JPH09291031A - Lipid metabolism improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a lipid metabolism improver comprising a specific compound as an active ingredient effective for preventing and treating diseases to be estimated cause deterioration of symptoms resulting from hyperlipemia, etc., having improving action in lipid metabolism abnormality. SOLUTION: This lipid metabolism improver comprises 1,4-bis[4-[ (3,5- dioxo-1,2,4-oxidiazolidin-2-yl)methyl]-2-butene or its pharmacologically permissible salt as an active ingredient. A cis(Z) isomer of the formula ids preferably as the compound. A dose is generally 1-1,000mg per adult daily by oral administration and 0.1-100mg by parental administration.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to 1,4-bis [4-[(3,5
-Dioxo-1,2,4-oxadiazolidin-2-yl) methyl]
The present invention relates to a lipid metabolism improving agent containing phenoxy] -2-butene or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

2. Description of the Related Art Arteriosclerotic diseases are diseases that are ranked high in the cause of death and show an increasing tendency with changes in eating habits, and their prevention and treatment are being studied. Hyperlipidemia is known as the first risk factor for arteriosclerotic disease and obstructive heart disease. According to a second report (ATP II) of the American Committee on Cholesterol Education Program in 1993 (ATP II), the positive risk factors for coronary artery disease were:
High LDL cholesterol, age (45 and over for men, 55 and over for women, or women who have undergone early menopause without estrogen replacement therapy), family history of coronary artery disease, smoking, high blood pressure, low HDL cholesterol (35m
g / dl or less), diabetes, and high HDL cholesterol (≧ 60 mg / dl) as a negative risk factor
It is shown. That is, high L, which is an abnormality in lipid metabolism
DL cholesterol and low HDL cholesterol (35 mg / dl
(Below) is a major factor in coronary artery disease, and conversely high HD
L-cholesterol (≧ 60 mg / dl) has been reported to help prevent coronary artery disease.

Therefore, improvement of lipid metabolism in hyperlipidemia, that is, normalization of lipid metabolism including decrease of LDL value and increase of HDL value, is expected to reduce the risk of arteriosclerotic disease. In particular, as diabetic is further cited as a positive risk factor for coronary artery disease described above, in diabetic patients, arteriosclerotic diseases of the heart and brain are often the direct cause of death, and high fats associated with diabetes mellitus. The importance of prevention and treatment of blood pressure has been pointed out (diagnosis and treatment
Vol.80 (9), 1692-1696 (1992)).

The first step in the treatment of hyperlipidemia associated with diabetes is diet therapy, but in many cases, further drug therapy is required and various therapeutic agents for hyperlipidemia are used. However, over-the-counter therapeutic drugs for hyperlipidemia often require caution in terms of side effects and safety in combination with other drugs (Diagnosis and Treatment Vol.80 (9), 1692-1696 (1992). ). A thiazolidinedione compound, pioglitazone or troglitazon, which is under development as a blood glucose lowering agent having an insulin sensitivity enhancing action.
e) is known to have a blood triglyceride lowering action (Arzneim.-forsch./Drug Res. 40 (I), Nr.
2 (1990) and Diabetes, Vol.37, 1549-58 (1988)),
There is no report on the effect of LDL and HDL on lipid metabolism. That is, a drug having not only a blood glucose lowering action but also a sufficient action of improving abnormal lipid metabolism is not known.

On the other hand, in International Publication WO94 / 25448, a structure completely different from that of the above-mentioned thiazolidinedione compound,
1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidine
It is disclosed that a novel bisoxadiazolidine derivative containing -2-yl) methyl] phenoxy] -2-butene has an insulin sensitivity enhancing action and is useful as a blood glucose lowering agent. However, there is no disclosure or suggestion about the lipid metabolism improving action of these compounds.

[0006]

It is desired to create a drug with few side effects, which improves lipid metabolism abnormality (for example, hyperlipidemia) which is a risk factor for arteriosclerotic diseases. In particular, it has been earnestly desired to create a drug useful for hyperlipidemia associated with diabetes, which has both an action of lowering a high blood glucose level and an action of improving abnormal lipid metabolism.

[0007]

Means for Solving the Problems The present inventors have studied the pharmacological action of a series of bisoxadiazolidine derivatives described in WO 94/25448, and found that 1,4-
Bis [4-[(3,5-dioxo-1,2,4-oxadiazolidine-2-
It was found that, unexpectedly, (yl) methyl] phenoxy] -2-butene (Compound I) or a pharmaceutically acceptable salt thereof has a good lipid metabolism-improving action, and completed the present invention. As the lipid metabolism improving action of Compound I, the improving action of the HDL value is particularly remarkable.

That is, the present invention provides 1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene (Compound I). Alternatively, it is a lipid metabolism improving agent containing a pharmaceutically acceptable salt thereof as an active ingredient. The present invention also relates to a prophylactic / therapeutic agent for hypoHDLemia containing Compound I or a pharmaceutically acceptable salt thereof as an active ingredient.
Furthermore, the present invention relates to a prophylactic / therapeutic agent for hyperlipidemia associated with diabetes, which comprises Compound I or a pharmaceutically acceptable salt thereof as an active ingredient because Compound I also has a strong hypoglycemic action. .

[0009]

The present invention will be further described as follows. (Active ingredient) The active ingredient of the medicine of the present invention is 1,4-bis [4-
[(3,5-Dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene (Compound I) or a pharmaceutically acceptable salt thereof, which is disclosed in International Publication WO94. It is a known compound disclosed in Japanese Patent Publication No. 25448 together with its production method.

Compound I has a cis (Z) form and a trans (E) form based on the presence of a double bond, and as the active ingredient of the drug of the present invention, these separated products or a mixture can be used. A cis (Z) form (compound Ia) represented by the following formula is preferred.

[0011]

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The pharmaceutically acceptable salt of compound I is a salt with a base because it has an acidic proton in the oxadiazolidine ring, and specifically, for example, alkali metals such as sodium and potassium, Alkaline earth metals such as magnesium and calcium, salts with inorganic bases such as trivalent metals such as aluminum, methylamine, ethylamine, dimethylamine, diethylamine, trimethylamine, triethylamine, monoethanolamine, diethanolamine, triethanolamine, cyclohexylamine , Salts with organic bases such as lysine and ornithine. Compound I or a pharmaceutically acceptable salt thereof which is an active ingredient of the medicine of the present invention is a hydrate or various solvates,
Alternatively, it may be isolated as a crystalline polymorphic substance, and the present invention includes all of these isolated substances and mixtures.

In fact, a plurality of crystalline polymorphs have been confirmed in the cis (Z) form of compound I, and the melting point disclosed in Example 10 of the above-mentioned International Publication WO94 / 25448 has a melting point of 139 to 144 ° C.
In addition to the crystal A, the melting point of the crystal B is 166 to 7 ° C., and 14
Crystal C at 7-8 ° C is also included in compound I of the present invention. Among them, the crystal B that is stable and does not have hygroscopicity is preferable. The compound I of the present invention is known from the above publications and can be easily obtained based on the method described in the publications. Further, the pharmaceutically acceptable salt of Compound I can be produced by a conventional method. If hydrates, solvates, or crystalline polymorphs of Compound I are present, they can be isolated using separation / purification methods known to those skilled in the art.

(Pharmaceutical Use) The lipid metabolism improving agent of the present invention is a drug for improving abnormalities in lipid metabolism caused by any reason. Examples of abnormal lipid metabolism include abnormal serum cholesterol levels and / or increased serum triglycerides that are diagnosed as hyperlipidemia. Here, the abnormal serum cholesterol includes an increase in total cholesterol, an extremely low specific gravity lipoprotein (VLDL-cholesterol), an abnormal low lipoprotein (LDL-cholesterol) increase, and a high specific gravity lipoprotein, which are recognized as abnormal serum lipoprotein balance. Abnormalities such as a decrease in (HDL-cholesterol) (particularly HDL2-cholesterol), an increase in remnant lipoprotein, etc., or a plurality of combined abnormalities are mentioned (clinical and research Vol. 72, No. 8, 1873-1879). The agent of the present invention has an action of improving these lipid metabolism disorders, particularly HDL.
-Has an action of improving cholesterol metabolism.

Further, in diabetic patients, 1/3 thereof
It is known that 10% of patients with hypolipidemia are accompanied by abnormal lipid metabolism (Diagnosis and Treatment Vol.80 (9), 1692-1).
696 (1992)), the drug of the present invention has a hypoglycemic action as well, and is therefore useful for the prevention / treatment of hyperlipidemia associated with diabetes. Therefore, the lipid metabolism improving agent of the present invention is preferably a prophylactic / therapeutic agent for hyperlipidemia associated with diabetes.

Specific indications of the drug of the present invention are diseases that exhibit abnormal lipid metabolism, for example, hyperlipidemia (for example, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, etc.). , Obesity and the like. In particular, it is useful as a prophylactic / therapeutic agent for hypoHDLemia. Furthermore,
Diseases that are expected to worsen due to abnormal lipid metabolism include ischemic heart disease such as arteriosclerosis, myocardial infarction and angina, cerebral arteriosclerosis such as cerebral infarction or aneurysm, nephrotic syndrome, etc. And the like, and can be used as a prophylactic / therapeutic agent for these diseases.

(Formulation Method, Administration Method, Dosage) The pharmaceutical of the present invention comprises compound I or a pharmaceutically acceptable salt thereof,
It is prepared as an oral, parenteral solid or liquid pharmaceutical composition by mixing with a pharmaceutically acceptable pharmaceutical carrier.

The solid composition for oral administration according to the present invention includes tablets, pills, capsules, fine granules, granules and the like. In such solid compositions, one or more active substances are at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, crystalline cellulose, various starches, polyvinylpyrrolidone, metasilicic acid. It is mixed with magnesium aluminate. The composition comprises, according to a conventional method, additives other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or It may contain a solubilizing or solubilizing agent such as aspartic acid. Further, tablets, pills, granules, and granules of capsules containing granules may be coated with sugar such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or a film of a gastric or enteric substance, if necessary. You may coat with. In addition, in order to improve the solubility of the formulation,
A known solubilization treatment may be applied to prepare a preparation.

The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like in a formulation form, and is generally used as a component of the composition. Inert diluents commonly used, such as purified water, ethanol and the like. This composition may contain, in addition to the inert diluent, auxiliary agents such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.

Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions and emulsions. Examples of the aqueous solution or suspension include distilled water for injection and physiological saline. Non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, pharmaceutically acceptable alcohols such as ethanol, and surface active agents such as polyoxyethylene sorbitan fatty acid ester. Agents are included. Such aqueous and non-aqueous compositions include, in addition to these additives, wetting agents, suspending agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizing or solubilizing agents (eg glutamic acid or aspartic acid). Etc.) and an antiseptic. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. They can also be manufactured as a sterile solid composition and dissolved in sterile water or a sterile solvent for injection before use.

In order to use the present invention for the purpose of preventing / treating the above-mentioned diseases, it is usually administered orally or parenterally. The dose varies depending on the patient's age, body weight, symptoms, therapeutic effect, administration route, etc., and is appropriately set in consideration of these, but usually 1 to 1000 mg, preferably 10 to 300 mg by oral administration per day for an adult, or , Parenteral administration 0.1-10
0 mg is preferable, and this is administered once a day or divided into 2 to several times. Since the dose varies depending on the preventive purpose and various other conditions, a dose smaller than the above dose range may be sufficient.

[0022]

EXAMPLES The present invention will be described in more detail with reference to the following examples. Needless to say, the present invention should not be limited to the technology described in the embodiments. (Z) -1,4-bis [4-[(3,5-dioxo-1,2, that can be used as an active ingredient of the present invention
4-Oxadiazolidin-2-yl) methyl] phenoxy] -2-
A method for producing a new crystal form of butene (compound Ia) is shown in Production Examples.

(Production Example 1) (Z) -1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene (Compound I
a) Production of crystal B (Z) -1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene 4. 68 g
Is suspended in 100 ml of water, and lithium hydroxide.
After adding 9.0 g of the hydrate and dissolving it, 1N hydrochloric acid 110
The pH was adjusted to 1-2 by adding ml. After stirring for 2 hours, the crystallized crystals were collected by filtration, washed with 100 ml of water and dried to obtain 4.5 g of the desired crystal B. Melting point 166-167 ° C

(Production Example 2) (Z) -1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene (Compound I
a) Preparation of crystal C (Z) -1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene 1. 80 g
20 ml of acetone was added to and heated to dissolve. 20 ml of water was added to the solution and allowed to cool with stirring. The precipitated crystals were collected by filtration and dried to obtain 1.64 g of the target crystal C. Melting point 147-148 ° C

The pharmacological action of the active ingredient of the present invention has been confirmed by the following tests. (Test Example 1) A genetic insulin resistance model animal
Zucker fatty rats (rats with spontaneous obesity:
Hyperinsulinemia, hypertriglyceridemia, and mild hyperglycemia) (male, 9 weeks old) were collected from the inferior tail vein before administration to measure triglyceride, total cholesterol, blood glucose and insulin levels. . These measurement values were grouped so that there was no difference between the groups, and (Z) -obtained in Production Example 1
1,4-bis [4-[(3,5-dioxo-1,2,4-oxadiazolidine
2-yl) methyl] phenoxy] -2-butene crystal B (hereinafter compound 1) 100 mg / kg and 300 mg / kg, or troglitazone (CS-045) 100 mg / kg and 300 mg / kg 0.5% methylcellulose suspension It was forcibly orally administered as a suspension once a day for 14 consecutive days. Blood was collected in the same manner on the 5th, 8th and 15th days of administration, and triglyceride (TG) was measured. 15 more
On the day, blood samples are dissected and each cholesterol fraction (total cholesterol (TC), HDL-cholesterol (HDL), H
Non-DL-cholesterol fraction (non-HDL)) was measured. The drug-untreated group was used as a control, and the change rate (average value:%) was calculated with the control being 100.

(Results and Discussion) Table 1 shows changes in plasma triglyceride concentration after continuous injection for 14 days, and Table 2 shows changes in plasma cholesterol concentration after continuous injection for 14 days. Compound 1 showed a significant decrease in TG from the 5th day of administration by continuous administration, and its effect was stronger than that of CS-045. Compound 1 did not change TC even after continuous injection for 14 days. This is HD
It is considered that L did not change apparently because L slightly increased and non-HDL decreased. on the other hand,
CS-045 did not change HDL, but non-
Since HDL showed a decrease, it is considered that TC also showed a decreasing tendency. From these results, Compound 1 was compared to CS-045, which is a known hypoglycemic agent known to have a TG lowering effect.
Has a strong TG-lowering effect and also has an effect of lowering non-HDL and increasing HDL, and has a good lipid metabolism-improving effect.

Table 1 Changes in plasma triglyceride concentration after 14 consecutive days (37) Compound 1 300 mg / kg 6 150.28 ± 16.32 * (20) CS-045 100 mg / kg 6 528.22 ± 76.71 (69) CS-045 300 mg / kg 6 396.86 ± 48.14 (52) _____________________

Table 2 Changes in Plasma Cholesterol Concentration After 14-day Continuous Injection _____________________________ Test Drug TC (mg / dl) HDL (mg / dl) non-HDL (mg / dl) (Change:%) (Change:%) Change rate:%) _____________________ Control 101.10 ± 5.58 67.37 ± 5.37 33.73 ± 4.66 (100) (100) (100) Compound 1300 mg / kg 102.05 ± 6.43 85.02 ± 5.45 17.03 ± 1.43 (101) -045 (101) -0 (126) (126) 300 mg / kg 83.80 ± 5.94 69.92 ± 5.02 13.88 ± 1.43 (83) (104) (41) _____________________________________________

(Test Example 2) In the same manner as in Test Example 1, Zuck
er fatty rats (male, 9 weeks old) were blood-collected from the inferior tail vein before administration, and triglyceride, total cholesterol, blood glucose level, and insulin level were measured. The measurement values were divided into groups so that there was no difference between the groups, and 300 mg / kg of Compound 1 as a test drug was forcibly orally administered as a 0.5% methylcellulose suspension once a day for 30 consecutive days. . Similarly, blood was collected 1, 2, and 4 weeks after administration, and triglyceride (TG), blood glucose (BG), and insulin (IR) were collected.
Each parameter of I) was measured. Further, on the 31st day, the blood was dissected and blood was collected, and each cholesterol fraction was measured.

(Results and Discussion) The changes in the concentration of each parameter after continuous administration for 4 weeks are shown in Table 3, and the changes in the plasma cholesterol concentration after continuous administration for 30 days are shown in Table 4. Continuous administration of Compound 1 showed a significant decrease in TG one week after administration as compared with the control group, and improvement in hypertriglycerideemia was observed. Similar to Test Example 1, it showed a significant increase in HDL and a decrease in non-HDL without changing TC. Furthermore, in this test, the compound 1-administered group showed a decrease in insulin (IRI) one week after administration as compared with the control group, and improvement in hyperinsulinemia was observed, and a decrease in blood glucose (BG) was observed. I was seen. These results indicate that, in Zucker fatty rats, which are genetic insulin resistance model animals, Compound 1 enhances insulin sensitivity, improves hyperinsulinemia and lowers blood glucose level, and at the same time, improves lipid metabolism abnormality. It suggests that Compound 1 may be a useful drug for improving abnormal lipid metabolism in abnormal lipid metabolism associated with non-insulin-dependent diabetes mellitus.

Table 3 Changes in concentration of each parameter after continuous injection for 4 weeks ____________________ Test drug TG (mg / dl) BG (mg / dl) IRI (ng / dl) (Change:%) (Change:%) :%) _______________ Control 846.3 ± 170.3 189.3 ± 45.1 133.6 ± 25.8 (100) (100) (100) Compound 1 300 mg / kg 183.2 ± 15.1 95.7 ± 4.2 65.9 ± 6.6 (22) * (51) (49) _______ 6 cases *: p <0.01 vs control

Table 3 Changes in Plasma Cholesterol Concentration After 30-Day Continuous Injection _________________ Test Drug TC (mg / dl) HDL (mg / dl) non-HDL (mg / dl) (Change:%) (Change:%) Rate of change:%) ______________________________________ Control 121.0 ± 13.6 69.8 ± 5.2 51.2 ± 11.4 (100) (100) (100) Compound 1 300 mg / kg 127.3 ± 7.7 106.8 ± 6.5 _______________________________ 6 patients in each group *: p <0.01 vs control

(Test Example 3) Normal rats (SD rats) were bled from the infused tail vein before administration, and triglyceride, total cholesterol, blood glucose and insulin levels were measured. Group these measurements so that there is no difference between them,
As a test drug, 300 mg / kg of Compound 1 was forcibly orally administered as a 0.5% methylcellulose suspension once a day for 14 consecutive days. Similarly, blood was collected 4, 7, and 14 days after administration, and triglyceride (TG) and blood glucose level (B
Each parameter of G) was measured. On the 15th day, the blood was dissected and blood was collected to measure each cholesterol fraction.

(Results and Discussion) From the 4th day after the administration of Compound 1, a significant decrease in TG was shown, and the action lasted until the 14th day. Tables 5 and 6 show changes in plasma concentrations after continuous administration for 14 days. Compound 1 has significant T compared to control
It showed a decrease in G, and the non-HDL was also significantly decreased. On the other hand, T
C showed a decreasing tendency and HDL showed an increasing tendency, but no significant change was observed. Compound 1 was shown to have a lipid metabolism improving action also in normal animals. The blood glucose level after continuous injection for 14 days showed no change relative to the control. From this, it was suggested that in animals having a normal blood glucose level, Compound 1 has only a lipid metabolism improving action without showing a blood glucose lowering action. .

[0035] 8 patients in each group *: p <0.01 vs control

Table 6 Changes in Plasma Cholesterol Concentration After 14-Day Continuous Injection _________________ Test Drug TC (mg / dl) HDL (mg / dl) non-HDL (mg / dl) (Change:%) (Change:%) Rate of change:%) ________________________ Control 61.92 ± 3.03 35.66 ± 1.85 26.26 ± 2.53 (100) (100) (100) Compound 1 300mg / kg 56.95 ± 4.71 38.10 ± 3.95 18.85 ± 1.32 (92) (107) (72) (72) (72) _________________________________________________________________Each group 8 examples **: p <0.05 vs control

An example of prescription of the medicine of the present invention is shown below. (Formulation Example 1) Tablet (Composition) Compound 1 50 mg Lactose 72 Corn starch 18 Hydroxypropylcellulose 5 Carboxymethylcellulose calcium 4 Magnesium stearate 1 _________ Total 150 mg

Compound 1 (200 g), lactose (288 g) and corn starch (72 g) were uniformly mixed using a fluidized bed granulator. Add 10% hydroxypropylcellulose solution 2 to this.
00 g was sprayed and granulated. After drying, pass through a 20-mesh sieve and carboxymethylcellulose calcium 1
Add 6 g and 4 g magnesium stearate and mix,
Tableted powder. This tableting powder is 7.5 mm on a rotary tableting machine.
Each tablet was made into 150 mg tablets using a × 9.0 R pestle.

[0039]

Effect of the Invention 1,4-bis [4-[(3,5-dioxo-1,
2,4-Oxadiazolidin-2-yl) methyl] phenoxy] -2
-Butene or a pharmaceutically acceptable salt thereof has a good lipid metabolism improving action and is useful for improving lipid metabolism abnormalities such as hyperlipidemia. In particular, it is useful as a prophylactic / therapeutic agent for hypoHDLemia. Furthermore, prevention of hyperlipidemia associated with diabetes
It is expected to be a useful drug for treatment. Therefore, the drug of the present invention is effective for diseases exhibiting abnormal lipid metabolism, such as hyperlipidemia (for example, hypertriglyceridemia, hypercholesterolemia, hypoHDLemia, etc.), obesity, and abnormal lipid metabolism. Diseases due to which symptoms are expected to worsen, for example, arteriosclerosis, myocardial infarction, ischemic heart disease such as angina,
It is useful as a prophylactic / therapeutic agent for cerebral arteriosclerosis such as cerebral infarction, aneurysm, renal diseases such as nephrotic syndrome.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Kunihiro Shingata 2-287 Nakabu, Ageo City, Saitama Prefecture

Claims (4)

[Claims] 1. 1,4-Bis [4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy] -2-butene or its pharmaceutically acceptable A lipid metabolism improving agent containing a salt as an active ingredient. 2. (Z) -1,4-bis [4-[(3,5-dioxo-1,2,4-
The lipid metabolism improving agent according to claim 1, which comprises oxadiazolidin-2-yl) methyl] phenoxy] -2-butene or a pharmaceutically acceptable salt thereof as an active ingredient. 3. The lipid metabolism improving agent according to claim 1, which is a prophylactic / therapeutic agent for hypoHDLemia. 4. The lipid metabolism improving agent according to claim 1, which is a prophylactic / therapeutic agent for hyperlipidemia associated with diabetes.