Effects of Spironolactone Combination Therapy on Proteinuria, Kidney Function, and Blood Pressure

• estimated glomerular filtration rate [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  estimated glomerular filtration rate calculated using the formula developed by Chronic Kidney Disease Epidemiology Collaboration. Measured at baseline, 3rd month, 6th month, 9th month, 12th month, 15th month, and 18th month.
• Blood pressure [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  Systolic and diastolic blood pressure assessed by mercury sphygnomanometry. Patients were placed in a sitting position and after ten minutes rest, two readings from right-side hand with five minutes interval were obtained. Measured at baseline, 3rd month, 6th month, 9th month, 12th month, 15th month, and 18th month.
• serum creatinine concentrations [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  serum creatinine concentrations assessed by Jaffe method. Measured at baseline, 3rd month, 6th month, 9th month, 12th month, 15th month, and 18th month.
• Serum potassium concentrations [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]
  Serum potassium concentrations measured at baseline, 1st month, 3rd month, 6th month, 9th month, 12th month, 15th month, and 18th month.

The detrimental effects of aldostrone are not adequately arrested by the use of angiotensin converting enzyme (ACE), angiotensin II receptor blocker (ARB) or a combination of both. Recent evidence has provided robust evidence that aldostrone escape plays an important role in this regard. It is believed that aldostrone escape occurs quite commonly with reports indicating prevalence rates as high as 22% with ARBs and 40% with ACE inhibitors. In a trial of patients with diabetes and hypertension it was shown that treatment of aldostrone escape with spironolactone 25 mg daily for three months significantly reduces proteinuria. A number of other trials have similarly observed that addition of spironolactone to an ACE inhibitor based regimen provides additional benefits on proteinuria reduction, blood pressure control, and prevention of glomerular filtration rate (GFR) decline. Most of the available trials in this regard are of short duration (e.g. three months), and have added spironolactone to an ACE or ACE+ARB based regimen (the so-called triple blockade). Currently, evidence evaluating efficacy of a combined ARB+spironolactone regimen compared with conventional double RAS blockade (i.e. ACE+ARB) is lacking. Hence, this randomized open label trial was initiated to determine the effects of addition of spironolactone 25 mg daily to losartan over a period of 18 months.

• Type 2 Diabetes Mellitus
• Diabetic Nephropathy
• Essential Hypertension

• No Intervention: ACE/ARB
  In 62 patients previously treated with enalapril (10-30 mg daily) + losartan (50-100 mg daily), this regimen was continued.
• Active Comparator: Spironolactone/ARB
  spironolacone 25 mg tablets added to losartan
  Intervention: Drug: spironolacone 25 mg tablets added to losartan

Inclusion Criteria:

• type 2 diabetes patients with diabetic nephropathy in the range of micro- or macroalbuminuria
• treatment with combination of enalapril and losartan for more than one year

Exclusion Criteria:

• history of non-adherence to prescribed medication assessed by the prescribing physician
• baseline potassium > 5.5 meq/L
• chronic kidney disease stages 4 or 5
• history or evidence of non-diabetic kidney disease