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.