Efficacy of ACE Inhibitors, MRAs and ACE Inhibitor/ MRA Combination

Antiproteinuric Efficacy of ACE Inhibitors, Selective MRAs and ACE Inhibitor/Selective MRA Combination Therapy in Diabetic Hypertensives With Microalbuminuria

The aim of our work is to compare the antiproteinuric efficacy of ACEI monotherapy, Selective MRA monotherapy and their combination in mildly hypertensive patients with type 2 diabetes mellitus and microalbuminuria

Diabetic nephropathy (DN) is the most common cause renal failure in Western countries, responsible for 45% of patients on renal replacement therapy.Diabetic nephropathy was characterized in the early stage by increased albumin excretion in urine, known as microalbuminuria. (DN) results from interactions between different pathological factors that include hyperglycemia, increased activity of the renin-angiotensin-aldosterone-system (RAAS), uncontrolled high systemic and glomerular pressure . (DN) optimal therapy continues to evolve. The main lines of treatment include strict glycemic and blood pressure (BP) control. The angiotensin converting enzyme (ACE) inhibitors have been known to reduce proteinuria both in normotensive and hypertensive patients with diabetic nephropathy and in hypertensive individuals with end stage renal failure . The mechanism by which ACE inhibitors exert their effect on proteinuria reduction is still unknown. The control of high systemic arterial pressure can be beneficial by reducing the filtration pressure. However, no association has been found between antihypertensive effect and proteinuria reduction in several studies. Microalbuminuria which is an early sign of nephropathy can be decreased also by use of Angiotensin receptor blockers (ARBs) in patients with type 2 diabetes mellitus . Insufficient blockade of aldosterone may lead to inadequate anti-albuminuric effects. Studies show that renin-angiotensin-aldosterone system inhibition with ACEI/ARB alone sometimes does not achieve optimal renoprotective effects and does not reduce progression of renal disease, despite therapy. Addition of mineralocorticoid receptor antagonists (MRAs) to angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker therapy was found to reduce proteinuria in patients diabetic nephropathy and can delay progression of renal dysfunction.

Three parallel groups of therapy; Ramipril 10 mg monotherapy (25 patients) ,Eplerenone 50 mg monotherapy (25 patients) and combination therapy of Eplernone/Ramipril 50/10 mg (25 patients)

25 patients with type 2 diabetes mellitus and mild hypertension will be randomized to Tritace (Ramipril) 10 mg/ day. Full doses will be reached by forced titration after 4 weeks

25 patients with type 2 diabetes mellitus and mild hypertension will be randomized to Eraloner (Eplerenone) 50 mg/ day. Full doses will be reached by forced titration after 4 weeks

25 patients with type 2 diabetes mellitus and mild hypertension will be randomized to Tritace/Eraloner (Ramipril 10 mg / Eplerenone 50 mg ) / day. Full doses will be reached by forced titration after 4 weeks

Inclusion Criteria: Adult male and non-pregnant female patients with established diagnosis of type 2 DM at least five years ago with glycosylated hemoglobin (HbA1c) ≤ 8.5% Age 30-80 Y Stage 1 hypertension (systolic BP 140-159 mmHg and/or diastolic BP 90-99 mmHg) and microalbuminuria diagnosed by measuring Urinary albumin/creatinine ratio (UACR) . Microalbuminuria was defined at a level between (30-300 mg/g) Patients included in our study had never been treated with ACEIs, ARBs or aldosterone antagonists, serum potassium level ≥ 3.5 and ≤ 5.0 mmol/L before randomization with estimated glomerular filtration rate (e GFR) ≥50 mL/min/1.73 m2 Exclusion Criteria: Patients with type 1 diabetes mellitus Patients with BP ≥ 160/100 mmHg Patients with secondary hypertension Non-diabetic nephropathy including (chronic glomerulonephritis, polycystic kidney disease and nephrosclerosis), Confirmed bilateral renal artery stenosis or stenosis of the renal artery in solitary functioning kidney History of New York Heart Association functional class III and IV heart failure Patients with rapid progression of kidney disease and women who were pregnant, breast-feeding, or planning to become pregnant during the study period

Espinel E, Agraz I, Ibernon M, Ramos N, Fort J, Seron D. Renal Biopsy in Type 2 Diabetic Patients. J Clin Med. 2015 May 18;4(5):998-1009. doi: 10.3390/jcm4050998.

Zelmanovitz T, Gerchman F, Balthazar AP, Thomazelli FC, Matos JD, Canani LH. Diabetic nephropathy. Diabetol Metab Syndr. 2009 Sep 21;1(1):10. doi: 10.1186/1758-5996-1-10.

Cao Z, Cooper ME. Pathogenesis of diabetic nephropathy. J Diabetes Investig. 2011 Aug 2;2(4):243-7. doi: 10.1111/j.2040-1124.2011.00131.x.

Satirapoj B, Adler SG. Prevalence and Management of Diabetic Nephropathy in Western Countries. Kidney Dis (Basel). 2015 May;1(1):61-70. doi: 10.1159/000382028. Epub 2015 May 1.

Jalal S, Sofi FA, Abass SM, Alai MS, Bhat MA, Rather HA, Lone NA, Siddiqi MA. Effect of amlodipine and lisinopril on microalbuminuria in patients with essential hypertension: A prospective study. Indian J Nephrol. 2010 Jan;20(1):15-20. doi: 10.4103/0971-4065.62090.

Galle J. Reduction of proteinuria with angiotensin receptor blockers. Nat Clin Pract Cardiovasc Med. 2008 Jul;5 Suppl 1:S36-43. doi: 10.1038/ncpcardio0806.

Cagnoni F, Njwe CA, Zaninelli A, Ricci AR, Daffra D, D'Ospina A, Preti P, Destro M. Blocking the RAAS at different levels: an update on the use of the direct renin inhibitors alone and in combination. Vasc Health Risk Manag. 2010 Aug 9;6:549-59. doi: 10.2147/vhrm.s11816.

Cooper LB, Lippmann SJ, Greiner MA, Sharma A, Kelly JP, Fonarow GC, Yancy CW, Heidenreich PA, Hernandez AF. Use of Mineralocorticoid Receptor Antagonists in Patients With Heart Failure and Comorbid Diabetes Mellitus or Chronic Kidney Disease. J Am Heart Assoc. 2017 Dec 23;6(12):e006540. doi: 10.1161/JAHA.117.006540.