Optimal dose of losartan for renoprotection in diabetic nephropathy

Steen Andersen1,, Peter Rossing1, Tina R. Juhl1, Jaap Deinum2 and Hans-Henrik Parving1,3

1 Steno Diabetes Center, Copenhagen, Denmark, 2 Department of Internal Medicine I, University Hospital Dijkzigt, Rotterdam, The Netherlands and 3 Faculty of Health Sciences, University of Aarhus, Denmark



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Angiotensin II subtype-1 receptor antagonists represent a valuable new class of drugs in the treatment of diabetic nephropathy. The aim of our study was to evaluate the optimal dose of losartan for renoprotection and blood pressure reduction in diabetic nephropathy.

Methods. Fifty consecutive hypertensive type 1 diabetic patients with diabetic nephropathy received increasing doses of losartan, 50, 100, and 150 mg once daily in three periods each lasting 2 months. At baseline and at the end of each treatment period, albuminuria, 24-h blood pressure (TM2420 A&D), and glomerular filtration rate (GFR) ([51Cr]EDTA plasma clearance) were determined.

Results. Baseline values of albuminuria (geometric mean (95% CI)) and GFR (means±SEM) were 1138 (904–1432) mg/24 h and 91±3 ml/min/1.73 m2, respectively. The blood pressure at baseline was 155/81±3/2 mmHg. All doses of losartan reduced albuminuria and blood pressure. Albuminuria was reduced by 30% (95% CI (15–41)) on losartan 50 mg, 48% (35–57) by losartan 100 mg, and 44% (32–56) by losartan 150 mg (all P values <0.01 vs baseline). Losartan 100 mg daily was significantly more effective than 50 mg daily in reducing albuminuria (P<0.01) without differences between the two high doses. Losartan 50, 100, and 150 mg daily decreased systolic/diastolic blood pressures by 7/4, 12/6, and 10/5 mmHg, respectively (all P<0.05). Losartan 100 mg daily was more effective than 50 mg daily in reducing systolic, diastolic, and mean arterial blood pressure (P=0.05), without differences between the high doses. Treatment with losartan 100 and 150 mg lowered GFR by 4 ml/min/1.73 m2 (P<0.05).

Conclusion. Our study suggests that the optimal dose of losartan is 100 mg daily for renoprotection and blood pressure reduction in type 1 diabetic patients with diabetic nephropathy.

Keywords: albuminuria; angiotensin II; diabetes; hypertension; losartan; nephropathy



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Diabetic nephropathy, characterized by persistent albuminuria, hypertension and declining glomerular filtration rate (GFR), develops in 30–40% of all type 1 diabetic patients [1]. Previous studies have documented that inhibition of the renin–angiotensin system by angiotensin I converting enzyme (ACE) inhibitors consistently reduce albuminuria and retard progression in diabetic nephropathy [2,3]. A new approach for blockade of the renin–angiotensin system is represented by the angiotensin II subtype-1 receptor antagonists (ARA). In type 1 diabetic patients with diabetic nephropathy, we have recently demonstrated that the blood pressure lowering and antiproteinuric effect of the ARA losartan is similar to the effect of ACE inhibition by enalapril in a short-term, double-blind, randomized cross-over study [4]. Moreover, recent studies in type 2 diabetes have documented that ARAs retard progression in diabetic kidney disease independently of their blood pressure lowering effects [5,6].

De Jong et al. [7] have previously highlighted evidence suggesting that proteinuria should be reduced as far as possible in diabetic and non-diabetic nephropathies. Firstly, the reduction in proteinuria when patients start antihypertensive treatment predicts subsequent renoprotection, i.e. the greater initial reduction the better the long-term outcome [810]. Secondly, the residual proteinuria during treatment with antihypertensive agents is directly proportional to the rate of loss of kidney function [8]. However, so far renoprotective therapy has been administered in doses extrapolated from the treatment of essential hypertension, with doses that may be suboptimal for renoprotection. Studies of dose-related efficacy of ACEI or ARA with dose titration based upon achieving the maximal antiproteinuric effect for renoprotection have not been performed.

Therefore, we conducted a study aiming to evaluate the optimal dose of the ARA losartan for reduction of proteinuria and blood pressure in diabetic nephropathy.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Diabetic nephropathy was diagnosed clinically in patients with persistent albuminuria (>300 mg/24 h), diabetic retinopathy, diabetes duration more than 10 years, and absence of other evidence of kidney or renal-tract disease [11]. Inclusion criteria were defined as follows: diabetic nephropathy, GFR >60 ml/min/1.73 m2, office blood pressure >135/85 mmHg, age between 18 and 70 years, and no need for additional concomitant antihypertensive or diuretic treatment. Patients were excluded if they participated in other clinical studies, had a history of malignant hypertension, congestive heart failure, myocardial infarction, or stroke within the last 3 months. We examined the records of all IDDM patients with persistent albuminuria due to diabetic nephropathy. All 75 patients fulfilling inclusion and exclusion criteria were invited to enter the study. Twenty-two did not want to participate. The remaining 53 patients were included in the study. Three were excluded because diuretic treatment was required. On the days of kidney function studies, patients had a normal breakfast, their morning dose of insulin, and took the study medication. Intake of protein or salt was not restricted. Drug compliance was assessed by tablet counts. The study was approved by the local ethical committee, and all patients gave their informed consent.

Our study consisted of three treatment periods each lasting 2 months. The patients received increasing doses of losartan, i.e. losartan 50 mg in the first 2 months treatment period, followed by 100 mg in the second period, and 150 mg in the third treatment period. Before enrolment, all antihypertensive medication including diuretics was withdrawn for at least 4 weeks. At baseline and at the end of each treatment period 24-h blood pressure, proteinuria, and GFR were determined.

Laboratory procedures
GFR was measured after a single intravenous injection of 3.7 MBq [51Cr]ethylenediaminetetraacetic acid (EDTA) at 8.00 a.m. by determining the radioactivity in venous blood samples taken 180, 200, 220, and 240 min after the injection [12,13]. The results were standardized for 1.73 m2 body surface area, using the patients' surface area at the start of the study. The mean coefficient of variation in GFR of each patient from day to day was 4%.

Albuminuria was determined as the geometric mean of at least two consecutive 24-h urine collections, completed immediately before each visit (turbidimetry). IgG-uria was determined by ELISA 14 from one 24-h urine collected immediately before the day of the visit. In addition, urinary excretion of sodium and urea (Cobas Mira Plus; Roche) were measured from all urine collections. The excretion of urea was used to calculate the protein intake from the nitrogen content of the urea and an estimated value of non-urea nitrogen of 31 mg/kg/day [15]. Uric acid in urine was measured from the urine collected during the GFR measurement (Cobas Mira Plus; Roche).

From venous blood samples, serum potassium, sodium, creatinine, uric acid, and cholesterol concentrations were determined (Cobas Mira Plus; Roche) and haemoglobin A1c(HbA1c) measured by high-performance liquid chromatography (normal range 4.1–6.4%) (Variant; Biorad Laboratories). Blood samples for determination of angiotensin II levels were drawn in pre-chilled tubes after 30 min supine rest, and were immediately centrifuged at 4°C. Plasma concentrations were measured radioimmunologically according to the method of Kappelgaard et al. [16]. Renin concentrations in plasma were determined by the method of Deinum et al. [17].

Blood pressure values were based on 24-h ambulatory blood pressure measurements performed with the Takeda TM2420 device (A&D, Tokyo, Japan). Blood pressures were measured every 15 min during the day (7.00 a.m. to 11.00 p.m.) and every 30 min during night (11.00 p.m. to 07.00 a.m.). Values were averaged for each hour before calculating the 24-h blood pressure.

Data analysis
Data are expressed as mean (SEM) except for excretion of albumin and IgG, which were logarithmically transformed before analysis because of their skewed distribution, and are given as the geometric means (95% CI). Data are analysed by analysis of variance (ANOVA) according to a general linear model, repeated measures method. If the repeated measurement analysis revealed a significant overall difference between visits, a priori defined pair-wise comparisons were made by Student's t-test without adjustment for multiple tests. A P value <0.05 was considered significant (two tailed). Data were analysed by SPSS 10.0 (SPSS Inc., Chicago, USA).



   Results
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Three patients were excluded because of a requirement for diuretic treatment. All the remaining 50 participants completed the study (Table 1Go). No concomitant antihypertensive or diuretic treatment was given throughout the study. One patient reported orthostatic dizziness in the two high-dose periods, but no other side-effects that could be related the study drug were registered.


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Table 1.  Characteristics of 50 type 1 diabetic patients with diabetic nephropathy

 
All three doses of losartan reduced albuminuria, IgG-uria, and arterial blood pressure compared to baseline (Table 2Go). Albuminuria was significantly reduced from baseline by 30% (15–41) (95% CI) during treatment with losartan 50 mg daily (P<0.01), whereas losartan 100 and 150 mg lowered albuminuria by 48% (35–57) and 44% (32–56), respectively (P<0.01). IgG-uria decreased by 21% (-5 to 42) (P=0.1), 42% (22–57) (P<0.01), and 36% (18–49) (P<0.01), respectively. Losartan 100 mg was significantly more effective in reducing both albuminuria and IgG-uria compared to 50 mg (P<0.05), without differences between the two higher doses. Baseline albuminuria below and above the median were 662 (238–1287) and 2394 (1328–6198) mg/24 h, respectively. Below the median, albuminuria was lowered by 30% (8–48), 50% (27–66), and 46% (18–64) by losartan 50, 100, and 150 mg, respectively. Above the median, the corresponding reductions were 30% (16–41), 45% (32–54), and 42% (32–50). There were no significant differences between the effectiveness of losartan in reducing albuminuria below or above the median. Systolic and diastolic blood pressures were significantly decreased (P<0.05) by losartan 50, 100, and 150 mg (Table 2Go). The higher doses were more effective in reducing blood pressure as compared to 50 mg without difference between 100 and 150 mg (P<0.05). Blood pressure was similarly reduced during the day (07.00 a.m. to 11.00 p.m.) and night (11.00 p.m. to 07.00 a.m.) time. Systolic blood pressure was lowered by 7, 11, and 10 mmHg during daytime by losartan 50, 100, and 150 mg, respectively, and 6, 13, and 10 mmHg during the night (P<0.05 vs baseline). Diastolic blood pressure was reduced by 4, 6, and 6 mmHg during daytime, and 3, 6, and 5 during the night (P<0.05 vs baseline). GFR declined by 4 ml/min/1.73 m2 in the two high-dose treatment periods. Laboratory parameters are given in Table 3Go. Potassium, sodium, and cholesterol, including HDL-cholesterol, remained unchanged at all doses. Levels of uric acid in serum did not exceed the upper normal range in our laboratory, whereas urinary concentration was increased by losartan treatment as expected (P=0.08). An increase in HbA1c of 0.3% was observed in all treatment periods (P<0.01). An expected increase in plasma renin and angiotensin II concentrations was observed (P<0.05) (Table 4Go). For both parameters, the increment was significantly larger in the high-dose periods compared to 50 mg. There were no correlations between the individual changes in plasma renin concentration and reduction in albuminuria (r=-0.1, P=0.4). However, separation into two groups by median baseline renin values demonstrated a non-significant difference in the anti-albuminuric effect: losartan 100 mg lowered albuminuria by 55% (32–70) in the high-renin group compared to 40% (30–53) in patients with renin values below the median (P=0.1 between groups).


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Table 2.  Kidney function and systemic blood pressure in 50 type 1 diabetic patients with diabetic nephropathy

 

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Table 3.  Laboratory data in 50 type 1 diabetic patients with diabetic nephropathy

 

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Table 4.  The renin–angiotensin–aldosterone system in 50 type 1 diabetic patients with diabetic nephropathy

 



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Our study suggests that the optimal dose of losartan for renoprotection and blood pressure reduction is 100 mg daily in hypertensive type 1 diabetic patients with diabetic nephropathy. Larger reductions in albuminuria, IgG-uria and systemic blood pressure were obtained by increasing the dose from 50 mg to 100 mg daily, but without any additional effect of a further increase to 150 mg daily. These physiological results are consistent with the observed changes in the renin–angiotensin system, i.e. a maximum blockade of the system by losartan 100 mg daily. The present beneficial effects must be regarded as conservative, since none of the participants received diuretic treatment. Moreover, levels of sodium intake, as evaluated by urinary sodium excretion, were above upper normal range (>150 mmol/24 h) in the majority of the patients. A high dietary sodium intake (=200 mmol/24 h) reduces the antiproteinuric effect of ACE inhibition, but this beneficial effect can be restored by adding diuretic treatment [18].

It has previously been demonstrated in diabetic and non-diabetic kidney disease that the maximal antiproteinuric effect of losartan 50 mg is reached after approximately 3 weeks of treatment [19,20]. Similarly, it has been documented that the antihypertensive effect of losartan 50 mg reaches a steady state 3 weeks after initiation of treatment, as demonstrated using repeated 24-h blood pressure readings [21]. We have recently demonstrated the absence of carry-over effects on albuminuria, blood pressure, and GFR in a double-blind, randomized, cross-over trial of losartan and enalapril, given in recommended therapeutic doses to type 1 diabetic patients suffering from diabetic nephropathy [4]. The study was conducted as a 5-armed cross-over trial, with each treatment period lasting 2 months. A similar design for the present study was not approved by the Ethical Committee because of the fact that some patients would start treatment with losartan 150 mg daily directly from baseline or placebo. This may induce severe hypotension due to varying degrees of autonomic nephropathy that are frequently present in our patients suffering from late diabetic complications. Therefore, this study was performed as an open trial with three 2-month treatment periods in which the patients received increasing doses of losartan. Finally, we are currently performing a study at Steno Diabetes Center, investigating the time course for the antiproteinuric and the antihypertensive effects after initiation of treatment with losartan 100 mg. Ten hypertensive type 1 diabetic patients with diabetic nephropathy, i.e. exactly the same category of patients as in the present dose-escalation study have been examined. Preliminary data from that study shows that the maximal antiproteinuric and antihypertensive effect is reached after 1 week of treatment. Therefore we are confident in concluding that the beneficial effect of losartan 100 mg daily is superior to 50 mg, and is not a consequence of time on treatment.

We have recently reported that the average rate of decline in GFR is 4 ml/min/1.73 m2/year during antihypertensive treatment of type 1 diabetic patients with diabetic nephropathy in this group of patients on antihypertensive treatment [22]. The reduction in GFR of 4 ml/min/1.73 m2 in the two higher-dose treatment periods in the present study is probably a haemodynamic reversible consequence of blood pressure reduction without clinical significant contribution from changes in nephropathy status.

Separate analysis of baseline albuminuria below and above the median revealed no indications of a superior effect of losartan 150 mg in the nephrotic range albuminuria. All tested doses of losartan exerted parallel anti-albuminuric effects, independent of baseline albuminuria. Since reliable safety data of losartan in doses above 150 mg daily were not available, higher doses could not be tested in our study.

Separate analysis of day and night blood pressure levels demonstrated a similar antihypertensive efficacy of losartan during day and night. Thus, the beneficial antihypertensive effect persisted during the night although the drug was given in the morning. In a previous study we found no differences between the antihypertensive effect of losartan 50 and 100 mg in a similar patient population [4]. However, the present study includes more than three times as many patients, which may explain the different outcome.

Markers of tubular function were not investigated in the present study. However, determination of retinol-binding protein as a marker of tubular function in a previous study with losartan revealed no indications of alterations during treatment [4].

Numerous studies have suggested that ACE inhibitors are superior to other antihypertensive agents in protecting the kidney against progressive deterioration in diabetic nephropathy [3,23]. We have recently demonstrated that angiotensin II receptor subtype-1 receptor blockade induces an equivalent reduction in albuminuria and blood pressure compared to ACE inhibition in diabetic nephropathy [4]. The initial reduction in albuminuria after the start of antihypertensive treatment is a strong predictor of long-term outcome in renal function [8]. However, prospective trials investigating the renoprotective effects of ACE inhibitors or other antihypertensive agents are performed using doses extrapolated from essential hypertension. Dose-response studies of losartan in primary hypertension have demonstrated that doses above 50 mg provide no further antihypertensive effect [24], in contrast to the present study, dealing with secondary hypertension. The diversity of the maximal effective antihypertensive dose may be related to different levels of RAS activation in diabetic nephropathy and primary hypertension. Unfortunately, dose-response studies of losartan in primary hypertension in diabetes are not available. However, studies with titration of the dose of ARAs or ACE inhibitors upon achieving the maximal antiproteinuric effect (surrogate end-point for renoprotection) in diabetic or non-diabetic kidney disease have not been performed previously.

Titration of renoprotective therapy upon achieving desirable changes in other markers of kidney disease might attract increasing attention in the future. Animal and human studies by Yamamoto et al. [25] have demonstrated a striking over-expression of the growth factor TGF-ß in diabetic nephropathy. Angiotensin II stimulates the production of TGF-ß, which has been demonstrated to decrease during treatment with ACE inhibitors or ARAs [26]. Since TGF-ß is known to play a crucial role in the induction of extracellular matrix production and fibrosis in diabetic nephropathy, it has been suggested as a supplementary therapeutic target in the treatment of diabetic nephropathy [26]. In a recent dose-response study in proteinuric Sprague–Dawley rats with non-diabetic kidney disease and major over-expression of TGF-ß, Peters et al. [27] demonstrated an additional blood pressure-independent reduction in TGF-ß during high-dose therapy with losartan and enalapril. This study reveals a clear dissociation between the dose required for maximal blood pressure reduction and the optimal dose of ACE inhibition and ARAs for inhibition of TGF-ß. Similarly, dissociation between the optimal antihypertensive doses of ACE inhibitors and ARAs and the doses required for regression of structural changes has been reported in animal studies of non-diabetic proteinuric kidney disease [28,29]. Consequently, new surrogate markers for progression of kidney disease may become pertinent in the titration of renoprotective therapy.

Our data revealed an unexpected, losartan dose-independent, increase in HbA1c of 0.3% in all treatment periods. No changes in dietary consumption, body weight, or insulin dose were observed during the trial, and no drift in the HbA1c standards during the study were observed. Whether this small increase in HbA1c can be linked to a blockade of the angiotensin II subtype 1-receptor is unknown.

In conclusion, this study is the first prospective trial investigating the dose-response relations for the antiproteinuric effect of the angiotensin II receptor antagonist losartan. Our study suggests that the optimal dose of losartan for blood pressure reduction and renoprotection in diabetic nephropathy is 100 mg daily, independent of levels of albuminuria.



   Acknowledgments
 
The study was supported by a medical school grant from Merck, Sharp&Dohme. We acknowledge the assistance of Ms Berit R. Jensen, Ms Ulla Smidt, Ms Inge-Lise Rossing, Ms Birgitte V. Hansen and Ms Marja Deckert.



   Notes
 
Correspondence and offprint requests to: Steen Andersen, Steno Diabetes Center, Niels Steensensvej 2, DK-2820 Gentofte, Denmark. Email: STAN{at}dadlnet.dk Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 19.11.01
Accepted in revised form: 25. 2.02