JP7396579B2 - Pharmaceutical composition for heart failure with preserved left ventricular ejection fraction - Google Patents

Description

Article 30, Paragraph 2 of the Patent Act applies February 2, 2021 Website https://jrct. niph. go. Published through jp/latest-detail/jRCTs051180139

The present invention relates to the treatment of heart failure. In particular, the present invention relates to the treatment of chronic heart failure, which is characterized by preserved ejection fraction and for which no treatment method has been established among heart failure.

Heart failure is an extremely serious disease in which the heart's ability to drive sufficient blood is impaired, making it unable to supply sufficient blood flow to internal organs.

Heart failure is broadly classified into heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF), depending on ventricular diastolic function. be done.

In particular, since there is still no definitive treatment for the latter type of heart failure, HFpEF, much debate has focused on its causes and treatments. This disease is said to be one of the diseases with unmet needs because of the high mortality rate of patients, the lack of a reliable risk assessment method, and the lack of a reliable treatment.

Although various factors are involved in this disease, hypertension and diabetes are said to be largely involved. For example, according to the Framingham Large-Scale Epidemiological Survey, the incidence of heart failure in diabetic patients is high, and it is thought that this has a negative impact on the patient's prognosis (Non-Patent Document 1).

In recent years, HFpEF type heart failure has become a hot topic as it exhibits drug resistance. That is, as drug therapy for heart failure, drugs that are effective for HFrEF type heart failure often cannot be confirmed to be useful for HFpEF type heart failure, which is a problem. Although its pathological elucidation is still under debate, it is characterized by ventricular diastolic dysfunction (Non-Patent Document 2).

Recently, inhibitors of SGLT2 (sodium glucose co-transporter 2), a type of transporter present in the renal proximal tubule that controls sugar reabsorption, have been shown to reduce mortality and hospitalization rates in patients with HFrEF heart failure. It has been reported (Non-Patent Document 3).

New England journal of medicine, 1971, 285(26), 1441-1446

Non-patent paper 2

“Guidelines for acute and chronic heart failure treatment” (2017 revised edition, Japanese Circulation Society/Japan Heart Failure Society joint guidelines)
New England Journal of Medicine, 2020, 383(15), 1413-1424

As mentioned above, no treatment has yet been established for HFpEF type heart failure. Although attempts have been made to apply SGLT2 inhibitors, which are said to be effective against HFrEF type heart failure, to HFpEF type heart failure, the details have not yet been elucidated (New England Journal of Medicine, 2021, 385( 16), 1451-1461). In other words, it has been reported that the administration of empagliflozin, one of the SGLT2 inhibitors, reduced the mortality and hospitalization rates of patients with HFpEF heart failure. It is possible that this was due to the effect of the drug, and it is not officially recognized whether empagliflozin has the effect of improving HFpEF type heart failure.

In view of this situation, the objective of the present invention is to establish a safe and effective treatment for chronic heart failure, which is a serious disease, and in particular for HFpEF type heart failure, for which no definitive treatment exists yet. be.

The inventors of the present invention evaluated heart failure based on cardiac ultrasound (echocardiography) after administering ipragliflozin to patients, and evaluated human brain natriuretic peptide precursor, which is an objective clinical indicator. By measuring the blood concentration of body N-terminal fragment (NT-proBNP) over time, the direct effect of ipragliflozin on improving heart failure was observed. As a result, it was confirmed that administration of ipragliflozin numerically improved test values and functional indices characteristic of HFpEF type heart failure, leading to the completion of the present invention.

The present invention relates to pharmaceutical compositions containing ipragliflozin used to treat heart failure of the HFpEF type.
[1] A pharmaceutical composition for treating HFpEF type heart failure, comprising ipragliflozin.
[2] The pharmaceutical composition according to [1], for treating patients with diabetes.
[3] The pharmaceutical composition according to [1] or [2], which improves left ventricular myocardial mass index (LVMi) of a patient.
[4] The pharmaceutical composition according to any one of [1] to [3], which improves the blood concentration of brain natriuretic peptide precursor N-terminal fragment (NT-proBNP) in a patient.
[5] The pharmaceutical composition according to any one of [1] to [4], for oral administration.
[6] The pharmaceutical composition according to any one of [1] to [5], which is used in combination with other heart failure therapeutics.
[7] The pharmaceutical composition according to any one of [1] to [6], which is used in combination with a therapeutic agent for other concurrent diseases.

The present invention has made it possible to safely and effectively treat chronic heart failure, which is a serious disease, particularly HFpEF type heart failure, for which no definitive treatment exists yet.

FIG. 1 is a graph showing the results of evaluating the left ventricular myocardial mass index (LVMi) of patients (left: ipragliflozin administration group, right: control group).

The present invention relates to a pharmaceutical composition for treating heart failure of the HFpEF type. According to the "Guidelines for Acute and Chronic Heart Failure Treatment" (2017 revised edition, joint guidelines of the Japanese Circulation Society/Japan Heart Failure Society), HFpEF type heart failure requires preservation of cardiac ejection force (EF), specific Specifically, it is heart failure characterized by a left ventricular ejection fraction (LVEF) determined by echocardiography of 50% or more. Although no effective treatment method has been established for HFpEF type heart failure, the present invention makes it possible to treat HFpEF type heart failure by administering ipragliflozin. Here, in the present invention, the term "treatment" includes not only improving HFpEF type heart failure, but also suppressing the deterioration of HFpEF type heart failure, delaying its onset, and preventing it.

Regarding HFpEF type heart failure, circulating B-type natriuretic peptide (BNP) and brain natriuretic peptide precursor N-terminal fragment (NT-proBNP) are also effective for diagnosis. In other words, for heart failure with preserved ejection fraction, the cutoff value for the blood concentration of NT-proBNP is said to be 125 pg/mL (40 pg/mL for BNP). The guidelines state that if the blood concentration of NT-proBNP is 400 pg/mL or higher, ``the patient should be examined closely or referred to a specialist as it may indicate heart failure that requires treatment.'' Symptoms of heart failure include shortness of breath, orthopnea, paroxysmal nocturnal dyspnea, decreased exercise tolerance, malaise, fatigue, ankle swelling, increased jugular venous pressure, third heart sound, weight loss, cachexia, and appetite. Symptoms include depression, heart murmur, peripheral edema, irregular heartbeat, chain-stoke breathing, and cold extremities.

The present invention treats HFpEF type heart failure by administering ipragliflozin. Ipragliflozin is a therapeutic drug widely used for diabetes as an SGLT2 inhibitor, and has the structure shown below, and its IUPAC name is (1S)-1,5-anhydro-1-C-[ 3-(benzo[b]thiophen-2-ylmethyl)-4-fluorophenyl]-D-glucitol.

In the present invention, simply the term ipragliflozin includes its pharmaceutically acceptable salts, prodrugs, co-crystals, solvates, and the like. One form of ipragliflozin is ipragliflozin L-proline. Furthermore, in the present invention, when simply referring to ipragliflozin, its form is not particularly limited, and includes crystalline solids and amorphous substances.

The pharmaceutical composition according to the present invention may contain, in addition to the active ingredient, drugs such as absorption enhancers that promote the effects of the active ingredient, such as fillers, lubricants, flavoring agents, coloring agents, and coatings. It can be formulated using additives such as agents, disintegrants, and glidants. The pharmaceutical composition according to the present invention can be administered by various routes, and the dosage form may be appropriately selected depending on the mode of administration. Examples of dosage forms include oral preparations such as tablets, granules, and capsules, injections, transdermal preparations, and eye drops.

The pharmaceutical composition according to the present invention can be administered at a dose appropriately determined depending on the patient's physical condition such as the state and stage of heart failure, other concurrent diseases, age, sex, and body weight. In one embodiment, for example, about 10-1000 mg/day of ipragliflozin can be administered as appropriate to the patient.

As one aspect of the present invention, the pharmaceutical composition according to the present invention can be used in combination with other medicines. Other drugs used in combination may or may not be administered simultaneously with the pharmaceutical composition of the present invention.

When used in combination with other heart failure drugs, other heart failure drugs include angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIs), and HCN channel blockers. , β-receptor blockers, diuretics, cardiotonic drugs, mineralocorticoid receptor antagonists (MRA), etc., and the following can be exemplified.
・ACE inhibitors: enalapril, trandolapril, captopril, lisinopril, benazepril ・ARB: candesartan, valsartan, losartan ・ARNI: sacubitril valsartan sodium,
・HCN channel blockers: ivabradine ・β receptor blockers: carvedilol, bisoprolol, metoprolol ・Diuretics: furosemide, azosemide, torasemide, trichlormethiazide, tolvaptan, soldactone ・Carotonic drugs: digoxin, methyldigoxin, deslanoside, dopamine, denopamine , docarpamine, dobutamine, noradrenaline, adrenaline, vesnarinone, milrinone, pimobendan/MRA: cortisol, spironolactone, eplerenone As one embodiment of the present invention, ipragliflozin can be administered to a disease complicated by heart failure. For example, when administering ipragliflozin to a diabetic patient with heart failure, an antidiabetic agent and the pharmaceutical composition of the present invention can be used together. In addition, anti-diabetic agents, anti-obesity agents, anti-hyperlipidemic agents, anti-hypertensive agents, etc. may be used in combination with the pharmaceutical composition of the present invention for patients with heart failure and other diseases. They may or may not be administered at the same time.

Examples of antidiabetic agents include SGLT2 inhibitors, biguanides, PPARγ agonists, sulfonylurea agents, DPP4 inhibitors, insulin secretagogues, α-glucosidase inhibitors, glucagon-like peptide-1 receptor agonists, and the like. , the following can be exemplified.
・SGLT2 inhibitors: dapagliflozin, empagliflozin, canagliflozin, tofogliflozin, luseogliflozin ・Biguanides: metformin, buformin ・PPARγ agonists: troglitazone, rosiglitazone, pioglitazone ・Sulfonylureas: acetohexamide, glycopyramide, glibenclamide , glimepiride, chlorpropamide, gliclazide/DPP4 inhibitors: sitagliptin, vildagliptin, alogliptin, linagliptin, anagliptin, saxagliptin, teneligliptin, trelagliptin, omagliptin/insulin secretagogues: nateglinide, mitiglinide, repaglinide/α-glucosidase inhibitors: acarbose, Miglitol, voglibose glucagon-like peptide-1 receptor agonist: exenatide, liraglutide, lixisenatide, dulaglutide, semaglutide Anti-obesity agents include, for example, β3 adrenergic agonist, lipase inhibitor, SSRI, 5-HT2c agonist, MC4 agonist, cannabinoid agonist Examples include.

Examples of antihyperlipidemic agents include statin drugs, nicotinic acid drugs, probucol, small intestinal cholesterol transporter inhibitors, anion exchange membrane resins, fibrate drugs, and the following are examples of each drug: I can do it.
・Statin drugs: lovastatin, pravastatin, simvastatin, flavastatin, cerivastatin, atorvastatin, pitavastatin, rosuvastatin ・Nicotinic acid drugs: nicotinic acid, nicotinic acid amide ・Small intestinal cholesterol transporter inhibitor: ezetimibe ・Anion exchange membrane resin: Coles Tyramine/fibrate drugs: bezafibrate, fenofibrate, pemafibrate Examples of antihypertensive drugs include β blockers, α1 blockers, calcium antagonists, diuretics, renin inhibitors, ACE inhibitors, ARBs, etc. , the following can be exemplified.
・Beta blockers: Amosralol, labetalol, arotinolol, carvedilol, bevantrol ・α1 blockers: prazosin, bunazosin, urapidil, doxazosin ・Calcium antagonists: amlodipine, efonidipine, cilnidipine, nicardipine, nitrendipine, nifedipine, nilvadipine, palnidipine, benidipine, azelnidipine, diltiazem , verapamil, diuretics: hydrochlorothiazide, trichlormethiazide, furosemide, torasemide, spironolactone, triamterene, eplerenone, renin inhibitors: aliskiren, ACE inhibitors: captopril, enalapril, aracepril, lisinopril, imidapril, temocapril, ARBs: valsartan, losartan , candesartan, telmisartan, olmesartan, irbesartan, azilsartan

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to the following Examples. In this specification, unless otherwise specified, concentrations and the like are based on weight, and numerical ranges are written including the end points thereof.

Administration of ipragliflozin to patients with HFpEF type heart failure Ipragliflozin was administered to type 2 diabetic patients with HFpEF type heart failure, and its effect on cardiac function was investigated in a randomized two-group comparative trial. investigated.
・Intervention group: Group receiving ipragliflozin (36 patients)
・Control group: Group that continued treatment with diabetes drugs other than SGLT2 inhibitors (32 cases)
■Targets to be administered At the time of registration of subjects to be administered, the intervention group and control group were assigned using the electronic case data collection system (EDC system). Subjects are type 2 diabetic patients with stable HFpEF type heart failure for at least 3 months who meet the following inclusion criteria and do not violate any of the exclusion criteria, and who have provided written informed consent. Targeted.
<Selection criteria>
(a) Type 2 diabetes with a blood concentration of NT-proBNP of 125 pg/mL or higher (or a blood concentration of BNP of 40 pg/mL or higher) and chronic heart failure (cardiac function classification I to III by the New York Heart Association) Patients (regardless of whether or not they are receiving diabetes treatment)
(b) Patients who have not taken SGLT2 inhibitors within the past 3 months (c) Patients with hemoglobin A1c (HbA1c) of 7.0% or higher. However, when administering drugs that are likely to cause severe hypoglycemia, such as insulin preparations, sulfonylurea drugs, and glinide drugs, those under 65 years of age should be at least 7.0%, those between 65 and 75 years old at least 7.5%, and those aged 75 and above at least 7.0%. The above shall be 8.0% or more.
(d) Outpatients over 20 years old (regardless of gender)
<Exclusion criteria>
(a) Patients with acute exacerbation of chronic heart failure (b) Patients who have had a stroke, acute coronary syndrome, percutaneous coronary angioplasty, or coronary artery bypass surgery within the past 3 months
(c) Patients with cardiac ejection fraction <50% or severe valvular disease (as determined by echocardiography)
(d) Patients with chronic atrial fibrillation
(e) Patients with severe liver dysfunction such as chronic hepatitis C (f) Patients with severe renal impairment or estimated glomerular filtration rate (eGFR) less than 30 mL/min/1.73 ^m2 (g) Malignant Patients with tumors (h) Patients with dementia (i) Patients who require long-term care (j) Patients who are pregnant or may become pregnant (k) Patients for whom SGLT2 inhibitors are contraindicated ■Administration Schedule Tablets containing ipragliflozin L-proline were orally administered to patients according to the schedule shown in Table 1 below, and the following test items were evaluated. The content of ipragliflozin L-proline per tablet was 25 mg or 50 mg.

■Inspection items The items shown in the table below were inspected. Test items at the start of administration were conducted within 2 weeks before the start of administration. The allowable range for observations and tests at 12 and 24 weeks was the reference date ± 2 weeks (14 days). In addition, the amount of blood collected for hematological and biochemical tests was 5 mL each time.

<Evaluation items>
・Early diastolic wave/valve annular velocity (E/e') by cardiac ultrasound (echocardiography), change in annulus velocity (e') ・Cardiac function test items, specifically left ventricular myocardial weight coefficient (LVMi), left atrial diameter (LAD), left atrial volume (LAV), left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), early diastolic wave/ Changes in atrial systolic wave (E/A), inferior aortic diameter (IVC), changes in NT-proBNP, HbA1c, early morning fasting blood sugar (FBS), changes in cardiac function classification by New York Heart Association (NYHA), Amount of change in blood pressure/frequency of adverse events ■Evaluation results According to the Chronic/Acute Heart Failure Treatment Guidelines (Revised 2017, Japanese Circulation Society/Japan Heart Failure Society Joint Guidelines), the blood concentration of NT-proBNP is 400 pg/mL or higher. If this is the case, the patient will be subject to further investigation or referral to a specialist as the patient may be suffering from heart failure, which can be treated. Therefore, we conducted a stratified analysis (n = 16) with the baseline NT-proBNP cutoff value of 400 pg/mL or higher, and as shown in the table below, we found that the intervention group (ipragliflozin administration group) The blood concentration of NT-proBNP decreased significantly. This fact indicates that administration of ipragliflozin can suppress the onset of heart failure in patients.

We also performed a subgroup analysis restricting participants over 70 years of age (n = 38) and found that the left ventricular myocardial mass index (LVMi) was significantly lower in the ipragliflozin group compared to the conventional treatment group. (Figure 1). This decrease in left ventricular myocardial mass index observed in elderly patients may represent a cardioprotective effect of ipragliflozin.

Claims (7)

A pharmaceutical composition for treating heart failure of the HFpEF type, comprising ipragliflozin. 2. The pharmaceutical composition according to claim 1, for treating patients concurrently suffering from diabetes. 3. A pharmaceutical composition according to claim 1 or 2, which improves left ventricular myocardial mass index (LVMi) in a patient. The pharmaceutical composition according to any one of claims 1 to 3, which improves the blood concentration of brain natriuretic peptide precursor N-terminal fragment (NT-proBNP) in a patient. Pharmaceutical composition according to any one of claims 1 to 4, for oral administration. The pharmaceutical composition according to any one of claims 1 to 5, which is used in combination with other heart failure therapeutics. The pharmaceutical composition according to any one of claims 1 to 6, which is used in combination with a therapeutic agent for other concurrent diseases.