Finerenone (Fn), is a non-steroidal selective mineralocorticoid receptor antagonist (MRA), that induces less hyper-k+but may possess other beneficial
Finerenone in patients with diabetic kidney disease (Nov. 2020)
Finerenone (Fn), is a non-steroidal selective mineralocorticoid receptor antagonist (MRA), that induces less hyper-k+ as compared to the steroidal MRAs (e.g., spironolactone) but may possess other beneficial effects of aborting the mineralocorticoid receptor, e.g. anti-inflammatory & antifibrotic effects. In the Fn in FIDELIO-DKD trial, in which almost 6000 ptns with type 2 DM & either severely or moderately increased albuminuria + retinopathy were randomly assigned to Fn or placebo, those receiving Fn had a 👉 slower decline in eGRF & non-significantly lower rates of ESRD & ALL-cause MR. However, the additive benefit of Fn in ptns with diabetic renal disease and receiving both an angiotensin inhibitor + sodium-glucose co-transporter 2 (SGLT2i) inhibitor has not been assessed, so, the role of Fn in the management of diabetic kidney disease still uncertain.
Treatment of diabetic kidney disease(DKD).
Abbreviations:
o Fn: Finerenone,
o DKD: Diabetic kidney disease
o ACEi: Angiotensin converting enzyme inhibitor
o ARBs: Angiotensin receptor antagonists
o CVS: Cardiovascular system
o RAS: Renin angiotensin system
o MRA: mineralocorticoid receptor antagonist,
o DPP-4i: Dipeptidyl peptidase inhibitors.
o SGLT2i: sodium-glucose co-transporter 2 inhibitor.
o GLP-1RA: Glucagon-like peptide 1 receptor agonists,
o DAPA-CKD: Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial,
o CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial
o FIDELIO-DKD: Reducing Kidney Failure & Disease Progression in Diabetic Kidney Disease trial,
o EMPA-REG OUTCOME: Empagliflozin CVS Outcome Event Trial in Type 2 DM Ptns trial,
o CANVAS: Canagliflozin CVS Assessment Study program,
o DECLARE-TIMI 58: Dapagliflozin Effect on CVS Events-Thrombolysis in MI 58 trial,
o EMPEROR: Reduced: Empagliflozin Outcome Trial in ptns with Chronic HF and Reduced Ejection Fraction trial
Type2DM +CKD: SGLT2i: added to the general measures + ACEi/ARB in albuminuric ptns, Na+-glucose co-transporter 2 inhibitors (SGLT2i) has been suggested:
o SGLT2i: addition to type 2 DM & DKD ptns therapy with SGLT2i. SGLT2i therapy should be generally avoided among ptns with eGFR <25-30 mL/min/1.73 m2 despite they can be given safely with eGFR < 25 mL/min/1.73 m2. These agents should be used cautiously with previous LL amputation or possibility of amputation (e.g., LL ulcer & PVD). If canagliflozin (Invokana) is given, target dose is 100 mg once/d. Initial dose of other SGLT2i (e.g., 10 mg once/d of dapagliflozin (Forxiga) or empagliflozin 10 mg once/d.) are accepted therapy for DKD in type 2 DM.
o SGLT2i can impede important renal endpoints e.g., ESKD. Despite the risk decline of RF is the same with/without highly elevated albuminuria (urinary albumin ≥300 mg/d), absolute risk decline is higher with severely elevated albuminuria. So, current recommendations are stronger for SGLT2i use with severely elevated albuminuria than normo-albuminuric ptns or moderately elevated albuminuria.
2 ✌ agents have been shown to improve outcome in type 2 DM + kidney disease:
1) GLP-1RA: SGLT2i have a weak glucose-lowering effect, especially with lowered eGFR, so, ptns with uncontrolled HBA1c may need additional anti-diabetic agents. Apart from SGLT2i, glucose-lowering agents with the strongest evidence of benefit on CVS & renal outcome with pre-existing CVS or renal disease are the 👉 GLP-1RA. Thus, with type 2 DM+DKD and no glycaemic control despite initial (metformin) & an SGLT2i, a GLP-1RA may provide better glycaemic control with additional benefits.
2) MRAs: 👉Fn, a non-steroidal selective MRA, decrease the progression of renal dysfunction & CVS events in type 2 DM+DKD, while not affecting BP & slightly elevated K+. Fn has been tested in ptns with maximal toleration of ACEi/ARBs but has not been studied in ptns taking SGLT2i + maximally tolerated doses of ACEi/ARBs.
SGLT2i can block glucose reabsorption in proximal tubule via SGLT2 that lowers renal glucose threshold and > evident glycosuria. Glycosuria relies mainly on renal function, so, level of glycosuria & decline of blood glucose is diminished with renal dysfunction.
SGLT2i have more impacts on the kidney, & considering their weak glucose-lowering impact, these beneficial effects are probably independent of glycemic control. By blocking co-transporter, they decrease Na+ reabsorption, that’s usually augmented in diabetics given the magnitude of tubular glucose load. Natriuresis limits the intra-vascular volume & BP, however, Na+ delivery to the macula densa will increase. Increasing Na+ delivery to macula densa normalizing tubulo-glomerular feedback & so reducing intraglomerular tension (i.e., reducing GFR) via constricting the abnormally dilated afferent arteriole. This decline in GFR may slow the rate of renal disease progression. A variety of mechanisms can explain the beneficial impacts of SGLT2i on renal disease deterioration, an effect that can be observed in ptns with DKD on ACEi/ ARBs, in addition to ameliorating CVS events. In DKD ptns + higher albuminuria, the best data can be derived from 2 large studies:
1) CREDENCE trial has compared canagliflozin (Invokana) (100 mg/once/d.) with placebo in 4401 diabetics with eGFR: 30-89 mL/min/1.73 m2 & urine ACR >300 mg/g despite therapy ACEi/ARB. After 2.6 ys, canagliflozin decreased the incidence of ESRD, doubled SCr, hospital admission for HF, CVS mortality, and all-cause MR.
2) In A similar (DAPA-CKD) trial, 4304 individuals with eGFR 25-75 mL/min/1.73 m2 & urine ACR 200-5000 mg/g were randomly given to dapagliflozin (Forxiga 10 mg/ d.) or placebo. About 2/3rds of the conducted ptns with type 2 DM; 98 % were on ACEi or ARB. At 2.4 ys, dapagliflozin decreased all-cause MR, as well as incidence of ESKD, and limited the risk by 50 % or more decline in eGFR. Benefits dapagliflozin was similar in DKD and in other causes of kidney disease, supporting that these benefits are independent of glycemic control.
Many trials of SGLT2i in type 2 DM involving ptns having mostly non-albuminuric DKD, including EMPA-REG OUTCOME, CANVAS program, DECLARE-TIMI 58 & EMPEROR-Reduced trial. Meta-analysis: 38,723 ptns in CREDENCE trial + 3 more studies, SGLT2i 👉 decreased the risk of developing ESKD, lost renal function (= doubled SCr or 40 % or more decline in eGFR), or death due to renal disease, regardless the baseline albumin excretion or use of RASi. Relative risk diminution induced by SGLT2i was similar with urine ACRs of <30 mg/g, 30-299 mg/g, & ≥300 mg/g. However, event rating was higher with ACR ≥300 mg/g as compared with ACR of 30-299 or <30 mg/g. So, despite the same relative risk reduction, absolute advantages were higher among ptns with higher albuminuria. SGLT2i also can reduce the rate of CVS events with established atherosclerotic CVS disease in EMPA-REG OUTCOME, CANVAS, & DECLARE-TIMI 58, regardless the presence of DKD. These agents may also reduce HF hospitalization & death in ptns having {HF + reduced EF}.
SGLT2i may increase genital infection risk by 2-4 folds; including vulvovaginal candid-iasis observed in 10-15 % of ladies receiving these agents. SGLT2i are also rarely show Fournier's gangrene. Moreover, SGLT2i can induce "euglycemic" diabetic ketoacidosis in type 1 DM (rare in type 2) and may be complicated with an increased risk of lower limbs amputation. So, ptns with PH of or risk factors for genital infection or LL amputation should NOT receive SGLT2i. In DKD with lowered risk for renal disease progression, and with no settled atherosclerotic CVS disease or HF, benefits/harms with SGLT2i should be optimized.
Contraindications & precautions: DO 👆NOT use SGLT2i with the following:
1) DM type 1.
2) Previous diabetic ketoacidosis (DKA.
3) DM Type 2 with eGFR <60 mL/min/1.73 m2 (ertugliflozin) or <45 mL/min/1.73 m2 (dapagliflozin, empagliflozin), or <30 mL/min/1.73 m2 (canagliflozin),
SGLT2i hv less glycemic benefit with more severe renal disease, and all SGLT2i should be stopped with eGFR <30 mL/min/1.73 m2. However, SGLT2i have documented renal benefits with eGFR ≥30 mL/min/1.73m2. Avoid SGLT2i with the following (higher risk):
1) Low BMD & higher risk fracture & falling.
2) Frequent bacterial UTI or genitourinary yeast infection.
3) Foot ulcers (e.g., neuropathy, deformed foot, PVD, previous foot ulcers).
4) Predisposing factors to DKA (ketosis-prone DM type 2, pancreatic deficiency, drug/alcohol abuse)
GLP-1RA liraglutide (Victoza) decreased incidence of composite renal endpoints (= newly observed albuminuria >300 mg/d, doubled SCr, ESRD & related deaths) shown in a large trial with DM type 2. However, this effect was mainly related to diminished new-onset albuminuria. Similar results, showed by the GLP-1RA dulaglutide (Trulicity) with slowing of eGFR decline + prevention of worsen albuminuria in trials of type 2 DM with /without CKD. So, if adding of anti-diabetic is warranted in DKD despite initial glucose-adjustment & an SGLT2i, then a GLP-1RA member is preferred. Moreover, GLP-1RA can also limit the rates of CVS events. By inhibiting DPP4, DPP-4i prohibit deactivation of bioactive peptides, including GLP-1 with modest rise in GLP-1. However, unlike GLP-1RA, DPP-4i cannot prevent evolution/progression of renal disease in DM, nor having any CVS benefit.
The activated mineralocorticoid receptor may lead > CVS & renal disease, primarily via triggering the inflammatory/fibrotic cascade. Steroidal MRAs, e.g., spironolactone, decreases albuminuria in DKD but can induce hyper-k+ with lowered eGFR, especially with ACEi/ARBs use. However, the non-steroidal MRA Fn can also decrease albuminuria with smaller impact on K+. Fn impact on renal disease progression has been tested in the Fn in FIDELIO-DKD trial, 5734 ptns with type 2 DM & either highly or moderately raised albuminuria + retinopathy were randomly given Fn (10-20 mg once/d) or placebo. All ptns received maximal tolerated basal dose of an ACEi/ARB. At 2.6 ys, Fn succussed to lower the incidence of 40 % or more decline in eGFR & non-significant reduction in the rates of all-cause MR & ESKD that includes eGFR <15 mL/min/1.73 m2 the need for maintenance DX. Hyper-k+ was unnoticeable but seen more frequently with Fn.
Abbreviations:
o Fn: Finerenone,
o ACR: Albumin creatinine ratio.
o DKD: Diabetic kidney disease.
o ACEi: Angiotensin converting enzyme inhibitor
o ARBs: Angiotensin receptor antagonists
o CVS: Cardiovascular system
o RAS(i): Renin angiotensin system (inhibitors).
o MRA: mineralocorticoid receptor antagonist,
o DPP-4i: Dipeptidyl peptidase inhibitors.
o SGLT2i: sodium-glucose co-transporter 2 inhibitor.
o GLP-1RA: Glucagon-like peptide 1 receptor agonists,
o DAPA-CKD: Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease trial,
o CREDENCE: Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation trial
o FIDELIO-DKD: Reducing Kidney Failure & Disease Progression in Diabetic Kidney Disease trial,
o EMPA-REG OUTCOME: Empagliflozin CVS Outcome Event Trial in Type 2 DM Ptns trial,
o CANVAS: Canagliflozin CVS Assessment Study program,
o DECLARE-TIMI 58: Dapagliflozin Effect on CVS Events-Thrombolysis in MI 58 trial,
o EMPEROR: Reduced: Empagliflozin Outcome Trial in ptns with Chronic HF and Reduced Ejection Fraction trial
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