Sacubitrile + valsartan combination drug is useless in the treatment of diastolic heart failure
The combination of sacubitrile + valsartan is ineffective in the treatment of diastolic heart failure
Sacubitrile, which can prolong the life of patients with systolic heart failure, did not live up to expectations in a global study in patients with diastolic heart failure for which there is still no effective drug therapy. The results of the PARAGON-HF study were presented at the Congress of the European Society of Cardiology (ESC) in Paris and published in The New England Journal of Medicine (NEJM).
In approximately 50% of all patients with chronic heart failure, the ejection fraction of the left ventricle does not decrease significantly. Diastolic heart failure, also called heart failure with preserved systolic pump function (Heart failure with preserved ejection fraction - HFpEF), is caused by a violation of the relaxing ability of the heart muscle. The disease is characterized by a decrease in blood filling of the left ventricle before the next heartbeat. Despite the normal ejection fraction of the left ventricle, too little blood enters the bloodstream.
HFpEF is the most common late consequence of hypertension, obesity, metabolic syndrome or lack of physical activity. There is no effective medication for pathology. Medicines — ACE inhibitors, AT1 receptor blockers, or beta blockers — which can improve the prognosis of patients with reduced ejection fraction have been found to be ineffective against HFpEF.
Hopes were based on the use of sacubitrile in combination with the AT1 receptor blocker, valsartan. Sacubitrile + valsartan significantly improved the prognosis of HFrEF patients in the 2014 PARADIGM-HF study.
The PARAGON-HF study in 848 centers in 43 countries (with Germany) included 4822 patients meeting the same inclusion criteria as the PARADIGM-HF study (essentially symptomatic NYHA grade II – IV heart failure), excluding the fraction ejection of the left ventricle. Patients were treated with either sacubitrile + valsartan or valsartan - in the PARADIGM-HF study, the comparison group received enalapril.
The primary endpoint in both studies was the number of patients hospitalized for heart failure or patients with cardiovascular disease.
According to Scott Solomon, 526 patients in the sakubitril + valsartan group had 894 primary endpoint events, compared to 1009 primary events in 557 patients in the valsartan-only group. The risk ratio was 0.87 and does not reach a significance level with a 95 percent confidence interval from 0.75 to 1.01.
In a previous PARADIGM-HF study, sacubitrile + valsartan slightly more significantly reduced the primary endpoint, and the risk ratio of 0.80 was significant with a 95 percent confidence interval of 0.73-0.87. Significantly fewer deaths from cardiovascular diseases occurred in the sacubitrile + valsartan group than in the PARADIGM-HF group over 27 months: 13.3 versus 16.5% (risk ratio 0.80, 0.71 - 0.89).
In the current PARAGON-HF study, mortality from cardiovascular disease was 8.5% versus 8.9% for 35 months (risk ratio 0.95; 0.79–1.16). Also, this slight advantage was not significant. The number of hospitalizations with heart failure decreased by 15%: 690 compared with 797 cases.
Renal function also decreased less frequently with sacubitrile + valsartan (1.4% versus 2.7%; risk coefficient 0.50, 0.33–0.77). The KCCQ symptom score (Kansas City Questionnaire for Cardiomyopathy; range from 0 to 100 points) improved slightly in the first eight months from 2.6 to 1.6 points (1.0 point difference; 0.0—2.1 point). Due to the lack of benefits at the primary endpoint, the results should be considered in further studies.
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The combination of sacubitrile + valsartan is ineffective in the treatment of diastolic heart failure
Sacubitrile, which can prolong the life of patients with systolic heart failure, did not live up to expectations in a global study in patients with diastolic heart failure for which there is still no effective drug therapy. The results of the PARAGON-HF study were presented at the Congress of the European Society of Cardiology (ESC) in Paris and published in The New England Journal of Medicine (NEJM).
In approximately 50% of all patients with chronic heart failure, the ejection fraction of the left ventricle does not decrease significantly. Diastolic heart failure, also called heart failure with preserved systolic pump function (Heart failure with preserved ejection fraction - HFpEF), is caused by a violation of the relaxing ability of the heart muscle. The disease is characterized by a decrease in blood filling of the left ventricle before the next heartbeat. Despite the normal ejection fraction of the left ventricle, too little blood enters the bloodstream.
HFpEF is the most common late consequence of hypertension, obesity, metabolic syndrome or lack of physical activity. There is no effective medication for pathology. Medicines — ACE inhibitors, AT1 receptor blockers, or beta blockers — which can improve the prognosis of patients with reduced ejection fraction have been found to be ineffective against HFpEF.
Hopes were based on the use of sacubitrile in combination with the AT1 receptor blocker, valsartan. Sacubitrile + valsartan significantly improved the prognosis of HFrEF patients in the 2014 PARADIGM-HF study.
The PARAGON-HF study in 848 centers in 43 countries (with Germany) included 4822 patients meeting the same inclusion criteria as the PARADIGM-HF study (essentially symptomatic NYHA grade II – IV heart failure), excluding the fraction ejection of the left ventricle. Patients were treated with either sacubitrile + valsartan or valsartan - in the PARADIGM-HF study, the comparison group received enalapril.
The primary endpoint in both studies was the number of patients hospitalized for heart failure or patients with cardiovascular disease.
According to Scott Solomon, 526 patients in the sakubitril + valsartan group had 894 primary endpoint events, compared to 1009 primary events in 557 patients in the valsartan-only group. The risk ratio was 0.87 and does not reach a significance level with a 95 percent confidence interval from 0.75 to 1.01.
In a previous PARADIGM-HF study, sacubitrile + valsartan slightly more significantly reduced the primary endpoint, and the risk ratio of 0.80 was significant with a 95 percent confidence interval of 0.73-0.87. Significantly fewer deaths from cardiovascular diseases occurred in the sacubitrile + valsartan group than in the PARADIGM-HF group over 27 months: 13.3 versus 16.5% (risk ratio 0.80, 0.71 - 0.89).
In the current PARAGON-HF study, mortality from cardiovascular disease was 8.5% versus 8.9% for 35 months (risk ratio 0.95; 0.79–1.16). Also, this slight advantage was not significant. The number of hospitalizations with heart failure decreased by 15%: 690 compared with 797 cases.
Renal function also decreased less frequently with sacubitrile + valsartan (1.4% versus 2.7%; risk coefficient 0.50, 0.33–0.77). The KCCQ symptom score (Kansas City Questionnaire for Cardiomyopathy; range from 0 to 100 points) improved slightly in the first eight months from 2.6 to 1.6 points (1.0 point difference; 0.0—2.1 point). Due to the lack of benefits at the primary endpoint, the results should be considered in further studies.
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TRESCH AND ARONOW'S CARDIOVASCULAR DISEASE IN THE ELDERLY 6th
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Mechanism of action.
Dapagliflozin is a potent (inhibitory constant (Ki) of 0.55 nM), a selective reversible inhibitor of sodium - type 2 glucose cotransporter (SGLT2).
SGLT2 is selectively expressed in the kidneys and is not found in more than 70 other body tissues (including the liver, skeletal muscle, adipose tissue, mammary glands, bladder, and brain).
SGLT2 is the main carrier involved in glucose reabsorption in the renal tubules. Glucose reabsorption in the renal tubules in patients with type 2 diabetes mellitus (T2DM) continues despite hyperglycemia. By inhibiting the renal transfer of glucose, dapagliflozin reduces its reabsorption in the renal tubules, which leads to the excretion of glucose by the kidneys.
The result of dapagliflozin is a decrease in fasting glucose and after eating, as well as a decrease in the concentration of glycosylated hemoglobin in patients with type 2 diabetes.
Withdrawal of glucose (glucosuric effect) is observed after taking the first dose of the drug, persists for the next 24 hours and continues throughout therapy. The amount of glucose excreted by the kidneys due to this mechanism depends on the concentration of glucose in the blood and on the glomerular filtration rate (GFR). Dapagliflozin does not interfere with the normal production of endogenous glucose in response to hypoglycemia. The effect of dapagliflozin is independent of insulin secretion and insulin sensitivity. In clinical studies of Forsig ™, an improvement in beta-cell function was noted (HOMA test, homeostasis model assessment).
The elimination of glucose by the kidneys caused by dapagliflozin is accompanied by a loss of calories and a decrease in body weight. Dapagliflozin inhibition of sodium glucose cotransport is accompanied by weak diuretic and transient natriuretic effects.
Dapagliflozin does not affect other glucose transporters that transport glucose to peripheral tissues and exhibits more than 1,400 times greater selectivity for SGLT2 than SGLT1, the main transporter in the intestine responsible for glucose absorption.
Pharmacodynamics
After taking dapagliflozin by healthy volunteers and patients with type 2 diabetes, an increase in the amount of glucose excreted by the kidneys was observed. When dapagliflozin was taken at a dose of 10 mg / day for 12 weeks, in patients with T2DM, approximately 70 g of glucose per day was excreted by the kidneys (which corresponds to 280 kcal / day). In patients with type 2 diabetes who took dapagliflozin at a dose of 10 mg / day for a long time (up to 2 years), glucose excretion was maintained throughout the course of therapy.
Excretion of glucose by the kidneys with dapagliflozin also leads to osmotic diuresis and an increase in urine volume. The increase in urine volume in patients with type 2 diabetes taking dapagliflozin at a dose of 10 mg / day remained for 12 weeks and amounted to approximately 375 ml / day. The increase in urine volume was accompanied by a small and transient increase in sodium excretion by the kidneys, which did not lead to a change in the concentration of sodium in the blood serum.
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Dapagliflozin is a potent (inhibitory constant (Ki) of 0.55 nM), a selective reversible inhibitor of sodium - type 2 glucose cotransporter (SGLT2).
SGLT2 is selectively expressed in the kidneys and is not found in more than 70 other body tissues (including the liver, skeletal muscle, adipose tissue, mammary glands, bladder, and brain).
SGLT2 is the main carrier involved in glucose reabsorption in the renal tubules. Glucose reabsorption in the renal tubules in patients with type 2 diabetes mellitus (T2DM) continues despite hyperglycemia. By inhibiting the renal transfer of glucose, dapagliflozin reduces its reabsorption in the renal tubules, which leads to the excretion of glucose by the kidneys.
The result of dapagliflozin is a decrease in fasting glucose and after eating, as well as a decrease in the concentration of glycosylated hemoglobin in patients with type 2 diabetes.
Withdrawal of glucose (glucosuric effect) is observed after taking the first dose of the drug, persists for the next 24 hours and continues throughout therapy. The amount of glucose excreted by the kidneys due to this mechanism depends on the concentration of glucose in the blood and on the glomerular filtration rate (GFR). Dapagliflozin does not interfere with the normal production of endogenous glucose in response to hypoglycemia. The effect of dapagliflozin is independent of insulin secretion and insulin sensitivity. In clinical studies of Forsig ™, an improvement in beta-cell function was noted (HOMA test, homeostasis model assessment).
The elimination of glucose by the kidneys caused by dapagliflozin is accompanied by a loss of calories and a decrease in body weight. Dapagliflozin inhibition of sodium glucose cotransport is accompanied by weak diuretic and transient natriuretic effects.
Dapagliflozin does not affect other glucose transporters that transport glucose to peripheral tissues and exhibits more than 1,400 times greater selectivity for SGLT2 than SGLT1, the main transporter in the intestine responsible for glucose absorption.
Pharmacodynamics
After taking dapagliflozin by healthy volunteers and patients with type 2 diabetes, an increase in the amount of glucose excreted by the kidneys was observed. When dapagliflozin was taken at a dose of 10 mg / day for 12 weeks, in patients with T2DM, approximately 70 g of glucose per day was excreted by the kidneys (which corresponds to 280 kcal / day). In patients with type 2 diabetes who took dapagliflozin at a dose of 10 mg / day for a long time (up to 2 years), glucose excretion was maintained throughout the course of therapy.
Excretion of glucose by the kidneys with dapagliflozin also leads to osmotic diuresis and an increase in urine volume. The increase in urine volume in patients with type 2 diabetes taking dapagliflozin at a dose of 10 mg / day remained for 12 weeks and amounted to approximately 375 ml / day. The increase in urine volume was accompanied by a small and transient increase in sodium excretion by the kidneys, which did not lead to a change in the concentration of sodium in the blood serum.
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Insulin, sulfonylureas, meglitinides, GLP-1 agonists, DPP-4 inhibitors
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Metformin, thiazolidinediones, pramlintide, SGLT2 inhibitors
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