The latest treatment progress of diabetic nephropathy, better medicine makes us look forward to it
TEDA Hospital, Tianjin University | Li Qing
On July 9, 2021, the U.S. FDA official website published an announcement approving the latest indications for Finerenone (non-nelione) "for reducing the risk of progression to severe kidney disease and cardiac complications in adults with type 2 diabetes mellitus and chronic kidney disease."
In other words, nonelidone can reduce the risk of renal decline, renal failure, cardiovascular death, non-fatal heart attack and heart failure hospitalization in adult patients with type 2 diabetes mellitus and chronic kidney disease, and has a clear cardioprotective effect like liecin hypoglycemic drugs.
The Chinese Guidelines for the Prevention and Treatment of Diabetic Nephrology (2021 Edition), released a few months ago, also recommends non-nelidone: the addition of MRA (aldosterone antagonists) to RAAS blockers (satans, ply antihypertensives) can effectively control blood pressure and reduce proteinuria, but requires attention to the risks of hyperkalemia, AKI (acute kidney injury) and gynecomastia.
As a third-generation MRA nonevelidone has a higher selectivity and affinity for mineralocorticoid receptors, reducing proteinuria in patients with chronic kidney disease without increasing the risk of hyperkalemia.
That is to say, the latest guidelines released by China also recommend non-nelidone for the treatment of type 2 diabetes, which has cardiovascular and renal protective effects and has a high safety profile.
What kind of medicine is nonelidone that has been so grandly recommended?
The first generation of aldosterone receptor antagonist spironolactone is an old diuretic with potassium preservation effect, the earliest combined with potassium excretion diuretic hydrochlorothiazide, furosemide, etc. to increase the diuretic effect and reduce the occurrence of hypokalemia. At present, spironolactone is mainly used for the treatment of hyperaldosteronism, refractory hypertension and heart failure, and is one of the core treatment drugs for heart failure.
However, spironolactone has a side effect, that is, antagonizing aldosterone androgens at the same time, long-term use causes male breast hyperplasia and sexual decline, which makes it difficult for many young and middle-aged male patients to accept.
The second-generation aldosterone antagonist eplerenone has a weak antagonistic effect on androgens, has little effect on male function, and has the same therapeutic effect as spironolactone, but with significantly fewer side effects. However, eplerenone has not been available in China despite many years of availability.
Nonelidone is a third-generation aldosterone receptor antagonist that has a higher selectivity and stronger affinity for aldosterone receptors than the first generation of spironolactone and the second generation of eplerenone, with better therapeutic effects and fewer side effects. What is even more surprising is that nonelidone also has a cardioprotective effect on patients with type 2 diabetes.
At the American College of Nephrology 2020 Kidney Week 2020 on October 26, 2020, the results of an exciting study, the FIDELIO-DKD study, were revealed, showing that the drug nonelidone under investigation can delay the progression of chronic kidney disease in patients with brady kidney disease and type 2 diabetes mellitus, which has a protective effect on both cardiovascular and renal diseases.
The findings were published simultaneously in the New England Journal of Medicine, one of the world's most prominent medical journals. Nonelidone will also become another drug with both cardiac and renal benefits after SGLT2 inhibitors (liecinoid hypoglycemic drugs).
The FIDELIO-DKD study was a randomized, double-blind, controlled, multicenter, event-driven Phase III clinical study that selected 5,734 patients with chronic kidney disease and type 2 diabetes from more than 1,000 centers in 48 countries worldwide.
Enrolled patients were randomly assigned in a 1:1 ratio, and all patients received standard therapy, including hypoglycemic therapy and the maximum tolerated dose of ACEI (praline antihypertensive) or ARB (sartan antihypertensive), with an average follow-up of 2.6 years.
The main indicators of observation and evaluation were: the compound endpoint event of nephropathy, including the first appearance of renal failure, the decrease in glomerular filtration rate (eGFR) by more than 40% in at least 4 weeks, and the risk of kidney death.
Secondary indicators of observation and evaluation were: cardiovascular compound endpoint events, including the first occurrence of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, and length of hospitalization for heart failure.
The study found that, on the basis of standard care, nonelidone significantly reduced renal compound endpoint events by up to 18% and cardiovascular compound endpoint events by up to 14% compared with placebo, as shown in Figure 1.
Figure 1
In layman's terms, Finerenone can significantly reduce the occurrence of kidney failure, delay the decline rate of kidney failure, reduce the occurrence of myocardial infarction and cerebral infarction, reduce death caused by heart and kidney causes and reduce the occurrence of heart failure, with clear cardiovascular and renal protective effects.
In terms of safety, nonelidone was well tolerated, most adverse events were mild or moderate, and the incidence of serious adverse events was even lower than that of placebo. However, the incidence of hyperkalemia-related adverse events was higher than in the placebo group, and the proportion of treatment discontinued due to hyperkalemia was slightly higher than that in the placebo group, but neither group died of hyperkalemia.
On August 28, 2021, the European Cardiovascular Congress published the results of another study of noneligone, THE FIGARO-DKD study, which once again confirmed the cardiovascular protective effect of nonelidone in patients with type 2 diabetes mellitus with renal impairment.
It is suggested that nonelidone can slow the progression of kidney disease and reduce the incidence of cardiovascular events in patients with type 2 diabetes mellitus with severe chronic kidney disease, and whether it is mild proteinuria patients or patients with moderate to severe renal failure (CKD stage 3 to 4), it can benefit the heart and kidneys.
Like the FIDELIO-DKD study, the FIGARO-DKD study was a large-sample, double-blind, 1:1 randomized, placebo-controlled, event-driven clinical study in which all selected patients received the best guideline recommended medications (RAS antagonists) and aggressive antihypertensive and hypoglycemic therapy. On this basis, treatment is carried out with nonelidone.
The study found that nonelidone reduced cardiovascular risk and 23% of renal adverse risk in patients with type 2 diabetes mellitus with all grades of renal insufficiency, and these benefits were obtained on the basis of the standard treatment recommended by the subjects, Figures 2 and 3.
Figure 2
Figure 3
In addition, the most significant effect of nonelidone is the treatment of heart failure, which reduces the occurrence of new heart failure events. In both studies, the significant benefit of nonelidone for cardiovascular events was largely due to a significant decrease in hospitalization rates due to heart failure.
In terms of safety, the incidence of hyperkalemia in the nonelidone group was indeed higher than in the placebo group, but the incidence of hyperkalemia was related to the patient's underlying renal function.
The patients selected in the FIDELLO-DKD study had poor renal function, with an average glomerular filtration rate of 44 ml/min, and the incidence of hyperkalemia was 18.3%, significantly higher than that of the placebo control group of 9.0%, while the kidney function of the patients selected for the FIGARO-DKD study was better, with an average glomerular filtration rate of 68 ml/min, and the incidence of hyperkalemia was 10.8%, significantly higher than that of the placebo control group of 5.3%.
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In both studies, the proportion of investigators who discontinued early due to hyperkalemia was 2.3% and 1.2%, respectively, higher than the 0.9% and 0.4% of the placebo-controlled group, respectively, but the overall proportion was very low, and no fatal adverse events occurred in either study.
In another controlled study with spironolactone, the incidence of hyperkalemia in the nonelidone 10 mg/day and spironolactone 25-50 mg/day groups was 4.5% versus 11.1%, respectively, and the incidence of nonelidone hyperkalemia was lower than that of spironolactone. Therefore, it is safe for nonelidone to be applied to patients with diabetes mellitus with different renal function.
To this end, Professor George L. Bakris of chicago medical university in the United States said that noneligilone will provide an important and evidence-backed new treatment strategy for patients with type 2 diabetes mellitus with chronic kidney disease, Figure 4.
Figure 4
Due to its excellent efficacy, nonelidone is expected to become another effective means of preventing cardiovascular risk in patients with type 2 diabetes mellitus and chronic kidney disease in the future.