Renin-angiotensin system blockers-SGLT2 inhibitors-mineralocorticoid receptor antagonists in diabetic kidney disease: A tale of the past two decades!

Table 1 Studies (in chronological order) that evaluated hard renal or cardiovascular composites in patients having diabetic kidney disease and type 2 diabetes mellitus with various pharmacological agents

Ref.	n	Comparator	Duration (mean/median)	Primary endpoints	Results	Remarks
Lewis et al[11], 2001, IDNT	1715	Irbesartan 75-300 mg vs Amlodipine 2.5-10 mg vs PBO	2.6 yr	Composite of doubling of serum Cr, development of ESKD or death from any cause	The primary outcome with IRBE was 20% lower than PBO and 23% lower than AMLO. Doubling of Cr was significantly 33% lower in IRBE vs PBO (P = 0.003) and 37% lower with IRBE vs AMLO (P < 0.001). The risk of ESKD was non-significantly 23% lower vs both PBO and AMLO (P = 0.07, for both comparisons). No difference in CV- or all-cause death was noted	Similar BP control with IRBE and AMLO. Protection is independent of reduction in BP
Brenner et al[12], 2001, RENAAL	1513	Losartan 50-100 mg vs PBO	3.4 yr	Composite of doubling of serum Cr, development of ESKD or death from any cause	Primary outcome reduced by 16% risk in LOSA vs PBO (P = 0.020). LOSA reduced the doubling of Cr by 25% (P = 0.006) and ESKD by 28% (P = 0.002) vs PBO but no effect on death was noted. HHF was reduced by 32% in LOSA (P = 0.005) while proteinuria was reduced by 35% (P < 0.001) vs PBO	There was no active comparator, and the mean blood pressure throughout the study was lower among those assigned losartan
Wanner et al[13], 2005, 4D	1255	Atorvastatin 20 mg vs PBO (receiving hemodialysis)	4.0 yr	Composite of 3P-MACE (death from CV causes, nonfatal MI, and stroke)	No benefit in 3P-MACE (RR: 0.92; 95%CI: 0.77-1.10; P = 0.37) but significant increase in fatal stroke (RR: 2.03; P = 0.04)	An increase in stroke could be a chance finding, given the data from the CARDS trial that showed atorvastatin lowers the incidence of stroke (HR: 0.52; 95%CI: 0.31-0.89)
Tuttle et al[14], 2007, PKC-DRS, PKC-DMES and PKC-DRS 2 study	1157	Ruboxistaurin vs PBO	33-39 mo	Composite of doubling of serum Cr, development of advanced chronic kidney disease (stages 4 to 5), and death	No difference between the two group	-
Pfeffer et al[15], 2009, TREAT	4038	Darbepoetin alfa vs PBO	4.0 yr	Composite outcomes of death or a CV event (nonfatal MI, CHF, stroke, or hospitalization for myocardial ischemia) and of death or ESKD	No difference in the composite of death or ESKD (HR: 1.06; 95%CI: 0.95-1.19; P = 0.29) or ESKD (HR: 1.02; 95%CI: 0.87-1.18; P = 0.83) between darbepoetin alfa and PBO. An increase in stroke (fatal or nonfatal stroke) occurred in darbepoetin alfa compared with PBO (HR: 1.92; 95%CI: 1.38-2.68; P < 0.001)	-
Mann et al[16], 2010, ASCEND	1392	Avosentan 25/50 mg vs PBO	4 mo	Composite of doubling of serum Cr, ESKD, or death	No difference in primary outcome (25 mg 8.1% vs PBO 9.6%; P = 0.46; 50 mg 8.6% vs PBO 9.6%; P = 0.79) but a significant increase in CHF with avosentan (25 mg 5.9% vs PBO 2.2%; P = 0.008; 50 mg 6.1% vs PBO 2.2%; P = 0.05) compared with PBO	The trial terminated prematurely after a median follow-up of 4 mo (maximum 16 mo) because of an excess of CV events with avosentan
Sharma et al[17], 2011	77	Pirfenidone 1200/2400 mg vs PBO	1 yr	Change in eGFR	Mean eGFR significantly increased the pirfenidone 1200-mg/d group vs PBO (+3.3 vs -2.2 mL/min; P = 0.03) but no improvement in 2400-mg/d group	-
Pergola et al[18], 2011, BEAM	227	Bardoxolone 25/75/150 mg OD vs PBO	12 mo	Change in eGFR at 6 mo	Significant increase in mean eGFR both at 6-mo (8.2-11.4 mL/min; P < 0.001) and 12-mo (5.8-10.5 mL/min) against PBO	Muscle spasms were the MC observed S/E with BDX
Lewis et al[19], 2012	317	Pyridoxamine 150/300 mg BID vs PBO	52-wk	Change in serum Cr	No difference in outcome observed	-
Packham et al[20], 2012, Sun-MACRO	1248	Sulodexide vs PBO	11 mo	Composite of a doubling of serum Cr, development of ESKD, or serum Cr ≥6.0 mg/dl	No difference in the outcome	The trial was stopped prematurely due to futility
Parving et al[21], 2012, ALTITUDE	8561	Aliskiren vs PBO	32.9 mo	Composite of CV death or the first occurrence of cardiac arrest with resuscitation; nonfatal MI; nonfatal stroke; unplanned HHF; ESKD, death attributable to kidney failure, or the need for RRT with no dialysis or transplantation available or initiated; or doubling of Cr level	Results of the primary endpoint were no different between the two arms (HR: 1.08; 95% 0.98-1.20; P = 0.12)	The trial was stopped prematurely after the second interim efficacy analysis because of significantly higher (11.2% vs 7.2%; P < 0.001) hyperkalemia (Serum K level ≥ 6 mmol/L) and hypotension (12.1% vs 8.3%; P < 0.001 in the aliskiren group vs PBO
Fried et al[22], 2013, VA NEPHRON-D	1448	Losartan plus lisinopril vs losartan plus PBO	2.2 yr	Composite of change in the eGFR, ESKD, or death	No difference in outcome (HR: 0.88; 95%CI: 0.70 to 1.12; P = 0.30). Combination therapy increased the risk of hyperkalemia (P < 0.001) and acute kidney injury (P < 0.001) compared to monotherapy	The trial was stopped prematurely
Mann et al[23], 2013, ONTARGET	3163	Ramipril 10 mg vs telmisartan 80 mg vs ramipril plus telmisartan (10 + 80)	56-mo	Composite of dialysis, doubling of serum Cr, and death	Combination therapy was associated with a non-significantly higher ESKD or doubling of serum creatinine (5.3% vs 4.8 %), but a similar death rate (2.3% vs 2.2 %) vs monotherapy. Combination therapy had higher rates of acute kidney injury requiring dialysis (1.4% vs 0.8 %)	This is the data of 3163 people having DKD from a total of 9628 patients with diabetes
de Zeeuw et al[24], 2013, BEACON	2185	Bardoxolone 20 mg OD vs PBO	9.0 mo	Composite of ESKD or CV death	No difference (HR: 0.98; 95%CI: 0.70-1.37; P = 0.92). Significant increase in HHF and death due to HHF with bardoxolone (HR: 1.83; 95%CI: 1.32-2.55; P < 0.001) vs PBO	The trial was stopped prematurely
Navarro-Gonzalez et al[25], 2015, PREDIAN	169	Pentoxyphylline 600 mg BID vs PBO	2-yr	Change in eGFR	Significant less decrease in eGFR in PTF vs PBO (-2.1 vs -6.5 mL/min; Group difference -4.3 mL/min; P < 0.001)	Open-label design and envelope (rather than computer-generated) randomization could have biased the results
Heerspink et al[26], 2019, SONAR	2648	Atrasentan 0.75 mg vs PBO	2.2 yr (Median)	Composite of doubling of serum Cr or ESKD or death from kidney failure	35% reduction in primary composite renal endpoint event (HR: 0.65; 95%CI: 0.49-0.88; P = 0.005)	HHF was insignificantly higher in atrasentan (HR: 1.33; 95%CI: 0.85-2.07; P = 0.208) vs PBO
Perkovic et al[37], 2019, CREDENCE	4401	Canagliflozin 100 mg vs PBO	2.6 yr	Composite of ESKD, doubling of serum Cr, or death from renal or CV causes	30% reduction in primary composite (HR: 0.70; 95%CI: 0.59-82; P = 0.00001), 34% reduction (HR: 0.66; 95%CI: 0.53-0.81; P < 0.001) in renal-specific composite (of ESKD, doubling of Cr, renal death) and 32% reduction in ESKD (HR: 0.68; 95%CI: 0.54-0.86; P = 0.002) in CANA vs PBO. Reduction in composite of 3P-MACE was 20% (HR: 0.80; 95%CI: 0.67-0.95; P = 0.01) while HHF reduced by 39% (HR: 0.61; 95%CI: 0.47-0.80; P < 0.001) in CANA arm vs PBO	The trial was stopped prematurely due to efficacy
Heerspink et al[38], 2020, DAPA-CKD	4304	Dapagliflozin 10 mg vs PBO	2.4 yr	Composite of ESKD, sustained decline in eGFR of at least 50%, or death from renal or CV causes	39% reduction in primary composite (HR: 0.61; 95%CI: 0.51-0.72; P < 0.001), 44% reduction (HR: 0.56; 95%CI: 0.45-0.68; P < 0.001) in renal-specific composite (of ESKD, decline in eGFR of at least 50%, or renal death), 29% reduction (HR: 0.71; 95%CI: 0.55-0.92; P = 0.009) in composite of CV death of HHF and 31% reduction in death (HR: 0.69; 95%CI: 0.53-0.88; P = 0.004) in DAPA arm vs PBO	The trial stopped prematurely due to efficacy
Bakris et al[44], 2020, FIDELIO-DKD	5734	Finerenone 10/20 mg vs PBO	2.6 yr	Composite of kidney failure, sustained decrease of at least 40% in the eGFR from baseline, or death from renal causes	18% reduction (HR: 0.82; 95%CI: 0.73-0.93; P = 0.001) in primary composite in FINE vs PBO arm. 14% reduction (HR: 0.86; 95%CI: 0.75-0.99; P = 0.03) in secondary outcome composite (CV death, non-fatal MI, non-fatal stroke, or HHF) in FINE vs PBO arm	Hyperkalemia-related discontinuation of the drug was higher in the FINE vs PBO (2.3% vs 0.9%) arm
Pitt et al[45], 2021, FIGARO-DKD	7437	Finerenone 10/20 mg vs PBO	3.4 yr	Composite of CV death, nonfatal MI, nonfatal stroke, or HHF. The secondary outcome was a composite of a decrease of eGFR by at least 40%, ESKD, or death from renal causes	13% reduction (HR: 0.87; 95%CI: 0.76-0.98; P = 0.03) in primary cardiac composite primarily driven due to 29% reduction (HR: 0.71; 95%CI: 0.56-0.90) in HHF with FINE vs PBO. Non-significant 13% reduction (HR: 0.87; 95%CI: 0.76-1.01) in secondary renal composite with FINE vs PBO	Hyperkalemia-related discontinuation of the drug was higher in the FINE vs PBO (1.2% vs 0.4%) arm

3P-MACE: 3-point major adverse cardiac events; AMLO: Amlodipine; BDX: Bardoxolone; BID: Twice daily; BP: Blood pressure; CANA; Canagliflozin; CHF: Congestive heart failure; CI: Confidence interval; Cr: Creatinine; CV: Cardiovascular; DAPA; Dapagliflozin; DKD: Diabetic kidney disease; eGFR: Estimated glomerular filtration rate; ESKD: End-stage kidney disease; FINE: Finerenone; HHF: Heart failure hospitalization; HR; Hazard ratio; IRBE: Irbesartan; LOSA: Losartan; MC: Most common; MI: Myocardial infarction; OD: Once daily; PBO: Placebo; PTF; Pentoxyphylline; RR: Relative risk; RRT: Renal replacement therapy; S/E: Side effects.