——Interpretation of new strategies for the management of patients with type 2 diabetes mellitus combined with CKD
Recently, the 2022 edition of the American Diabetes Association (ADA) Diabetes Diagnosis and Treatment Standards was updated and released [1]. Among them, regarding the treatment of type 2 diabetes mellitus (T2D) combined with chronic kidney disease (CKD), the new drug finerenone debuted and was highly recommended, which has aroused clinical attention as a major update highlight of the 2022 ADA guidelines.
I. Quick Overview of Key Points: Comprehensive Management Strategies for T2D patients with CKD, What are the main recommendations of the 2022 ADA Guidelines?
Screening for CKD
The overall management of CKD in diabetic patients includes screening and treatment. With regard to screening, for patients with type 1 diabetes with a duration of ≥ 5 years and all patients with T2D, the 2022 ADA guideline recommends that urinary albumin (e.g., urine albumin-to-creatinine ratio, UACR) and estimated glomerular filtration rate (eGFR) should be checked at least once a year for patients with diabetes with a UACR ≥300 mg/g or eGFR 30 to 60 ml/min/1.73 m2, and that testing should be done at least twice a year to guide treatment [1]. The guidelines also state that for patients with CKD with a UACR ≥300 mg/g, it is recommended to reduce the UACR by ≥30% to slow the progression of CKD.
Treatment of CKD
CKD treatment for diabetics includes nutritional therapy, treatment of underlying diseases, and drug interventions. The maximum daily protein intake should be 0.8 g/kg bw in nondialysis patients with stage CKD and above, and an appropriate increase in protein intake should be considered in dialysis patients [1]. Treatment of underlying disease includes good glucose control, blood pressure reduction, etc., and ACEI/ARB drugs are recommended for patients with hypertension, but not for those with normal blood pressure [1].
In addition to the above standard treatments, the biggest update of the 2022 ADA guidelines for T2D combined with CKD treatment is the first introduction of the new drug nonelidone, which is highly recommended [1]:
For patients with CKD who have an increased risk of cardiovascular events or CKD progression, or who are unable to use SGLT2 inhibitors, the use of nonsteroidal mineralocorticoid receptor antagonists (MRA) non-nelidones is recommended to reduce the risk of CKD progression and cardiovascular events. A
Evidence-based support: What is the basis for the strong recommendation of the 2022 ADA guidelines?
The first time that nonelidone has appeared on the stage of ADA guidelines and has been recommended at the highest level is based on sufficient evidence-based medical evidence that has emerged in recent years. Let's take a look at what are the main clinical research evidence for noneliglione? What are the clinical benefits for patients with T2D and CKD?
FIDELIO-DKD study: A key study of noneligone recommended by ADA guidelines and approved by the U.S. FDA
The nonelidone phase III clinical program, which included two studies, FIDELIO-DKD and FIGARO-DKD, included more than 13,000 patients worldwide, covering patients with CKD with T2D of varying severity from early to advanced disease, and aimed to assess the renal and cardiovascular benefits of nonelidone compared with placebo on the basis of standard care.
Among them, the FIDELIO-DKD study was first published in October 2020[2], a milestone study that makes noneligone the first MRA drug to be confirmed to provide cardiac and kidney benefits for patients with T2D and CKD!
The FIDELIO-DKD study was a randomized, double-blind, placebo-controlled, parallel, multicenter, event-driven Phase III study enrolling 5734 patients with T2D with CKD from 48 countries worldwide. On the basis of standard therapy, patients were randomized to receive either noneliglione 10 mg/20 mg or placebo (n=2841) once daily; standard therapy consisted of hypoglycemic therapy and a maximum tolerated dose of RAS blockers such as ACEI or ARB. Median follow-up was 2.6 years. The inclusion criteria covered patients with moderate to severe CKD with T2D, with UACR in the range of 30 to 5000 mg/g and eGFR ≥ 25 to 2.
Results showed that fenailidone significantly improved renal and cardiovascular outcomes:
Renal outcomes: nonelidone significantly reduced the risk of major renal event complex endpoints (renal failure, sustained reduction of eGFR from baseline for at least four weeks≥40 percent, or death from kidney disease) by 18 percent (HR 0.82, 95 percent CI: 0.73 to 0.93, P=0.001, figure 1) [2].
Figure 1. FIDELIO-DKD study:
Nonelidone significantly reduced the risk of a composite endpoint of major renal events
Cardiovascular outcomes: noneliglione significantly reduced the risk of complex endpoints for key secondary cardiovascular events (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) by 14 percent (HR 0.86, 95% CI: 0.75 to 0.99, P=0.03, Figure 2) [2].
Figure 2. FIDELIO-DKD study:
Nonelidone significantly reduced the risk of a composite endpoint of critical secondary cardiovascular events
Based on strong evidence from the FIDELIO-DKD study, the U.S. Food and Drug Administration (FDA) approved non-nelidone in July 2021 to reduce the risk of persistent decline in eGFR, end-stage renal disease (ESRD), cardiovascular death, nonfatal myocardial infarction, and hospitalization for heart failure in adult patients with CKD and T2D. The 2022 ADA guidelines include noneliglione for the first time and are highly recommended for the treatment of patients with T2D with CKD, with the FIDELIO-DKD study being the main evidence-based underpinning. The 2022 ADA guidelines also specifically state that 4.5 percent of patients in the overall population of the study have been treated with SGLT2 inhibitors, on the basis of which nonelidone can still provide further benefits [1].
Other new evidence is emerging: the FIGARO-DKD and FIDELITY studies
Following the FIDELIO-DKD study, the FIGARO-DKD and FIDELITY studies were released in 2021, adding evidence to the renal benefits of noneligone treatment in patients with T2D combined with CKD.
FIGARO-DKD study[3]: This is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, event-driven phase III clinical study in which 7437 patients with T2D with mild to moderate CKD were enrolled in 47 countries worldwide. On the basis of standard therapy (the largest dose of RAS inhibitor therapy available to patients), patients were randomized to receive either oral or placebo with nonneeridone 10 mg/20 mg per day, with a median follow-up of 3.4 years. On the basis of standard care, noneliglione significantly reduced the risk of a compound endpoint of cardiovascular events by 13%, the risk of a sustained decline in eGFR by ≥ the risk of a 57% renal compound endpoint by 23%.
FIDELITY study[4]: This is a pre-programmed meta-analysis of individualized patient data from two fidelio-DKD and FIGARO-DKD studies, including 13,171 patients with T2D with mild to severe CKD, randomized noneligone or placebo on a standard basis, with a median follow-up of 3 years. On the basis of standard care, nonelidone significantly reduced sustained reduction in eGFR≥ 57% risk of renal compound endpoints by 23%, and cardiovascular event composite endpoint risk by 14%.
The FIGARO-DKD and FIDELITY studies reaffirm that nonelidone significantly delays nephropathy progression and improves cardiovascular outcomes in a wide range of patients with T2D with varying severity, with the main results shown in table 1 [3-6].
Table 1. A list of key findings from the FIGARO-DKD and FIDELITY studies
(Nonelidone group vs. placebo group)
Third, the clinical prospects: non-nerolidone or change the treatment pattern of diabetic nephropathy
Patients with diabetes mellitus with CKD have a severe disease burden, and treatment has been slow and difficult over the past many years, and patients with T2DM with CKD have a fairly high risk of nephropathy progression and residual cardiovascular disease even with existing standard therapy [7,8]. There is an urgent need for new treatment methods to further improve the prognosis of patients, and the emergence of nonelidone provides a new and powerful means to break through the existing treatment dilemma.
So why can nonelidones benefit the kidney heart in patients with T2D and CKD? From a mechanism point of view, hyperactivation of the mineralocorticoid receptor (MR) can lead to damage to target organs such as kidneys (proteinuria, glomerulosclerosis, etc.), heart (myocardial hypertrophy, ventricular remodeling, myocardial ischemia/infarction, etc.), and blood vessels (fibrosis, increased stiffness, etc.). Therefore, blocking MR hyperactivation is an important therapeutic target for T2D combined with CKD. As a new generation of NSAIS with high selectivity, nonelidone is more selective, more affinity, more potent and safer than previous steroidal MRAs[9], effectively blocking many damages caused by overactivation of mineralocorticoid receptors.
Currently, fernalidone is the only MRA approved by the U.S. FDA for the treatment of patients with T2D and CKD. Recently, the European Medicines Agency's (EMA) Commission on Medicinal Products for Human Use (CHMP) has issued a positive review opinion recommending the approval of non-nerolidone for the treatment of T2D-related chronic kidney disease in adult patients. On the mainland, fenailidone has filed a marketing application with China's State Drug Administration (NMPA) and is in the review stage.
IV. Conclusion
A major update to the 2022 ADA guidelines, which for the first time includes and highly recommends noneligilone therapy for patients with T2D combined with CKD, opens up a new paradigm in the treatment of diabetic nephropathy. Nonelidone is the first MRA drug to be shown to provide renal and cardiovascular benefits for patients with T2D and CKD, with strong evidence-based support for FIDELIO-DKD, FIGARO-DKD and FIDELITY studies, and has broad clinical application prospects. It is expected that the drug will be approved in China as soon as possible to benefit more patients.
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