Review Article

Present and Future in the Treatment of Diabetic Kidney Disease

Table 1

Most relevant clinical trials assessing dual blockade of renin-angiotensin-aldosterone system in diabetic nephropathy.

StudyPatients and treatment armsCommentary

Dual blockade using ACEI and ARB

VA NEPHRON-D [41]724 (losartan 100 mg/day)  Stopped due to adverse effects.  
724 (losartan 100 mg/day + lisinopril 10–40 mg/day)Primary endpoint included change in eGFR, death, or end-stage renal disease.

ONTARGET [43]8576 (ramipril 10 mg/day)  
8542 (telmisartan 80 mg/day)  
8502 (both)
Telmisartan equivalent to ramipril.    
No benefit of combination in proteinuria.  
Worse eGFR in combination group.

PRONEDI [42]35 (lisinopril 40 mg/day)  
28 (irbesartan 600 mg/day)  
70 (lisinopril 20 mg/day + irbesartan 300 mg/day)
No benefit of combination in proteinuria or renal function.

Dual blockade using aliskiren

ALTITUDE [45]8561 (ACE/ARB + aliskiren 300 mg/day)Stopped due to adverse effects.  
Greater reduction in proteinuria.  
Renal function was included in the primary endpoint.

AVOID [46]298 (losartan 100 mg/day)  Greater reduction in proteinuria without differences in the decline of eGFR.  
301 (losartan 100 mg/day + aliskiren 150–300 mg/day)No increased risk of adverse events.

Dual blockade using aldosterone blockers

Sato et al. [47]55 (spironolactone 25 mg/day to those patients with aldosterone escape after ACEI) Early stage of CKD (eGFR >60 mL/min/1.73 m2).  
Greater reduction in proteinuria.  
No increased risk of adverse events.

Esteghamati et al. [48]62 (enalapril 30–40 mg/day + losartan 50–100 mg/day)  Greater reduction in proteinuria.
74 (spironolactone 25 mg/day + losartan 50 mg/day)Greater loss of eGFR.

Epstein et al. [49]91 (enalapril 20 mg/day)  
91 (enalapril 20 mg/day + eplerenone 50 mg)  
86 (enalapril 20 mg/day + eplerenone 100 mg/day)
Greater reduction in proteinuria in combination.  
No differences in eGFR reduction.  
No increased risk of hyperkalemia in combination.

ACEI: angiotensin converting enzyme inhibitor; ARB: angiotensin II receptor blockers; mg: milligram; eGFR: estimated glomerular filtration rate; CKD: chronic kidney disease.