Treatment of Type 2 Diabetes

Abstract

The present invention relates to a pharmaceutical combination comprising (a) a pharmaceutical formulation comprising (i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof, and (b) an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof.

Description

[Technical Field]

[0001] The present invention relates to a pharmaceutical combination comprising (a) a pharmaceutical formulation comprising (i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof, and (b) an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof. [Background technology]

[0002] Diabetes is classified into the following general categories (Non-Patent Document 1): 1. Type 1 diabetes (caused by autoimmune B cell destruction, usually leading to absolute insulin deficiency) 2. Type 2 diabetes (due to progressive loss of b-cell insulin secretion, often on a background of insulin resistance) 3. Gestational diabetes mellitus (GDM) (diabetes diagnosed in the second or third trimester of pregnancy that was not clearly overt diabetes before gestational age) 4. Specific forms of diabetes due to other causes, such as monogenic diabetes syndromes (such as neonatal diabetes and maturity-onset diabetes of the young [MODY]), diseases of the exocrine pancreas (such as cystic fibrosis and pancreatitis), and drug- or chemical-induced diabetes (such as associated with glucocorticoid use, in the treatment of HIV / AIDS, or after organ transplantation)

[0003] Diabetes is diagnosed on the basis of plasma glucose criteria, either fasting plasma glucose (FPG) or 2-hour plasma glucose (2-hour PG) values during a 75 g oral glucose tolerance test (OGTT), or HbA1C criteria.

[0004] Criteria for diagnosing diabetes FPG ≥ 126 mg / dL (7.0 mmol). Fasting is defined as no caloric intake for at least 8 hours. * or PG ≥ 200 mg / dL (11.1 mmol / L) after 2 hours during an OGTT. The test should be performed using a glucose load containing the equivalent of 75 g of anhydrous glucose dissolved in water as described by WHO. * or A1C ≥ 6.5% (48 mmol / mol). Testing must be performed in a laboratory using NGSP-accredited and standardized methods for the DCCT assay. * or In patients with typical symptoms of hyperglycemia or acute hyperglycemic episodes, random plasma glucose ≥ 200 mg / dl (11.1 mmol / L). * In the absence of overt hyperglycemia, diagnosis requires two abnormal test results from the same sample or two separate test samples.

[0005] Type 2 diabetes is a heterogeneous syndrome characterized by abnormalities in carbohydrate and fat metabolism. The cause of type 2 diabetes is multifactorial and includes both genetic and environmental factors that affect beta cell function and tissue (muscle, liver, adipose tissue, and pancreas) insulin sensitivity (Non-Patent Document 2). Normal regulation of glucose metabolism is determined by a feedback loop involving islet beta cells and insulin-sensitive tissues, where tissue sensitivity to insulin determines the magnitude of the beta cell response. In the presence of insulin resistance, beta cells maintain normal glucose tolerance by increasing insulin output. Glucose levels rise only when beta cells are unable to release sufficient insulin in the presence of insulin resistance. While beta cell dysfunction has a clear genetic component, environmental changes also play an important role (Non-Patent Document 3).

[0006] People with type 2 diabetes are at increased risk for many complications, primarily due to complex and interrelated mechanisms such as hyperglycemia, insulin resistance, low-grade inflammation, and accelerated atherogenesis. Cardiovascular and cerebrovascular disease is frequently associated with type 2 diabetes and can become life-threatening, specifically coronary artery disease, stroke, and heart failure. Type 2 diabetes must be considered an independent cardiovascular risk factor. Nephropathy, although common in type 2 diabetes, has diverse origins. It is now the leading cause of end-stage renal disease. Better metabolic and blood pressure control and improved management of microalbuminuria can slow the disease course. However, retinopathy, which is paradoxically slightly progressive, must be screened for and treated in these somewhat older patients, who are at high ophthalmic risk worldwide (Non-Patent Document 4).

[0007] Overweight or obese patients with type 2 diabetes, e.g., a body mass index (BMI) of ≥ 30 kg / m 2 Particular risks exist for patients with type 2 diabetes, in which the risk of diabetes overlaps with the risk of being overweight, which can lead to increased cardiovascular disease, for example, compared to normal-weight type 2 diabetic patients.

[0008] Type 2 diabetes is a progressive disease that often requires gradual intensification of treatment to maintain good glycemic control. It is also well established that timely treatment of people with type 2 diabetes has a beneficial effect on outcomes, so tight glycemic control is advocated to reduce the risk of developing or progressing capillary or macrovascular complications (Non-Patent Document 5).

[0009] Progression occurs despite long-term use of standard oral antidiabetic drug therapy: even with the use of multiple oral antidiabetic drugs (OADs), most patients ultimately require the addition of insulin to achieve and maintain HbA1c targets (Non-Patent Document 5; Non-Patent Document 6).

[0010] Patients with poorly controlled T2DM typically progress stepwise from monotherapy with oral antidiabetic agents to dual or triple therapy before initiating injectable therapy.

[0011] Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are the preferred initial injectable therapy in most patients poorly controlled on oral therapy, with the individualized option for incorporation of basal insulin therapy if needed.

[0012] Several studies have demonstrated the effectiveness of combining a GLP-1 RA with a basal insulin as separate injection therapies administered sequentially (Non-Patent Document 7; Non-Patent Document 8). Fixed ratio combinations (FRCs) that add a GLP-1 RA to basal insulin offer the added advantage of facilitating management, providing the simultaneous administration of two effective injection therapies with complementary modes of action for treating type 2 diabetes with a single injection.

[0013] Compound Death Pro 36 Exendin-4(1-39)-Lys-NH (AVE0010, lixisenatide) is a derivative of exendin-4. AVE0010 is disclosed in US Pat. No. 5,629,493 as SEQ ID NO: 93: SEQ ID NO: 1: Lixisenatide (44 amino acids) HGEGTFTSDLSKQMEEEAVRL-FlEWLKNGGPSSGAPPSKKKK-KK-NH2 SEQ ID NO: 2: Exendin-4 or exenatide (39 amino acids) HGEGTFTSDLSKQMEEEAVRL-FlEWLKNGGPSSGAPPPS-NH2

[0014] Exendins are a group of peptides that can lower blood glucose levels. The exendin analog lixisenatide is characterized by a C-terminal truncation of the native exendin-4 sequence. Lixisenatide contains six C-terminal lysine residues that are not present in exendin-4.

[0015] Lixisenatide is also known as des-38-proline-exendin-4 (Heloderma suspectum)-1-39)-peptidylpenta-L-lysyl-L-lysinamide (CAS No. 320367-13-3). In the present invention, "lixisenatide" includes pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of lixisenatide are known to those skilled in the art.

[0016] Insulin glargine is an analogue of human insulin. It has an additional substitution of asparagine with glycine at position A21. B -32 B -Di-Arg human insulin. Insulin glargine is also called Gly(A21)-Arg(B31)-Arg(B32) human insulin. The CAS number of insulin glargine is 160337-95-1. In the present invention, "insulin glargine" includes pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of insulin glargine are known to those skilled in the art. 100 U of insulin glargine is equivalent to 3.6378 mg of insulin glargine.

[0017] Combination formulations of lixisenatide and insulin glargine are disclosed in Patent Document 2. These formulations contain a fixed dose ratio of insulin glargine 100 U / mL and lixisenatide 50 μg / mL, or insulin glargine 100 U / mL and lixisenatide 33 μg / mL. These formulations are sold under the trade names "Soliqua" or "Suliqua."

[0018] Insulin doses used in Japan are generally lower than those used in Caucasian patients, mainly due to the lower body mass index (BMI) and insulin resistance of Japanese patients (Non-Patent Document 9).

[0019] Lixisenatide is approved for use in the EU, US and Japan at the same maintenance dose of 20 μg once daily.

[0020] The pharmacokinetics (PK) and pharmacodynamics of lixisenatide in Caucasian and Japanese patients were determined in the Phase 1 study PDY6797 (Non-Patent Document 10). Similarities in safety and tolerability were observed between Caucasian and Japanese patients, with highly overlapping PK profiles between the two ethnicities. In addition, optimal efficacy in terms of changes in postprandial glucose control was observed in both Caucasian and Japanese patients at the 20 μg dose level of lixisenatide.

[0021] Metformin has the international nonproprietary name 1,1-dimethylbiguanide (CAS number 657-24-9). Metformin is a biguanide hypoglycemic drug used to treat non-insulin-dependent diabetes mellitus (type 2 diabetes) that does not respond to dietary changes. Metformin improves glycemic control by improving insulin sensitivity and reducing intestinal glucose absorption. Metformin is usually administered orally. However, metformin may not adequately control type 2 diabetes in obese patients. Therefore, these patients require additional measures to control type 2 diabetes. As used herein, "metformin" includes pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of metformin are known to those skilled in the art.

[0022] Sodium-glucose cotransporter 2 (SGLT2) inhibitors have a mechanism of action independent of insulin secretion and insulin action. By inhibiting SGLT2 in the renal proximal tubule, SGLT2 inhibitors reduce renal glucose reabsorption, leading to urinary glucose excretion, and thereby lowering plasma glucose. This unique mechanism of action not only lowers plasma glucose but also corrects many metabolic and hemodynamic abnormalities that are risk factors for cardiovascular disease (Non-Patent Documents 11 and 12). Urinary glucose loss creates a negative calorie balance, resulting in weight loss. SGLT2 inhibition reduces sodium reabsorption in the proximal tubule, exerting a diuretic / natriuretic effect (Non-Patent Document 13). SGLT2 inhibition also promotes urinary sodium excretion by causing osmotic diuresis. This natriuretic effect, combined with longer-term weight loss, contributes in part to reduced systolic and diastolic blood pressure (Non-Patent Document 14). [Prior art documents] [Patent documents]

[0023] [Patent Document 1] WO 01 / 04156 [Patent Document 2] WO 2014 / 202483 [Non-patent literature]

[0024] [Non-Patent Document 1] Classification and Diagnosis of Diabetes:Standards of Medical Care in Diabetes-2019-Diabetes Care 2019;42(Suppl.1):S13-S28 [Non-patent document 2] Acta Clin Belg.2003, November-December;58(6):335-41.Pathophysiology of type 2 diabetes.Scheen AJ [Non-patent document 3] Lancet. 2014, March 22; 383(9922): pages 1068~1083. Pathophysiology and treatment of type 2 diabetes:perspectives on the past,present and future Steven E.Kahn,MB,Ch.B.,1 Mark E. Cooper,MB,BS,Ph.D.,2 and Stefano Del Prato,MD3

Non-patent document 4

Non-patented document 5

Non-patent document 6

Non-patent document 7

Non-patent document 8

[0025] SGLT2 inhibitors are usually administered orally. However, the control of type 2 diabetes in obese patients with SGLT2 inhibitors may be insufficient. Therefore, these patients require additional measures to control type 2 diabetes.

[0026] An SGLT2 inhibitor alone may be insufficient to achieve adequate glycemic control. Also, an SGLT2 inhibitor may be insufficient even in combination with a second antidiabetic drug, such as metformin or / and a GLP-1 receptor agonist. Therefore, there is a need for a suitable treatment regimen in these patients. The problem of the present invention can be seen in providing a suitable treatment regimen in these patients.

[0027] The addition of a second or third antidiabetic drug poses the problem of potential unwanted side effects.

[0028] The examples of the present invention demonstrate that in patients with type 2 diabetes receiving an SGLT2 inhibitor that is insufficient to achieve adequate glycemic control, the addition of a fixed-dose ratio formulation of insulin glargine and lixisenatide can improve glycemic control with an improved side effect profile. [Means for solving the problem]

[0029] A first aspect of the present invention is (a)(i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof and a pharmaceutical formulation comprising (b) an SGLT2 inhibitor, or / and a pharmaceutically acceptable salt thereof It is a combination medicine comprising:

[0030] In the present invention, the combination of a fixed-dose ratio formulation of lixisenatide and insulin glargine in combination with an SGLT-2 inhibitor was found to be effective and safe when compared with a fixed-dose ratio formulation of lixisenatide and insulin glargine not combined with an SGLT-2 inhibitor.In the study described herein, a total of 119 patients with type 2 diabetes received a fixed-ratio combination (FRC) of insulin glargine / lixisenatide and also received an SGLT-2 inhibitor.

[0031] Because insulin doses used in Japan are generally lower than those used in Caucasian patients, primarily due to Japanese patients' lower body mass index (BMI) and insulin resistance (Moller et al., Diabetes Care. 2014;37(3):796-804), different fixed-ratio combinations are used in the examples of the present invention. Examples 1 and 4 include patients from nine countries considered "Caucasian" (Canada, Estonia, Germany, Israel, Italy, Romania, Slovakia, Spain, and the United States) and use fixed-dose ratio formulations of 2 units of insulin glargine U100 per μg of lixisenatide (i.e., 100 U / ml) and 3 units of insulin glargine U100 per μg of lixisenatide. Examples 2, 3, 5, and 6 include Japanese patients and use fixed-dose ratio formulations containing 1 unit of insulin glargine U100 per μg of lixisenatide. These formulations provide an appropriate dose range that encompasses the needs of the majority of patients in each of the two populations: 10-60 units in Examples 1 and 4, and 5-20 units in Examples 2, 3, 5 and 6.

[0032] Example 1 relates to a study to determine the efficacy and safety of an insulin glargine / lixisenatide fixed-ratio combination, followed by a single-arm 26-week extension period of the fixed-ratio combination, in adults with type 2 diabetes poorly controlled on a GLP-1 receptor agonist and metformin (alone or in combination with pioglitazone and / or an SGLT2 inhibitor) (Study EFC13794).

[0033] In Example 1, the study treatment included metformin plus a fixed-dose ratio formulation containing insulin glargine 100 U / mL and lixisenatide 50 μg / mL, or insulin glargine 100 U / mL and lixisenatide 33 μg / mL, with or without an SGLT2 inhibitor. The study treatment was compared to metformin plus a continuation of a GLP-1 receptor agonist as an active control, with or without an SGLT2 inhibitor.

[0034] Example 4 summarizes the subgroup analysis of the data from Example 1, comparing patients receiving SGLT2 inhibitors with those not receiving SGLT2 inhibitors. Patients with type 2 diabetes were included who received metformin; a GLP-1 receptor agonist selected from liraglutide, exenatide, exenatide extended-release formulations, albiglutide, and dulaglutide, with or without a concomitant SGLT2 inhibitor. Improvements in efficacy outcomes (changes in glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-hour postprandial plasma glucose [PPG] from baseline to week 26) were observed in both treatment groups.

[0035] Based on Example 4, in patients receiving an SGLT2 inhibitor, the effect of the fixed ratio formulation was greater than the effect in the comparator treatment continuing a GLP-1 RA compared to the group of patients not receiving an SGLT2 inhibitor.

[0036] In patients receiving an SGLT2 inhibitor, the improvement in HbA1c after 26 weeks was 0.88% considering the active comparator, compared to 0.61% in patients not receiving an SGLT2 inhibitor (Table 3 in Example 4).

[0037] In patients receiving an SGLT2 inhibitor, the improvement in fasting plasma glucose after 26 weeks was 2.06 mmol / L considering the active comparator, compared to 1.64 mmol / L in patients not receiving an SGLT2 inhibitor (Table 4 in Example 4).

[0038] In patients receiving an SGLT2 inhibitor, the improvement in 2-hour postprandial glucose after 26 weeks was 3.26 mmol / L considering the active comparator, compared to 2.81 mmol / L in patients not receiving an SGLT2 inhibitor (Table 5 in Example 4).

[0039] In Example 4 (Table 8), documented symptomatic hypoglycemia (plasma glucose ≦3.9 mmol / L [≦70 mg / dL]) was reported less frequently in the FRC group using SGLT2i versus non-users (0.72 events per patient-year for SGLT2i users vs. 1.62 for non-users).

[0040] In conclusion, Example 4 demonstrates that improved glycemic control and an improved side effect profile are achieved in patients using an SGLT2 inhibitor in combination with a fixed-dose ratio formulation of insulin glargine and lixisenatide compared to patients not using an SGLT2 inhibitor.

[0041] Examples 2 and 3 refer to a clinical trial in Japanese patients receiving a fixed dose ratio formulation containing insulin glargine 100 U / mL and lixisenatide 100 μg / mL.

[0042] Example 2 relates to a study comparing the efficacy and safety of a fixed-ratio combination of insulin glargine / lixisenatide to lixisenatide in combination with oral antidiabetic agents, with a 26-week safety extension period, in Japanese patients with type 2 diabetes poorly controlled on oral antidiabetic agents.

[0043] Example 3 relates to a study comparing the efficacy and safety of a fixed-ratio combination of insulin glargine / lixisenatide to insulin glargine in combination with oral antidiabetic agents in Japanese patients with type 2 diabetes poorly controlled on oral antidiabetic agents.

[0044] In Examples 2 and 3, one or two of the following oral antidiabetic drugs could be used as background therapy during the study: biguanides (e.g., metformin), thiazolidinediones (TZDs), alpha-glucosidase inhibitors (alpha-GIs), SGLT2 inhibitors, glinides, and sulfonylureas (SUs).

[0045] Example 5 summarizes a subgroup analysis of the data from Example 2, comparing patients receiving SGLT2 inhibitors with those not receiving SGLT2 inhibitors. In both treatment groups, efficacy results (changes in HbA1c and FPG from baseline to week 26) were generally similar in SGLT2i users and non-users (Tables 3 and 4 in Example 5).

[0046] Regarding common treatment-emergent adverse events (TEAEs) (Table 6 in Example 5), TEAEs in the system organ class (SOC) gastrointestinal disorders were reported less frequently in SGLT2i users compared with SGLT2i non-users in the FRC treatment group (17.6% vs. 32.3%, respectively). Similarly, documented symptomatic hypoglycemia (plasma glucose ≦3.9 mmol / L [≦70 mg / dL]) was reported less frequently in SGLT2i users compared with non-users in the FRC group (events per patient-year: 0.18 and 1.14, respectively) (Table 7 in Example 5).

[0047] Example 6 summarizes a subgroup analysis of the data from Example 3, comparing patients receiving SGLT2 inhibitors with those not receiving SGLT2 inhibitors. In both treatment groups, efficacy results (changes in HbA1c, FPG, and 2-hour PPG from baseline to week 26) were generally similar in SGLT2i users and non-users (Tables 3, 4, and 5 in Example 6). There was no evidence of reduced efficacy of FRC in the subgroup of SGLT2i users.

[0048] Regarding common TEAEs (Table 7 in Example 6), TEAEs in the gastrointestinal system system organ class (SOC) were also reported numerically less frequently in SGLT2i users compared with SGLT2i non-users in the FRC group (22.0% vs. 27.4%, respectively). Documented symptomatic hypoglycemia (plasma glucose ≦3.9 mmol / L) was reported in similar proportions of SGLT2i users and non-users (Table 8 in Example 6).

[0049] In conclusion, Examples 5 and 6 demonstrate that an improved side effect profile is achieved in patients using an SGLT2 inhibitor in combination with a fixed-dose ratio formulation of insulin glargine and lixisenatide compared to patients not using an SGLT2 inhibitor.

[0050] As used herein, "SGLT2 inhibitor" includes pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of SGLT2 inhibitors are known to those skilled in the art. "SGLT2 inhibitors" are also referred to herein as "SGLT-2 inhibitors" or "SGLT2i".

[0051] In the present invention, the SGLT2 inhibitor is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin. For example, the SGLT2 inhibitor is selected from empagliflozin, canagliflozin, and dapagliflozin.

[0052] Those skilled in the art will know the appropriate dosages of SGLT2 inhibitors to administer. In the combination of the present invention, canagliflozin is administered in a daily dose range of 100 to 300 mg. In the combination of the present invention, empagliflozin is administered in a daily dose range of 10 to 25 mg. In the combination of the present invention, dapagliflozin is administered in a daily dose range of 5 to 20 mg.

[0053] In the combination pharmaceutical of the present invention, pharmaceutical preparation (a) may contain insulin glargine at a concentration of 100 to 500 U / mL. For example, pharmaceutical preparation (a) may contain insulin glargine at a concentration of 100 U / mL.

[0054] In the combination pharmaceutical of the present invention, pharmaceutical formulation (a) may contain lixisenatide at a concentration of 20 to 150 μg / mL, for example, 33 μg / mL, 50 μg / mL, or 100 μg / mL.

[0055] In another embodiment of the invention, the pharmaceutical formulation (a) comprises insulin glargine in a concentration of 100 U / mL and lixisenatide in a concentration of 33 μg / mL, 50 μg / mL or 100 μg / mL.

[0056] The pharmaceutical combination of the present invention is used, for example, in human patients, for the treatment of type 2 diabetes.

[0057] The patient may be a Caucasian patient or an Asian patient, such as a Chinese or Japanese patient.

[0058] Formulation (a) may contain insulin glargine at a concentration of 100 U / mL and lixisenatide at a concentration of 33 μg / mL or 50 μg / mL. This formulation is suitable for treating Caucasian type 2 diabetes patients, although the use of this formulation is not limited to Caucasian patient populations.

[0059] Formulation (a) may contain insulin glargine at a concentration of 100 U / mL and lixisenatide at a concentration of 100 μg / mL. This formulation is suitable for treating Asian type 2 diabetes patients, such as Chinese or Japanese patients, although the use of this formulation is not limited to Asian patient populations.

[0060] As demonstrated by the examples of the present invention, the combinations described herein are used to improve glycemic control in patients with type 2 diabetes. In the present invention, "improved glycemic control" or "glycemic control" refers to, for example, improved 2-hour postprandial plasma glucose concentrations, improved fasting plasma glucose concentrations, improved self-monitored plasma glucose (SMPG) or / and improved HbA 1c Refers to an improvement in value.

[0061] For example, "improved glycemic control" or "glycemic control" can include improved 2-hour postprandial plasma glucose concentrations.

[0062] For example, "improved glycemic control" or "glycemic control" can include a reduction in 2-hour postprandial plasma glucose concentrations, where reduction means, for example, that 2-hour postprandial plasma glucose concentrations reach or at least approach normoglycemic levels.

[0063] For example, "improved glycemic control" or "glycemic control" can include improved fasting plasma glucose levels.

[0064] For example, improving fasting plasma glucose levels can include reducing fasting plasma glucose levels, where reducing means, for example, that fasting plasma glucose levels reach or at least approach normoglycemic levels.

[0065] For example, "improved glycemic control" or "glycemic control" can include improvements in self-monitored glucose concentrations.

[0066] For example, improving self-monitored glucose concentrations can include reducing self-monitored glucose concentrations, where reducing means, for example, that the self-monitored glucose concentrations reach or at least approach normoglycemic levels.

[0067] For example, "improved glycemic control" or "glycemic control" refers to the HbA 1c This may include improving the value.

[0068] For example, HbA 1c The improvement in HbA 1c This may include a reduction in HbA 1c The reduction in HbA 1c This means that the value is reduced to less than 6.5% or 7%.

[0069] In the present invention, a normal glycemic level of fasting plasma glucose is, for example, a blood glucose concentration of <5.6 mmol / L.

[0070] In the present invention, a euglycemic level of postprandial plasma glucose, as defined herein, is, for example, a blood glucose concentration of <7.8 mmol / L.

[0071] In the present invention, a normoglycemic HbA1c value is, for example, <6.5% or <7%.

[0072] In another embodiment of the invention, the type 2 diabetes being treated is not adequately controlled by an SGLT2 inhibitor alone, such as empagliflozin, canagliflozin, dapagliflozin or ertugliflozin alone.

[0073] As used herein, the term "oral antidiabetic agent" includes, but is not limited to, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, glinides, and sulfonylureas. An example of a biguanide is metformin.

[0074] As used herein, the term "GLP-1 receptor agonist" or "GLP-1 RA" includes, but is not limited to, lixisenatide, exenatide, dulaglutide, liraglutide, and albiglutide. Exenatide is also administered in an extended-release formulation.

[0075] In another embodiment, the type 2 diabetes being treated is not adequately controlled by an SGLT2 inhibitor and an oral antidiabetic drug alone, or an SGLT2 inhibitor and a GLP-1 receptor agonist alone. The oral antidiabetic drug is selected from the group consisting of biguanides, thiazolidinediones, alpha-glucosidase inhibitors, glinides, and sulfonylureas. For example, the biguanide is metformin.

[0076] In another embodiment, the type 2 diabetes being treated is not adequately controlled with (i) an SGLT2 inhibitor and metformin alone, or (ii) an SGLT2 inhibitor and a GLP-1 receptor agonist alone.

[0077] In yet another embodiment, the type 2 diabetes being treated is not adequately controlled with an SGLT2 inhibitor, metformin and a GLP-1 receptor agonist alone.

[0078] In the present invention, "not adequately controlled" by antidiabetic drug treatment means that the treatment is not sufficient to eliminate the symptoms of type 2 diabetes. For example, "not adequately controlled" by the treatment means that the patient does not achieve normoglycemia, for example, in terms of 2-hour postprandial plasma glucose concentration, SMPG, HbA1c value, or / and fasting plasma glucose concentration. For example, antidiabetic drug pretreatment is insufficient to achieve adequate glycemic control.

[0079] In the present invention, "pre-treatment", "treatment prior to administration of the combination of the present invention", or treatment of "a patient treated according to the present invention" relates to antidiabetic drug treatment that the patient receives, for example within 1, 2, 3 months before receiving the combination of the present invention, or within a longer period before receiving the combination of the present invention.

[0080] As used herein, "treated according to the present invention", "treatment according to the present invention" or "therapy according to the present invention" relates to the treatment of patients with type 2 diabetes with the pharmaceutical combination of the present invention.

[0081] The metformin used in the treatment prior to administration of the combination of the present invention is, for example, administered at a dose of at least 1.0 g / day of metformin or at least 1.5 g / day of metformin for at least 3 months, or / and at a dose of up to 2.0 g / day of metformin for at least 3 months or at a dose of up to 3.5 g / day of metformin for at least 3 months. The daily dose may also be in the range of 500 to 3000 mg, for example 1000 to 2600 mg.

[0082] The GLP-1 receptor agonist used for treatment prior to administration of the combination of the present invention is selected from lixisenatide, exenatide, dulaglutide, liraglutide, and albiglutide. Exenatide is also administered in an extended release formulation.

[0083] For example, the GLP-1 receptor agonist used for treatment prior to administration of the combination of the present invention is selected from lixisenatide, exenatide, dulaglutide, and liraglutide.

[0084] Formulations containing GLP-1 receptor agonists, such as those selected from lixisenatide, exenatide, dulaglutide, liraglutide and albiglutide, are known to those skilled in the art.

[0085] Typical doses of GLP-1 receptor agonists are known to those skilled in the art. In the present invention, the daily dose of exenatide can range from 10 to 20 μg. The weekly dose of exenatide in extended-release formulations can be 2 mg. The daily dose of dulaglutide can range from 0.75 to 1.5 mg. The daily dose of liraglutide can range from 1.2 to 1.8 mg. The daily dose of albiglutide can range from 30 to 50 mg. The daily dose of lixisenatide can range from 10 to 20 μg.

[0086] A typical daily dose of insulin glargine administered in pharmaceutical formulation (a) of the present invention is 5 to 60 U, which corresponds to the dose of lixisenatide. For example, in a formulation containing 100 U / mL of insulin glargine and 50 μg / mL of lixisenatide, this dosage range corresponds to a daily dose of 2.5 to 30 μg of lixisenatide. For example, in a formulation containing 100 U / mL of insulin glargine and 33 μg / mL of lixisenatide, this dosage range corresponds to a daily dose of approximately 1.6 to 20 μg of lixisenatide.

[0087] For example, a dose of 10 to 60 U is administered. This dosage range is suitable for treating Caucasian type 2 diabetes patients, but its use is not limited to Caucasian patients. For example, in a formulation containing 100 U / mL insulin glargine and 50 μg / mL lixisenatide, this dosage range corresponds to a daily dose of 5 to 30 μg of lixisenatide. For example, in a formulation containing 100 U / mL insulin glargine and 33 μg / mL lixisenatide, this dosage range corresponds to a daily dose of approximately 3.3 to 20 μg of lixisenatide.

[0088] For example, a dose of 5-20 U is administered. This dosage range is suitable for treating Asian type 2 diabetes patients, such as Japanese or Chinese patients, but the use of this dosage is not limited to Asian patient groups. For example, in a formulation containing insulin glargine 100 U / mL and lixisenatide 100 μg / mL, this dosage range corresponds to a daily dose of 5-20 μg of lixisenatide.

[0089] As described herein, pretreatment that is insufficient for adequate control of type 2 diabetes can also include treatment with pioglitazone. Formulations containing pioglitazone for use in treatment prior to administration of the combinations of the invention are known to those skilled in the art.

[0090] In the present invention, the daily dose of pioglitazone may be in the range of 15 to 45 mg, for example 30 mg.

[0091] The type 2 diabetes patient treated according to the present invention may be obese. The patient has a body mass index of at least 30 kg / m 2 (Caucasian patients) or at least 25 kg / m 2 (Asian patients, e.g., Chinese or Japanese patients) are considered obese.

[0092] In the present invention, an obese type 2 diabetic patient has a blood sugar level of at least 30 kg / m, for example, if the patient is Caucasian. 2 , at least 31 kg / m 2 or at least 32 kg / m 2 If the patient is an Asian patient, e.g., a Chinese or Japanese patient, the patient may have a body mass index of at least 25 kg / m 2 or at least 26 kg / m 2 The type 2 diabetic patient may be obese prior to initiation of treatment with a combination according to the present invention.

[0093] The patient to be treated may have an age of less than 50 years. The patient may also have an age of at least 50 years.

[0094] In the present invention, a type 2 diabetes patient may have an HbA1c value in the range of 7% to 9%, in the range of 7.5% to 9.5%, or in the range of 7.5% to 10%. A type 2 diabetes patient may have an HbA1c of at least 7.5%, at least 7.8%, or at least 8%. These HbA1c values above normal blood glucose levels indicate that type 2 diabetes is not adequately controlled when treated with an antidiabetic compound.

[0095] Prior to initiation of treatment with a combination according to the present invention, the patient: (a) SGLT2 inhibitor alone, (b) an SGLT2 inhibitor in combination with an oral antidiabetic agent, as described herein; (c) an SGLT2 inhibitor in combination with metformin, or (d) When treated with an SGLT2 inhibitor in combination with metformin and a GLP-1 receptor agonist as described herein, may have an HbA1c as described herein, e.g., of at least 7.5%, at least 7.8%, or at least 8%.

[0096] Oral antidiabetic drug treatment is selected from the group of biguanide, thiazolidinedione, alpha-glucosidase inhibitor, glinide drug and sulfonylurea.For example, as described herein, biguanide is metformin.As described herein, GLP-1 receptor agonist is selected from liraglutide, lixisenatide, exenatide, exenatide extended release formulation, albiglutide and dulaglutide.

[0097] Type 2 diabetes patients treated according to the present invention may have a fasting plasma glucose concentration of at least 8 mmol / L, at least 8.5 mmol / L, or at least 9 mmol / L. These plasma glucose concentrations above normoglycemic levels indicate that type 2 diabetes is not adequately controlled when treated with an antidiabetic compound.

[0098] Prior to initiation of treatment with a combination according to the present invention, the patient: (a) SGLT2 inhibitor alone, (b) an SGLT2 inhibitor in combination with an oral antidiabetic agent, as described herein; (c) an SGLT2 inhibitor in combination with metformin, or (d) may have a fasting plasma glucose of at least 8 mmol / L, at least 8.5 mmol / L, or at least 9 mmol / L HbA1c when treated with an SGLT2 inhibitor in combination with metformin and a GLP-1 receptor agonist as described herein.

[0099] Oral antidiabetic drug treatment is selected from the group of biguanide, thiazolidinedione, alpha-glucosidase inhibitor, glinide drug and sulfonylurea.For example, biguanide is metformin.GLP-1 receptor agonist is selected from liraglutide, lixisenatide, exenatide, exenatide extended release formulation, albiglutide and dulaglutide as described herein.

[0100] For example, in patients treated according to the present invention, type 2 diabetes was diagnosed at least one year or at least two years prior to the initiation of therapy according to the present invention.

[0101] "Self-monitored plasma glucose (SMPG)," as used herein, can be "four-point self-monitored plasma glucose" or "seven-point self-monitored plasma glucose." Four-point and seven-point self-monitored plasma glucose values are, for example, average plasma glucose concentrations, including fasting and postprandial states.

[0102] "Four-point self-monitoring plasma glucose" refers to, for example, four daily plasma glucose measurements and calculation of an average plasma glucose concentration therefrom, e.g., four self-monitoring plasma glucose measurements taken before breakfast, after breakfast, before dinner, and after dinner.

[0103] "Seven-point self-monitoring plasma glucose" refers to, for example, seven daily plasma glucose measurements and calculation of an average plasma glucose concentration therefrom, e.g., seven self-monitoring plasma glucose measurements taken before breakfast, after breakfast, before lunch, after lunch, before dinner, after dinner, and at bedtime.

[0104] "Self-monitored fasting plasma glucose (SMPG)" as used herein is measured by the patient before breakfast, for example, before insulin glargine or / and lixisenatide injection and optionally metformin intake.

[0105] Type 2 diabetes patients treated according to the present invention may have a 2-hour postprandial plasma glucose concentration of at least 11.1 mmol / L. These plasma glucose concentrations above normoglycemic concentrations indicate that type 2 diabetes is not adequately controlled when treated with an antidiabetic compound.

[0106] "Postprandial" is a term well known to those skilled in the field of diabetology. The term "postprandial" refers to the phase following, for example, a meal intake or / and exposure to glucose under experimental conditions. In healthy individuals, this phase is characterized by an increase in blood glucose concentration followed by a decrease. The postprandial phase typically ends by 2 hours after a meal or / and exposure to glucose (2-hour postprandial plasma glucose concentration).

[0107] The determination of postprandial plasma glucose is well known (see, eg, Crapo et al., Diabetes, 1977, 26(12):1178-1183).

[0108] As disclosed herein, the patient may be an Asian patient, e.g., a Chinese or Japanese patient. For example, the Asian patient, e.g., a Chinese or Japanese patient, may be obese. The Asian patient, e.g., a Chinese or Japanese patient, may be at least 25 kg / m 2 or at least 26 kg / m 2Asian patients, such as Chinese or Japanese patients, may be obese prior to initiation of treatment with a combination according to the present invention.

[0109] Formulation (a) of the present invention, when used in Asian patients, such as Chinese or Japanese patients, may contain insulin glargine in a concentration of 100 U / mL and lixisenatide in a concentration of 100 μg / mL.

[0110] In another embodiment of the present invention, the type 2 diabetes being treated in Asian patients, e.g., Chinese or Japanese patients, is not adequately controlled by an SGLT2 inhibitor and an oral antidiabetic drug alone. The oral antidiabetic drug is selected from the group consisting of biguanides, thiazolidinediones, alpha-glucosidase inhibitors, glinides, and sulfonylureas. For example, the biguanide is metformin.

[0111] In the present invention, metformin is administered according to the commonly known administration protocol of metformin, and is in compliance with the terms of marketing authorization.Those skilled in the art know suitable dosage forms.For example, metformin is administered once a day, twice a day or three times a day.For example, the metformin dosage that is applied before the start of the treatment disclosed herein is continued together with the treatment of the present invention as disclosed herein.

[0112] In the present invention, metformin is administered orally. For oral administration, metformin is formulated into a solid dosage form such as a tablet or pill. Metformin is formulated with a suitable pharmaceutically acceptable carrier, adjuvant, or / and auxiliary substance.

[0113] In the present invention, the SGLT-2 inhibitor is administered according to the commonly known administration protocol of the SGLT-2 inhibitor, which complies with the provisions of marketing authorization.Those skilled in the art know suitable dosage forms.For example, the SGLT-2 inhibitor is administered once a day, twice a day, or three times a day.For example, the SGLT-2 inhibitor dose applied before the start of the treatment disclosed herein is continued together with the treatment of the present invention as disclosed herein.

[0114] In the present invention, the SGLT-2 inhibitor is administered orally. For oral administration, the SGLT-2 inhibitor is formulated into a solid dosage form such as a tablet or pill. The SGLT-2 inhibitor is formulated together with a suitable pharmaceutically acceptable carrier, adjuvant, or / and auxiliary substance.

[0115] The pharmaceutical combination of the present invention allows for the simultaneous, separate or sequential administration of (a) a pharmaceutical formulation comprising lixisenatide or / and a pharmaceutically acceptable salt thereof and insulin glargine or / and a pharmaceutically acceptable salt thereof, and (b) an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof, and, optionally, (c) metformin or / and a pharmaceutically acceptable salt thereof.

[0116] In the present invention, "separate administration" means that the pharmaceutical combination according to the present invention is administered in separate pharmaceutical formulations, where one pharmaceutical formulation (a) contains lixisenatide or / and a pharmaceutically acceptable salt thereof, and insulin glargine or / and a pharmaceutically acceptable salt thereof, and a second pharmaceutical formulation (b) contains an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof, and optionally a third pharmaceutical formulation (c) containing metformin or / and a pharmaceutically acceptable salt thereof is administered.

[0117] The pharmaceutical preparations are administered simultaneously or sequentially in any order.Accordingly, the present invention relates to a combination pharmaceutical comprising, for example, an injectable pharmaceutical preparation comprising lixisenatide or / and a pharmaceutically acceptable salt thereof and insulin glargine or / and a pharmaceutically acceptable salt thereof, and an oral pharmaceutical preparation comprising an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof, and optionally an oral pharmaceutical preparation comprising metformin or / and a pharmaceutically acceptable salt thereof, by simultaneous, separate or sequential administration, particularly for use in treating patients with type 2 diabetes.

[0118] In the present invention, co-administration can include administration of a formulation of the present invention at the same time or within a time interval, for example, 5 minutes, 10 minutes, or 15 minutes, required to administer a composition of the present invention.

[0119] In the present invention, sequential administration can include administration of the formulations of the present invention at intervals of at least 15 minutes, at least 1 hour, or at least 2 hours, or at intervals of up to 3 hours. Optionally, when a formulation containing metformin or / and a pharmaceutically acceptable salt thereof is administered, the intervals between the administration of the formulations are independently selected. Any order of administration can be selected. For example, administration can begin with (a) a pharmaceutical formulation containing lixisenatide or / and a pharmaceutically acceptable salt thereof and insulin glargine or / and a pharmaceutically acceptable salt thereof, followed by (b) a formulation containing an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof, or vice versa. Optionally, when a formulation (c) containing metformin or / and a pharmaceutically acceptable salt thereof is administered, this formulation can be administered before, during, or after formulations (a) and (b). For example, administration may begin with formulation (c) comprising metformin or / and a pharmaceutically acceptable salt thereof, continued with pharmaceutical formulation (a) comprising lixisenatide or / and a pharmaceutically acceptable salt thereof and insulin glargine or / and a pharmaceutically acceptable salt thereof, and then with formulation (b) comprising an SGLT2 inhibitor or / and a pharmaceutically acceptable salt thereof, or vice versa.

[0120] As disclosed herein, the preparation comprising lixisenatide or / and its pharmaceutically acceptable salt and insulin glargine or / and its pharmaceutically acceptable salt is administered by one injection per day.For example, when the oral preparation comprising SGLT2 inhibitor or / and its pharmaceutically acceptable salt is administered more than once a day, for example twice a day or three times a day, one of the doses is administered simultaneously with the preparation comprising lixisenatide or / and its pharmaceutically acceptable salt and insulin glargine or / and its pharmaceutically acceptable salt.For example, in some cases, when the oral preparation comprising metformin or / and its pharmaceutically acceptable salt is administered more than once a day, for example twice a day or three times a day, one of the doses is administered simultaneously with the preparation comprising lixisenatide or / and its pharmaceutically acceptable salt and insulin glargine or / and its pharmaceutically acceptable salt.

[0121] In the present invention, the pharmaceutical combination is administered in an adjunctive therapy as described herein.

[0122] In the present invention, the terms "add-on," "add-on treatment," and "add-on therapy" relate to a treatment according to the present invention in which pretreatment with at least one antidiabetic drug is continued. "Add-on," "add-on treatment," and "add-on therapy" mean, for example, that a dose of at least one antidiabetic drug administered before the start of treatment according to the present invention, as disclosed herein, is continued during the treatment according to the present invention. In the add-on therapy, if the pretreatment includes administration of an SGLT2 inhibitor, the treatment with the SGLT2 inhibitor is continued, for example, at the same dose. If necessary, one or more doses or multiple doses of the at least one antidiabetic drug administered in the pretreatment regimen are adapted.

[0123] In the present invention, lixisenatide as used herein includes its pharmaceutically acceptable salts.Those skilled in the art will know suitable pharmaceutically acceptable salts of lixisenatide.An exemplary pharmaceutically acceptable salt of lixisenatide used in the present invention is acetic acid salt of lixisenatide.

[0124] In the present invention, insulin glargine, as used herein, includes pharmaceutically acceptable salts thereof. Suitable pharmaceutically acceptable salts of insulin glargine are known to those skilled in the art.

[0125] Formulation (a) is provided as a liquid composition, for example an aqueous formulation, as described herein.

[0126] Formulation (a) may also contain preservatives (e.g., phenol, m-cresol, p-cresol, parabens), isotonicity agents (e.g., mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerin), buffer substances, salts, acids and alkalis, and further excipients, as described herein, which may in each case be present individually or alternatively as mixtures.

[0127] Formulation (a) may contain a buffering substance, as described herein. For example, buffering substances such as phosphate, acetate, citrate, arginine, glycylglycine, or TRIS (i.e., 2-amino-2-hydroxymethyl-1,3-propanediol) buffers and corresponding salts may be present at a concentration of 5 to 250 mM, e.g., 10 to 100 mM. Additional excipients may be, inter alia, salts or arginine.

[0128] Formulation (a) may contain a surfactant, e.g., a nonionic surfactant, as described herein. For example, the surfactant may be a pharmaceutically conventional surfactant, such as partial esters and ethers of polyhydric alcohols such as glycerin, sorbitol, and fatty acids (Span®, Tween®, e.g., Tween® 20 and Tween® 80, Myrj®, Brij®), Cremophor®, or poloxamer. The surfactant is present in pharmaceutical formulation (a) at a concentration of 5 to 200 μg / ml, e.g., 5 to 120 μg / mL or 20 to 75 μg / ml.

[0129] Formulation (a) may contain an isotonicity agent, as described herein. Suitable isotonicity agents are selected from glycerin, dextrose, lactose, sorbitol, mannitol, glucose, NaCl, calcium- or magnesium-containing compounds such as CaCl2. The concentrations of glycerin, lactose, sorbitol, mannitol, and glucose may range from 100 to 250 mM. The concentration of NaCl may be up to 150 mM.

[0130] An exemplary tonicity agent is glycerin. Glycerin 85% may be present in an amount of 10-30 mg / mL, for example 20 mg / mL.

[0131] The pharmaceutical formulation (a) may contain methionine at a concentration selected from 0.3 mg / mL to 20 mg / mL, for example, 1 mg / mL to 5 mg / mL, as described herein. An exemplary concentration of methionine is 3 mg / mL. For example, the liquid composition contains L-methionine.

[0132] The pharmaceutical formulation (a) may contain a suitable preservative as described herein. Suitable preservatives are selected from phenol, m-cresol, benzyl alcohol, and p-hydroxybenzoic acid esters. An exemplary preservative is m-cresol. The preservative, e.g., m-cresol, may be present at a concentration of up to 3 mg / mL, e.g., 1 to 3 mg / mL. For example, the concentration is 2.7 mg / mL.

[0133] The pharmaceutical formulation (a) may contain zinc as described herein. The zinc concentration may range from 0 to 1000 μg / mL, for example, from 20 to 400 μg / mL of zinc. An exemplary zinc concentration is 30 μg / mL. The zinc may be present in the form of zinc chloride, but the salt is not limited to zinc chloride.

[0134] The pH of the pharmaceutical formulation (a) is adjusted with hydrochloric acid or / and sodium hydroxide as described herein. The pH can be in the range of pH 1 to 6.8, pH 3.5 to 6.8, or pH 3.5 to 4.5. For example, the pH is in the range of 4.0 to 4.5. Exemplary pH values are 4.0 and 4.5.

[0135] In the present invention, the pharmaceutical formulation (a) is administered to a type 2 diabetes patient in need thereof in an amount sufficient to induce a therapeutic effect.

[0136] Pharmaceutical formulation (a) is administered parenterally as described herein, for example, pharmaceutical formulation (a) is administered by injection, such as by subcutaneous injection, as described herein.

[0137] The pharmaceutical formulation (a) may be an injectable formulation, as described herein. Suitable injection devices, such as so-called "pens", which comprise a cartridge containing the formulation and an injection needle, are known.

[0138] Formulation (a) is administered by injection once daily, for example, formulation (a) is administered before breakfast, such as about 30 minutes before breakfast.

[0139] For example, 1 mL of pharmaceutical formulation (a) containing 50 μg / mL of lixisenatide contains: [Table 1] may contain

[0140] This formulation is suitable for subcutaneous injection. In this formulation, the amount of zinc chloride reflects the total amount in the drug composition, including the pharmaceutical agent insulin glargine and zinc chloride (calculated as zinc chloride) from zinc chloride introduced during the manufacture of the drug product.

[0141] For example, 1 mL of pharmaceutical formulation (a) containing lixisenatide 33 μg / mL contains: [Table 2] may contain

[0142] This formulation is suitable for subcutaneous injection. In this formulation, the amount of zinc chloride reflects the total amount in the drug composition, including the pharmaceutical agent insulin glargine and zinc chloride (calculated as zinc chloride) from zinc chloride introduced during the manufacture of the drug product.

[0143] Pharmaceutical formulation (a) containing lixisenatide 100 μg / mL and insulin glargine 100 U / mL may contain the same excipients in the same concentrations as formulations containing lixisenatide 50 μg / mL and insulin glargine 100 U / mL, or lixisenatide 33 μg / mL and insulin glargine 100 U / mL.

[0144] Yet another aspect of the invention is the use of a compound of formula (I) or (II) in the manufacture of a medicament for the treatment of type 2 diabetes, comprising: (a)(i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof and a pharmaceutical formulation comprising (b) an SGLT2 inhibitor, or / and a pharmaceutically acceptable salt thereof; The present invention relates to the use of a pharmaceutical combination comprising: (a) a serotonin-containing compound (serotonin-containing compound) and (b) a serotonin-containing compound (serotonin-containing compound) or ...

[0145] Yet another aspect of the present invention relates to a method of treating a patient with type 2 diabetes in need thereof, the method comprising: (a)(i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof and a pharmaceutical formulation comprising (b) an SGLT2 inhibitor, or / and a pharmaceutically acceptable salt thereof and administering a combination pharmaceutical comprising:

[0146] The patient may be any patient described herein. The pharmaceutical formulation (a) may be any pharmaceutical formulation described herein. The SGLT2 inhibitor (b) may be any SGLT2 inhibitor described herein.

[0147] The following aspects are also the subject of the present invention: Item 1. (a)(i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof and a pharmaceutical formulation comprising (b) an SGLT2 inhibitor, or / and a pharmaceutically acceptable salt thereof A combination medicine comprising: Item 2. (c) The pharmaceutical combination according to item 1, further comprising metformin or / and a pharmaceutically acceptable salt thereof. Item 3. 3. The pharmaceutical combination according to item 1 or 2, wherein the SGLT2 inhibitor is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin and ertugliflozin. Item 4. The combination pharmaceutical according to any one of items 1 to 3, wherein the SGLT2 inhibitor is selected from the group consisting of empagliflozin, canagliflozin and dapagliflozin. Item 5. 5. The combination pharmaceutical according to any one of items 1 to 4, wherein the pharmaceutical preparation (a) contains insulin glargine at a concentration of 100 to 500 U / mL. Item 6. 6. The pharmaceutical combination according to any one of items 1 to 5, wherein the pharmaceutical preparation (a) comprises insulin glargine at a concentration of 100 U / mL. Item 7. 7. The pharmaceutical combination according to any one of items 1 to 6, wherein the pharmaceutical preparation (a) contains lixisenatide in a concentration of 20 to 150 μg / ml. Item 8. 8. The pharmaceutical combination according to any one of items 1 to 7, wherein the pharmaceutical formulation (a) comprises lixisenatide in a concentration of 33 μg / mL, 50 μg / mL or 100 μg / mL. Item 9. 9. The pharmaceutical combination according to any one of items 1 to 8, wherein the pharmaceutical formulation comprises lixisenatide in a concentration of 33 μg / mL or 50 μg / mL. Item 10. 9. The pharmaceutical combination according to any one of items 1 to 8, wherein the pharmaceutical formulation comprises lixisenatide in a concentration of 100 μg / mL. Item 11. 9. The pharmaceutical combination according to any one of items 1 to 8, wherein the pharmaceutical formulation (a) comprises insulin glargine in a concentration of 100 U / mL and lixisenatide in a concentration of 33 μg / mL, 50 μg / mL or 100 μg / mL. Item 12. 12. The pharmaceutical combination according to any one of items 1 to 8 and 11, wherein the pharmaceutical formulation comprises insulin glargine in a concentration of 100 U / mL and lixisenatide in a concentration of 33 μg / mL or 50 μg / mL. Item 13. 12. The pharmaceutical combination according to any one of items 1 to 8 and 11, wherein the pharmaceutical formulation comprises insulin glargine in a concentration of 100 U / mL and lixisenatide in a concentration of 100 μg / mL. Item 14. 14. The pharmaceutical combination according to any one of items 1 to 13 for use in treating patients with type 2 diabetes. Item 15. 15. The pharmaceutical combination for use according to item 14, wherein the patient is a human patient. Item 16. 16. The pharmaceutical combination for use according to item 14 or 15, wherein the patient is an Asian patient. Item 17. 17. The pharmaceutical combination for use according to any one of items 14 to 16, wherein the patient is a Chinese or Japanese patient. Item 18. 16. The pharmaceutical combination for use according to item 14 or 15, wherein the patient is a Caucasian patient. Item 19. 19. The pharmaceutical combination for use according to any one of items 14 to 18, wherein the type 2 diabetes to be treated is not adequately controlled with an SGLT2 inhibitor alone. Item 20. 19. The pharmaceutical combination for use according to any one of items 14 to 18, wherein the type 2 diabetes to be treated is not adequately controlled with an SGLT2 inhibitor selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin and ertugliflozin, or from the group consisting of empagliflozin, canagliflozin and dapagliflozin. Item 21. 19. The pharmaceutical combination for use according to any one of items 14 to 18, wherein the type 2 diabetes to be treated is not adequately controlled with an SGLT2 inhibitor and an oral antidiabetic drug alone. Item 22. The type 2 diabetes to be treated is (a) an SGLT2 inhibitor selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin and ertugliflozin, or from the group consisting of empagliflozin, canagliflozin and dapagliflozin, and (b) an oral antidiabetic agent selected from the group consisting of a biguanide, a thiazolidinedione, an alpha-glucosidase inhibitor, a glinide, and a sulfonylurea, wherein the biguanide can be metformin; 22. The combination pharmaceutical for use according to item 21, wherein the above alone is not adequately controlled. Item 23. 19. The pharmaceutical combination for use according to any one of items 14 to 18, wherein the type 2 diabetes to be treated is not adequately controlled with an SGLT2 inhibitor and metformin alone, or an SGLT2 inhibitor and a GLP-1 receptor agonist alone. Item 24. The type 2 diabetes to be treated is (a) (i) an SGLT2 inhibitor selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, or from the group consisting of empagliflozin, canagliflozin, and dapagliflozin, and (ii) metformin, or (b) (i) an SGLT2 inhibitor selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin, and ertugliflozin, or from the group consisting of empagliflozin, canagliflozin, and dapagliflozin, and (ii) a GLP-1 receptor agonist selected from liraglutide, lixisenatide, exenatide, albiglutide, and dulaglutide. 24. The combination pharmaceutical for use according to item 23, wherein the above alone is not adequately controlled. Item 25. 19. The pharmaceutical combination for use according to any one of items 14 to 18, wherein the type 2 diabetes to be treated is not adequately controlled with an SGLT2 inhibitor, metformin and a GLP-1 receptor agonist alone. Item 26. The type 2 diabetes to be treated is (a) an SGLT2 inhibitor selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin and ertugliflozin, or from the group consisting of empagliflozin, canagliflozin and dapagliflozin; (b) an oral antidiabetic agent selected from the group consisting of a biguanide, a thiazolidinedione, an alpha-glucosidase inhibitor, a glinide, and a sulfonylurea, wherein the biguanide can be metformin; and (c) a GLP-1 receptor agonist selected from liraglutide, lixisenatide, exenatide, albiglutide, and dulaglutide 26. The combination medicine for use according to item 25, wherein the above-mentioned combination medicine is not adequately controlled by itself. Item 27. 27. The pharmaceutical combination for use according to any one of items 23 to 26, wherein the GLP-1 receptor agonist is selected from lixisenatide, exenatide, dulaglutide, and liraglutide. Item 28. 28. The pharmaceutical combination for use according to any one of items 14 to 27, wherein the patient to be treated is obese. Item 29. Patients must be at least 30 kg / m 2 , at least 31 kg / m 2 or at least 32 kg / m 2 29. The combination pharmaceutical for use according to any one of items 14 to 28, wherein the patient has a body mass index (BMI) of Item 30. 30. The combination medicine for use according to item 29, wherein the patient is a Caucasian patient. Item 31. Patients must be at least 25 kg / m 2 , or at least 26 kg / m 2 29. The combination pharmaceutical for use according to any one of items 14 to 28, wherein the patient has a body mass index (BMI) of Item 32. 32. The pharmaceutical combination for use according to item 31, wherein the patient is an Asian patient, such as a Chinese or Japanese patient. Item 33. The pharmaceutical combination for use according to any one of items 14 to 32, wherein prior to the start of treatment with the combination according to any one of items 1 to 8, the patient to be treated has an HbA1c of at least 7.5%. Item 34. 34. The pharmaceutical combination for use according to any one of items 14 to 33, wherein prior to the start of treatment with the combination according to any one of items 1 to 8, the patient to be treated has a fasting plasma glucose concentration of at least 8 mmol / L.

[0148] The present invention is further illustrated by the following examples. [Brief explanation of the drawings]

[0149] [Figure 1] Figure 1 depicts the study design. *Additional titration call - for the FRC arm only.** Insulin glargine / lixisenatide fixed ratio combination (FRC) treatment will be initiated with the Peach Pen. The initial daily dose administered is 10 U, equivalent to an initial associated dose of 10 U insulin glargine and 5 μg lixisenatide, based on the fixed ratio of 2 U / μg used in the Peach Pen. Doses will then be individually titrated throughout the study to achieve and maintain a test SMPG of 80-100 mg / dL (4.4-6.6 mmol / L) while avoiding hypoglycemia. †Liraglutide, exenatide, albiglutide, or dulaglutide will be discontinued at Visit 3 for patients randomized to FRC treatment. Any patient treated with a weekly GLP-1 RA who is assigned to receive FRC treatment at the time of study entry must not receive their first dose until at least 1 week after their last dose of GLP-1 RA. [Figure 2] Figure 2 shows a plot of mean HbA1c (%) by visit during the 26-week randomized treatment period - mITT population. S = Screening (Week 2), B = Baseline, FRC = Fixed Ratio Combination, GLP-1 RA = GLP-1 Receptor Agonist. The plot included all scheduled measurements obtained during the 26-week randomized treatment period, including measurements obtained after IMP discontinuation or introduction of rescue medication. [Figure 3] Figure 3 presents a plot of mean fasting plasma glucose (mmol / L [mg / dL]) by visit during the 26-week randomized treatment period - mITT population. S = screening (week 2), B = baseline, FRC = fixed ratio combination, GLP-1 RA = GLP-1 receptor agonist. Analyses included all scheduled measurements obtained during the 26-week randomized treatment period, including measurements obtained after IMP discontinuation or introduction of rescue medication therapy. [Figure 4]Figure 4 presents a plot of the mean 7-point SMPG (mmol / L [mg / dL]) at baseline and 26 weeks during the on-treatment period—mITT population. SMPG = self-monitored plasma glucose. FRC = fixed ratio combination, GLP-1 RA = GLP-1 receptor agonist. Analyses included all scheduled measurements obtained during the 26-week randomized treatment period, including measurements obtained after IMP discontinuation or introduction of rescue therapy. DETAILED DESCRIPTION OF THE INVENTION [Example]

[0150] A 26-week randomized, open-label, active-controlled, parallel-group study (EFC13794) to determine the efficacy and safety of the insulin glargine / lixisenatide fixed-ratio combination, followed by a single-arm 26-week extension period, in adults with type 2 diabetes poorly controlled on a GLP-1 receptor agonist and metformin (alone or in combination with pioglitazone and / or an SGLT2 inhibitor)

[0151] [Table 3-1] [Table 3-2] [Table 3-3]

[0152] 2. Research blueprint The study design is described in Figure 1 .

[0153] [Table 4-1] [Table 4-2] [Table 4-3]

[0154] 4 Results 4.1 Study patients 4.1.1 Patient Accountability [Table 5]

[0155] 4.1.2 Research Processing [Table 6-1] [Table 6-2]

[0156] *Patient 376000200001 was a 65-year-old woman with a history of obesity, hypertension, hyperlipidemia, persistent depressive disorder, and diabetic complications (neuropathy and nephropathy). She was treated with metformin (1.7 g / day) and Victoza (1.8 mg / day) at screening. Her baseline HbAlc was 7.1%. After 91 days of FRC use and titration to 60 U, fasting SMPG did not improve compared to baseline. No reasonable explanation for the poor glucose control was found. The investigators decided to early and permanently discontinue FRC treatment and resume previous GLP-1RA treatment.

[0157] 4.1.3 Demographic and baseline characteristics [Table 7-1] [Table 7-2]

[0158] [Table 8-1] [Table 8-2] [Table 8-3] [Table 8-4] [Table 8-5]

[0159] 4.2 Efficacy 4.2.1 Primary Efficacy Endpoint [Table 9]

[0160] [Table 10-1] [Table 10-2]

[0161] 4.2.2 Secondary Efficacy Endpoints [Table 11]

[0162] [Table 12]

[0163] [Table 13]

[0164] [Table 14]

[0165] [Table 15]

[0166] [Table 16]

[0167] [Table 17]

[0168] [Table 18]

[0169] 4.3 Safety Hypoglycemic events were recorded on a specific hypoglycemic event form, not on the AE CRF page, and therefore were not included in the TEAE summary. They are summarized separately from TEAEs. If the criteria for an SAE were met, the event must be reported as an SAE using the appropriate AE CRF page, and therefore the event was included in the TEAE summary.

[0170] 4.3.1 Treatment-emergent adverse events [Table 19]

[0171] [Table 20]

[0172] 4.3.2 Deaths and serious treatment-emergent adverse events No patients experienced a TEAE leading to death during the 26-week randomized treatment period. [Table 21-1] [Table 21-2] [Table 21-3]

[0173] 4.3.3 Adverse events leading to withdrawal [Table 22-1] [Table 22-2]

[0174] 4.3.4 Other significant adverse events (including AESI, lab) A 41-year-old female FRC patient became pregnant 125 days after the procedure. There were no complications with the pregnancy, and labor or delivery was reported. The patient delivered a healthy baby. No congenital anomalies were recorded. No TEAEs of increased calcitonin (≥20 pg / mL) were reported during the 26-week randomized treatment period.

[0175] [Table 23]

[0176] [Table 24]

[0177] [Table 25]

[0178] [Table 26]

[0179] 4.3.5 Other Safety Observations - Hypoglycemia [Table 27-1] [Table 27-2]

[0180] One 69-year-old patient in the FRC group experienced a severe hypoglycemic event associated with loss of consciousness and was reported as an SAE (PT: hypoglycemic loss of consciousness). The event occurred at 8:30 AM, approximately 40 minutes after the FRC injection and 10 hours after his last meal. The woman who helped the patient lie down in bed and gave him sugar reported that the patient experienced dizziness, confusion, and loss of consciousness for 3 minutes. Blood glucose levels were 42 mg / dL at 08:51 and 70 mg / dL at 09:16. The patient fully recovered by 09:45. The investigator considered the event to be treatment-related and reduced the FRC dose accordingly. [Example]

[0181] A randomized, 26-week, active-controlled, open-label, two-treatment-arm, parallel-group, multicenter study comparing the efficacy and safety of a fixed-ratio combination of insulin glargine / lixisenatide (LixiLan) to lixisenatide added to oral antidiabetic agents, with a 26-week safety extension period, in Japanese patients with type 2 diabetes poorly controlled on oral antidiabetic agents (EFC14112)

[0182] [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4] [Table 28-5] [Table 28-6] [Table 28-7] [Table 28-8] [Table 28-9] [Example]

[0183] A randomized, 26-week, active-controlled, open-label, two-treatment-arm, parallel-group, multicenter study comparing the efficacy and safety of insulin glargine / lixisenatide fixed-ratio combination (LixiLan) to insulin glargine added to oral antidiabetic agents in Japanese patients with type 2 diabetes poorly controlled on oral antidiabetic agents (EFC14114)

[0184] [Table 29-1] [Table 29-2] [Table 29-3] [Table 29-4] [Table 29-5] [Table 29-6] [Table 29-7] [Example]

[0185] Concurrent use of a fixed-dose ratio formulation of insulin glargine and lixisenatide with an SGLT2i - Subgroup analysis of Example 1 The concurrent use of a fixed ratio combination (FRC) of insulin glargine and lixisenatide with an SGLT2 inhibitor (SGLT2i) was supported by a subgroup analysis of the patient population included in Example 1 (Study EFC13794). In this study, 26 patients (10.1%) received a FRC, metformin, and an SGLT2i concomitantly.

[0186] The FRC was provided as a single formulation as described in Example 1.

[0187] Improvements in efficacy outcomes (changes in glycated hemoglobin [HbA1c], fasting plasma glucose [FPG], and 2-hour postprandial plasma glucose [PPG] from baseline to week 26) were observed in both treatment groups (Tables 3, 4, and 5).

[0188] In patients receiving SGLT2 inhibitors, the effect of fixed-ratio formulations was greater than that of comparator treatments compared with patients not receiving SGLT2 inhibitors.

[0189] In patients receiving SGLT2 inhibitors, the improvement in HbA1c after 26 weeks was 0.88%, taking into account the active comparator (GLP-1 RA), compared with 0.61% in patients not receiving SGLT2 inhibitors (Table 3).

[0190] In patients receiving SGLT2 inhibitors, the improvement in fasting plasma glucose after 26 weeks was 2.06 mmol / L considering the active comparator (GLP-1 RA), compared with 1.64 mmol / L in patients not receiving SGLT2 inhibitors (Table 4).

[0191] In patients receiving SGLT2 inhibitors, the improvement in 2-hour postprandial glucose after 26 weeks was 3.26 mmol / L considering the active comparator (GLP-1 RA), compared with 2.81 mmol / L in patients not receiving SGLT2 inhibitors (Table 5).

[0192] The safety summary revealed no relevant differences for SGLT2i users compared with non-users. In the FRC group, no SGLT2i users discontinued treatment due to adverse events, and no patients reported the adverse event of weight gain. Among SGLT2i users, no patients in either treatment group reported nausea or diarrhea, and only one patient in the FRC group reported vomiting (Tables 6 and 7).

[0193] Documented symptomatic hypoglycemia (plasma glucose ≤ 3.9 mmol / L [≤ 70 mg / dL]) was reported less frequently in the FRC group using SGLT2i versus non-users (0.72 events per patient-year for SGLT2i users vs. 1.62 for non-users) (Table 8).

[0194] [Table 30]

[0195] [Table 31]

[0196] [Table 32]

[0197] [Table 33]

[0198] [Table 34]

[0199] [Table 35]

[0200] [Table 36]

[0201] [Table 37]

[0202] [Table 38]

[0203] [Table 39] [Example]

[0204] Concurrent use of a fixed-dose ratio formulation of insulin glargine and lixisenatide with an SGLT2i - Subgroup analysis of Example 2 The use of a fixed ratio combination (FRC) of insulin glargine and lixisenatide concomitantly with an SGLT2 inhibitor (SGLT2i) was supported by a subgroup analysis of the patient population included in Example 2 (Study EFC14112). In this study, 34 patients (21.1%) received an FRC and an SGLT2i concomitantly.

[0205] The FRC was provided as a single formulation as described in Example 2.

[0206] In both treatment groups, efficacy outcomes (changes in HbA1c and FPG from baseline to week 26) were generally similar in SGLT2i users and non-users (Table 3, Table 4).

[0207] The safety summary revealed no differences between SGLT2i users and nonusers (Table 5). Regarding common treatment-emergent adverse events (TEAEs) (Table 6), gastrointestinal system organ class (SOC) TEAEs were reported less frequently in SGLT2i users compared with nonusers in the FRC-treated group (17.6% vs. 32.3%, respectively). Similarly, documented symptomatic hypoglycemia (plasma glucose ≤ 3.9 mmol / L [≤ 70 mg / dL]) was reported less frequently in SGLT2i users compared with nonusers in the FRC group (events per patient-year: 0.18 and 1.14, respectively) (Table 7). No new safety signals were identified when patients in the FRC-treated group used SGLT2i as background therapy compared with nonusers.

[0208] [Table 40]

[0209] [Table 41]

[0210] [Table 42]

[0211] [Table 43]

[0212] [Table 44]

[0213] [Table 45]

[0214] [Table 46]

[0215] [Table 47]

[0216] [Table 48] [Example]

[0217] Concurrent use of a fixed-dose ratio formulation of insulin glargine and lixisenatide with an SGLT2i - Subgroup analysis of Example 3 The concurrent use of a fixed ratio combination (FRC) of insulin glargine and lixisenatide with an SGLT2 inhibitor (SGLT2i) was supported by a subgroup analysis of the patient population included in Example 3 (Study EFC14114). In this study, 59 patients (22.7%) received an FRC and an SGLT2i concomitantly.

[0218] The FRC was provided as a single formulation as described in Example 3.

[0219] In both treatment groups, efficacy outcomes (changes in HbA1c, FPG, and 2-hour PPG from baseline to week 26) were generally similar in SGLT2i users and non-users (Table 3, Table 4, Table 5). Specifically, there was no evidence of a decrease in FRC efficacy in the subgroup of SGLT2i users.

[0220] The safety summary revealed no differences between SGLT2i users and non-users (Table 6). Regarding common TEAEs (Table 7), TEAEs in the gastrointestinal SOC were also reported numerically less frequently in SGLT2i users compared with SGLT2i non-users in the FRC group (22.0% vs. 27.4%, respectively). No new safety signals were identified when patients in the FRC-treated group used SGLT2i as background therapy compared with SGLT2i non-users.

[0221] [Table 49]

[0222] [Table 50]

[0223] [Table 51]

[0224] [Table 52]

[0225] [Table 53]

[0226] [Table 54]

[0227] [Table 55]

[0228] [Table 56]

[0229] Table 57

[0230] Table 58

Claims

1. 1. A pharmaceutical combination for use in treating patients with type 2 diabetes, comprising: (a)(i) lixisenatide or / and a pharmaceutically acceptable salt thereof, and (ii) insulin glargine or / and a pharmaceutically acceptable salt thereof and a pharmaceutical formulation comprising (b) an SGLT2 inhibitor, or / and a pharmaceutically acceptable salt thereof; (c) metformin or / and a pharmaceutically acceptable salt thereof; Including, The type 2 diabetes to be treated is (i) SGLT2 inhibitors only; (ii) SGLT2 inhibitors and oral antidiabetic drugs only; (iii) an SGLT2 inhibitor and metformin alone, or an SGLT2 inhibitor and a GLP-1 receptor agonist alone; and / or (iv) SGLT2 inhibitor, metformin and GLP-1 receptor agonist only It is not properly controlled, the SGLT2 inhibitor is selected from the group consisting of empagliflozin, canagliflozin, dapagliflozin and ertugliflozin; the oral antidiabetic agent is selected from the group consisting of a biguanide, a thiazolidinedione, an alpha-glucosidase inhibitor, a glinide, and a sulfonylurea; The combination pharmaceutical, wherein the GLP-1 receptor agonist is selected from the group consisting of lixisenatide, exenatide, dulaglutide, liraglutide, and albiglutide.

2. The pharmaceutical combination for use according to claim 1, wherein the pharmaceutical preparation (a) comprises insulin glargine at a concentration of 100 to 500 U / mL.

3. 3. The pharmaceutical combination for use according to claim 1 or 2, wherein the pharmaceutical preparation (a) comprises insulin glargine in a concentration of 100 U / mL.

4. The pharmaceutical combination for use according to any one of claims 1 to 3, wherein the pharmaceutical preparation (a) comprises lixisenatide in a concentration of 20 to 150 μg / ml.

5. The pharmaceutical combination for use according to any one of claims 1 to 4, wherein the pharmaceutical preparation (a) comprises lixisenatide in a concentration of 33 μg / mL, 50 μg / mL or 100 μg / mL.

6. 6. The pharmaceutical combination for use according to any one of claims 1 to 5, wherein the pharmaceutical preparation (a) comprises insulin glargine in a concentration of 100 U / mL and lixisenatide in a concentration of 33 μg / mL, 50 μg / mL or 100 μg / mL.

7. The pharmaceutical combination for use according to any one of claims 1 to 6, wherein the patient to be treated is obese.

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