CN112516137A - Use of sitagliptin and derivatives thereof for the treatment of type 2 diabetes accompanied by lipid metabolism disorders - Google Patents

Abstract

The invention belongs to the technical field of medicines, and particularly relates to application of sitagliptin and derivatives thereof in treatment of type 2 diabetes accompanied with lipid metabolism disorder. The sitagliptin sodium not only can effectively control blood sugar, but also has a targeted effect on controlling blood fat, particularly lipid metabolism disorder (such as higher triglyceride level and lower high density lipoprotein cholesterol level) accompanied by diabetes, and can resist the problem of insulin resistance brought by statin treatment. The 48mg dose can achieve better blood sugar and blood fat reducing effects than the existing control treatment medicaments and 32 mg of sitagliptin sodium for the type 2 diabetes mellitus patients with abnormal lipid metabolism, and does not increase the risk of new side effects. From the clinical treatment perspective, the dosage of the cyglifloxaspool and the derivatives thereof is not less than 48mg, which is an ideal component in a combined treatment scheme aiming at diabetes patients with lipid metabolism disorder.

Description

Use of sitagliptin and derivatives thereof for the treatment of type 2 diabetes accompanied by lipid metabolism disorders

The present application claims priority from chinese patent application entitled "use of xigliac and derivatives thereof for the treatment of type 2 diabetes with lipid metabolism disorders" filed on 19/09.2019 with chinese patent office, application No. 201910889254.6, the entire contents of which are incorporated herein by reference.

Technical Field

The invention belongs to the technical field of medicines, and particularly relates to application of sitagliptin and derivatives thereof in treatment of type 2 diabetes accompanied with lipid metabolism disorder.

Background

Diabetes is the highest global incidence of chronic diseases, of which more than 90% are type 2 diabetes. Type 2 diabetes is a disease caused by environmental and genetic factors, and the main pathological mechanisms of the disease are the decline of the sensitivity of the body to insulin and the progressive reduction of the pancreatic islet function. Type 2 diabetic patients are often accompanied by metabolic syndromes such as hypertension and hyperlipidemia, in addition to abnormal rise of blood sugar. Diabetes-related complications are the leading cause of death in patients, 80% of which are due to cardiovascular complications, and current guidelines for clinical treatment of diabetes have evolved from simple glucose lowering in the past to glucose lowering and the comprehensive management of their complications.

More than 40% of diabetic patients are associated with lipid metabolism abnormalities that are characterized clinically by elevated plasma triglyceride levels, reduced high density lipoprotein levels, and elevated or maintained normal low density lipoprotein levels. The existing diabetes treatment medicines comprise biguanides, sulfonylureas, dipeptidyl peptidase 4 inhibitors, sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 analogues and thiazolidinediones besides insulin, and all of the medicines have the curative effect of controlling the blood sugar level. Other drugs, besides the thiazolidinediones pioglitazone, have no significant effect on blood lipid levels, particularly triglyceride levels.

Although low density lipoprotein cholesterol levels are the primary control criteria for primary prevention of cardiovascular risk, patients still have a high residual risk of cardiovascular disease even in the setting of statin therapy, where elevated triglyceride levels are an important pathological factor. Many clinical studies have demonstrated that increasing drugs that lower triglyceride levels, such as fibrates or high purity fish oil, over statins can further reduce the risk of atherosclerotic cardiovascular disease or overall cardiovascular death. The consensus of experts in prevention and treatment of type 2 diabetes mellitus complicated with dyslipidemia in China, 2017 (the division of fat metabolism in endocrinology of the Chinese medical society: the journal of Chinese endocrine metabolism, 2017,33(11):925 one of the formulas 936.) suggests that for type 2 diabetes mellitus patients with dyslipidemia, triglyceride levels are still high (more than or equal to 2.25mmo/L) under statin treatment, and fibrates or other lipid-lowering drugs are required to be added for prevention and control so as to reduce residual cardiovascular risk.

Because of the complex interplay between glycolipid metabolism, statin lipid lowering drugs increase insulin resistance and the risk of new onset diabetes, and some of the glucose lowering drugs adversely affect blood lipid levels, careful selection of clinical treatment regimens for diabetic patients with lipid metabolism disorders is required. At present, no medicine can be used alone to realize good control on blood sugar and blood fat abnormality, and reasonable combined treatment needs to be carried out according to the curative effect and the safety characteristics of different medicines.

Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor family and play a regulatory role in a variety of biological processes including glycolipid metabolism, inflammation, energy balance, and the like. The PPAR family includes three subtypes, PPAR α, γ, and δ. Activating PPAR γ can promote absorption and storage of free fatty acid in adipose tissue, reduce glucose output in liver, increase insulin sensitivity and glucose absorption and utilization in peripheral tissue, and thus lower plasma glucose level; activating PPAR alpha can promote oxidative decomposition of fatty acid in liver, muscle and other tissues, reduce triglyceride level in plasma and lipid accumulation in tissues, and simultaneously promote synthesis of apolipoprotein AI and AII by liver and increase plasma high density lipoprotein level; activation of PPAR δ promotes heat generation and energy conversion. Activation of all three PPAR subtypes has a reducing effect on inflammation in vivo (Vzquez-Carrera M.trends Endocrinol Metab.2016; 27(5):319-334.Gross B, Pawlak M, Lefebvre P, Staels B.Nat Rev Endocrinol.2017; 13(1): 36-49.). At present, different PPAR agonist drugs are respectively used for clinical treatment of type 2 diabetes mellitus or dyslipidemia, for example, PPAR gamma agonist thiazolidinedione drugs are used for treating diabetes mellitus as insulin sensitizers, and PPAR alpha agonist fibrate drugs are used for treating dyslipidemia. Currently, no drug effective in the treatment of type 2 diabetes accompanied by lipid metabolism disorder is approved for clinical treatment.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provide a treatment method capable of effectively treating type 2 diabetes accompanied with lipid metabolism disorder.

Although statins are the first choice for the lipid control in clinical treatment of type 2 diabetes with lipid metabolism abnormalities, patients still have significant residual risk of cardiovascular disease and need to be treated with additional drugs for combination therapy. Conventional hypoglycemic drugs have no significant effect on blood lipid levels, while statins and other hypolipidemic drugs do not contribute to blood glucose control.

A plurality of clinical tests prove that the different doses of the sitagliptin sodium can obviously reduce the blood sugar level of a type 2 diabetes patient, and the dose of 32 mg or more can achieve the blood sugar reduction curative effect which is comparable to the clinical existing therapeutic drugs. And the 48mg dosage can realize better blood sugar and blood fat reducing effects than the prior control treatment medicament and 32 mg of sitagliptin sodium for the type 2 diabetes mellitus patients with abnormal lipid metabolism, and does not increase the risk of new side effects. Therefore, the invention provides the application of the sitagliptin and the derivatives thereof in preparing the medicine for treating the type 2 diabetes accompanied with lipid metabolism disorder, wherein the dosage of the sitagliptin and the derivatives thereof is more than or equal to 48 mg.

Preferably, the sitagliptin and derivatives thereof are used in an amount of 48 mg.

It will be understood by those skilled in the art that the sitagliptin derivative includes stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystalline forms, amorphous forms of sitagliptin and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salt of sitagliptin carboxylic acid comprises sitagliptin sodium or sitagliptin potassium.

The lipid metabolism disorder includes, but is not limited to, an increase in plasma triglycerides compared to normal levels, a decrease in high density lipoprotein cholesterol compared to normal levels, and the like.

In some embodiments, the type 2 diabetes with lipid metabolism disorders is type 2 diabetes with lipid metabolism disorders with baseline levels of triglycerides of 2.25 mmoles/liter or more.

The invention has the beneficial effects that:

the sitagliptin and the derivatives thereof not only can effectively control blood sugar, but also have targeted effect on controlling blood fat, particularly lipid metabolism disorder (such as higher triglyceride level and lower high density lipoprotein cholesterol level) accompanied by diabetes, and can also solve the problem of insulin resistance caused by statin treatment. The 48mg dose can achieve better blood sugar and blood fat reducing effects than the existing control treatment medicaments and 32 mg of sitagliptin sodium for the type 2 diabetes mellitus patients with abnormal lipid metabolism, and does not increase the risk of new side effects. From the clinical treatment perspective, the dosage of the cyglifloxate and the derivatives thereof which is more than or equal to 48 mg/day is an ideal component in a combined treatment scheme aiming at diabetes patients with lipid metabolism disorder.

Detailed Description

The invention discloses an application of sitagliptin and derivatives thereof in treating type 2 diabetes accompanied with lipid metabolism disorder. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.

In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.

The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out according to conventional conditions or according to conditions recommended by the manufacturers. All percentages, ratios, proportions, or parts are by weight unless otherwise specified.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred embodiments and materials described herein are intended to be exemplary only.

Through clinical trials, the effects of different doses of sitagliptin sodium compared to placebo or positive control drug treatment on various blood glucose, blood lipids and other clinical indicators as well as safety of patients were compared in type 2 diabetic patients. The therapeutic use of sitagliptin sodium for type 2 diabetes and type 2 diabetes with lipid metabolism abnormalities was confirmed by the above experiments.

Example 1: the dosage of 8-24 mg/day of sitagliptin sodium is compared with the hypoglycemic effect of 30 mg/day of pioglitazone serving as a control drug

And (3) experimental design: the clinical trial adopts a multi-center, random and double-blind design, and uses 30 mg of pioglitazone as a control. The group subjects include type 2 diabetic patients who are newly diagnosed and still have poor blood sugar control after taking the hypoglycemic agent. The drug treatment time was 12 weeks.

The test process comprises the following steps: 224 patients actually enrolled in the trial received 8mg, 16 mg, 24 mg of cilastatin sodium tablets or 30 mg of pioglitazone tablets, respectively, 1 time a day for 12 consecutive weeks. The main curative effect index is the change of fasting blood sugar at week 12 and blood sugar level at 2 hours after meal compared with baseline, and the secondary curative effect index is the change of each index of insulin and blood fat.

And (3) test results: on the two main efficacy indexes of reducing fasting blood glucose and blood glucose 2 hours after meal, the sitagliptin sodium shows a dose-effect dependence relationship, but the action strength of the pioglitazone with the maximum dose of 24 mg does not reach 30 mg. The overall safety of the various doses of sitagliptin sodium and the control drug was good with no significant difference. The test results suggest that dosage levels of cilastatin sodium up to 24 mg may have insufficient drug exposure and fail to achieve the level of therapeutic efficacy of the positive control drug.

Example 2: the dosage of 32-48 mg/day of sitagliptin sodium is compared with the hypoglycemic effect of 30 mg/day of pioglitazone serving as a control drug

And (3) experimental design: the clinical test adopts a multi-center, random and double-blind design, takes 30 mg of pioglitazone as a contrast, and is used for the group of type 2 diabetes patients without hypoglycemic drug treatment. Patients received 32 mg, 40 mg and 48mg of cilastatin sodium tablets or 30 mg of pioglitazone tablets, respectively, once daily for 16 weeks.

The test process comprises the following steps: the experiment actually included 200 patients. The primary efficacy observation index is the change of the glycated hemoglobin level from the baseline at 16 weeks, and the secondary efficacy observation index is the change of fasting blood glucose, blood glucose 2 hours after meal, fasting insulin and the like from the baseline at 16 weeks. The results are shown in Table 1.

TABLE 1 comparison of blood glucose and glycated hemoglobin levels at baseline and 16 weeks post-treatment in four treatment groups

Note: the comparison before and after treatment has obvious difference (P is less than 0.05); there were no statistical differences (P > 0.05) compared between treatment groups.

And (3) test results: the sitagliptin sodium tablet has a remarkable effect of reducing the glycosylated hemoglobin level of a type 2 diabetic within a dosage range of 32-48 mg, and the strength of the tablet is equivalent to the dosage of 30 mg of pioglitazone. Within the range of the tested dose, each dose of the sitagliptin sodium also has obvious effect of reducing fasting blood sugar and 2h blood sugar after meal, and the effect is equivalent to the dose of 30 mg of the pioglitazone tablet. In the aspect of safety, the dose of the sitagliptin sodium is equivalent to 30 mg of pioglitazone, and the sitagliptin sodium has better tolerance and drug compliance. The content of the sitagliptin in 32 mg reaches the blood sugar reduction curative effect level of the positive control drug, the curative effect is not further remarkably improved by higher dose, and 32 mg is the lowest dose of the clinical blood sugar reduction curative effect generated by the sitagliptin.

Example 3: safety of clinical efficacy of sitagliptin sodium 32 and 48 mg/day dose compared with control drug sitagliptin 100 mg and placebo

And (3) experimental design: the method is divided into two clinical trials, both adopt multi-center, random and double-blind designs, and respectively use 100 mg of sitagliptin or placebo as treatment control, patients WHO are grouped are type 2 diabetes patients meeting diabetes diagnosis standards issued by the World Health Organization (WHO)1999, and the glycosylated hemoglobin level is still more than or equal to 7.5% and less than or equal to 10.0% after life style dry prognosis of diet, exercise and the like.

The test process comprises the following steps: 1. placebo controlled trial, 535 patients received 32 mg (167), 48mg (166) or similar placebo tablets (202), respectively, of sitagliptin sodium tablets, once daily; after 24 weeks of continuous dosing, patients taking placebo were randomized again and given either 32 mg (85) or 48mg (77) of sitagliptin sodium, respectively, and patients in the former sitagliptin sodium treatment group were maintained on the original regimen and all patients continued to treatment for 52 weeks. 2. Sitagliptin control test, a total of 739 patients received 32 mg (245 cases), 48mg (246 cases) or 100 mg (248 cases) of sitagliptin sodium tablets, respectively, and were taken once a day for 24 weeks.

The main efficacy indicators for both trials were the change in glycated hemoglobin levels after 24 weeks of treatment from baseline. Secondary efficacy indices included glycated hemoglobin level changes from baseline at 12 and 52 weeks (placebo-controlled trial); 12. change in indices such as fasting blood glucose, postprandial blood glucose, fasting insulin, various blood lipids (free fatty acids, triglycerides, cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, etc.) from baseline at 24 weeks and 52 weeks (placebo-controlled test); and the standard-reaching rate of blood sugar reduction and the like. The safety index includes various safety events, physical examination changes (weight, waist circumference, etc.), blood pressure, clinical laboratory examination index, etc. The results are shown in Table 2.

TABLE 2 comparison of baseline changes in blood glucose and glycated hemoglobin levels after 24 weeks of treatment with sitagliptin and control in two trials

Note: significant difference compared to placebo treatment (P < 0.05); there was no statistical difference in # versus sitagliptin treatment (P > 0.05); # was significantly different (P <0.05) compared to sitagliptin treatment.

And (3) test results: the sitagliptin sodium tablet has the dose range of 32-48 mg, has the effect of reducing the blood sugar, is similar to the examples 1 and 2, and has the trend of increasing the blood sugar reducing effect from the dose of 32 mg to 48mg but has no statistical difference. On the two secondary efficacy indexes of fasting blood glucose and postprandial blood glucose reduction, the efficacy of 48mg of sitagliptin is remarkably stronger than that of the existing clinical treatment drug sitagliptin, but on the main efficacy index of reducing the glycosylated hemoglobin level, two doses of sitagliptin are equivalent to that of sitagliptin but have no remarkably better efficacy, and no remarkable difference exists between the two doses of sitagliptin (Table 2). The tolerability of the two doses of sitagliptin sodium was good, with no significant difference in overall adverse event incidence from placebo and the positive drug sitagliptin.

Diabetes is an independent risk factor for atherosclerotic cardiovascular disease, with over 40% of diabetic patients being associated with abnormal lipid metabolism, which is clinically characterized by high plasma triglyceride levels, low high density lipoprotein levels, high low density lipoprotein levels, or in the normal range. For this group of patients, there is a high risk of residual cardiovascular disease even in the context of statin therapy. The consensus among experts in the prevention and treatment of type 2 diabetes combined with dyslipidemia in china (2017 edition) indicates that patients with triglyceride levels still higher than 2.25 mmol/l on the basis of statin therapy should be treated with drugs that lower triglycerides. On the other hand, higher levels of triglycerides can also reduce the therapeutic effect of hypoglycemic drugs on glycemic control.

Of the patients of example 3, approximately 30% had higher baseline triglyceride levels (≧ 2.25 mmol/L), as classified by baseline triglyceride levels of 2.25 mmol/L as the threshold criteria, and these patients had not only higher triglyceride levels but also lower HDL cholesterol levels than others, with slightly higher total cholesterol levels but no significant difference or even lower LDL cholesterol levels, consistent with the clinical pathology of typical type 2 diabetic patients with lipid metabolism abnormalities. The results are shown in Table 3.

TABLE 3 comparison of baseline levels of various blood lipid indicators for patients with baseline levels of different triglycerides

In two groups of patients with different baseline levels of triglycerides, the level of efficacy of each treatment group in lowering glycated hemoglobin and fasting and postprandial blood glucose for patients with lower baseline levels of triglycerides (<2.25 mmol/l) was substantially the same as for the entire population; however, for patients with higher baseline triglyceride levels (≧ 2.25 mmole/l), either placebo, 100 mg sitagliptin or 32 mg sitagliptin sodium, their efficacy for glycated hemoglobin and fasting and postprandial blood glucose lowering was significantly worse than for the entire population, indicating that this group of patients responded poorly to conventional therapy. However, the effect of 48mg of sitagliptin in lowering blood glucose in patients with higher baseline level of triglycerides was not different from that in the whole population or patients with lower baseline level of triglycerides, and the effect of lowering blood glucose was not affected by the baseline level of triglycerides. The results are shown in Table 4.

TABLE 4 comparison of the efficacy of sitagliptin and control treatment on lowering blood glucose and glycated hemoglobin levels in patients with different baseline triglyceride levels

Note: statistical difference compared to placebo group (p < 0.05); the # vs sitagliptin group had statistical differences (p <0.05)

The two doses of sitagliptin sodium were consistent with placebo and the positive control drug sitagliptin in overall safety with no significant difference, but sitagliptin was slightly higher in edema and weight gain events than the two control treatments. The overall safety of different doses of sitagliptin sodium in patients with different baseline levels of triglycerides, which do not carry a new risk of side effects for clinical use of sitagliptin sodium, is consistent with the profile in all patients. The results are shown in Table 5.

Table 5 comparison of overall safety profile of sitagliptin sodium and control treatment in patients with different baseline levels of triglycerides

For patients with type 2 diabetes, the sitagliptin sodium has a dose-dependent hypoglycemic effect, and under the dose of 32 mg once a day, the sitagliptin sodium can achieve the curative effect equivalent to that of the existing clinical hypoglycemic medicament. For patients with lipid metabolism disorder, the curative effect response of the patients to conventional blood sugar reduction treatment is reduced, and the 48-mg dose of sitagliptin sodium can further promote the blood sugar reduction curative effect by reducing the blood fat, particularly the triglyceride level, so that the stronger blood sugar reduction curative effect is realized, and meanwhile, the comprehensive advantage is brought to the reduction of cardiovascular residual risk.

Based on the existing evidence, the application potential of the sitagliptin for treating the type 2 diabetes is shown, and particularly for type 2 diabetes patients with abnormal lipid metabolism, the sitagliptin with the dosage of 48mg and above can provide better comprehensive curative effect compared with the conventional treatment.

Claims (6)

1. Use of sitagliptin and derivatives thereof in the preparation of a medicament for the treatment of type 2 diabetes accompanied by lipid metabolism disorders, wherein the amount of the sitagliptin and derivatives thereof is not less than 48 mg.

2. Use according to claim 1, characterized in that the amount of sitagliptin and its derivatives is 48 mg.

3. Use according to claim 1 or 2, characterized in that the sitagliptin derivative comprises a stereoisomer, a geometric isomer, a tautomer, a solvate, a metabolite, a crystalline form, an amorphous form of sitagliptin and pharmaceutically acceptable salts thereof.

4. The use according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt of sitagliptin comprises sitagliptin sodium or sitagliptin potassium.

5. The use according to any one of claims 1 to 4, wherein the lipid metabolism disorder is an increase in plasma triglycerides compared to normal levels or a decrease in high density lipoprotein cholesterol compared to normal levels, or the like.

6. The use according to any one of claims 1 to 5, wherein the type 2 diabetes mellitus accompanied by lipid metabolism disorders is type 2 diabetes mellitus accompanied by lipid metabolism disorders with a baseline level of triglycerides of 2.25 mmol/l or more.