Method for reducing or preventing cardiovascular events in patients with type II diabetes
阅读说明：本技术 用于减少或预防患有ii型糖尿病的患者中的心血管事件的方法 (Method for reducing or preventing cardiovascular events in patients with type II diabetes ) 是由 N.R.罗森塔尔 D.K.韦斯 于 2018-06-11 设计创作，主要内容包括：本发明公开了用于减少、预防或减慢心血管风险因素和/或心血管疾病的进程的方法,所述方法包括施用卡格列净。(Methods for reducing, preventing, or slowing the progression of cardiovascular risk factors and/or cardiovascular disease comprising administering canagliflozin are disclosed.)
1, a method for reducing or preventing or more cardiovascular events comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin;
wherein the patient in need thereof is a patient diagnosed with type II diabetes and wherein the patient further exhibits symptoms of or is diagnosed with symptoms of or is diagnosed with one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
2, a method for reducing or preventing or more Major Adverse Cardiac Events (MACEs) comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin;
wherein the patient in need thereof is a patient diagnosed with type II diabetes and wherein the patient further exhibits symptoms of or is diagnosed with symptoms of or is diagnosed with one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
3. The method of claim 1 or 2, wherein the measured HbA1c of the patient diagnosed with type II diabetes is in the range of ≥ 7.0% and ≤ 10.5%.
4. The method of of any one of claims 1-3, wherein the patient is also diagnosed with microalbuminuria or macroalbuminuria.
5. The method of of any one of claims 1-3, wherein the or more cardiovascular risk factors are selected from the group consisting of obesity, hypertension, hyperlipidemia, hypertriglyceridemia, microalbuminuria and macroalbuminuria.
6. The method of of any one of claims 1-4, wherein said or more cardiovascular risk factors are selected from the group consisting of obesity, hypertension, hyperlipidemia, and hypertriglyceridemia.
7. The method of of any one of claims 1-6, wherein the cardiovascular disease is selected from the group consisting of a history of non-fatal myocardial infarction, a history of non-fatal stroke, peripheral arterial disease, hypertensive heart disease, ischemic heart disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease, arrhythmia (other than sinus tachycardia), cardiomyopathy, angina, heart failure, and coronary valve disease.
8. The method of of any one of claims 1-6, wherein the cardiovascular risk or cardiovascular disease is or more selected from the group consisting of heart failure, coronary artery disease, cerebrovascular disease, peripheral vascular disease, and hypertension.
9. The method of of any one of claims 1-7, wherein the cardiovascular event is selected from the group consisting of cardiovascular hospitalization, non-fatal myocardial infarction, non-fatal ischemia or stroke, and cardiovascular mortality.
10. The method of of any of claims 1-9, wherein the canagliflozin is administered in an amount ranging from about 50mg to about 500 mg.
11. The method of of any of claims 1-9, wherein the canagliflozin is administered in an amount ranging from about 100mg to about 300 mg.
12. The method of claim 1 or 2, which is safe and effective.
13. The method of according to any one of claims 1-9, wherein the method reduces the patient's risk ratio (HR) for developing a cardiovascular event selected from the group consisting of cardiovascular hospitalization, non-fatal myocardial infarction, non-fatal stroke, and cardiovascular mortality to a value in the range of about 0.95 to about 0.60.
14. The method of any one of claims 1-9, wherein the method reduces the predicted severity of an adverse cardiovascular event or reduces the predicted mortality due to an adverse cardiovascular event, or reduces the progression of cardiovascular disease.
15. The method of any one of claims 1-9, wherein the method increases the predicted life expectancy of the subject, the predicted time period between adverse cardiovascular events, or the effectiveness of cardiovascular intervention on the subject.
16. The method of of any one of claims 1-9, wherein the method increases the time before th occurrence of or more events selected from the group consisting of cardiovascular death, non-fatal myocardial infarction, stroke, non-fatal hospitalization, and cardiovascular mortality.
17. The method of claim 1 or 2, wherein the patient, when treated, has or more of a) a high likelihood of an existing cardiovascular disease or cardiovascular disease, b) congestive heart failure, c) a family history of cardiovascular disease, d) current smoking, e) is genetically predisposed to cardiovascular disease, f) has or has suffered from an arrhythmia directly, g) has or has suffered from atrial fibrillation, ventricular fibrillation, or tachyarrhythmia directly, h) does not have sinus tachycardia, i) has unstable angina, j) has hypertension, k) has had or has an increased risk of stroke, l) has an aneurysm, and/or m) has high triglycerides, high LDL, and/or low HDL.
18. The method of claim 1 or 2, wherein the patient has a confirmed diagnosis of cardiovascular disease or a high likelihood of cardiovascular disease, and further wherein the patient has at least of a) a recorded history of myocardial infarction, b) a history of coronary revascularization, c) a history of carotid or peripheral revascularization, d) angina with ischemic changes, e) ECG changes on a fractionated exercise test, f) a positive cardiac image examination, g) ankle brachial index <0.9, and/or h) > 50% coronary, carotid or lower limb arterial stenosis.
19. The method of claims 1-2, wherein the patient has or more of (a) myocardial infarction, (b) a history of angina pectoris, (c) a history of cerebrovascular disease, (d) a history of stroke, (e) a history of tachycardia other than sinus tachycardia, or (f) planned bariatric surgery, cardiac surgery, or coronary angioplasty.
20, methods of treatment as described herein.
Technical Field
Methods for reducing, preventing or slowing the progression of cardiovascular risk factors and/or cardiovascular disease comprising administering canagliflozin are disclosed.
Background
Cardiovascular disease (CVD) is a -class disease involving the heart or blood vessels.
There are many cardiovascular diseases involving blood vessels. They are called vascular diseases and include: coronary artery disease (also known as coronary heart disease and ischemic heart disease, including but not limited to angina pectoris, myocardial infarction, etc.), peripheral artery disease (disease of blood vessels supplying blood to arms and legs), cerebrovascular disease (disease of blood vessels supplying blood to the brain, including stroke or ischemia), renal artery stenosis, aortic aneurysm.
There are also many cardiovascular diseases involving the heart, including cardiomyopathy (heart muscle disease), hypertensive heart disease (heart disease secondary to high blood pressure or hypertension), heart failure (clinical syndrome due to the heart not being able to supply sufficient blood to the tissues to meet its metabolic requirements), pulmonary heart disease (failure of the respiratory system to the right of the heart), cardiac dysrhythmia (arrhythmia), inflammatory heart disease, endocarditis (lining of the heart, endocardium, most commonly inflammation of the heart valves), inflammatory cardiac hypertrophy, myocarditis (inflammation of the muscle of the heart), valvular heart disease, congenital heart disease (malformation of the heart structure at birth), rheumatic heart disease (damage to the heart muscle and valves due to rheumatic fever).
The underlying pathogenesis varies from disease to disease, and there are many cardiac risk factors, age, gender, smoking, lack of physical exercise, excessive alcohol consumption, unhealthy diet, obesity, familial history of genetic and cardiovascular disease, elevated blood pressure (hypertension), elevated blood glucose (including type II diabetes), elevated blood cholesterol (hyperlipidemia), psychosocial factors, poverty and low educational levels, and air pollution.
Coronary artery disease, stroke, and peripheral artery disease are implicated in atherosclerosis, which in turn may be caused by hypertension, smoking, diabetes, lack of exercise, obesity, high blood cholesterol, poor diet, and excessive alcohol consumption. Hypertension resulted in 13% of CVD deaths, while tobacco resulted in 9% of CVD deaths, diabetes resulted in 6% of CVD deaths, lack of exercise resulted in 6% of CVD deaths and obesity resulted in 5% of CVD deaths.
Existing cardiovascular disease or previous cardiovascular events, such as heart attack or stroke, are the most powerful predictors of future cardiovascular events. Age, gender, smoking, blood pressure, blood lipids, and diabetes are important predictors of future cardiovascular disease in people known not to have cardiovascular disease. These measures, and sometimes others, can be combined into a composite risk score to estimate the risk of an individual for future cardiovascular disease. There are many risk scores, but their respective advantages are at issue. Other diagnostic tests and biomarkers are still under evaluation, but these tests and biomarkers currently lack clear evidence to support their routine use. They include family history, coronary calcification score, high sensitivity C-reactive protein (hs-CRP), ankle brachial blood pressure index, lipoprotein subclasses and particle concentrations, lipoprotein (a), apolipoproteins a-I and B, fibrinogen, white blood cell count, homocysteine, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and markers of renal function. Hyperphosphatemia is also associated with increased risk.
It is estimated that 90% of CVD is preventable. Preventing atherosclerosis from affecting risk factors is improved by: healthy diet, exercise, smoking avoidance and alcohol restriction. It is also beneficial to treat risk factors such as hypertension, blood lipids, and diabetes. The effect of using aspirin in otherwise healthy persons has beneficial effects that are not yet clear.
Cardiovascular disease is a leading cause of death worldwide. This is true in all regions of the world, except in africa. Since cardiovascular disease caused 12.3 million deaths (25.8%) in 1990, cardiovascular disease caused 17.9 million deaths (32.1%) in 2015. Coronary artery disease and stroke account for 80% of CVD deaths in the male population and 75% of CVD deaths in the female population. Most cardiovascular diseases affect the elderly. In the united states, 11% of the population between 20 and 40 years of age suffers from CVD, while 37% of the population between 40 and 60 years of age, 71% of the population between 60 and 80 years of age, and 85% of the population over 80 years of age suffer from CVD.
There remains a need for additional safe and effective therapies for patients with type II diabetes and concomitant or comorbid cardiovascular disease or risk of cardiovascular disease.
Disclosure of Invention
The present invention relates to a method for reducing or preventing one or more cardiovascular events, the method comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin;
wherein the patient in need thereof is a patient diagnosed with type II diabetes and wherein the patient further exhibits symptoms of or is diagnosed with symptoms of or is diagnosed with one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
The present invention relates to a method for reducing or preventing one or more MACEs (major adverse cardiovascular events), the method comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin;
wherein the patient in need thereof is a patient diagnosed with type II diabetes and wherein the patient further exhibits symptoms of or is diagnosed with symptoms of or is diagnosed with one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
The present invention also relates to methods of treating patients having an increased risk of Major Adverse Cardiovascular Events (MACEs), the method comprising selecting a therapy for a patient having an increased risk of MACEs and administering a therapeutically effective amount of canagliflozin to the patient, wherein the patient having an increased risk of MACEs is also diagnosed with type II diabetes and wherein the therapeutically effective amount of canagliflozin is sufficient to reduce the increased risk of MACEs.
The present invention also relates to a method for reducing or preventing one or more cardiovascular events, the method comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin;
wherein the patient in need thereof is a patient diagnosed with type II diabetes and wherein the patient further exhibits symptoms of or is diagnosed with symptoms of or is diagnosed with one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
And wherein the cardiovascular event (to be reduced or prevented) is selected from the group consisting of cardiovascular hospitalization, non-fatal myocardial infarction, non-fatal ischemia or stroke, and cardiovascular mortality (including but not limited to sudden cardiac death).
The present invention also relates to a method for reducing or preventing one or more cardiovascular events, the method comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin;
wherein the patient in need thereof is a patient diagnosed with type II diabetes, wherein the patient is also diagnosed with microalbuminuria (ACR ≧ 30mg/g and ≤ 300mg/g) or macroalbuminuria (ACR >300mg/g), and wherein the patient further exhibits symptoms of or is diagnosed with one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases;
and wherein the cardiovascular event (to be reduced or prevented) is selected from the group consisting of cardiovascular hospitalization, non-fatal myocardial infarction, non-fatal ischemia or stroke, and cardiovascular mortality (including but not limited to sudden cardiac death).
Drawings
Fig. 1 shows a flow chart detailing a pre-established hypothesis testing protocol for assessing cardiovascular outcome.
FIG. 2 shows the effect of canagliflozin on a) glycated hemoglobin, b) body weight, c) systolic blood pressure and d) diastolic blood pressure.
Figure 3 shows the effect of canagliflozin on cardiovascular, renal, hospitalization and death outcomes.
Fig. 4a) to 4h) show the effect of canagliflozin on cardiovascular and renal fatalities, more specifically fig. 4a) shows the effect of canagliflozin on cardiovascular death, non-lethal stroke or non-lethal myocardial infarction, fig. 4b) shows the effect of canagliflozin on cardiovascular death, fig. 4c) shows the effect of canagliflozin on non-lethal stroke, fig. 4d) shows the effect of canagliflozin on non-lethal myocardial infarction, fig. 4e) shows the effect of canagliflozin on hospitalized heart failure, fig. 4f) shows the effect of canagliflozin on total mortality, fig. 4g) shows the effect of canagliflozin on the progression of proteinuria, and fig. 4h) shows the effect of canagliflozin on renal complex disease.
Detailed Description
The present invention relates to a method for reducing or preventing one or more cardiovascular events, the method comprising administering to a patient in need thereof a therapeutically effective amount of canagliflozin, as described in more detail herein.
In certain embodiments, the invention relates to methods for reducing or preventing cardiovascular events, cardiovascular hospitalizations, non-fatal myocardial infarction, non-fatal ischemic events or stroke, or cardiovascular mortality.
In certain embodiments, the invention relates to methods for preventing cardiovascular hospitalization of at least about 2%, 3%, 5%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% of patients diagnosed with type II diabetes and one or more concomitant or co-morbid cardiovascular risk factors or cardiovascular diseases.
In certain embodiments, the invention relates to methods for preventing at least about 2%, 3%, 5%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% of non-fatal myocardial infarction in patients diagnosed with type II diabetes and or one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
In certain embodiments, the invention relates to methods for preventing at least about 2%, 3%, 5%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% of non-fatal ischemic events or strokes in patients diagnosed with type II diabetes and or one or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
In certain embodiments, the invention relates to methods for preventing at least about 2%, 3%, 5%, 10%, 12%, 15%, 18%, 20%, 22%, 25%, 28%, or 30% of cardiovascular deaths in patients diagnosed with type II diabetes and or more concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
In certain embodiments, the present invention relates to safe and effective methods for treating a patient having type II diabetes, the method comprising administering to the patient a therapeutically effective amount of canagliflozin.
In certain embodiments, the present invention relates to methods of reducing the risk of cardiovascular hospitalization, cardiovascular event, or cardiovascular mortality in a patient, the method comprising administering to the patient a therapeutically effective amount of canagliflozin;
wherein the patient is diagnosed with type II diabetes mellitus, and wherein the patient is also diagnosed with or exhibits symptoms of or more cardiovascular risk factors selected from the group consisting of hypertension (hypertension or highblood pressure) (e.g., high systolic pressure, high diastolic pressure, or blood pressure greater than 140/90mmHg, preferably greater than about 145/95 mmHg), high cholesterol (hyperlipidemia), high LDL, low HDL levels, high triglycerides, obesity (as defined by BMI, e.g., greater than 30, preferably morbid obesity defined by BMI greater than 40), cardiovascular disease (e.g., previous myocardial infarction, angina, heart failure, stroke), microalbuminuria (as defined, e.g., by ACR ≧ 30mg/g and ≦ 300mg/g), macroalbuminuria (as defined, e.g., by ACR >300mg/g), peripheral vascular disease (e.g., carotid stenosis, femoral stenosis), cardiovascular disease family or past smoking, and gender group of males.
In certain embodiments, the present invention relates to methods for preventing or reducing cardiovascular events in a heart failure (including grade I to IV, preferably grade II to IV, more preferably grade III or IV) patient, wherein the heart failure is indicated by or more of:
a) history or current symptoms of congestive heart failure;
b) least tiring symptoms of heart failure;
c) the patient is hospitalized for heart failure;
d) patients were hospitalized for NYHA class IV heart failure;
e) patients were hospitalized for NYHA grade III heart failure;
f) patients were hospitalized for NYHA class II heart failure;
g) patients were hospitalized for NYHA class I heart failure; or
h) Patients are hospitalized for heart failure, with current dyspnea, requiring hospitalization or intravenous therapy to treat heart failure.
In certain embodiments, the present invention relates to methods for preventing or reducing cardiovascular events in a patient suffering from congestive heart failure, wherein the congestive heart failure is:
a) congestive heart failure under stable hemodynamic conditions;
b) congestive heart failure defined as a decrease in left ventricular ejection fraction to below 0.35 under stable hemodynamic conditions;
c) congestive heart failure, defined as NYHA class I under stable hemodynamic conditions;
d) congestive heart failure, defined as NYHA class II under stable hemodynamic conditions;
e) congestive heart failure defined as NYHA class III under stable hemodynamic conditions; or
f) Congestive heart failure, defined as NYHA class IV under stable hemodynamic conditions.
In certain embodiments, the present invention relates to methods for preventing or reducing cardiovascular events in a patient diagnosed with type II diabetes and with or without concomitant or comorbid congestive heart failure (including, e.g., NYHA class IV, NYHA class III, NYHA class II, and NYHA class I).
In certain embodiments, the present invention relates to a method for preventing or reducing a cardiovascular event in a patient with heart failure under unstable hemodynamic conditions, wherein heart failure under unstable hemodynamic conditions can be defined by any of:
a) worsening of symptoms of heart failure at rest or with minimal exertion;
b) history or current symptoms of congestive heart failure at rest;
c) symptoms of heart failure that are least tiring within the past months, i.e., months prior to initiating treatment or hospitalization for heart failure;
d) NYHA class IV;
e) NYHA class III;
f) NYHA II grade;
g) NYHA I class; or
h) Dyspnea currently requires hospitalization or intravenous therapy to treat heart failure.
In certain embodiments, the invention relates to methods of advantageously modulating (or improving) or more diagnostic indices that predict major adverse cardiovascular events a plurality of such diagnostic indices exist, including, for example, blood pressure, plating tests, troponin tests, fluid volume, cardiac output, ejection fraction, cardiomyopathy, cardiac hypertrophy, ECG abnormalities, external oxygen dependence, diuretic requirements, hospitalization for cardiac insufficiency, unstable plaque, angina pectoris, arrhythmia, Q-T intervals, hypertriglyceridemia, high LDL or low HDL, and the like.
In certain embodiments, the methods of the invention result in a patient's risk ratio (HR) (comparing risk in treatment group to risk in placebo group according to industry standards) in the range of about 1.0 to about 0.50, or any amount or range therein, preferably in the range of about 0.90 to about 0.60, more preferably in the range of about 0.90 to about 0.75, more preferably in the range of about 0.85 to about 0.65, e.g., less than about 1.0, 0.99, 0.98, 0.97, 0.96, 0.95, 0.94, 0.93, 0.92, 0.91, 0.90, 0.88, 0.87, 0.84, 0.85, 0.82, 0.83, 0.82, 0.83, 0.85, 0.82, 0.83, 0.82, 0.85, 0.82, 0.80, 0.82, 0.85, 0.80, 0, 0.80, 0.79, 0.78, 0.77, 0.76, 0.75, 0.74, 0.73, 0.72, 0.71, 0.70, 0.69, 0.68, 0.67, 0.66, 0.65, 0.64, 0.63, 0.62, 0.61, 0.60, 0.59, 0.58, 0.57, 0.56, 0.55, 0.54, 0.53, 0.52, 0.51, or 0.50 or any range defined by any two of the foregoing values.
In certain embodiments, the improvements provided by the methods of the invention (e.g., reducing the risk of MACEs, reducing the severity of a predicted adverse cardiovascular event, reducing mortality due to a predicted adverse cardiovascular event, reducing the progression of cardiovascular disease in a patient, increasing the predicted expected life span of a patient, or increasing the predicted time period before the next adverse cardiovascular events occur, increasing the effectiveness of a cardiovascular intervention on a patient, or beneficially adjusting a diagnostic index that predicts a major adverse cardiovascular event) can last for a period of after discontinuing administration of canagliflozin in certain embodiments, the period of time is, or is at least, about 1, 2, 3, 4, 5, or 6 months, or is 0.5, 1, 2, 3, 4, or 5 years, or is between 1 to 6 months, 1 month to 1 year, 4 months to 2 years, or 6 months to 5 years.
In certain embodiments of the invention, the improvements provided by the methods of the invention are seen in the treated patient population (e.g., reducing the risk of MACEs, reducing the severity of a predicted adverse cardiovascular event, reducing mortality due to a predicted adverse cardiovascular event, reducing the progression of cardiovascular disease in a patient, increasing the predicted expected life span of a patient, or increasing the predicted time period before the next occurrences of an adverse cardiovascular event, increasing the effectiveness of a cardiovascular intervention on a patient, or beneficially modulating a diagnostic index that predicts a major adverse cardiovascular event) as compared to a control population, e.g., between patients receiving canagliflozin and patients receiving placebo.
In certain embodiments of the invention, the patient in need thereof is a patient diagnosed with type II diabetes and further exhibits symptoms of or is diagnosed with symptoms of or with multiple concomitant or comorbid cardiovascular risk factors or cardiovascular diseases.
In certain embodiments of the invention, the measured HbA1c of a patient diagnosed with type II diabetes is in the range of ≥ 7.0% and ≤ 10.5%.
In certain embodiments of the invention, the patient is over the age of 30 years and has a history of at least non-fatal myocardial infarction, non-fatal stroke, or symptomatic atherosclerotic vascular disease. In certain embodiments of the invention, the patient is over the age of 50 and exhibits or is at risk for two or more vascular diseases (including but not limited to, high urinary albumin: creatinine ratio).
In certain embodiments of the invention, or more cardiovascular risk factors are independently selected from the group consisting of hypertension (e.g., high systolic pressure, high diastolic pressure, or blood pressure greater than about 145/95 mmHg), high cholesterol (hyperlipidemia), high LDL, low HDL levels, high triglycerides, obesity (morbid obesity as defined by, for example, a BMI greater than 30, preferably a BMI greater than 40), cardiovascular disease (e.g., previous myocardial infarction, angina pectoris, heart failure, stroke), microalbuminuria (as defined, for example, by ACR ≧ 30mg/g and ≦ 300mg/g), macroalbuminuria (as defined, for example, by ACR >300mg/g), peripheral vascular disease (e.g., carotid stenosis, femoral stenosis), or current or past smoking, family history of cardiovascular disease, or male gender.
In certain embodiments of the invention, the measured eGFR of the patient is greater than about 30mL/min/1.73m2Preferably greater than about 60mL/min/1.73m2. In certain embodiments of the invention, the measured eGFR of the patient is less than about 90mL/min/1.73m2And greater than about 60mL/min/1.73m2。
In certain embodiments of the invention, the cardiovascular disease is selected from the group consisting of heart failure (including but not limited to congestive heart failure), cardiac arrhythmias, atrial fibrillation, ventricular fibrillation, tachyarrhythmias (non-sinus tachycardia), angina (including but not limited to unstable angina), and hypertension.
In certain embodiments of the invention, the patient has a history of or more coronary bypass surgeries or coronary stent implantations in certain embodiments of the invention, the patient has a history of or more venous thromboembolic events or pulmonary embolisms in certain embodiments of the invention, the patient has a history of or more non-lethal strokes in certain embodiments of the invention, the patient has a history of or more non-lethal myocardial infarctions in certain embodiments of the invention.
In certain embodiments of the invention, the measured ACR of the patient is ≧ 30mg/g and ≦ 300mg/g (i.e., the patient was diagnosed for microalbuminuria). In certain embodiments of the invention, the measured ACR of the patient is >300mg/g (i.e., the patient is diagnosed with a large amount of albuminuria).
In certain embodiments of the invention, the patient in need thereof is a patient diagnosed with type II diabetes, is also diagnosed with microalbuminuria (ACR ≧ 30mg/g and ≦ 300mg/g) or macroalbuminuria (ACR >300mg/g), and also exhibits symptoms of or is diagnosed with or more concomitant or co-morbid cardiovascular risk factors or cardiovascular diseases.
In certain embodiments of the invention, the patient has type II diabetes and is treated with or more of a) a high likelihood of existing cardiovascular disease or cardiovascular disease, b) congestive heart failure, c) a family history of cardiovascular disease, d) current smoking, e) a genetic predisposition to cardiovascular disease, f) having or direct arrhythmia, g) having or direct atrial fibrillation, ventricular fibrillation, or tachyarrhythmia, h) not having sinus tachycardia, i) having unstable angina, j) having hypertension, k) direct stroke or increased risk of stroke, l) having an aneurysm, and/or m) having high triglycerides, high LDL and/or low HDL.
In certain embodiments of the invention, a patient has a confirmed diagnosis of cardiovascular disease or a high likelihood of cardiovascular disease, and further, the patient has at least of a) a recorded history of myocardial infarction, b) a history of coronary revascularization, c) a history of carotid or peripheral revascularization, d) angina with ischemic changes, e) changes in ECG on a fractionated exercise test, f) a positive cardiac image examination, g) ankle brachial index <0.9, and/or h) > 50% coronary, carotid or lower limb arterial stenosis.
In certain embodiments of the invention, the patient has or more of (a) myocardial infarction, (b) a history of angina pectoris, (c) a history of cerebrovascular disease, (d) a history of stroke, (e) a history of tachycardia other than sinus tachycardia, or (f) scheduled bariatric surgery, cardiac surgery, or coronary angioplasty.
In certain embodiments, the methods described herein reduce the risk of a Major Adverse Cardiovascular Event (MACE).
In certain embodiments of the invention, the major adverse cardiovascular event is cardiovascular death, non-fatal myocardial infarction, arrhythmia, or non-fatal stroke. In certain embodiments of the invention, the major adverse cardiovascular event is cardiovascular death. In certain embodiments of the invention, cardiovascular death is caused by fatal myocardial infarction and/or stroke. In certain embodiments of the invention, the major adverse cardiovascular event is non-fatal stroke. In certain embodiments of the invention, the major adverse cardiovascular event is non-fatal myocardial infarction.
In certain embodiments of the invention, the method reduces the predicted severity of an adverse cardiovascular event. In certain embodiments of the invention, the method reduces the predicted mortality due to an adverse cardiovascular event. In certain embodiments of the invention, the method increases the predicted life expectancy of the subject. In certain embodiments of the invention, the method increases the predicted time period between adverse cardiovascular events. In certain embodiments of the invention, the method increases the effectiveness of the cardiovascular intervention in the subject. In certain embodiments of the invention, the method advantageously modulates a diagnostic index that is predictive of a major adverse cardiovascular event. In certain embodiments of the invention, the method reduces the progression of cardiovascular disease.
In certain embodiments of the invention, the adverse outcome is or more events selected from the group consisting of MACE (including CV death, non-fatal MI, stroke, fatal stroke, non-fatal stroke), non-fatal HUSA (hospitalization for unstable angina), coronary revascularization surgery, and/or total mortality.
In certain embodiments of the invention, the methods comprise increasing the time before occurrence of or more events selected from the group consisting of MACE (including CV death, non-fatal MI, stroke, fatal stroke, non-fatal stroke), non-fatal HUSA (hospitalization due to unstable angina), coronary revascularization surgery, and/or total mortality.
In certain embodiments, the methods of the invention reduce the predicted severity of an adverse cardiovascular event, or reduce the predicted mortality rate due to an adverse cardiovascular event, or reduce the progression of cardiovascular disease.
In certain embodiments, the methods of the invention increase the predicted life expectancy of a subject, the predicted time period between adverse cardiovascular events, or increase the effectiveness of a cardiovascular intervention in a subject.
In certain embodiments of the invention, the method reduces at least of the risk of or more Major Adverse Cardiovascular Events (MACEs) in the subject, the predicted severity of the adverse cardiovascular event, the predicted mortality due to the adverse cardiovascular event, and combinations thereof, wherein the reduction in risk, predicted severity, or predicted mortality is at least or at least about 2%, 3%, 5%, 8%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% relative to a subject at the same MACE risk level, predicted severity of the adverse cardiovascular event, or predicted mortality of the adverse cardiovascular event but not being treated by administration of canagliflozin.
In certain embodiments of the invention, the method is effective to reduce the progression of cardiovascular disease in a patient, wherein reducing the progression of cardiovascular disease is at least or at least about 2%, 3%, 5%, 8%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% less relative to a patient at the same level of cardiovascular disease progression but not being treated by administration of canagliflozin.
In certain embodiments of the invention, the method is effective to increase the predicted expected life span of the patient, or increase the predicted time period before the next occurrences of the adverse cardiovascular event, wherein the increase is at least or at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, 14 months, 16 months, 18 months, 20 months, or 24 months relative to a patient at the same risk level of MACE but not being treated by administration of canagliflozin.
In certain embodiments of the invention, the method increases the effectiveness of the cardiovascular intervention in the patient, wherein the increase is at least or at least about 2%, 3%, 5%, 8%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% increase relative to the expected effectiveness of the cardiovascular intervention in a patient receiving the same cardiovascular intervention at the same risk level of MACE but not being treated by administration of canagliflozin.
In certain embodiments of the invention, the method advantageously modulates a diagnostic index predictive of a major adverse cardiovascular event, wherein advantageously modulating is at least or at least about 2%, 3%, 5%, 8%, 10%, 12%, 15%, 20%, 25%, 30%, 35%, 40%, 45% or 50% relative to a diagnostic index predictive of a major adverse cardiovascular event in a patient at the same risk level of MACE but not treated by administration of canagliflozin.
Canagliflozin can be administered in any composition and according to any dosage regimen determined in the art, as long as treatment or prevention as described herein is desired.
The optimal dose (of canagliflozin) to be administered can be readily determined by one skilled in the art and will vary with, for example, the mode of administration, the strength of the formulation and the course of the condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust the dosage.
In certain embodiments, the present invention relates to methods for treating or preventing a cardiovascular event, wherein canagliflozin is administered at a dose ranging from about 25mg to about 500mg, preferably selected from about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, about 300mg and about 500 mg.
Definition of
As used herein, unless otherwise indicated, the term "canagliflozin" shall refer to a compound of formula (I-X)
Or a crystalline hemihydrate form of the compound of formula (I-X).
The compounds of formula (I-X) exhibit inhibitory activity against sodium-dependent glucose transporters such as, for example,
As used herein, the term "canagliflozin" shall also include a mixture of stereoisomers, or each pure or substantially pure isomer. In addition, the term "canagliflozin" shall include an intramolecular salt, hydrate, solvate or polymorph thereof.
In embodiments, the term "canagliflozin" shall refer to the crystalline hemihydrate form of the compound of formula (I-X), as described in WO 2008/069327, the disclosure of which is hereby incorporated by reference in its entirety.
As used herein, unless otherwise specified, the terms "treated," "treating," and the like shall include the management and care of a subject or patient (preferably a mammal, more preferably a human) for the purpose of combating a disease, condition, or disorder, and includes the administration of a compound of the invention to prevent the onset of symptoms or complications, alleviate symptoms or complications, or eliminate the disease, condition, or disorder.
As used herein, unless otherwise indicated, the terms "delay … … progression" and "slowing … … progression" shall include (a) delaying or slowing the development of or more symptoms or complications of a disease, condition, or disorder, (b) delaying or slowing the development of or more novel/additional symptoms or complications of a disease, condition, or disorder, and/or (c) delaying or slowing the progression of a disease, condition, or disorder to a later stage or more severe form of the disease, condition, or disorder.
As used herein, unless otherwise indicated, the terms "preventing," "prevention," and the like shall include (a) reducing the frequency of or more symptoms, (b) reducing the severity of or more symptoms, (c) delaying or avoiding the development of additional symptoms, and/or (d) delaying or avoiding the development of a disorder or condition.
One skilled in the art will recognize that where the present invention relates to a method of prevention, a subject in need thereof (i.e., a subject or patient in need of prevention) shall include any subject or patient (preferably a mammal, more preferably a human) who has experienced or exhibited at least symptoms of the disorder, disease or condition to be prevented.
The term "therapeutically effective amount" as used herein, means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
The term "euglycemia" is defined as the following condition: wherein the subject's fasting blood glucose concentration is within a normal range of greater than 70mg/dL (3.89mmol/L) and less than 100mg/dL (5.6mmol/L), and the 2 hour post-prandial blood glucose concentration is less than 140 mg/dL.
The term "hyperglycemia" is defined as the following condition: wherein the subject has a fasting blood glucose concentration above the normal range, greater than 100mg/dL (5.6 mmol/L).
The term "hypoglycemia" is defined as the following condition: wherein the subject's blood glucose concentration is below the normal range, in particular below 70mg/dL (3.89 mmol/L).
The term "postprandial hyperglycemia" is defined as the following condition: wherein the subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 200mg/dL (11.11 mmol/L).
The term "impaired fasting blood glucose" or "IFG" is defined as the following condition: wherein the subject's fasting blood glucose concentration or fasting serum glucose concentration is in the range of 100mg/dL to 125mg/dL (i.e., 5.6mmol/L to 6.9 mmol/L). A subject with "normal fasting plasma glucose" has a fasting plasma glucose concentration of less than 100mg/dl, i.e., less than 5.6 mmol/l.
The term "impaired glucose tolerance" or "IGT" is defined as the following conditions: wherein the subject has a 2 hour postprandial blood glucose or serum glucose concentration greater than 140mg/dL (7.78mmol/L) and less than 200mg/dL (11.11 mmol/L). Glucose tolerance abnormalities, i.e., 2 hours postprandial blood glucose or serum glucose concentrations, can be measured as blood glucose levels in mg glucose/
The term "hyperinsulinemia" is defined as the following condition: wherein fasting or postprandial serum or plasma insulin levels of a subject with insulin resistance (whether or not having normal blood glucose) are elevated above levels of normal lean individuals who have no insulin resistance, a waist-to-hip ratio <1.0 (for males), or <0.8 (for females).
The term "insulin resistance" is defined as the following state: where circulating insulin levels in excess of those normally responsive to glucose load are required to maintain euglycemic status (Ford E S et al, JAMA.2002, Vol 287, p 356-359). The method of determining insulin resistance is the euglycemic-hyperinsulinemic clamp test. The ratio of insulin to glucose is determined within the scope of a combination insulin-glucose infusion technique. Insulin resistance is considered to be present if glucose uptake is below 25% of the background population studied (WHO definition). Less frequent than the jaw test is the so-called mini-model, in which the insulin and glucose concentrations in the blood are measured at regular time intervals during the intravenous glucose tolerance test, and the insulin resistance is then calculated therefrom. With this method, hepatic insulin resistance and peripheral insulin resistance cannot be distinguished.
Typically, other parameters are used in daily clinical practice to assess insulin resistance. Preferably, the triglyceride concentration of the patient is used to assess insulin resistance, e.g. because elevated triglyceride levels are significantly associated with the presence of insulin resistance.
Patients with a predisposition to develop IGT or IFG or
The scientific and medical basis for identifying pre-Diabetes as a serious health threat is set forth in The foundational statement entitled "The preliminary of Diabetes and Diabetes mellitus" issued by The American Diabetes Association (American Diabetes Association) and The National Institute of Diabetes digestion and nephropathy (National Institute of Diabetes and Diabetes mellitus) in combination (Diabetes Care 2002; Vol. 25, page 742. 749) or those individuals with elevated blood lipid levels, two or more of The easily resistant insulin attributes of insulin, 353 or 3583, or more of The individuals with elevated blood lipid levels,
The terms "type 2 diabetes" and "type II diabetes" are defined as conditions in which a subject's fasting (i.e., no caloric intake for 8 hours) blood glucose or serum glucose concentration is greater than 125mg/dL (6.94mmol/L) as measured on a minimum of two separate occasions, type 2 diabetes is also defined as a condition in which the subject has a random glucose concentration equal to or greater than 6.5% HbA1c, two hours plasma glucose equal to or greater than 200mg/dL (11.1mmol/L) during an Oral Glucose Tolerance Test (OGTT), or equal to or greater than 200mg/dL (11.1mmol/L) and with classic symptoms of hyperglycaemia or hyperglycaemia critical, if there are no definite hyperglycaemia symptoms, with most diagnostic tests -like, the results of the diagnostic test for diabetes should be repeated to rule out laboratory errors using a standardized glycemia program (NGSP) and taking a standardized test for glucose tolerance between 200mg/dL and 140 hours and after taking glucose tolerance test for glucose levels less than 200mg/dL (OGTT) and taking glucose levels normally measured 10mg/dL after a 2 g and taking glucose test for glucose tolerance test for glucose levels less than 140 hours, if they are taken between 200mg/dL, after a 2 mg/dL, and after taking glucose tolerance test for glucose levels equal to be taken for glucose tolerance test (OGTT) and 8 hours, normal glucose levels after 8 hours, and taking glucose levels before eating a glucose 8 hours, normal glucose test (OGTT) and after 8 hours, normal glucose levels).
The term "
The term "HbA 1 c" refers to the non-enzymatic glycosylation product of the hemoglobin β chain, the assay of which is well known to those skilled in the art, HbA1c values are important during the monitoring of diabetes treatment, HbA1c in the sense of "glycemic memory" reflects the average blood glucose level of the previous 4-6 weeks, since the production of HbA1c is mainly dependent on blood glucose level and red blood cell life, consistently good regulation of HbA1c values (i.e., < 6.5% total hemoglobin in the sample) by diabetes intensive therapy results in significantly better protection of the diabetic patient from diabetic microangiopathy, for example, metformin alone can improve the HbA1c values of the diabetic patient by about 1.0% to 1.5% on average, such a reduction in HbA1C values in all diabetic patients is not sufficient to achieve the desired target range of < 6.5%, and preferably < 6% HbA1 c.
The terms "metabolic syndrome", "syndrome X" (when used in the context of metabolic disorders) and "abnormal metabolic syndrome" refer to complex syndromes characterized primarily by insulin resistance (Laaksonen D E et al, Am J epidemic 2002; Vol.156, p.1070; 1077.) according to the ATP III/NCEP guidelines (Executive Summary of the third Report of the National Cholesterol Evolution Program (NCEP) Expert Panel Detection, Evaluation, and statement of High Blood Cholesterol in additives (additive statement III) JAMA: Journal of the American Medical Association (2001)285: 2486-:
1. abdominal obesity, defined as waist circumference greater than about 40 inches or 102cm for men and greater than about 35 inches or 94cm for women;
2. triglycerides equal to or greater than about 150 mg/dL;
3. (ii) less than about 40mg/dL HDL-cholesterol in men and less than about 50 HDL-cholesterol in women;
4. blood pressure equal to or greater than about 130/85mm Hg (SBP equal to or greater than about 130, or DBP equal to or greater than about 85);
5. fasting blood glucose is equal to or greater than about 100 mg/dL.
Patients diagnosed with metabolic syndrome or syndrome X are intended to be included in the methods of the invention.
The term "body mass index" or "BMI" for a human patient is defined as the weight in kilograms divided by the square of the height in meters, so the unit of BMI is kg/m2. The term "overweight" is defined as an overweight condition in which the BMI of an adult European is equal to or greater than 25kg/m2And less than 30kg/m2The disorder of (1). For asian subjects, the term "overweight" is defined as where the BMI of an adult individual is equal to or greater than 23kg/m2And less than 25kg/m2The disorder of (1). The terms "overweight" and "pre-obesity" are used interchangeably.
The term "obesity" is defined as BMI equal to or greater than 30kg/m in European adults2The disorder of (1). According to the WHO definition, the term obesity can be classified as follows: the term "class I obesity" is where the BMI is equal to or greater than 30kg/m2But less than 35kg/m2The disorder of (a); the term "class II obesity" is where the BMI is equal to or greater than 35kg/m2But less than 40kg/m2The disorder of (a); the term "class III obesity" is where the BMI is equal to or greater than 40kg/m2The disorder of (1). For asian subjects, the term "obesity" is defined as an adult subject having a BMI equal to or greater than 25kg/m2Asian obesity can be further classified by , the term "class I obesity" is one in which the BMI is equal to or greater than 25kg/m2But less than 30kg/m2The disorder of (a); the term "class II obesity" is where the BMI is equal to or greater than 30kg/m2The disorder of (1).
The term "visceral adiposity" is defined as a condition wherein the waist-to-hip ratio measured in men is greater than or equal to 1.0 and the waist-to-hip ratio measured in women is greater than or equal to 0.8. Which defines the risk of insulin resistance and the pre-diabetic development. The term "abdominal obesity" is generally defined as a condition in which the waist circumference of men is >40 inches or 102cm and the waist circumference of women is >35 inches or 94cm (see, e.g., "Joint scientific statement (IDF, NHLBI, AHA, WHO, IAS, IASO). Circulation 2009; 120: 1640-) 1645", to understand the normal range of the population).
The term "morbid obesity" is defined herein as a condition in which an European individual has a BMI >40 or a BMI >35 and is suffering from a comorbidity such as diabetes or hypertension (see World Health organization. Objective: preventing and Managing the Global Epidemic: Report on a WHO administration. World Health organization. Tech Rep Ser. 2000; 894: i-xii, 1-253).
According to the usual definition, hypertension is diagnosed if the value of the Systolic Blood Pressure (SBP) exceeds 140mm Hg and the value of the Diastolic Blood Pressure (DBP) exceeds 90 mmHg. If a patient suffers from overt diabetes, it is currently recommended to reduce systolic pressure to below 130mmHg and diastolic pressure to a level below 80 mmHg.
As used herein, unless otherwise indicated, the term "cardiovascular risk factor" includes, but is not limited to, hypertension (hyper tension or high blood pressure) (e.g., high systolic pressure, high diastolic pressure, or blood pressure greater than about 145/95 mmHg), high cholesterol (hyperlipidemia), high LDL, low HDL levels, high triglycerides, obesity (as defined by BMI of, for example, greater than 30, preferably, morbid obesity defined by BMI of greater than 40), cardiovascular disease (including, but not limited to, prior myocardial infarction, angina, heart failure, stroke), microalbuminuria (as defined, for example, by ACR ≧ 30mg/g and ≦ 300mg/g), macroalbuminuria (as defined, for example, by ACR >300mg/g), peripheral vascular disease (including, but not limited to, carotid stenosis, femoral stenosis, etc.), underlying structural heart disease, atrial fibrillation, tachycardia, coronary artery disease, non-rheumatic heart disease, ablative ablation, atrial dilation or flutter (including, atrial fibrillation), atrial tachycardia, or atrial tachycardia including, atrial tachycardia, or other than conventional cardiac defibrillation devices ("heart ablation devices"), or cardiac devices including, heart failure, heart.
In certain embodiments, cardiovascular risk factors include hypertension (e.g., high systolic pressure, high diastolic pressure, or blood pressure greater than about 145/95 mmHg), high cholesterol (hyperlipidemia), high LDL, low HDL levels, high triglycerides, obesity (as defined by, for example, a BMI greater than 30, preferably, a BMI greater than 40), cardiovascular disease (including, but not limited to, morbid obesity as defined by, for example, a BMI greater than 40), cardiovascular disease (including, but not limited to, prior myocardial infarction, angina, heart failure, stroke), microalbuminuria (as defined, for example, by ACR ≧ 30mg/g and ≦ 300mg/g), and macroalbuminuria (as defined, for example, by ACR >300 mg/g).
In certain embodiments, the or more cardiovascular risk factors are selected from those identified in a population of patients who completed a CANVAS or CANVAS-R clinical trial detailed herein.
As used herein, unless otherwise indicated, the term "reducing cardiovascular risk" shall include reducing a symptom or characteristic of a cardiovascular disease, halting or slowing the progression of a cardiovascular disease, and/or halting, slowing the progression, or controlling any or more risk factors associated with a cardiovascular disease.
As used herein, unless otherwise indicated, the term "cardiovascular disease" shall include, but is not limited to, non-fatal history of myocardial infarction, non-fatal history of stroke (ischemic), peripheral arterial disease, hypertensive heart disease, ischemic heart disease, coronary artery disease, peripheral vascular disease, cerebrovascular disease, cardiac arrhythmias (other than sinus tachycardia), cardiomyopathy, angina (including, but not limited to unstable angina), heart failure (including, but not limited to, heart failure requiring hospitalization, congestive heart failure, etc.), and coronary valve disease.
In certain embodiments of the invention, or more cardiovascular diseases are selected from those identified in a population of patients who completed a CANVAS or CANVAS-R clinical trial detailed herein.
As used herein, unless otherwise indicated, the term "major adverse cardiovascular event (" MACE ")" shall include three major measures of non-fatal myocardial infarction ("MI"), non-fatal stroke, and cardiovascular death.
In certain embodiments of the invention, the major adverse cardiovascular event is cardiovascular death. In certain embodiments of the invention, cardiovascular death includes death resulting from fatal myocardial infarction and/or fatal stroke.
In certain embodiments of the invention, the major adverse cardiovascular event is non-fatal stroke. In certain embodiments of the invention, the major adverse cardiovascular event is non-fatal myocardial infarction. In certain embodiments of the invention, the major adverse cardiovascular event is cardiac arrhythmia. In certain embodiments of the invention, major adverse cardiovascular events also include progression from unstable angina to myocardial infarction or death.
As used herein, unless otherwise indicated, the term "cardiovascular event" shall include, but is not limited to, cardiovascular hospitalization, non-fatal myocardial infarction, non-fatal ischemia or stroke, and cardiovascular mortality.
As used herein, unless otherwise indicated, the term "reducing the risk of a cardiovascular event" shall include or more of reducing the risk of a non-fatal myocardial infarction, reducing the risk of a non-fatal ischemic event or stroke, reducing the risk of hospitalization for or more cardiac symptoms or events, or reducing the risk of cardiovascular mortality.
The term "cardiovascular hospitalization" means hospitalization resulting from at least of the following conditions (Hohnloser et al, Journal of cardiovascular electrophysiology, 2008,
atherosclerosis, myocardial infarction or unstable angina, stable angina or atypical chest pain, syncope, transient ischemic events or strokes (other than intracranial hemorrhage), atrial fibrillation and other supraventricular dysrhythmias, non-fatal cardiac arrest, ventricular disorganized heart rhythms, cardiovascular surgery (other than heart transplantation), heart transplantation, implantation of cardiac stimulators (pacemakers), implantation of implantable defibrillators ("ICDs") or another cardiac device, percutaneous coronary, cerebrovascular, or peripheral intervention, changes in arterial pressure (hypotension, hypertension, other than syncope), cardiovascular infection, major/severe hemorrhage (requiring two or more clumps of blood cells or any intracranial hemorrhage), pulmonary embolism or deep vein thrombosis, congestive heart failure exacerbation, including acute pulmonary edema or dyspnea due to cardiac etiology.
In the methods of the present invention, preventing cardiovascular hospitalization may be understood as preventing cardiovascular hospitalization for any or more of the conditions described above.
As used herein, unless otherwise indicated, the terms "mortality" or "death" are equivalent and include death due to any cause, whether cardiovascular or non-cardiovascular or unknown.
As used herein, unless otherwise indicated, the term "cardiovascular death" includes death due to any cardiovascular cause (any death other than those due to non-cardiovascular causes), including death due to:
a) aortic dissection/aneurysm;
b) cardiac tamponade;
c) cardiogenic shock;
d) congestive heart failure;
e) death during cardiovascular percutaneous intervention or cardiovascular surgical intervention;
f) myocardial infarction or unstable angina (including myocardial infarction complications, other than arrhythmia);
g) pulmonary or peripheral embolism;
h) stroke (ischemic);
i) sudden cardiac death (e.g., unproven death or recorded cardiac arrest);
j) ventricular arrhythmias, subdivided into torsade de pointes, premature ventricular contractions, ventricular fibrillation, ventricular tachycardia (non-persistent and persistent ventricular tachycardias) or other ventricular disorganized rhythms; and
k) the reason is unknown.
As used herein, unless otherwise indicated, the term "sudden death" generally refers to death occurring within hours or less than hours after the appearance of a new symptom or unexpected death without indication.
As used herein, unless otherwise indicated, the term "coronary artery disease" or "coronary heart disease" refers to:
a) coronary artery disease: acute myocardial infarction record history and/or history of significant (about 70%) coronary stenosis and/or revascularization surgery (percutaneous transluminal coronary angioplasty, coronary stenting, coronary bypass graft, etc.), and/or positive exercise test and/or positive cardiac perfusion nuclear scan; and
b) ischemic dilated cardiomyopathy: clinically significant left ventricular dilatation secondary to coronary artery disease.
One skilled in the art will recognize that "preventing cardiovascular hospitalization and/or death" results in a reduced risk of cardiovascular hospitalization and/or death or a reduced need for cardiovascular hospitalization and/or mortality.
As used herein, unless otherwise indicated, the term "structural heart disease" shall include coronary heart disease and/or ischemic and/or non-ischemic dilated cardiomyopathy and/or rheumatic heart valve disease and/or non-rheumatic heart valve disease and/or hypertrophic cardiomyopathy and/or LVEF < 45% and/or a history of congestive heart failure, wherein congestive heart failure may be defined, for example, as a reduction in NYHA (new york heart association) class III or left ventricular ejection fraction below 0.35.
As used herein, unless otherwise indicated, the term "renal disease" shall refer to any disease associated with or affecting renal function and/or renal hyperfiltration. Renal diseases include, but are not limited to, high urinary albumin levels, high serum albumin/creatinine ratios, microalbuminuria, macroalbuminuria, hyperfiltration injury of the kidney, diabetic nephropathy (including, but not limited to, hyperfiltration diabetic nephropathy), hyperfiltration, glomerular hyperfiltration, renal allograft hyperfiltration, compensatory hyperfiltration, hyperfiltration chronic nephropathy, hyperfiltration acute renal failure, and obesity.
Microalbuminuria was diagnosed for subjects (patients) with an albumin-creatinine ratio (ACR) between 30mg/g and 300mg/g according to the american kidney foundation (NKF) renal disease outcome quality initiative (KDOQI), screening and diagnostic guidelines for diabetic nephropathy; and a large amount of albuminuria was diagnosed for subjects (patients) with an albumin-creatinine ratio (ACR) greater than 300 mg/g.
In aspects, hyperfiltration is defined as a total renal filtration rate equal to or greater than about 125mL/min/1.73m2And especially equal to or greater than about 140mL/min/1.73m2As measured using the method described below. Hyperfiltration can also be defined as being associated with an absolute GFR greater than about the 90 th percentile or about the 95 th percentile of the study population after adjustments are made for sex, age, weight, height, and use of ACE inhibitors or ARBs (Melcom et al, Diabetes Care 2011; DOI:10.2337/dc 11-0235).
The term "Glomerular Filtration Rate (GFR)" is defined as the volume of fluid filtered from the renal (kidney) glomerular capillaries into the bowman's capsule per unit time. Which is indicative of overall renal function. Glomerular Filtration Rate (GFR) can be calculated by measuring any of the following chemicals: the chemical has a steady level in the blood that is freely filtered by the kidneys but is neither reabsorbed nor secreted by the kidneys. The filtration rate thus measured is the amount of the substance in urine that results from a calculable blood volume. GFR is typically measured in units of volume per unit time (e.g., milliliters per minute) and can be calculated using the following equation:
GFR can be determined by injection of inulin into plasma. Since inulin is neither reabsorbed by nor secreted by the kidneys after glomerular filtration, its excretion rate is proportional to the filtration rate of water and solutes through the glomerular filter. The normal values are: GFR is 90-125mL/min/1.73m2In particular, GFR is 100-125mL/min/1.73m2. Other principles for determining GFR involve measuring 51Cr-EDTA, [125I]Iophthalate or iohexol.
The "estimated glomerular filtration rate (eGFR)" is defined as being derived upon screening from serum creatinine values based on, for example, the chronic kidney disease epidemiological collaboration group (CKD-EPI) equation, the Cockcroft-Gault equation, or the renal disease dietary improvement experiment (MDRD) equation, all of which are known in the art. A subject with an eGFR equal to or greater than 90ml/min is defined as having normal renal function. Subjects with an eGFR equal to or greater than 60ml/min and less than 90ml/min are defined as having a mild impairment of renal function. Subjects with an eGFR equal to or greater than 30ml/min and less than 60ml/min are defined as moderately impaired renal function. Subjects with an eGFR equal to or greater than 15ml/min and less than 30ml/min are defined as severely impaired renal function.
The term "hyperfiltration injury" is defined as the manifestation of renal injury caused primarily by hyperfiltration, which is usually the early link in the event chain of further renal injuries, confirming that hyperfiltration is often synergistic with other chronic kidney disease risk factors in the pathogenesis of renal injury.
In addition, to provide a more concise description, the quantitative representations of given herein are not limited by the term "about," it being understood that each amount given herein is intended to refer to the actual given value, whether or not the term "about" is explicitly used, and also to refer to the approximation to such given value that would reasonably be inferred by one of ordinary skill in the art, including approximations due to experimental and/or measurement conditions for such given value.
Pharmaceutical compositions of canagliflozin as an active ingredient can be prepared according to conventional pharmaceutical compounding techniques by intimately bringing or more compounds into association with a pharmaceutical carrier, which can take a wide variety of forms depending on the desired route of administration (e.g., oral, parenteral).
To prepare such pharmaceutical compositions, canagliflozin as an active ingredient is intimately mixed with a pharmaceutical carrier, which may take a wide variety of forms depending on the form of preparation desired for administration (e.g. oral or parenteral such as intramuscular injection), according to conventional pharmaceutical compounding techniques. In preparing the compositions for oral dosage form, any of the pharmaceutically acceptable media that can be employed. Thus for liquid oral preparations such as suspensions, elixirs and solutions, suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like; for solid oral formulations (such as, for example, powders, capsules, caplets, and tablets), suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like. Because of their ease in administration, tablets and capsules represent the most advantageous oral unit dosage form, in which case solid pharmaceutically acceptable carriers are obviously employed. Tablets may be sugar-coated or enteric-coated, if desired, by standard techniques. For parenteral administration, the carrier will typically comprise sterile water, but may also comprise other ingredients, for example for purposes such as to aid solubility or preservation. Suspensions for injection may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed. The pharmaceutical compositions of the present invention will contain per dosage unit (e.g., per tablet, per capsule, per powder, per injection, per teaspoonful, etc.) the amount of active ingredient necessary to deliver the effective dose described above. The pharmaceutical compositions herein will contain from about 25mg to about 500mg of canagliflozin per unit dosage unit (e.g., per tablet, per capsule, per powder, per injection, per suppository, per teaspoon, etc.), or any amount or range therein (preferably selected from the group consisting of about 50mg, about 75mg, about 100mg, about 150mg, about 200mg, and about 300mg of canagliflozin). However, the dosage may vary depending on the needs of the patient, the severity of the condition being treated and the compound being employed. The use pattern of daily administration or post-cycle administration may be employed.
Preferably, the pharmaceutical composition is in unit dosage form, such as a tablet, pill, capsule, powder, granule, sterile parenteral solution or suspension, metered aerosol or liquid spray, drops, ampoule, autoinjector device or suppository, for oral, parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation to prepare solid compositions such as tablets, the principal active ingredient (e.g., canagliflozin) is mixed with a pharmaceutically acceptable carrier (e.g., conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gum) and other pharmaceutical diluents (e.g., water) to form a solid preformulation composition containing a homogeneous mixture of the compound of the invention or a pharmaceutically acceptable salt thereof.
Liquid forms in which the compositions of the present invention may be incorporated for oral administration or administration by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles. Dispersing or suspending agents suitable for use in aqueous suspensions include synthetic or natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone or gelatin.
The methods described herein can also be performed using a pharmaceutical composition comprising canagliflozin and a pharmaceutically acceptable carrier. Carriers include necessary and inert pharmaceutical excipients including, but not limited to, binders, suspending agents, lubricants, flavoring agents, sweetening agents, preservatives, dyes, and coatings. Compositions suitable for oral administration include solid forms such as pills, tablets, caplets, capsules (each including immediate release, timed release and sustained release), granules and powders; and liquid forms such as solutions, syrups, elixirs, emulsions and suspensions. Forms useful for parenteral administration include sterile solutions, emulsions and suspensions.
Advantageously, canagliflozin can be administered in a single daily dose, or the total daily dose can be administered in divided doses of two, three or four times daily.
For example, for oral administration in the form of a tablet or capsule, the active pharmaceutical ingredient (e.g., canagliflozin) can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier (such as ethanol, glycerol, water, and the like). in addition, suitable binders, lubricants, disintegrants, and colorants can also be incorporated into the mixture, as desired or necessary.
In liquid form in a suitably flavoured suspending or dispersing agent such as synthetic and natural gums, for example tragacanth, acacia, methyl cellulose and the like. For parenteral administration, sterile suspensions and solutions are desirable. When intravenous administration is desired, isotonic formulations, which typically contain suitable preservatives, are employed.
For the preparation of the Pharmaceutical compositions of the present invention, canagliflozin as the active ingredient may be intimately admixed with a Pharmaceutical carrier which may take a wide variety of forms depending on the form of preparation desired for administration, e.g. oral or parenteral, according to conventional Pharmaceutical compounding techniquesThe Handbook of Pharmaceutical ExcipientsThe disclosure of this document is hereby incorporated by reference in the handbook of pharmaceutical adjuvants.
Methods of formulating pharmaceutical compositions are described in various publications, such asPharmaceutical Dosage Forms: Tablets,Second Edition,Revised and ExpandedVolumes 1-3, edited by Lieberman et al;Pharmaceutical Dosage Forms:Parenteral Medicationsvol.1-2, edited by Avis et al; andPharmaceutical Dosage Forms:Disperse Systemsvol.1-2, edited by Lieberman et al; published by Marcel Dekker, inc, the disclosures of which are hereby incorporated by reference.
The following examples are presented to aid in understanding the invention and are not intended to, and should not be construed to, limit in any way the invention as set forth in the claims that follow the examples.
For the clinical studies detailed below, in certain cases (e.g. at the primary endpoint), "prevention of cardiovascular events or cardiovascular death" constitutes those referred to as the combined standard or combined endpoint.
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