NZ556545A - Combination comprising a beta-hydroxy-beta-methylglutaryl-co-enzyme-A reductase inhibitor and a glucagon-like peptide-1 agonist - Google Patents

Abstract

Disclosed is a combination of at least two components selected from the group consisting of: (i) a (3-hydroxy-(3-methylglutaryl-co-enzyme-A reductase (HMG GoA reductase) inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, and (ii) a glucagon-like peptide-1 (GLP-1) agonist or a pharmaceutically acceptable salt thereof. These combinations are suitable for the prevention of, delay of progression of or treatment of a disease or condition selected from the group consisting of hyperlipidaemia and dyslipidaemia,atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, hypothyroidism, survival post myocardial infarction (MI), coronary heart diseases, hypertension in the elderly, familial dyslipidaemic hypertension, remodelling following hypertension, non-alcoholic fatty liver disorders, polycystic ovary syndrome (PCaS).

Description

New Zealand Paient Spedficaiion for Paient Number 556545 556545 PATENTS FORM NO. 5 Our ref: FIP227693NZPR Divisional Application out of NZ 535386 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION COMBINATION COMPRISING A 0-HYDROXY- p-METHYLGLUTARYL-CO-ENZYME-A REDUCTASE INHIBITOR AND A GLUCAGON-LIKE PEPTIDE-1 AGONIST We, Novartis AG a corporation organised under the laws of Switzerland, of Lichtstrasse 35,4056 Basel, Switzerland hereby declare the invention, for which we pray that a patent may be granted to us and the method by which it is to be performed, to be particularly described in and by the following statement: (followed by page 1a) intellectual property office of n.z. 16 OCT 2008 RECEIVED 556545 - la - COMBINATION COMPRISING A (3-HYDROXY- (5-METHYLGLUTARYL-CO-ENZYME-A REDUCTASE INHIBITOR AND A GLUCAGON-LIKE PEPTIDE-1 AGONIST The present invention relates to a combination of at least two components selected from the group consisting of: (i) a P-hydroxy-P-methylglutaryl-co-enzyme-A reductase (HMG CoA reductase) inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, and (ii) a glucagon-iike peptide-1 (GLP-1) agonist or a pharmaceutically acceptable salt thereof.

The invention furthermore relates to the use of a (3-bydroxy-(S-methylglutaryl-co-enzyme-A reductase inhibitor or a pharmaceutically acceptable salt thereof selected from the group consisting of atorvastatin, cerivastatin, fluvastatin,lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin in combination with a glucagon-fike peptide 1 (GLP-1) agonist or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the prevention of, delay of progression of or treatment of a disease or condition selected from the group consisting of hyperlipidaemia and dyslipidaemia, atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidaemic hypertension, remodelling following hypertension, non-alcoholic fatty liver disorders (for example, non alcoholic steatohepatitis), polycystic ovary syndrome (PCOS) and diseases, illnesses, conditions or symptoms related to or encountered or associated therewith.

Non-alcoholic steatohepatitis (NASH), is a critical link in the chain of metabolic fatty liver disorders that spans steatosis to cryptogenic cirrhosis. It is the hepatic manifestation of the insulin resistance (or metabolic) syndrome, and provides a clue to understanding fibrotic progression of other chronic liver diseases, particularly hepatitis C. Non-alcoholic steatohepatitis is often the first clinical indication of insulin resistance, with its complications of high blood pressure, coronary heart disease and type 2 diabetes. (followed by pg 2) 0 CC7 2008 556545 PCOS is a variable disorder that is marked especially by amenorrhea, hirsutism, obesity, infertility, and ovarian enlargement and is usually initiated by an elevated level of luteinizing hormone, androgen, or estrogen which results in an abnormal cycle of gonadotropin release by the pituitary gland.

PCOS is a major concern of women in the reproductive age since it is estimated that about 5-10% of these women exhibit this disorder and it is one of the leading causes for infertility. Although PCOS is known for more than 50 years the etiology of said syndrome remains unclear. The symptoms of PCOS can be mild or severe, and can vary widely from woman to woman. Someone with PCOS may, for example, have one or all of the following symptoms in varying degrees: irregular periods: abnormal, irregular, heavy or scanty, generally designated as oligomenorrhea, absent periods or amenorrhea, ovarian cysts, hirsutism, alopecia, obesity, acne, skin tags, acanthosis nigricans, high cholesterol levels, high blood pressure, exhaustion or lack of mental alertness, decreased sex drive, excess male hormones, such as androgens or testosterone, infertility, decreased breast size, enlarged ovaries and enlarged uterus. However, it is necessary to exclude specific disorders for the diagnosis of PCOS. Disorders to be excluded are such as nonclassic adrenal 21-hydroxylase deficiency, hyperprolactinemia or androgen-secreting neoplasms. It is further particularly striking that the polycystic ovary morphology is consistent with, but not essential for the diagnosis of the syndrome. This means that in spite of the absence of polycystic ovary morphology PCOS may nevertheless be diagnosed.

Another embodiment of the invention relates to a combination according to the invention wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, and simvastatin.

Another preferred embodiment of the invention relates to a combination according to the invention wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of fluvastatin, pitavastatin, and simvastatin.

Another more preferred embodiment of the invention relates to a combination according to the invention wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is atorvastatin.

The invention furthermore relates to a combination according to the invention wherein the the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is simvastatin. intellectual property office of n.z. 16 OCT 2008 RECEIVED 556545 The invention furthermore also relates to a combination according to the invention wherein the combination is a pharmaceutical composition that can be administered simultaneously or sequentially in any order or for separate use.

The invention furthermore also relates to the combination of the present invention wherein the combination is in the form of a fixed combination.

In a further aspect, the combination includes an HMG-CoA-reductase inhibitor and the GLP-1 agonist exendin-4 or a pharmaceutically acceptable salt thereof.

Especially, the combination according to the present invention may be used, e.g., for the prevention, delay of progression or treatment of diseases and disorders selected from the group consisting of hyperlipidaemia and dysiipidaemia, atherosclerosis, type 2 diabetes mellitus, nephropathy, renal failure, syndrome X, survival post myocardial infarction (Ml), coronary heart diseases, insulin resistance, obesity, hypothyroidism, hypertension in the elderly, familial dyslipidaemic hypertension, remodelling following hypertension, nonalcoholic fatty liver disorders (for example, non alcoholic steatohepatitis), polycystic ovary syndrome (PCOS) and diseases, illnesses, conditions or symptoms related to or encountered or associated therewith.

GLP-1 is an insulintropic protein which was described, e.g. by W. E. Schmidt et al. in Diabetologica 28, 1985. 704-707 and in US 5,705,483. The term "GLP-1 agonists" used herein means variants and analogs of GLP-1 (7-36)NH2 which are disclosed in particular in US 5,120,712, US 5,118,666, US 5,512,549, WO 91/11457 and by C. Orskov et al in J. Biol. Chem. 264 (1989) 12826.

The term "GLP-1 agonists" comprises especially compounds like GLP-1 (7-37), in which compound the carboxy-terminal amide functionality of Arg36 is displaced by Gly at the 37th postion of the GLP-1 (7-36) NH2 molecule and variants and analogs thereof including GLN9-GLP-1(7-37), D-GLN9-GLP-1 (7-37), acetyl LYS9-GLP-1(7-37), LYS18-GLP-1(7-37) and, in particular, GLP-1 (7-37)OH, VAL8-GLP-1(7-37), GLY8-GLP-1 (7-37), THR8-GLP-1(7-37), MET8-GLP-1(7-37) and 4-imidazopropionyl-GLP-1. Special preference is also given to the GLP agonist analog exendin-4, described by Grieg et al in Diabetologica 1999, 42, 45-50. intellectual PROPERTY office of n.2. 1 6 OCT 2008 RECEIVED 556545 The compounds to be combined can be present as pharmaceutically acceptable salts. If these compounds have, for example, at least one basic center, they can form acid addition salts. Corresponding acid addition salts can also be formed having, if desired, an additionally present basic center. The compounds having an acid group (for example COOH) can also form salts with bases.

Preferably, the jointly therapeutically effective amounts of the active agents according to the combination of the present invention can be administered simultaneously or sequentially in any order, e.g. separately or in a fixed combination.

Under certain circumstances, drugs with different mechanisms of action may be combined. However, just considering any combination of drugs having different modes of action but acting in the similar field does not necessarily lead to combinations with advantageous effects.

All the more surprising is the experimental finding that the combination of the present invention results not only in a beneficial, especially a potentiating or a synergistic, therapeutic effect. Independent thereof, additional benefits resulting from combined treatment can be achieved such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with diabetes, e.g. less gain of weight. An additional and preferred aspect of the present invention is the prevention, delay of progression or treatment of the condition of isolated systolic hypertension and impaired vascular compliance which means decreased vascular elasticity.

In particular, all the more surprising is the experimental finding that the combination of the present invention results in a beneficial, especially a synergistic, therapeutic effect but also in benefits resulting from combined treatment such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions as specified hereinbefore or hereinafter.

The pharmaceutical activities as effected by administration of the combination of active agents used according to the present invention can be demonstrated e. g. by using corresponding pharmacological models known in the pertinent art. The person skilled in the intellectual property office of n.2. 1 6 OCT 2008 [received 556545 pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.

The pharmaceutical activities as effected by administration of the combination of active agents used according to the present invention can be demonstrated e.g. by using corresponding pharmacological models known in the pertinent art. The person skilled in the pertinent art is fully enabled to select a relevant animal test model to prove the hereinbefore and hereinafter indicated therapeutic indications and beneficial effects.

Furthermore, it has been found that the chronic co-administration of either an insulin sensitizer or an insulin secretion enhancer imparts the beneficial effect on blood vessel morphology and function and results in a decrease of vascular stiffness and correspondingly in a maintenance and in an improvement of vascular compliance.

Accordingly, it has been found that the combination of the present invention would potentiate the effect on systolic blood pressure and further improve vascular stiffness/compliance. The benefit of these combinations may also extend to an additional or potentiated effect on endothelial function, and improve vascular function and structure in various organs/tissues including the kidney, heart, eye and brain. Through the reduction in glucose levels, an antithrombotic and anti-atherosclerotic effect can also be demonstrated. Reduction of glucose would prevent or minimize the glycosylation of any structural or functional protein within the cardio-renal system.

All the more surprising is the experimental finding that the combination of the present invention results not only in a beneficial, especially a potentiating or a synergistic, therapeutic effect. Independent thereof, additional benefits resulting from combined treatment can be achieved such as a surprising prolongation of efficacy, a broader variety of therapeutic treatment and surprising beneficial effects on diseases and conditions associated with diabetes, e.g. less gain of weight.

The term "potentiation" shall mean an increase of a corresponding pharmacological activity or therapeutical effect, respectively. Potentiation of one component of the combination according to the present invention by co-administration of an other component according to the present invention means that an effect is being achieved that is greater than that achieved with one component alone.

OFFIC6 Op f\j.£ 1 6 OCT 20QB 556545 the present invention means that an effect is being achieved that is greater than that achieved with one component alone.

The term "synergistic" shall mean that the drugs, when taken together, produce a total joint effect that is greater than the sum of the effects of each drug when taken alone.

Hypertension, in connection with a "disease or condition which may be inhibited by the inhibition of HMG-CoA reductase inhibitor", a "disease or condition which may be inhibited by the enhancement of insulin secretion", a "disease or condition that may be inhibited by insulin sensitization" includes and is not limited to mild, moderate and severe hypertension as defined in Journal of Hypertension 1999,17:151-183, especially on page 162.

Further benefits are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce the dosage, for example, that the dosages need not only often be smaller but are also applied less frequently, or can be used in order to diminish the incidence of side effects. This is in accordance with the desires and requirements of the patients to be treated.

For example, it has turned out that the combination according to the present invention provides benefit especially in the treatment of modest hypertension or isolated systolic hypertension that is beneficial to all diabetic patients regardless of their hypertensive status, e.g. reducing the risk of negative cardiovascular events by two different modes of action.

The pharmaceutical composition according to the present invention as described hereinbefore and hereinafter may be used for simultaneous use or sequential use in any order, for separate use or as a fixed combination.

Under certain circumstances, drugs with different mechanisms of action may be combined. However, just considering any combination of drugs having different modes of action but acting in the similar field does not necessarily lead to combinations with advantageous effects.

The pharmaceutical composition according to the present invention comprises a "kit of parts" in the sense that the components can be dosed independently or by use of different fixed combinations with distinguished amounts of the components at different time points. The parts of the "kit of parts" can then e.g. be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any INTELLECTUAL PROPERTY OFFICE OF N.Z. 18 OCT 2008 556545 part of the "kit of parts". Preferably, the time intervals are chosen such that the effect on the treated disease or condition in the combined use of the parts is larger than the effect that would be obtained by use of only any one of the components. Preferably, there is at least one beneficial effect, e.g. a mutual enhancing of the effect of (i) a p-hydroxy-p-methylgiutaryl-co-enzyme-A reductase (HMG CoA reductase) inhibitor or a pharmaceutically acceptable salt thereof; (ii) a glucagon-like peptide-1 (GLP-1) agonist or a pharmaceutically acceptable salt thereof pharmaceutically acceptable salt thereof; in particular a potentiation or a synergism, e.g. a more than additive effect, additional advantageous effects, less side effects, a combined therapeutical effect in a non-effective dosage of one or each of the components, especially a potentiation or a strong synergism.

These pharmaceutical preparations are for enteral, such as oral, and also rectal or parenteral, administration to homeotherms, with the preparations comprising the pharmacological active compound either alone or together with customary pharmaceutical auxiliary substances. For example, the pharmaceutical preparations consist of from about 0.1 % to 90 %, preferably of from about 1 % to about 80 %, of the active compound. Pharmaceutical preparations for enteral or parenteral, and also for ocular, administration are, for example, in unit dose forms, such as coated tablets, tablets, capsules or suppositories and also ampoules. These are prepared in a manner that is known per se, for example using conventional mixing, granulation, coating, solubulizing or lyophilizing processes. Thus, pharmaceutical preparations for oral use can be obtained by combining the active compound with solid excipients, if desired granulating a mixture which has been obtained, and, if required or necessary, processing the mixture or granulate into tablets or coated tablet cores after having added suitable auxiliary substances.

The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition.

Preferred dosages for the active ingredients of the pharmaceutical combination according to the present invention are therapeutical effective dosages, especially those which are commercially available.

Normally, in the case of oral administration, an approximate daily dose of from about 1 mg to about 360 mg is to be estimated e.g. for a patient of approximately 75 kg in weight.

INTELLECTUAL s ^Yy OFFICE < <r w * - OCT 7SWL RECEIVED 556545 The dosage of the active compound can depend on a variety of factors, such as mode of administration, homeothermic species, age and/or individual condition. In case of HMG-CoA reductase inhibitors, preferred dosage unit forms of HMG-CoA reductase inhibitors are, for example, tablets or capsules comprising e.g. from about 5 mg to about 120 mg, preferably, when using fluvastatin, for example, 20 mg, 40 mg or 80 mg (equivalent to the free acid) of fluvastatin, for example, administered once a day.

Although the combinations of the following Examples fall outside the scope of the claims of this application, the Examples may help to illustrate the invention and are retained herein for clarity and completeness. 'nte!±ectual property office of n.z. 1 6 OCT 2008 RECEiVFn 556545 Example 12: Hard gelatin capsule: J- , J r r Capsule Fluvastatin Sodium 21.481 2) Calcium Carbonate 62.840 Sodium Bicarbonate 2.000 Microcrystalline Cellulose 57.220 Fregelatinized Starch 41.900 Purified Water 3) Q.S.

Magnesium Stearate 1.050 Talc 9.430 Target Capsule Fill Weight 195.92 Capsule Shell i* Bard gelatin Capsule Shell 48.500 Branding Ink (pre-printed) White Ink Trace Red Ink Trace Target Capsule Weight 244.42 1} includes a 2% overage for moisture 2) 20 mg of free acid is equivalent to 21 .OS mg Na salt 3) partially removed during processing 556545 Example 13: Hard gelatin capsule Fluvastatin Sodium 42.962 vz> Calcium Carbonate 125.680 Sodium Bicarbonate 4.000 Microcrystalline Cellulose 114.440 Pregelatinized Starch 83.800 Purified Water 3> Q.S.

Magnesium Stearate 2.100 Talc 18.860 Target Capsule Rll Weight 391.840 Capsule Shell t THard gelatin Capsule Shell 76.500 Branding Ink (pre-printed) White Ink Trace Red Ink Trace Target Capsule Weight 468.34 2) 20 mg of free acid equivalent to 21.06 mg Na salt 3) partially removed during processing j""eom"SAoFXPER1Y] I S OCT 2008 LRECElVPn 556545 Example 14: Round, slightly bi-convex, film-coated tablets with beleved edges: " " Table Core Fluvastatin Sodium B4.24 2> Cellulose Microcrystalline / Micro-crystalline cellulose fine powder 111.27 Hypromeflose / Hydroxypropyl methyl cellulose (Methocel K100LVP CR; HPMC100 cps) 97.50 Hydroxypropyl cellulose (Klucel HXF) 16.25 Potassium hydrogen carbonate/ potassium bicarbonate 8.42 Povidone 4.88 Magnesium stearate 2.44 Core Tablet Weight 325.00 Coating Coating premix - Opadry Yellow (00F22737) 9.75 Total Weight 334.75 Water, purified 3) Q.S. 2) to be adjusted for moisture (LOD) 3) removed during processing ' « OCT 2008 LR E C FI v f 556545 Example 12: 108,000 tablets, each which contain 120 mg of nategiinide are prepared as follows: Preparation process: The microcrystalline cellulose, povidone, part of the croscarmellose sodium, nategiinide and lactose are mixed in a high shear mixer and afterwards granulated using purified water. Alternatively, the microcrystalline cellulose, povidone, a portion of the croscarmellose sodium, nategiinide and lactose are granulated in a collette gral granulator with the addition of purified water. The wet granules are dried in a fluid bed dryer and passed through a screen. The colloidal silicon dioxide and the rest of the croscarmellose sodium are mixed, passed through a screen and blended with the dried granules in a V-blender. The magnesium stearate is passed through a screen, blended with the blend from the V-blender and afterwards the total mixture is compressed to tablets. The opadry yellow is suspended in purified water and the tablets are coated with the coating suspension.

Composition: nategiinide lactose, NF microcrystalline cellulose, NF povidone, USP croscarmellose sodium, NF colloidal silicon dioxide, NF magnesium stearate, NF coating: opadry yellow purified water, USP* 12.960 kg 30.564 kg 15.336 kg 2.592 kg 3.974 kg 1.382 kg 1.231 kg 1.944 kg Q.S. ,nte^l|CTUaL property OFFICEOF N2 ^ 6 OCT 2008

Claims (20)

556545 -13- Examples13-15: Component 60mg 120mg 1B0mg Starlix DS (H-form crystal modification) 60 120 180 Lactose Monohydrate 141.5 283 214 MicrocrystaliineCellulose 71 142 107 Povidone K30 12 24 23 Croscarmellose Sodium 12 24 34 Sub-Total (Granulation) 296.5 593 558 Croscarmellose Sodium 6.4 12.8 24.5 Colloidal Silicone Dioxide 6.4 12.8 12.3 Magnesium Stearate 5.7 11.4 15.2 ^Sub-Total (Core) (315) (630) (610) * Opadry 9 18 18 Total 324 648 628 intellectual property office of n.2. 16 OCT 2008 RECEIVED 556545 - 14- What is claimed is:

1. A combination of at least two components selected from the group consisting of: (i) a {3-hydroxy-p-methylglutary[-co-enzyme-A reductase (HMG CoA reductase) inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, and (ii) a glucagon-like peptide-1 (GLP-1) agonist or a pharmaceutically acceptable salt thereof.

2. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, and simvastatin.

3. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of fluvastatin, pitavastatin, and simvastatin.

4. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is atorvastatin.

5. A combination according to claim 1 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is simvastatin.

6. A combination according to any one of claims 1 to 5 wherein the combination is adapted for administration simultaneously or sequentially in any order, or for separate use.

7. A combination according to any one of claims 1 to S wherein the combination is in the form of a fixed combination.

8. A combination according to any one of claims 1 to 7 wherein the GLP-1 agonist is exendin-4 or a pharmaceutically acceptable salt thereof.

9. Use of a |5-hydroxy-f3-methylgiutaryl-co-enzyme-A reductase (HMG CoA reductase) inhibitor or a pharmaceutically acceptable salt thereof, selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin, and a glucagon-like peptide-1 (GLP-1) agonist or a pharmaceutically acceptable intellectual property OFFICE OF N.Z. R £ C £ i v £ D 556545 - 15- salt thereof for the manufacture of a medicament for the prevention of, delay of progression of or treatment of a disease or condition selected from the group consisting of hyperiipidaemia and dysiipidaemia, atherosclerosis, insulin resistance and syndrome X, diabetes mellitus type 2, obesity, nephropathy, renal failure, hypothyroidism, survival post myocardial infarction (Ml), coronary heart diseases, hypertension in the elderly, familial dyslipidaemic hypertension, remodelling following hypertension, non-alcoholic fatty liver disorders, polycystic ovary syndrome (PCOS).

10. Use according to claim 9 wherein the non-alcoholic fatty liver disorder is non alcoholic steatohepatitis.

11. Use according to claim 9 or 10 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of atorvastatin, fluvastatin, pitavastatin, and simvastatin.

12. Use according to claim 9 or 10 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is selected from the group consisting of fluvastatin, pitavastatin, and simvastatin.

13. Use according to claim 9 or 10 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is atorvastatin.

14. Use according to claim 9 or 10 wherein the HMG CoA reductase inhibitor or a pharmaceutically acceptable salt thereof is simvastatin.

15. Use according to any one of claims 9 to 14 wherein the medicament is adapted for administration simultaneously or sequentially in any order, or for separate use.

16. Use according to any one of claims 9 to 14 wherein the medicament is in the form of a fixed combination.

17. Use according to any one of claims 9 to 16 wherein the GLP-1 agonist is exendin-4 or a pharmaceutically acceptable salt thereof.

18. A combination according to claim 1, substantially as herein described with reference to any one of the Examples thereof. intellectual property office of n.z. 16 OCT RECEIVED 556545 -16-

19. A combination according to any one of claims 1 to 8, substantially as herein described.

20. Use according to any one of claims 9 to 17, substantially as herein described. 1 6 OCT 2008 £ECE/ved, intellectual property office of N,z. 16 OCT 2008 RECEIVED]