MXPA00000633A - Treatment of diabetes with thiazolidinedione, insulin secretagogue and diguanide - Google Patents

Abstract

A method for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal, which method comprises administering an effective non-toxic and pharmaceutically acceptable amount of an insulin sensitiser, an insulin secretagogue and a biguanide antihyperglycaemic agent, to a mammal in need thereof;and composition for use in such method.

Description

TREATMENT OF DIABETES WITH TIAZOLIDINODIONA, SECRETAGOGO OF INSULIN AND DIGUANIDA DESCRIPTIVE MEMORY This invention relates to a method of treatment, in particular to a method for the treatment of diabetes mellitus, especially non-insulin dependent diabetes (NIDDM) (or type 2 diabetes) and conditions associated with diabetes mellitus. Insulin secretagogues are compounds that promote an increase in insulin secretion by pancreatic beta cells. Sulfonylureas are well-known examples of insulin secretagogues. The sulfonylureas act as hypoglycemic agents and are used in the treatment of type 2 diabetes. Examples of sulfonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide. Biguanide antihyperglycaemic agents are commonly used in the treatment of type 2 diabetes. 1, 1-dimethylbiguanidine (or Metformin) is an example of an antihyperglycemic biguanide agent. European patent application, publication number 0,306,228 relates to certain thiazolidinedione derivatives described as possessing antihyperglycemic and antihyperlipidemic activity. A particular thiazolidinedione described in EP 0306228 is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-2,4-dione (hereinafter 'compound (I)' ).

WO94 / 05659 describes certain salts of compound (I) which include the maleate salt. Compound (I) is an example of a class of antihyperglycemic agents known as 'insulin sensitizers'. In particular, the compound (I) is an insulin sensitizer of thiazolidinedione. European patent applications, publication numbers: 0008203, 0139421, 0032128, 0428312, 0489663, 0155845, 0257781, 0208420, 0177353, 0319189, 0332331, 0332332, 0528734, 0508740; International patent application, publication numbers 92/18501, 93/02079, 93/22445 and U.S. Patent Nos. 5104888 and 5478852, also disclose certain thiazolidinedione insulin sensitizers. Another series of compounds generally recognized to have insulin sensitizing activity are those typified by the compounds described in the international patent applications, publication numbers WO93 / 21166 and WO94 / 01420. These compounds are referred to herein as 'acyclic insulin sensitizers'. Other examples of acyclic insulin sensitizers are those described in U.S. Patent No. 5232945 and international patent applications, publication numbers WO92 / 03425 and WO91 / 19702. Examples of other insulin sensitizers are those described in the European patent application, publication number 0533933, Japanese patent application publication number 05271204 and United States patent number 5264451.

The publications mentioned above are incorporated herein by reference. Surprisingly it is indicated that the compound (I) in combination with an insulin secretagogue and an antihyperglycemic agent of biguanide provides a beneficial effect in particular on glycemic control, said combination therefore being useful in particular for the treatment of diabetes mellitus , especially type 2 diabetes and conditions associated with diabetes mellitus. It is also indicated that the treatment continues with minimal side effects. Accordingly, the invention provides a method for the treatment of diabetes mellitus, especially type 2 diabetes and conditions associated with diabetes mellitus in a mammal, such as a human, which method comprises the administration of a pharmaceutically acceptable, effective and non-toxic amount. of an insulin sensitizer, an insulin secretagogue and an antihyperglycemic agent of biguanide, to a mammal in need thereof. The method comprises the co-administration of the insulin sensitizer, an insulin secretagogue and an antihyperglycemic biguanide agent or the sequential administration thereof. Co-administration includes the administration of a formulation that includes an insulin sensitizer, an insulin secretagogue and an antihyperglycemic biguanide agent or the essentially simultaneous administration of separate formulations of each agent.

In another aspect, the invention provides the use of an insulin sensitizer, such as compound (I), an insulin secretagogue and an antihyperglycaemic agent of biguanide in the manufacture of a composition for the treatment of diabetes mellitus, especially diabetes mellitus. type 2 and conditions associated with diabetes mellitus. A suitable insulin sensitizer is an insulin sensitizer of thiazolidinedione. A suitable thiazolidinedione insulin sensitizer is compound (I). Other suitable thiazolidinedione insulin sensitizers include (+) - 5 - [[4 - [(3 > 4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl ) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4 - [(1-methyl-cyclohexyl) methoxy] benzyl] thiazolidino-2,4-dione (or ciglitazone), 5- [4- [2- (5-etl-pyridin-2-yl) ethoxy] benzyl] t-azolidino-2,4-dione (or pioglitazone) or 5 - [(2-benzyl-2, 3-dihydrobenzopyran) -5-ylmethyl) thiazolidino-2,4-dione (or englitazone). Suitable insulin secretagogues include sulfonylureas. Suitable sulfonylureas include glibenclamide, glipizide, gliclazide, glimepiride, tolazamide and tolbutamide. Other sulfonylureas include acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glycopramide and glycylamide. Other suitable insulin secretagogues include repaglinide.

A suitable biguanide antihyperglycaemic agent is metformin, buformin or phenformin, especially metformin. In a particular aspect, the method comprises the administration of 2 to 12 mg of compound (I), especially when administered per day. In particular, the method comprises administering from 2 to 4, 4 to 8 or 8 to 12 mg of compound (I) per day. In particular, the method comprises the administration of 2 to 4 mg of the compound (I), especially when administered per day. In particular, the method comprises the administration of 4 to 8 mg, especially when administered per day. In particular, the method comprises the administration of 8 to 12 mg of compound (I), especially when administered per day. Preferably, the method comprises administering 2 mg of compound (I), especially when administered per day. Preferably, the method comprises administering 4 mg of compound (I), especially when administered per day. Preferably, the method comprises administering 8 mg of compound (I), especially when administered per day. It should be understood that the insulin sensitizer, such as the compound (I), the insulin secretagogue and an antihyperglycemic biguanide agent are each administered in a pharmaceutically acceptable form, including pharmaceutically acceptable derivatives such as pharmaceutically acceptable salts, esters and solvates of the themselves, as appropriate. In some instances the names used herein for the insulin secretagogues and the relevant biguanide antihyperglycemic agents may relate to a particular dosage form of the active agents in question: it should be understood that this invention comprises all pharmaceutically acceptable forms of the agents assets per se. Suitable pharmaceutically acceptable salt forms of insulin sensitizers, such as compound (I), include those described in the aforementioned patents and patent applications as in EP 0306228 and WO94 / 05659 for compound (I). A preferred pharmaceutically acceptable salt for compound (I) is a maleate. Suitable pharmaceutically acceptable solvate forms of insulin sensitizers, such as compound (I), include those described in the aforementioned patents and patent applications, as in EP 0306228 and WO94 / 05659 for compound (I), in particular hydrates . Suitable pharmaceutically acceptable forms of the insulin secretagogue and the antihyperglycemic agent of biguanide depend on the particular compound used, but include known pharmaceutically acceptable forms of the particular compound chosen. Such derivatives are found or mentioned in standard reference texts, such as British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) (for example, see the 31st edition, page 341 and pages cited therein).

Insulin sensitizers, such as compound (I) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate thereof, can be prepared using known methods, for example those described in the aforementioned patents and patent applications, as EP 0306228 and WO94 / 05659 for the compound (I). The descriptions of the already mentioned patents and patent applications, such as EP 0306228 and WO94 / 05659, are incorporated herein by reference. The compound (I) can exist in one of several tautomeric forms, which are encompassed by the term "compound (I)" as individual tautomeric forms or as mixtures thereof. Compound (I) contains a chiral carbon atom, and therefore can exist in up to two stereoisomeric forms, the term compound (I) encompasses all of these isomeric forms, either as individual isomers or as mixtures of isomers, including racemates. The insulin secretagogue and selected biguanide antihyperglycaemic agent are prepared by known methods, such methods are found or mentioned in standard reference texts, such as British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia ( London, The Pharmaceutical Press) (for example, see the 31st edition, page 341 and pages cited therein). When used herein, the term "conditions associated with diabetes" includes those conditions associated with diabetes mellitus itself and complications associated with diabetes mellitus. Also, in "conditions associated with diabetes" are included the conditions related to the pre-diabetic state. When the term "conditions associated with the pre-diabetic state" is used herein, it includes conditions such as insulin resistance, including hereditary insulin resistance, impaired glucose tolerance and hyperinsulinemia. "Conditions associated with diabetes mellitus itself" include hyperglycemia, insulin resistance, including resistance to acquired insulin. Other conditions associated with diabetes mellitus itself include hypertension and cardiovascular disease, especially atherosclerosis, and conditions associated with insulin resistance. Conditions associated with insulin resistance include polycystic ovarian syndrome and steroid-induced insulin resistance and gestational diabetes. "Complications associated with diabetes mellitus" include kidney disease, especially renal diseases associated with type 2 diabetes, neuropathy and retinopathy. Renal diseases associated with type 2 diabetes include nephropathy, glomerulonephritis, glomerular sclerosis, hypertensive nephrosclerosis, and end-stage renal disease. Other kidney diseases associated with type 2 diabetes include nephrotic syndrome. For the avoidance of doubt, when reference is made to scalar amounts, including amounts in mg, of the compound (I) in a pharmaceutically acceptable form, the scalar amount referred to is with respect to the compound (I) per se, for example, 2 mg of compound (I) in the maleate salt form is the amount of maleate salt containing 2 mg of compound (I). Diabetes mellitus is preferably type 2 diabetes. The particularly beneficial effect on glycemic control provided by the treatment of the invention indicates that it is a synergistic effect relative to the expected control for the sum of the effects of the individual active agents. Suitably, the insulin sensitizer is the first administration agent. Glycemic control can be characterized by conventional methods, for example by measuring a commonly used glycemic control index, such as fasting plasma glucose or glucose hemoglobin (HbA1c). These indices are determined using standard methodology, for example those described in: Tuesdays A, Richterich and P., Schweiz. med. Wschr. 101 (1971), 345 and 390 and Frank P., "Monitoring the Diabetic Patient with Glycosolated Hemoglobin Measurements", Clinical Products 1988. In a preferred aspect, the dosage level of each of the active agents when used in accordance with the treatment of the invention will be less than that which would have been required in a purely additive effect with respect to glycemic control. Also, there is an indication that the treatment of the invention will effect an improvement, over the individual agents, in the levels of advanced glycosylation end products (AGE), leptin and serum lipids, including total cholesterol , HDL-cholesterol, LDL-cholesterol, including improvements in the ratios thereof, in particular an improvement in serum lipids, including total cholesterol, HDL-cholesterol, LDL-cholesterol including improvements in their ratios. As used herein, the term "pharmaceutically acceptable" encompasses both human and veterinary use, for example, the term "pharmaceutically acceptable" includes a compound accepted in veterinary. In the method of the invention, preferably, the active medicaments are administered in the form of a pharmaceutical composition. As indicated above, said compositions may include all medications or only one of the medications. Accordingly, in one aspect, the invention also provides a pharmaceutical composition comprising an insulin sensitizer, such as compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and an antihyperglycemic agent of biguanide and a carrier pharmaceutically acceptable therefor. Said compositions can be prepared by mixing an insulin sensitizer such as compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycemic agent and a pharmaceutically acceptable carrier therefor.

Usually the compositions are adapted for oral administration; however, they can be adapted for other modes of administration, for example, parenteral, sublingual or transdermal administration. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, suppositories, reconstitutable powders or liquid preparations, such as sterile oral or parenteral solutions or suspensions. To obtain administration consistency it is preferable that a composition of the invention is in the form of a unit dose. The forms of presentation of the unit dose for oral administration may be tablets and capsules and may contain conventional excipients, such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrators, for example starch, polyvinyl pyrrolidone, sodium starch glycolate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulfate. Preferably, the compositions are in unit dosage form in an amount appropriate for the relevant daily dose. Suitable doses for insulin sensitizers include those described in the aforementioned patents and patent applications. Suitable doses including unit doses of compound (I) comprise 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 mg of compound (I).

In the treatment, the medicines can be administered from 1 to 6 times a day, but more preferably 1 to 2 times a day. Particular doses of compound (I) are 2 mg / day, 4 mg / day, including 2 mg twice daily and 8 mg / day, including 4 mg twice daily. Suitable doses that include unit doses of the insulin secretagogue, such as the sulfonylurea or the antihyperglycemic agent of biguanide, include known doses that include unit doses for these compounds, as described or mentioned in reference texts, such as British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press) and Harry's Cosmeticology (Leonard Hill Books) (for example, see the 31st edition, page 341 and pages cited therein). Therefore, for sulfonylureas, a typical daily dose of glibenclamide is on a scale of 2.5 to 20 mg, for example, 10 mg twice a day or 20 mg once a day; a typical daily dose of glipizide is in the range of 2.5 to 40 mg; a typical daily dose of gliclazide is on the scale of 40 to 320 mg; a typical daily dose of tolazamide is on a scale of 100 to 1000 mg; a typical daily dose of tolbutamide is on a scale of 1000 to 3000 mg; a typical daily dose of chlorpropamide is on a scale of 100 to 500 mg; and a typical daily dose of gliquidone is on a scale of 15 to 180 mg. Repaglinide can be taken in amounts, usually on the 0.5 mg to 4 mg scale and usually with food, up to a typical maximum daily dose of 16 mg per day.

With respect to the antihyperglycaemic agents of biguanide, suitable doses of metformin include up to 3000 mg per day, in unit doses of 500 mg (for example two or three times a day) or 850 mg (for example twice a day), a example of a dose for metformin is 500 mg once until reaching five times a day. The solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It is possible to use mixing operations as many times as necessary to distribute the active agent through the compositions using large amounts of fillers. Said operations are of course conventional in the art. The tablets may be coated according to methods well known in normal pharmaceutical practice, in particular with an enteric coating. The liquid oral preparations may be in the form of, for example, emulsions, syrups or elixirs, or presented in the form of a dry product to be reconstituted with water or other suitable vehicle before use. Said liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methylcellulose, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats.; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, fatty esters such as glycerin esters, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if so desired, conventional flavoring or coloring agents. For parenteral administration, fluid unit dosage forms are prepared using the compound and a sterile vehicle, and depending on the concentration used, they can be suspended or dissolved in the vehicle. In the preparation of the solutions, the compound can be dissolved in water for injection and sterilized by filter before filling in a suitable container or ampoule and sealed. Conveniently, adjuvants, such as local anesthetics, a preservative and pH regulating agents, can be dissolved in the vehicle. To improve stability, the composition can be frozen after filling it into the container and removing the water under vacuum. Parenteral suspensions are prepared in substantially the same manner, except that the compound (I) is suspended in the vehicle instead of being dissolved, and the sterilization can not be completed by filtration. The compound can be sterilized by exposure to ethylene oxide before suspending it in the sterile vehicle. For convenience a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound. The compositions may contain from 0.1% to 99% by weight, preferably 10-60% by weight, of the active material, depending on the method of administration. If desired, the composition may be in the form of a package accompanied by written or printed instructions for use.

The compositions are prepared and formulated according to conventional methods, such as those described in standard reference texts, for example, British and US Pharmacopoeias, Remington's Pharmaceutical Sciences (Mack Publishing Co.), Martindale The Extra Pharmacopoeia (London, The Pharmaceutical Press ) and Harry's Cosmeticology (Leonard Hill Books) (for example, see the 31st edition, page 341 and pages cited therein). The present invention also provides a pharmaceutical composition comprising an insulin sensitizer, such as compound (I) and, in particular, 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycemic agent and a pharmaceutically acceptable carrier for themselves, to be used as an active therapeutic substance. Also, the invention provides the use of an insulin sensitizer, such as compound (I) and especially 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycemic agent for the preparation of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes. In particular, the present invention provides a pharmaceutical composition comprising an insulin sensitizer, such as compound (I) and especially from 2 to 12 mg thereof, an insulin secretagogue and a biguanide antihyperglycemic agent and a pharmaceutically acceptable carrier for the same, for use in the treatment of diabetes mellitus and conditions associated with diabetes mellitus.

A scale of 2 to 4 mg includes a scale of 2.1 to 4, 2.2 to 4, 2.3 to 4, 2.4 to 4, 2.5 to 4, 2.6 to 4, 2.7 to 4, 2.8 to 4, 2.9 to 4 or 3 to 4 mg. A scale of 4 to 8 mg includes a scale of 4.1 to 8, 4.2 to 8, 4.3 to 8, 4.4 to 8, 4.5 to 8, 4.6 to 8, 4.7 to 8, 4.8 to 8, 4.9 to 8, 5 to 8 , 6 to 8 or 7 to 8 mg. A scale of 8 to 12 mg includes a scale of 8.1 to 12, 8.2 to 12, 8. 3 to 12, 8.4 to 12, 8.5 to 12, 8.6 to 12, 8.7 to 12, 8.8 to 12, 8.9 to 12, 9 to 12, 10 to 12 or 11 to 12 mg. No adverse toxicological effects are expected for the compositions or methods of the invention in the aforementioned dose scales.

COMPOSITIONS OF THE COMPOUND (I) Preparation of the concentrate: The concentrate for tableting was prepared using the following materials.

Ingredient Amount (%) Compound (I) crushed as salt of 13.25 (pure maleate maleate salt) Sodium starch glycolate 5.00 Hydroxypropylmethylcellulose 2910 5.00 Microcrystalline Cellulose 20.00 Lactose Monohydrate, regular grade at 100 Purified water * * Removed during the process Then, the concentrate was formulated into tablets using the following: Amount (mg per tablet) Concentration of the tablet 1.0 mg 2.0 mg 4.0 mg 8.0 mg Active ingredient: 10.00 20.00 40.00 80.00 Granules of the maleate concentrate of compound (I) Other ingredients: Sodium starch glycolate 6.96 6.46 5.46 10.92 Microcrystalline Cellulose (Avicel 27.85 25.85 21.85 43.70 PH102) Lactose Monohydrate 104.44 96.94 81.94 163.88 (Pharmatose DCL15) Magnesium Stearate 0.75 0.75 0.75 1.50 Total weight of the center 150.0 150.0 150.0 300.0 tablet Opadry 4.5 4.5 4.5 9.0 Total weight of the tablet 154.5 154.5 154.5 309.0 film-coated The compositions for other active agents are as described in the publications mentioned above.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS

1. - The use of a non-toxic and pharmaceutically acceptable effective amount of an insulin sensitizer in combination with an insulin secretagogue and an anti-hyperglycemic agent of biguanide, for the preparation of a medicament for the treatment of diabetes mellitus and conditions associated with diabetes mellitus in a mammal.

2. The use according to claim 1, wherein the insulin secretagogue is glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glyclopramide and glycylamide. or repaglinide.

3. The use according to claim 1, wherein the anti-hyperglycemic agent of biguanide is metformin, buformin or phenformin.

4. The use according to any of claims 1 to 3, wherein the insulin sensitizer is 5- [4- [2- (N-methyl-N- (2-pyridyl) amino) ethoxy] benzyl] thiazolidino-2,4-dione (compound I).

5. The use according to any of claims 1 to 4, wherein the medicament provides 2 to 12 mg of compound (I) to the mammal.

6. - The use according to any of claims 1 to 5, wherein the medicament provides 2 to 4 mg, 4 to 8 or 8 to 12 mg of compound (I) to the mammal.

7. The use according to any of claims 1 to 6, wherein the medicament provides 2 to 4 mg of compound (I) to the mammal.

8. The use according to any of claims 1 to 6, wherein the medicament provides 4 to 8 mg of compound (I) to the mammal.

9. The use according to any of claims 1 to 6, wherein the medicament provides 8 to 12 mg of compound (I) to the mammal.

10. The use according to any of claims 1 to 6, wherein the medicament provides 2 mg of compound (I) to the mammal.

11. The use according to any of claims 1 to 6, wherein the medicament provides 4 mg of compound (I) to the mammal.

12. The use according to any of claims 1 to 6, wherein the medicament provides 8 mg of compound (I) to the mammal.

13. The use according to claim 1, wherein the insulin sensitizer is (+) - 5 - [[4 - [(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl -2H-1-benzopyran-2-yl) methoxy] phenyl] methyl] -2,4-thiazole-dinodione (or troglitazone), 5- [4 - [(1-methylcyclohexyl) methoxy] benzyl] thiazolidino-2,4 -dione (or ciglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidino-2,4-dione (or pioglitazone) or 5 - [(2-benzyl) 2,3-dihydrobenzopyran) -5-ylmethyl) thiazolidino-2,4-dione (or englitazone); or a pharmaceutically acceptable form thereof.

14. - A pharmaceutical composition comprising an insulin sensitizer, an insulin secretagogue, an antihyperglycemic biguanide agent and a pharmaceutically acceptable carrier therefor.

15. A composition according to claim 14, further characterized in that the insulin secretagogue is a sulfonylurea.

16. A composition according to claim 14 or 15, further characterized in that the insulin secretagogue is glibenclamide, glipizide, gliclazide, glimepiride, tolazamide, tolbutamide, acetohexamide, carbutamide, chlorpropamide, glibornuride, gliquidone, glisentide, glisolamide, glisoxepide, glycolyamide and glycylamide or repaglinide.

17. A composition according to claim 1, further characterized in that the anti-hyperglycemic agent of biguanide is metformin, buformin or phenformin.

18. A composition according to any of claims 14 to 17, further characterized in that the insulin sensitizer is the compound (I).

19. A composition according to any of claims 14 to 17, further characterized in that it comprises 2 to 12 mg of the compound (I).

20. A pharmaceutical composition comprising an insulin sensitizer, an insulin secretagogue and a pharmaceutically acceptable vehicle therefor, to be used as an active therapeutic substance.

21. A pharmaceutical composition comprising an insulin sensitizer, an insulin secretagogue, a biguanide antihyperglycemic agent and a pharmaceutically acceptable carrier therefor, for use in the treatment of diabetes mellitus and conditions related to diabetes mellitus. 21. A composition according to any of claims 14, 20 or 21, further characterized in that the insulin sensitizer is (+) -df ^ -KS ^ -dihydro-e-hydroxy ^ .d .d-tetramethyl ^ Hl -benzopyran ^ -yl) methoxy] phenyl] methyl] -2,4-thiazolidinedione (or troglitazone), 5- [4 - [(1-methyl-cyclohexyl) methoxy] benzyl] thiazole-2,4-dione ( or ciglitazone), 5- [4- [2- (5-ethylpyridin-2-yl) ethoxy] benzyl] thiazolidino-2,4-dione (or pioglitazone) or 5 - [(2-benzyl-2,3-dihydrobenzopyran ) -5-ylmethyl) thiazolidino-2,4-dione (or englitazone); or a pharmaceutically acceptable form thereof.