"Extraordinary Voice" l Big coffee gathered to discuss a new chapter in T2D-related CKD management

New progress in the diagnosis and treatment of T2D-related CKD

Professor Tong Nanwei of West China Hospital of Sichuan University, Professor Lei Minxiang of Xiangya Hospital of Central South University, and Professor Xu Yushan of the First Affiliated Hospital of Kunming Medical University shared their views on the management and treatment of T2D-related CKD
.

Professor Tong Nanwei pointed out T2D combined with CKD seriously threatens the life and health of patients, and the prevalence of T2D combined with CKD in China is 21.
8%¹, which urgently needs to be effectively managed
.
As the first line of defense for the treatment and delay of the progression of diabetes-related kidney disease, endocrinology should do early screening and early management
.
Lifestyle improvement and risk factor management are the two core concepts of diabetes-related CKD treatment, but the pathogenesis of diabetes-related CKD is complex, and the management of risk factors such as blood glucose and blood pressure is not enough to completely delay the disease process
.
Professor Lei Minxiang emphasized that in addition to optimizing lifestyle management and risk factor management, attention should be paid to drugs that can directly bring heart and kidney benefits to delay disease progression
early.

About For the treatment of T2D-related CKD, Professor Xu Yushan pointed out that blocking the excessive activation of mineralocorticoid receptor (MR) is one of the
important therapeutic targets for adverse cardiac and renal outcomes in patients with T2D-related CKD.
The new generation of nonsteroidal MRA phenirenal ketone has higher potency and selectivity for MR2, which can effectively prevent MR overactivation, strongly inhibit inflammatory fibrosis in the kidneys and heart3,4, and reduce T2D-related Renal risk in patients with ^CKD5, providing a new option
for clinical treatment strategies for T2D-related CKD.

Proteinuria is associated with diabetes Professor Xu Yong of the Affiliated Hospital of Southwest Medical University introduced the
necessity and management strategy of proteinuria management in patients with T2D-related CKD.

Professor Xu Yong pointed out that the presence of proteinuria suggests that the kidney structure and endothelial function are impaired, which is a marker of heart and kidney structure ^damage6-8, and when patients have proteinuria, it will increase the risk of cardiovascular disease and kidney disease9,10^, so the management
of proteinuria should be paid attention to.
Professor Xu Yong emphasized that T2D should initiate urine albumin/creatinine ratio (UACR) screening at the time of diagnosis, and proteinuria management needs to strengthen intervention for underlying diseases, and give priority to drugs
that can improve proteinuria and have both heart and kidney benefits.
The ARTS-DN study confirmed that in patients with diabetic kidney disease (DKD) treated with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor antagonists (ARBs), the addition of phenelidone significantly reduced UACR compared with placebo, and dose-dependent (Figure 1)¹¹
.

Figure 1.
Effect of fenerone vs.
placebo combined with ACEi/ARB on UACR

Fenelidone has sufficient evidence-based medical evidence to fully endorse
its guideline status.
Professor Ji Qiuhe of Xijing Hospital affiliated to the Fourth Military Medical University pointed out in the sharing of "Update and Interpretation of Comprehensive Management Guidelines for Patients with T2D Combined CKD" that the 2022 version of the clinical practice guidelines issued by the Improvement of Kidney Disease Prognosis Organization (KDIGO) added an MRA chapter, which is applicable to the population of fenerolidone, combination drugs, Specific clinical practice guidance
is provided for blood potassium monitoring.
Guidelines recommend that for T2D, estimated glomerular filtration rate (eGFR) ≥ 25 ml/min/1.
73^m2, normal potassium, and proteinuria after using the maximum tolerable dose of renin-angiotensin system inhibitors (RASi) [ In patients ≥30 mg/g (≥3 mg/mmol)], nonsteroidal MRAs (2A) with clear evidence of cardiorenal benefit are recommended, emphasizing that fenerrenone is the only MRA with confirmed evidence of cardiorenal ^benefit12
。

In addition, Professor Tang Zhe of Kunming Yan'an Hospital gave a wonderful speech on the topic of "Management of Hyperkalemia in Patients with T2D-Related CKD", and focused on the harm of hyperkalemia, the prediction of hyperkalemia, the management of acute and chronic hyperkalemia, and the coping strategies
of hyperkalemia during drug treatment.

Professor Tang Zhe pointed out that in addition to its own diseases, daily medication ( RASi, spironolactone, etc.
) also increases the risk of hyperkalemia in patients with T2D and ^CKD13
.
The ARTS study confirmed that patients treated with phenelidone had a lower incidence of hyperkalemia (5.
3% vs.
12.
7%, P = 0.
048)¹⁴ compared with steroidal MRA, with a favorable safety profile
.

Mechanism of action and principle of neosteroidal MRA phenirenal ketone

The pro-inflammatory and profibrotic effects mediated by MR overactivation are key factors leading to adverse renal cardiac outcomes, and fenerone is based on the targeted development of MR pathway, which can effectively delay the progression
of T2D-related CKD.
Professor Yu Xuefeng of Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science and Technology comprehensively analyzed the unique advantages of phenelidone from the molecular structure and mechanism of action of
drugs.

Professor Yu Xuefeng pointed out that fenerone is related to steroids MRA differs
in molecular structure, pharmacological properties, and mechanism of action.
Compared with the flat structure of spironolactone and eplerenone, the bulky stereostructure of fenerone is more selective for ^MR15 and can bind stably to MR
proteins.
In terms of recruitment of transcriptional co-regulators, phenirenal has a stronger effect on blocking MR coactivator binding and inducing co-inhibitor binding4, which can strongly inhibit the expression
of downstream inflammatory and fibrotic genes.
In addition, phenirenal redone has no distribution in the gonads, and the distribution ratio of the kidney heart is close to 1:1^2,3, which can achieve double benefit of the kidney and heart, and the risk of sex-related adverse reactions is low
.

Professor Wang Xinling of Xinjiang Uygur Autonomous Region People's Hospital introduced in detail the dosage, pharmacokinetic characteristics, drug interactions, and safety of fenelidone in the theme sharing of "Clinical Rational Application and Precautions of New MRA", in order to further promote the standardized application
of fenineurone.

• Dosage: Determine the initiation of fenerone, the starting dose and the timing of discontinuation based on serum potassium level and eGFR (Figure 2)¹⁶
  .
  Monitor serum potassium and adjust dose within 4 weeks of initiation of treatment, within 4 weeks after dose adjustment and throughout treatment, and adjust dose as needed (Figure 3)¹⁶
  .
  

  
  

  
  

Figure 2 Usage and dosage of fenerone

Figure 3.
Dose adjustment scheme of fenelidone during treatment

• Pharmacokinetic profile and drug interactions: Phenelidone has a good pharmacokinetic profile and is not affected by age, sex, race/ethnicity, or ^weight16
  .
  There is no interaction with common hypoglycemic drugs, proton pump inhibitors, antacids, etc.
  , and there is no need to adjust the dose when taken ^{together16,17}
  .
  

  
  

• Safety: The incidence of serious adverse reactions and kidney-related adverse reactions of phenirenal refrone was similar to that of placebo, and the effect on blood pressure was moderate, and there was no effect on blood ^glucose17
  .
  

  
  

A list of clinical studies of the new generation of nonsteroidal MRA phenirenal ketone

A new generation MRA fenerone is approved for the treatment of patients with T2D-related CKD, and has attracted clinical attention
because of its significant advantages and good safety in renal and cardiovascular prognosis.
Professor Liu Ping, Professor Tong Nanwei of Ningxia Medical University General Hospital and Professor Yuan Huijuan of Henan Provincial People's Hospital respectively gave in-depth interpretation of the clinical research and Chinese subgroup data of fenelidone, and recognized
the renal and cardiac benefits of fenichlorone.

Professor Liu Ping pointed out that the two phase III clinical studies of fenelidone, FIDELIO-DKD and FIGARO-DKD studies, and the meta-analysis (FIDELITY study) that included these two studies, fully confirmed the treatment of T2D-related CKD by fenerone of cardiorenal benefits and safety
.

• The results of the FIDELIO-DKD study showed that in patients with moderate to severe T2D-related CKD, compared to placebo Phenerone significantly reduced the risk of renal composite endpoints (i.
  e.
  , development of renal failure, persistent decrease in eGFR from baseline ≥40%, or nephropathy-related death) by 18% [hazard ratio (HR) = 0.
  82, 95% confidence interval (CI) 0.
  73–0.
  93, P=0.
  001] and cardiovascular composite endpoint (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) by 14% (HR=0.
  86, 95% CI 0.
  75–0.
  99, P=).
  0.
  03), and the rate of adverse events was comparable to that of the placebo ^group17
  .
  

  
  

• The results of the FIGARO-DKD study showed that in patients with mild to moderate T2D-related CKD, fenerolidone significantly reduced the risk of cardiovascular composite endpoint by 13% compared with placebo (HR=0.
  87, 95% CI 0.
  76-0.
  98, P=0.
  026) (Figure 4), and significantly reduced the risk of exploratory renal composite endpoint by 23% without increasing the risk of renal composite endpoint, The difference was statistically significant (HR=0.
  77, 95% CI 0.
  60-0.
  99, P=0.
  041) (Figure 5).
  
  In addition, there was no significant difference in the overall incidence of adverse events between the finelidone and placebo ^groups18
  .
  

  
  

Figure 4.
Cardiovascular composite endpoint risk of phenirenal versus placebo

Figure 5.
Renal composite endpoint risk of fenerone vs.
placebo

• The FIDELITY study, a pre-set meta-analysis that pooled data from FIDELIO-DKD and FIGARO-DKD, showed that fenelidone significantly reduced renal composite endpoints in patients with mild to severe T2D-related CKD compared with placebo (ie, renal failure, a sustained decrease in eGFR from baseline ≥57%, or nephropathy-related death) risk of 23% (HR 0.
  77, 95% CI 0.
  67–0.
  88, P = 0.
  0002) (Figure 6), The composite cardiovascular endpoint risk was 14% (HR 0.
  86, 95% CI 0.
  78–0.
  95, P=0.
  0018) (Figure 7), suggesting that phenifrone is associated with mild to severe T2D-associated CKD Significant renal cardiac benefit was achieved in all ^patients19
  .
  

  
  

Figure 6.
Renal composite endpoint risk of phenirenal refractorone vs.
placebo

Figure 7.
Cardiovascular composite endpoint risk of phenerone vs.
placebo

Professor Tong Nanwei combined with the current situation of diabetic patients in China, based on China's national conditions, and targeted in the report The Chinese subgroup data of FIDELIO-DKD study were elaborated, which further confirmed the benefits and safety
of fenerone on the heart and kidney of T2D-related CKD patients in China.

The results of the Chinese subgroup ²⁰ of the FIDELIO-DKD study showed that compared with the placebo group, the risk of renal composite endpoint in the fenelidone group was reduced by 41% (HR=0.
59, 95% CI 0.
39-0.
88, P=0.
009), showing a trend of more benefit (Figure).
8）； The risk of cardiovascular composite endpoints was numerically reduced by 25% (HR=0.
75, 95% CI 0.
38-1.
48, P=0.
408), and the trend of cardiovascular benefit was consistent with the overall population (Figure 9).

In addition, the overall incidence of adverse effects and acute kidney injury of phenirenal done was comparable to that of the placebo group, and hyperkalemia was generally controllable
.

Figure 8.
Renal composite endpoint risk of phenirenal refractorone vs.
placebo

Figure 9.
Cardiovascular composite endpoint risk of phenirenal versus placebo

Professor Yuan Huijuan introduced the important subgroup data of phenirenal clinical research and the exploration of other therapeutic areas in detail, further demonstrating the extraordinary therapeutic potential
of fenichlordone.

• Fenelidone in combination with sodium-glucose co-transporter 2 inhibitor (SGLT2i) can achieve significant renal heart benefit: FIDELITY study subgroup analysis showed that fenelidone further improved the cardiovascular composite endpoint and renal composite endpoint compared with placebo when SGLT2i was used at baseline.
  and further reduce the UACR (Figure 10)²¹
  .
  

  
  

Figure 10.
Cardiovascular and renal composite endpoint risk of phenirenal versus placebo plus SGLT2i

• Phenirenal is explored in other therapeutic areas: The FINEARTS-HF study, a multicenter, randomized, double-blind, placebo-controlled trial to explore the impact of phenirenone on morbidity and mortality in patients with symptomatic heart failure, was initiated in November 2020 and is expected to be completed
  in 2024.
  Another ongoing FIND-CKD study to explore the efficacy of fenerrenone in patients with non-diabetic CKD was officially launched in September 2021 with the primary efficacy endpoint being the mean rate of change in eGFR, and the results of the study are awaited
  .
  

summary

T2D-related CKD is a major public health problem facing the world, but the management status of T2D-related CKD in China is not good, and effective therapeutic drugs
are urgently needed clinically.
As the world's first MRA for T2D-related CKD, fenelidone can effectively block the overactivation of MR caused by aldosterone, exert anti-inflammatory and anti-fibrotic effects, delay the progression of kidney disease and reduce the risk of cardiovascular adverse events, and the Chinese subgroup data confirm that fenielidone shows a more obvious renal benefit trend
in Chinese patients.
In the future, it is expected that phenirenal will accumulate more clinical practice evidence and accelerate the benefit of Chinese patients
.

References:

1.
Microvascular Complications Group, Diabetes Branch of Chinese Medical Association.
Chinese Journal of Diabetes, 2021,13(08):762-784.

2.
Kolkhof P, et al.
Handb Exp Pharmacol.
2017; 243:271-305.

3.
Kolkhof P, et al.
J Cardiovasc Pharmacol.
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4.
Grune J, et al.
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5.
Agarwal R, et al.
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6.
Expert Group of Shanghai Clinical Quality Control Center of Nephrology.
Chinese Journal of Nephrology, 2022,38(05):453-464.

7.
Rabelink TJ, et al.
Nat Rev Nephrol.
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2022 Jun 2; 13:858267.

11.
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2015 Sep 1; 314(9):884-94.

12.
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2022 Nov; 102(5S):S1-S127.

13.
Valdivielso JM, et al.
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2021 Sep; 81(13):1467-1489.

14.
Pitt B, Kober L, et al.
Eur Heart J.
2013 Aug; 34(31):2453-63.

15.
Bärfacker L, et al.
ChemMedChem.
2012 Aug; 7(8):1385-403.

16.
Fenelidone (phenirenal tablets) instructions.

17.
Bakris GL, et al.
N Engl J Med.
2020 Dec 3; 383(23):2219-2229.

18.
Pitt B, et al.
N Engl J Med.
2021 Dec 9; 385(24):2252-2263.

19.
Agarwal R, et al.
Eur Heart J.
2022 Feb 10; 43(6):474-484.

20.
Effect of Finerenone on CKD Outcomes in Type 2 Diabetes: A Chinese Subgroup Analysis of the FIDELIO-DKD Study.
2022ASN.
Poster: SA-PO273.

21.
Rossing P, et al.
ASN Kidney Week 2021:oral presentation.
Abstract SA-OR22.

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