RU2721406C1 - Medicinal complex for treating type 2 diabetes and diabetic dyslipidemia - Google Patents

Abstract

FIELD: medicine; pharmaceuticals.SUBSTANCE: invention refers to medicine and pharmacy. Disclosed is a combined medicinal preparation for treating type 2 diabetes and dyslipidemia in diabetic patients, comprising a peptidase IV inhibitor gemigliptin or its salt, an inhibitor of HMG-CoA reductase, rosuvastatin or its salt and an excipient of calcium hydrophosphate dihydrate.EFFECT: technical result: invention provides effective control of blood sugar levels and reduced risk factors of cardiovascular diseases; wherein calcium hydrophosphate dihydrate (trade name DI-TAB, Innophos) plays the role of stabilizer of both active ingredients, gemigliptin (unstable under alkaline conditions) and rosuvastatin (stable in alkaline conditions and unstable in acidic conditions, therefore in usual dosage forms a strong base is often used as its excipient).11 cl, 2 dwg, 28 tbl

Description

FIELD OF THE INVENTION

The present invention relates to a combination preparation for the effective treatment of type 2 diabetes and dyslipidemia in diabetic patients. More specifically, the present invention provides a combination preparation comprising hemigliptin, which is a dipeptidyl peptidase IV inhibitor, or a pharmaceutically acceptable salt thereof, and rosuvastatin, which is an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, for effectively controlling blood glucose and reducing factor risk of cardiovascular disease.

BACKGROUND OF THE INVENTION

In 2011, the International Diabetes Federation (IDF) estimates that 366 million people worldwide had diabetes. In addition, IDF reports that 80% of people with diabetes live in low- and middle-income countries, and about 36% of people with diabetes live in the Western Pacific, including Korea. However, given that about 183 million people have diabetes but are not diagnosed, IDF estimates that more than 549 million people have diabetes in the world, and diabetes has been reported to cause 4.6 million deaths in 2011. (International Diabetes Federation, One out of ten adults will have diabetes by 2030, Press release, Brussels, November 14, 2011).

Diabetes is a metabolic disorder in which blood glucose levels are high due to a deficiency in insulin secretion, a deficiency in insulin action, or both. Type 1 diabetes is the result of the destruction of pancreatic beta cells (β cells) and is a serious disease that can cause ketosis if left untreated. In patients with type 1 diabetes, blood glucose levels should be monitored by insulin treatment. Type 1 diabetes usually occurs in children or young people, but it can occur in adults who are not obese, and the first symptom of high blood glucose appears over the years. Type 2 diabetes, the number of cases of which has increased recently, ranges from 90 to 95% of all cases of diabetes. Type 2 diabetes is a complex disease, and its mechanism is still unknown. This usually occurs in adults, but also occurs in adolescents. Its symptoms are not serious and manifest in various forms. These symptoms include beta-cell dysfunction, peripheral insulin resistance, abnormal glucose metabolism in the liver, etc. In type 2 diabetes, glycemic control becomes more difficult over time, and therefore, a new hypoglycemic agent should be introduced every three or four years to properly control glycemia. In addition, proper glycemic control is difficult despite combination therapy and insulin therapy.

As recommended by the American Diabetes Association (ADA), when hemoglobin A1c (HbA1c) is 6.5% or more in patients with type 2 diabetes, treatment should be started or a new hypoglycemic agent should be administered. In addition, ADA recommended that the level of HbA1c be controlled as close to the non-diabetic range as possible, or be reduced to at least 7% as a treatment goal, and the treatment goal should be classified according to the period of the diabetic disease or CVD risk factor (CVD) ) in patients. (Standards of Medical Care in Diabetes. Diabetes Care. 2016; 39: S1-112).

Diabetes is a major risk factor for cardiovascular disease, while cardiovascular disease is a leading cause of death in adult diabetes patients. Hypertension and dyslipidemia are also major factors in cardiovascular disease, thereby significantly increasing the risk of cardiovascular disease. Therefore, in patients with type 2 diabetes mellitus, it is recommended that risk factors for cardiovascular disease be evaluated at least once a year. (Standards of Medical Care in Diabetes. Diabetes Care. 2016; 39: S1-112).

According to UKPDS, a large-scale clinical study conducted in the United Kingdom, it was reported that myocardial infarction or stroke and angina pectoris occurred in approximately 22% of patients with type 2 diabetes within 10 years after diagnosis, and approximately 30% of patients died from macrovascular complications. In this study, as a result of the analysis of risk factors for cardiovascular diseases, HDL-C (low-density lipoprotein cholesterol) shows the highest correlation, and then LDL-C (high-density lipoprotein cholesterol), HbA1c, systolic blood pressure and smoking are in order (Turner RC et al., British Medical Journal, 1998, Vol. 316, pp. 823-828). In this regard, the Steno-2 study was the first to show that effective control of many early-stage cardiovascular risk factors can prevent the risk of cardiovascular events or reduce mortality among patients with type 2 diabetes (Gaede P et al., The New England Journal of Medicine, 2003, Vol 348, pp. 383-393). This has shown the need for active monitoring of other multiple risk factors, as well as strict glycemic control to prevent cardiovascular disease in patients with diabetes.

When statins were used, it was known that lowering blood cholesterol, among many risk factors for cardiovascular disease, can reduce mortality from cardiovascular disease. According to a 4S study using simvastatin, when 20 mg of simvastatin was administered to patients with angina pectoris or myocardial infarction, mortality was reduced by about 30%. As a result, statins have been recognized as drugs that can reduce the incidence and mortality from cardiovascular disease by preventing the detachment of atherosclerotic plaque (Pedersen TR et al., Atherosclerosis Supplements, 2004, Vol. 5, pp. 81-87) . Most guidelines currently recommend statins as first-line drugs for dyslipidemia with LDL-C as the main target.

It is known that, as a rule, the risk of a serious vascular event, mortality from cardiovascular diseases and non-fatal myocardial infarction is reduced by 20-25% with a decrease in LDL-C by about 1.0 mmol / L, and in patients with a risk of cardiovascular diseases, the maintenance of LDL-C≤1.8 mmol / L or a decrease of 50% compared with the initial value shows a sufficient secondary preventive effect. These results did not differ in patients with diabetes. (Baigent C et al., Lancet, 2010, Vol. 376, pp. 1670-1681). From the results of many clinical trials and meta-analyzes, it has been confirmed that statins as therapeutic agents for dyslipidemia in patients with diabetes significantly reduce the risk of cardiovascular disease by lowering the concentration of LDL-C. Thus, statins have been recommended as therapeutic agents for dyslipidemia in patients with diabetes. In addition, even for patients who have a lower risk of cardiovascular disease (for example, patients without cardiovascular disease and under the age of 40), it was recommended that LDL-C be maintained at 100 mg / dl and consider using statins for lifestyle changes if there are several risk factors for cardiovascular disease. (Reiner Ž et al., European Heart Journal, 2011 Vol. 32, pp. 1769-1818)

That is, since both glycemic control and a decrease in risk factors for cardiovascular diseases directly affect the occurrence of cardiovascular diseases, access to complex treatment is mandatory for patients with type 2 diabetes.

Disclosure of invention

Technical challenge

Therefore, the technical task of the present invention is the provision of a combination drug that improves adherence to the drug in patients with type 2 diabetes and effectively treats dyslipidemia, which is one of the main risk factors for cardiovascular diseases in diabetes, and also controls the level of glucose in the blood.

The solution of the problem

To solve the above technical problem, the present invention provides a combination preparation comprising hemigliptin, which is an inhibitor of dipeptidyl peptidase IV, or a pharmaceutically acceptable salt thereof, and rosuvastatin, which is an inhibitor of HMG-CoA reductase, or a pharmaceutically acceptable salt thereof as active ingredients.

The present invention is described in detail below.

Hemigliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-IV), which was developed relatively recently. A DPP-IV inhibitor is a medicament for inhibiting the degradation of glucagon-like peptide-1 (GLP-1) by DPP-IV. GLP-1 is an incretin that plays a role in stimulating insulin secretion by beta cells, increasing peripheral tissue glucose uptake, inhibiting glucagon secretion by alpha cells, and decreasing liver glucose production.

Hemigliptin can be used in various forms of a pharmaceutically acceptable salt. In the present invention, examples of a pharmaceutically acceptable salt of hemigliptin include a salt of hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, trifluoroacetic acid, formic acid, maleic acid, oxalic acid, succinic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, ascorbic acid, malic acid and methanesulfonic acid, and most preferably a tartaric acid salt (tartrate) can be used .

Rosuvastatin is a statin drug that is an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA). Rosuvastatin has a structure similar to HMG-CoA, so it can treat dyslipidemia by inhibiting HMG-CoA reductase by competitive inhibition to delay cholesterol production.

Rosuvastatin can be used in various forms of a pharmaceutically acceptable salt. In the present invention, examples of a pharmaceutically acceptable salt of rosuvastatin include a calcium, ammonium, lithium, zinc or magnesium salt, and most preferably a calcium salt can be used.

In one embodiment of the present invention, the combination preparation may be a fixed dose combination, where hemigliptin or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof are contained in a single dosage form. In the present invention, it was confirmed that hemigliptin or its pharmaceutically acceptable salt and rosuvastatin or its pharmaceutically acceptable salt do not change their dissolution rates or pharmacokinetic properties in one dosage form without affecting each other, thus providing a combination of fixed doses.

In one embodiment of the present invention, a fixed dose combination may further include a stabilizer, a binder, a disintegrant, a lubricant, a bulking agent, and the like. as a pharmaceutically acceptable excipient. Examples of a binder include, but are not limited to, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, gelatin, alginate, corn starch and potato starch. Examples of the disintegrant include, but are not limited to, croscarmellose sodium, crospovidone and sodium starch glycolate. Examples of a lubricant include, but are not limited to, colloidal silica, aqueous silica, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, calcium stearate, stearic acid and talc. Examples of the bulking agent include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol and lactose.

In one embodiment of the present invention, a fixed-dose combination may include calcium hydrogen phosphate dihydrate (trade name: DI-TAB, Innophos), which acts as a stabilizer, as a pharmaceutically acceptable excipient. Since rosuvastatin is stable under alkaline conditions and unstable under acidic conditions, a strong base is often used as an excipient in conventional dosage forms. However, hemigliptin is unstable under alkaline conditions. The use of calcium hydrogen phosphate dihydrate can give stability to both active ingredients hemigliptin and rosuvastatin.

In one embodiment of the present invention, the combination preparation may be a two-layer tablet that includes a layer containing hemigliptin or a pharmaceutically acceptable salt thereof and a layer containing rosuvastatin or a pharmaceutically acceptable salt thereof. In the case of providing a combined preparation in the dosage form of a two-layer tablet, the dosage form can be obtained more easily without taking into account the differences in physicochemical properties between hemigliptin and rosuvastatin.

In one embodiment of the present invention, the bilayer tablet may further include a stabilizer, a binder, a disintegrant, a lubricant, a bulking agent, and the like. as a pharmaceutically acceptable excipient. Examples of a binder include, but are not limited to, polyvinyl acetate, vinylpyrrolidone-vinyl acetate copolymer, hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, gelatin, alginate, corn starch and potato starch. Examples of the disintegrant include, but are not limited to, croscarmellose sodium, crospovidone and sodium starch glycolate. Examples of a lubricant include, but are not limited to, colloidal silica, aqueous silica, magnesium stearate, sodium stearyl fumarate, glyceryl behenate, calcium stearate, stearic acid and talc. Examples of filler include, but are not limited to, microcrystalline cellulose, silicified microcrystalline cellulose, mannitol, lactose and lactose monohydrate.

In one embodiment of the present invention, the hemigliptin-containing layer of a two-layer tablet may preferably contain sodium stearyl fumarate as a lubricant. If sodium stearyl fumarate is contained in a layer comprising hemigliptin as a lubricant, this lubricant can give hemigliptin more stability compared to other lubricants.

In one embodiment of the present invention, a layer comprising rosuvastatin of a two-layer tablet may include calcium hydrogen phosphate dihydrate (trade name: DI-TAB, Innophos), which acts as a stabilizer, as a pharmaceutically acceptable excipient. If the filler contains calcium hydrogen phosphate dihydrate, the formation of impurities can be prevented, since it helps to stabilize rosuvastatin.

In one embodiment of the present invention, the combination preparation may preferably comprise from 25 to 100 mg of hemigliptin or a pharmaceutically acceptable salt thereof, and more preferably from 40 to 80 mg of hemigliptin or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the combination preparation may preferably comprise from 1 to 50 mg of rosuvastatin or a pharmaceutically acceptable salt thereof, and more preferably from 3 to 40 mg of rosuvastatin or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the combination preparation may include, for example, 50 mg of hemigliptin or its pharmaceutically acceptable salt and 5 mg of rosuvastatin or its pharmaceutically acceptable salt, 50 mg of hemigliptin or its pharmaceutically acceptable salt and 10 mg of rosuvastatin or its pharmaceutically acceptable salt, 50 mg of hemigliptin or its pharmaceutically acceptable salt and 20 mg of rosuvastatin or its pharmaceutically acceptable salt, or 50 mg of hemigliptin or its pharmaceutically acceptable salt and 40 mg of rosuvastatin or its pharmaceutically acceptable salt.

In one embodiment of the present invention, the combination preparation may be film coated. Substances present in the film coating layer may include, but are not limited to, conventional substances such as hydroxypropyl methylcellulose, polyvinylpyrrolidone, copovidone, the Opadry® series, the Eudragit® series.

Effects of the invention

In accordance with the present invention, there is provided a combination preparation comprising hemigliptin or a pharmaceutically acceptable salt thereof and rosuvastatin or a pharmaceutically acceptable salt thereof which can improve patient adherence, effectively treat dyslipidemia in diabetic patients, and also effectively treat type 2 diabetes by glycemic control.

Brief Description of the Drawings

FIG. 1 is a graph showing changes in Hb1Ac (%) at each visit.

FIG. 2 is a graph showing changes in LDL-C (mg / dl) at each visit.

The method of carrying out the invention

Further, the present invention is explained in more detail using the following examples. However, it should be understood that the scope of legal protection of the present invention is not limited to these examples.

Example 1: Getting a fixed dose

Received combinations of fixed doses of 3 compositions with different contents of rosuvastatin in accordance with the corresponding composition of Table 1.

Table 1 No. Ingredient Composition I (50/20) Composition II (50/10) Composition III (50/5) mg / tab. % mg / tab. % mg / tab. % 1 Rosuvastatin Calcium 20.8 4.00 10,4 2.00 5.2 1.00 2 Supertab 21AN ¹⁾ 215.8 41.50 222.2 42.73 225,4 43.35 3 Prosolv SMCC 50 ²⁾ 100 19.23 104 20.00 106 20.38 4 DI-TAB ³⁾ 44 8.46 44 8.46 44 8.46 5 Kollidon VA64 ⁴⁾ eighteen 3.46 eighteen 3.46 eighteen 3.46 6 Crospovidone 25 4.81 25 4.81 25 4.81 7 Hemigliptin tartrate 68.9 13.25 68.9 13.25 68.9 13.25 8 Magnesium stearate 7.5 1.44 7.5 1.44 7.5 1.44 9 Film coating twenty 3.85 twenty 3.85 twenty 3.85 Total 520 100 520 100 520 100 1) Supertab 21AN: Anhydrous Lactose
2) Prosolv SMCC 50: silicate microcrystalline cellulose
3) DI-TAB: calcium hydrogen phosphate dihydrate
4) Collidone VA64: vinylpyrrolidone-vinyl acetate copolymer

Example 2: Obtaining a two-layer tablet

Two-layer tablets of 3 compositions with different contents of rosuvastatin were obtained in accordance with the corresponding composition of Table 2. The production method is presented in Table 3.

table 2 No. Ingredient Composition I (50/20) Composition II (50/10) Composition III (50/5) mg / tab. % mg / tab. % mg / tab. % First layer 1 Hemigliptin tartrate 68.9 12.09 68.9 12.09 68.9 12.09 2 Flowlac 100 ¹⁾ 177.1 12.28 177.1 12.28 177.1 12.28 3 Microcrystalline cellulose 70.0 31.07 70.0 31.07 70.0 31.07 4 Croscarmellose Sodium 14.0 2.46 14.0 2.46 14.0 2.46 5 Sodium Stearyl Fumarate 10.0 1.75 10.0 1.75 10.0 1.75 Second layer 6 Rosuvastatin Calcium 20.8 3.56 10,4 1.82 5.2 0.91 7 Flowlac 100 ¹⁾ 110.6 19,4 121.0 21.23 126.2 22.14 8 Microcrystalline cellulose 40,0 7.02 40,0 7.02 40,0 7.02 9 DI-TAB ²⁾ 21.0 3.68 21.0 3.68 21.0 3.68 10 Kollidon VA64 ³⁾ 5,0 0.88 5,0 0.88 5,0 0.88 eleven Crospovidone 10.5 1.84 10.5 1.84 10.5 1.84 12 Magnesium stearate 2.1 0.37 2.1 0.37 2.1 0.37 Film coating 20,0 3,51 20,0 3,51 20,0 3,51 Total 570.0 100.0 570.0 100.0 570.0 100.0 1) Flowlac 100: Lactose Monohydrate
2) DI-TAB: calcium hydrogen phosphate dihydrate
3) Collidone VA64: vinylpyrrolidone-vinyl acetate copolymer Table 3 No. Way Ingredient Equipment 1 Weighing Hemigliptin tartrate Libra Rosuvastatin Calcium Microcrystalline cellulose Lactose Monohydrate Dicalcium Phosphate Dihydrate Copovidone Croscarmellose Sodium Crospovidone Magnesium stearate Sodium Stearyl Fumarate 2 Screening 1 Hemigliptin tartrate Cone mill 3 Mix 1 Prefabricated Screening 1 IBC Microcrystalline cellulose Lactose Monohydrate Croscarmellose Sodium 4 Lubrication 1 Prefabricated Mixing 1 IBC Sodium Stearyl Fumarate 5 Mix 2 Rosuvastatin Calcium IBC Lactose Monohydrate Microcrystalline cellulose Dicalcium Phosphate Dihydrate 6 Granulation 1 Prefabricated Mix 2 Cone mill 7 Mix 3 Prefabricated Granulation 1 IBC Copovidone Crospovidone Lactose Monohydrate 8 Lubrication 2 Prefabricated Mix 3 IBC Magnesium stearate 9 Tabletting Prefabricated Method 4 Tablet machine Prefabricated Method 8 10 Film coating Coating agent Coating Plant

Example 3: Stability Test

The stability test of the compositions of the two-layer tablets obtained in Example 2 was carried out under conditions of accelerated testing (40 ° C, 75% humidity) for 6 months. The results are presented in Table 4.

Table 4 Organic impurity (percentage of peak area,%) Composition Time (month) Analysis Hemigliptin (Gemi.) Rosuvastatin (Rosu.) Total Hemi. The rose. DP-IMP-1 DP-IMP-2 DP-IMP-3 5-oxo Lacton GS-IMP-1 Composition I (50/20) 0 100,2 98.0 0.38 0.00 0.01 0.05 0,03 0.00 0.60 3 98.5 97.7 1.13 0.02 0.01 0.18 0.19 0.00 1,69 6 97.8 97.4 1.19 0,03 0.02 0.28 0.30 0,03 2.23 Composition II (50/10) 0 102.3 99.3 0.41 0.00 0.01 0.06 0,03 0.00 0.71 3 101.6 98.8 1.13 0.02 0.01 0.17 0.37 0,03 2.06 6 101,4 98.3 1.24 0.05 0,03 0.30 0.87 0.14 3.43 Composition III (50/5) 0 100.7 101.8 0.41 0.00 0.01 0.05 0,03 0.00 0.89 3 99.9 10.9 1.36 0.01 0.01 0.17 0.32 0.01 2,38 6 98.9 100.6 1.48 0,03 0.02 0.29 0.45 0.04 3.10 Eligibility criteria - - ≤2.0 ≤0.2 ≤0.2 ≤1.5 ≤1.5 ≤0.2 ≤5.0

DP-IMP-1:

2 - [(2 S ) -6,6-difluoro-2,3,5,6,7,8-hexahydroimidazo [1,2- a ] pyridin-2-yl] -1- [2,4-di ( trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidin-7-yl] -1-ethanone

DP-IMP-2:

2,4-di (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3,4- d ] pyrimidin-8-one

DP-IMP-3:

(3 S ) -3-amino-4- (5,5-difluoro-2-oxopiperidino) -1- [8-hydroxy-2,4-di (trifluoromethyl) -5,6,7,8-tetrahydropyrido [3 , 4- d ] pyrimidin-7-yl] butan-1-one, tartaric acid salt

5-oxo:

Bis (6E) -7- [4- (4-fluorophenyl) -6-isopropyl-2- [methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R) -3-hydroxy-5-oxohept-6-ene acid

Lacton:

N- (4- (4-fluorophenyl) -5- (1E) -2 - [(2S, 4R) -4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl] ethenyl] -6-isopropylpyrimidin-2 -yl} -N-methylmethanesulfonamide

GS-IMP-1:

1 - [(S) -2 - [(3R, 5R, E) -7- {2- [N-Methyl (methylsulfonyl) amino] -4- (p-fluorophenyl) -6-isopropyl-5-pyrimidinyl} - 3,5-dihydroxy-6-heptenoylamino] -4- [2,4-bis (trifluoromethyl) -1,3,7-triase-5,6,7,8-tetrahydronaphth-7-yl] -4-oxobutyl] -5,5-difluoro-2-piperidinone

As can be seen from Table 4, from the results of the stability test, we can conclude that all compositions meet the criteria for acceptability, with regard to impurities.

Example 4: Clinical Study

To evaluate the efficacy and safety of the fixed-dose combination (FDC) of hemigliptin / rosuvastatin in patients with type 2 diabetes with concomitant dyslipidemia, in accordance with the guidelines for clinical trials of combination drugs, efficacy and safety were compared with each monotherapy.

According to the guidelines for clinical trials published by the Ministry of Food and Drug Safety of Korea, usually in phase III of clinical trials of therapeutic agents for diabetes, drugs should be administered for 24 weeks or more, and in phase III of clinical trials of therapeutic agents for For the treatment of dyslipidemia, medicines should be administered for 12 weeks or more. Thus, after administration of drugs for clinical trials within 24 weeks, which was considered sufficient to confirm the effectiveness of hemigliptin and rosuvastatin, the effectiveness was evaluated.

Metformin, which is intended for background therapy, is an oral hypoglycemic agent widely used as first-line monotherapy for patients with type 2 diabetes. As with other hypoglycemic agents for oral administration, since continuous glycemic control is difficult to obtain, a combination with a new oral hypoglycemic agent is necessary, which is effective and has good drug resistance. Since the effect of hemigliptin on lowering blood glucose levels when combined with metformin was confirmed in phase III of clinical trials, hemigliptin can be used in combination therapy with metformin. Therefore, in this clinical study, patients who did not respond to metformin were included in the study population.

In addition, given the dose-dependent adverse event and increased systemic exposure to rosuvastatin in Asian patients (about 2 (two) times higher than the average AUC and Cmax), known from various studies, the dose of rosuvastatin was forcibly increased at eight-week intervals from the initial dose to the maximum ( 20 mg) and efficacy and safety were evaluated every 8 weeks.

Since patients with type 2 diabetes with concomitant dyslipidemia, in case they are patients who do not respond to fixed dose metformin monotherapy (≥1000 mg / day), themselves or their representatives gave written consent, a screening test was conducted to determining whether patients meet inclusion / exclusion criteria. Subjects meeting the inclusion / exclusion criteria underwent a TLC (change in therapeutic life cycle) period of 2 weeks, and then they were given a total of 3 placebo tablets (placebo (hemigliptin / rosuvastatin FDC), placebo (hemigliptin) and placebo (rosuvastatin) ) during a 2-week introductory period using one blind study. In the case of administration of a therapeutic agent for dyslipidemia within 4 weeks prior to Visit 1, after a 4-week washout period, a 2-week TLC period and a 2-week induction period followed.

And then, subjects following each background drug regimen (metformin, ≥1000 mg / day) and a total of 3 placebo tablets (placebo (hemigliptin / rosuvastatin FDC), placebo (hemigliptin) and placebo (rosuvastatin)) for 2 -weekly introductory period to Visit 3 (randomization; week 0), which were 70% or more and which met inclusion / exclusion criteria according to the results of the test conducted at Visit 2, were randomly assigned to one of 3 groups.

And then, during the 24-week administration period, subjects were scheduled for visits after 8 weeks, 16 weeks and 24 weeks, and the total period of the clinical study, including the washout period, the TLC period and the induction period, was about 28-32 weeks.

The visit was planned based on Visit 3 (randomization; week 0), and then the valid period for Visit 4 (week 8), Visit 5 (week 16) and Visit 6 (week 24) was ± 10 days.

During the entire period of clinical trials, including the washout period, the TLC period and the introductory period, subjects stopped taking the drug for dyslipidemia (including additional dietary nutrition), which can affect lipid levels, with the exception of drugs for the clinical study, supported background therapy ( metformin, ≥1000 mg / day), and regular exercise / diet control was allowed without significant lifestyle changes.

Example 4-1: Introduced Treatment

After randomization, a total of 3 tablets (1 tablet each), as shown in Table 5, were administered once a day at the same time every morning for a total of 24 weeks. However, in some cases, subjects were allowed to receive them at the time prescribed immediately before the visit.

Table 5 Hemigliptin FDC
/ rosuvastatin hemigliptin rosuvastatin FDC Hemigliptin / Rosuvastatin Active agent Placebo Placebo Hemigliptin Placebo Active agent Placebo Rosuvastatin Placebo Placebo Active agent

Background therapy: metformin (≥1000 mg / day) was administered at the same time every day in accordance with the prescribed dose.

For all subjects, the dose of rosuvastatin was necessarily increased in accordance with the following method, regardless of the level of LDL-C. However, if the dose for the subject could not be forcibly increased for safety reasons, the cause was appropriately indicated in the medical history and the dose of rosuvastatin was adjusted.

- The introduction of rosuvastatin 5 mg every day for 8 weeks from Visit 3 (Week 0) to Visit 4 (Week 8).

- The introduction of rosuvastatin 10 mg every day for 8 weeks from Visit 4 (Week 8) to Visit 5 (Week 16).

- The introduction of rosuvastatin 20 mg every day for 8 weeks from Visit 5 (Week 16) to Visit 6 (Week 24).

Example 4-2: Method for the allocation of subjects to treatment groups

This clinical study compiled a randomization table using stratified block randomization with a double blind trial. For randomization of statistics, a sufficient size of randomization numbers is assigned when considering a predetermined block size and stratified factor (greater or less than 8.5% of HbA1c at Visit 2) using SAS® ver. 9.2. To randomize this clinical trial, an interactive Internet access system (IWRS) was used. Test persons had access to the IWRS website with the assigned ID and password and randomized by entering information about the subjects to be randomized in the order in which these subjects were enrolled in the test. Noob numbers along with a randomization number were assigned to maintain double anonymity, and the randomization code during an emergency should also be publicly available through the IWRS. The randomization code was not made public during this clinical trial.

Example 4-3: Blind Method

This clinical trial is a double-blind trial in which both the trial participants and the subjects did not know whether the drugs for the clinical trial are test drugs or a placebo to maintain the objectivity of the test results. However, since only a placebo was administered during the introductory period, this period passed with a simple blind trial.

To maintain double anonymity, this study used a placebo in the same dosage form that could not be distinguished from the test drug in appearance, and they differed in the randomized kit number. Thus, only the person responsible for the preparation of the randomization code, the code dispatcher and the IWRS dispatcher knew which group the subjects were assigned to, and the other study participants, including the test takers and the subjects, did not know.

After all test results have been entered into the database and access to the database has been protected, the person in charge of LG Chem. Ltd. (formerly LG Life Sciences Ltd.) could know the results of randomization.

Example 4-4: Compliance with the study treatment

To assess compliance, the number of test drugs / combination drugs provided to the subjects, returned drugs and drugs taken by the subjects was recorded on the patient’s medical record. Compliance with the regimen of the drug was calculated according to the following formula.

* Calculation of the dosage of each drug

[FDC hemigliptin / rosuvastatin and hemigliptin 50 mg]

- Visit 3 (Week 0) - Visit 4 (Week 8), Visit 4 (Week 8) - Visit 5 (Week 16), Visit 5 (Week 16) - Visit 6 (Week 24): 56 tablets (once a day within 8 weeks)

[rosuvastatin]

- Visit 3 (Week 0) - Visit 4 (Week 8): 5 mg * 56 days (1 tablet (5 mg) once a day for 8 weeks (single dose * amount per day))

- Visit 4 (Week 8) - Visit 5 (Week 16): X mg * 56 days (1 tablet (X mg) once a day for 8 weeks (single dose * amount per day))

- Visit 5 (Week 16) - Visit 6 (Week 24): X mg * 56 days (1 tablet (X mg) once a day for 8 weeks (single dose * amount per day))

- When a dose reduction of rosuvastatin was prescribed during Visit 3 - Visit 6, the dosage was calculated as X mg from the immediately preceding regular visit to the day before the start of the decline, and was calculated as the reduced dosage from the day the decrease began to the day before the next regular visit.

- X mg: daily dose of rosuvastatin taken by subjects during visit 4 - visit 6

- In case of retirement, compliance for the period of the visit was calculated based on the amount that the subject should have taken from the moment of the immediately preceding regular visit, and included in the general compliance.

Example 4-5: Performance Evaluation

The definitions of the parameters used to evaluate effectiveness are as follows:

• Hemoglobin A1c (HbA1c)

It is known that a decrease in HbA1c levels is associated with a reduced risk of microvascular complications. HbA1c is the most appropriate primary measure of efficacy, commonly used to measure the long-term status of glycemic control in type 1 and type 2 diabetes, and reflects the average blood glucose level over the past 2–3 months. Collected blood was analyzed using a standardized and validated HbA1c assay.

• Low Density Lipoprotein Cholesterol (LDL-C)

LDL-C levels are a key parameter in evaluating cholesterol-lowering therapy. Diseases of lipid metabolism are mainly related to hypercholesterolemia, and, in particular, there is a lot of epidemiological evidence for a correlation and a causal relationship between serum LDL-C and the risk of coronary artery disease. In addition, other clinical symptoms of atherosclerosis are associated with blood LDL-C levels. That is, since the risk of coronary artery disease decreases when LDL-C is reduced, this parameter is set as a surrogate indicator to prevent cardiovascular disease and death, which is the main goal of treating lipid metabolism diseases.

• Fasting Plasma Glucose (FPG)

As a parameter for evaluating efficacy, changes in fasting plasma glucose control after administration of drugs for a clinical study were investigated.

• Fasting serum insulin

In the case of a decrease in the amount of insulin in the blood in accordance with the use of an oral hypoglycemic agent, an improvement in insulin resistance can be considered along with consideration of a decrease in the level of HbA1c. As such, this parameter was designed to evaluate the effect of drugs used in a clinical trial.

• Proinsulin in fasting serum

In type 2 diabetes, insulin is not completely produced due to beta cell dysfunction, and the proinsulin concentration increases. This parameter was developed to evaluate the effect of clinical trial drugs on beta cell function by determining the fasting proinsulin / insulin ratio).

• C-peptide in fasting serum

The C-peptide is the part that separates during the formation of insulin from the proinsulin precursor. Since it is present in a 1: 1 ratio with insulin, the ability of pancreatic beta cells to secrete insulin can be indirectly confirmed through this. As such, this parameter was designed to evaluate the effect of drugs used in a clinical study.

• HOMA-β (evaluation of the homeostatic model)

This parameter was developed to evaluate the effect of clinical trial drugs on beta cell function and is calculated using the following formula.

• HOMA-IR (HOMA-Insulin Resistance)

This parameter was designed to evaluate the effect of drugs for clinical trials on insulin resistance.

• Body weight and waist circumference

Since obesity increases insulin resistance and cardiovascular disease, these parameters were developed to evaluate the effect of drugs for clinical research in this regard.

• Fasting lipid parameters (total cholesterol, HDL-C, triglycerides)

Since total cholesterol (TC), triglycerides (TG), and HDL-C are increasingly used as subparameters for the treatment of dyslipidemia, they should be evaluated as secondary assessed parameters. Hypertriglyceridemia is another independent risk factor for cardiovascular disease and a risk factor for pancreatitis. In contrast, low levels of HDL-C in the blood are a risk factor for cardiovascular disease, and in particular, it is often accompanied by hypertriglyceridemia in patients with type 2 diabetes and is considered as an important factor as LDL-C.

• Fasting LDL-C / HDL-C Ratio

Blood lipoprotein distribution characteristics leading to arteriosclerosis include high LDL-C, low HDL-C, and a concomitant increase in TG. The LDL-C / HDL-C ratio is a more convincing predictor of cardiovascular risk than LDL-C alone. It has been reported that if the ratio of LDL-C / HDL-C is> 5 or more, the likelihood of developing coronary artery disease within 8 years is 19.2%, and this probability is further increased with a concomitant increase in TG. This parameter was developed to evaluate the effect of drugs for clinical research in this regard.

• Apo A-I level in fasting serum, fasting serum Apo B level, fasting serum Apo B / Apo A-I ratio

Apo A-1 is the main apolipoprotein that makes up HDL-C and is considered a risk factor for cardiovascular disease, as is HDL-C. Apo B is the main apolipoprotein that makes up LDL-C and exists in a 1: 1 ratio with LDL-C. It is used equivalently to LDL-C scores, and it is known that high TG is a more accurate measure for scoring than LDL-C. Therefore, the ratio of Apo B / Aro A-I is one of the factors predicting the risk of cardiovascular disease.

• Lp (a) in fasting serum

Lipoprotein (a) is a low density lipoprotein attached to apolipoprotein (a). High levels of Lp (a) are associated with an increased risk of coronary artery disease and ischemic stroke, in particular, for patients with a high risk of cardiovascular disease, its assessment is recommended.

(1) Results of the assessment of key performance parameters

The main parameters for evaluating the efficacy in this clinical study were changes in HbA1c and LDL-C at Visit 6 (week 24) compared to baseline at Visit 3 (randomization; week 0). The magnitude of the change and percent change (%) was used for HbA1c and LDL-C, respectively.

For HbA1c, the magnitude of the change between the hemigliptin / rosuvastatin FDC group and the rosuvastatin group was compared. For LDL-C, the percent change between the hemigliptin / rosuvastatin FDC group and the hemigliptin group was compared. Each comparison confirms the superiority of the hemigliptin / rosuvastatin FDC group.

<HbA1c>

The initial HbA1c level in each group was 7.79 ± 0.79% in the hemigliptin / rosuvastatin group and 7.78 ± 0.78% in the rosuvastatin group, respectively, and there was no significant difference between the groups (P = 0.9537).

The results of covariance analysis (ANCOVA) with baseline HbA1c as covariates are presented in table 6.

At Visit 6 (week 24), the least-squares mean (average values obtained by the least squares method) of the change in HbA1c compared to the initial level was -0.539 ± 0.081% in the hemigliptin / rosuvastatin FDC group and 0.273 ± 0.080% in the rosuvastatin group. The hemigliptin / rosuvastatin FDC group showed a significant decrease compared to the baseline (P <0.0001), while the rosuvastatin group showed a significant increase compared to the baseline (P = 0.0007).

The difference in the magnitude of the change between the two groups was -0.812 ± 0.113%, and the HbA1c level in the hemigliptin / rosuvastatin FDC group significantly decreased compared to the rosuvastatin group. Based on the 95% confidence interval (CI) (-1.035, -0.588), where the upper limit is less than 0, the superiority of the hemigliptin / rosuvastatin FDC group was confirmed in terms of the effectiveness of HbA1c reduction (P <0.0001).

<LDL-C>

The initial LDL-C level in each group was 133.39 ± 25.84 mg / dl in the hemigliptin / rosuvastatin FDC group and 141.99 ± 29.58 mg / dl in the hemigliptin group, respectively, and there was a significant difference between these groups ( P = 0.0263).

The results of covariance analysis (ANCOVA) with baseline LDL-C as covariates are presented in Table 7.

At Visit 6 (Week 24), the least-squares least-squares mean (average values obtained by the least squares method) of the percent change in LDL-C level (%) compared with the baseline was -53.002 ± 1.929% in the FDC group of hemigliptin / rosuvastatin and -1.135 ± 1.939% in the hemigliptin group. The hemigliptin / rosuvastatin FDC group showed a significant decrease compared to the baseline ( P <0.0001), while the hemigliptin group showed no significant change (P = 0.5587).

The difference in the percentage change between the two groups was -51.867 ± 2.745%, and the hemigliptin / rosuvastatin LDL-C in the FDC group was significantly lower compared to the hemigliptin group. Based on 95% CI (-57.271, -46.463), in which the upper limit is less than 0, the superiority of the hemigliptin / rosuvastatin FDC group in the effectiveness of LDL-C reduction was confirmed ( P <0.0001).

Table 7 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) P value ¹⁾ Initial Level (Week 0) 94 94 Average value (± SD) 133.39 (± 25.84) 141.99 (± 29.58) 0.0263 ** Median value (min., Max.) 130 (87, 217) 142.5 (62, 242) Interquartile range (Q1, Q3) (113, 150) (121, 160) Week 24 94 94 Average value (± SD) 61.80 (± 26.28) 137.37 (± 31.99) <0.0001 ** Median value (min., Max.) 56 (24, 201) 134 (59, 238) Interquartile range (Q1, Q3) (47, 71) (118, 157) % change from baseline at week 24 94 94 Average value (± SD) -52.57 (± 20.56) -1.98 (± 19.86) <0.0001 ** Median value (min., Max.) -56.64 (-80.65, 45.37) -3.85 (-34.44, 109.68) Interquartile range (Q1, Q3) (-64.29, -46) (-12.75, 6.87) P-value (comparison within groups) <, 0001 ‡ 0.0418 ‡ Least squares averages and treatment differences Rating ²⁾  MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC -53.002 (± 1.929) (-56.8, -49.205) <0.0001 Hemigliptin -1.135 (± 1.939) (-4.952, 2.662) 0.5587 (FDC hemigliptin / rosuvastatin) - (hemigliptin) -51.867 (± 2.745) (-57,271, -46,463) <0.0001 Interaction Research3) Treatment * Baseline 0.0623 1) Comparison between Hemigliptin / Rosuvastatin and Hemigliptin FDC Groups
2) Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline LDL-C as covariates
3) P-value obtained by the ANCOVA method,
The ANCOVA model included a treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

(2) Secondary Performance Indicator Assessment Results

As secondary parameters for evaluating efficacy, changes in HbA1c and LDL-C at Visit 6 (Week 24) were compared with baseline. For HbA1c, the magnitude of the change was compared in the hemigliptin / rosuvastatin FDC group and the hemigliptin group. For LDL-C, the percent change in the hemigliptin / rosuvastatin FDC group and the rosuvastatin group were compared.

<HbA1c>

The initial HbA1c level in each group was 7.79 ± 0.79% in the hemigliptin / rosuvastatin FDC group and 7.79 ± 0.78% in the hemigliptin group, respectively, and there was no significant difference between these groups ( P = 0, 8923).

The results of covariance analysis (ANCOVA) with baseline LDL-C as covariates are presented in Table 8.

At Visit 6 (Week 24), the least-squares least-squares mean (average values obtained by the least squares method) of the change in HbA1c compared to the baseline was -0.539 ± 0.081% in the hemigliptin / rosuvastatin FDC group and -1.007 ± 0.081% in the hemigliptin group. Both groups showed a significant decrease compared to baseline ( P <0.0001), but the hemigliptin / rosuvastatin FDC group showed a lower decrease in HbA1c than the hemigliptin group, and there was a statistically significant difference ( P = 0.0001).

Table 8 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) P value ¹⁾ Initial Level (Week 0) 94 94 Average value (± SD) 7.79 (± 0.79) 7.79 (± 0.78) 0.8923 ** Median value (min., Max.) 7.61 (6.7, 10.24) 7.54 (6.82, 11.09) Interquartile range (Q1, Q3) (7.21, 8.25) (7.25, 8.2) Week 24 94 94 Average value (± SD) 7.25 (± 1.01) 6.79 (± 0.92) 0.0001 ** Median value (min., Max.) 7.11 (5.5, 11.34) 6.65 (5.27, 12.77) Interquartile range (Q1, Q3) (6.53, 7.67) (6.23, 7.12) Change from baseline at week 24 94 94 Average value (± SD) -0.54 (± 0.79) -1.01 (± 0.74) <, 0001 ** Median value (min., Max.) -0.58 (-2.49, 1.59) -0.97 (-3.2, 1.68) Interquartile range (Q1, Q3) (-1.09, -0.03) (-1.35, -0.59) P-value (comparison within groups) <, 0001 † <, 0001 ‡ Least squares averages and treatment differences Rating ²⁾  MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC -0.539 (± 0.081) (-0.698, -0.380) <0.0001 Hemigliptin -1.007 (± 0.081) (-1.166, -0.848) <0.0001 (FDC hemigliptin / rosuvastatin) - (hemigliptin) 0.468 (± 0.114) (0.244, 0.693) 0.0001 Interaction Research3) Treatment * Baseline 0,1608 1) Comparison between groups of FDC hemigliptin / rosuvastatin and hemigliptin 50mg
2) Least squares estimates (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
3) P-value obtained by the ANCOVA method,
The ANCOVA model included a treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<LDL-C>

The initial LDL-C level in each group was 133.39 ± 25.84 mg / dl in the hemigliptin / rosuvastatin FDC group and 133.63 ± 27.20 mg / dl in the rosuvastatin group, respectively, and there was no significant difference between these groups ( P = 0.9747).

The results of covariance analysis (ANCOVA) with baseline LDL-C as covariates are presented in Table 9.

At Visit 6 (Week 24), the least-squares least-squares mean (average values obtained by the least squares method) of the percent change in LDL-C (%) compared with the baseline was -53.002 ± 1.929% in the hemigliptin / rosuvastatin FDC group and -54.288 ± 1.099% in rosuvastatin group. Both groups showed a significant decrease compared to baseline ( P <0.0001), and there was no significant difference in the percentage change in LDL-C between the two groups ( P = 0.6354).

Table 9 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Rosuvastatin
(N = 96) P value ¹⁾ Initial Level (Week 0) 94 96 Average value (± SD) 133.39 (± 25.84) 133.63 (± 27.20) 0.9747 ** Median value (min., Max.) 130 (87, 217) 129 (77, 237) Interquartile range (Q1, Q3) (113, 150) (116, 149.5) Week 24 94 96 Average value (± SD) 61.80 (± 26.28) 61.52 (± 25.34) 0.8908 ** Median value (min., Max.) 56 (24, 201) 57 (22, 153) Interquartile range (Q1, Q3) (47, 71) (43.5, 72.5) % change from baseline at week 24 94 96 Average value (± SD) -52.57 (± 20.56) -53.89 (± 16.64) 0.8825 ** Median value (min., Max.) -56.64 (-80.65, 45.37) -57.04 (-79.25, 10.45) Interquartile range (Q1, Q3) (-64.29, -46) (-63.96, -47.32) P-value (comparison within groups) <, 0001 ‡ <, 0001 ‡ Least squares averages and treatment differences Rating ²⁾  MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC -53.002 (± 1.929) (-56.8, -49.205) <, 0001 Rosuvastatin -54.288 (± 1.909) (-58,045, -50,531) <, 0001 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) 1,286 (± 2,709) (-4,047, 6,618) 0.6354 Interaction Research3) Treatment * Baseline 0.0623 1) Comparison between groups of FDC hemigliptin / rosuvastatin and hemigliptin 50mg
2) Least squares estimates (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
3) P-value obtained by the ANCOVA method,
The ANCOVA model included a treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

(3) Results of an additional performance evaluation

<HbAlc level changes (%) at each visit>

Changes in Hb1Ac (%) in subjects over the entire period of the clinical trial are shown in FIG. 1.

The initial HbA1c level in each group was 7.79 ± 0.79% in the hemigliptin / rosuvastatin FDC group, 7.79 ± 0.78% in the hemigliptin group, and 7.78 ± 0.78% in the rosuvastatin group, and there was no significant difference between these groups ( P = 0.9900). In the FDC group, hemigliptin / rosuvastatin and hemigliptin group HbA1c was significantly lower than the initial level at each visit until Visit 6 (Week 24) ( P <0.0001), but in the rosuvastatin group HbA1c did not change significantly, but on the contrary it was significantly higher at Visit 6 (Week 24) (0.27 ± 0.83%, P = 0.0016).

The results of covariance analysis (ANCOVA) with baseline HbA1c as covariates are presented in Table 10.

When comparing the least-squares least-squares least-squares mean changes in HbA1c from baseline between these groups at each visit, the hemigliptin / rosuvastatin FDC group showed a significant decrease in HbA1c compared to the rosuvastatin group at all visits, but showed a smaller decrease than the group hemigliptin (a significantly smaller decrease in HbA1c after Visit 5 (Week 16)).

Table 10 Grade * MNC average (± SE) 95% CI P value Visit 4 (Week 8) (FDC Hemigliptin / Rosuvastatin) -0.686 (± 0.055) (-0.794, -0.578) (Hemigliptin 50 mg) -0.776 (± 0.055) (-0.885, -0.667) (Rosuvastatin) -0.074 (± 0.055) (-0.182, 0.035) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 0.090 (± 0.078) (-0.064, 0.243) 0.2501 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -0.613 (± 0.078) (-0.766, -0.460) <0.0001 Interaction Study (Treatment * Baseline) ** 0.6070 Visit 5 (Week 16) (FDC Hemigliptin / Rosuvastatin) -0.660 (± 0.075) (-0.808, -0.511) (Hemigliptin 50 mg) -0.963 (± 0.075) (-1.111, -0.814) (Rosuvastatin) 0.073 (± 0.075) (-0.074, 0.220) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 0.303 (± 0.107) (0,093, 0,513) 0.0048 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -0.732 (± 0.106) (-0.941, -0.523) <, 0001 Interaction Study (Treatment * Baseline) ** 0.6271 Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -0.539 (± 0.081) (-0.698, -0.380) (Hemigliptin 50 mg) -1.007 (± 0.081) (-1.166, -0.848) (Rosuvastatin) 0.273 (± 0.080) (0.116, 0.430) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 0.468 (± 0.114) (0.244, 0.693) 0.0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -0.812 (± 0.113) (-1.035, -0.588) <, 0001 Interaction Study (Treatment * Baseline) ** 0,1608 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<LDL-C level changes (%) at each visit>

Changes in LDL-C levels in subjects over the entire period of the clinical study are shown in FIG. 2.

The initial LDL-C level in each group was 133.39 ± 25.84 mg / dl in the hemigliptin / rosuvastatin FDC group, 141.99 ± 29.58 mg / dl in the hemigliptin group and 133.63 ± 27.20 mg / dl in the rosuvastatin group, and there was a statistically significant difference ( P = 0.0267). In the hemigliptin / rosuvastatin FDC group and the rosuvastatin group, the LDL-C level was significantly reduced compared to the baseline level at each visit up to Visit 6 (Week 24) ( P <0.0001), and in the hemigliptin group the LDL-C level was significantly reduced from baseline at Visit 4 (Week 8) and Visit 6 (Week 24) ( P <0.05).

The results of covariance analysis (ANCOVA) with baseline LDL-C as covariates are presented in Table 11.

When comparing the least-squares least-squares least-squares average LDL-C changes between the groups at each visit, the hemigliptin / rosuvastatin FDC group showed a significant decrease in LDL-C compared to the hemigliptin group at all visits, and did not show any significant difference compared with the rosuvastatin group at all visits.

Table 11 Grade * MNC
(± SE) 95% CI P value Visit 4 (Week 8) (FDC Hemigliptin / Rosuvastatin) -42.906 (± 1.804) (-46,456, -39,355) (Hemigliptin 50 mg) -2.126 (± 1.822) (-5.712, 1.460) (Rosuvastatin) -45.031 (± 1.802) (-48,578, -41,485) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -40,780 (± 2,573) (-45,846, -35,713) <0.0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) 2.126 (± 2.545) (-2.885, 7.136) 0.4043 Interaction Study (Treatment * Baseline) ** 0,0259 Visit 5 (Week 16) (FDC Hemigliptin / Rosuvastatin) -47.983 (± 1.896) (-51,716, -44,251) (Hemigliptin 50 mg) 0.039 (± 1.906) (-3,712, 3,791) (Rosuvastatin) -49.981 (± 1.876) (-53,673, -46,288) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -48.023 (± 2.698) (-53,334, -42,712) <0.0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) 1,997 (± 2,662) (-3,244, 7,238) 0.4538 Interaction Study (Treatment * Baseline) ** 0.0067 Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -53.002 (± 1.929) (-56.8, -49.205) (Hemigliptin 50 mg) -1.135 (± 1.939) (-4.952, 2.662) (Rosuvastatin) -54.288 (± 1.909) (-58,045, -50,531) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -51.867 (± 2.745) (-57,271, -46,463) <0.0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) 1,286 (± 2,709) (-4,047, 6,618) 0.6354 Interaction Study (Treatment * Baseline) ** 0.0623 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in fasting plasma glucose (mg / dl) at each visit>

The results of covariance analysis (ANCOVA) with baseline FPG as covariates are presented in Table 12.

When comparing the least-squares least-squares least-squares mean changes in FPG from baseline between these groups at each visit, the hemigliptin / rosuvastatin FDC group showed a significantly lower decrease in FPG than the hemigliptin group at all visits, but showed a significantly larger decrease in FPG than rosuvastatin group, at all visits.

Table 12 Grade * MNC average (± SE) 95% CI P value Visit 4 (Week 8) (FDC Hemigliptin / Rosuvastatin) -11.962 (± 2.801) (-17,476, -6,448) (Hemigliptin 50 mg) -20.821 (± 2.796) (-26,326, -15,317) (Rosuvastatin) 4,570 (± 2,783) (-0.909, 10.049) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 8,860 (± 3,960) (1,064, 16,655) 0,0261 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -16.532 (± 3.94) (-24,316, -8,749) <0.0001 Interaction Study (Treatment * Baseline) ** <0.0001 Visit 5 (Week 16) (FDC Hemigliptin / Rosuvastatin) -11.906 (± 3.177) (-18,161, -5,651) (Hemigliptin 50 mg) -21.390 (± 3.139) (-27,569, -15,211) (Rosuvastatin) 9.948 (± 3.108) (3.83, 16.065) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 9.484 (± 4.469) (0.687, 18.281) 0,0347 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -21.853 (± 4.449) (-30,612, -13,095) <0.0001 Interaction Study (Treatment * Baseline) ** <0.0001 Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -9.105 (± 3.146) (-15,298, -2,913) (Hemigliptin 50 mg) -17.844 (± 3.125) (-23,994, -11,693) (Rosuvastatin) 11.522 (± 3.094) (5,432, 17,612) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 8.738 (± 4.436) (0.005, 17.471) 0.0499 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -20.627 (± 4.417) (-29,322, -11,933) <, 0001 Interaction Study (Treatment * Baseline) ** 0,0004 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in total cholesterol (mg / dl) at each visit>

When comparing the least-squares least-squares least-squares mean TG changes from baseline between groups at Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed a significantly larger decrease in TG than the hemigliptin group, and showed no significant difference in the change TC compared with the rosuvastatin group (table 13).

Table 13 Grade * MNC
(± SE) 95% CI P value Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -78.175 (± 2.761) (-83,609, -72,740) (Hemigliptin 50 mg) -3.150 (± 2.790) (-8,643, 2,343) (Rosuvastatin) -78.175 (± 2.761) (-83,609, -72,740) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -75,024 (± 3,935) (-82,769, -67,279) <0.0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -2.857 (± 3.899) (-10,512, 4,798) 0.4631 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in HDL-C (mg / dl) at each visit>

When comparing the least-squares least-squares MELs of the change in HDL-C from baseline between groups at Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed no significant difference in HDL-C change compared to the hemigliptin group , and showed a significantly lower increase in HDL-C than the rosuvastatin group (Table 14).

Table 14 Grade * MNC
(± SE) 95% CI P value Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) 1.452 (± 0.804) (-0.13, 3.034) (Hemigliptin 50 mg) -0.594 (± 0.804) (-2.176, 0.988) (Rosuvastatin) 4.535 (± 0.796) (2,969, 6,101) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 2.046 (± 1.137) (-0.192, 4.283) 0,0729 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -3.084 (± 1.131) (-5.31, -0.857) 0.0068 Interaction Study (Treatment * Baseline) ** 0,0268 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in triglycerides (TG, mg / dl) at each visit>

When comparing the least-squares least-squares least-squares mean TG changes from baseline between groups at Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed a significant decrease in TG level compared to the hemigliptin group, and showed no significant difference in the change in TG compared to the rosuvastatin group (table 15).

Table 15 Grade * MNC average (± SE) 95% CI P value Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -62.433 (± 8.771) (-79,699, -45,167) (Hemigliptin 50 mg) -6,993 (± 8,777) (-24.27, 10.285) (Rosuvastatin) -61.823 (± 8.718) (-78,984, -44,662) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -55.440 (± 12.391) (-79.832, -31.048) <, 0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -0.610 (± 12.397) (-25.013, 23.793) 0.9608 Interaction Study (Treatment * Baseline) ** <, 0001 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in the LDL-C / HDL-C relationship at each visit>

When comparing the least-squares least-squares least-squares average changes in the LDL-C / HDL-C ratio from baseline between groups at Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed a significantly larger decrease in LDL-C / HDL- C than the hemigliptin group, and showed no significant difference in the LDL-C / HDL-C ratio compared to the rosuvastatin group (Table 16).

Table 16 Grade * MNC average (± SE) 95% CI P value Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -1.649 (± 0.059) (-1.765, -1.532) (Hemigliptin 50 mg) -0.012 (± 0.059) (-0.128, 0.105) (Rosuvastatin) -1.746 (± 0.059) (-1.862, -1.631) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -1.637 (± 0.084) (-1.802, -1.472) <0.0001 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) 0.098 (± 0.083) (-0.066, 0.262) 0.2421 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in body weight (kg) at each visit>

When comparing the least-squares least-squares average of body mass changes from baseline between groups at Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed a significantly lower body weight decrease than the rosuvastatin group, and showed no significant difference in body weight compared to the hemigliptin group (table 17).

Table 17 Grade * MNC average (± SE) 95% CI P value Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -0.132 (± 0.244) (-0.612, 0.348) (Hemigliptin 50 mg) -0.407 (± 0.243) (-0.887, 0.072) (Rosuvastatin) -0.893 (± 0.241) (-1.367, -0.418) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) 0.275 (± 0.344) (-0.403, 0.954) 0.4245 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) 0.761 (± 0.343) (0,086, 1,436) 0,0274 Interaction Study (Treatment * Baseline) ** 0.2405 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Change in waist circumference (cm) at each visit>

When comparing the least-squares least-squares average of the waist circumference change from baseline between the groups at Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed no significant difference in waist circumference compared to the other two control groups (Table eighteen).

Table 18 Grade * MNC average (± SE) 95% CI P value Visit 6 (Week 24) (FDC Hemigliptin / Rosuvastatin) -0.738 (± 0.373) (-1,472, -0,005) (Hemigliptin 50 mg) -0.144 (± 0.372) (-0.877, 0.590) (Rosuvastatin) -0.150 (± 0.369) (-0.876, 0.576) (FDC Hemigliptin / Rosuvastatin) - (Hemigliptin 50 mg) -0.595 (± 0.527) (-1.631, 0.442) 0.2597 (FDC Hemigliptin / Rosuvastatin) - (Rosuvastatin) -0.589 (± 0.525) (-1.621, 0.444) 0.2629 Interaction Study (Treatment * Baseline) ** 0.1854 Comparison Between Hemigliptin / Rosuvastatin and Rosuvastatin FDC Groups
Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
: P-value obtained using the chi-square test: P-value obtained using the exact Fisher test
#: P-value obtained by the ANOVA method, ##: P-value obtained using the Kruskal-Wallis test

<Changes in fasting serum insulin levels (μMU / ml) at week 24>

Changes in fasting serum insulin levels in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 19.

The initial fasting serum insulin level in each group, 9.26 ± 4.42 μIU / ml in the hemigliptin / rosuvastatin FDC group, 11.02 ± 10.59 μI / ml in the hemigliptin group and 9.12 ± 3.95 μI / ml in the rosuvastatin group was similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin group FDC and the rosuvastatin group showed a significant increase in fasting serum insulin levels compared to baseline, while the hemigliptin group showed no significant difference compared to baseline.

When comparing the least-squares least-squares mean of fasting serum insulin levels from baseline between Visit Group 6 (Week 24) using covariance analysis (ANCOVA), with baseline fasting insulin serum as covariates, the hemigliptin / rosuvastatin FDC group showed an increase in fasting serum insulin compared to the fasting hemigliptin group and a decrease in fasting serum insulin compared to the rosuvastatin group. However, both differences were not significantly significant.

Table 19 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 96 Average value (± SD) 9.26 (± 4.42) 11.02 (± 10.59) 9.12 (± 3.95) Median value (min., Max.) 8.25 (2, 33.4) 8.95 (4, 101.2) 8.1 (1.9, 23.4) Interquartile range (Q1, Q3) (6.2, 11.2) (6.3, 12) (6.2, 10.95) Visit 6 (Week 24) 89 85 79 Average value (± SD) 10.17 (± 4.70) 10.50 (± 5.69) 10.33 (± 5.33) Median value (min., Max.) 9.7 (2, 26) 9 (3.5, 38.6) 8.7 (2.1, 32) Interquartile range (Q1, Q3) (131, 157) (6.6, 12.7) (7.1, 12.5) Change from baseline at week 24 89 85 79 Average value (± SD) 0.79 (± 3.47) -0.81 (± 9.66) 1.26 (± 4.22) Median value (min., Max.) 0.4 (-16.6, 10.9) -0.1 (-79, 15.4) 1 (-7.3, 19.8) Interquartile range (Q1, Q3) (-1, 2.7) (-2, 2.5) (-1,2, 2,5) P-value (comparison within groups) 0.0197 ‡ 0.9360 ‡ 0.0186 ‡ P-value (comparison between groups) 0.1731 ** 0.6702 ** Least squares averages and treatment differences Grade * MNC
(± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 0.444 (± 0.479) (-0.499, 1.387) Hemigliptin 0.059 (± 0.492) (-0.911, 1.029) Rosuvastatin 0.717 (± 0.509) (-0.285, 1.719) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 0.385 (± 0.688) (-0.971, 1.741) 0.5764 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) -0.273 (± 0.697) (-1.647, 1,100) 0.6955 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy
(Hemigliptin 50 mg or rosuvastatin)
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<Changes in fasting serum proinsulin level (μMU / ml) at week 24>

Changes in fasting serum proinsulin levels in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 20.

The initial fasting serum proinsulin level in each group, 14.99 ± 11.11 μI / ml in the hemigliptin / rosuvastatin FDC group, 17.64 ± 15.77 μI / ml in the hemigliptin group and 14.77 ± 10.52 μI / ml in the rosuvastatin group was similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group showed no significant change from baseline, the hemigliptin group showed a significant decrease in fasting serum proinsulin compared to the baseline, and the rosuvastatin group showed a significant increase in fasting serum proinsulin compared to baseline.

When comparing the least-squares least-squares average of fasting serum proinsulin changes from the baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with the fasting serum proinsulin level as covariates, the hemigliptin / rosuvastatin FDC group showed a significant increase in fasting serum proinsulin compared with the hemigliptin group and no significant difference in the magnitude of the change compared with the ro group zuvastatin.

Table 20 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 96 Average value (± SD) 14.99 (± 11.11) 17.64 (± 15.77) 14.77 (± 10.52) Median value (min., Max.) 12.08 (2, 59.59) 13.02 (2, 101.5) 11.86 (2.35, 54.21) Interquartile range (Q1, Q3) (6.2, 11.2) (6.85, 20.22) (7.72, 20.59) Visit 6 (Week 24) 89 85 79 Average value (± SD) 17.52 (± 21.50) 15.12 (± 11.35) 16.75 (± 14.01) Median value (min., Max.) 11.94 (2, 160.24) 13.04 (2, 56.02) 15.22 (2, 108.16) Interquartile range (Q1, Q3) (131, 157) (7.01, 19.02) (7.03, 18.92) Change from baseline at week 24 89 85 79 Average value (± SD) 2.28 (± 14.38) -3.18 (± 13.22) 2.30 (± 9.34) Median value (min., Max.) -0.07 (-18.52, 100.65) -1.85 (-76.5, 34.15) 1.57 (-23.28, 56.22) Interquartile range (Q1, Q3) (-2.91, 4.3) (-5.84, 2.37) (-1.99, 5.72) P-value (comparison within groups) 0.8361 ‡ 0.0128 ‡ 0,0077 ‡ P-value (comparison between groups) 0.0257 ** 0.0856 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 2,137 (± 1,316) (-0.455, 4.729) Hemigliptin -2.779 (± 1.353) (-5.444, -0.115) Rosuvastatin 2,024 (± 1,399) (-0.732, 4.779) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 4.916 (± 1.891) (1,192, 8,640) 0.0099 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) 0.113 (± 1.919) (-3,666, 3,892) 0.9530 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<Changes in fasting serum C-peptide (ng / ml) at week 24>

Changes in fasting serum C-peptide levels in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 21.

The initial level of fasting serum C-peptide in each group, 2.14 ± 0.89 ng / ml in the hemigliptin / rosuvastatin FDC group, 2.48 ± 1.29 ng / ml in the hemigliptin group, and 2.23 ± 0.86 ng / ml in the rosuvastatin group was similar. At Visit 6 (Week 24), all 3 groups showed no significant change from baseline.

When we compared the least-squares least-squares average of fasting serum C-peptide changes from baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with the fasting serum C-peptide baseline as covariates, the hemigliptin / rosuvastatin FDC group showed a significant increase in fasting serum C-peptide compared to the hemigliptin group and no significant difference in the magnitude of the change compared to the rosuvastatin group on the.

Table 21 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 96 Average value (± SD) 2.14 (± 0.89) 2.48 (± 1.29) 2.23 (± 0.86) Median value (min., Max.) 2.04 (0.49, 4.59) 2.27 (1.13, 10.72) 2.21 (0.69, 5.48) Interquartile range (Q1, Q3) (6.2, 11.2) (1.47, 2.75) (1.63, 2.93) Visit 6 (Week 24) 89 85 79 Average value (± SD) 2.30 (± 1.05) 2.29 (± 0.90) 2.23 (± 1.02) Median value (min., Max.) 2.11 (0.79, 6.08) 2.14 (0.86, 5.29) 2.06 (0.62, 6.76) Interquartile range (Q1, Q3) (131, 157) (1.44, 2.89) (1.72, 2.69) Change from baseline at week 24 89 85 79 Average value (± SD) 0.13 (± 0.59) -0.24 (± 1.08) 0.03 (± 0.82) Median value (min., Max.) 0.05 (-0.93, 2.72) -0.11 (-7.23, 1.3) -0.09 (-2.33, 3.56) Interquartile range (Q1, Q3) (-0.21, 0.37) (-0.53, 0.38) (-0.42, 0.27) P-value (comparison within groups) 0.1712 ‡ 0.1573 ‡ 0.4151 ‡ P-value (comparison between groups) 0.0446 ** 0.1386 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 0.080 (± 0.080) (-0.077, 0.238) Hemigliptin -0.148 (± 0.082) (-0.311, 0.014) Rosuvastatin -0.006 (± 0.085) (-0.173, 0.161) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 0.229 (± 0.116) (0.001, 0.456) 0,0488 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) 0.086 (± 0.117) (-0.143, 0.316) 0.4595 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<Changes in the ratio of proinsulin / insulin in fasting serum at week 24>

Changes in fasting serum proinsulin / insulin ratios in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 22.

The initial fasting serum proinsulin / insulin ratio in each group, 0.23 ± 0.13 in the hemigliptin / rosuvastatin FDC group, 0.24 ± 0.13 in the hemigliptin group and 0.23 ± 0.13 in the rosuvastatin group, was similar . At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group and the rosuvastatin group showed no significant change from the baseline, and the hemigliptin group showed a significant decrease in the fasting serum proinsulin / insulin ratio compared to the baseline.

When comparing the least-squares least-squares average of fasting serum proinsulin / insulin ratios from the baseline value between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with the fasting serum proinsulin / insulin ratio as covariates, the hemigliptin / rosuvastatin FDC group showed an increase in the fasting serum proinsulin / insulin ratio compared to the hemigliptin group, but the difference was not significant, and showed no significant difference in the magnitude of the change compared to the rosuvastatin group.

Table 22 FDC hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin (N = 96) Initial Level (Week 0) 94 94 96 Average value (± SD) 0.23 (± 0.13) 0.24 (± 0.13) 0.23 (± 0.13) Median value (min., Max.) 0.2 (0.04, 0.76) 0.2 (0.05, 0.66) 0.21 (0.06, 0.94) Interquartile range (Q1, Q3) (0.14, 0.27) (0.15, 0.29) (0.14, 0.27) Visit 6 (Week 24) 89 85 79 Average value (± SD) 0.23 (± 0.16) 0.21 (± 0.14) 0.24 (± 0.12) Median value (min., Max.) 0.2 (0.03, 0.97) 0.17 (0.05, 0.89) 0.2 (0.05, 0.55) Interquartile range (Q1, Q3) (0.13, 0.26) (0.13, 0.26) (0.16, 0.32) Change from baseline at week 24 89 85 79 Average value (± SD) 0.00 (± 0.14) -0.03 (± 0.10) 0.01 (± 0.10) Median value (min., Max.) -0.01 (-0.49, 0.46) -0.04 (-0.3, 0.29) 0.02 (-0.38, 0.24) Interquartile range (Q1, Q3) (-0.07, 0.05) (-0.09, 0.01) (-0.02, 0.06) P-value (comparison within groups) 0.6804 ‡ 0,0018 ‡ 0.1220 ‡ P-value (comparison between groups) 0,0728 ** 0.1799 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 0.003 (± 0.011) (-0.02, 0.025) Hemigliptin -0.026 (± 0.012) (-0.05, -0.003) Rosuvastatin 0.005 (± 0.012) (-0.019, 0.029) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 0.029 (± 0.016) (-0.003, 0.061) 0,0770 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) -0.002 (± 0.017) (-0.035, 0.031) 0.8882 Interaction Study (Treatment * Baseline) ** 0.5170 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included treatment group and baseline HbA1c as covariates and Treatment * Baseline as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<HOMA-β Level Changes at Week 24>

Changes in HOMA-β levels in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 23.

The baseline HOMA-β level in each group, 46.86 ± 27.22 in the FDC group of hemigliptin / rosuvastatin, 50.76 ± 37.16 in the hemigliptin group and 42.76 ± 25.74 in the rosuvastatin group, was similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group and hemigliptin group showed a significant increase in HOMA-β compared to baseline, but the rosuvastatin group showed no significant change in HOMA-β compared to baseline.

When comparing the least-squares least-squares least-squares mean HOMA-β level changes from baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with baseline HOMA-β as covariates, FDC group hemigliptin / rosuvastatin showed a significant increase in HOMA-β compared with the rosuvastatin group and no significant difference in the magnitude of the changes compared with the hemigliptin group.

Table 23 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 93 94 96 Average value (± SD) 46.86 (± 27.22) 50.76 (± 37.16) 42.76 (± 25.74) Median value (min., Max.) 40.65 (8.9, 148.6) 42.18 (8.65, 319.99) 38.17 (11.64, 182.76) Interquartile range (Q1, Q3) (28.44, 58.26) (29.74, 59.32) (25.91, 48.58) Visit 6 (Week 24) 89 85 79 Average value (± SD) 59.13 (± 31.48) 64.96 (± 34.46) 45.10 (± 24.47) Median value (min., Max.) 54.3 (6.2, 174.36) 56.15 (9.87, 215.37) 40.5 (10.66, 133.3) Interquartile range (Q1, Q3) (35.46, 72.2) (41.68, 81.17) (26.86, 53.3) Change from baseline at week 24 88 85 79 Average value (± SD) 10.94 (± 26.04) 13.11 (± 37.67) 3.21 (± 25.15) Median value (min., Max.) 7.61 (-100.44, 92.24) 11.63 (-179.53, 163.99) 1.71 (-75.1, 87.53) Interquartile range (Q1, Q3) (-2.28, 22.62) (-1.87, 25.58) (-6.93, 10.14) P-value (comparison within groups) <, 0001 ‡ <, 0001 ‡ 0.1838 ‡ P-value (comparison between groups) 0.5487 ** 0.0140 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 11,249 (± 2,832) (5,671, 16,826) Hemigliptin 15,279 (± 2,892) (9,583, 20,975) Rosuvastatin 0.531 (± 3.005) (-5.386, 6.449) (FDC hemigliptin / rosuvastatin) - (hemigliptin) -4.031 (± 4.045) (-11,998, 3,937) 0.3200 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) 10,717 (± 4,131) (2,58, 18,854) 0,0100 Interaction Study (Treatment * Baseline) ** 0,0683 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included a treatment group and baseline HbA1c as covariates and
Treatment * Initial value as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<HOMA-IR changes in week 24>

Changes in HOMA-IR in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 24.

The initial HOMA-IR value in each group, 3.23 ± 1.67 in the hemigliptin / rosuvastatin FDC group, 4.10 ± 4.65 in the hemigliptin group and 3.37 ± 1.63 in the rosuvastatin group, was similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group and the hemigliptin group showed no significant change in HOMA-IR compared to the baseline, and the rosuvastatin group showed a significant increase in HOMA-IR compared to the baseline.

When comparing the least-squares least-squares least-squares mean changes in the HOMA-IR value from the baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with the baseline HOMA-IR as covariates, the FDC group hemigliptin / rosuvastatin showed a significant decrease in HOMA-IR compared with the rosuvastatin group and no significant difference in the magnitude of the change compared with the hemigliptin group.

Table 24 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 93 94 96 Average value (± SD) 3.23 (± 1.67) 4.10 (± 4.65) 3.37 (± 1.63) Median value (min., Max.) 3.04 (0.71, 12.28) 3.14 (1.08, 44.19) 2.87 (0.4, 8.98) Interquartile range (Q1, Q3) (2.18, 3.76) (2.15, 4.59) (2.17, 4.15) Visit 6 (Week 24) 89 85 79 Average value (± SD) 3.40 (± 1.98) 3.43 (± 2.32) 4.19 (± 3.23) Median value (min., Max.) 3.03 (0.42, 10.65) 2.99 (0.8, 15.81) 3.32 (0.69, 21.31) Interquartile range (Q1, Q3) (1.88, 4.14) (2.01, 4.2) (2.46, 4.59) Change from baseline at week 24 88 85 79 Average value (± SD) 0.14 (± 1.52) -0.77 (± 4.46) 0.83 (± 2.45) Median value (min., Max.) -0.08 (-3.33, 6.57) -0.32 (-37.62, 4.68) 0.47 (-3.57, 12.86) Interquartile range (Q1, Q3) (-0.66, 0.63) (-1.42, 0.47) (-0.37, 1.1) P-value (comparison within groups) 0.9605 ‡ 0.0517 ‡ 0,0044 ‡ P-value (comparison between groups) 0,0749 ** 0.0289 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC -0.092 (± 0.245) (-0.574, 0.391) Hemigliptin -0.382 (± 0.250) (-0.875, 0.111) Rosuvastatin 0.670 (± 0.258) (0,161, 1,179) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 0.291 (± 0.352) (-0.402, 0.983) 0.4092 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) -0.762 (± 0.356) (-1,462, -0,061) 0,0331 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included a treatment group and baseline HbA1c as covariates and
Treatment * Initial value as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<Changes in serum Apo A-I level (mg / dl) at week 24>

Changes in Apo A-I level in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 25.

Baseline Apo AI level in each group, 145.24 ± 24.51 mg / dl in the hemigliptin / rosuvastatin FDC group, 144.47 ± 22.37 mg / dl in the hemigliptin group and 142.14 ± 24.75 mg / dl in the rosuvastatin group was similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group and the hemigliptin group showed no significant change in Apo A-I level compared to baseline, and rosuvastatin group showed a significant increase in Apo A-I compared to baseline.

When the least-squares least-squares least-squares comparisons were compared, the changes in Apo AI level from baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with baseline Apo AI as covariates, hemigliptin FDC group / rosuvastatin showed no significant difference in the magnitude of the change compared with the two control groups.

Table 25 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 95 Average value (± SD) 145.24 (± 24.51) 144.47 (± 22.37) 142.14 (± 24.75) Median value (min., Max.) 143 (70, 212) 143 (92, 203) 141 (94, 201) Interquartile range (Q1, Q3) (130, 160) (128, 158) (122, 159) Visit 6 (Week 24) 89 85 79 Average value (± SD) 145.04 (± 23.02) 140.89 (± 23.55) 150.08 (± 29.68) Median value (min., Max.) 142 (72, 220) 138 (81, 220) 148 (90, 257) Interquartile range (Q1, Q3) (131, 157) (123, 157) (129, 168) Change from baseline at week 24 89 85 79 Average value (± SD) 0.84 (± 23.86) -2.94 (± 18.58) 6.96 (± 20.80) Median value (min., Max.) 2 (-53, 81) -4 (-48, 43) 3 (-41, 59) Interquartile range (Q1, Q3) (-14, 16) (-13, 10) (-8, 19) P-value (comparison within groups) 0.7398 † 0.1482 † 0.0039 † P-value (comparison between groups) 0.2437 * 0.08 * Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 0.996 (± 2.092) (-3.125, 5.117) Hemigliptin -2.909 (± 2.141) (-7,126, 1,307) Rosuvastatin 6.755 (± 2.221) (2,381, 11,129) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 3,905 (± 2,993) (-1.99, 9,801) 0.1932 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) -5.759 (± 3.051) (-11.769, 0.250) 0,0603 Interaction Study (Treatment * Baseline) ** 0.0087 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included a treatment group and baseline HbA1c as covariates and
Treatment * Initial value as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

<Changes in serum Apo B (mg / dl) at week 24>

Changes in Apo B level in subjects compared to baseline at Visit 6 (Week 24) are presented in Table 26.

The initial Apo B level in each group, 121.90 ± 20.57 mg / dl in the hemigliptin / rosuvastatin FDC group, 128.40 ± 23.65 mg / dl in the hemigliptin group and 119.46 ± 22.15 mg / dl in the rosuvastatin group was similar. At Visit 6 (Week 24), all 3 groups showed a significant decrease in Apo B compared to baseline.

When the least-squares least-squares least-squares comparisons were compared, the changes in Apo B level from baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with baseline Apo B as covariates, hemigliptin FDC group / rosuvastatin showed a significant decrease in Apo B compared with the hemigliptin group and no significant difference in the magnitude of the change compared with the rosuvastatin group.

Table 26 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 95 Average value (± SD) 121.90 (± 20.57) 128.40 (± 23.65) 119.46 (± 22.15) Median value (min., Max.) 121 (80, 174) 126 (80, 233) 118 (76, 191) Interquartile range (Q1, Q3) (108, 134) (113, 144) (102, 133) Visit 6 (Week 24) 89 85 79 Average value (± SD) 65.78 (± 18.54) 120.86 (± 25.57) 64.71 (± 19.38) Median value (min., Max.) 61 (38, 143) 119 (80, 217) 62 (34, 147) Interquartile range (Q1, Q3) (52, 74) (101, 133) (52, 72) Change from baseline at week 24 89 85 79 Average value (± SD) -55.82 (± 24.53) -6.71 (± 15.64) -54.34 (± 20.97) Median value (min., Max.) -57 (-115, 31) -7 (-42, 35) -56 (-96, 31) Interquartile range (Q1, Q3) (-72, -40) (-16, 6) (-65, -46) P-value (comparison within groups) <, 0001 † 0,0002 † <0.0001 ‡ P-value (comparison between groups) <, 0001 * 0.7882 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC -56.393 (± 1.903) (-60,141, -52,645) Hemigliptin -4,456 (± 1,961) (-8,318, -0,593) Rosuvastatin -56.118 (± 2.028) (-60,112, -52,124) (FDC hemigliptin / rosuvastatin) - (hemigliptin) -51.937 (± 2.738) (-57,331, -46,544) <0.0001 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) -0.275 (± 2.777) (-5.744, 5.194) 0.9212 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included a treatment group and baseline HbA1c as covariates and
Treatment * Initial value as interaction effects †: P-value obtained using paired t-test, ‡: P-value obtained using Wilcoxon's signed rank test
*: P-value obtained using the two-sample t-test,
**: P-value obtained using the Wilcoxon rank sum test

<Changes in Lipoprotein (a) level (mg / dl) at week 24>

Changes in the level of lipoprotein (a) (Lp (a)) in subjects compared to the baseline at Visit 6 (Week 24) are presented in Table 27.

The initial level of Lp (a) in each group, 17.27 ± 19.72 mg / dl in the hemigliptin / rosuvastatin FDC group, 19.41 ± 19.31 mg / dl in the hemigliptin group and 16.12 ± 14.06 mg / dl in the rosuvastatin group was similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group and the rosuvastatin group showed a significant increase in Lp (a) compared to the baseline, and the hemigliptin group showed no significant change in Lp (a) compared to the baseline.

When comparing the least-squares least-squares least-squares mean Lp (a) changes from baseline between these groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with baseline Lp (a) as covariates, group Hemigliptin / rosuvastatin FDC showed a significant increase in Lp (a) compared to the hemigliptin group and no significant difference in the magnitude of the change compared to the rosuvastatin group.

Table 27 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 95 Average value (± SD) 17.27 (± 19.72) 19.41 (± 19.31) 16.12 (± 14.06) Median value (min., Max.) 10 (6, 122) 13 (6, 108) 11 (6, 68) Interquartile range (Q1, Q3) (6, 21) (6, 22) (6, 22) Visit 6 (Week 24) 89 85 79 Average value (± SD) 22.76 (± 26.84) 18.58 (± 17.47) 21.39 (± 23.18) Median value (min., Max.) 12 (6, 157) 12 (6, 93) 11 (6, 106) Interquartile range (Q1, Q3) (6, 27) (7, 23) (6, 30) Change from baseline at week 24 89 85 79 Average value (± SD) 5.85 (± 13.02) -0.26 (± 7.19) 4.70 (± 12.36) Median value (min., Max.) 2 (-22, 67) 0 (-48, 12) 1 (-22, 49) Interquartile range (Q1, Q3) (0, 8) (-2, 3) (0, 7) P-value (comparison within groups) <0.0001 ‡ 0.4002 ‡ 0,0003 ‡ P-value (comparison between groups) 0.0018 ** 0.4616 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC 5,930 (± 1,160) (3,645, 8,215) Hemigliptin -0.435 (± 1.188) (-2,776, 1,905) Rosuvastatin 4,800 (± 1,232) (2,375, 7,226) (FDC hemigliptin / rosuvastatin) - (hemigliptin) 6.366 (± 1.661) (3,093, 9,638) 0,0002 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) 1,130 (± 1,692) (-2,202, 4,461) 0.5049 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included a treatment group and baseline HbA1c as covariates and
Treatment * Initial value as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon sign test *: P-value obtained using the two-sample t-test **: P-value obtained from using the Wilcoxon rank sum test

<Apo A-I / Apo B Relationship Changes in Week 24>

Changes in the Apo A-I / Apo B ratio in subjects included in the total population for analysis compared to the baseline at Visit 6 (Week 24) are presented in Table 28.

The initial Apo A-I / Apo B ratio in each group, 0.87 ± 0.25 in the hemigliptin / rosuvastatin FDC group, 0.91 ± 0.23 in the hemigliptin group, and 0.86 ± 0.21 in the rosuvastatin group, were similar. At Visit 6 (Week 24), the hemigliptin / rosuvastatin FDC group and the rosuvastatin group showed a significant decrease in the Apo A-I / Apo B ratio compared to the baseline ratio, and the hemigliptin group showed no significant change in the Apo A-I / Apo B ratio compared to the baseline ratio.

When comparing the least-squares least-squares least-squares average of the change in the Apo AI / Apo B ratio from the baseline between the groups at Visit 6 (Week 24) using covariance analysis (ANCOVA), with the original Apo AI / Apo B ratio as covariates, the hemigliptin / rosuvastatin FDC group showed a significant decrease in the Apo AI / Apo B ratio compared to the hemigliptin group and no significant difference in the magnitude of the change compared to the rosuvastatin group.

Table 28 FDC Hemigliptin
/ Rosuvastatin
(N = 94) Hemigliptin
(N = 94) Rosuvastatin
(N = 96) Initial Level (Week 0) 94 94 95 Average value (± SD) 0.87 (± 0.25) 0.91 (± 0.23) 0.86 (± 0.21) Median value (min., Max.) 0.83 (0.49, 2.4) 0.89 (0.51, 1.86) 0.84 (0.46, 1.55) Interquartile range (Q1, Q3) (0.72, 1) (0.75, 1.02) (0.7, 1.03) Visit 6 (Week 24) 89 85 79 Average value (± SD) 0.47 (± 0.16) 0.88 (± 0.25) 0.44 (± 0.14) Median value (min., Max.) 0.42 (0.21, 1.01) 0.85 (0.46, 1.81) 0.43 (0.17, 1.18) Interquartile range (Q1, Q3) (0.36, 0.55) (0.73, 1) (0.36, 0.51) Change from baseline at week 24 89 85 79 Average value (± SD) -0.41 (± 0.22) -0.03 (± 0.13) -0.41 (± 0.18) Median value (min., Max.) -0.39 (-1.47, 0.30) -0.03 (-0.37, 0.41) -0.43 (-0.93, 0.32) Interquartile range (Q1, Q3) (-0.51, -0.28) (-0.13, 0.05) (-0.5, -0.33) P-value (comparison within groups) <, 0001 ‡ 0.0543 † <0.0001 ‡ P-value (comparison between groups) <0.0001 ** 0.4785 ** Least squares averages and treatment differences Grade * MNC average (± SE) 95% CI P value Hemigliptin / Rosuvastatin FDC -0.409 (± 0.015) (-0.439, -0.379) Hemigliptin -0.014 (± 0.016) (-0.045, 0.016) Rosuvastatin -0.425 (± 0.016) (-0.457, -0.393) (FDC hemigliptin / rosuvastatin) - (hemigliptin) -0.394 (± 0.022) (-0.437, -0.351) <0.0001 (FDC hemigliptin / rosuvastatin) - (Rosuvastatin) 0.016 (± 0.022) (-0.028, 0.060) 0.4713 Interaction Study (Treatment * Baseline) ** <0.0001 Comparison between Combination (Hemigliptin / Rosuvastatin FDC) and Monotherapy (Hemigliptin 50 mg or Rosuvastatin)
Least squares scores (type III) obtained using covariance analysis (ANCOVA), the ANCOVA model included a treatment group and baseline HbA1c as covariates
P-value obtained by ANCOVA, ANCOVA model included a treatment group and baseline HbA1c as covariates and
Treatment * Initial value as interaction effects
†: P-value obtained using the paired t-test, ‡: P-value obtained using the Wilcoxon signed rank test
*: P-value obtained using the two-sample t-test **: P-value obtained using the Wilcoxon rank sum test

(3) Summary of performance assessment results

For HbA1c, the magnitude of the changes in the hemigliptin / rosuvastatin FDC group and the rosuvastatin group were compared. For LDL-C, the percent change in the hemigliptin / rosuvastatin FDC group and the hemigliptin group were compared. Each comparison confirmed the superiority of the hemogliptin / rosuvastatin FDC group.

- At Visit 6 (Week 24), the mean square mean change in the level of HbA1c compared to the baseline was -0.539 ± 0.081% in the hemigliptin / rosuvastatin FDC group and 0.273 ± 0.080% in the rosuvastatin group. Based on 95% CI (-1.035, -0.588), in which the upper limit is less than 0, the superiority of the hemigliptin / rosuvastatin FDC group in the effectiveness of HbA1c reduction compared with the rosuvastatin group was confirmed.

- At Visit 6 (Week 24), the mean square percent change in LDL-C level (%) compared to baseline was -53.002 ± 1.929% in the hemigliptin / rosuvastatin FDC group and -1.135 ± 1.939% in the hemigliptin group. Based on 95% CI (-57.271, -46.463), in which the upper limit is less than 0, the superiority of the hemigliptin / rosuvastatin FDC group in the efficiency of lowering LDL-C compared with the hemigliptin group was confirmed.

Secondly, to assess changes in the levels of HbA1c and LDL-C in the hemogliptin / rosuvastatin FDC group, HbA1c was compared with the hemigliptin group, and LDL-C was compared with the rosuvastatin group.

- At Visit 6 (Week 24), the mean square mean change in HbA1c compared to the baseline was -0.539 ± 0.081% in the hemigliptin / rosuvastatin FDC group and -1.007 ± 0.081% in the hemigliptin group. Both groups showed a significant decrease compared to baseline ( P <0.0001), but the hemigliptin / rosuvastatin FDC group showed a lower decrease in HbA1c than the hemigliptin group, and there was a statistically significant difference ( P = 0.0001).

- At Visit 6 (Week 24), the mean square percent change in LDL-C (%) compared to baseline was -52.57 ± 20.56% in the FDC group of hemigliptin / rosuvastatin and -53.89 ± 16.64% in rosuvastatin group. Both groups showed a significant decrease compared to baseline ( P <0.0001), and there was no significant difference in the percentage change in LDL-C between the two groups ( P = 0.6354).

At each 24-week visit, the hemigliptin / rosuvastatin FDC group showed a significant decrease in HbA1c and FPG compared to the rosuvastatin group and a significant decrease in LDL-C compared to the hemigliptin group.

- Within 24 weeks, the HbA1c in the FDC group of hemigliptin / rosuvastatin was significantly lower than the baseline at each visit. The mean square change in HbA1c level from baseline of -0.686 ± 0.055% at Visit 4 (Week 8) was the largest decrease. On the other hand, in the rosuvastatin group, HbA1c was slightly reduced to -0.074 ± 0.055% at Visit 4 (Week 8), but then increased again. At each visit, the hemigliptin / rosuvastatin FDC group showed a significant decrease in HbA1c compared to the rosuvastatin group, and the difference in the magnitude of the change between the groups was the largest at week 24 (-0.812 ± 0.113% ( P < 0.0001)). At the same time, when compared with the hemigliptin group, the hemigliptin group showed a significantly greater decrease in HbA1c than the hemigliptin / rosuvastatin FDC group after Visit 5 (Week 16).

- Within 24 weeks, the FPG level in the hemigliptin / rosuvastatin FDC group was significantly lower compared to the baseline at each visit. The mean square change in FPG level from baseline of -11.962 ± 2.801 mg / dL at Visit 4 (Week 8) was the largest decrease. On the other hand, in the rosuvastatin group, FPG was constantly elevated. At each visit, the hemigliptin / rosuvastatin FDC group showed a significant decrease in FPG compared to the rosuvastatin group, and the difference in the magnitude of the change between the groups at week 24 was -20.627 ± 4.417 mg / dl. At the same time, when compared with the hemigliptin group, the hemigliptin group showed a significantly greater decrease in FPG than the hemigliptin / rosuvastatin FDC group at each visit.

- Within 24 weeks, the LDL-C level in the hemigliptin / rosuvastatin FDC group was significantly lower compared to the baseline at each visit. The root mean square change in LDL-C from baseline of -53.002 ± 1.929% at Visit 6 (Week 24) was the largest decrease. On the other hand, in the hemigliptin group, the level of LDL-C did not significantly change from the initial level. At each visit, the hemigliptin / rosuvastatin FDC group showed a significant decrease in LDL-C compared with the hemigliptin group, and the difference in the percentage change between the groups at week 24 was -51.867 ± 2.745%. At the same time, when compared with the rosuvastatin group, the decrease in LDL-C in the hemigliptin / rosuvastatin FDC group did not differ significantly from the rosuvastatin group at each visit.

For other evaluation parameters indicating diabetes, the hemigliptin / rosuvastatin FDC group showed a significant improvement in HOMA-β and HOMA-IR at Visit 6 (Week 24).

- The hemigliptin / rosuvastatin FDC group showed no significant change in the fasting serum proinsulin / insulin ratio compared with the baseline value or each control group at Visit 6 (Week 24).

- The hemigliptin / rosuvastatin FDC group showed no significant change in fasting serum C-peptide compared to baseline at Visit 6 (Week 24), no significant difference in the magnitude of the change compared to the rosuvastatin group, but showed a statistically significant increase in C -peptide in fasting serum compared with the hemigliptin group ( P = 0.0488).

- At Visit 6 (Week 24), the mean square mean change in HOMA-β compared to the baseline in the hemigliptin / rosuvastatin FDC group was 11.249 ± 2.832, which was a significant increase compared to the value (0.531 ± 3.005) of the rosuvastatin group ( P = 0, 0100), and did not significantly differ from the value (15.279 ± 2.892) of the hemigliptin group.

- At Visit 6 (Week 24), the root-mean-square mean change in HOMA-IR compared to the baseline value in the hemigliptin / rosuvastatin FDC group was -0.092 ± 0.245, which was not a significant change compared to the baseline value, and was significantly lower compared to the value (0.670 ± 0.258) of the rosuvastatin group ( P = 0.0331) and did not significantly differ from the value (-0.382 ± 0.250) of the hemigliptin group.

Most of the assessed parameters associated with dyslipidemia in the hemogliptin / rosuvastatin FDC group were significantly improved at Visit 6 (Week 24).

- At Visit 6 (Week 24), the mean square mean change in Apo B compared to baseline was -56.393 ± 1.903 mg / dL in the hemigliptin / rosuvastatin FDC group, which was a significant decrease from baseline. The hemigliptin / rosuvastatin FDC group showed a significant decrease compared to the hemigliptin group (-4.456 ± 1.961) ( P <0.0001), and there was no significant difference compared to the rosuvastatin group (-56.118 ± 2.028). These results are consistent with the LDL-C trend.

- Within 24 weeks, the total cholesterol (TC) in the hemogliptin / rosuvastatin FDC group was significantly lower than the baseline at each visit. The root mean square change in TC level from baseline of 78.175 ± 2.761 mg / dl at Visit 6 (Week 24) was the largest decrease. At each visit, the hemigliptin / rosuvastatin FDC group showed a significantly greater decrease in TC than the hemigliptin group, and the difference in the magnitude of the change between the groups at week 24 was -75.024 ± 3.935 mg / dl. At the same time, when compared with the rosuvastatin group, the hemigliptin / rosuvastatin FDC group showed no significant difference in TC reduction at each visit.

- Within 24 weeks, the level of triglycerides (TG) in the hemigliptin / rosuvastatin FDC group was significantly lower compared with the initial level at each visit. The mean square TG change from baseline of -62.433 ± 8.771 mg / dL at Visit 6 (Week 24) was the largest decrease. At each visit, the hemigliptin / rosuvastatin FDC group showed a significantly greater decrease in TG than the hemigliptin group, and the difference in the magnitude of the change between the groups at week 24 was -55.440 ± 12.391 mg / dl. At the same time, when compared with the rosuvastatin group, the hemigliptin / rosuvastatin FDC group showed no significant difference in the decrease in TG at each visit.

- Within 24 weeks, the ratio of LDL-C / HDL-C in the FDC group of hemigliptin / rosuvastatin was significantly lower compared with the initial level at each visit. The mean square mean change in the LDL-C / HDL-C ratio from baseline of -1.649 ± 0.059 at Visit 6 (Week 24) was the largest decrease. At each visit, the hemigliptin / rosuvastatin FDC group showed a significantly larger decrease in the LDL-C / HDL-C ratio than the hemigliptin group, and the difference in the magnitude of the change between the groups at week 24 was -1.637 ± 0.084. At the same time, when compared with the rosuvastatin group, the hemigliptin / rosuvastatin FDC group showed no significant difference in the decrease in the LDL-C / HDL-C ratio at each visit.

- At Visit 6 (Week 24), the rms average of the change in the Apo AI / Apo B ratio compared to the baseline was –0.409 ± 0.015 in the hemigliptin / rosuvastatin FDC group, which was a significant decrease compared to the baseline. The hemigliptin / rosuvastatin FDC group showed a significant decrease compared with the hemigliptin group (-0.014 ± 0.016) ( P <0.0001), and no significant difference compared with the rosuvastatin group (-0.425 ± 0.016). These results are consistent with the trend of the LDL-C / HDL-C relationship.

- At Visit 6 (Week 24), the mean-square mean change in HDL-C compared to baseline was 1.452 ± 0.804 mg / dL in the hemigliptin / rosuvastatin FDC group, which was not a significant change from baseline. The hemigliptin / rosuvastatin FDC group showed no significant difference compared to the hemigliptin group (-0.594 ± 0.804 mg / dl), but showed a significantly lower increase than the rosuvastatin group (4.535 ± 0.796 mg / dl).

- At Visit 6 (Week 24), the mean square change in Apo A-I compared to baseline was 0.996 ± 2.092 mg / dL in the hemigliptin / rosuvastatin FDC group, which was not a significant change from baseline. The hemigliptin / rosuvastatin FDC group showed no significant difference compared to the hemigliptin group (-2.909 ± 2.141 mg / dl) or the rosuvastatin group (6.755 ± 2.221 mg / dl).

- At Visit 6 (Week 24), the rms mean change in lipoprotein (a) compared to baseline was 5.930 ± 1.160 mg / dL in the hemigliptin / rosuvastatin FDC group, which was a significant increase from baseline. The hemigliptin / rosuvastatin FDC group showed a significant decrease compared to the hemigliptin group (-0.435 ± 1.188 mg / dl), but no significant difference compared to the rosuvastatin group (4,800 ± 1,232 mg / dl).

At the same time, at Visit 6 (Week 24), there was no significant change in waist circumference and body weight in the hemogliptin / rosuvastatin FDC group.

- At Visit 6 (Week 24), the mean square mean change in the waist circumference compared to the baseline was -0.738 ± 0.373 cm in the hemigliptin / rosuvastatin FDC group, which was a significant decrease compared to the baseline. The hemigliptin / rosuvastatin FDC group showed no significant difference compared with the hemigliptin group (-0.144 ± 0.372 cm) or the rosuvastatin group (-0.150 ± 0.369 cm).

- At Visit 6 (Week 24), the mean square mean change in body weight compared to baseline was -0.132 ± 0.244 kg in the hemigliptin / rosuvastatin FDC group, which was not a significant change from baseline. The hemigliptin / rosuvastatin FDC group showed no significant difference compared to the hemigliptin group (-0.407 ± 0.0.243 kg), but showed a significantly smaller decrease than the rosuvastatin group (-0.893 ± 0.241 kg).

Claims (13)

1. The combined drug for the treatment of type 2 diabetes and dyslipidemia in diabetic patients, which is in the dosage form of a combination of fixed doses, including: hemigliptin, which is a dipeptidyl peptidase IV inhibitor, or a pharmaceutically acceptable salt thereof, and rosuvastatin, which is an HMG-CoA reductase inhibitor, or a pharmaceutically acceptable salt thereof, as active ingredients and calcium hydrogen phosphate dihydrate as a pharmaceutically acceptable excipient. 2. The combined preparation according to claim 1, which is in the dosage form of a two-layer tablet comprising a layer comprising hemigliptin or a pharmaceutically acceptable salt thereof and a layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof. 3. The combined preparation according to claim 1, wherein the pharmaceutically acceptable salt of hemigliptin is tartrate. 4. The combined preparation according to claim 1, wherein the pharmaceutically acceptable salt of rosuvastatin is a calcium salt. 5. The combined preparation according to claim 2, which further comprises a pharmaceutically acceptable excipient. 6. The combined preparation according to claim 5, wherein the pharmaceutically acceptable excipient contained in the layer comprising hemigliptin or a pharmaceutically acceptable salt thereof is sodium stearyl fumarate. 7. The combined preparation according to claim 5, wherein the pharmaceutically acceptable excipient contained in the layer comprising rosuvastatin or a pharmaceutically acceptable salt thereof is calcium hydrogen phosphate dihydrate. 8. The combination preparation according to claim 1 or 2, which includes 50 mg of hemigliptin or its pharmaceutically acceptable salt and 5 mg of rosuvastatin or its pharmaceutically acceptable salt. 9. The combined preparation according to claim 1 or 2, which includes 50 mg of hemigliptin or its pharmaceutically acceptable salt and 10 mg of rosuvastatin or its pharmaceutically acceptable salt. 10. The combined preparation according to claim 1 or 2, which includes 50 mg of hemigliptin or its pharmaceutically acceptable salt and 20 mg of rosuvastatin or its pharmaceutically acceptable salt. 11. The combined preparation according to claim 1 or 2, which includes 50 mg of hemigliptin or its pharmaceutically acceptable salt and 40 mg of rosuvastatin or its pharmaceutically acceptable salt.

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