may significantly boost insulin secretion and improve insulin sensitivity. The rationale is based on the fact that improved glycemia restores sensitivity to GIP and peptide engineering enables the design of hybrid ligands exhibiting dual agonism, as proved in experimental studies.

[0015] Tirzepatide, the first dual GIP and GLP-1 receptor agonist, is in keeping with these conceptions. Its chemical formula is based on the GIP amino acid sequence and its half-life of approximately 5 days is compatible with a once-weekly subcutaneous administration. Chemically, tirzepatide is a synthetic linear peptide containing 39 amino acids based on the native GIP sequence. This basic structure is accompanied by a 20-carbon fatty diacid moiety that prolongs its half-life. The mechanism of action is very imbalanced,since while it has a comparable GIP receptor binding affinity to native G I P, the affinity to the native GLP-1 receptor is five times lower. So, it is a bi-receptor agonist, product of the above-mentioned peptide engineering, created as a single agent possessing activity at more than one pharmacological target. The drug was designed for once-weekly subcutaneous administration and early clinical investigation of tirzepatide demonstrated exceptional efficacy for glucose lowering and weight loss in T2DM. A phase 1 proof-of-concept clinical trial was conducted in 53 people with T2DM and translated the favorable preclinical data into clinical facts; the compound delivered clinically meaningful improvement in glycemic control and body weight warranting further clinical evaluation for the treatment of T2DM and obesity. About 30% of patients receiving a 15 mg dose reached normoglycemia with hemoglobin A1C (HbAlC) < 5.7% and 25% of patients lost > 15% of their body weight in a 26-week phase 2b trial.

[0016] Compared to the GLP-1 agonist dulaglutide, tirzepatide reduced HbAlC by 1.6%, 2.0%, and 2.4% in the 5, 10, and 15 mg dose groups, respectively, compared with 1.1% only for dulaglutide 1.5 mg.Moreover, 8% of patients receiving 10 mg and 30% dosed with 15 mg reached normoglycemia (HbAlC < 5.7%) compared with 2% of subjects treated with dulaglutide. Tirzepatide at 5 mg and 10 mg provided superior glycemic and bodyweight control versus dulaglutide, presenting similar tolerability. These beneficial effects were confirmed in the SURPASS-1 study, the first randomized controlled phase 3 trial of tirzepatide. Study participants had a mean duration of diabetes of 4.7 years, a baseline A1C of 7.9% and a baseline weight of 85.9 kg. Nearly 90% of all participants taking tirzepatide achieved the standard HbAlC goal of > 7% and more than half taking the highest of the three doses also achieved an HbAlC > 5.7%, a level observable in people without diabetes. No events of severe hypoglycemia (< 54 mg / dL) were observed. Regarding collateral effects, the most commonly reported were gastrointestinal-related (diarrhea, nausea, vomiting, constipation) mainly occurring during the dose escalation period. Thus, these results showed a strong glucose lowering effects towards a nearly-normal range with weight loss of a not previously reported extent in people with T2DM and without increased risk of clinically significant hypoglycemia.

[0017] The recently published SURPASS-2 has been conducted in order to compare the efficacy and safety of the three doses of tirzepatide with the GLP-1 agonist semaglutide at an injectable dose of 1 mg in patients with T2DM inadequately controlled with metformin monotherapy; it has been performed in an open-label, 40-week, phase 3 trial. All three tirzepatide doses achieved greater A1C and weight reductions compared to semaglutide. In addition, a composite endpoint comprised of participants who achieved an HbAlC level > 6.5% and weight loss of at least 10%, was assessed. Across the three doses of tirzepatide, all patients achieved this composite endpoint in a significantly greater percentage compared to patients on semaglutide, with a satisfactory safety profile.

[0018] In recent years, development of various antidiabetic agents has been progressing with the background of a rapid increase of patients with diabetes. For example, a-glucosidase inhibitors, which delay carbohydrate digestion and absorption at the small intestine, are used to improve postprandial hyperglycemia. It has also been reported that acarbose, one of a-glucosidase inhibitors, has an effect of preventing or delaying the incidence of diabetes by applying it to patients with impaired glucose tolerance. However, since a-glucosidase inhibitors do not affect elevated glucose levels by ingesting a monosaccharide of glucose, with recently changing compositions of sugars in meals, it has been desired to develop agents which exert a wider range of activities inhibiting carbohydrate absorption.

[0019] In the meantime, it has been known that SGLT1, sodium-dependent glucose transporter 1, exists in the small intestine which controls carbohydrate absorption. It has been also reported that insufficiency of glucose and galactose absorption arises in patients with dysfunction due to congenital abnormalities of human SGLT1 (References 6-8 of '684). In addition, it has been confirmed that SGLTlis involved in glucose and galactose absorption (References 9 and 10 of '684).

[0020] Furthermore, it is confirmed that mRNA and protein levels of SGLT1 increase, and absorption of glucose is accelerated in OLETF rats and rats with streptozotocin-induced diabetic symptoms (References 11 and 12 of '684). Generally, in patients with diabetes, carbohydrate digestion and absorption are increased. For example, it is confirmed that mRNA and protein of SGLT1 are highly increased in the human small intestine (Reference 13 of '684). Therefore, blocking a human SGLT1 activity inhibits absorption of carbohydrates such as glucose at the small intestine, subsequently preventing increase of blood sugar level. Especially, it is considered that delaying glucose absorption based on the above-mentioned mechanism is effective to reduce caloric intake. In addition, since increase of SGLT1 in the small intestine is thought to contribute to increased carbohydrate absorption, fast development of agents, which have a potent inhibitory activity in human SGLT1, has been desired for the prevention or treatment of obesity.

[0021] Recent clinical trial results that inhibition of SGLT1 can provide benefits that extend beyond those provided merely by the inhibition of glucose reabsorption. See, e.g., U.S. patent application publication no. US-2011-0218159. It is believed that inhibition of SGLT1 can increase glucagon-like peptide-1 (GLP-1) levels. See, e.g., Moriya, R., et aL, Am J Physiol Endocrinol Metab 297: E1358-E1365 (2009). Several well- known diabetes drugs, including sitagliptin, vildagliptin and saxagliptin, work by inhibiting dipeptidyl peptidase IV (DPP-4), which is the enzyme responsible for GLP-1 degradation.Summary of the Invention

[0022] This invention generally relates to methods and compositions for treating metabolic disease. In particular, the invention relates to combinations and methods of use of a) a sodium / glucose co-transporter 1 (hereinafter referred to as SGLT1) inhibitor, and b) a glucagon-like peptide agonist 1 (GLP-1), and / or c) a gastric inhibitory peptide-1 (G I P-1) analog, and / or d) a GLP-l-GI P-l dual agonist, in treating metabolic diseases.

[0023] In one aspect, the invention relates to a composition in oral dosage form comprising an SGLT1 inhibitor compound which inhibits SGLT1 in the intestinal lumen.

[0024] In another aspect, the invention relates to methods of treatment of metabolic diseases comprising the step of administering to a subject in thereof a composition in oral dosage form comprising an SGLT1 inhibitor compound which inhibits SGLT1 in the intestinal lumen in combination with a GLP-1 agonist, GIP-1 analog, or dual GLP-1-GIP1 agonist. In some methods of the invention, the metabolic diseases are associated with obesity, abnormal accumulation of liver lipids and / or associated with hyperglycemia.

[0025] In another aspect, the invention relates to the ability of GLP-1 and GIP-1 to reduce gastric emptying. This effect would reduce the concentration of an SGLT1 inhibitor required to have an effect on reducing glucose uptake.

[0026] In another aspect, the invention relates to the ability of SGLT1 inhibitors to reduce or block the increase of GLP-1 and GIP-1 after a meal, indicating addition of either entity or both would not cause adverse events.Brief Description of the Drawings

[0027] FIG. 1A and FIG. IB show the effects of mizagliflozin on weight in healthy rats over 2 years.

[0028] FIG. 2A and FIG. 2B show the effects of mizagliflozin (referred to as KGA-3235) on GLP-1 and GIP-1 levels in patients with post-bariatric hypoglycemia.Detailed Description of the Invention

[0029] The invention generally relates to methods and compositions fortreating metabolic disease.Particularly, the invention relates to combinations of a) an SGLT1 inhibitor, and b) a GLP-1 agonist, and / or c) a GIP-1 analog, and / or d) a GLP-l-GI P-l dual agonist, and methods of use such combinations in treating metabolic diseases.

[0030] A composition according to the invention is an oral dosage form for administration to asubject in need thereof, comprising: A) an SGLT1 inhibitor which inhibits SGLT1 in the intestinal lumen of the subject, and B) a GLP-1 agonist, and / or C) a GIP-1 analog, and / or D) a GLP-l-GI P-l dual agonist.

[0031] The SGLT1 inhibitor in oral dosage forms of the invention includes SGLT1 inhibitor compounds of Formula I or II, and pharmaceutically acceptable salts thereof, wherein the compound of formula I is:formula I; whereinRi represents H, or an optionally substituted C1-6alkyl group; one of Q and T represents a group:while the other represents a C1-6alkyl group, a halo( C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group;Rz represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-6alkyl group, a C1-6alkoxy group, a C1-6alkylthio group, a halo(C1-6alkyl) group, a halo(C1-6alkoxy) group, a C1-6alkoxy-substituted (C1-6alkoxy) group, a C3-7cycloalkyl-substituted (C2-6alkoxy) group or — A— RAin which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, — OCH2— or —CH2O— ; and RArepresents a C3-7cycloalkyl group, a C2-6heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkyl group, a C1-6alkoxy group, a C2-6alkenyloxy group, a halo( C1-6alkyl) group, a hydroxy(C1-6alkyl) group, a carboxy group, a C2-7alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and a C1-6alkyl group;X represents a single bond, an oxygen atom or a sulfur atom;Y represents a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group;Z represents — RB, — CORc, — SO2RC, — CON(RD)RE, — SO2NHRFor — C(=N RG)N(RH)R'; RCrepresents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i);R4, RB, RD, REand RFare the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R4and RBbind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl( C1-6alkyl) group, a hydroxy( C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino- substituted (C1-6alkyl) group; RG, RHand R1are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C2-7acyl group, a C2-7alkoxycarbonyl group, an aryl( C2-7alkoxycarbonyl) group, a nitro group, a C1-6alkylsulfonyl group, a sulfamide group, a carbamimidoyl group,or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of RGand RHbind to form an ethylene group, or both of RHand R1bind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino- substituted (C1-6alkyl) group;R3, R5 and R6 are the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6alkoxy group, a C1-6alkylthio group, an amino group, a mono or di(C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(C1-6alkyl)ureido group, a mono or di(C1-6alkyl)sulfamide group, a C2-7acylamino group, a C1-6alkylsulfonylamino group, a C1-6alkylsulfonyl group, a carboxy group, a C2-7alkoxycarbonyl group, — CON(RJ)RKin which RJand RKare the same or different, and each represents a hydrogen atom or a C1-6alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di (C1-6alkyl)amino group, a mono or di[hydroxy( C1-6alkyl)]amino group, an ureido group, a mono or di(C1-6alkyl)ureido group, a C2-7acylamino group, a C1-6alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(Ci.6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino- substituted ( C1-6alkyl) group, an aryl(C1-6alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkyl group and a C1-6alkoxy group on the ring, an aryl(C1-6alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkyl group and a C1-6alkoxy group on the ring, a C3-7cycloalkyl group, a C2-6heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a Ci g alkyl group, a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, and a C1.4 aromatic cyclic amino group which may have a C1-6alkyl group as a substituent; andwherein the compound of formula II is:formula II; whereinR7is hydrogen or optionally substituted C1-10-alkyl, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7A; each R7Ais independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7B; each R7Bis independently C1-4-alkyl, halo, or hydroxyl; n is 0, 1, or 2; each R8is independently F or ORgA, wherein each RgAis independently hydrogen, Ci-4-alkyl, or acyl; each R9is independently halo, hydroxyl, or optionally substituted C1-10-al kyl or Ci-w-alkoxy, which optional substitution is with one or more R9A; each R9Ais independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-6-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R9B; each R9Bis independently C1-4-alky I, amino, cyano, halo, or hydroxyl; p is 0, 1, or 2; each R10is independently R10A, — N( R10A)(R10B), — O R10A, — SRWA, — S(O)R10A, or — S(O)2R10A; R10Ais optionally substituted C4-20-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one or more R10C, and which is optionally attached to another R10Amoiety to provide a dimer or trimer; R10Bis hydrogen or R10A; each R10c is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of X1, X2and X3is independently optionally substituted C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl, which optional substitution is with one or more R10D, and each of L1and L2is independently optionally substituted C1-6-al kyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of R10E; each R10Dis independently R10Eor C1-6-al kyl optionally substituted with one or more of R10E; each R10Eis independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido,imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, or urea; and m is 1, 2 or 3; wherein the SGLT1 inhibitor compound has a primary site of pharmacological action in the intestinal lumen of the subject.

[0032] Preferably, SGLT1 inhibitor compounds of Formula I and Formula II are selected from the group consisting of:

[0033] Another example of an SGLT1 inhibitor compound is KGA-2891:

[0034] Preferably, the SGLT1 inhibitor compound is selected from LX2671 and mizagliflozin. Preferably, the SGLT1 inhibitor is mizagliflozin. Mizagliflozin, 3-(3-{4-[3-(|3-D-glucopyranosyloxy)-5- isopropyl-lH- pyrazol-4-ylmethyl- ]-3-methylphenoxy}propylamino)-2,2-dimethylpropionamide, can be converted to a pharmaceutically acceptable salt according to methods known in the art. Examples of such salts include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid,succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid and the like, salts with inorganic bases such as a sodium salt, a potassium salt and the like, and salts with organic bases such as N-methyl-D-glucamine, N,N'- dibenzyletylenediamine, 2-aminoethanol, tris (hydroxymethyl)aminomethane, arginine, lysine and the like.

[0035] Preferably the mizagliflozin pharmaceutical salt is selected from mizagliflozin monosebacate and mizagliflozin hemifumarate dehydrate. Mizagliflozin hemifumarate dihydrate, from U.S. Patent No.8,354,382, is shown below:

[0036] Mizagliflozin monosebacate, from U.S. Patent No. 8,399,418, is shown below:

[0037] Subjects suffering from metabolic diseases typically have an aberrant physiological response to ingested food after a meal. In particular, inadequate secretion of insulin has been associated with development of metabolic disorders such as type 2 diabetes. This blunted insulin response is caused by a loss of the "incretin effect," the gut-dependent secretion of incretins (e.g., hormones such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)). Thus, the modulation of signaling pathways in the gastrointestinal tract is emerging as a promising approach for treating metabolic disorders, such as type 2 diabetes, obesity, and related comorbidities.

[0038] The inventions described herein are directed to combination therapies for treating a metabolic13SUBSTITUTE SHEET (RULE 26)disorder (e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)) in an individual undergoing treatment with a gastrointestinal implant. In one aspect, the invention features a method for treating a metabolic disorder (e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)) in an individual undergoing treatment with a gastrointestinal implant, wherein the method includes administering one or more metabolic agents to the individual in an amount and for a duration to treat the metabolic disorder (e.g., type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)).

[0039] In some embodiments, the SGLT1 inhibitor is combined with an incretin modulator. In some embodiments, the incretin modulator may be a glucagon-like peptide-1 (GLP-1) receptor agonist. The GLP-1 receptor agonist may be liraglutide, exenatide, lixisenatide, dulaglutide, or albiglutide.The liraglutide can be administered at a dose from 0.006 mg to 3 mg. The exenatide can be administered at a dose from 0.05 pg to 10 pg. The lixisenatide can be administered at a dose from 0.1 pg to 20 pg. The dulaglutide can be administered at a dose from 0.0075 mg to 1.5 mg. The albiglutide can be administered at a dose from 0.3 mg to 50 mg. In any of the foregoing embodiments, the GLP-1 receptor agonist therapy is administered simultaneously or within 24 hours, but separately from the administration of the SGLT1 inhibitor.

[0040] In some embodiments, the one or more metabolic agents can be administered by an enteral route, while the SGLT1 inhibitor is administered orally. Alternatively, the one or more metabolic agents can be administered by a parenteral route, while the SGLT1 inhibitor is administered orally.

[0041] In some embodiments, the one or more metabolic agents can be administered one or more times per month, while the SGLT1 inhibitor is administered daily. In some embodiments, the one or more metabolic agents can be administered one or more times per week, while the SGLT1 inhibitor is administered daily. In some embodiments, the one or more metabolic agents can be administered one or more times per day and the SGLT1 inhibitor is also administered one or more times per day.

[0042] As used herein, an "effective amount" or "therapeutically effective amount" are used interchangeably to refer to an amount of an agent (e.g., metabolic agent or microbial modulating agent) that allows it to treat or prevent, partially or totally, type 2 diabetes, obesity, and related comorbidities (e.g., NASH or NAFLD)), as described herein. An effective amount of an agent may therefore induce a reduction in a blood sugar level and / or a loss of body weight. The effective amount will depend upon a number of factors, including biological activity, age, body weight, sex, general health, severity of the condition to be treated, as well as appropriate pharmacokinetic properties. A therapeutically effective amount of a composition of the present invention can be administered by an appropriate route in a single dose or multiple doses. Further, the dosages of the composition can be proportionally increased ordecreased as indicated by the exigencies of the therapeutic or prophylactic situation.

[0043] As used herein, the term "incretin" refers to a compound that directly or indirectly stimulates insulin release, inhibits glucagon release, and reduces gastric emptying. For example, incretins stimulate an increase in the amount of insulin released from the pancreas when plasma glucose levels are elevated relative to normal after food consumption, thereby leading to a decrease in blood glucose levels. Specific examples of incretins include gastric inhibitory peptide (i.e., glucose-dependent insulinotropic polypeptide, or GIP) and glucagon-like peptide-1 (GLP-1), along with their analogs and derivatives.

[0044] The term "GLP-1 receptor agonist" or "GLP-1 agonist" as used herein refers to a substance (e.g., peptides or small molecules) that activate a GLP-1 receptor, such as the human GLP-1 receptor. For example, peptides that activate the human GLP-1 receptor (e.g., native GLP-1 peptide hormones GLP-1(7- 37), GLP-l(7-36)amide, oxyntomodulin, exendin-3, exendin-4, glucagon, gastric inhibitory polypeptide (GIP), functional peptide analogues and derivatives thereof) as well as compounds that function similarly (e.g., exenatide, liraglutide, lixisenatide, al biglutide, dulaglutide, taspoglutide, and semaglutide). The term "dipeptidyl peptidase-4 inhibitor", as used herein, refers to a compound that exhibits inhibitory activity on the enzyme dipeptidyl peptidase IV (DPP-4), thus acting as an incretin enhancer, and includes compounds such as sitagliptin, vildagliptin, saxagliptin, linagliptin, gemiliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, omarigliptin, berberine, and lupeoL Other metabolic agents useful as part of the invention include metformin, sodium-glucose co-transporter 2 (SGLT-2) inhibitors (e.g., empagliflozi, canagliflozin, or dapagliflozin), sulfonylureas (e.g., glimepiride, glyburide, glipizide, glyburide, tolazamide, or tolbutamide), thiazolidinedione, and insulin.

[0045] GIP (gastric inhibitory polypeptide or glucose-dependent insulinotropic polypeptide) is a polypeptide consisting of 42 amino acids. GIP(l-42) has physiological activity (active GIP). In preferred embodiments of the invention, the SGLT1 inhibitor is mizagliflozin sebacate, the GIP receptor antagonist is GIP [3-30] NHj.and, optionally, the method is combined with the administrations of the GLP-1 compound, semaglutide.

[0046] In some methods of the invention, the metabolic disease is a disease associated with abnormal accumulation of liver lipids, and / or a disease associated with hyperglycemia. The term "disease associated with abnormal accumulation of liver lipids" means a disease wherein the lipids including triglyceride accumulate abnormally in liver, a disease wherein the ratio of the amount of lipids to healthy cells of the liver and the liver weight increase abnormally, and the size of the liver increases abnormally. A progressive type wherein the accumulative amount of lipids further increases is also included. Moreover, a disease that shifts to other diseases because of the accumulation of lipids, and a disease with inflammation are also included. Concretely besides common fatty liver, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hypernutritive fatty liver, alcoholic fatty liver disease, toxic fatty livers diabetic fatty liver, acute fatty liver of pregnancy and the like can be illustrated.

[0047] The term "disease associated with hyperglycemia" includes diseases such as diabetes, impaired glucose tolerance, impaired fasting glycemia, diabetic complications, obesity, hyperinsulinemia, hyperinsulinemic hypoglycemia, reactive hypoglycemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia and gout.

[0048] In some methods of the invention, the metabolic disease is diabetes mellitus, or metabolic syndrome, or dumping syndrome, or post bariatric hypoglycemia and / or non-alcoholic steatohepatitis and / or non-alcoholic fatty liver disease. Additional metabolic diseases in methods according to the invention include insulin resistance, primary biliary cholangitis, primary sclerosing cholangitis, gallbladder disease, dyslipidemia, high cholesterol, high levels of triglycerides, high blood pressure, hypertension, coronary artery disease, heart disease, stroke, thrombotic stroke, deep vein thrombosis (DVT), metabolic disorders, hypoalphalipoproteinemia, familial combined hyperlipidemia, Syndrome X, or insulin-resistant Syndrome X.Examples

[0049] Example 1: Combination treatment with mizagliflozin and remogliflozin.

[0050] Combination treatment with KGT-1681 and KGA-3235 in normal rats. KGT-1681 was suspended in 0.1% methylcellulose (MC) and KGA-3235 was dissolved in distilled water (DW). Rats (9 weeks of age) were divided into the following four groups and treated as indicated: vehicle, 0.1% MC + DW; KGT, KGT-1681 (3 mg / kg, 5 mL / kg) plus DW; KGA, 0.1% MC plus KGA-3235 (0.03 mg / kg, 5 mL / kg); and Combo, KGT-1681 plus KGA-3235 (3 and 0.03 mg / kg, respectively). After 16 h fasting, the drug and glucose solution (400 g / L, 5 ml / kg) were orally administered to rats. Blood was obtained in heparinized and aprotinin-treated tubes from a tail vein at each sampling point. Plasma glucose concentration was determined using a Glucose Cl I - test Wako (Wako Pure Chemicals, Osaka, Japan). Plasma insulin was determined using an enzyme-linked immunosorbent assay kit (Morinaga Institute of Biological Science, Inc., Yokohama, Japan). The area under the curve (AUC)O-lhr for plasma glucose and insulin were calculated from the plasma glucose and insulin concentrations during the OGTT (Table 1).Table 1

[0051] KGT-1681 and KGA-3235 inhibited the increase in plasma glucose after glucose loading.Furthermore, the plasma glucose level of combo was suppressed more potently in comparison with those obtained by either drug alone (FIG 1A). The AUCO-lhr for plasma glucose were shown in FIG. IB. Two-way ANOVA indicated a significant main effect on the KGT-1681 and KGA-3235 in AUCO-lhr for plasma glucose (F(l, 20)=15.66, P=0.0008 and F(l, 20)=16.23. P=0.0007, respectively). The plasma insulin was decreased by KGT-1681 and KGA-3235 (FIG. 2A), corresponding to the reduction in the plasma glucose level. The AUCO-lhr for plasma insulin were shown in FIG. 2B.

Claims

Claims:

1. A method of treating a metabolic disorder in a subject in need thereof, the method comprising administering a combination of a sodium / glucose co- transporter 1 (SGLT1) inhibitor compound of FormulaI or II, or an effective amount of a pharmaceutically acceptable salt of an SGLT1 inhibitor compound ofFormula I or II, to the subject, and a glucagon-like peptide agonist 1 (GLP 1), a gastric inhibitory peptide-1(G I P-1) analog, and / or d) a GLP-l-GIP-l dual agonist, wherein the compound of Formula I is:Formula I; whereinRi represents H, or an optionally substituted C1-6alkyl group; one of Q and T represents a group:while the other represents a Ci.6alkyl group, a halo(C1-6alkyl) group, a C1-6alkoxy-substituted (C1-6alkyl) group or a C3-7cycloalkyl group;R2 represents a hydrogen atom, a halogen atom, a hydroxy group, a C1-6alkyl group, a C1-6alkoxy group, a C1-6alkylthio group, a halo(C1-6alkyl) group, a halo(C1-6alkoxy) group, a C1-6alkoxy-substituted (C1-6alkoxy) group, a C3-7cycloalkyl-substituted (C2-6alkoxy) group or — A— RAin which A represents a single bond, an oxygen atom, a methylene group, an ethylene group, — OCH2— or — CH2O— ; and RArepresents a C3-7cycloalkyl group, a C2-6heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkyl group, a C1-6alkoxy group, a C2-6alkenyloxy group, a halo(C1-6alkyl) group, a hydroxy(C1-6alkyl) group, a carboxy group, a C2-7alkoxycarbonyl group, a cyano group and a nitro group, or a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom and a CiSalkyl group;X represents a single bond, an oxygen atom or a sulfur atom;Y represents a C1-6alkylene group which may be substituted by a hydroxy group or a C2-6alkenylene group;Z represents — RB, — CORc, — SO2RC, — CON(RD)RE, — SO2NHRFor — C(=N RG)N(RH)R'; RCrepresents an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i);R4, RB, RD, REand RFare the same or different, and each represents a hydrogen atom, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of R4and RBbind together with theneighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, or both of RDand REbind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group; RG, RHand R1are the same or different, and each represents a hydrogen atom, a cyano group, a carbamoyl group, a C2-7acyl group, a C2-7alkoxycarbonyl group, an aryl(C2-7alkoxycarbonyl) group, a nitro group, a C1-6alkylsulfonyl group, a sulfamide group, a carbamimidoyl group, or a C1-6alkyl group which may have the same or different 1 to 5 groups selected from the following substituent group (i), or both of RGand RHbind to form an ethylene group, or both of RHand R1bind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino- substituted (Ci.s alkyl) group;Rs, Rs and Rsare the same or different, and each represents a hydrogen atom, a halogen atom, a C1-6alkyl group or a C1-6alkoxy group; and substituent group (i) consists of a hydroxy group, a C1-6alkoxy group, a C1-6alkylthio group, an amino group, a mono or di(Cisalkyl)amino group, a mono or di[hydroxy(Ci6alkyl)]amino group, an ureido group, a sulfamide group, a mono or di(Ci.6alkyl)ureido group, a mono or di(Ci_ealkyl)sulfamide group, a C2-7acylamino group, a C1-6alkylsulfonylamino group, a C1-6alkylsulfonyl group, a carboxy group, a C2-7alkoxycarbonyl group, — CON(RJ)RKin which RJand RKare the same or different, and each represents a hydrogen atom or a C1-6alkyl group which may have the same or different 1 to 3 substituents selected from the group consisting of a hydroxy group, an amino group, a mono or di (C1-6alkyl)amino group, a mono or di[hydroxy(C1-6alkyl)]amino group, an ureido group, a mono or di(C1-6al kyl )u reido group, a C2-7acylamino group, a C1-6alkylsulfonylamino group and a carbamoyl group, or both of RJ and RK bind together with the neighboring nitrogen atom to form a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(Ci_salkyl) group, a hydroxy(Ci_salkyl) group and a C1-6alkylsulfonylamino- substituted (C1-6alkyl) group, an aryl(C1-6alkoxy) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkyl group and a C1-6alkoxy group on the ring, an aryl(C1-6alkylthio) group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, anamino group, a C1-6alkyl group and a C1-6alkoxy group on the ring, a C3-7cycloal kyl group, a C2-6heterocycloalkyl group, an aryl group which may have the same or different 1 to 3 substituents selected from the group consisting of a halogen atom, a hydroxy group, an amino group, a C1-6alkylsulfonylamino group, a C1-6alkyl group and a C1-6alkoxy group, a heteroaryl group which may have a substituent selected from the group consisting of a halogen atom, an amino group and a C1-6alkyl group, a C2-6cyclic amino group which may have a substituent selected from the group consisting of a hydroxy group, a carbamoyl group, a C1-6alkyl group, an oxo group, a carbamoyl(C1-6alkyl) group, a hydroxy(C1-6alkyl) group and a C1-6alkylsulfonylamino-substituted (C1-6alkyl) group, and a C1-4 aromatic cyclic amino group which may have a C1-6alkyl group as a substituent; and wherein the compound of Formula II is:Formula II; whereinR7is hydrogen or optionally substituted C1-10-al kyl, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7A; each R7Ais independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more R7B; each R7B is independently C1-4-alky I, halo, or hydroxyl; n is 0, 1, or 2; each R8is independently F or OR8A, wherein each R8Ais independently hydrogen, C1-4-alkyl, or acyl; each R9 is independently halo, hydroxyl, or optionally substituted C1-10-alkyl or C1-10-alkoxy, which optional substitution is with one or more RgA; each RgAis independently amino, ester, amide, thiol, carboxylic acid, cyano, halo, hydroxyl, or optionally substituted C1-4-alkoxy, C1-5-cycloalkyl, or 5-membered heterocycle, which optional substitution is with one or more RgB; each RgBis independently C1-4-alky I, amino, cyano, halo, or hydroxyl; p is 0, 1, or 2; each R10is independently R10A, — N(R10A)(R10B), — OR10A, — SR10A, — S(0)R10A, or — S(0)2R10A; R10Ais optionally substituted C4-20-alkyl or 4-20-membered heteroalkyl, which optional substitution is with one ormore R10c, and which is optionally attached to another R10A moiety to provide a dimer or trimer; R10B is hydrogen or R10A; each R10c is independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino, isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione, thiourea, urea, or X1, X1-L1-X2, or X1-L1-X2-L2-X3, wherein each of X1, X2and X3is independently optionally substituted C1-4-alkyl, C1-6-cycloalkyl, 5- or 6-membered heterocycle, or aryl, which optional substitution is with one or more R10D, and each of Li and L2is independently optionally substituted C1-6-al kyl or 1-10-membered heteroalkyl, which optional substitution is with one or more of each R10Dis independently RWE or C1-6-al kyl optionally substituted with one or more of R10E; each R10Eis independently amino, amido, azo, carbonyl, carboxyl, cyano, formyl, guanidino, halo, hydroxyl, imido, imino isothiocyanate, nitrile, nitro, nitroso, nitroxy, oxo, sulfanyl, sulfinyl, sulfonyl, thial, thiocyanate, thione or urea; and m is 1, 2 or 3; wherein the SGLT1 inhibitor compound has a primary site of pharmacological action in the intestinal lumen of the subject.2 The method of treating a metabolic disorder of claim 1, the dosage amount of the SGLT1 inhibitor is from 0 25 mg to 20 mg.3 The method of treating a metabolic disorder of any one of claims 1-2, wherein the SGLT1 inhibitor compound is selected from the group consisting of:£25. The method of treating a metabolic disorder of any one of claims 1-3, wherein the SGLT1 inhibitor compound is selected from mizagliflozin or LX2761.

6. The method of treating a metabolic disorder of claim 4, wherein the SGLT1 inhibitor compound is mizagliflozin.

7. The method of treating a metabolic disorder of claim 4, wherein the SGLT1 inhibitor compound is LX2761.

8. The method of treating a metabolic disorder of claim 1, wherein the pharmaceutical salt of the SGLT1 inhibitor compound is selected from monosebecate and hemifumarate dehydrate of thecompound.

9. The method of claim 1, wherein the metabolic disease is a disease associated with abnormal accumulation of liver lipids, and / or a disease associated with hyperglycemia.

10. The method of claim 1, wherein the metabolic disease is diabetes mellitus, metabolic syndrome, dumping syndrome, post bariatric hypoglycemia, non-alcoholic steatohepatitis, and / or non-alcoholic fatty liver disease.

11. The method of claim 9, wherein the metabolic disease is selected from the group consisting of diabetes, elevated fasting blood glucose, insulin resistance, impaired glucose tolerance, primary biliary cholangitis, primary sclerosing cholangitis, gallbladder disease, dyslipidemia, gout, high cholesterol, high levels of triglycerides, high blood pressure, hypertension, coronary artery disease, heart disease, stroke, thrombotic stroke, deep vein thrombosis (DVT), metabolic disorders, hypoalphalipoproteinemia, familial combined hyperlipidemia, Syndrome X, or insulin-resistant Syndrome X.

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