WO2024063568A1

WO2024063568A1 - Composition and combination therapy for treatment of type 2 diabetes mellitus

Info

Publication number: WO2024063568A1
Application number: PCT/KR2023/014414
Authority: WO
Inventors: Min Young Kim; Min Kwan Cho; Shin Jung Park
Original assignee: Chong Kun Dang Pharmaceutical Corp.
Priority date: 2022-09-23
Filing date: 2023-09-21
Publication date: 2024-03-28
Also published as: KR20240041755A

Abstract

The present invention relates to combination therapy for the treatment of type 2 diabetes, and the combination therapy may achieve clinically significant effects in patients with type 2 diabetes whose blood glucose is not adequately controlled by a combination therapy of metformin and sitagliptin, such as reduction of blood glucose, long-term maintenance of controlled blood glucose, and improvement of lipids related to dyslipidemia accompanying diabetes as well as various glucose metabolism indexes.

Description

COMPOSITION AND COMBINATION THERAPY FOR TREATMENT OF TYPE 2 DIABETES MELLITUS

The present invention relates to combination therapy for the treatment of type 2 diabetes mellitus.

Diabetes is a disease in which metabolic abnormalities, including hyperglycemia, persist due to insufficient action of insulin, and also chronic disease with a high possibility of vascular complications, which can be largely divided into type 1 diabetes and type 2 diabetes. Among these diabetes types, type 2 diabetes is a disease associated with both insulin resistance (i.e., a state in which the responsiveness of cells or tissues to insulin is reduced than normal at a given insulin concentration) and insulin secretion disorders due to decreased pancreatic β-cell function, and that more than 85% of diabetic patients have adult type 2 diabetes, and the prevalence of type 2 diabetes continues to increase as modern people's westernized lifestyle and obesity increase.

According to the guidelines for diabetes management of each country, including Korea, reducing the risk of microvascular complications (retinopathy, nephropathy, and neuropathy) and macrovascular complications is the main treatment goal for diabetes, and strict blood glucose control is recommended as the most effective method to treat diabetes. In most patients, since it is difficult to reach the target level of glycated hemoglobin and maintain it for a long period of time only by improving lifestyle, it is required to use oral hypoglycemic agents. In addition, since there is a correlation between the period of exposure to hyperglycemia and the occurrence of diabetic complications, active treatment with early drug administration is required to shorten the period of exposure to hyperglycemia (Korean Diabetes Association, Diabetes Guidelines, 2015). However, among diabetic patients in Korea, only 23.3% of patients are able to control their blood glucose below the target level (HbA1c<6.5%) (Diabetes Fact Sheet in Korea 2016, Korean Diabetes Association), and therefore, continuous use of hypoglycemic drugs is required to increase the treatment effect.

Oral hypoglycemic agents used for the treatment of diabetes may be divided into 1) insulin secretion stimulants (sulfonylureas, non-sulfonylureas), 2) biguanide-based drugs, 3) alpha-glucosidase inhibitors, 4) glitazone-based drugs, 5) DPPIV inhibitors, and 6) SGLT-2 inhibitors, and the like, depending on the mechanism of action.

Metformin, one of the biguanide-based drugs, is a first-line drug recommended for use in oral drug monotherapy for patients with type 2 diabetes and is advantageous in view of cost-effectiveness. Important mechanisms for metformin are known to inhibit gluconeogenesis in the liver, increase glucose uptake in peripheral tissues, and activate AMP-dependent protein kinase. However, metformin is also known to have side effects such as loss of appetite, abdominal distension, nausea, diarrhea, skin rash, and hives, and in most cases, these side effects are transient and disappear after 2 to 3 weeks after taking the drug, but if diarrhea or severe abdominal bloating does not disappear, it is recommended to discontinue use of the drug.

Sitagliptin, one of DPPIV (dipeptidyl peptidase-4) inhibitors, is able to effectively control the decrease in secretion or the decrease in action of GLP-1 (glucagon like peptide-1). DPPIV is an aminopeptidase present in various tissues, including the intestinal mucosa, and degrades GLP-1 and GIP. DPPIV inhibitors degrade the DPPIV to increase the concentration of GLP-1, thereby stimulating insulin secretion and suppressing glucagon secretion. Here, due to the actions of appetite suppression and delay in gastric release of GLP-1, sitagliptin is widely used recently because the risk of hypoglycemia and weight gain is low.

Meanwhile, glitazone-based drugs are peroxisome proliferator activated receptor gamma agonist (PPARγ agonists), which are expressed in adipocytes to stimulate PPARγ that promotes adipogenesis and glucose uptake, thereby improving the sensitivity to insulin in the body. The glitazone-based drugs are advantageous for protecting β-cells of the pancreas and improve insulin resistance since they do not promote insulin secretion, which is particularly effective for diabetic patients with insulin resistance, and these drugs are known to maintain blood glucose for a long time, slow down the progression of type 2 diabetes, and exhibit a stronger therapeutic effect on early diabetes. As for these glitazone-based drugs, drugs having a thiazolidinedione (TZD) structure are currently the mainstream of the market. However, it is known that glitazone-based drugs do not have high antidiabetic efficacy when used alone, and thus there is a limit to treatment with a single drug, and side effects such as edema or weight gain may occur depending on the person.

Lobeglitazone, one of these glitazone-based drugs, is a domestic novel drug for diabetes developed by the present applicant, which is a drug not only having a stable molecular dynamic energy structure, but also having a structural feature that best matches the active site pocket of PPARγ, thereby exhibiting high pharmacological activity, and enhancing the weak blood lipid-lowering effect, which was pointed out as a disadvantage of existing glitazone-based drugs.

Diabetes has a very complex etiology, and each antidiabetic drug has distinct advantages and disadvantages. Thus, dual combination therapy using antidiabetic agents having different mechanisms of action to simultaneously act on multiple targets is frequently prescribed in clinical practice. Considering not only that combination treatment with drugs shortens the patient's exposure period to hyperglycemia, but also that type 2 diabetes is caused by complex pathophysiology of beta cell dysfunction and insulin resistance, the combination therapy in the treatment of diabetes may have a positive effect on treatment continuation and blood glucose control.

However, if the target blood glucose level is not able to be achieved despite the dual combination therapy, an additional combination of a new class of hypoglycemic enhancers may be considered, and there has been no study on the therapeutic effect or side effects when a novel glitazone-based drug, lobeglitazone, is administered together with dual combination therapy of other classes.

An object of the present invention is to provide a triple combination therapy for treating type 2 diabetes in patients whose blood glucose is not adequately controlled by the combination therapy of metformin and sitagliptin.

The present disclosure will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present disclosure may be applied to each of the other descriptions and embodiments. In other words, all combinations of various elements disclosed in the present disclosure fall within the scope of the present disclosure. In addition, it cannot be considered that the scope of the present disclosure is limited by specific descriptions described below.

In one general aspect, the present invention provides a pharmaceutical composition for treating type 2 diabetes comprising lobeglitazone, metformin and sitagliptin, or pharmaceutically acceptable salts thereof as active ingredients.

The present invention provides a pharmaceutical composition comprising a specific combination of combination drug capable of achieving an efficient therapeutic effect when a plurality of anti-diabetic agents having different action mechanisms are administered in combination so as to simultaneously act on multiple targets for the treatment of type 2 diabetes.

In order to achieve clinically significant treatment of type 2 diabetes with multiple etiologies and high complexity, it is necessary to select anti-diabetic drugs used in combination therapy and to set a target patient group capable of showing the optimal treatment effect depending on this combination therapy, wherein the setting of the patient group to which the combination drug is administered has meaning as a factor that allows the drug to fully exert its efficacy along with the target disease or drug effect for medicinal use.

Specifically, the present invention provides a pharmaceutical composition for treating patients with type 2 diabetes who do not respond to a combination therapy of metformin and sitagliptin, comprising: lobeglitazone, metformin and sitagliptin, or pharmaceutically acceptable salts thereof as active ingredients.

The composition of the present invention comprises the following components as active ingredients:

i) metformin or a pharmaceutically acceptable salt thereof;

ii) sitagliptin or a pharmaceutically acceptable salt thereof; and

iii) lobeglitazone or a pharmaceutically acceptable salt thereof.

In the present invention, metformin is a biguanide-based drug, which is a compound represented by the following Chemical Formula 1:

[Chemical Formula 1]

.

The metformin may be a pharmaceutically acceptable salt in various forms, and according to an embodiment of the present invention, the metformin may be metformin hydrochloride.

In the present invention, sitagliptin is a drug in the class of DPPIV inhibitors, which is a compound represented by the following Chemical Formula 2:

[Chemical Formula 2]

.

The sitagliptin may be a pharmaceutically acceptable salt in various forms, and according to an embodiment of the present invention, the sitagliptin may be sitagliptin phosphate hydrate.

In the present invention, lobeglitazone is a glitazone-based drug, which is a compound represented by the following Chemical Formula 3:

[Chemical Formula 3]

.

The lobeglitazone may be a pharmaceutically acceptable salt in various forms, and according to an embodiment of the present invention, the lobeglitazone may be lobeglitazone sulfate.

The patient with type 2 diabetes to be treated in the present invention may be a patient who does not respond to the combination therapy of metformin and sitagliptin, for example a patient whose blood glucose is not properly controlled by the combination therapy, and specifically, may be a patient whose blood glucose is not controlled below the target value, more specifically, a patient with a glycated hemoglobin (HbA1c) value of 7.0 to 10%, despite the combination therapy of metformin and sitagliptin for at least 10 weeks or more.

A patient to be treated using the pharmaceutical composition of the present invention may be a patient who satisfies all of the following criteria:

1) male or female between the ages of 19 and 80,

2) patients with type 2 diabetes,

3) patients who have taken oral hypoglycemic agents for at least 8 weeks and whose glycated hemoglobin (HbA1c) is 7% or more and 10% or less as a result of screening (or patients whose HbA1c measured after 2 weeks of combination therapy with metformin and sitagliptin is 7% or more and 10% or less),

4) patients with a BMI of 21 kg/m² or more and 40 kg/m² or less, and

5) patients with C-peptide ≥ 1.0 ng/ml.

In addition, patients who satisfy one or more of the following criteria may be excluded from subjects to be treated using the pharmaceutical composition of the present invention:

1) patients with type 1 diabetes or secondary diabetes,

2) patients who received insulin treatment for more than 7 days in a continuous or discontinuous manner within 3 months prior to screening,

3) patients who have been treated with TZD-based drugs within 3 months prior to screening, or who have experienced hypersensitivity or serious adverse events to the main component or other components of TZD, biguanides, or sitagliptin in the past,

4) patients who have been treated with oral or parenteral corticosteroids chronically (more than 7 consecutive days) within 1 month prior to screening,

5) patients who have taken anti-obesity medication within 3 months prior to screening,

6) patients with a history of lactic acidosis or patients with genetic problems such as galactose intolerance, lapp lactase deficiency, glucose-galactose malabsorption, and the like,

7) patients with a history of acute or chronic metabolic acidosis including diabetic ketoacidosis,

8) patients with a history of proliferative diabetic retinopathy,

9) patients with severe infections, before and after surgery, or severe trauma,

10) patients with malnutrition, starvation, weakness, pituitary dysfunction or adrenal insufficiency,

11) patients with a history of malignant tumor within 5 years prior to screening (provided that differentiated thyroid carcinoma and localized basal cell carcinoma of the skin are allowed),

12) patients with a history of drug abuse or alcoholism confirmed within 12 weeks prior to screening through patient interview, diagnosis record and past treatment record,

13) patients with severe gastrointestinal disorders such as dehydration, diarrhea, and vomiting, and

14) patients with a history of myocardial infarction, heart failure (corresponding to class III and IV in New York Heart Association classification), cerebral infarction, cerebral hemorrhage, unstable angina, etc., within 6 months prior to screening.

15) patients corresponding to any of the following cases:

- patients with fasting plasma glucose (FPG) exceeding 270 mg/dL,

- patients with triglyceride (TG) of 500 mg/dL or higher,

- patients undergoing treatment for active liver disease, or patients with significant liver function abnormalities, such as AST or ALT greater than 3 times the upper limit of normal, total bilirubin greater than 2 times the upper limit of normal, and the like,

- anemic patients with Hb < 10.5 g/dL,

- a case where the TSH level is judged to be clinically significantly out of the normal range according to the judgment of the researcher,

16) patients with estimated glomerular filtration rate (eGFR by CKD-EPI) of less than 60 mL/min/1.73 m²,

17) patients with acute pancreatitis including hemorrhagic pancreatitis or necrotizing pancreatitis,

18) pregnant or lactating women, and

19) patients who do not consent to the use of appropriate contraceptive methods during the clinical trial period for subjects of childbearing potential.

The pharmaceutical composition of the present invention may be administered to the type 2 diabetic patient to appropriately control the patient's blood glucose without side effects, and specifically, may effectively reduce the HbA1c value.

According to an embodiment of the present invention, it was confirmed that the patient group administered with the composition of the present invention had mean HbA1c value decreased after 24 weeks compared to baseline, which showed a significant difference even compared to the patient group administered with lobeglitazone placebo, so that the composition of the present invention had a clinically excellent effect in the treatment of type 2 diabetic patients, specifically type 2 diabetic patients whose blood glucose was not adequately controlled by a combination therapy of metformin and sitagliptin.

In addition, the pharmaceutical composition of the present invention is able to improve glycemic parameters and lipid parameters while simultaneously reducing the HbA1c value of type 2 diabetic patients.

According to an embodiment of the present invention, it was found that the patient group administered with the composition of the present invention had significantly improved glycemic parameters in the analysis of changes in glycemic parameters at Week 24 compared to baseline, such as a decrease in fasting plasma glucose (FPG), a decrease of homeostasis model assessment for insulin resistance (HOMA-IR) which is a surrogate marker for insulin resistance, and an increase in HOMA-β which is a beta cell function evaluation index, an increase in quantitative insulin sensitivity check index (QUICKI) which is an insulin sensitivity index, and the like. In addition, the analysis of changes in lipid parameter at Week 24 compared to the baseline showed that the lipid parameters were significantly improved such as an increase in high density lipoprotein (HDL-C), a decrease in free fatty acid (FFA), a decrease in apolipoprotein B (Apo-B), a decrease in triglyceride (TG), a change in patterns of LDL-C particles (increase to Intermediate or Pattern A from Pattern B / decrease to Intermediate or Pattern B from Pattern A), and the like. It was confirmed from the above results that the composition of the present invention had clinically excellent effects in the treatment of type 2 diabetic patients by controlling the glycemic parameters and the lipid parameters.

Therefore, the pharmaceutical composition of the present invention may exhibit an effect of improving lipids related to dyslipidemia accompanying diabetes as well as glucose metabolism indexes, thus showing an effective therapeutic effect in the treatment of type 2 diabetes.

The pharmaceutical composition of the present invention may exhibit at least one of the following clinical characteristics by being administered to type 2 diabetic patients:

1) a decrease in fasting plasma glucose (FPG),

2) a decrease of homeostasis model assessment for insulin resistance (HOMA-IR),

3) an increase in HOMA-β,

4) an increase in quantitative insulin sensitivity check index (QUICKI),

5) an increase in high density lipoprotein (HDL-C),

6) a decrease in free fatty acid (FFA),

7) a decrease in apolipoprotein B (Apo-B),

8) a decrease in triglyceride (TG), and

9) a change in patterns of LDL-C particles.

The composition of the present invention may maintain the significant clinical effect for a long period of time on type 2 diabetic patients without side effects.

Specifically, according to an embodiment of the present invention, it was confirmed that the effect of reducing HbA1c and improving glycemic parameters and lipid parameters during the treatment period (0 to 24 weeks) was maintained in the extension period analysis after 52 weeks compared to the baseline. In addition, it was confirmed that the cross-administration group administered with lobeglitazone placebo during the treatment period but with lobeglitazone along with metformin and sitagliptin during the extension period (24 to 52 weeks) showed a significant effect on the reduction of HbA1c and the improvement of glycemic parameters and lipid parameters.

In the present invention, treatment refers to all activities including beneficial changes such as improvement, alleviation, amelioration, suppression, and the like, of symptoms of type 2 diabetic patients by administration of the composition. Specifically, the treatment may be an effective reduction in blood glucose in type 2 diabetic patients, such as a significant reduction in HbA1c, specifically may mean a statistically significant decrease among the composition of the present invention and the baseline and lobeglitazone placebo administration group.

The dosage of the pharmaceutical composition according to the present invention may include a pharmaceutically effective amount, that is, an amount sufficient to treat type 2 diabetes with a reasonable benefit/risk ratio applicable to medical prevention or treatment, and may be appropriately adjusted by the frequency and period of administration. Specifically, the dosage of the pharmaceutical composition according to the present invention is an amount effective for treating type 2 diabetic patients, particularly type 2 diabetic patients who do not respond to the combination therapy of metformin and sitagliptin, which is an amount that provides desired outcome or objective or subjective advantage in a subject.

According to an embodiment of the present invention, metformin may be administered as metformin hydrochloride at a dose of 500 to 2,000 mg/day, specifically 1,000 to 2,000 mg/day.

According to an embodiment of the present invention, sitagliptin may be administered as sitagliptin at a dose of 25 to 100 mg/day, specifically 100 mg/day.

According to an embodiment of the present invention, lobeglitazone may be administered as lobeglitazone sulfate at a dose of 0.4 to 2 mg/day, specifically 0.5 mg/day.

The composition of the present invention may be administered once a day or divided into several times within the daily dosage range of each active ingredient, specifically once or twice a day, and more specifically once a day.

The pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredient. Examples of the carrier, excipient and diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, but the carrier, excipient and diluent are not limited thereto.

The pharmaceutical composition of the present invention may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, and the like, external preparations, suppositories or sterile injection solutions according to conventional methods, respectively. Specifically, when formulated, the pharmaceutical composition of the present invention may be prepared using diluents or excipients such as commonly used fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants.

Solid preparation for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. The solid preparation may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, and the like. In addition, lubricants such as magnesium stearate, talc, etc., may be used in addition to simple excipients. Examples of liquid preparation for oral administration may include suspensions, internal solutions, emulsions, syrups, and the like. The liquid preparation may be prepared by adding various excipients such as wetting agents, sweeteners, aromatics, preservatives, and the like, in addition to commonly used diluents such as water, liquid paraffin, and the like.

Preparations for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried formulations, and suppositories, etc. Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate, may be used as non-aqueous solvents and suspending agents. As the base of the suppository, Witepsol, Macrogol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like, may be used.

Regarding the administration method, the composition of the present invention may be administered orally or parenterally depending on the desired method, and the parenteral administration may include intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. Specifically, the composition of the present invention may be administered orally.

The administration period of the pharmaceutical composition according to the present invention may be appropriately selected by those skilled in the art depending on the degree of improvement of the disease, the activity of the drug, the patient's age, weight, health, gender, the patient's sensitivity to the drug, etc. According to an embodiment, the administration period may be 24 weeks to 52 weeks, but is not limited thereto.

The composition of the present invention may be used alone or in combination with methods using surgery, hormone therapy, chemotherapy, and biological response modifiers for the treatment of type 2 diabetes.

In addition, in another aspect to achieve the above object, the present invention provides a method for controlling blood glucose or for treating type 2 diabetes comprising administering the pharmaceutical composition to a patient who does not respond to a combination therapy of metformin and sitagliptin.

In another aspect to achieve the above object, the present invention provides a combination for treating or improving type 2 diabetes, administered to a patient who does not respond to a combination therapy of metformin and sitagliptin, the combination comprising:

(i) a first agent comprising metformin or a pharmaceutically acceptable salt thereof;

(ii) a second agent comprising sitagliptin or a pharmaceutically acceptable salt thereof, and

(iii) a third agent comprising lobeglitazone or a pharmaceutically acceptable salt thereof.

In the present invention, the term 'combination' means a combination of two or more active substances in a formulation and a combination in the sense of individual formulations of active substances administered at specified intervals from each other in therapy. Thus, the term combination, when described in relation to the present invention, includes the clinical realization of co-administration of two or more therapeutically effective compounds.

In the combination of the present invention, the first agent, the second agent and/or the third agent may be administered parenterally or orally, respectively, or may specifically be administered orally.

In the combination of the present invention, the first agent, the second agent and the third agent may be administered simultaneously, sequentially or separately.

The combination of the present invention may be a combination formulation comprising the first agent, the second agent, and the third agent, specifically a combination formulation for oral administration.

In another aspect to achieve the above object, the present invention provides use of the composition or combination for preventing or treating type 2 diabetes.

In another aspect to achieve the above object, the present invention provides use of the composition or combination for use in the preparation of a medicament for use in preventing or treating type 2 diabetes.

Matters described in all compositions, combinations, treatment methods, and uses of the present invention are equally applied unless they contradict each other.

The novel combination therapy of the present invention may achieve clinically significant effects in patients with type 2 diabetes such as reduction of blood glucose, long-term maintenance of controlled blood glucose, and improvement of lipids related to dyslipidemia accompanying diabetes as well as various glucose metabolism indexes in type 2 diabetes patients whose blood glucose is not adequately controlled by a combination therapy of metformin and sitagliptin.

FIG. 1 is a graph (mFAS) showing changes in mean HbA1c for each visit during the treatment period (weeks 0 to 24).

FIG. 2 is a graph (mFAS) showing changes in mean HbA1c for each visit over the entire period (weeks 0 to 52).

Hereinafter, the constitution and effects of the present invention will be described in more detail through the following Examples. These Examples are only provided for illustrating the present invention, but the scope of the present invention is not limited by these Examples.

Example 1. Clinical trial design and analysis method

1.1 Test method

This clinical trial is a multicenter, randomized, double-blind, parallel, placebo-controlled, therapeutic confirmatory phase 3 clinical trial to compare and evaluate the efficacy and safety when lobeglitazone is additionally co-administered in patients with type 2 diabetes whose blood glucose is not adequately controlled by the combination therapy of metformin and sitagliptin.

This clinical trial was composed of screening, run-in period, treatment period, and extension period. Subjects were evaluated and tested according to the plan for each visit on Visit 3 (Day 0), Visit 4 (Week 4), Visit 5 (Week 12), and Visit 6 (Week 24) during the treatment period, and E-V1 (Week 28), E-V2 (Week 40), and E-V3 (Week 52) during the extension period.

Only for test subjects who consented to the document to participate in the clinical trial, clinical trials were conducted according to the following criteria:

1) patients who have taken Metformin 1000 mg or more and Sitagliptin 100 mg per day for at least 10 weeks in combination without any change in dose, when receiving the screening results that HbA1c is 7% or more and 10% or less and other selection/exclusion criteria are satisfied, immediately entered the 2-week run-in period, or

2) patients who have not taken Metformin 1000 mg or more and Sitagliptin 100 mg per day for at least 10 weeks in combination without any change in dose, when receiving the screening results that HbA1c is 7% or more and 10% or less and other selection/exclusion criteria are satisfied, stopped taking other oral hypoglycemic agents for at least 10 weeks, and entered the 2-week run-in period after oral administration of Metformin 1000 mg or more and Sitagliptin 100 mg per day without any change in dose.

Patients corresponding to any of the following cases were tested:

① when taken with Metformin monotherapy or Sitagliptin monotherapy,

② when taken with Metformin ≥ 1000 mg/day and Sitagliptin 100 mg, but the duration of taking does not meet the criteria (at least 10 weeks), or

③ when taken with oral hypoglycemic agents other than Metformin ≥ 1000 mg/day and Sitagliptin 100 mg alone or in combination.

After the completion of the 2-week single blind run-in period, test subjects who received re-test results with glycated hemoglobin (HbA1c) of 7% or more and 10% or less were randomly assigned to either the lobeglitazone administration group or the placebo administration group while maintaining the existing dose of Metformin and Sitagliptin in the open state, wherein stratified randomization was performed based on the glycated hemoglobin (HbA1c) test result of less than or equal to 8.5% or greater than 8.5%. During the treatment period of 24 weeks, the subjects were double-blinded and administered with drugs for clinical trials.

Among the test subjects who completed the 24-week treatment period, all test subjects entered the extension period, except for those who meet the criteria for suspension and dropout or who do not want to enter the extension period, and the clinical trial was conducted on the corresponding subjects for up to 52 weeks. All subjects entering the extension period were equally orally administered with lobeglitazone for up to 52 weeks, regardless of the drugs for clinical trials administered during the 24-week clinical trial period, while being administered with Metformin and Sitagliptin at the existing dose without blinding.

1.2 Drugs for Clinical Trials

- Test drug: lobeglitazone sulfate 0.5 mg (0.415 mg as lobeglitazone)

- Control drug: lobeglitazone sulfate placebo

- Combination drug: Metformin Hydrochloride (≥1,000 mg), Sitagliptin 100 mg (128.5 mg as Sitagliptin phosphate hydrate)

1.3 Endpoints

1.3.1 Efficacy endpoints

Primary efficacy endpoint

- Change in glycated hemoglobin (HbA1c) after 24 weeks compared to baseline

Secondary efficacy endpoint

- Change in glycemic parameters after 24 weeks and 52 weeks compared to baseline

- Change in lipid parameters after 24 weeks and 52 weeks compared to baseline

- Change in HbA1c after 52 weeks compared to baseline

- Percentage of subjects whose glycated hemoglobin (HbA1c) was less than 6.5% or 7% at Week 24 and Week 52

1.3.2 Safety endpoints

- Vital signs, physical examination, clinical adverse events, laboratory tests, and the like.

1.4 Number of subjects

◆ Number of target subjects: 226 (113 per group, considering a dropout rate of 15%)

◆ Number of subjects to be screened: 336

◆ Number of subjects for record: 231

◆ Number of subjects who completed:

- Treatment period (0-24 weeks): 217

- Extension period (24~52 weeks): 195

◆ Number of subjects included in analysis

1.5 Selection of test subjects

1.5.1 Selection criteria

◆ Screening Time Visit 1 (Screening Time)

1) male or female between the ages of 19 and 80,

2) patients with type 2 diabetes,

3) patients who have taken oral hypoglycemic agents for at least 8 weeks and received screening results with glycated hemoglobin (HbA1c) of 7% or more and 10% or less,

4) patients with a BMI of 21 kg/m² or more and 40 kg/m² or less,

5) patients with C-peptide ≥ 1.0 ng/ml,

6) patients who consented to the document, and

◆ Time before entering the treatment period Visit 2-1

7) patients with glycated hemoglobin (HbA1c) of 7% or more and 10% or less, measured after completion of the run-in period.

1.5.2 Exclusion criteria

◆ Screening Time Visit 1 (Screening Time)

1) patients with type 1 diabetes or secondary diabetes,

8) patients with a history of proliferative diabetic retinopathy,

9) patients with severe infections, before and after surgery, or severe trauma,

15) patients corresponding to any of the following cases:

- patients with fasting plasma glucose (FPG) exceeding 270 mg/dL,

- patients with triglyceride (TG) of 500 mg/dL or higher,

- anemic patients with Hb < 10.5 g/dL,

18) pregnant or lactating women,

19) patients who do not consent to the use of appropriate contraceptive methods during the clinical trial period for subjects of childbearing potential,

20) patients currently participating in other clinical trials under research and development other than the present clinical trial, or who have participated in other clinical trials within 4 weeks prior to screening, or

21) patients unable to participate in clinical trials according to the judgment of other researchers.

1.6 Statistical analysis method

1.6.1 Analysis of efficacy endpoints

1.6.1.1 Primary efficacy evaluation

The primary purpose of the present clinical trial was to evaluate the change in glycated hemoglobin (HbA1c) after 24 weeks compared to baseline to confirm the superiority of lobeglitazone combination therapy. Descriptive statistics for baseline, 24-week glycated hemoglobin (HbA1c) values and the change after 24 weeks were presented for each administration group, and significance between groups was confirmed through analysis of covariance (ANCOVA) considering HbA1c stratification conditions (HbA1c ≤ 8.5% or HbA1c > 8.5%) of baseline and treatment group as factors.

1.6.1.2 Secondary efficacy evaluation

Descriptive statistics for baseline, glycemic parameters (fasting plasma glucose, HOMA-IR, HOMA-β, and QUICKI), lipid parameters (total cholesterol, triglycerides, LDL-C, HDL-C, non-HDL-C, small dense LDL-C, FFA, and Apo-AI/B/CIII) at 24 and 52 weeks, glycated hemoglobin (HbA1c) values at 52 weeks, and changes compared to baseline after 24 and 52 weeks for each administration group were presented. Between-group comparison was made through analysis of covariance (ANCOVA) considering the baseline HbA1c stratification condition (HbA1c ≤ 8.5% or HbA1c > 8.5%) and the treatment group as factors. In addition, the number and percentage (%) of subjects with glycated hemoglobin (HbA1c) of less than 6.5% or 7% at Week 24 and Week 52 were presented, and group comparisons were performed using Pearson's chi-square test or Fisher's exact test according to the expected frequency.

1.6.2 Analysis of safety endpoints

1.6.2.1 Adverse events

Adverse events were coded using MedDRA version 20.1. Based on the time of onset, adverse events were classified into adverse events that occurred before administration of drugs for clinical trials and those that occurred after administration of drugs for clinical trials, wherein as to the adverse events that occurred after the administration of drugs for clinical trials, the number of test subjects and the incidence rate (%) were presented for each administration group according to system organ class (SOC) and preferred term (hereinafter referred to as PT), and between-group comparison was performed using Pearson's chi-square test or Fisher's exact test according to the expected frequency. The adverse events were analyzed by dividing into serious adverse events (SAE), adverse drug reactions (ADR), serious adverse drug reactions (SADR), and adverse events by severity, and presented as Data Listing if necessary according to the number of test subjects expressed.

1.6.2.2 Laboratory test

The number and percentage (%) of test subjects evaluated as clinically significant abnormalities were presented by baseline, Week 24, and Week 52. Changes before and after administration were compared through the McNemar test, and between-group comparison was performed through Pearson's chi-square test or Fisher's exact test according to the expected frequency.

1.6.2.3 Vital signs, body measurements

Results for vital signs and body measurements (weight, waist circumference) were presented as descriptive statistics at each time point. The paired t-test was performed to confirm within-group changes, and the independent sample t-test was performed to confirm between-group comparison.

Example 2. Treatment period analysis result

2.1 Efficacy evaluation result

2.1.1 Primary efficacy endpoint: Change in mean HbA1c after 24 weeks compared to baseline

Table 1 shows the change in mean HbA1c after 24 weeks compared to baseline in mFAS which is the main analysis group, and FIG. 1 shows the mean HbA1c for each visit during the treatment period (0 to 24 weeks).

The change in mean HbA1c between the treatment groups after 24 weeks compared to baseline was compared between the administration groups, and as a result, the test group showed a statistically significant decrease (-1.00%, p<0.0001), whereas the control group showed an increasing trend (+0.02%, p=0.7944), showing a statistically significant difference when comparing the administration groups (p<0.0001). As a result, it was confirmed that the HbA1c reduction effect of the test group was superior to that of the control group, which showed a similar trend in the mPPS analysis.

[Table 1]

2.1.2 Secondary efficacy endpoint

2.1.2.1 Changes in glycemic parameters at Week 24 compared to baseline

Table 2 shows changes in glycemic parameters after 24 weeks compared to baseline.

As a result of mFAS analysis, the test group showed statistically significant improvement in all glycemic parameters (FPG, HOMA-IR, HOMA-β, and QUICKI) after 24 weeks compared to baseline, and confirmed statistically significant differences even at the time of between-group comparison, which showed excellent improvement in glucose metabolism indexes compared to the control group. These results were also the same in the mPPS assay.

- A significant decrease in FPG (fasting plasma glucose) was seen in the test group, whereas a significant increase thereof was confirmed in the control group.

- A significant decrease in HOMA-IR which is a surrogate marker for insulin resistance was also seen in the test group, whereas an increase thereof was confirmed in the control group.

- A significant increase in HOMA-β known as a beta cell function evaluation index, was also seen in the test group, whereas a significant decrease thereof was confirmed in the control group.

- QUICKI for insulin sensitivity evaluation was significantly increased in the test group, whereas no significant change was confirmed in the control group.

[Table 2]

2.1.2.2 Changes in lipid parameters at Week 24 compared to baseline

Changes in TC, TG, LDL-C, HDL-C, Non-HDL-C, FFA, Apo-AI, Apo-B, and Apo-CIII

Table 3 shows changes in lipid parameters after 24 weeks compared to baseline.

As to HDL-C, FFA, and Apo-B values, the test group showed statistically significant lipid improvement compared to the control group, and no difference between the administration groups was found in other lipid parameters. As to TG values, there was no statistically significant difference when compared between the administration groups, but the test group showed a statistically significant decrease after 24 weeks of administration compared to the baseline. These results showed a similar trend even in mPPS analysis.

[Table 3]

Small Dense LDL-C

Changes in small dense LDL-C after 24 weeks compared to baseline are shown in Table 4.

The number of subjects with improved LDL-C particle patterns from 'Pattern B' before administration to 'Intermediate' or 'Pattern A' after 24 weeks was 11 (9.82%) and 14 (12.50%) in the test group, respectively, and 9 (8.18%) and 4 (3.64%) in the control group, respectively, which confirmed that the number of subjects in the test group was greater than that of the control group. On the other hand, the number of subjects with deteriorated LDL-C particle patterns from 'Pattern A' before administration to 'Intermediate' or 'Pattern B' after 24 weeks was 6 (5.36%) and 1 (0.89%) in the test group, respectively, and 9 (8.18%) and 2 (1.82%) in the control group, respectively, which confirmed that the number of subjects in the control group was greater than that of the test group.

The test group showed a significant pattern change of LDL particles after 24 weeks compared to before administration, whereas the control group showed no significant change, and there was no statistically significant difference between groups. These results were similar even in mPPS analysis results.

[Table 4]

2.1.2.3 Percentage of test subjects with glycated hemoglobin (HbA1c) of less than 6.5% or 7% at Week 24

Table 5 shows the percentage of test subjects with glycated hemoglobin (HbA1c) of less than 6.5% or 7% at Week 24.

In both the percentage of subjects with glycated hemoglobin (HbA1c) of less than 6.5% and less than 7% at Week 24, the test group was statistically significantly higher than the control group, and this result was also confirmed in the mPPS analysis.

[Table 5]

2.2 Safety evaluation results

Table 6 shows the total incidence rate of adverse events (Safety set) during the treatment period (0 to 24 weeks).

[Table 6]

2.2.1 Treatment-emergent adverse event (TEAE)

During the treatment period, 67 out of 231 subjects (29.00%, 87 cases) in the safety set developed one or more adverse events, and there was no significant difference between the administration groups in total incidence rate of adverse event (p=0.6333).

Most of the adverse reactions reported were of moderate severity or less, and the causal relationship with drugs for clinical trials was evaluated as 'no relevance' or 'less relevance'.

2.2.2 Adverse Drug Reaction (ADR)

Adverse drug reactions were reported in 33 (14.29%, 43 cases) out of 231 subjects in the safety set, and no statistically significant difference was observed between the administration groups (p=0.3611). There was no statistically significant difference in the comparison between the administration groups for each detailed adverse event incidence rate (all p>0.05). Most of the reported adverse drug reactions were known adverse reactions that had already been reported in previous clinical trials of drugs for clinical trials.

2.2.3 Serious Adverse Event (SAE)

Adverse drug reactions were reported in 6 subjects (2.60%, 6 cases) out of 231 subjects in the safety set, and no statistically significant difference was confirmed between the administration groups (p=1.0000). When comparing the administration groups for each detailed adverse event, there were no item showing a statistically significant difference (all p>0.05). Except for 'Pneumonia', all were evaluated to have no causal relationship with drugs for clinical trials, and most of the test subjects were confirmed to be recovering or recovered with the co-administration of therapeutic drugs.

2.2.4 Serious Adverse Drug Reaction (SADR)

One case (pneumonia) was reported in 1 (0.43%) of 231 subjects in the safety set, and no statistically significant difference was identified between the administration groups (p=1.0000). 'Pneumonia' was a known adverse reaction that had already been reported in previous clinical trials of drugs for clinical trials, and the subject recovered with co-administration of therapeutic drugs during the clinical trial period.

2.2.5 Laboratory test

After 24 weeks of administration, hematology test, glycemic parameters test, urinalysis, and other laboratory tests were performed, and as a result, 1 test subject was evaluated as showing clinically significant abnormalities in the eosinophils in hematology test, BUN, creatinine, and eGFR (CKD-EPI) in general chemistry test, and microalbumin/creatinine ratio in urine test, respectively, and 2 test subjects were evaluated as showing clinically significant abnormalities in TSH section of other laboratory tests (all p=1.0000). There were no test subjects who showed abnormality in all other test items.

2.2.6 Other

From the results of vital signs, body measurements, physical examinations, and other tests (electrocardiogram, fundus examination, and bone density test) after administration of drugs for clinical trials compared to before administration thereof during the treatment period, no significant differences were observed between the administration groups in all items except diastolic blood pressure, weight, and waist circumference.

2.3 Conclusion on evaluation of treatment period

In the clinical trial during the treatment period, changes in HbA1c at Week 24 compared to baseline in test group and control group, the primary efficacy endpoint, were confirmed. As a result, it was confirmed that the HbA1c reduction effect of the test group was superior to that of the control group. As a result of the secondary efficacy evaluation, the test group statistically significantly improved all glycemic parameters (FPG, HOMA-IR, HOMA-β, and QUICKI) after 24 weeks compared to baseline. Further, a percentage of subjects achieving HbA1c less than 6.5% and a percentage of subjects achieving HbA1c less than 7% at 24 weeks were also found to be statistically significantly higher in the test group than in the control group. In addition, after 24 weeks of administration, it was confirmed that the test group showed a statistically significant improvement compared to the control group in some lipid parameters (HDL-C, FFA, and Apo-B), and in the small dense LDL pattern analysis result, only the test group showed significant pattern changes compared to the baseline. In addition, the test group significantly improved Adiponectin and Leptin compared to the control group.

During the treatment period, it was reported that 67 (29.00%) out of 231 subjects in the safety set developed 87 cases of treatment-emergent adverse event and 33 (14.29%) subjects developed 43 cases of adverse drug reaction. It was confirmed that 6 (2.60%) subjects developed 6 cases of serious adverse event, and the serious adverse drug reaction was 1 case of pneumonia in the test group, wherein the pneumonia patient recovered without sequelae. Most of the adverse reactions that occurred were mild or moderate, and most of the adverse drug reactions were known adverse reactions that had already been reported in previous clinical trials of drugs for clinical trials, and no other notable safety issues were identified. In addition, no significant differences were observed between the administration groups in all items of other safety-related test results including laboratory tests, physical examinations, and other test results. After 24 weeks of administration, statistically significant differences between the administration groups were confirmed in diastolic blood pressure, weight, and waist circumference, but these differences were not clinically meaningful results or only a level similar to that reported in clinical trials for approval of lobeglitazone. No significant differences were observed between the administration groups for other items.

Example 3. Extension period analysis result

3.1 Efficacy evaluation result

3.1.1 Change in HbA1c after 52 weeks compared to baseline

The mean HbA1c for each visit during the entire period (weeks 0 to 52) was shown in FIG. 2.

As a result of analyzing the change in HbA1c for 52 weeks, the change in mean HbA1c after 24 weeks from baseline in the test group was -1.08% (± 0.10), and the change in mean HbA1c after 52 weeks was -1.03% (± 0.09), and statistically significant HbA1c reduction effects were shown at all time points. In the cross-administration group, the mean HbA1c change after 24 weeks from baseline was 0.00% (± 0.09), i.e., there was no statistically significant change (p=0.9828), but after 52 weeks, it was confirmed that the change in mean HbA1c was -0.89% (± 0.09), which was statistically significant decreased (p<0.0001).

It was confirmed in the test group that improved HbA1c during the 24-week treatment period was maintained up to 52 weeks, and in the cross-administration group that HbA1c, which was not controlled during the treatment period, decreased statistically significantly after co-administration of lobeglitazone during the extension period (Table 7).

[Table 7]

3.1.2 Changes in glycemic parameters at 52 weeks compared to baseline

Table 8 shows changes in glycemic parameters after 52 weeks compared to baseline.

As a result of fasting plasma glucose (FPG) analysis, the test group had a statistically significantly decrease in FPG after 24 weeks of administration, showing an excellent blood glucose lowering effect, and this FPG reducing effect was maintained until 52 weeks. It was confirmed in the cross-administration group that FPG increased significantly after 24 weeks compared to baseline, but when lobeglitazone was co-administered in the extension period, FPG gradually decreased, and decreased statistically significantly compared to baseline at Week 52.

The test group showed significant improvements after 24 weeks of administration in all of HOMA-IR which is a surrogate marker for insulin resistance, HOMA-β which is a beta cell function evaluation index, and quantitative insulin sensitivity check index (QUICKI) which is an insulin sensitivity index, and these improvement effects tended to be maintained up to 52 weeks. The cross-administration group showed improvements in HOMA-IR, HOMA-β, and QUICKI that had not been controlled for 24 weeks, when lobeglitazone was co-administered in the extension period.

[Table 8]

3.1.3 Changes in lipid parameters after 52 weeks compared to baseline

3.1.3.1 Changes in TC, TG, LDL-C, HDL-C, Non-HDL-C, FFA, Apo-AI, Apo-B, and Apo-CIII

Table 9 shows changes in TC, TG, LDL-C, HDL-C, Non-HDL-C, FFA, Apo-AI, Apo-B, and Apo-CIII after 52 weeks from baseline.

In the test group, there was no statistical significance in TG, but TG decreased continuously after 24 weeks and 52 weeks compared to baseline, and HDL-C increased. In the cross-administration group, both TG and HDL-C showed no statistically significant changes after 24 weeks compared to baseline, but after 52 weeks when lobeglitazone was co-administered in the extension period, TG decreased statistically significantly, and HDL-C increased statistically significantly.

With respect to FFA, it could be confirmed that the test group showed a statistically significant decrease after 24 weeks and 52 weeks from baseline, and the cross-administration group showed an increase compared to baseline until 24 weeks, and the change significantly decreased after co-administration of lobeglitazone in the extension period.

[Table 9]

3.1.3.2 Small Dense LDL-C

Changes in small dense LDL-C after 52 weeks compared to baseline are shown in Table 10.

It could be confirmed that both the test group and the cross-administration group an increase in percentage of subjects with improved LDL particle patterns from 'Pattern B' or 'Intermediate' before administration to 'Pattern A' after 52 weeks. Upon reviewing the detailed results, the percentage of subjects showing an improvement with 'Pattern A' at Week 52 was 28.42% (27/95) in the test group and 34.07% (31/91) in the cross-administration group, confirming that when compared with the results at Week 24, there was a significant increase, especially in the cross-administration group (percentage of subjects showing an improvement with Pattern A at Week 24: 23.21% (26/112) in the test group, 12.73% (14/110) in the control group). Changes in small dense LDL-C at Week 52 compared to baseline were statistically significant in both test and cross-administration groups.

[Table 10]

3.1.4 Percentage of test subjects with glycated hemoglobin (HbA1c) of less than 6.5% or 7% at Week 52

Table 11 shows the percentage of test subjects with glycated hemoglobin (HbA1c) of less than 6.5% or 7% at Week 52.

The percentage of subjects who achieved an HbA1c of less than 6.5% at Week 52 in the test group was 22.12%, similar to the result at Week 24 (21.74%). The percentage of subjects who achieved an HbA1c of less than 6.5% at Week 52 in the cross-administration group was 23.76%, confirming that when compared with the result at Week 24 (0.87%), the percentage of subjects achieving an HbA1c of less than 6.5% increased significantly after co-administration of lobeglitazone in the extension period. The percentage of subjects achieving an HbA1c of less than 7% at Week 52 also showed a similar trend to the percentage of subjects achieving an HbA1c of less than 6.5%.

[Table 11]

3.2 Safety evaluation results

Table 12 shows the total incidence rate of adverse events in the extension period (24 to 52 weeks).

[Table 12]

3.2.1 Treatment-Emergent Adverse Event (TEAE)

New adverse reactions that occurred during the extension period were reported in 23 subjects (22.12%, 39 cases) in the test group and 20 subjects (19.61%, 30 cases) in the cross-administration group among 206 patients in the safety set.

Most of the adverse reactions reported were of moderate severity or less, and the causal relationship with drugs for clinical trials was evaluated as 'no relevance' or 'less relevance'. As to the major adverse reactions of TZD-based drugs among the adverse reactions expressed, heart failure and AST/ALT increase were not reported, 3 cases of edema was reported in 2 subjects, and 2 cases of fracture was reported in 1 subject.

3.2.2 Adverse Drug Reaction (ADR)

New adverse drug reactions that occurred during the extension period were reported in 11 subjects (10.58%, 20 cases) in the test group and 7 subjects (6.86%, 11 cases) in the cross-administration group. For each adverse drug reaction, 'Chronic gastritis' and 'Gastrooesophageal reflux disease' were reported in 2 cases each in 2 subjects (1.92%) in the test group, and 'Constipation' was reported in 2 cases in 2 subjects (1.96%) in the cross-administration group. Other adverse drug reactions were reported in 1 case in 1 subject in both the test group and the cross-administration group.

3.2.3 Serious Adverse Event (SAE)

New serious adverse events that occurred during the extension period were 3 subjects (2.88%, 4 cases) in the test group and 4 subjects (3.92%, 4 cases) in the cross-administration group, and all of the adverse reactions were moderate except for two cases of severe adverse reactions (Facial bones fracture, Gastroenteritis). The causal relationship with drugs for clinical trials of the serious adverse reactions that occurred was all evaluated as 'no relevance' or 'less relevance', and most of adverse reactions recovered within the clinical trial period by co-administration of therapeutic drugs.

3.2.4 Serious Adverse Drug Reaction (SADR)

New serious adverse drug reactions that occurred during the extension period were 1 subject (0.96%, 1 case) in the test group and 3 subjects (2.94%, 3 cases) in the cross-administration group, and specifically, 'Facial paralysis' was reported in the test group and 'Thrombocytopenia', 'Chest pain', and 'Gastroenteritis' (one case for each response) were reported in the cross-administration group. Serious adverse drug reactions that occurred were of moderate severity except for one case of 'Gastroenteritis', and the causal relationship with drugs for clinical trials was judged to be 'less relevance', and all were confirmed to be recovered with co-administration of treatment drugs.

3.2.5 Laboratory test

When examining the laboratory test results before administration of drugs for clinical trials and at Week 52 after administration, no clinically significant abnormal subjects were observed at any time point in hematology, general chemistry, glycemic parameters, urinalysis, and other laboratory tests.

3.2.6 Other

From the results of vital signs, body measurements, physical examinations, and other tests (electrocardiogram, fundus examination, bone density test) at 52 weeks after administration, no statistically significant changes were observed compared to baseline in all items except for diastolic blood pressure, weight, and waist circumference.

3.3 Conclusion on evaluation of extension period

As a result of the efficacy evaluation of the extension period clinical trial, it was confirmed in the test group that the HbA1c reduction effect of the treatment period (0 to 24 weeks) was maintained until the extension period (24 to 52 weeks), and in the cross-administration group that HbA1c was not controlled and increased during the treatment period, but HbA1c decreased statistically significantly up to week 52 after lobeglitazone was co-administered in the extension period. In addition, the test group tended to maintain the improvement of glycemic parameters (FPG, HOMA-IR, HOMA-β, and QUICKI) and some lipid parameters (TG, HDL-C, and FFA) during the treatment period up to 52 weeks. In comparison, the cross-administration group showed the improvement effects after co-administration of lobeglitazone in the extended period. In addition, as a result of analyzing the percentage of subjects with improved small dense LDL-C and the percentage of subjects with HbA1c of less than 6.5% and 7% at Week 52 compared to baseline, it was confirmed in the test group that the percentage of subjects showing the improvement during the treatment period was maintained until the extension period, and in the cross-administration group that the percentage of subjects showing the improvement compared to the end of the treatment period increased when co-administered with lobeglitazone after participating in the extension period. In addition, it could be confirmed that adiponectin and leptin were statistically significantly improved after 52 weeks compared to baseline in the test group and cross-administration group.

Total adverse events that occurred during the extension period up to 52 weeks were reported in 23 subjects (22.12%, 39 cases) in the test group and 20 subjects (19.61%, 30 cases) in the cross-administration group. Adverse drug reactions were reported in 11 subjects (10.58%, 20 cases) in the test group and 7 subjects (6.86%, 11 cases) in the cross-administration group, and serious adverse reactions were reported in 3 subjects (2.88%, 4 cases) in the test group and 4 subjects (3.92%, 4 cases) in the cross-administration group. As for serious adverse drug reactions, 'Facial paralysis' was reported in the test group, and 'Thrombocytopenia', 'Chest pain', and 'Gastroenteritis' were reported one case each in the cross-administration group. In addition, no specific findings were reported in the results of other laboratory tests and physical examinations related to the safety. After 52 weeks of administration, a decrease in diastolic blood pressure was confirmed in the vital signs, but it was not a clinically meaningful change, and the weight gain confirmed in the body measurement results was similar to that reported for the same TZD-based drug. In other items, no significant differences were observed within the entire test subject group.

Claims

A pharmaceutical composition for treating patients with type 2 diabetes who do not respond to combination therapy of metformin and sitagliptin, comprising: lobeglitazone, metformin and sitagliptin, or pharmaceutically acceptable salts thereof as active ingredients.
The pharmaceutical composition of claim 1, wherein the metformin is metformin hydrochloride.
The pharmaceutical composition of claim 1, wherein the sitagliptin is sitagliptin phosphate hydrate.
The pharmaceutical composition of claim 1, wherein lobeglitazone is lobeglitazone sulfate.
The pharmaceutical composition of claim 1, wherein the patient has a glycated hemoglobin (HbA1c) value of 7.0 to 10% with a combination therapy of metformin and sitagliptin for at least 10 weeks or more prior to administration of the composition.
The pharmaceutical composition of claims 1 to 4, wherein the composition reduces the value of HbA1c.
The pharmaceutical composition of claims 1 to 4, wherein the composition exhibits at least one glycemic parameter improving effect selected from the group consisting of a decrease in fasting plasma glucose (FPG), a decrease of homeostasis model assessment for insulin resistance (HOMA-IR), an increase in HOMA-β, and an increase in quantitative insulin sensitivity check index (QUICKI).
The pharmaceutical composition of claims 1 to 4, wherein the composition exhibits at least one lipid parameter improving effect selected from the group consisting of an increase in high density lipoprotein (HDL-C), a decrease in free fatty acid (FFA), a decrease in apolipoprotein B (Apo-B), a decrease in triglyceride (TG), a change in patterns of LDL-C particles.
The pharmaceutical composition of claim 2, wherein the metformin is administered at 1,000 mg/day or more.
The pharmaceutical composition of claim 3, wherein the sitagliptin is administered at 100 mg/day.
The pharmaceutical composition of claim 4, wherein the lobeglitazone is administered at 0.5 mg/day.
The pharmaceutical composition of claim 1, wherein the composition is administered orally once a day.
A combination for treating or improving type 2 diabetes, administered to a patient who does not respond to a combination therapy of metformin and sitagliptin, the combination comprising:

(i) a first agent comprising metformin or a pharmaceutically acceptable salt thereof;

(ii) a second agent comprising sitagliptin or a pharmaceutically acceptable salt thereof, and

(iii) a third agent comprising lobeglitazone or a pharmaceutically acceptable salt thereof.
The combination of claim 13, wherein each agent is administered simultaneously, sequentially or separately.
The combination of claim 13, wherein the combination is a combination formulation for oral administration.