Low dose triple combination formulations

Abstract

Provided herein are pharmaceutical compositions useful for the treatment of diabetes and related conditions, diseases, and disorders. The present invention relates to compositions comprising a) a dipeptidyl peptidase IV (DPP IV) inhibitor, such as sitagliptin, b) a subtype 2 sodium-glucose transport (SGLT2) inhibitor, such as dapagliflozin or empagliflozin, and c) a biguanide, such as metformin. The DPP IV inhibitor, SGLT2 inhibitor, and biguanide are in a dose of about 20-75% of a minimum diabetes therapeutic dose.

Description

[0001] This application is a divisional application of the Chinese patent application with application date of March 25, 2020, application number 202080038969.1, and invention name “Low-dose triple combination preparation” (the application date of the corresponding PCT application is March 25, 2020, and application number PCT / IB2020 / 000214).

[0002] Cross-references

[0003] This application claims the benefit of U.S. Provisional Patent Application No. 16 / 364,063, filed on March 25, 2019, which is incorporated by reference in its entirety. Background Art

[0004] Diabetes mellitus (DM), commonly referred to as diabetes, is a group of metabolic disorders characterized by chronically high blood sugar levels. Symptoms of high blood sugar levels include frequent urination, increased thirst, and increased hunger. If left untreated, diabetes can lead to many complications. Summary of the invention

[0005] In certain embodiments, provided herein is a pharmaceutical composition comprising: a) a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a biguanide; c) a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a), (b) and (c) are each about 20% to about 75% of the minimum diabetes therapeutic dose (LDTD). In certain embodiments, provided herein is a pharmaceutical composition consisting essentially of the following ingredients: a) a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a biguanide; c) a SGLT2 inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a), (b) and (c) are each about 20% to about 75% of the minimum diabetes therapeutic dose (LDTD). In certain embodiments, provided herein are pharmaceutical compositions comprising: a) a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a biguanide; and c) a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; wherein (a) and (b) are each about 65%-75% of the minimum diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the minimum diabetes therapeutic dose (LDTD). In certain embodiments, provided herein are pharmaceutical compositions consisting essentially of the following ingredients: a) a DPP IV inhibitor; b) a biguanide; c) an SGLT2 inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a) and (b) are each about 65%-75% of the minimum diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the minimum diabetes therapeutic dose (LDTD). In some embodiments, the DPP IV inhibitor is a gliptin. In some embodiments, the DPP IV inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, anagliptin, tenagliptin, alogliptin, trelagliptin, aologliptin, evogliptin, gogliptin, dulagliptin or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof. In some embodiments, the DPP IV inhibitor is sitagliptin phosphate. In some embodiments, the biguanide is metformin or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the biguanide is metformin hydrochloride. In some embodiments, the metformin is formulated for immediate release. In some embodiments, the metformin is formulated for slow release. In some embodiments, the SGLT2 inhibitor is gliflozin.In some embodiments, the SGLT2 inhibitor is dapagliflozin, empagliflozin, canagliflozin, ipragliflozin (ASP-1941), tofogliflozin, remogliflozin, sergliflozin, ertugliflozin, sotagliflozin, or a pharmaceutically acceptable salt, hydrate or combination thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, hydrate or combination thereof. In some embodiments, the SGLT2 inhibitor is empagliflozin or a pharmaceutically acceptable salt, hydrate or combination thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin hydrate. In some embodiments, the SGLT2 inhibitor is dapagliflozin propylene glycol monohydrate. In some embodiments, the SGLT2 inhibitor is a hydrate of dapagliflozin complexed with (2S)-1,2-propylene glycol in a ratio of about 1:1:1. In some embodiments, the dose of each of (a), (b) and (c) is about 40% to about 75% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 60% to about 75% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 65% to about 75% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 70% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 40% to about 70% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 40% to about 60% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 45% to about 55% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 50% of the minimum diabetes treatment dose (LDTD). In some embodiments, the DPP IV inhibitor is about 70% of the minimum diabetes treatment dose (LDTD) of the DPP IV inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg. In some embodiments, the DPP IV inhibitor is about 50% of the minimum diabetes treatment dose (LDTD) of the DPP IV inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 12.5 mg.In some embodiments, the biguanide is about 70% of the minimum diabetes treatment dose (LDTD) of the biguanide. In some embodiments, the biguanide is metformin hydrochloride, and the dose of metformin hydrochloride is about 350mg. In some embodiments, the biguanide is about 50% of the minimum diabetes treatment dose (LDTD) of the biguanide. In some embodiments, the biguanide is metformin hydrochloride, and the dose of metformin hydrochloride is about 250mg. In some embodiments, the SGLT2 inhibitor is about 50% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5mg. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of dapagliflozin is about 1.0 mg to about 3.75 mg. In some embodiments, the dose of sitagliptin is about 10 mg to about 16.25 mg, the dose of metformin is about 200 mg to about 325 mg, and the dose of dapagliflozin is about 2.0 mg to about 3.25 mg. In some embodiments, the dose of sitagliptin is about 10 mg to about 15 mg, the dose of metformin is about 200 mg to about 300 mg, and the dose of dapagliflozin is about 2 mg to about 3 mg. In some embodiments, the dose of sitagliptin is about 11.25 mg to about 13.75 mg, the dose of metformin is about 225 mg to about 275 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the dose of sitagliptin is about 12.5 mg, the dose of metformin is about 250 mg, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the dose of each of (a), (b) and (c) is about 30% to about 40% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dose of each of (a), (b) and (c) is about 30% to about 35% of the minimum diabetes treatment dose (LDTD). In some embodiments, the SGLT2 inhibitor is about 33% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.65 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.3 mg. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.In some embodiments, the dosage of sitagliptin is about 7.5mg to about 10mg, and the dosage of metformin is about 150mg to about 200mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dosage of dapagliflozin is about 1.5mg to about 2.0mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 3.0mg to about 4.0mg. In some embodiments, the dosage of sitagliptin is about 8.25mg, and the dosage of metformin is about 165mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dosage of dapagliflozin is about 1.65mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 3.3mg. In some embodiments, the dosage of each of (a), (b) and (c) is about 20% to about 30% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of each of (a), (b) and (c) is about 22% to about 28% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of the SGLT2 inhibitor is about 25% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dosage of dapagliflozin is about 1.25mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 2.5mg. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin. In some embodiments, the dosage of sitagliptin is about 5mg to about 7.5mg, and the dosage of metformin is about 100mg to about 150mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dosage of dapagliflozin is about 1.0mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 2.0 mg. In some embodiments, the dose of sitagliptin is about 6.25 mg, and the dose of metformin is about 150 mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.5 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.0 mg. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg. In some embodiments, the biguanide is metformin, and the dose of metformin is about 325 mg to about 375 mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 4.5mg to about 7.5mg. In some embodiments, the DPP IV inhibitor is about 70% of the minimum diabetes treatment dose (LDTD) of the DPP IV inhibitor. In some embodiments, the biguanide is about 70% of the minimum diabetes treatment dose (LDTD) of the biguanide. In some embodiments, the SGLT2 inhibitor is about 50% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin. In some embodiments, the dosage of sitagliptin is about 17.5mg, the dosage of metformin is about 350mg, and the dosage of dapagliflozin is about 2.5mg. In some embodiments, the dosage of sitagliptin is about 17.5mg, the dosage of metformin is about 350mg, and the dosage of empagliflozin is about 5.0mg. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dosage of sitagliptin is about 17.5mg. In some embodiments, the biguanide is metformin, and the dosage of metformin is about 350mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dosage of dapagliflozin is about 2.5mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 5.0mg. In some embodiments, (a), (b) and (c) are provided in one preparation. In some embodiments, (a), (b) and (c) are each provided in a separate preparation. In some embodiments, two of (a), (b) and (c) are provided in one preparation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet or capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0006] In certain embodiments, provided herein is a method for treating diabetes in a subject in need, comprising administering any pharmaceutical composition disclosed herein. In some embodiments, the treatment results in improvement of metabolic disorders, slowing down the progress of metabolic disorders or delaying metabolic disorders, such as diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, impaired renal function, gestational diabetes, new-onset diabetes after transplantation (NODAT) and its related complications, and post-transplantation metabolic syndrome (PTMS) and its related complications. In some embodiments, the treatment results in improvement of metabolic disorders, slowing down of progress or delaying the effect obtained by using any of the complete minimum diabetes treatment dose (LDTD) in (a), (b) and (c) in the pharmaceutical composition. In some embodiments, compared with the treatment of any of the minimum diabetes treatment dose (LDTD) in (a), (b) and (c) in the pharmaceutical composition, the treatment results in higher long-term tolerance and reduced side effect risks. In some embodiments, the treatment is the initial or first-line treatment of diabetes. In some embodiments, the subject does not receive any diabetes therapy before treatment. In some embodiments, the subject is receiving diabetes therapy prior to treatment, and treatment with the formulations disclosed herein is a second-line or maintenance therapy.

[0007] In certain embodiments, provided herein is a pharmaceutical composition comprising: a) a low dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a low dose, therapeutically effective amount of a biguanide; c) a low dose, therapeutically effective amount of a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a), (b) and (c) are each about 20-75% of the lowest diabetes treatment dose (LDTD). In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin. In some embodiments, the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of dapagliflozin is about 1.0 mg to about 2.75 mg. In some embodiments, the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of empagliflozin is about 2.0 mg to about 7.5 mg. In some embodiments, (a) and (b) are each about 65%-75% of the minimum diabetes treatment dose (LDTD), and (c) is about 45%-55% of the minimum diabetes treatment dose (LDTD). In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg. In some embodiments, the biguanide is metformin, and the dose of metformin is about 325 mg to about 375 mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 4.5mg to about 7.5mg. In some embodiments, the DPP IV inhibitor is about 70% of the minimum diabetes treatment dose (LDTD) of the DPP IV inhibitor. In some embodiments, the biguanide is about 70% of the minimum diabetes treatment dose (LDTD) of the biguanide. In some embodiments, the SGLT2 inhibitor is about 50% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin. In some embodiments, the dosage of sitagliptin is about 17.5mg, the dosage of metformin is about 350mg, and the dosage of dapagliflozin is about 2.5mg. In some embodiments, the dosage of sitagliptin is about 17.5mg, the dosage of metformin is about 350mg, and the dosage of empagliflozin is about 5.0mg.In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg. In some embodiments, the biguanide is metformin, and the dose of metformin is about 350 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 5.0 mg. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the metformin is formulated for immediate release. In some embodiments, the metformin is formulated for slow release. In some embodiments, the pharmaceutical composition does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, a), b) and c) combination produces a synergistic effect. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction than the maximum reduction in postprandial blood glucose obtained from about 850 mg of metformin. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction than the maximum reduction in postprandial blood glucose obtained from about 1700 mg of metformin.

[0008] In certain embodiments, provided herein is a pharmaceutical composition comprising: a) a low dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a low dose, therapeutically effective amount of a biguanide; c) a low dose, therapeutically effective amount of a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a) and (b) are each about 65%-75% of the minimum diabetes treatment dose (LDTD), and (c) is about 45%-55% of the minimum diabetes treatment dose (LDTD). In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg. In some embodiments, the biguanide is metformin, and the dose of metformin is about 325 mg to about 375 mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 4.5mg to about 7.5mg. In some embodiments, the DPP IV inhibitor is about 70% of the minimum diabetes treatment dose (LDTD) of the DPP IV inhibitor. In some embodiments, the biguanide is about 70% of the minimum diabetes treatment dose (LDTD) of the biguanide. In some embodiments, the SGLT2 inhibitor is about 50% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin. In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is empagliflozin. In some embodiments, the dosage of sitagliptin is about 17.5mg, the dosage of metformin is about 350mg, and the dosage of dapagliflozin is about 2.5mg. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg. In some embodiments, the biguanide is metformin, and the dose of metformin is about 350 mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 5.0 mg. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the metformin is formulated for immediate release. In some embodiments, the metformin is formulated for slow release. In some embodiments, the pharmaceutical composition does not contain any further additional antihyperglycemic or antidiabetic drugs.In some embodiments, the combination of a), b) and c) produces a synergistic effect. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg of sitagliptin. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 850 mg of metformin. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 1700 mg of metformin.

[0009] In certain embodiments, provided herein is a pharmaceutical composition comprising a combination of the following ingredients: a) about 17.5 mg of sitagliptin; b) about 350 mg of metformin; c) about 2.5 mg of dapagliflozin; and d) at least one pharmaceutically acceptable excipient. In some embodiments, the combination is synergistic. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the metformin is formulated for immediate release. In some embodiments, the metformin is formulated for slow release. In some embodiments, the pharmaceutical composition does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, a), b) and c) combination produces a synergistic effect. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg of sitagliptin, about 850 mg of metformin, or about 1700 mg of metformin.

[0010] In certain embodiments, provided herein is a pharmaceutical composition comprising a combination of the following ingredients: a) about 17.5 mg of sitagliptin; b) about 350 mg of metformin; c) about 5.0 mg of empagliflozin; and d) at least one pharmaceutically acceptable excipient. In some embodiments, the combination is synergistic. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet, or capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration. In some embodiments, the metformin is formulated for immediate release. In some embodiments, the metformin is formulated for slow release. In some embodiments, the pharmaceutical composition does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, a), b) and c) combination produces a synergistic effect. In some embodiments, the pharmaceutical composition produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg of sitagliptin, about 850 mg of metformin, or about 1700 mg of metformin.

[0011] In certain embodiments, provided herein is a synergistic, ultra-low-dose antidiabetic drug combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg of sitagliptin or its salt or hydrate; b) about 325 mg to about 375 mg of metformin or its salt or hydrate; c) about 2.25 mg to about 2.75 mg of dapagliflozin or its salt or hydrate; and d) at least one excipient. In some embodiments, the combination of a), b) and c) produces a synergistic effect. In some embodiments, the combination does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, the combination produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from 100 mg sitagliptin, 850 mg metformin or 1700 mg metformin.

[0012] In certain embodiments, provided herein is a synergistic, ultra-low-dose antidiabetic drug combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg of sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 4.5 mg to about 7.5 mg of empagliflozin or a salt or hydrate thereof; and d) at least one excipient. In some embodiments, the combination of a), b) and c) produces a synergistic effect. In some embodiments, the combination does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, the combination produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

[0013] In certain embodiments, provided herein is a method for treating diabetes in a subject in need thereof, comprising administering a pharmaceutical composition as described herein. In some embodiments, after treatment with one or both of a DPP IV inhibitor, biguanide or SGLT2 inhibitor at LDTD or higher doses, the subject has a sustained increase in blood sugar. In some embodiments, the administration of the pharmaceutical composition is the initial or first-line treatment of diabetes.

[0014] In certain embodiments, provided herein is a method for improving a metabolic disorder, slowing the progression of a metabolic disorder, or delaying a metabolic disorder, wherein the metabolic disorder comprises diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, impaired renal function, gestational diabetes, new onset diabetes mellitus after transplantation (NODAT) and its related complications, or post-transplant metabolic syndrome (PTMS) and its related complications, the method comprising administering a pharmaceutical composition as described herein to a subject in need thereof.

[0015] In certain embodiments, provided herein is a method for treating diabetes in a subject in need thereof, comprising administering a synergistic, ultra-low dose antidiabetic drug combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg of sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 2.25 mg to about 2.75 mg of dapagliflozin or a salt or hydrate thereof; and d) at least one excipient. In some embodiments, the combination of a), b) and c) produces a synergistic effect. In some embodiments, the combination does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, the combination produces a greater reduction in postprandial blood glucose 2 hours after the meal compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg of sitagliptin, about 850 mg of metformin, or about 1700 mg of metformin.

[0016] In certain embodiments, provided herein is a method for treating diabetes in a subject in need thereof, comprising administering a synergistic, ultra-low dose antidiabetic drug combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg of sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 4.5 mg to about 7.5 mg of empagliflozin or a salt or hydrate thereof; and d) at least one excipient. In some embodiments, the combination of a), b) and c) produces a synergistic effect. In some embodiments, the combination does not contain any further additional antihyperglycemic or antidiabetic drugs. In some embodiments, the combination produces a greater 2-hour postprandial blood glucose reduction compared to the maximum reduction in postprandial blood glucose obtained from about 100 mg of sitagliptin, about 850 mg of metformin, or about 1700 mg of metformin. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 Post-dose non-fasting whole blood glucose (mg / dL) is shown by treatment group.

[0018] Figure 2 Post-dose hemoglobin A1c (%) is shown by treatment group. Error bars represent standard error of the mean (SEM).

[0019] Figure 3 Serum creatinine (mg / dL) after dosing is shown by treatment group. Error bars represent standard error of the mean (SEM).

[0020] Figure 4 Post-dose plasma insulin (pg / mL) is shown by treatment group.

[0021] Figure 5 The study design for the Phase I clinical trial of Composition A is shown.

[0022] Figure 6 Illustrated is the time course of plasma glucose concentrations (mean and standard error) before and after administration of a single dose of placebo and Composition A in type 2 diabetic patients (n=30) in a crossover study.

[0023] Figure 7 Illustrated is the time course of serum insulin concentrations (mean and standard error) before and after administration of a single dose of placebo and Composition A in type 2 diabetic patients (n=30) in a crossover study.

[0024] Figure 8 Graph illustrating the effect of a single dose of sitagliptin 100 mg on plasma glucose (PG). DETAILED DESCRIPTION

[0025] In certain embodiments, disclosed herein is a pharmaceutical composition for treating diabetes, comprising a low dose, a therapeutically effective amount of a DPP IV inhibitor (e.g., sitagliptin), a low dose, a therapeutically effective amount of a biguanide (e.g., metformin), and a low dose, a therapeutically effective amount of an SGLT2 inhibitor (e.g., dapagliflozin). In some embodiments, the dose of each component is lower than the lowest dose approved for the treatment of diabetes. In some embodiments, this low dose does not produce or substantially does not produce a therapeutic effect as a monotherapy.

[0026] The present disclosure recognizes the technical effect of the low-dose conjoint therapy set forth herein.Surprisingly, the therapeutic effect produced by the combination of low-dose DPP IV inhibitor (e.g., sitagliptin), low-dose biguanide (e.g., metformin) and low-dose SGLT2 inhibitor (e.g., dapagliflozin) is greater than the effect of any individual component used in equal doses as a monotherapy.In some cases, when used as a monotherapy, an individual component does not produce or substantially does not produce a therapeutic effect at equal doses.

[0027] The use of various components of low dose produces beneficial effects, including but not limited to avoiding or alleviating negative side effects while maintaining or improving benefits. Known side effects of DPP IV inhibitors (e.g., sitagliptin), biguanides (e.g., metformin) and SGLT2 inhibitors (e.g., dapagliflozin) include stomach discomfort, nausea and hypoglycemia. Long-term side effects also include reduced absorption of vitamin B12 and lactic acidosis. Reducing these side effects further allows early introduction of conjoint therapy to improve therapeutic effect. On the one hand, described herein is a low-dose combined composition for the treatment of diabetes, the treatment including the initial or first-line treatment of diabetes.

[0028] Certain terms

[0029] As used in this specification and the appended claims, the following terms have the meanings set forth below unless indicated otherwise.

[0030] As used herein and in the appended claims, the singular forms "a", "an" and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "an agent" includes a plurality of such agents, and reference to "the composition" includes reference to one or more compositions (or multiple compositions) and equivalents thereof known to those skilled in the art, and so on. When ranges are used herein for physical properties such as molecular weight or chemical properties such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments herein are intended to be included. The term "about" used when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within the experimental variability (or within the statistical experimental error range), so in some embodiments, the number or numerical range varies between 1% and 10% of the number or numerical range. The term "comprising" (and related terms such as "including" or "having" or "containing") is not intended to exclude the following situations: in other certain embodiments, for example, any embodiment of the composition of matter, composition, method or process, etc. described herein may be "consisting of" or "essentially consisting of" the features.

[0031] As used herein, "pharmaceutically acceptable salts" include acid addition salts and base addition salts. In some embodiments, any pharmaceutically acceptable salt of the compounds described herein is a form approved for use by the U.S. Food and Drug Administration. Preferred pharmaceutically acceptable salts of the compounds described herein are pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0032] "Pharmaceutically acceptable acid addition salts" refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid, hydrofluoric acid, phosphorous acid, etc. Also included are salts formed with organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, and the like, and include, for example, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like. Thus, exemplary salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, trifluoroacetates, propionates, octanoates, isobutyrates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, mandelates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates, phenylacetates, citrates, lactates, malates, tartrates, methanesulfonates, etc. Also contemplated are salts of amino acids such as arginates, gluconates, and galacturonates (see, e.g., Berge SM et al., "Pharmaceutical Salts," Journal of Pharmaceutical Science, 66: 1-19 (1997), which is incorporated herein by reference in its entirety). The acid addition salts of basic compounds can be prepared by contacting the free base form with a sufficient amount of the desired acid to produce the salt according to methods and techniques familiar to the skilled artisan.

[0033] "Pharmaceutically acceptable base addition salts" refer to those salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable. These salts are prepared by adding an inorganic or organic base to the free acid. Pharmaceutically acceptable base addition salts can be formed with metals or amines such as alkali metals and alkaline earth metals or organic amines. Salts derived from organic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines (including naturally occurring substituted amines), cyclic amines, and basic ion exchange resins, for example, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine, hydrabamine, choline, betaine, ethylenediamine, ethylenediphenylamine, N-methylglucamine, glucamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. See Berge et al., supra.

[0034] As used herein, a "hydrate" is a compound containing a stoichiometric or non-stoichiometric amount of water, and in some embodiments, is formed during crystallization with water. Hydrates are intended to include hydrates of any of the compounds described herein that are approved for use by the U.S. Food and Drug Administration.

[0035] As used herein, the term "acceptable" with respect to a formulation, composition or ingredient means having no persistent detrimental effect on the general health of the subject being treated.

[0036] As used herein, the terms "administering", "administration" and similar terms refer to methods that can be used to enable a compound or composition to be delivered to a desired biological site of action. These methods include, but are not limited to, oral routes, intraduodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those skilled in the art are familiar with administration techniques that can be used with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0037] The terms "subject," "patient," or "individual" include mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates, such as chimpanzees and other apes and monkey species. In one aspect, the mammal is a human. "Subject," "patient," or "individual" should not be construed as requiring or not requiring the intervention of a medical professional.

[0038] As used herein, "treat" or "treat" or "alleviate" or "improve" are used interchangeably herein. These terms refer to approaches to obtain beneficial or desired results (including but not limited to anti-diabetic effects, therapeutic benefits and / or preventive benefits). By "therapeutic benefit" or "anti-diabetic effect" is meant the elimination or improvement of the underlying condition being treated. Therapeutic benefit can be achieved by eradicating or improving one or more physiological symptoms associated with the underlying condition (e.g., hyperglycemia, polyuria, polydipsia, polyphagia, diabetic dermatosis, etc.) so that an improvement is observed in the patient, although the patient may still be suffering from the underlying condition. In addition, therapeutic benefit is achieved by eradicating or improving one or more complications associated with the underlying condition (e.g., cardiovascular disease). For preventive benefit, the composition can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though a diagnosis of the disease may not have been made.

[0039] The terms "diabetes" and "diabetes mellitus" are used interchangeably herein. These terms refer to type 1 diabetes, type 2 diabetes, complications of diabetes, and complications of adjacent disease states. As used herein, diabetes mellitus (DM) refers to a group of metabolic disorders characterized by chronically high blood sugar levels.

[0040] Triple Composition

[0041] Described herein are pharmaceutical compositions comprising: (a) a dipeptidyl peptidase IV (DPP IV) inhibitor; (b) a biguanide; and (c) a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; wherein each of (a), (b) and (c) is about 20% to about 75% of the minimum diabetes therapeutic dose (LDTD).

[0042] Described herein are pharmaceutical compositions consisting essentially of: a) a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a biguanide; and c) a subtype 2 sodium-glucose transporter (SGLT2) inhibitor;

[0043] wherein (a), (b) and (c) are each about 20% to about 75% of the lowest diabetes therapeutic dose (LDTD).

[0044] Described herein are pharmaceutical compositions comprising: a) a dipeptidyl peptidase IV (DPP IV) inhibitor; b) a biguanide; and c) a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; wherein (a) and (b) are each about 65%-75% of the minimum diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the minimum diabetes therapeutic dose (LDTD).

[0045] Described herein are pharmaceutical compositions consisting essentially of: (a) a DPP IV inhibitor; (b) a biguanide; and (c) an SGLT2 inhibitor;

[0046] wherein (a) and (b) are each about 65%-75% of the lowest diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the lowest diabetes therapeutic dose (LDTD).

[0047] In some embodiments, the DPP IV inhibitor is a gliptin. In some embodiments, the DPP IV inhibitor is selected from sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, alagliptin, tenagliptin, alogliptin, trelagliptin, ogliptin, emlagliptin, gogliptin, dulagliptin or a pharmaceutically acceptable salt or hydrate thereof.

[0048] In some embodiments, the DPP IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof. In some embodiments, the DPP IV inhibitor is sitagliptin phosphate.

[0049] In some embodiments, the biguanide is metformin or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the biguanide is metformin hydrochloride.

[0050] In some embodiments, the metformin is formulated for immediate release. In some embodiments, the metformin is formulated for slow release.

[0051] In some embodiments, the SGLT2 inhibitor is a gliflozin drug. In some embodiments, the SGLT2 inhibitor is dapagliflozin, empagliflozin, canagliflozin, ispagliflozin (ASP-1941), togliflozin, repagliflozin, sergliflozin, ergliflozin, sogliflozin, or a pharmaceutically acceptable salt, hydrate or combination thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, hydrate or combination thereof. In some embodiments, the SGLT2 inhibitor is empagliflozin or a pharmaceutically acceptable salt, hydrate or combination thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin hydrate. In some embodiments, the SGLT2 inhibitor is dapagliflozin propylene glycol monohydrate. In some embodiments, the SGLT2 inhibitor is a hydrate of dapagliflozin compounded with (2S)-1,2-propylene glycol in a ratio of about 1:1:1.

[0052] In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 75% of the lowest diabetes therapeutic dose (LDTD).

[0053] In some embodiments, the dosage of each of (a), (b) and (c) is about 60% to about 75% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of each of (a), (b) and (c) is about 65% to about 75% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of each of (a), (b) and (c) is about 70% of the minimum diabetes treatment dose (LDTD).

[0054] In some embodiments, the dose of each of (a), (b), and (c) is about 40% to about 70% of the lowest diabetes therapeutic dose (LDTD).

[0055] In some embodiments, the dosage of each of (a), (b) and (c) is about 40% to about 60% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of each of (a), (b) and (c) is about 45% to about 55% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of each of (a), (b) and (c) is about 50% of the minimum diabetes treatment dose (LDTD).

[0056] In some embodiments, the DPP IV inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg.

[0057] In some embodiments, the DPP IV inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor. In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 12.5 mg.

[0058] In some embodiments, the biguanide is about 70% of the lowest diabetes therapeutic dose (LDTD) of the biguanide. In some embodiments, the biguanide is metformin hydrochloride, and the dose of metformin hydrochloride is about 350 mg.

[0059] In some embodiments, the biguanide is about 50% of the lowest diabetes therapeutic dose (LDTD) of the biguanide. In some embodiments, the biguanide is metformin hydrochloride, and the dose of metformin hydrochloride is about 250 mg.

[0060] In some embodiments, the SGLT2 inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg.

[0061] In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin.

[0062] In some embodiments, the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of dapagliflozin is about 1.0 mg to about 3.75 mg. In some embodiments, the dose of sitagliptin is about 10 mg to about 16.25 mg, the dose of metformin is about 200 mg to about 325 mg, and the dose of dapagliflozin is about 2.0 mg to about 3.25 mg. In some embodiments, the dose of sitagliptin is about 10 mg to about 15 mg, the dose of metformin is about 200 mg to about 300 mg, and the dose of dapagliflozin is about 2 mg to about 3 mg. In some embodiments, the dose of sitagliptin is about 11.25 mg to about 13.75 mg, the dose of metformin is about 225 mg to about 275 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the dose of sitagliptin is about 12.5 mg, the dose of metformin is about 250 mg, and the dose of dapagliflozin is about 2.5 mg.

[0063] In some embodiments, the respective dosage of (a), (b) and (c) is about 30% to about 40% of the minimum diabetes treatment dose (LDTD). In some embodiments, the respective dosage of (a), (b) and (c) is about 30% to about 35% of the minimum diabetes treatment dose (LDTD). In some embodiments, the SGLT2 inhibitor is about 33% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor.

[0064] In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.65 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.3 mg.

[0065] In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0066] In some embodiments, the dose of sitagliptin is about 7.5mg to about 10mg, and the dose of metformin is about 150mg to about 200mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.5mg to about 2.0mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.0mg to about 4.0mg. In some embodiments, the dose of sitagliptin is about 8.25mg, and the dose of metformin is about 165mg. In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.65mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.3mg.

[0067] In some embodiments, the dosage of each of (a), (b) and (c) is about 20% to about 30% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of each of (a), (b) and (c) is about 22% to about 28% of the minimum diabetes treatment dose (LDTD). In some embodiments, the dosage of the SGLT2 inhibitor is about 25% of the minimum diabetes treatment dose (LDTD) of the SGLT2 inhibitor.

[0068] In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.25 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 2.5 mg.

[0069] In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0070] In some embodiments, the dose of sitagliptin is about 5 mg to about 7.5 mg, and the dose of metformin is about 100 mg to about 150 mg.

[0071] In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.0 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 2.0 mg.

[0072] In some embodiments, the dose of sitagliptin is about 6.25 mg and the dose of metformin is about 150 mg.

[0073] In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.5 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.0 mg.

[0074] In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg.

[0075] In some embodiments, the biguanide is metformin, and the dosage of metformin is about 325 mg to about 375 mg.

[0076] In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dosage of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 4.5 mg to about 7.5 mg.

[0077] In some embodiments, the DPP IV inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor.

[0078] In some embodiments, the biguanide is about 70% of the lowest diabetes therapeutic dose (LDTD) of the biguanide.

[0079] In some embodiments, the SGLT2 inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0080] In some embodiments, the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0081] In some embodiments, the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of empagliflozin is about 5.0 mg.

[0082] In some embodiments, the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg.

[0083] In some embodiments, the biguanide is metformin, and the dosage of metformin is about 350 mg.

[0084] In some embodiments, the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 5.0 mg.

[0085] In some embodiments, (a), (b) and (c) are provided in one formulation. In some embodiments, (a), (b) and (c) are each provided in a separate formulation. In some embodiments, two of (a), (b) and (c) are provided in one formulation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet or capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0086] In some embodiments, the pharmaceutical compositions described herein comprise at least one pharmaceutically acceptable excipient.In some embodiments, the pharmaceutical compositions described herein comprising (a) a DPP IV inhibitor, (b) a biguanide, and (c) an SGLT2 inhibitor are substantially free of additional antihyperglycemic or antidiabetic agents.

[0087] In some embodiments, the pharmaceutical composition comprises an antidiabetic or antihyperglycemic combination of antidiabetic or antihyperglycemic agents, wherein the antidiabetic or antihyperglycemic agents consist of a DPP IV inhibitor, a biguanide, and a SGLT2 inhibitor.

[0088] In some embodiments, the pharmaceutical compositions disclosed herein achieve significant anti-diabetic effects or therapeutic benefits in subjects suffering from diabetes. In some embodiments, the pharmaceutical compositions disclosed herein achieve significant anti-diabetic effects or therapeutic benefits in subjects suffering from diabetes, and side effects are minimal, not obvious or no side effects. In some embodiments, the combination of (a) DPP IV inhibitors, (b) biguanides and (c) SGLT2 inhibitors in the composition achieves a synergistic effect.

[0089] DPP IV inhibitors

[0090] As used herein, a DPP IV inhibitor is a compound that blocks the enzyme dipeptidyl peptidase-4 (DPP IV) and lowers glucagon and blood glucose levels.

[0091] In some embodiments, the DPP IV inhibitor is a gliptin. In some embodiments, the DPP IV inhibitor is sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, alagliptin, tenagliptin, alogliptin, trelagliptin, ogliptin, emlagliptin, gogliptin, dulagliptin or a pharmaceutically acceptable salt or hydrate thereof.

[0092] In some embodiments, the DPP IV inhibitor is sitagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is sitagliptin phosphate or a hydrate thereof. In some embodiments, the DPP IV inhibitor is vildagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is saxagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is linagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is gemagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is anagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is tenagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is alogliptin. In some embodiments, the DPP IV inhibitor is trelagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is ogliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is emlagliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is gogliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the DPP IV inhibitor is dulagliptin, or a pharmaceutically acceptable salt or hydrate thereof.

[0093] Biguanide

[0094] As used herein, biguanides refer to compounds as a class of drugs that are used as oral antihyperglycemic agents for the treatment of diabetes or prediabetes.

[0095] In some embodiments, the biguanide is metformin. In some embodiments, the biguanide is metformin hydrochloride or a hydrate thereof.

[0096] SGLT2 inhibitors

[0097] As used herein, an SGLT2 inhibitor is a compound that causes a decrease in blood glucose levels.

[0098] In some embodiments, it is selected from dapagliflozin, empagliflozin, canagliflozin, ipagliptin (ASP-1941), togliflozin, repagliflozin, sergliflozin, erpagliflozin, sogliptin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is dapagliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is empagliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is canagliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is ipagliptin (ASP-1941), or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is togliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is repagliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is sergliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is ergliflozin, or a pharmaceutically acceptable salt or hydrate thereof. In some embodiments, the SGLT2 inhibitor is sogliflozin, or a pharmaceutically acceptable salt or hydrate thereof.

[0099] Minimum dose for diabetes treatment

[0100] As used herein, the minimum diabetes treatment dose (LDTD) refers to the lowest strength dose of a single diabetes medicament approved by the U.S. Food and Drug Administration and, as of the filing date of this application, has not been marked as "discontinued" by the Orange Book database (World Wide Web address accessdata.fda.gov / scripts / cder / ob / ). For situations where the minimum diabetes treatment dose is different from the minimum manufacturing dose, the minimum diabetes treatment dose does not include the minimum manufacturing dose. In addition, for situations where the minimum diabetes treatment dose is different from the dose recommended by the doctor, the minimum diabetes treatment dose does not include the dose recommended by the doctor. In addition, the minimum diabetes dose of the DPP IV inhibitors, biguanides and SGLT2 inhibitors described herein refers to the dose of the DPP IV inhibitors, biguanides and SGLT2 inhibitor forms approved for use by the U.S. Food and Drug Administration, including free bases, pharmaceutically acceptable salts or hydrates thereof.

[0101] In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 75% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 70% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 65% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 60% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 55% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 50% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 45% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 40% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 35% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 20% to about 30% of the lowest diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 25% of the minimum diabetes treatment dosage.

[0102] In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 75% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 70% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 65% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 60% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 55% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 50% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 45% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 40% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 35% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 30% of the lowest diabetes treatment dose.

[0103] In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 30% to about 35% of the minimum diabetes treatment dose.

[0104] In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 35% to about 40% of the minimum diabetes treatment dose.

[0105] In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 45% of the minimum diabetes treatment dose.

[0106] In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 50% of the minimum diabetes treatment dose.

[0107] In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 55% of the minimum diabetes treatment dose.

[0108] In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 60% of the minimum diabetes treatment dose.

[0109] In some embodiments, the dose of the DPP IV inhibitor is about 60% to about 75% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 60% to about 70% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 60% to about 65% of the lowest diabetes treatment dose.

[0110] In some embodiments, the dose of the DPP IV inhibitor is about 65% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 65% to about 70% of the minimum diabetes treatment dose.

[0111] In some embodiments, the dosage of the DPP IV inhibitor is about 70% to about 75% of the minimum diabetes treatment dosage.

[0112] In some embodiments, the dose of biguanide is about 20% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 30% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 25% of the minimum diabetes treatment dose.

[0113] In some embodiments, the dose of biguanide is about 25% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 30% of the minimum diabetes treatment dose.

[0114] In some embodiments, the dose of biguanide is about 30% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 35% of the minimum diabetes treatment dose.

[0115] In some embodiments, the dose of biguanide is about 35% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 35% to about 40% of the minimum diabetes treatment dose.

[0116] In some embodiments, the dose of biguanide is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 45% of the minimum diabetes treatment dose.

[0117] In some embodiments, the dose of biguanide is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 50% of the minimum diabetes treatment dose.

[0118] In some embodiments, the dose of biguanide is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 55% of the minimum diabetes treatment dose.

[0119] In some embodiments, the dosage of biguanide is about 55% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 55% to about 70% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 55% to about 65% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 55% to about 60% of the minimum diabetes treatment dosage.

[0120] In some embodiments, the dosage of biguanide is about 60% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 60% to about 70% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 60% to about 65% of the minimum diabetes treatment dosage.

[0121] In some embodiments, the dosage of the biguanide is about 65% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of the biguanide is about 65% to about 70% of the minimum diabetes treatment dosage.

[0122] In some embodiments, the dosage of the biguanide is about 70% to about 75% of the minimum diabetes treatment dosage.

[0123] In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 75% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 70% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 65% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 60% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 55% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 50% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 45% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 40% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 35% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 30% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 25% of the minimum diabetes treatment dosage.

[0124] In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 75% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 70% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 65% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 60% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 55% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 50% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 45% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 40% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 35% of the lowest diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 30% of the lowest diabetes treatment dose.

[0125] In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 35% of the minimum diabetes treatment dose.

[0126] In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 40% of the minimum diabetes treatment dose.

[0127] In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 45% of the minimum diabetes treatment dose.

[0128] In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 50% of the minimum diabetes treatment dose.

[0129] In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 55% of the minimum diabetes treatment dose.

[0130] In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 60% of the minimum diabetes treatment dose.

[0131] In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 65% of the minimum diabetes treatment dose.

[0132] In some embodiments, the dosage of the SGLT2 inhibitor is about 65% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of the SGLT2 inhibitor is about 65% to about 70% of the minimum diabetes treatment dosage.

[0133] In some embodiments, the dosage of the SGLT2 inhibitor is about 70% to about 75% of the minimum diabetes treatment dose.

[0134] In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 30% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 20% to about 25% of the minimum diabetes treatment dose.

[0135] In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% to about 30% of the minimum diabetes treatment dose.

[0136] In some embodiments, the dose of the DPP IV inhibitor is about 30% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 30% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 30% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 30% to about 35% of the minimum diabetes treatment dose.

[0137] In some embodiments, the dose of the DPP IV inhibitor is about 35% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 35% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 35% to about 40% of the minimum diabetes treatment dose.

[0138] In some embodiments, the dose of the DPP IV inhibitor is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 50% of the minimum diabetes treatment dose.

[0139] In some embodiments, the dose of biguanide is about 20% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 30% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 20% to about 25% of the minimum diabetes treatment dose.

[0140] In some embodiments, the dose of biguanide is about 25% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 25% to about 30% of the minimum diabetes treatment dose.

[0141] In some embodiments, the dose of biguanide is about 30% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 30% to about 35% of the minimum diabetes treatment dose.

[0142] In some embodiments, the dosage of biguanide is about 35% to about 50% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 35% to about 45% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 35% to about 40% of the minimum diabetes treatment dosage.

[0143] In some embodiments, the dosage of the biguanide is about 40% to about 50% of the minimum diabetes treatment dosage. In some embodiments, the dosage of the biguanide is about 45% to about 50% of the minimum diabetes treatment dosage.

[0144] In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 30% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 20% to about 25% of the minimum diabetes treatment dose.

[0145] In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 35% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% to about 30% of the minimum diabetes treatment dose.

[0146] In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 30% to about 35% of the minimum diabetes treatment dose.

[0147] In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 45% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 35% to about 40% of the minimum diabetes treatment dose.

[0148] In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 50% of the minimum diabetes treatment dosage. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 50% of the minimum diabetes treatment dosage.

[0149] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 20% to about 40% of the minimum diabetes treating dosage.

[0150] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 20% to about 30% of the minimum diabetes treating dosage.

[0151] In some embodiments, the dose of the DPP IV inhibitor is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 25% of the minimum diabetes treatment dose. In some embodiments, the DPP IV inhibitor is sitagliptin. In some embodiments, the dose of sitagliptin is about 5.0, about 5.25, about 5.5, about 5.75, about 6.0, about 6.25, about 6.5, about 6.75, about 7.0, about 7.25, or about 7.5 mg.

[0152] In some embodiments, the dosage of the biguanide inhibitor is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29%, or about 30% of the minimum diabetes treatment dose. In some embodiments, the dosage of the biguanide is about 25% of the minimum diabetes treatment dose. In some embodiments, the biguanide is metformin or metformin hydrochloride. In some embodiments, the dosage of metformin or metformin hydrochloride is about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, or about 150 mg.

[0153] In some embodiments, the dosage of the SGLT2 inhibitor is about 20%, about 21%, about 22%, about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about 29% or about 30% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 25% of the minimum diabetes treatment dose. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the dosage of dapagliflozin is about 1.0, about 1.1, about 1.2, about 1.3, about 1.4 or about 1.5 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the dosage of empagliflozin is about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9 or about 3.0 mg.

[0154] In some embodiments, the lowest diabetes therapeutic dose (LDTD) of the following compounds and the corresponding recommended doses and recommended dose ranges are as described in Table 1:

[0155] Table 1.

[0156]

[0157] In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) dapagliflozin as an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) empagliflozin as an SGLT2 inhibitor. In some embodiments, the dose of sitagliptin is about 5 mg to about 7.5 mg, the dose of metformin is about 100 mg to about 150 mg, and the dose of dapagliflozin is about 1.0 mg to about 1.5 mg. In some embodiments, the dose of sitagliptin is about 5 mg to about 7.5 mg, the dose of metformin is about 100 mg to about 150 mg, and the dose of empagliflozin is about 2.0 mg to about 3.0 mg.

[0158] In some embodiments, the dose of each of (a) DPP IV inhibitors, (b) biguanides, and (c) SGLT2 inhibitors is about 25% of the lowest diabetes treatment dose (LDTD) of each of (a), (b), and (c). In some embodiments, the dose of sitagliptin is about 6.25 mg, the dose of metformin is about 125 mg, and the dose of dapagliflozin is about 1.25 mg. In some embodiments, the dose of sitagliptin is about 6.25 mg, the dose of metformin is about 125 mg, and the dose of empagliflozin is about 2.5 mg. In some embodiments, the metformin is metformin hydrochloride.

[0159] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 30% to about 40% of the minimum diabetes treating dosage.

[0160] In some embodiments, the dose of the DPP IV inhibitor is about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 33% of the minimum diabetes treatment dose. In some embodiments, the DPP IV inhibitor is sitagliptin. In some embodiments, the dose of sitagliptin is about 7.5, about 7.75, about 8.0, about 8.25, about 8.5, about 8.75, about 9.0, about 9.25, about 9.5, about 9.75 or about 10 mg.

[0161] In some embodiments, the dosage of the biguanide inhibitor is about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the biguanide is about 33% of the minimum diabetes treatment dose. In some embodiments, the biguanide is metformin or metformin hydrochloride. In some embodiments, the dosage of metformin or metformin hydrochloride is about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195 or about 200 mg.

[0162] In some embodiments, the dosage of the SGLT2 inhibitor is about 30%, about 31%, about 32%, about 33%, about 34%, about 35%, about 36%, about 37%, about 38%, about 39% or about 40% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 33% of the minimum diabetes treatment dose. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the dosage of dapagliflozin is about 1.5, about 1.55, about 1.6, about 1.65, about 1.7, about 1.75, about 1.8, about 1.85, about 1.9, about 1.95 or about 2.0 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the dose of empagliflozin is about 3.0, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4.0 mg.

[0163] In some embodiments, the lowest diabetes therapeutic dose (LDTD) of the following compounds and the corresponding recommended doses and recommended dose ranges are as described in Table 2:

[0164] Table 2.

[0165]

[0166] In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) dapagliflozin as an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) empagliflozin as an SGLT2 inhibitor. In some embodiments, the dose of sitagliptin is about 7.5 mg to about 10 mg, the dose of metformin is about 150 mg to about 200 mg, and the dose of dapagliflozin is about 1.5 mg to about 2.0 mg. In some embodiments, the dose of sitagliptin is about 7.5 mg to about 10 mg, the dose of metformin is about 150 mg to about 200 mg, and the dose of empagliflozin is about 3.0 mg to about 4.0 mg.

[0167] In some embodiments, the dose of each of (a) DPP IV inhibitors, (b) biguanides, and (c) SGLT2 inhibitors is about 33% of the lowest diabetes treatment dose (LDTD) of each of (a), (b), and (c). In some embodiments, the dose of sitagliptin is about 8.25 mg, the dose of metformin is about 165 mg, and the dose of dapagliflozin is about 1.65 mg. In some embodiments, the metformin is metformin hydrochloride. In some embodiments, the dose of sitagliptin is about 8.25 mg, the dose of metformin is about 165 mg, and the dose of empagliflozin is about 3.3 mg.

[0168] In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the DPP IV inhibitor is about 40% to about 45% of the minimum diabetes treatment dose.

[0169] In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 45% to about 50% of the minimum diabetes treatment dose.

[0170] In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% to about 55% of the minimum diabetes treatment dose.

[0171] In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 55% to about 60% of the minimum diabetes treatment dose.

[0172] In some embodiments, the dose of the DPP IV inhibitor is about 60% to about 75% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 60% to about 70% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 60% to about 65% of the lowest diabetes treatment dose.

[0173] In some embodiments, the dose of the DPP IV inhibitor is about 65% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 65% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 70% to about 75% of the minimum diabetes treatment dose.

[0174] In some embodiments, the dose of biguanide is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 40% to about 45% of the minimum diabetes treatment dose.

[0175] In some embodiments, the dose of biguanide is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 45% to about 50% of the minimum diabetes treatment dose.

[0176] In some embodiments, the dose of biguanide is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of biguanide is about 50% to about 55% of the minimum diabetes treatment dose.

[0177] In some embodiments, the dosage of biguanide is about 55% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 55% to about 70% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 55% to about 65% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 55% to about 60% of the minimum diabetes treatment dosage.

[0178] In some embodiments, the dosage of biguanide is about 60% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 60% to about 70% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 60% to about 65% of the minimum diabetes treatment dosage.

[0179] In some embodiments, the dosage of biguanide is about 65% to about 75% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 65% to about 70% of the minimum diabetes treatment dosage. In some embodiments, the dosage of biguanide is about 70% to about 75% of the minimum diabetes treatment dosage.

[0180] In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 45% of the minimum diabetes treatment dose.

[0181] In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 50% of the minimum diabetes treatment dose.

[0182] In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 55% of the minimum diabetes treatment dose.

[0183] In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 60% of the minimum diabetes treatment dose.

[0184] In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 65% of the minimum diabetes treatment dose.

[0185] In some embodiments, the dosage of the SGLT2 inhibitor is about 65% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 65% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 70% to about 75% of the minimum diabetes treatment dose.

[0186] In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 50% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 40% to about 45% of the minimum diabetes treatment dose.

[0187] In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 55% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 45% to about 50% of the minimum diabetes treatment dose.

[0188] In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% to about 55% of the minimum diabetes treatment dose.

[0189] In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 65% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 55% to about 60% of the minimum diabetes treatment dose.

[0190] In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 65% of the minimum diabetes treatment dose.

[0191] In some embodiments, the dosage of the SGLT2 inhibitor is about 65% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 65% to about 70% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 70% to about 75% of the minimum diabetes treatment dose.

[0192] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 40% to about 60% of the minimum diabetes treating dosage.

[0193] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 40% to about 50% of the minimum diabetes treating dosage.

[0194] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 50% to about 60% of the minimum diabetes treating dosage.

[0195] In some embodiments, the dosage of each of the DPP IV inhibitor, the biguanide, and the SGLT2 inhibitor is about 45% to about 55% of the minimum diabetes treating dosage.

[0196] In some embodiments, the dose of the DPP IV inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 50% of the minimum diabetes treatment dose. In some embodiments, the DPP IV inhibitor is sitagliptin. In some embodiments, the dose of sitagliptin is about 10, about 10.25, about 10.5, about 10.75, about 11, about 11.25, about 11.5, about 11.75, about 12, about 12.25, about 12.5, about 12.75, about 13, about 13.25, about 13.5, about 13.75, about 14, about 14.25, about 14.5, about 14.75, or about 15 mg.

[0197] In some embodiments, the dose of the biguanide inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59%, or about 60% of the minimum diabetes treatment dose. In some embodiments, the dose of the biguanide is about 50% of the minimum diabetes treatment dose. In some embodiments, the biguanide is metformin or metformin hydrochloride. In some embodiments, the dosage of metformin or metformin hydrochloride is about 200, about 205, about 210, about 215, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, or about 300 mg.

[0198] In some embodiments, the dosage of the SGLT2 inhibitor is about 40%, about 41%, about 42%, about 43%, about 44%, about 45%, about 46%, about 47%, about 48%, about 49%, about 50%, about 51%, about 52%, about 53%, about 54%, about 55%, about 56%, about 57%, about 58%, about 59% or about 60% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 50% of the minimum diabetes treatment dose. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the dosage of dapagliflozin is about 2.0, about 2.1, about 2.2, about 2.3, about 2.4, about 2.5, about 2.6, about 2.7, about 2.8, about 2.9 or about 3.0 mg. In some embodiments, the dose of dapagliflozin is about 2.0, about 2.25, about 2.5, about 2.75, or about 3.0 mg. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the dose of empagliflozin is about 4.0, about 4.1, about 4.2, about 4.3, about 4.4, about 4.5, about 4.6, about 4.7, about 4.8, about 4.9, about 5.0, about 5.1, about 5.2, about 5.3, about 5.4, about 5.5, about 5.6, about 5.7, about 5.8, about 5.9, or about 6.0 mg.

[0199] In some embodiments, the lowest diabetes treatment dose (LDTD) of the following compounds and the corresponding recommended doses and recommended dose ranges are as described in Table 3:

[0200] Table 3.

[0201]

[0202] In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) dapagliflozin as an SGLT2 inhibitor. In some embodiments, the dose of sitagliptin is about 10 mg to about 15 mg, the dose of metformin is about 200 mg to about 300 mg, and the dose of dapagliflozin is about 2.0 mg to about 3.0 mg. In some embodiments, the dose of sitagliptin is about 10 mg to about 15 mg, the dose of metformin is about 200 mg to about 300 mg, and the dose of empagliflozin is about 4.0 mg to about 6.0 mg.

[0203] In some embodiments, the dose of sitagliptin is about 11.25 mg to about 12.5 mg, the dose of metformin is about 225 mg to about 275 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the dose of sitagliptin is about 11.25 mg to about 12.5 mg, the dose of metformin is about 225 mg to about 275 mg, and the dose of empagliflozin is about 4.5 mg to about 5.5 mg.

[0204] In some embodiments, the dose of each of (a) DPP IV inhibitors, (b) biguanides, and (c) SGLT2 inhibitors is about 50% of the lowest diabetes treatment dose (LDTD) of each of (a), (b), and (c). In some embodiments, the dose of sitagliptin is about 12.5 mg, the dose of metformin is about 250 mg, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the dose of sitagliptin is about 12.5 mg, the dose of metformin is about 250 mg, and the dose of empagliflozin is about 5.0 mg. In some embodiments, the metformin is metformin hydrochloride.

[0205] In some embodiments, the dosage of the DPP IV inhibitor is about 60% to about 75% of the minimum diabetes treatment dosage.

[0206] In some embodiments, the dose of the DPP IV inhibitor is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74% or about 75% of the lowest diabetes treatment dose. In some embodiments, the dose of the DPP IV inhibitor is about 70% of the lowest diabetes treatment dose. In some embodiments, the DPP IV inhibitor is sitagliptin. In some embodiments, the dose of sitagliptin is about 15, about 15.25, about 15.5, about 15.75, about 16, about 16.25, about 16.5, about 16.75, about 17, about 17.25, about 17.5, about 17.75, about 18, about 18.25, about 18.5 or about 18.75 mg.

[0207] In some embodiments, the dose of the biguanide is about 60% to about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the biguanide inhibitor is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74% or about 75% of the minimum diabetes treatment dose. In some embodiments, the dose of the biguanide is about 70% of the minimum diabetes treatment dose. In some embodiments, the biguanide is metformin or metformin hydrochloride. In some embodiments, the dosage of metformin or metformin hydrochloride is about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, or about 375 mg.

[0208] In some embodiments, the dosage of the SGLT2 inhibitor is about 60% to about 75% of the minimum diabetes treatment dosage.

[0209] In some embodiments, the dosage of the SGLT2 inhibitor is about 60%, about 61%, about 62%, about 63%, about 64%, about 65%, about 66%, about 67%, about 68%, about 69%, about 70%, about 71%, about 72%, about 73%, about 74% or about 75% of the minimum diabetes treatment dose. In some embodiments, the dosage of the SGLT2 inhibitor is about 70% of the minimum diabetes treatment dose. In some embodiments, the SGLT2 inhibitor is dapagliflozin. In some embodiments, the dosage of dapagliflozin is about 3.0, about 3.05, about 3.10, about 3.15, 3.20, about 3.25, about 3.30, about 3.35, about 3.40, about 3.45, about 3.5, about 3.55, about 3.60, about 3.65, about 3.70 or about 3.75mg. In some embodiments, the SGLT2 inhibitor is empagliflozin. In some embodiments, the dose of empagliflozin is about 6.0, about 6.1, about 6.2, about 6.3, about 6.4, about 6.5, about 6.6, about 6.7, about 6.8, about 6.9, about 7.0, about 7.1, about 7.2, about 7.3, about 7.4, or about 7.5 mg.

[0210] In some embodiments, the lowest diabetes treatment dose (LDTD) of the following compounds and the corresponding recommended doses and recommended dose ranges are as described in Table 4:

[0211] Table 4.

[0212]

[0213]

[0214] In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) dapagliflozin as an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) empagliflozin as an SGLT2 inhibitor. In some embodiments, the dose of sitagliptin is about 15 mg to about 18.75 mg, the dose of metformin is about 300 mg to about 375 mg, and the dose of dapagliflozin is about 3.0 mg to about 3.75 mg. In some embodiments, the dose of sitagliptin is about 15 mg to about 17.5 mg, the dose of metformin is about 300 mg to about 350 mg, and the dose of empagliflozin is about 6.0 mg to about 7.5 mg.

[0215] In some embodiments, the dose of sitagliptin is about 15 mg to about 17.5 mg, the dose of metformin is about 300 mg to about 350 mg, and the dose of dapagliflozin is about 3.0 mg to about 3.5 mg. In some embodiments, the dose of sitagliptin is about 15 mg to about 17.5 mg, the dose of metformin is about 300 mg to about 350 mg, and the dose of empagliflozin is about 6.0 mg to about 7.0 mg.

[0216] In some embodiments, the dosage of (a) DPP IV inhibitor, (b) biguanide and (c) SGLT2 inhibitor is about 70% of the lowest diabetes treatment dose (LDTD) of each of (a), (b) and (c). In some embodiments, the dosage of sitagliptin is about 17.5 mg, the dosage of metformin is about 350 mg, and the dosage of dapagliflozin is about 3.5 mg. In some embodiments, the dosage of sitagliptin is about 17.5 mg, the dosage of metformin is about 350 mg, and the dosage of empagliflozin is about 7.0 mg. In some embodiments, metformin is metformin hydrochloride.

[0217] In some embodiments, the dosage of (a) a DPP IV inhibitor, (b) a biguanide, and (c) an SGLT2 inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of each of (a) and (b), and about 50% of the lowest diabetes therapeutic dose (LDTD) of (c).

[0218] In some embodiments, the lowest diabetes therapeutic dose (LDTD) of the following compounds and the corresponding recommended doses and recommended dose ranges are as described in Table 5:

[0219] Table 5.

[0220]

[0221] In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) dapagliflozin as an SGLT2 inhibitor. In some embodiments, the pharmaceutical composition comprises: (a) sitagliptin as a DPP IV inhibitor; (b) metformin as a biguanide; and (c) empagliflozin as an SGLT2 inhibitor. In some embodiments, the dose of sitagliptin is about 1.625 mg to about 18.75 mg, the dose of metformin is about 325 mg to about 375 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.

[0222] In some embodiments, the dose of sitagliptin is about 1.625 mg to about 18.75 mg, and the dose of metformin is about 325 mg to about 375 mg. In some embodiments, the dose of sitagliptin is about 1.625 mg to about 18.75 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg. In some embodiments, the dose of metformin is about 325 mg to about 375 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.

[0223] In some embodiments, the dose of sitagliptin is about 1.625 mg to about 18.75 mg, the dose of metformin is about 325 mg to about 375 mg, and the dose of empagliflozin is about 4.5 mg to about 5.5 mg.

[0224] In some embodiments, the dose of sitagliptin is about 1.625 mg to about 18.75 mg, and the dose of empagliflozin is about 4.5 mg to about 5.5 mg. In some embodiments, the dose of metformin is about 325 mg to about 375 mg, and the dose of empagliflozin is about 4.5 mg to about 5.5 mg.

[0225] In some embodiments, the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the dose of sitagliptin is about 17.5 mg, and the dose of metformin is about 350 mg. In some embodiments, the dose of sitagliptin is about 17.5 mg, and the dose of dapagliflozin is about 2.5 mg. In some embodiments, the dose of metformin is about 350 mg, and the dose of dapagliflozin is about 2.5 mg.

[0226] In some embodiments, the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of empagliflozin is about 5.0 mg. In some embodiments, the dose of sitagliptin is about 17.5 mg, and the dose of metformin is about 350 mg. In some embodiments, the dose of sitagliptin is about 17.5 mg, and the dose of empagliflozin is about 5.0 mg. In some embodiments, the dose of metformin is about 350 mg, and the dose of empagliflozin is about 5.0 mg.

[0227] preparation

[0228] In some embodiments, the DPP IV inhibitor, biguanide and SGLT2 inhibitor are provided in one preparation. In some embodiments, the DPP IV inhibitor, biguanide and SGLT2 inhibitor are each provided in a separate preparation. In some embodiments, two of the DPP IV inhibitor, biguanide and SGLT2 inhibitor are provided in one preparation. In some embodiments, the DPP IV inhibitor and biguanide are provided in one preparation. In some embodiments, the DPP IV inhibitor and SGLT2 inhibitor are provided in one preparation. In some embodiments, the biguanide and SGLT2 inhibitor are provided in one preparation. In some embodiments, the pharmaceutical composition is in the form of a pill, tablet or capsule. In some embodiments, the pharmaceutical composition is in the form of a pill. In some embodiments, the pharmaceutical composition is in the form of a tablet. In some embodiments, the pharmaceutical composition is in the form of a capsule. In some embodiments, the pharmaceutical composition is suitable for oral administration.

[0229] Other suitable formulations include, but are not limited to, those suitable for rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous), vaginal or aerosol administration, although the most suitable form of administration in any given case will depend on the extent and severity of the condition being treated and the nature of the specific compound used. For example, the disclosed compositions can be formulated as a unit dosage.

[0230] Exemplary pharmaceutical compositions can be used in the form of pharmaceutical preparations, such as solid, semisolid or liquid forms, containing one or more disclosed compounds as active ingredients mixed with organic or inorganic carriers or excipients suitable for external, enteral or parenteral application. For example, the active ingredients can be compounded with pharmaceutically acceptable carriers that are generally non-toxic and used in tablets, pellets, capsules, suppositories, solutions, emulsions, suspensions, and any other form suitable for use. The pharmaceutical composition contains an amount of the active target compound sufficient to produce the desired effect on the disease process or condition.

[0231] To prepare solid compositions such as tablets, the main active ingredient can be mixed with a pharmaceutical carrier (e.g., conventional tableting ingredients, such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a uniform mixture of the disclosed compound or a non-toxic pharmaceutically acceptable salt thereof. When these preformulation compositions are referred to as uniform, it is meant that the active ingredient is uniformly dispersed throughout the composition so that the composition can be easily subdivided into equivalent unit dosage forms, such as tablets, pills, and capsules.

[0232] In solid dosage forms for oral administration (capsules, tablets, pills, lozenges, powders, granules, etc.), the compositions of the present invention are mixed with one or more pharmaceutically acceptable carriers such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders such as carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; (5) dissolution retardants such as paraffin; (6) absorption accelerators such as quaternary ammonium compounds; (7) wetting agents such as acetyl alcohol. alcohol) and glyceryl monostearate; (8) absorbents such as kaolin and bentonite; (9) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the composition may also contain a buffer. A similar type of solid composition may also be employed as a filler in soft and hard-filled gelatin capsules using excipients such as lactose or milk sugar and high molecular weight polyethylene glycols and the like.

[0233] Tablets can be made by compressing or molding optionally with one or more auxiliary ingredients. Compressed tablets can be prepared using a binder (e.g., gelatin or hydroxypropyl methylcellulose), a lubricant, an inert diluent, a preservative, a disintegrant (e.g., sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), a surfactant or a dispersant. Molded tablets can be prepared by molding a mixture of the present composition moistened with an inert liquid diluent in a suitable machine. In some embodiments, capsules are prepared by encapsulating tablets in hard gelatin capsules (e.g., encapsulation). Tablets and other solid dosage forms, such as lozenges, capsules, pills and granules, can be optionally scored or prepared with coatings and shells, such as enteric coatings and other coatings known in the art of pharmaceutical formulations.

[0234] Treatment

[0235] The pharmaceutical compositions described herein can be used to treat a metabolic disorder in a subject in need thereof. The pharmaceutical compositions described herein can be used to treat diabetes in a subject in need thereof.

[0236] The high incidence of treatment failure is the main reason for the high incidence of long-term hyperglycemia-related complications or chronic damage (including microvascular complications such as diabetic nephropathy, retinopathy or neuropathy, and macrovascular complications such as coronary heart disease, cerebrovascular disease and peripheral vascular disease) in patients with type 2 diabetes. Therefore, there is an unmet medical need for methods, drugs and pharmaceutical compositions that have good efficacy in glycemic control, in modifying the nature of the disease and in reducing cardiovascular morbidity and mortality, while showing an improved safety profile.

[0237] In some embodiments, the treatments or methods of the present disclosure result in one or more of the following:

[0238] i. Prevent metabolic disorders, slow down the progression of metabolic disorders, delay or treat metabolic disorders;

[0239] ii. Prevent diabetes, slow the progression of diabetes, delay or cure diabetes;

[0240] iii. Improved glycemic control and / or reduced fasting plasma glucose, postprandial plasma glucose, continuously measured blood glucose and / or glycosylated hemoglobin HbA1c;

[0241] iv. Prevent, slow down, delay or reverse the progression of impaired glucose tolerance, impaired fasting glucose and / or insulin resistance caused by metabolic syndrome and / or type 2 diabetes;

[0242] v. preventing, slowing the progression, delaying or treating a condition or disorder selected from vascular and non-vascular complications of diabetes;

[0243] vi. Prevent, slow down the progression of, delay or treat renal impairment;

[0244] vii. Prevent, slow down the progression of, delay or treat renal impairment;

[0245] viii. Prevent, slow down the progression of, delay or treat retinal vascular disease;

[0246] ix. reducing body weight and / or body fat, or preventing the increase of body weight and / or body fat, or promoting the reduction of body weight and / or body fat;

[0247] x. Preventing or treating the degeneration of pancreatic β cells, and / or improving and / or restoring the function of pancreatic β cells, and / or restoring the function of pancreatic insulin secretion;

[0248] xi. Preventing, slowing, delaying or treating diseases or conditions attributable to the abnormal accumulation of ectopic fat;

[0249] xii. maintaining and / or improving insulin sensitivity, and / or treating or preventing hyperinsulinemia and / or insulin resistance,

[0250] xiii. Prevent new-onset diabetes after transplantation (NODAT) and / or post-transplant metabolic syndrome (PTMS), slow the progression, delay or treat NODAT and / or PTMS;

[0251] xiv. Prevent, delay or reduce complications associated with NODAT and / or PTMS, including microvascular and macrovascular diseases and events, transplant rejection, infection and death;

[0252] xv. Treatment of hyperuricemia and hyperuricemia-related conditions;

[0253] xvi. Treat or prevent kidney stones; and / or

[0254] xvii.Treatment of hyponatremia.

[0255] In some embodiments, the treatment results in slowing, delaying, or treating the progression of a metabolic disorder, particularly type 2 diabetes.

[0256] In some embodiments, the treatment results in improved glycemic control in a patient in need thereof, particularly in a patient with type 2 diabetes.

[0257] In some embodiments, the treatment results in improved glycemic control in a patient with inadequate glycemic control despite monotherapy with an antidiabetic agent or despite combination therapy with two antidiabetic agents.

[0258] In some embodiments, the treatment results in a blood sugar lowering effect, an effect on insulin levels, or a combination thereof. In some embodiments, the treatment results in a blood sugar lowering effect, an effect on insulin levels, or a combination thereof, without a low incidence of any adverse events or adverse signs.

[0259] In some embodiments, the treatment results in a blood glucose lowering effect at about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, or more than about 6 hours after treatment. In some embodiments, the blood glucose lowering effect is determined by measuring a primary endpoint, a secondary endpoint, a tertiary endpoint, or a combination thereof.

[0260] In some embodiments, the primary and secondary endpoints are respectively the average absolute changes of plasma glucose and serum insulin at a specific time after a meal compared with pre-prandial after a single dose of treatment. In some embodiments, the primary and secondary endpoints are respectively the average absolute changes of plasma glucose and serum insulin at about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours or more than about 6 hours after a meal compared with pre-meal. In some embodiments, the primary and secondary endpoints are respectively the average absolute changes of plasma glucose and serum insulin at about 2 hours after a meal compared with pre-meal after a single dose of treatment. In some embodiments, the primary and secondary endpoints are compared with pre-meal plasma glucose, serum insulin or a combination thereof.

[0261] In some embodiments, the tertiary endpoint is determined as the area under the concentration time curve (AUC) of plasma glucose, serum insulin or a combination thereof after administration. In some embodiments, the tertiary endpoint is determined as the area under the concentration time curve (AUC) of postprandial plasma glucose, serum insulin or a combination thereof. In some embodiments, the tertiary endpoint is determined as the AUC of plasma glucose, serum insulin or a combination thereof at about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours or more than about 8 hours after administration. In some embodiments, the tertiary endpoint is determined as the AUC of plasma glucose, serum insulin, or a combination thereof at about 0.5 hours, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, or more than about 8 hours after a meal. In some embodiments, the tertiary endpoint is compared to pre-meal plasma glucose, serum insulin, or a combination thereof.

[0262] In some embodiments, treatment with a composition described herein (e.g., Composition A) results in a blood glucose lowering effect. In some embodiments, treatment with a composition described herein (e.g., Composition A) results in at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% of a blood glucose lowering effect compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition.

[0263] In some embodiments, the treatment results in a reduction in postprandial plasma glucose of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95%, compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition. In some embodiments, the treatment results in a reduction in plasma glucose of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% at about 0.5 hour, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, or more than about 8 hours after a meal, compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition. In some embodiments, the treatment results in a reduction in plasma glucose of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% from about 0.5 hour to about 6 hours, from about 1 hour to about 5 hours, or from about 2 hours to about 4 hours after a meal, compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition. In some embodiments, the blood glucose lowering effect of the treatment is compared to before a meal.

[0264] In some embodiments, treatment with a composition described herein (e.g., Composition A) results in an increase in insulin levels. In some embodiments, treatment with a composition described herein (e.g., Composition A) results in an increase in insulin levels of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95%, compared to no treatment, placebo treatment, or treatment with one or two active agents of the composition. In some embodiments, the treatment results in an increase in postprandial insulin levels of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95%, compared to no treatment, placebo treatment, or treatment with one or two active agents of the composition. In some embodiments, the treatment results in an increase in insulin levels of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% at about 0.5 hour, about 1 hour, about 1.5 hours, about 2 hours, about 2.5 hours, about 3 hours, about 3.5 hours, about 4 hours, about 4.5 hours, about 5 hours, about 5.5 hours, about 6 hours, about 6.5 hours, about 7 hours, about 7.5 hours, about 8 hours, or more than about 8 hours after a meal, compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition. In some embodiments, the treatment results in an increase in insulin levels of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% from about 0.5 hour to about 6 hours, from about 1 hour to about 5 hours, or from about 2 hours to about 4 hours after a meal, compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition. In some embodiments, the increase in insulin levels from the treatment is compared to before a meal.

[0265] In some embodiments, treatment with a composition described herein (e.g., Composition A) results in a faster return of plasma glucose levels, insulin levels, or a combination thereof to pre-meal levels compared to no treatment, placebo treatment, or treatment with one or both active agents of the composition. In some embodiments, treatment with a composition described herein (e.g., Composition A) results in a return of plasma glucose levels, insulin levels, or a combination thereof to pre-meal levels at a rate of at least or about 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, or more than 95% faster than no treatment, placebo treatment, or treatment with one or both active agents of the composition.

[0266] In some embodiments, the treatment results in a slowing or delay in the progression from impaired glucose tolerance (IGT), impaired fasting glucose (IFG), insulin resistance, and / or metabolic syndrome to type 2 diabetes.

[0267] In some embodiments, the method results in the prevention, slowing of progression, delay, or treatment of a condition or disorder selected from a diabetic complication.

[0268] In some embodiments, the treatment results in weight loss or prevents weight gain in a patient in need thereof.

[0269] In some embodiments, the methods result in effective treatment of metabolic disorders such as diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and / or hyperglycemia, with favorable pharmacological and / or pharmacokinetic and / or physicochemical properties.

[0270] In some embodiments, the methods result in effective treatment of metabolic disorders such as diabetes, impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and / or hyperglycemia, with improved long-term tolerability and reduced risk of side effects (e.g., hypoglycemia, pancreatic cancer, hypersensitivity reactions (including anaphylaxis), angioedema, rash, urticaria, cutaneous vasculitis, and exfoliative skin diseases (including Stevens-Johnson syndrome); elevated liver enzymes; acute pancreatitis, including fatal and non-fatal hemorrhagic and necrotizing pancreatitis; worsening renal function, including acute renal failure (sometimes requiring dialysis); severe and disabling arthralgias; constipation; vomiting; headache; myalgia; pain in the extremities; back pain; pruritus; and / or pemphigoid, arthralgia, lactic acidosis, vitamin B12 and folate deficiencies, nasopharyngitis, upper respiratory tract infections).

[0271] In some embodiments, the treatment results in an improvement in diabetes treatment that is greater than treatment obtained with the full minimum diabetes treating dose of any of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor in the pharmaceutical composition.

[0272] In some embodiments, treatment results in an improvement in diabetes treatment that is greater than treatment obtained with the full minimum diabetes treatment dose of the DPP IV inhibitor in the pharmaceutical composition. In some embodiments, treatment results in an improvement in diabetes treatment that is greater than treatment obtained with the full minimum diabetes treatment dose of the biguanide in the pharmaceutical composition. In some embodiments, treatment results in an improvement in diabetes treatment that is greater than treatment obtained with the full minimum diabetes treatment dose of the SGLT2 inhibitor in the pharmaceutical composition.

[0273] In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to the treatment with the complete minimum diabetes treatment dose of any one of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to the treatment with the complete minimum diabetes treatment dose of the DPP IV inhibitor in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to the treatment with the complete minimum diabetes treatment dose of the biguanide in the pharmaceutical composition. In some embodiments, the treatment results in higher long-term tolerance and reduced risk of side effects compared to the treatment with the complete minimum diabetes treatment dose of the SGLT2 inhibitor in the pharmaceutical composition.

[0274] In some embodiments, the treatment results in an improvement in diabetes and / or related conditions that is greater than or equal to the improvement obtained by using a combination of any two of the DPP IV inhibitors, biguanides, and SGLT2 inhibitors in the pharmaceutical composition. In some embodiments, the treatment results in an improvement in diabetes and / or related conditions that is greater than or equal to the improvement obtained by using a combination of any two of the DPP IV inhibitors, biguanides, and SGLT2 inhibitors in the pharmaceutical composition, wherein the dose of each of the DPP IV inhibitor, biguanides, and SGLT2 inhibitor is about 25% of the lowest diabetes treatment dose. In some embodiments, the treatment results in an improvement in diabetes and / or related conditions that is greater than or equal to the improvement obtained by using a combination of any two of the DPP IV inhibitors, biguanides, and SGLT2 inhibitors in the pharmaceutical composition, wherein the dose of each of the DPP IV inhibitor, biguanides, and SGLT2 inhibitor is about 33% of the lowest diabetes treatment dose. In some embodiments, treatment results in an improvement in diabetes and / or related conditions that is greater than or equal to the improvement obtained by using a combination of any two of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor in the pharmaceutical composition, wherein the dose of each of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor is about 50% of the lowest diabetes treatment dose. In some embodiments, treatment results in an improvement in diabetes and / or related conditions that is greater than or equal to the improvement obtained by using a combination of any two of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor in the pharmaceutical composition, wherein the dose of each of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor is about 70% of the lowest diabetes treatment dose. In some embodiments, treatment results in an improvement in diabetes and / or related conditions that is greater than or equal to the improvement obtained by using a combination of any two of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor in the pharmaceutical composition, wherein the dose of the DPP IV inhibitor and biguanide is about 70% of the lowest diabetes treatment dose of each of the DPP IV inhibitor and biguanide, and the dose of the SGLT2 inhibitor is about 50% of the lowest diabetes treatment dose of the SGLT2 inhibitor.

[0275] In some embodiments, the treatment results in greater long-term tolerability and reduced risk of side effects compared to treatment with a combination of any two of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor in the pharmaceutical composition, wherein the dose of each of the DPP IV inhibitor, biguanide, and SGLT2 inhibitor is about 50% of the lowest diabetes treatment dose.

[0276] In some embodiments, the treatment is the initial or first-line treatment of diabetes. In some embodiments, the subject has a very slight increase in blood sugar before treatment. In some embodiments, the subject has not received any previous diabetes treatment before treatment. In some embodiments, the subject has a very slight increase in blood sugar before treatment and has not received any previous diabetes treatment before treatment. In some embodiments, after treatment with one or both of LDTD or higher doses of DPP IV inhibitors, biguanides or SGLT2 inhibitors, the subject has a sustained increase in blood sugar.

[0277] The present disclosure recognizes that, in some embodiments, use of a DPP IV inhibitor in a pharmaceutical composition disclosed herein provides beneficial therapeutic effects including, but not limited to, significant reductions in blood glucose, significant reductions in blood glucose in subjects with mildly elevated blood glucose, better long-term tolerability, and reduced risk of side effects.

[0278] It is also recognized herein that, in some embodiments, the triple low-dose combination formulations described herein comprising a DPP IV inhibitor, a biguanide, and a SGLT2 inhibitor provide a blood glucose reduction greater than the LDTD of each individual drug administered alone. For example, in some embodiments, the blood glucose reduction provided by a triple combination formulation comprising 70% DPP IV inhibitor, 50% biguanide, and 70% SGLT2 inhibitor is greater than or significantly greater than the LDTD of the DPP IV inhibitor administered alone, or the LDTD of the biguanide, or the LDTD of the SGLT2 inhibitor. As another example, in some embodiments, the blood glucose reduction provided by a triple combination formulation comprising 50% DPP IV inhibitor, 50% biguanide, and 50% SGLT2 inhibitor is greater than or significantly greater than the LDTD of the DPP IV inhibitor administered alone, or the LDTD of the biguanide, or the LDTD of the SGLT2 inhibitor.

[0279] It is also recognized herein that in some embodiments, the triple low-dose combination formulations comprising a DPP IV inhibitor, a biguanide, and a SGLT2 inhibitor as described herein provide a blood glucose reduction greater than twice the LDTD of each individual drug administered alone. For example, in some embodiments, the blood glucose reduction provided by the triple combination formulation comprising 70% DPP IV inhibitor, 50% biguanide, and 70% SGLT2 inhibitor is greater than or significantly greater than twice the LDTD of each individual drug administered alone. As another example, in some embodiments, the blood glucose reduction provided by the triple combination formulation comprising 50% DPP IV inhibitor, 50% biguanide, and 50% SGLT2 inhibitor is greater than or significantly greater than twice the LDTD of each individual drug administered alone.

[0280] Other Implementations

[0281] The embodiments include the following embodiments 1 to 92.

[0282] Embodiment 1. A pharmaceutical composition comprising:

[0283] a) dipeptidyl peptidase IV (DPP IV) inhibitors;

[0284] b) biguanides; and

[0285] c) inhibitors of subtype 2 sodium-glucose transporter (SGLT2);

[0286] wherein (a), (b) and (c) are each about 20-75% of the lowest diabetes therapeutic dose (LDTD).

[0287] Embodiment 2. The pharmaceutical composition according to embodiment 1, wherein the DPP IV inhibitor is a gliptin.

[0288] Embodiment 3. The pharmaceutical composition according to embodiment 1, wherein the DPP IV inhibitor is sitagliptin, vildagliptin, saxagliptin, linagliptin, gemagliptin, alagliliptin, tenagliptin, alogliptin, trelagliptin, ogliptin, oelagliptin, ipagliptin, gogliptin, dulagliptin or a pharmaceutically acceptable salt or hydrate thereof.

[0289] Embodiment 4. The pharmaceutical composition according to any one of embodiments 1-3, wherein the DPP IV inhibitor is sitagliptin or a pharmaceutically acceptable salt thereof.

[0290] Embodiment 5. The pharmaceutical composition according to embodiment 4, wherein the DPP IV inhibitor is sitagliptin phosphate.

[0291] Embodiment 6. The pharmaceutical composition according to any one of Embodiments 1-5, wherein the biguanide is metformin or a pharmaceutically acceptable salt or hydrate thereof.

[0292] Embodiment 7. The pharmaceutical composition according to embodiment 6, wherein the biguanide is metformin hydrochloride.

[0293] Embodiment 8. The pharmaceutical composition according to embodiment 6 or 7, wherein the metformin is formulated for immediate release.

[0294] Embodiment 9. The pharmaceutical composition according to embodiment 6 or 7, wherein the metformin is formulated for slow release.

[0295] Embodiment 10. A pharmaceutical composition according to any one of Embodiments 1-9, wherein the SGLT2 inhibitor is a gliflozin-type drug.

[0296] Embodiment 11. A pharmaceutical composition according to Embodiment 10, wherein the SGLT2 inhibitor is dapagliflozin, empagliflozin, canagliflozin, iplagliflozin (ASP-1941), topagliflozin, repagliflozin, sergliflozin, erpagliflozin, sogliflozin, or a pharmaceutically acceptable salt, hydrate or combination thereof.

[0297] Embodiment 12. A pharmaceutical composition according to Embodiment 11, wherein the SGLT2 inhibitor is dapagliflozin or a pharmaceutically acceptable salt, hydrate or combination thereof.

[0298] Embodiment 13. A pharmaceutical composition according to Embodiment 12, wherein the SGLT2 inhibitor is dapagliflozin hydrate.

[0299] Embodiment 14. The pharmaceutical composition according to embodiment 13, wherein the SGLT2 inhibitor is dapagliflozin propylene glycol monohydrate.

[0300] Embodiment 15. The pharmaceutical composition according to any one of embodiments 1-14, wherein the dose of each of (a), (b) and (c) is about 40% to about 75% of the lowest diabetes therapeutic dose (LDTD).

[0301] Embodiment 16. The pharmaceutical composition of any one of embodiments 1-14, wherein the dose of each of (a), (b) and (c) is about 60% to about 75% of the lowest diabetes therapeutic dose (LDTD).

[0302] Embodiment 17. The pharmaceutical composition of any one of embodiments 1-14, wherein the dose of each of (a), (b) and (c) is about 65% to about 75% of the lowest diabetes therapeutic dose (LDTD).

[0303] Embodiment 18. The pharmaceutical composition of any one of embodiments 1-14, wherein the dose of each of (a), (b) and (c) is about 40% to about 70% of the lowest diabetes therapeutic dose (LDTD).

[0304] Embodiment 19. The pharmaceutical composition of any one of embodiments 1-14, wherein the dose of each of (a), (b) and (c) is about 40% to about 60% of the lowest diabetes therapeutic dose (LDTD).

[0305] Embodiment 20. The pharmaceutical composition of any one of embodiments 1-14, wherein the dose of each of (a), (b) and (c) is about 45% to about 55% of the lowest diabetes therapeutic dose (LDTD).

[0306] Embodiment 21. The pharmaceutical composition according to any one of embodiments 1-18, wherein the DPP IV inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor.

[0307] Embodiment 22. The pharmaceutical composition according to embodiment 18, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg.

[0308] Embodiment 23. The pharmaceutical composition according to any one of embodiments 1-15 or 18-20, wherein the DPP IV inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor.

[0309] Embodiment 24. The pharmaceutical composition according to embodiment 23, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 12.5 mg.

[0310] Embodiment 25. The pharmaceutical composition of any one of embodiments 1-18, wherein the biguanide is about 70% of the lowest diabetes therapeutic dose (LDTD) of the biguanide.

[0311] Embodiment 26. The pharmaceutical composition according to embodiment 25, wherein the biguanide is metformin hydrochloride, and the dosage of metformin hydrochloride is about 350 mg.

[0312] Embodiment 27. The pharmaceutical composition of any one of embodiments 1-15 or 18-24, wherein the biguanide is about 50% of the lowest diabetes therapeutic dose (LDTD) of the biguanide.

[0313] Embodiment 28. The pharmaceutical composition according to embodiment 27, wherein the biguanide is metformin hydrochloride, and the dosage of metformin hydrochloride is about 250 mg.

[0314] Embodiment 29. The pharmaceutical composition according to any one of embodiments 1-15 or 18-28, wherein the SGLT2 inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0315] Embodiment 30. The pharmaceutical composition according to Embodiment 29, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg.

[0316] Embodiment 31. The pharmaceutical composition according to Embodiment 1, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0317] Embodiment 32. The pharmaceutical composition of embodiment 31, wherein the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of dapagliflozin is about 1.0 mg to about 3.75 mg.

[0318] Embodiment 33. The pharmaceutical composition of embodiment 31, wherein the dose of sitagliptin is about 5.0 mg to about 18.75 mg, the dose of metformin is about 100 mg to about 375 mg, and the dose of empagliflozin is about 2.0 mg to about 7.5 mg.

[0319] Embodiment 34. The pharmaceutical composition of embodiment 31, wherein the dose of sitagliptin is about 10 mg to about 16.25 mg, the dose of metformin is about 200 mg to about 325 mg, and the dose of dapagliflozin is about 2.0 mg to about 3.25 mg.

[0320] Embodiment 35. The pharmaceutical composition of embodiment 31, wherein the dose of sitagliptin is about 10 mg to about 15 mg, the dose of metformin is about 200 mg to about 300 mg, and the dose of dapagliflozin is about 2 mg to about 3 mg.

[0321] Embodiment 36. The pharmaceutical composition of embodiment 31, wherein the dose of sitagliptin is about 11.25 mg to about 13.75 mg, the dose of metformin is about 225 mg to about 275 mg, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.

[0322] Embodiment 37. The pharmaceutical composition of embodiment 31, wherein the dose of sitagliptin is about 12.5 mg, the dose of metformin is about 250 mg, and the dose of dapagliflozin is about 2.5 mg.

[0323] Embodiment 38. The pharmaceutical composition of any one of embodiments 1-11, wherein the dose of each of (a), (b) and (c) is about 30% to about 40% of the lowest diabetes therapeutic dose (LDTD).

[0324] Embodiment 39. The pharmaceutical composition of any one of embodiments 1-11, wherein the dose of each of (a), (b) and (c) is about 30% to about 35% of the lowest diabetes therapeutic dose (LDTD).

[0325] Embodiment 40. The pharmaceutical composition according to embodiment 38 or 39, wherein the SGLT2 inhibitor is about 33% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0326] Embodiment 41. A pharmaceutical composition according to Embodiment 40, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.65 mg.

[0327] Embodiment 42. A pharmaceutical composition according to Embodiment 40, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.3 mg.

[0328] Embodiment 43. The pharmaceutical composition according to Embodiment 38, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0329] Embodiment 44. The pharmaceutical composition of embodiment 43, wherein the dose of sitagliptin is about 7.5 mg to about 10 mg, and the dose of metformin is about 150 mg to about 200 mg.

[0330] Embodiment 45. The pharmaceutical composition according to Embodiment 44, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.5 mg to about 2.0 mg.

[0331] Embodiment 46. The pharmaceutical composition according to Embodiment 44, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.0 mg to about 4.0 mg.

[0332] Embodiment 47. The pharmaceutical composition of embodiment 40, wherein the dose of sitagliptin is about 8.25 mg and the dose of metformin is about 165 mg.

[0333] Embodiment 48. The pharmaceutical composition according to Embodiment 44, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.65 mg.

[0334] Embodiment 49. The pharmaceutical composition according to Embodiment 44, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.3 mg.

[0335] Embodiment 50. The pharmaceutical composition of any one of embodiments 1-11, wherein the dose of each of (a), (b) and (c) is about 20% to about 30% of the lowest diabetes therapeutic dose (LDTD).

[0336] Embodiment 51. The pharmaceutical composition of any one of embodiments 1-11, wherein the dose of each of (a), (b) and (c) is about 22% to about 28% of the lowest diabetes therapeutic dose (LDTD).

[0337] Embodiment 52. The pharmaceutical composition according to embodiment 50 or 51, wherein the dosage of the SGLT2 inhibitor is about 25% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0338] Embodiment 53. The pharmaceutical composition according to Embodiment 52, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.25 mg.

[0339] Embodiment 54. The pharmaceutical composition according to Embodiment 52, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 2.5 mg.

[0340] Embodiment 55. The pharmaceutical composition according to Embodiment 51, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0341] Embodiment 56. The pharmaceutical composition of embodiment 55, wherein the dose of sitagliptin is about 5 mg to about 7.5 mg, and the dose of metformin is about 100 mg to about 150 mg.

[0342] Embodiment 57. The pharmaceutical composition according to Embodiment 56, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.0 mg.

[0343] Embodiment 58. The pharmaceutical composition according to Embodiment 56, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 2.0 mg.

[0344] Embodiment 59. The pharmaceutical composition of embodiment 55, wherein the dose of sitagliptin is about 6.25 mg and the dose of metformin is about 150 mg.

[0345] Embodiment 60. The pharmaceutical composition according to Embodiment 59, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 1.5 mg.

[0346] Embodiment 61. The pharmaceutical composition according to Embodiment 59, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 3.0 mg.

[0347] Embodiment 62. The pharmaceutical composition of any one of Embodiments 1-61, wherein (a), (b) and (c) are provided in one formulation.

[0348] Embodiment 63. The pharmaceutical composition of any one of Embodiments 1-61, wherein (a), (b) and (c) are each provided in separate formulations.

[0349] Embodiment 64. The pharmaceutical composition of any one of Embodiments 1-61, wherein two of (a), (b) and (c) are provided in one formulation.

[0350] Embodiment 65. The pharmaceutical composition according to any one of Embodiments 1-64, wherein the pharmaceutical composition is suitable for oral administration.

[0351] Embodiment 66. The pharmaceutical composition according to any one of Embodiments 1-65, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

[0352] Embodiment 67. A pharmaceutical composition comprising:

[0353] a) dipeptidyl peptidase IV (DPP IV) inhibitors;

[0354] b) biguanides; and

[0355] c) inhibitors of subtype 2 sodium-glucose transporter (SGLT2);

[0356] wherein (a) and (b) are each about 65%-75% of the lowest diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the lowest diabetes therapeutic dose (LDTD).

[0357] Embodiment 68. The pharmaceutical composition according to embodiment 67, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg.

[0358] Embodiment 69. The pharmaceutical composition according to embodiment 67, wherein the biguanide is metformin, and the dosage of metformin is about 325 mg to about 375 mg.

[0359] Embodiment 70. The pharmaceutical composition according to Embodiment 67, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.

[0360] Embodiment 71. The pharmaceutical composition according to Embodiment 67, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 4.5 mg to about 7.5 mg.

[0361] Embodiment 72. The pharmaceutical composition according to embodiment 67, wherein the DPP IV inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor.

[0362] Embodiment 73. The pharmaceutical composition according to embodiment 71, wherein the biguanide is about 70% of the lowest diabetes therapeutic dose (LDTD) of the biguanide.

[0363] Embodiment 74. The pharmaceutical composition according to any one of Embodiments 67 or 72-73, wherein the SGLT2 inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0364] Embodiment 75. The pharmaceutical composition according to any one of Embodiments 67 or 72-74, wherein the DPPIV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0365] Embodiment 76. The pharmaceutical composition of embodiment 75, wherein the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of dapagliflozin is about 2.5 mg.

[0366] Embodiment 77. The pharmaceutical composition of embodiment 75, wherein the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of empagliflozin is about 5.0 mg.

[0367] Embodiment 78. The pharmaceutical composition according to any one of Embodiments 67 or 72-74, wherein the DPPIV inhibitor is sitagliptin and the dose of sitagliptin is about 17.5 mg.

[0368] Embodiment 79. The pharmaceutical composition according to any one of Embodiments 67 or 72-74, wherein the biguanide is metformin and the dose of metformin is about 350 mg.

[0369] Embodiment 80. The pharmaceutical composition according to any one of Embodiments 67 or 72-74, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg.

[0370] Embodiment 81. A pharmaceutical composition according to any one of Embodiments 67 or 72-74, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 5.0 mg.

[0371] Embodiment 82. The pharmaceutical composition of any one of Embodiments 67-82, wherein (a), (b) and (c) are provided in one formulation.

[0372] Embodiment 83. The pharmaceutical composition of any one of Embodiments 67-82, wherein (a), (b) and (c) are each provided in separate formulations.

[0373] Embodiment 84. The pharmaceutical composition of any one of Embodiments 67-82, wherein two of (a), (b) and (c) are provided in one formulation.

[0374] Embodiment 85. The pharmaceutical composition of any one of Embodiments 67-84, wherein the pharmaceutical composition is suitable for oral administration.

[0375] Embodiment 86. The pharmaceutical composition according to any one of Embodiments 67-85, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

[0376] Embodiment 87. The pharmaceutical composition of any one of Embodiments 67-86, wherein the metformin is formulated for immediate release.

[0377] Embodiment 88. The pharmaceutical composition of any one of Embodiments 67-86, wherein the metformin is formulated for slow release.

[0378] Embodiment 89. A method of treating diabetes in a subject in need thereof, comprising administering the pharmaceutical composition of any one of embodiments 1-88.

[0379] Embodiment 90. The method of embodiment 89, wherein the subject has persistent elevated blood glucose following treatment with LDTD or higher doses of one or both of a DPP IV inhibitor, a biguanide, or a SGLT2 inhibitor.

[0380] Embodiment 91. The method of embodiment 89, wherein administration of the pharmaceutical composition is an initial or first-line treatment for diabetes.

[0381] Embodiment 92. A method for improving metabolic disorders, slowing the progression of metabolic disorders, or delaying metabolic disorders, such as diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, impaired renal function, gestational diabetes, new-onset diabetes after transplantation (NODAT) and its related complications, and post-transplant metabolic syndrome (PTMS) and its related complications, comprising administering a pharmaceutical composition of any one of Embodiments 1-88 to a subject in need thereof.

[0382] The present disclosure will be further understood by the following non-limiting examples.

[0383] The present invention provides embodiments including but not limited to the following:

[0384] 1. A pharmaceutical composition comprising:

[0385] a) a low-dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor;

[0386] b) low-dose, therapeutically effective amounts of biguanides;

[0387] c) a low-dose, therapeutically effective amount of a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and

[0388] d) at least one pharmaceutically acceptable excipient,

[0389] wherein (a), (b) and (c) are each about 20-75% of the lowest diabetes therapeutic dose (LDTD).

[0390] 2. The pharmaceutical composition according to embodiment 1, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0391] 3. The pharmaceutical composition according to embodiment 2, wherein the dosage of sitagliptin is about 5.0 mg to about 18.75 mg, the dosage of metformin is about 100 mg to about 375 mg, and the dosage of dapagliflozin is about 1.0 mg to about 2.75 mg.

[0392] 4. The pharmaceutical composition according to embodiment 2, wherein the dosage of sitagliptin is about 5.0 mg to about 18.75 mg, the dosage of metformin is about 100 mg to about 375 mg, and the dosage of empagliflozin is about 2.0 mg to about 7.5 mg.

[0393] 5. The pharmaceutical composition of embodiment 1, wherein (a) and (b) are each about 65%-75% of the minimum diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the minimum diabetes therapeutic dose (LDTD).

[0394] 6. The pharmaceutical composition according to embodiment 5, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg.

[0395] 7. The pharmaceutical composition according to embodiment 5, wherein the biguanide is metformin, and the dosage of metformin is about 325 mg to about 375 mg.

[0396] 8. The pharmaceutical composition according to embodiment 5, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.

[0397] 9. The pharmaceutical composition according to embodiment 5, wherein the SGLT2 inhibitor is empagliflozin, and the dosage of empagliflozin is about 4.5 mg to about 7.5 mg.

[0398] 10. The pharmaceutical composition according to embodiment 5, wherein the DPP IV inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor.

[0399] 11. The pharmaceutical composition according to embodiment 5, wherein the biguanide is about 70% of the lowest diabetes therapeutic dose (LDTD) of the biguanide.

[0400] 12. The pharmaceutical composition according to embodiment 5, wherein the SGLT2 inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0401] 13. The pharmaceutical composition according to embodiment 5, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin or empagliflozin.

[0402] 14. The pharmaceutical composition according to embodiment 13, wherein the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of dapagliflozin is about 2.5 mg.

[0403] 15. The pharmaceutical composition of embodiment 13, wherein the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of empagliflozin is about 5.0 mg.

[0404] 16. The pharmaceutical composition according to embodiment 5, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg.

[0405] 17. The pharmaceutical composition according to embodiment 5, wherein the biguanide is metformin, and the dosage of metformin is about 350 mg.

[0406] 18. The pharmaceutical composition according to embodiment 5, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg.

[0407] 19. The pharmaceutical composition according to embodiment 5, wherein the SGLT2 inhibitor is empagliflozin, and the dose of empagliflozin is about 5.0 mg.

[0408] 20. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition is suitable for oral administration.

[0409] 21. The pharmaceutical composition according to embodiment 1, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

[0410] 22. The pharmaceutical composition of embodiment 1, wherein the metformin is formulated for immediate release.

[0411] 23. The pharmaceutical composition of embodiment 1, wherein the metformin is formulated for slow release.

[0412] 24. A pharmaceutical composition according to any one of embodiments 1-23, wherein the pharmaceutical composition does not contain any further additional antihyperglycemic or antidiabetic drugs.

[0413] 25. The pharmaceutical composition according to any one of embodiments 1-23, wherein the combination of a), b) and c) produces a synergistic effect.

[0414] 26. The pharmaceutical composition of any one of embodiments 1-25, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin.

[0415] 27. The pharmaceutical composition of any one of embodiments 1-25, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 850 mg of metformin.

[0416] 28. A pharmaceutical composition according to any one of embodiments 1-25, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 1700 mg of metformin.

[0417] 29. A pharmaceutical composition comprising:

[0418] a) a low-dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor;

[0419] b) low-dose, therapeutically effective amounts of biguanides;

[0420] c) a low-dose, therapeutically effective amount of a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and

[0421] d) at least one pharmaceutically acceptable excipient,

[0422] wherein (a) and (b) are each about 65%-75% of the lowest diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the lowest diabetes therapeutic dose (LDTD).

[0423] 30. The pharmaceutical composition according to embodiment 29, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 16.25 mg to about 18.75 mg.

[0424] 31. The pharmaceutical composition of embodiment 29, wherein the biguanide is metformin, and the dosage of metformin is about 325 mg to about 375 mg.

[0425] 32. A pharmaceutical composition according to embodiment 29, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.25 mg to about 2.75 mg.

[0426] 33. A pharmaceutical composition according to embodiment 29, wherein the SGLT2 inhibitor is empagliflozin and the dose of empagliflozin is about 4.5 mg to about 7.5 mg.

[0427] 34. The pharmaceutical composition according to embodiment 29, wherein the DPP IV inhibitor is about 70% of the lowest diabetes therapeutic dose (LDTD) of the DPP IV inhibitor.

[0428] 35. The pharmaceutical composition of embodiment 29, wherein the biguanide is about 70% of the lowest diabetes therapeutic dose (LDTD) of the biguanide.

[0429] 36. The pharmaceutical composition of embodiment 29, wherein the SGLT2 inhibitor is about 50% of the lowest diabetes therapeutic dose (LDTD) of the SGLT2 inhibitor.

[0430] 37. The pharmaceutical composition according to embodiment 29, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is dapagliflozin.

[0431] 38. The pharmaceutical composition according to embodiment 29, wherein the DPP IV inhibitor is sitagliptin, the biguanide is metformin, and the SGLT2 inhibitor is empagliflozin.

[0432] 39. The pharmaceutical composition of embodiment 37, wherein the dose of sitagliptin is about 17.5 mg, the dose of metformin is about 350 mg, and the dose of dapagliflozin is about 2.5 mg.

[0433] 40. The pharmaceutical composition according to embodiment 29, wherein the DPP IV inhibitor is sitagliptin, and the dose of sitagliptin is about 17.5 mg.

[0434] 41. The pharmaceutical composition of embodiment 29, wherein the biguanide is metformin, and the dose of metformin is about 350 mg.

[0435] 42. A pharmaceutical composition according to embodiment 29, wherein the SGLT2 inhibitor is dapagliflozin, and the dose of dapagliflozin is about 2.5 mg.

[0436] 43. A pharmaceutical composition according to embodiment 29, wherein the SGLT2 inhibitor is empagliflozin and the dose of empagliflozin is about 5.0 mg.

[0437] 44. A pharmaceutical composition according to any one of embodiments 29-43, wherein the pharmaceutical composition is suitable for oral administration.

[0438] 45. The pharmaceutical composition of any one of embodiments 29-43, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

[0439] 46. ​​The pharmaceutical composition of any one of embodiments 31-45, wherein the metformin is formulated for immediate release.

[0440] 47. The pharmaceutical composition of any one of embodiments 31-45, wherein the metformin is formulated for slow release.

[0441] 48. A pharmaceutical composition according to any one of embodiments 29-47, wherein the pharmaceutical composition does not contain any further additional anti-hyperglycemic or anti-diabetic drugs.

[0442] 49. A pharmaceutical composition according to any one of embodiments 29-47, wherein the combination of a), b) and c) produces a synergistic effect.

[0443] 50. The pharmaceutical composition of any one of embodiments 29-49, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin.

[0444] 51. A pharmaceutical composition according to any one of embodiments 29-49, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 850 mg of metformin.

[0445] 52. A pharmaceutical composition according to any one of embodiments 29-49, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 1700 mg of metformin.

[0446] 53. A pharmaceutical composition comprising a combination of the following ingredients:

[0447] e) about 17.5 mg sitagliptin;

[0448] f) about 350 mg of metformin;

[0449] g) about 2.5 mg dapagliflozin; and

[0450] h) at least one pharmaceutically acceptable excipient.

[0451] 54. A pharmaceutical composition according to embodiment 53, wherein the combination is synergistic.

[0452] 55. The pharmaceutical composition of embodiment 53 or 54, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

[0453] 56. The pharmaceutical composition of embodiment 53 or 54, wherein the pharmaceutical composition is suitable for oral administration.

[0454] 57. A pharmaceutical composition according to any one of embodiments 53-56, wherein the metformin is formulated for immediate release.

[0455] 58. A pharmaceutical composition according to any one of embodiments 53-56, wherein the metformin is formulated for slow release.

[0456] 59. A pharmaceutical composition according to any one of embodiments 53-58, wherein the pharmaceutical composition does not contain any further additional anti-hyperglycemic or anti-diabetic drugs.

[0457] 60. A pharmaceutical composition according to any one of embodiments 53-58, wherein the combination of a), b) and c) produces a synergistic effect.

[0458] 61. A pharmaceutical composition according to any one of embodiments 53-60, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

[0459] 62. A pharmaceutical composition comprising a combination of the following ingredients:

[0460] e) about 17.5 mg sitagliptin;

[0461] f) about 350 mg of metformin;

[0462] g) about 5.0 mg empagliflozin; and

[0463] h) at least one pharmaceutically acceptable excipient.

[0464] 63. A pharmaceutical composition according to embodiment 62, wherein the combination is synergistic.

[0465] 64. The pharmaceutical composition of embodiment 62 or 63, wherein the pharmaceutical composition is in the form of a pill, tablet or capsule.

[0466] 65. The pharmaceutical composition of embodiment 62 or 63, wherein the pharmaceutical composition is suitable for oral administration.

[0467] 66. A pharmaceutical composition according to any one of embodiments 62-65, wherein the metformin is formulated for immediate release.

[0468] 67. A pharmaceutical composition according to any one of embodiments 62-65, wherein the metformin is formulated for slow release.

[0469] 68. A pharmaceutical composition according to any one of embodiments 62-67, wherein the pharmaceutical composition does not contain any further additional anti-hyperglycemic or anti-diabetic drugs.

[0470] 69. A pharmaceutical composition according to any one of embodiments 62-67, wherein the combination of a), b) and c) produces a synergistic effect.

[0471] 70. A pharmaceutical composition according to any one of embodiments 62-69, wherein the pharmaceutical composition produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

[0472] 71. A synergistic, ultra-low-dose antidiabetic drug combination consisting of the following ingredients:

[0473] e) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof;

[0474] f) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof;

[0475] g) about 2.25 mg to about 2.75 mg of dapagliflozin or a salt or hydrate thereof; and

[0476] h) at least one excipient.

[0477] 72. The combination according to embodiment 71, wherein the combination of a), b) and c) produces a synergistic effect.

[0478] 73. The combination according to embodiment 71, wherein the combination does not contain any further additional antihyperglycemic or antidiabetic drugs.

[0479] 74. The combination of embodiment 71, wherein the combination produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from 100 mg sitagliptin, 850 mg metformin, or 1700 mg metformin.

[0480] 75. A synergistic, ultra-low-dose antidiabetic drug combination consisting of the following ingredients:

[0481] e) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof;

[0482] f) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof;

[0483] g) about 4.5 mg to about 7.5 mg of empagliflozin or a salt or hydrate thereof; and

[0484] h) at least one excipient.

[0485] 76. The combination according to embodiment 75, wherein the combination of a), b) and c) produces a synergistic effect.

[0486] 77. The combination according to embodiment 75, wherein the combination does not contain any further additional antihyperglycemic or antidiabetic drugs.

[0487] 78. The combination of embodiment 75, wherein the combination produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

[0488] 79. A method of treating diabetes in a subject in need thereof, comprising administering the pharmaceutical composition of any one of embodiments 1-70.

[0489] 80. The method of embodiment 79, wherein the subject has persistent elevated blood glucose following treatment with LDTD or higher doses of one or both of a DPP IV inhibitor, a biguanide, or a SGLT2 inhibitor.

[0490] 81. The method of embodiment 79, wherein administration of the pharmaceutical composition is an initial or first-line treatment for diabetes.

[0491] 82. A method for improving a metabolic disorder, slowing the progression of a metabolic disorder, or delaying a metabolic disorder, wherein the metabolic disorder comprises diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, impaired renal function, gestational diabetes, new-onset diabetes after transplantation (NODAT) and its related complications, or post-transplant metabolic syndrome (PTMS) and its related complications, the method comprising administering the pharmaceutical composition of any one of embodiments 1-70 to a subject in need thereof.

[0492] 83. A method of treating diabetes in a subject in need thereof, comprising administering a synergistic, ultra-low-dose combination of anti-diabetic drugs consisting of:

[0493] e) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof;

[0494] f) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof;

[0495] g) about 2.25 mg to about 2.75 mg of dapagliflozin or a salt or hydrate thereof; and

[0496] h) at least one excipient.

[0497] 84. The method of embodiment 83, wherein the combination of a), b) and c) produces a synergistic effect.

[0498] 85. The method of embodiment 83, wherein the combination does not comprise any further additional antihyperglycemic or antidiabetic agent.

[0499] 86. The method of embodiment 83, wherein the combination produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

[0500] 87. A method of treating diabetes in a subject in need thereof, comprising administering a synergistic, ultra-low-dose anti-diabetic drug combination consisting of:

[0501] e) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof;

[0502] f) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof;

[0503] g) about 4.5 mg to about 7.5 mg of empagliflozin or a salt or hydrate thereof; and

[0504] h) at least one excipient.

[0505] 88. The method of embodiment 87, wherein the combination of a), b) and c) produces a synergistic effect.

[0506] 89. The method of embodiment 87, wherein the combination does not comprise any further additional antihyperglycemic or antidiabetic agent.

[0507] 90. The method of embodiment 87, wherein the combination produces a greater reduction in 2-hour postprandial blood glucose than the maximum reduction in postprandial blood glucose obtained from about 100 mg sitagliptin, about 850 mg metformin, or about 1700 mg metformin.

[0508] Example

[0509] The examples set forth below are provided to provide a person of ordinary skill in the art with a complete disclosure and description of how to make and use the claimed embodiments, but are not intended to limit the scope of the disclosure herein. Modifications that are obvious to those skilled in the art will fall within the scope of the following claims.

[0510] Example 1: Study of the effects of a combination of a DPP IV inhibitor, a biguanide and a SGLT2 inhibitor on whole blood glucose (WBG), glycosylated hemoglobin (HbA1c), insulin and creatinine levels.

[0511] Study Design: Zucker Diabetic FattyRats model of diet-induced diabetes was used. The study was a parallel randomized study. Ten animals were used in each of the 4 treatment groups. Treatment consisted of 21 days of treatment.

[0512] Main study outcomes: Blood glucose (measured at multiple time points before and during treatment); HbA1c (before and at the end of the treatment period); insulin (before and at the end of the treatment period); creatinine (before and at the end of the treatment period).

[0513] Table 6. Treatment groups and doses of ultra-low-dose blood glucose lowering drugs in combination

[0514]

[0515] Ten Zucker Diabetic Fatty (ZDF) rats were randomly assigned to each of four different treatment groups (Table 6). Whole blood glucose measurements were performed starting 4 days before dosing, then daily until day 8, and then at a reduced frequency. HbA1c and creatinine measurements were performed one day before dosing, then on days 9 and 21. Insulin measurements were performed one day before dosing, then on day 20. Clinical chemistry samples were not available for one animal in the vehicle group on day 9, so creatinine and HbA1c measurements were missing for that day.

[0516] method

[0517] Statistical analysis

[0518] Whole blood glucose, HbA1c and creatinine were analyzed separately using linear mixed models (proc mixed in SAS / STAT 14.2). For WBC, unstructured, autoregressive, exchangeable and Toeplitz correlation structures for repeated measurements throughout the study were compared using the Akaike Information Criterion and the Bayesian Information Criterion. The Toeplitz correlation structure was selected as the best fitting structure. For HbA1c and creatinine, an exchangeable structure was used because there were only two measurements. The denominator degrees of freedom were calculated using the inter-subject-within method. The model included coefficients for baseline measurements (the closest measurement before administration), type of drug treatment, time, and the interaction between drug treatment and time. The marginal mean (with 95% confidence interval) of the measurements for each drug in each period was estimated, and the overall marginal mean (with 95% confidence interval) of the measurements across time was estimated using weights reflecting the different amounts of time for each measurement period (assuming that each measurement represents all time since the last measurement). The likelihood ratio test for the overall difference between treatments was used initially, and if significant (p < 0.05), the difference between each treatment combination was tested.

[0519] For insulin, baseline and day 20 measurements were available, so differences in this measure between treatments were tested using the ANCOVA method (linear regression with baseline values ​​as covariate). An interaction between baseline value and treatment was tested, but there was no evidence of interaction, so the main effect was retained.

[0520] To test the robustness of linear mixed and ANCOVA models, bootstrapped 95% CIs (percentile method) were estimated for weighted marginal means of measurements over the entire study period or single outcome measurements using 2000 replications. Bootstrapped sampling (using complete measurements) was performed for individual animals, stratified by treatment type.

[0521] result

[0522] Overall differences between treatments were found for the primary outcome WBG (p<0.001, Table 7) and the secondary outcomes HbA1c (p<0.0001, Table 8), insulin (p<0.0001, Table 9) and serum creatinine (p<0.0001, Table 10).

[0523] Table 7. Number of measurements available for analysis by outcome, time and treatment

[0524] Table 7.

[0525]

[0526] Table 8. Effect of Combinations of Glucose-lowering Drugs on Whole Blood Glucose (mg / dL)

[0527]

[0528] Table 9. Effect of combination of hypoglycemic drugs on HbA1c (%)

[0529]

[0530] For WBG, Composition A (p<0.0001) and Composition B (p=0.0026) groups were significantly lower throughout the post-dose measurement period. Composition A reduced WBG by 205 mg / dL relative to vehicle, and Composition B reduced WBG by 47 mg / dL relative to vehicle. There was a significant interaction between time and treatment (p<0.0001), with small increases in WBG in most treatments except Composition B ( Figure 1 Composition B had similar WBG to the other treatments shortly after dosing (Day 1), but then declined and remained low for the remainder of the study.

[0531] Evidence of differences in HbA1c between the study groups was found throughout the study (p<0.0001, Table 9), with Composition A (p<0.0001) and Composition B (p<0.0001) having HbA1c lower than vehicle, and all other drug combinations (p<0.001). The estimated overall level of HbA1c in the Composition A group (4.75) was estimated to be 1.1% lower than Composition B (5.83, p<0.0001). HbA1c levels over the time course of the study varied between treatments ( Figure 2 , interaction: p<0.0001). HbA1c in the Combination A group remained about the same as at baseline. HbA1c increased over time in Combination B, but not as much as the other treatments.

[0532] Insulin measurements were significantly different between treatments (p<0.0001, Table 10), with Composition A (p<0.0001) and Composition B (p=0.0054) having higher insulin levels than vehicle at 20 days, and no evidence of a difference between vehicle and 1K-MET (p=0.2955). By day 20, the Composition A group reached an estimated mean of 10,186 (pg / mL), which was significantly higher (p<0.0001) than Composition B (5259 pg / mL).

[0533] Table 10. Effect of Combinations of Glucose-lowering Drugs on Insulin (pg / mL)

[0534]

[0535]

[0536] There were significant (p<0.0001) differences in mean creatinine levels between treatment groups. Creatinine levels were lower in Composition A (p<0.0001) and Composition B (p=0.0082) groups than in the vehicle group. Creatinine levels in Composition A (0.69 mg / dL) were significantly lower (p<0.001) than in Composition B (0.75 mg / dL). Throughout the study, creatinine levels were similar in Composition A and Composition B groups, with increases in levels in the other study groups ( Figure 3 ).

[0537] Table 11. Effect of Combinations of Glucose-lowering Drugs on Creatinine (mg / dL)

[0538]

[0539] Table 12 Outcome estimates by treatment using bootstrapped medians and confidence intervals

[0540]

[0541] Both Composition A Group and Composition B Group showed lower WBC, HbA1c, creatinine and higher insulin levels compared to the control group. On the other hand, all the measured results of the 1K-MET group showed no substantial differences compared to the control.

[0542] ULD compositions A and B reduced blood glucose and HbA1c, suggesting potential therapeutic effects at ultra-low doses. ULD compositions A and B prevented or reduced the decline in insulin, suggesting that pancreatic beta cell function is preserved at ultra-low doses. Similarly, ULD compositions A and B prevented or reduced the increase in creatinine, suggesting that renal function is preserved at ultra-low doses. The effect of the triple ULD combination containing an SGLT-2 antagonist was greater than that of the ULD combination not containing an SGLT-2 antagonist, suggesting a drug-specific therapeutic benefit. The effect of the triple ULD combination containing an SGLT-2 antagonist was greater than that of standard-dose metformin. Composition A had a greater effect on all outcomes than composition B, indicating that there was a difference in the effects of ULD dapagliflozin and ULD empagliflozin.

[0543] Example 2. Analysis of blood glucose and insulin profiles in patients with type 2 diabetes

[0544] The purpose of this study was to evaluate the pharmacodynamics (blood glucose lowering effect) and tolerability of Composition A in diabetic patients.

[0545] In this study, 30 adult patients with type 2 diabetes (23 women and 7 men) who were treatment-naïve, previously treated, or currently treated with only one glucose-lowering therapeutic class (excluding insulin and glucagon-like peptide-1 analogs) were randomized to receive either placebo or Composition A containing 350 mg of metformin, 17.5 mg of sitagliptin, and 2.5 mg of dapagliflozin in a 3-treatment, 3-sequence, 3-period crossover study with a one-week washout period between phases, as described in the literature. Figure 5 As shown. The primary and secondary endpoints were the mean absolute changes in plasma glucose and serum insulin, respectively, 2 hours (h) postprandial compared with preprandial after administration of a single dose of treatment. Tertiary outcomes were the area under the concentration-time curve (AUC) of plasma glucose and serum insulin at 120 minutes and 210 minutes postprandial, and the area under the concentration-time curve (AUC) of plasma glucose and serum insulin at 120 minutes and 240 minutes postdose. A special analysis was performed to determine the differences between the study groups in the mean absolute changes in plasma glucose and serum insulin compared with preprandial at the following time points after administration of a single dose of study treatment: 1, 1.5, 2, 2.5, 3, 3.5, and 4h.

[0546] Participating patients did not receive any hypoglycemic treatment within 24 hours before the screening visit and within 7 days before the study visit until the end of the study. During the study visit, blood samples were collected from participants at the following times before and after the administration of a single dose of randomized treatment: 0.5, 1, 1.5, 2, 2.5, 3, 3.5 and 4h. Participants consumed a standard meal (550kcal; composed of 55% carbohydrates, 15% protein and 30% fat) immediately after 0.5h blood collection. Plasma glucose and serum insulin were measured for all samples by validated methods. Plasma glucose was measured.

[0547] method

[0548] Statistical analysis

[0549] Data from each treatment group were combined. One-way analysis of variance (ANOVA) was performed using SPSS version 17.0 to examine treatment differences in the primary endpoint (mean absolute change in plasma glucose 2 h after a meal compared with before a meal) and the secondary endpoint (mean absolute change in serum insulin 2 h after a meal compared with before a meal). Post hoc multiple pairwise comparisons were performed using the Tukey test. The AUC of postprandial glucose and insulin were calculated using the standard trapezoidal method. 120min and AUC 210min And the AUC after administration 120min and AUC 240minStudy treatment pairs were compared using WinNonlin version 8.2, and the effects of sequence and time period were estimated. An ad hoc analysis was performed using RStatistical Programming version 3.6.1 to determine between-study group differences in mean absolute changes in plasma glucose and serum insulin compared with preprandial concentrations (0.5 h collection time point) at the following time points after administration of a single dose of study treatment: 1, 1.5, 2, 2.5, 3, 3.5, and 4 h. p values ​​< 0.05 were considered statistically significant.

[0550] result

[0551] Baseline characteristics are summarized in Table 13. Thirty patients with type 2 diabetes were enrolled in this study. Baseline plasma glycosylated hemoglobin (HBA1c) and fasting plasma glucose ranges of participating patients were ≥6.1% to ≤11.9% and >119 to 260 mg / dL, respectively (Table 13).

[0552] Table 13. Demographics and characteristics of the study population at screening

[0553]

[0554]

[0555] In terms of efficacy, there were overall statistically significant differences between treatments for the primary endpoint (p<0.05, Table 14), secondary endpoints (p<0.05, Table 15), and tertiary outcomes (p<0.05, Table 16).

[0556] Table 14. Effect of a single dose of study treatment on plasma glucose (2h PPG) from pre-meal to 2 hours post-meal in patients with type 2 diabetes (n=30)

[0557]

[0558]

[0559] *Statistically significant

[0560] Table 15. Effect of a single dose of study treatment on serum insulin from pre-meal to 2 hours post-meal in patients with type 2 diabetes (n=30).

[0561]

[0562] *Statistically significant

[0563] Table 16. Tertiary endpoints following a single dose of study treatment in patients with type 2 diabetes (n=30).

[0564]

[0565]

[0566] *Statistically significant p value < 0.05

[0567] In terms of safety and tolerability, there were no relevant adverse events in patients with type 2 diabetes (n=30) who were administered a single dose of placebo or composition A.

[0568] Effects on plasma glucose

[0569] Time course of plasma glucose: Figure 6 The time course of plasma glucose after single dose composition A and placebo is presented in. In the placebo group, as expected, plasma glucose increased by an average of 58 mg / dL after a standard meal compared to pre-meal concentration, reaching a peak at 1.5 h time point (1 h after a meal), and then plasma glucose began to gradually decrease, returning to approximately pre-meal concentration at 4 h collection time point. In contrast, in the composition A group, plasma glucose slightly and insignificantly increased by an average of 10.1 mg / dL (reached at 1.5 h collection time point) compared to pre-meal concentration, and then plasma glucose steadily decreased until the last collection time point (4 h). Compared with placebo, in the composition A group, plasma glucose remained above the pre-meal concentration in composition A for about 45 minutes, and then remained below the pre-meal concentration at the remaining collection time points (2, 2.5, 3, 3.5 and 4 h).

[0570] Primary endpoint: The primary endpoint was the mean absolute change in 2h plasma glucose (2h PPG) after a meal compared with that before a meal. Composition A significantly reduced plasma glucose concentration at this endpoint compared with placebo (Table 14 and Figure 6 The difference in the mean absolute change in 2h PPG between Composition A and the placebo group compared with pre-meal was -61.7 mg / dL, which was statistically significant (p = 5.0 x 10 -9 , Table 14).

[0571] Special Analysis: Composition A resulted in significantly lower plasma glucose throughout the 1-4h sampling window compared to placebo, as seen in Table 17. The difference in the mean absolute change in plasma glucose from pre-meal to 1-4h time points post-dose between Composition A and the placebo group was statistically significant (Table 17). The difference in the mean absolute change in plasma glucose from pre-meal between Composition A and the placebo group over this time interval (1-4h post-dose) ranged from -24.1 to -64.7 mg / dL (Table 17). The blood glucose lowering effect of Composition A peaked at the 2.5h sampling time point and was maintained until the last sampling collection time point (Table 17). Table 17. Effect of single-dose study treatment on absolute change in plasma glucose from pre-meal in patients with type 2 diabetes (n=30).

[0572]

[0573] *Statistically significant effect on serum insulin

[0574] Time course of serum insulin: e.g. Figure 7 As seen in the Table 1, the time course of serum insulin in Composition A and placebo groups was generally similar. In both groups, serum insulin after a standard meal rose and fell to somewhat similar concentrations ( Figure 7 ). It is noteworthy that in both groups, serum insulin did not return to pre-meal concentrations by the 4-h time point.

[0575] Secondary endpoint: The secondary endpoint is the mean absolute change in serum insulin 2 h after the meal compared with before the meal. Compared with placebo, Composition A had no effect on serum insulin at this time point (p = 0.6, Table 15 and Figure 7 ).

[0576] Special Analysis: The difference in mean absolute change in serum insulin from pre-meal between Composition A group and placebo group is shown in Table 18.

[0577] Table 18. Effect of a single dose of study treatment on absolute change in serum insulin from preprandial levels in patients with type 2 diabetes (n=30).

[0578]

[0579] *Statistically significant

[0580] Tertiary results: Composition A resulted in significantly lower plasma glucose concentration-time area under the curve (AUC) throughout the blood sampling window compared to placebo. See Table 16. Composition A resulted in a serum insulin concentration-time area under the curve (AUC) similar to placebo. See Table 16.

[0581] The data showed that Composition A had a significant blood glucose lowering effect in male and female type 2 diabetes patients and was not associated with any adverse events after a single dose administration.

[0582] Example 3. Comparative Analysis

[0583] The plasma glucose time course following single-dose monotherapy based on published studies was compared to Composition A.

[0584] Table 23 shows the percent change in plasma glucose from pre-meal adjusted for placebo at various doses of single monotherapy compared to Composition A.

[0585] Table 23. Percentage change

[0586]

[0587]

[0588] like Figure 8 As shown, the difference between the average postprandial 2h blood glucose (PPG) and placebo (180min) is about 1mmol / L. Compared with composition A (drug-free, sitagliptin 100mg), the baseline (fasting PG) is much lower. The maximum difference between sitagliptin and placebo is about 1.5mmol / L at 120min (90min postprandial) after administration. The maximum PPG and serum insulin are reached at about 1h after administration (0.5h postprandial).

[0589] Although preferred embodiments of the present disclosure have been shown and described herein, it will be apparent to those skilled in the art that these embodiments are provided by way of example only. Without departing from the present disclosure, those skilled in the art will appreciate that many variations, changes, and substitutions may be made. It should be understood that various alternatives to the embodiments of the present disclosure described herein may be employed in implementing the present disclosure. It is intended that the scope of the present disclosure be limited to the appended claims, and that methods and structures and their equivalents within the scope of these claims are thereby covered.

Claims

1. A pharmaceutical composition comprising: a) a low-dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor; b) low-dose, therapeutically effective amounts of biguanides; c) a low-dose, therapeutically effective amount of a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a), (b) and (c) are each about 20-75% of the lowest diabetes therapeutic dose (LDTD).

2. A pharmaceutical composition comprising: a) a low-dose, therapeutically effective amount of a dipeptidyl peptidase IV (DPP IV) inhibitor; b) low-dose, therapeutically effective amounts of biguanides; c) a low-dose, therapeutically effective amount of a subtype 2 sodium-glucose transporter (SGLT2) inhibitor; and d) at least one pharmaceutically acceptable excipient, wherein (a) and (b) are each about 65%-75% of the lowest diabetes therapeutic dose (LDTD), and (c) is about 45%-55% of the lowest diabetes therapeutic dose (LDTD).

3. A pharmaceutical composition comprising a combination of the following ingredients: a) about 17.5 mg sitagliptin; b) about 350 mg of metformin; c) about 2.5 mg dapagliflozin; and d) at least one pharmaceutically acceptable excipient.

4. A pharmaceutical composition comprising a combination of the following ingredients: a) about 17.5 mg sitagliptin; b) about 350 mg of metformin; c) about 5.0 mg empagliflozin; and d) at least one pharmaceutically acceptable excipient.

5. A synergistic, ultra-low-dose antidiabetic drug combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 2.25 mg to about 2.75 mg of dapagliflozin or a salt or hydrate thereof; and d) at least one excipient.

6. A synergistic, ultra-low-dose antidiabetic drug combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 4.5 mg to about 7.5 mg of empagliflozin or a salt or hydrate thereof; and d) at least one excipient.

7. Use of the pharmaceutical composition of any one of claims 1 to 6 in the preparation of a medicament for treating diabetes in a subject in need thereof.

8. Use of the pharmaceutical composition of any one of claims 1 to 6 in the preparation of a medicament for improving metabolic disorders, slowing down the progression of metabolic disorders or delaying metabolic disorders, wherein the metabolic disorders include diabetes, impaired glucose tolerance, impaired fasting glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, impaired renal function, gestational diabetes, new onset diabetes after transplantation (NODAT) and its related complications, or post-transplant metabolic syndrome (PTMS) and its related complications.

9. Use of an antidiabetic drug combination in the preparation of a medicament for treating diabetes in a subject in need thereof, the combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 2.25 mg to about 2.75 mg of dapagliflozin or a salt or hydrate thereof; and d) at least one excipient.

10. Use of an antidiabetic drug combination in the preparation of a medicament for treating diabetes in a subject in need thereof, the combination consisting of the following ingredients: a) about 16.25 mg to about 18.75 mg sitagliptin or a salt or hydrate thereof; b) about 325 mg to about 375 mg of metformin or a salt or hydrate thereof; c) about 4.5 mg to about 7.5 mg of empagliflozin or a salt or hydrate thereof; and d) at least one excipient.

Images