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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
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


Medical Unit I, Jinnah Hospital, Lahore, Pakistan

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   Abstract 

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.

Keywords: Diabetes mellitus type 2, Diabetic nephropathy, Microalbuminuria, Losartan, Angiotensin receptor blocker

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;20:429-35

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 2020 Jun 6];20:429-35. Available from: http://www.sjkdt.org/text.asp?2009/20/3/429/50774

   Introduction Top


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. [1]

Pakistan is currently sixth in the list of countries with highest number of estimated cases of dia­betes mellitus. [2] 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). [3] 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), [4] which has dis­mal survival rates even in the developed coun­tries. [5]

Microalbuminuria is an early indicator of DN and is associated with increased risk of pro­gression of renal disease in T2DM. [6] Besides, it is also an independent risk factor for cardiovas­cular diseases causing up to 50% mortality in patients with T2DM and microalbuminuria. [7] Therefore, it is recommended that screening for microalbuminuria be done on an annual basis in patients with T2DM for early identification and intervention. [8] The reported prevalence of micro­albuminuria is 38.9% in the Asian T2DM pa­tients microalbuminuria prevalence study cohort, [9] and 34% in Karachi, Pakistan [10] as compared to 17-21% in overall population-based studies in western countries. [11] 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. [12] 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. [13] The anti-albuminuric effects appear to be at least partly independent of the blood pressure reduction caused by these agents, [14],[15],[16] although some studies have not confirmed this finding. [17] 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. [18] Apart from their antihypertensive properties, some ARBs like losartan demonstrate anti platelet activity, [19] as well as uricosuric properties. [20]

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. [21],[22],[23] 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. [24],[25] 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.

Study Design

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.

Patients

A total of 383 consecutive patients with T2DM (according to the ADA criteria, [26] ) 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. [27] 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.


   Results Top


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< 0.0001). The changes in blood pressure were insignificant and did not correlate with the reduction in microalbuminuria; the baseline mean blood pressures were 134.3 ± 8.6 mmHg systolic and 82.3 ± 11.4 mmHg dias­tolic and at the end of six months treatment, the mean blood pressures were 131.1 ± 12.6 mmHg systolic and 78.6 ± 13.4 mmHg diastolic [Table 2].

After the end of the six months study period, we continued to follow-up these patients for another two months and observed that 142 pa­tients had stopped using losartan while 29 pa­tients were using losartan, either regularly or on and off 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.

Limitations

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.


   Discussion Top


Diabetic nephropathy is the single largest cause of ESRD worldwide and accounts for 20 to 40% of new cases. [28] Microalbuminuria is a hallmark of DN, [29] and studies have shown that reduction of this parameter improves cardiovascular and renal outcomes, not only in diabetics but also in non diabetics. [30],[31] 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. [32] Another study, the ELITE trial, has shown that losartan is tolerated better in the elderly with reduction in mortality. [33] In the MARVAL study, blockage of the renin-angiotensin system by valsartan has shown beneficial effects in the form of decreased urinary albumin excretion. [34] Studies have shown that ACEI reduce albumin excretion in normoten-sive patients with type 1 or type 2 diabetes, [35],[36] 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. [37] 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. [38] 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. [39]


   Conclusions Top


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.

Funding Source

The study was funded via hospital resources and using generic losartan sample supplies and researchers had no financial implications in this study.

 
   References Top

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Correspondence Address:
Adnan Agha
144-A Model Town, Lahore
Pakistan
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    Tables

  [Table 1], [Table 2], [Table 3]

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