Year : 2009 | Volume
: 20 | Issue : 3 | Page : 429--435
Reduction of microalbuminuria by using losartan in normotensive patients with type 2 diabetes mellitus: A randomized controlled trial
Adnan Agha, Wasim Amer, Eram Anwar, Kaukab Bashir
Medical Unit I, Jinnah Hospital, Lahore, Pakistan
144-A Model Town, Lahore
Type 2 diabetes mellitus (T2DM) is a worldwide pandemic that may lead to diabetic kidney disease (DKD), a complication which is the single most important and globally prevalent cause of chronic kidney disease. Microalbuminuria has been shown to be an early indicator of DKD and data suggest that angiotensin receptor blockers (ARBs) reduce urinary albumin excretion and retard the progression of renal disease in hypertensive T2DM patients. However, the effects of ARBs on preventing microalbuminuria and ensuing DKD in normotensive patients with T2DM is yet to be fully established. The objective of this study is to assess the anti-microalbuminuric effects of losartan therapy versus placebo in normotensive T2DM patients. This randomized single blinded controlled trial was performed at the Diabetic Clinic, Jinnah Hospital, Lahore over a period of 10 months. A total of 361 normotensive patients with T2DM and microalbuminuria were selected; of them, 171 patients were randomly allocated to the test group and 190 enrolled into the control group. The patients in the test group were started on losartan 50 mg/day for a six month period while those in the control group were put on vitamin B-12 500 mcg/day. The patients as well as the primary attending physicians/lab evaluators were blinded to the study. All study patients were followed up on a monthly basis. Quantitative microalbuminuria was tested at the beginning and at the end of the study. Out of the 171 patients in the test group, 149 (87.1%) had significant reduction of albuminuria by > 30% of their baseline (mean 101.9 ± 21.7 baseline and, 47.5 ± 12.9 post-therapy). The corresponding values for albuminuria in the 190 patients in the control group was mean 104.7 ± 26.3 baseline and post 6-month mean 103.9 ± 22.9, with P< 0.0001. The anti-albuminuric effect of losartan was reversible as seen on re-checking the urinary albumin two months after discontinuation of treatment. Our study shows that losartan was well tolerated and demonstrated significant anti-proteinuric effects in patients with T2DM with early nephropathy independent of hypertension.
|How to cite this article:|
Agha A, Amer W, Anwar E, Bashir K. Reduction of microalbuminuria by using losartan in normotensive patients with type 2 diabetes mellitus: A randomized controlled trial.Saudi J Kidney Dis Transpl 2009;20:429-435
|How to cite this URL:|
Agha A, Amer W, Anwar E, Bashir K. Reduction of microalbuminuria by using losartan in normotensive patients with type 2 diabetes mellitus: A randomized controlled trial. Saudi J Kidney Dis Transpl [serial online] 2009 [cited 2021 Feb 26 ];20:429-435
Available from: https://www.sjkdt.org/text.asp?2009/20/3/429/50774
Type 2 diabetes mellitus (T2DM) is a global epidemic and the WHO predicts that the current figure of 170 million affected patients with diabetes will more than double by the year 2030. 
Pakistan is currently sixth in the list of countries with highest number of estimated cases of diabetes mellitus.  Approximately one third of patients with T2DM will eventually develop diabetic nephropathy (DN), which is one of the leading causes of chronic kidney disease (CKD).  Diabetic nephropathy is a clinical syndrome characterized by persistent albuminuria > 300 mg/dL or 200 mcg/min, along with relentless decline in the glomerular filtration rate (GFR) and elevated blood pressure. The first sign of renal involvement in DN is microalbuminuria i.e. 24 hour urinary albumin of 30-300 mg/dL or urinary microalbumin excretion rate of 20-200 mcg/min, which cannot be detected on routine methods of protein estimation. Gradually, this progresses to proteinuria and overt nephropathy following which the GFR declines by 10-12 mL/min/year and hypertension ensues, ultimately leading to end stage renal disease (ESRD),  which has dismal survival rates even in the developed countries. 
Microalbuminuria is an early indicator of DN and is associated with increased risk of progression of renal disease in T2DM.  Besides, it is also an independent risk factor for cardiovascular diseases causing up to 50% mortality in patients with T2DM and microalbuminuria.  Therefore, it is recommended that screening for microalbuminuria be done on an annual basis in patients with T2DM for early identification and intervention.  The reported prevalence of microalbuminuria is 38.9% in the Asian T2DM patients microalbuminuria prevalence study cohort,  and 34% in Karachi, Pakistan  as compared to 17-21% in overall population-based studies in western countries.  Therapeutic measures that reduce albuminuria/proteinuria also retard the progression of renal disease as shown in trials with T2DM patients with overt nephropathy, where reduction in proteinuria > 30% below baseline value was associated with better preservation of renal function.  These measures include achieving a target blood pressure of less than 130/80 mmHg and use of various pharmacological agents like angiotensin receptor blockers (ARB), angiotensin converting enzyme inhibitors (ACEI) and non-dihydropyridine calcium channel blockers, which have been shown to be successful in reducing albuminuria.  The anti-albuminuric effects appear to be at least partly independent of the blood pressure reduction caused by these agents, ,, although some studies have not confirmed this finding.  Since a prominent role in the pathogenesis of DN is played by angiotensin II via the renin angiotensin system, it is logical that preventing the formation of angiotensin II by ACE inhibition and blockade of the angiotensin receptor may be considered as renoprotective. Recent trials have shown that ARBs are superior in reducing DN as compared to ACEI by specifically inhibiting angiotensin II mediated efferent arteriolar vasoconstriction and reducing intra-glomerular pressure with less bradykinin mediated side effects.  Apart from their antihypertensive properties, some ARBs like losartan demonstrate anti platelet activity,  as well as uricosuric properties. 
The trials of ARBs in hypertensive patients with type 1 or 2 diabetes mellitus and microalbuminuria, have shown a reduction in albumin excretion, regardless of pre-treatment levels. ,, In the RENAAL (The Reduction of Endpoints in T2DM with the Angiotensin II Antagonist Losartan study) and the IDNT (Irbesartan Diabetic Nephropathy Trial) studies, losartan and irbesartan, respectively, reduced proteinuria and slowed the progression of DN in hypertensive patients with T2DM. , Therefore, therapy that interferes with the rennin angiotensin aldosterone system should be initiated when microalbuminuria develops in order to reduce albumin excretion and the associated risk for progression to overt nephropathy.
The purpose of this study was to see whether losartan, a potent, orally active and highly specific angiotensin II type 1 receptor blocker, could reduce microalbuminuria in normotensive patients with T2DM. Almost all the previous international studies on this subject have investigated hypertensive patients; also, there have been no local studies on reduction of microalbuminuria.
The principal objective of this study was to assess the change in 24 hour urinary microalbuminuria in patients with T2DM without pre existing hypertension with the use of losartan, over a six month period, and comparing it to placebo/ control.
The study was a single blinded randomized controlled trial. All patients gave written informed consent to the study and guidelines of good clinical practice were followed. The hospital's medical unit ethical committee approved the study design. The end points of the study were microalbuminuria reduction in both control and test groups and recording of any adverse effects.
Place and Duration of Study
This prospective study was performed at the outpatient diabetic clinic of the Jinnah Hospital, Lahore, Pakistan. The period of study initially was six months from June 27, 2006 to January 22, 2007; we continued to follow up these patients for another two months from January 23, 2007 to April 2, 2007.
A total of 383 consecutive patients with T2DM (according to the ADA criteria,  ) without hypertension and having detectable microalbuminuria on urinary spot test were selected; informed consent was obtained from all the patients and the risks and benefits of the study were explained. The patients were known diabetics for at least two years, on oral glycemics and/or diet control. Microalbuminuria was defined as urinary albumin excretion rate of 20 to 200 mcg/min or 24 hour urinary albumin of 30300 mg/dL. The current definition of normotension is blood pressure less than 140/90 mmHg, with a blood pressure lowering target of less than 130/80 mmHg in hypertensive adults with diabetes mellitus. Hypertension was ruled out by history and examination. History regarding any past renal illness and drug history was taken and the patients underwent routine investigations, esp. urinalysis, to exclude patients with proteinuria or evidence of non diabetic renal disease. Patients with history of hypersensitivity reactions to losartan, postural hypotension with systolic postural drop > 20 mmHg, co-morbid illnesses, pregnant ladies and poorly controlled diabetics (at least two episodes of symptomatic hypoglycemia or blood glucose levels > 400 mg/dL on follow up or baseline HbA1C > 8) were excluded. We also excluded patients with myocardial infarction or cerebrovascular events within the past one year, unstable angina pectoris, or symptomatic heart failure. Patients with electrocardiographic abnormalities (atrioventricular conduction disturbances, sick sinus syndrome, atrial fibrillation, or other clinically significant rhythm disturbances), acute renal failure, chronic glomerulonephritis, polycystic kidney disease and those with serum creatinine level greater than 1.5 mg/dL were also excluded. All the study patients were selected after testing positive for microalbuminuria by MICRAL test.  The patients were advised against using ophthalmic preparations containing beta blocking agents, steroids, lithium or any nephrotoxic drugs.
Intervention and Measurements
The patients who met all study criteria were selected and they underwent 24 hour urinary microalbuminuria quantification. These patients were then randomly allocated into control and test groups equally [Table 1]. The patients in the test group (n = 193) were then put on losartan 50 mg/day while the patients in the control group (n = 190) were put on vitamin B-12 mecobalamin 500 mcg/ day for a six month period, during which time these patients were followed up monthly for monitoring of blood pressure, glycemic control and routine tests like urea, creatinine, urinalysis etc. Both losartan and vitamin placebo were provided to the patients free of cost by the hospital administration. Quantitative microalbuminuria was rechecked at three months and at the end of six months. Losartan therapy was stopped at six months and quantitative microalbuminuria was repeated two months after stopping treatment.
The data collected via proforma were analyzed by SPSS package for Microsoft Windows, version 10.0. The variable of final out come of intervention (losartan) was computed as means and standard deviations of baseline and after treatment. The numerical difference observed was tested for significance by applying the t-test.
Out of the 383 patients, 22 patients were lost to follow up (3 in control group and 19 in test group). There were 81 females (47.4%) and 90 males (52.6%) in the 171 patients in the test group. Of these 171 patients, 149 (87.1%) had significant reduction of albuminuria > 30% of their baseline, 14 patients (8.2%) had mild reduction of 10-30% and eight patients (4.7%) had minimal or no change. Of the 190 control patients, only three (1.6%) had significant reduction of albuminuria > 30% of their baseline, 34 patients (17.9%) had mild reduction of 10-30% and 153 (76.5%) had minimal or no change. The mean urinary albumin in mg/dL in the losartan group was 101.9 ± 21.7 at baseline, and 47.5 ± 12.9 after six months, while in the control group the baseline value was 104.7 ± 26.3 and 103.9 ± 22.9, after six months. The differrence observed between the two groups was found to be statistically significant (P via self purchase. We had advised all the patients regarding the usefulness of the drug, giving them the choice to purchase. We repea ted quantitative microalbuminuria in these 142 patients (77 males and 65 female), two months after stopping losartan and found that 119 patients (84%) had again achieved microalbuminuria levels nearly equivalent to their initial baseline values. The final urinary albumin level in these patients was 91.8 ± 17.3 mg/dL, two months after stopping losartan, which showed that the anti-albuminuric effects of losartan were reversible after discontinuation of treatment and this effect was disproportionate to the changes in blood pressure [Table 3].
During the study period, 15 patients in the losartan group reported mild dizziness in the first week of treatment, which resolved on its own; however, three of these patients continued to report postural lightheadedness with postural drop in blood pressure greater than 10 mmHg. In these patients, the losartan tablet of 50 mg was divided into two equal doses of 25 mg each, given 12 hours apart and all three patients reported improvement in their symptoms. In all study patients, the creatinine, urea and potassium levels remained within the normal range throughout the period of study.
Our study was a single center, non-randomized study due to lack of resources and the setup of our tertiary care hospital, and our sample size and duration of study was probably not enough to make very significant recommendations.
Diabetic nephropathy is the single largest cause of ESRD worldwide and accounts for 20 to 40% of new cases.  Microalbuminuria is a hallmark of DN,  and studies have shown that reduction of this parameter improves cardiovascular and renal outcomes, not only in diabetics but also in non diabetics. , Major clinical trials such as the REENAL study have shown to effectively limit the progression of DN to ESRD by 18% while using losartan, with a concomi-tant decrease in proteinuria by 35% as compared to placebo.  Another study, the ELITE trial, has shown that losartan is tolerated better in the elderly with reduction in mortality.  In the MARVAL study, blockage of the renin-angiotensin system by valsartan has shown beneficial effects in the form of decreased urinary albumin excretion.  Studies have shown that ACEI reduce albumin excretion in normoten-sive patients with type 1 or type 2 diabetes, , but the anti-proteinuric effects of ARBs in normotensive diabetic patients have not been fully established.
A randomized clinical trial in the Netherlands has earlier shown losartan to be effective in reduction of microalbuminuria in normotensive T2DM patients over a 10 week period, which was independent of associated reduction in blood pressure.  Therefore, therapy that interferes with the rennin-angiotensin-aldosterone system should be initiated when microalbuminuria develops to reduce albumin excretion and diabetic nephropathy. A possible site of action of angiotensinreceptor antagonists in normotensive diabetic patients is the vascular endothelium. Endothelial dysfunction has been associated with increased urinary albumin excretion, as well as with an increased risk for cardiovascular events in T2DM.  Reduction of urinary albumin excretion may reflect recovery of endothelial function and may predict a reduction in the risk for complications.
Most previous studies on this subject have investigated hypertensive patients but our study emphasized on the use of losartan to prevent early DN unrelated to hypertension, so that development, progression and other long term complications of DKD can be halted.
A similar interventional phase II trial was done earlier by the same authors, which showed initial beneficial effects of losartan in reducing microalbuminuria in normotensive T2DM patients over a 6 month period. 
Losartan, an ARB, demonstrated significant anti-albuminuric ability in normotensive patients with T2DM with early nephropathy independent of hypertension. Losartan was well tolerated in our study with desirable anti albuminuric effects. We recommend that further large-scale long-term prospective placebo controlled clinical trials should be done in normotensive diabetic patients using ARBs. More evidence is needed to advocate early start of these drugs in T2DM patients with normal blood pressures in order to prevent morbidity and mortality associated with diabetic nephropathy.
The study was funded via hospital resources and using generic losartan sample supplies and researchers had no financial implications in this study.
|1||World Health Organization. The Diabetes Program 2004. Available at: http//www.who.int/diabetes/en/. September 21, 2004.|
|2||Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 2004;27:1047-53.|
|3||Remuzzi G, Schieppati A, Ruggenenti P. Clinical Practice. Nephropathy in patients with type2 diabetes. N Engl J Med 2002;346:1145-51.|
|4||Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephro-pathy in patients with type 2 diabetes. N Engl J Med 2001;345:870-8.|
|5||Ritz E, Rychlik I, Locatelli F, Halimi S. End-stage renal failure in type 2 diabetes a medical catas-trophe of worldwide dimensions. Am J Kidney Dis 1999;34:795-808.|
|6||Ghafoor F, Bano KA, Malik T, Mahmood S, Khan A. Microalbuminuria as an indicator of kidney function among diabetics. J Coll Physicians Surg Pak 2004;14:670-2.|
|7||Ritz E. Albuminuria and vascular damage-the vicious twins. N Engl J Med 2003;348:2349-52.|
|8||American Diabetes Association. Diabetic nephro-pathy: Position Statement. Diabetes Care 2002;25: 85-9.|
|9||Wu AY, Kong NC, de Leon FA, et al. An alarmingly high prevalence of diabetic nephro-pathy in Asian type 2 diabetic patients: the Micro-Albuminuria Prevalence (MAP) Study. Diabetologia 2005;48:17-26.|
|10||Ahmedani MY, Hydrie MZ, Iqbal A, Gul A, Mirza WB, Basit A. Prevalence of microalbuminuria in type 2 diabetic patients in Karachi: Pakistan: A multi-center study. J Pak Med Assoc 2005;55:382-6.|
|11||Parving HH, Osterby R, Ritz E. Diabetic nephro-pathy. In: Brenner BM, editor. The kidney. Philadelphia: Saunders, 2000: 1731-73.|
|12||Onuigbo M, Weir MR. Evidence-based treatment of hypertension in patients with diabetes mellitus. Diabetes 2003;5:13-26.|
|13||Ruggenenti P, Fassi A, Ilieva AP, et al. Bergamo Nephrologic Diabetes Complications Trial (BENEDICT) Investigations. Preventing micro-albuminuria in type 2 diabetes. N Engl J Med 2004;351:1941-51|
|14||Effects of ramipril on cardiovascular and micro-vascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE sub study. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253-9.|
|15||Mathiesen ER, Hommel E, Hansen HP, Smidt UM, Parving HH. Randomized controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 1999;319:24-5.|
|16||Ahmad J, Siddiqui MA, Ahmad H. Effective post-ponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care 1997;20: 1576-81.|
|17||Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 1998; 317:713-20.|
|18||Parvanova A, Chiurchiu C, Ruggenenti P, Remuzzi G. Inhibition of the renin-angiotensin system and cardio-renal protection: focus on losartan and angiotensin receptor blockade. Expert Opin Pharmacother 2005;6:1931-42|
|19||Nunez A, Gomez J, Zalba LR, et al. Losartan inhibits in vitro platelet activation: comparison with candesartan and valsartan. J Renin Angio-tensin Aldosterone Syst 2000;1:175-9.|
|20||Sica DA, Schoolwerth AC. Part 1. Uric acid and losartan. Curr Opin Nephrol Hypertens 2002;11: 475-82.|
|21||Andersen S, Tarnow L, Rossing P, Hansen BV, Parving HH. Renoprotective effects of angiotensin II receptor blockade in type 1 diabetic patients with diabetic nephropathy. Kidney Int 2000;57: 601-6.|
|22||Lacourcie`e Y, Be´langer A, Godin C, et al. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int 2000;58:762-9.|
|23||Lozano JV, Llisterri JL, Aznar J, Redon J. Losartan reduces microalbuminuria in hyperten-sive microalbuminuric type 2 diabetics. Nephrol Dial Transplant 2001;16:85-9.|
|24||Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345: 851-60.|
|25||Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001;345:861-9.|
|26||American Diabetes Association. Report of the expert committee on diagnosis and classification of Diabetes Mellitus. Diabetes Care 1997;7: 1183-97.|
|27||Spooren PF, Lekkerkerker JF, Vermes I. Micra l-test: a qualitative dipstick test for microalbuminuria. Diabetes Res Clin Pract 18:83-7.|
|28||National Institutes of Health: Excerpts from United States Renal Data System′s 2000 annual data report: atlas of end-stage renal disease in the United States: economic costs of ESRD. Am J Kidney Dis 2000;36:163-76.|
|29||Rossing P. Diabetic nephropathy: worldwide epidemic and effects of current treatment on natural history. Curr Diabetes Rep 2006;6:479-83.|
|30||Basi S, Lewis JB. Microalbuminuria as a target to improve cardiovascular and renal outcomes. Am J Kidney Dis 2006;47:927-46.|
|31||Jensen JS. Microalbuminuria is a strong deter-minant for ischemic heart disease also among non-diabetics. Ugeskr Laeger 2007;169:485-7|
|32||Hostetter TH. Prevention of end-stage renal disease due to type 2 diabetes. N Engl J Med 2001; 345:910-2.|
|33||Cowley AJ, Wiens BL, Segal R, et al. Randomized comparison of losartan vs. captopril on quality of life in elderly patients with symptomatic heart failure: the losartan heart failure ELITE quality of life sub study. Qual Life Res 2000;9:377-84.|
|34||Viberti G, Wheeldon NM. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure independent effect. Circulation 2002;106:672-8|
|35||Randomised placebo controlled trial of lisino-pril in normotensive patients with insulin-dependent diabetes and normoalbuminuria or microalbumi-nuria. The EUCLID Study Group. Lancet 1997; 349:1787-92.|
|36||Ravid M, Brosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R. Use of enalapril to attenuate decline in renal function in normotensive, normo-albuminuric patients with type 2 diabetes mellitus. A randomized, controlled trial. Ann Intern Med 1998;128:982-8.|
|37||Zandbergen AA, Baggen MG, Lamberts SW, Bootsma AH, de Zeeuw D, Ouwendijk RJ. Effect of losartan on microalbuminuria in normotensive patients with type 2 diabetes mellitus. A rando-mized clinical trial. Ann Intern Med 2003;139:90-6.|
|38||Stehouwer CD, Nauta JJ, Zeldenrust GC, Hackeng WH, Donker AJ, den Ottolander GJ. Urinary albumin excretion, cardiovascular disease, and endothelial dysfunction in non-insulin-dependent diabetes mellitus. Lancet. 1992;340:319-23.|
|39||Agha A, Bashir K, Anwar E. Use of losartan in reducing microalbuminuria in normotensive patients with type-2 diabetes mellitus. Nepal Med Coll J 2007;9(2):79-83.|