Discussion:
Diabetes is the most prevalent cause of chronic kidney disease (CKD) and a risk factor for its development to end-stage renal disease. Patients with diabetes and chronic kidney disease are at a very high risk for cardiovascular (CV) disease, the leading cause of morbidity and mortality.[18] Activation of the RAAS, hypertension, hyperglycemia, dyslipidemia, and proteinuria are well-established risk factors for diabetic kidney disease development. Angiotensin converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), and, more recently, renin inhibitors are therefore routinely administered to these patients. Full doses of these medications slow but do not prevent the deterioration in renal function.[19] Increasing data indicates that mineralocorticoid receptor (MR) signaling is implicated in the development of renal damage, resulting to glomerular and tubular sclerosis independent of angiotensin II. Therefore, mineralocorticoid receptor antagonists (MRAs) have been identified as a dynamic approach for slowing the advancement of CKD progression in patients with residual kidney disease. [20,21] Finerenone, a new MRA have exhibited clinically significant effects on improving renal outcomes and decreasing cardiovascular mortality and morbidity among patients with CKD and T2D. [18] A recent study of FIDELIO-DKD revealed that finerenone decreases the probability of new-onset atrial fibrillation or flutter as well as the risk of kidney or cardiovascular events, regardless of underlying arrhythmia history. In a recent review of FIGARO-DKD in patients with T2D and CKD without a history of symptomatic HFrEF, finerenone resulted to a substantial reduction in the likelihood of clinically significant time-to-event HF outcomes and lowered the likelihood of new-onset hospitalization for HF by 32% compared to placebo. [15,16]
In the total population, patients in the finerenone therapy group had a lower risk of cumulative kidney outcomes such as renal failure, sustained drop to 15 ml/min/1.73 m2, sustained fall of eGFR of >40% from baseline, and mortality from renal etiology as compared to placebo. Similarly, phase 2 trials (ARTS, ARTS-DN, and ARTS-HF) examined the safety and efficacy of different oral dosages of finerenone in diabetic patients with albuminuria taking ACE inhibitors or ARBs. Time to kidney failure, sustained 57% eGFR drop, or renal death was considerably lower in the finerenone group than in the placebo group. [22] In contrast, FIGARO-DKD, a phase 3 trial, demonstrated no significant difference in the incidence of the first secondary composite endpoints (time until first occurrence of kidney failure, a 40% drop from baseline in eGFR for four weeks, or deaths from renal etiologies) between finerenone and placebo groups.[10] Considering cardiovascular outcomes, risks of deaths due to cardiovascular outcomes along with hospitalization due to heart failure and non-fatal MI were significantly decrease as reported by major studies. However, finerenone therapy had no effects in reduction of non-fatal stroke as compared to placebo. In a prototype of post-MI heart failure, smaller doses of finerenone (0.1, 0.3, and 1 mg/kg/day) were compared with 100 mg/kg/day of eplerenone. At a dosage of 1 mg/kg per day, finerenone demonstrated therapeutic efficacy; smaller doses had no effect and were equivalent to eplerenone. Following administration of finerenone, both systolic and diastolic LV functions were significantly enhanced, as were cardiac contractility and relaxation. Likewise, finerenone decreased plasma levels of pro-BNP without affecting blood pressure.[23] In the ARTS-HF trial, it was determined that the proportions of patients achieving a reduction in NT-proBNP levels of >30% at the end of 90 days were comparable for all dosages of finerenone and eplerenone. The combined endpoint of all-cause mortality, cardiovascular hospitalization, or emergency presentation for worsening HF was attained by very few participants receiving finerenone compared to those who received eplerenone, except for those receiving the lowest effective dose of finerenone (2.5–5 mg). Individually, all-cause mortality and cardiovascular hospitalization were more prevalent in the eplerenone group than in the finerenone group (all dosages pooled), with analysis of the maximum finerenone dose (10–20mg) revealing a substantially lower likelihood of each event.[24] In all studies, the incidence of adverse events during treatment was comparable between finerenone and placebo. In contrast, discontinuation due to trial regimen was significantly more prevalent in the treatment group.[5,10,13-17]
Numerous studies have defined the effects of finerenone therapy on the baseline potassium level. Our study analyzed the increased incidence of investigator-reported hyperkalemia, the risk of hyperkalemia as a result of the trial regimen, and the discontinuation of the drug due to elevated potassium levels. Also, the incidence of severe hyperkalemia and hospitalizations due to hyperkalemia increased. Different comparative studies indicate that Finerenone has a lower incidence of hyperkalemia than spironolactone, but comparable effects on NT-ProBNP and albuminuria. [25] While eplerenone is the more sustainable alternative to spironolactone, relatively new therapies such as finerenone may be a viable substitute with a reduced risk of hyperkalemia and equivalent cardiovascular and renal benefits to other selective and nonselective MRAs. Finerenone seems to be well tolerated, has a safe pharmacological profile, and has predictable dose-dependent effects.[25] Finerenone was associated with a reduced risk of hypokalemia compared to placebo. Numerous participants in our study had extensive medical (such as cardiovascular and diabetic outcomes) and medication history at baseline (antihypertensive and antihyperglycemic drugs). We discovered that as a patient’s heart failure worsens, their kidney function will be compromised to varying degrees. The use of potassium-sparing diuretics increases the risk of hyperkalemia in CHF patients receiving MRA therapy who have renal dysfunction. Consequently, it is essential to monitor serum potassium levels. Finerenone has fewer detrimental effects on blood potassium and eGFR than spironolactone or eplerenone.[26]Finerenone therapy was associated with a slight reduction in the risk of acute kidney injury (AKI), while the risk of hospitalization due to AKI and ARF (acute renal failure) remained unchanged. Data supporting the potential MR antagonism as a curative method for preventing the acute and long-term implications of renal ischemia/reperfusion has accumulated in recent years. The majority of studies demonstrating the protective effect of MR antagonism in AKI and its advantage against CKD progression have used steroidal MR antagonists.[27] In patients with CKD and T2DM, the benefits of finerenone outweigh the risks associated with its discontinuation due to AKI.
Our meta-analysis has several benefits (1) As a result of the inclusion of additional studies, the sample size of our meta-analysis is more significant than that of previous meta-analyses, lending credibility to our findings. (2) Various plots and tests, including the funnel plot, Egger’s test, and Begg’s test, were used to calculate publication biases, which revealed no publication bias. (3) The effect of heterogeneous studies on the pooled estimate was determined by a sensitivity analysis. Despite the fact that this analysis produced sufficient statistical evidence, some limitations should be acknowledged. (1) First, the follow-up periods for most studies varied, with some reporting longer periods. Long-term follow-ups are more useful when assessing the efficacy of this therapy in patients with chronic diseases such as CKD and T2DM. (2) A few studies used different doses of finerenone at different time intervals, and the majority of studies did not include doses of finerenone or control groups, which may have created uncertainty. (3) Half of the studies conducted on patients with CKD and T2DM failed to report vital renal and cardiovascular outcomes, such as the number of End-stage kidney disease patients, deaths from renal as well as cardiovascular causes, etc.
Conclusion: According to our meta-analysis, finerenone therapy is associated with favorable renal and cardiovascular outcomes, including a reduction in the risk of end-stage kidney disease and renal failure, as well as a significant decrease in death and hospitalization due to cardiovascular outcomes. The therapy’s favorable therapeutic profile enables it to counteract potassium fluctuations. Therefore, we recommend this therapy in patients with T2DM and CKD. Additionally, additional RCTs of standard quality are required to investigate the additional effects of finerenone therapy in CKD patients with T2DM.