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Finerenone is a new, non-steroidal, highly selective, mineralocorticoid receptor antagonist (MRA).
Different from steroidal MRA (ie spironolactone or eplerenone), Finerenone has higher selectivity for mineralocorticoid receptor (MR), which greatly avoids the occurrence of adverse reactions such as gynecomastia; huge block structure , Stronger affinity, powerfully change the spatial conformation of the mineralocorticoid receptor complex, block the excessive activation of the mineralocorticoid receptor caused by aldosterone, reduce the transcriptional expression of inflammation and fibrosis genes, and inhibit inflammation and fibrosis The effect of chemistry on the structure/function of the kidney ¹.
In November 2020, ASN and NEJM simultaneously released the first phase III clinical study-FIDELIO-DKD, which confirmed the effectiveness and safety of Finerenone in patients with CKD and type 2 diabetes (T2DM) who are using the maximum tolerated dose of ACEI or ARB.
Sex².
The results show that Finerenone can significantly reduce the composite endpoint risk of major renal events by 18%, and significantly reduce the composite endpoint risk of major cardiovascular events by 14%; 4 months after the start of the study, Finerenone can increase the urine albumin/creatinine ratio (UACR) Compared with the baseline, it was reduced by 31%, and continued to maintain a low level.
In terms of safety, the incidence of adverse events in the Finerenone group was comparable to that in the placebo group; however, the rate of discontinuation due to hyperkalemia in the Finerenone group was 2.
3% (vs.
0.
9%), resulting in 1.
4% (vs.
0.
3%) of hospitalized patients.
), all higher than the placebo group.
Finerenone is the world's first mineralocorticoid receptor antagonist (MRA) that is proven to bring both heart and kidney benefits to type 2 diabetes combined with chronic kidney disease.
In a phase II study, it was found that compared with spironolactone, the incidence of hyperkalemia in patients treated with Finerenone was significantly reduced (5.
3% vs 12.
7%), which also triggered academics’ concerns about risk factors for hyperkalemia and management strategies.
Follow ³.
On April 19, 2021, the 2021 World Nephropathy Conference (WCN 21) announced the post-analysis results of the FIDELIO-DKD study, aiming to evaluate the occurrence of blood potassium levels higher than 5.
5mmol/L in patients with CKD and T2DM in the FIDELIO-DKD study Rates and risk factors⁴.
Risk factors for hyperkalemia: Mainly related to baseline serum potassium levels, eGFR levels, and drugs.
Rajiv Agarwal, MD, Indiana University School of Medicine pointed out that the clinical characteristics of patients play an important role in the occurrence and development of hyperkalemia³.
The results of multivariate analysis showed that the baseline serum potassium level>4.
5mmol/L, eGFR<45 mL/min/1.
73m², elevated UACR, and the use of β-blockers and Finerenone were significantly associated with hyperkalemia At baseline, the use of diuretics, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and other drugs can reduce the risk of hyperkalemia (Figure 1), which is in line with the academic community’s previous research on risk factors for hyperkalemia.
Cognition is almost the same⁴.
Figure 1 Multivariate analysis of risk factors for serum potassium levels> 5.
5 mmol/L.
In CKD patients, the imbalance of potassium intake and excretion is the root cause of hyperkalemia.
The main risk factors can be roughly divided into patient clinical characteristics and Drugs affect two major categories.
In terms of the clinical characteristics of patients, they mainly include metabolic acidosis, failure to receive timely dialysis treatment, and insufficient dialysis.
In addition, the use of potassium-sparing diuretics and renin-angiotensin system blockers (RAASi) and other potassium-increasing drugs can also increase the risk of hyperkalemia.
Studies have shown that G3~5 CKD with heart failure, diabetes, and those who are taking potassium-increasing drugs (such as RAASi) over the age of 75 are high-risk groups of hyperkalemia⁵.
Drug-related hyperkalemia: Don’t stop eating due to choking, reduce the dose or discontinue the drug, and ignore the protection of the heart and kidney organs.
Clinicians need to pay attention to: Although RAASi can increase the risk of hyperkalemia, it has important organs such as heart and kidney.
The protective effect can reduce urine protein and delay the progression of kidney disease.
In order to ensure the maximum survival benefit of patients, it is recommended to avoid stopping or reducing the dose as much as possible under the condition of active control of serum potassium.
The process is shown in Figure 26,7.
Figure 2 During the dose adjustment of ACEi or ARB treatment, serum creatinine and serum potassium levels and side effects should be monitored.
Source: 2020KDIGO Clinical Practice Guidelines: Diabetes Management in Patients with Chronic Kidney Disease Although FIDELIO-DKD post-mortem analysis found that during the average follow-up study period of 2.
6 years , Both groups of patients continue to have the risk of serum potassium levels> 5.
5mmol/L, and the cumulative incidence of the Finerenone group is higher than that of the placebo group (21.
4% vs 9.
2%), but the following blood potassium management strategies were followed during the study period (as shown in the figure) 3) Effectively control the adverse clinical outcome caused by hyperkalemia: The proportion of the Finerenone group who discontinued the drug due to hyperkalemia was only 2.
3%, resulting in only 1.
4% of hospitalized patients, and no deaths.
At the same time, it ensures the medium and long-term protective effect of CKD combined with T2DM on the important organs of the kidney and heart: Finerenone significantly reduces proteinuria, delays the progression of renal function, and reduces the occurrence of major renal and cardiac adverse events; subgroup analysis also shows that regardless of the patient’s age and gender , Baseline serum potassium, eGFR and UACR levels, Finerenone maintained consistent benefits, as shown in Table 1.
Figure 3 Blood potassium management strategy Table 1 The analysis of each subgroup indicates that Finerenone brings consistent organ protection benefits.
How to detect and intervene in CKD patients with hyperkalemia as soon as possible? Regular follow-up is the key! Once hyperkalemia occurs in patients with CKD, they are prone to frequent attacks afterwards.
Therefore, reasonable monitoring of serum potassium is an important part of ensuring long-term serum potassium management in CKD patients.
Due to the continuous progress of CKD disease, there may be multiple complications and comorbidities at the same time.
Studies have shown that CKD patients and one or more aggravating factors (such as hyperglycemia, insulin deficiency, low renin aldosterone deficiency, use of RAASi) superimposed, can cause repeated episodes of hyperkalemia.
In addition, blood potassium levels in CKD patients are constantly changing, and abnormal blood potassium usually has no obvious symptoms and signs.
Therefore, it is necessary to increase the frequency of blood potassium testing in high-risk groups in order to detect abnormal fluctuations in blood potassium in time.
Regular follow-up and monitoring of serum potassium are of great significance for preventing recurrent episodes of hyperkalemia in CKD patients.
Specific recommendations are shown in Table 2⁶.
Table 2 Serum potassium monitoring in CKD patients Summary Finerenone is the world's first mineralocorticoid receptor antagonist (MRA) that has been proven to bring both heart and kidney benefits to CKD combined with T2DM.
Although compared with steroidal MRAs such as spironolactone, there are fewer side effects and a lower risk of hyperkalemia.
However, based on the maximum tolerated dose of RAASi, hyperkalemia still occurs in the study.
Fortunately, the FIDELIO DKD study aimed at the blood potassium level, through an appropriate dose adjustment program, to minimize the clinical harm caused by hyperkalemia, and effectively took into account the long-term protection and safety of the heart and kidney of patients with CKD and T2DM.
The risk factors of hyperkalemia mainly depend on the blood potassium level, eGFR level and drug influence before the medication; but in order to ensure the long-term benefit for the heart and kidney of CKD patients, it is necessary to avoid rashly reducing the blood potassium level when the blood potassium is found to be elevated.
Or stop drugs such as RAASi.
For high-risk populations of hyperkalemia, regular follow-up and monitoring of blood potassium levels should be carried out to achieve early detection and timely effective blood potassium management to improve the prognosis of patients and improve the quality of life of patients.
This is the long-term solution. References: 1.
Gerasimos Filippatos,etal.
Arandomized controlled study of finerenone vs.
eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidneydisease Eur Heart J.
2016 Jul 14; 37(27): 2105–2114.
2.
George L.
Bakris, RajivAgarwal, Stefan D.
Anker, et al.
Effect of Finerenone on Chronic Kidney DiseaseOutcomes in Type 2 Diabetes.
N Engl J Med 2020; 383: 2219-2229.
3.
Bertram Pitt, LarsKober, Piotr Ponikowski, et al.
Safety and tolerability of the novelnon-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: arandomized, double-blind trial.
Eur Heart J.
2013 Aug 14; 34(31): 2453–2463.
4 .
Rajiv Agarwal, DanWilson, Amer Joseph, et al.
Incidence and predictors of hyperkalemia in patients with CKD and T2D in the FIDELIO-DKD trial.
WCN21-0607.
5.
Mei Changlin, Chen Xiaonong, Hao Chuanming, et al.
Expert advice on risk assessment and management of chronic kidney disease hyperkalemia (2020 edition).
Chinese Medical Journal.
2020;100(44):3489-3493.
6.
Chinese Medical Association Nephrology Branch Expert Group.
Expert consensus on the practice of potassium management for patients with chronic kidney disease in China.
Chinese Journal of Kidney.
2020;36(10):781-792.
7.
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group.
KDIGO 2020 ClinicalPractice Guideline for Diabetes Management in Chronic Kidney Disease.
KidneyInt.
2020 Oct;98(4S):S1-S115.
Different from steroidal MRA (ie spironolactone or eplerenone), Finerenone has higher selectivity for mineralocorticoid receptor (MR), which greatly avoids the occurrence of adverse reactions such as gynecomastia; huge block structure , Stronger affinity, powerfully change the spatial conformation of the mineralocorticoid receptor complex, block the excessive activation of the mineralocorticoid receptor caused by aldosterone, reduce the transcriptional expression of inflammation and fibrosis genes, and inhibit inflammation and fibrosis The effect of chemistry on the structure/function of the kidney ¹.
In November 2020, ASN and NEJM simultaneously released the first phase III clinical study-FIDELIO-DKD, which confirmed the effectiveness and safety of Finerenone in patients with CKD and type 2 diabetes (T2DM) who are using the maximum tolerated dose of ACEI or ARB.
Sex².
The results show that Finerenone can significantly reduce the composite endpoint risk of major renal events by 18%, and significantly reduce the composite endpoint risk of major cardiovascular events by 14%; 4 months after the start of the study, Finerenone can increase the urine albumin/creatinine ratio (UACR) Compared with the baseline, it was reduced by 31%, and continued to maintain a low level.
In terms of safety, the incidence of adverse events in the Finerenone group was comparable to that in the placebo group; however, the rate of discontinuation due to hyperkalemia in the Finerenone group was 2.
3% (vs.
0.
9%), resulting in 1.
4% (vs.
0.
3%) of hospitalized patients.
), all higher than the placebo group.
Finerenone is the world's first mineralocorticoid receptor antagonist (MRA) that is proven to bring both heart and kidney benefits to type 2 diabetes combined with chronic kidney disease.
In a phase II study, it was found that compared with spironolactone, the incidence of hyperkalemia in patients treated with Finerenone was significantly reduced (5.
3% vs 12.
7%), which also triggered academics’ concerns about risk factors for hyperkalemia and management strategies.
Follow ³.
On April 19, 2021, the 2021 World Nephropathy Conference (WCN 21) announced the post-analysis results of the FIDELIO-DKD study, aiming to evaluate the occurrence of blood potassium levels higher than 5.
5mmol/L in patients with CKD and T2DM in the FIDELIO-DKD study Rates and risk factors⁴.
Risk factors for hyperkalemia: Mainly related to baseline serum potassium levels, eGFR levels, and drugs.
Rajiv Agarwal, MD, Indiana University School of Medicine pointed out that the clinical characteristics of patients play an important role in the occurrence and development of hyperkalemia³.
The results of multivariate analysis showed that the baseline serum potassium level>4.
5mmol/L, eGFR<45 mL/min/1.
73m², elevated UACR, and the use of β-blockers and Finerenone were significantly associated with hyperkalemia At baseline, the use of diuretics, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and other drugs can reduce the risk of hyperkalemia (Figure 1), which is in line with the academic community’s previous research on risk factors for hyperkalemia.
Cognition is almost the same⁴.
Figure 1 Multivariate analysis of risk factors for serum potassium levels> 5.
5 mmol/L.
In CKD patients, the imbalance of potassium intake and excretion is the root cause of hyperkalemia.
The main risk factors can be roughly divided into patient clinical characteristics and Drugs affect two major categories.
In terms of the clinical characteristics of patients, they mainly include metabolic acidosis, failure to receive timely dialysis treatment, and insufficient dialysis.
In addition, the use of potassium-sparing diuretics and renin-angiotensin system blockers (RAASi) and other potassium-increasing drugs can also increase the risk of hyperkalemia.
Studies have shown that G3~5 CKD with heart failure, diabetes, and those who are taking potassium-increasing drugs (such as RAASi) over the age of 75 are high-risk groups of hyperkalemia⁵.
Drug-related hyperkalemia: Don’t stop eating due to choking, reduce the dose or discontinue the drug, and ignore the protection of the heart and kidney organs.
Clinicians need to pay attention to: Although RAASi can increase the risk of hyperkalemia, it has important organs such as heart and kidney.
The protective effect can reduce urine protein and delay the progression of kidney disease.
In order to ensure the maximum survival benefit of patients, it is recommended to avoid stopping or reducing the dose as much as possible under the condition of active control of serum potassium.
The process is shown in Figure 26,7.
Figure 2 During the dose adjustment of ACEi or ARB treatment, serum creatinine and serum potassium levels and side effects should be monitored.
Source: 2020KDIGO Clinical Practice Guidelines: Diabetes Management in Patients with Chronic Kidney Disease Although FIDELIO-DKD post-mortem analysis found that during the average follow-up study period of 2.
6 years , Both groups of patients continue to have the risk of serum potassium levels> 5.
5mmol/L, and the cumulative incidence of the Finerenone group is higher than that of the placebo group (21.
4% vs 9.
2%), but the following blood potassium management strategies were followed during the study period (as shown in the figure) 3) Effectively control the adverse clinical outcome caused by hyperkalemia: The proportion of the Finerenone group who discontinued the drug due to hyperkalemia was only 2.
3%, resulting in only 1.
4% of hospitalized patients, and no deaths.
At the same time, it ensures the medium and long-term protective effect of CKD combined with T2DM on the important organs of the kidney and heart: Finerenone significantly reduces proteinuria, delays the progression of renal function, and reduces the occurrence of major renal and cardiac adverse events; subgroup analysis also shows that regardless of the patient’s age and gender , Baseline serum potassium, eGFR and UACR levels, Finerenone maintained consistent benefits, as shown in Table 1.
Figure 3 Blood potassium management strategy Table 1 The analysis of each subgroup indicates that Finerenone brings consistent organ protection benefits.
How to detect and intervene in CKD patients with hyperkalemia as soon as possible? Regular follow-up is the key! Once hyperkalemia occurs in patients with CKD, they are prone to frequent attacks afterwards.
Therefore, reasonable monitoring of serum potassium is an important part of ensuring long-term serum potassium management in CKD patients.
Due to the continuous progress of CKD disease, there may be multiple complications and comorbidities at the same time.
Studies have shown that CKD patients and one or more aggravating factors (such as hyperglycemia, insulin deficiency, low renin aldosterone deficiency, use of RAASi) superimposed, can cause repeated episodes of hyperkalemia.
In addition, blood potassium levels in CKD patients are constantly changing, and abnormal blood potassium usually has no obvious symptoms and signs.
Therefore, it is necessary to increase the frequency of blood potassium testing in high-risk groups in order to detect abnormal fluctuations in blood potassium in time.
Regular follow-up and monitoring of serum potassium are of great significance for preventing recurrent episodes of hyperkalemia in CKD patients.
Specific recommendations are shown in Table 2⁶.
Table 2 Serum potassium monitoring in CKD patients Summary Finerenone is the world's first mineralocorticoid receptor antagonist (MRA) that has been proven to bring both heart and kidney benefits to CKD combined with T2DM.
Although compared with steroidal MRAs such as spironolactone, there are fewer side effects and a lower risk of hyperkalemia.
However, based on the maximum tolerated dose of RAASi, hyperkalemia still occurs in the study.
Fortunately, the FIDELIO DKD study aimed at the blood potassium level, through an appropriate dose adjustment program, to minimize the clinical harm caused by hyperkalemia, and effectively took into account the long-term protection and safety of the heart and kidney of patients with CKD and T2DM.
The risk factors of hyperkalemia mainly depend on the blood potassium level, eGFR level and drug influence before the medication; but in order to ensure the long-term benefit for the heart and kidney of CKD patients, it is necessary to avoid rashly reducing the blood potassium level when the blood potassium is found to be elevated.
Or stop drugs such as RAASi.
For high-risk populations of hyperkalemia, regular follow-up and monitoring of blood potassium levels should be carried out to achieve early detection and timely effective blood potassium management to improve the prognosis of patients and improve the quality of life of patients.
This is the long-term solution. References: 1.
Gerasimos Filippatos,etal.
Arandomized controlled study of finerenone vs.
eplerenone in patients with worsening chronic heart failure and diabetes mellitus and/or chronic kidneydisease Eur Heart J.
2016 Jul 14; 37(27): 2105–2114.
2.
George L.
Bakris, RajivAgarwal, Stefan D.
Anker, et al.
Effect of Finerenone on Chronic Kidney DiseaseOutcomes in Type 2 Diabetes.
N Engl J Med 2020; 383: 2219-2229.
3.
Bertram Pitt, LarsKober, Piotr Ponikowski, et al.
Safety and tolerability of the novelnon-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: arandomized, double-blind trial.
Eur Heart J.
2013 Aug 14; 34(31): 2453–2463.
4 .
Rajiv Agarwal, DanWilson, Amer Joseph, et al.
Incidence and predictors of hyperkalemia in patients with CKD and T2D in the FIDELIO-DKD trial.
WCN21-0607.
5.
Mei Changlin, Chen Xiaonong, Hao Chuanming, et al.
Expert advice on risk assessment and management of chronic kidney disease hyperkalemia (2020 edition).
Chinese Medical Journal.
2020;100(44):3489-3493.
6.
Chinese Medical Association Nephrology Branch Expert Group.
Expert consensus on the practice of potassium management for patients with chronic kidney disease in China.
Chinese Journal of Kidney.
2020;36(10):781-792.
7.
Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group.
KDIGO 2020 ClinicalPractice Guideline for Diabetes Management in Chronic Kidney Disease.
KidneyInt.
2020 Oct;98(4S):S1-S115.
