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Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy
Diabetes Research and Clinical Practice 57 (2002) 179– 183 www.elsevier.com/locate/diabres
Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy Katsunori Suzuki *, Satoshi Souda, Tomoo Ikarashi, Susumu Kaneko, Osamu Nakagawa, Yoshifusa Aizawa Department of Homeostatic Regulation and De6elopment, Di6ision of Endocrinology and Metabolism, Niigata Graduate School of Medical and Dental Sciences, 1 -754 Asahimachi, Niigata 951 -8510, Japan Received 4 January 2002; received in revised form 3 April 2002; accepted 16 April 2002
Abstract It is unknown whether the angiotensin receptor antagonist valsartan exerts a renoprotective effect on patients with type 2 diabetes and diabetic nephropathy independent of its hypotensive effects. Forty patients with type 2 diabetes participated in this study. All patients received valsartan 40 mg, a dose with no clinical effect on blood pressure levels. Blood pressure, urinary albumin excretion (UAE), and creatinine clearance were determined at baseline and at the end of the 6-month treatment period. Antihypertensive and/or antidiabetic drugs, including insulin, were permitted throughout the study. After 6 months of valsartan therapy, mean UAE decreased from 86.8 9196 to 46.9 9 97 mg/min (n=37). In addition, a significant decrease was observed in the UAE of the subgroup of patients displaying diabetic nephropathy (UAE\ 20 mg/min, n= 14), from 219.4 9 275 to 102.7 9 141 mg/min, (P B0.01). Changes in UAE for valsartan correlated significantly with UAE at baseline (r = −0.935, PB 0.0001). Serum creatinine levels and creatinine clearance remained stable before and after treatment with valsartan. No significant differences were observed between pre- and post-treatment body mass index, glycosylated hemoglogin, or systolic and diastolic blood pressure. In type 2 diabetic patients with diabetic nephropathy, 6 months of treatment with low dose valsartan, an angiotensin-II receptor antagonist, thus reduced UAE with no reduction in systemic blood pressure. The drug may be safely administered in this subset of type 2 diabetic patients. The long-term benefits in terms of risk reduction must still be evaluated in further trials. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diabetic nephropathy; Valsartan; Type 2 diabetes
1. Introduction Diabetic nephropathy is the most serious complication of diabetes mellitus, and as both the * Corresponding author. Tel.: +81-25-227-2185; fax: + 8125-227-0774 E-mail address: [email protected] (K. Suzuki).
principal cause of end-stage renal failure and the strongest predictor of premature death and cardiovascular disease in patients with diabetes. Various studies have shown that increased urinary albumin excretion (UAE) is a valid predictor of clinical proteinuria and increased morbidity in patients with type 2 diabetes [1–4]. A new class of drugs that selectively inhibits the renin –an-
0168-8227/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 2 ) 0 0 0 9 8 - 0
180
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
giotensin –aldosterone system by specifically targeting the angiotensin type 1 (AT1) receptor has recently been developed for the treatment of hypertension. The Reduction of Endpoints in non-insulin-dependent diabetes mellitus (NIDDM) with the Angiotensin Antagonist Losartan (RENAAL) study demonstrated renal benefits of losartan, an AT1 receptor antagonist, in patients with type 2 diabetes and nephropathy [5]. At the same time, the renoprotective effects of another AT1 receptor antagonist, irbesartan, were reported in patients with type 2 diabetes displaying incipient and long-term overt diabetic nephropathy [6,7]. However, the renal protection conferred by both drugs may be partially attributable to the reduction in blood pressure occurring with these agents. To date, no studies have investigated the effects of valsartan, another AT1 receptor antagonist, in type 2 diabetic patients with diabetic nephropathy. The present study was therefore conducted to assess the effects of low-dose valsartan in patients with type 2 diabetes; the low dose of valsartan used in our study has no clinical effect on blood pressure.
2. Patients and methods
2.1. Subjects and design Patients with type 2 diabetes mellitus (according to World Health Organization criteria) were studied at Niigata University Hospital. Exclusion criteria comprised: type 2 diabetes for B 1 year; history of myocardial infarction; history of angina as defined by the Rose questionnaire [8]; abnormality of segmental wall motion in the left ventricle as seen on echocardiography; heart failure; uncontrolled hypertension (blood pressure \180/100 mmHg); significant aortic stenosis; known serious arrhythmia; left bundle branch block; previous coronary artery bypass surgery; atrial fibrillation; treatment with digoxin; severe chronic or acute illness; renal disease other than
diabetic nephropathy; or urinary tract infection. Antihypertensive and/or antidiabetic drugs, including insulin, were permitted during the study. In addition, patients were not required to follow a protein- or salt-restricted diet. All patients provided informed consent. All patients received valsartan 40 mg, a dose that has been shown to have no clinical effect on blood pressure levels. Blood pressure, UAE, and creatinine clearance were determined at baseline and at the end of the 6-month treatment period. UAE and creatinine clearance was determined from overnight urine samples that patients collected at home. Patients were instructed to empty their bladders before going to bed, and then during the night (or next morning), to void into a plastic container. The time at which urine was saved was noted. Overnight urine samples were collected once at baseline and at the end of the 6-month treatment period.
2.2. Clinical measurements Arterial blood pressure was measured in the sitting position after 10 min rest, using a standard sphygmomanometer with an appropriately sized cuff. Measurements were taken three times at each monthly office visit. Blood pressure at baseline and at the end of the 6-month treatment period was calculated as means of all measurements. Presence of diabetic retinopathy was determined by fundus photography after pupillary dilatation and graded as ‘nil’, ‘simple’, or ‘proliferative’.
2.3. Laboratory measurements Urinary albumin concentration was measured using an enzyme immunoassay [9]. Glycosylated hemoglobin (HbA1c) was measured by high performance liquid chromatography (Bio-Rad DIAMAT, Richmond, California) and averaged for the previous year. The normal upper limit at our clinics is 5.9%. Serum and urinary creatinine levels were measured by standard laboratory techniques (clearance was corrected to a body surface area of 1.73 m2).
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
2.4. Statistical analysis Values are presented as mean9standard deviation (SD). The significance of differences before and after treatment was evaluated using Wilcoxon signed-ranks test. DUAE was determined as follows: DUAE = (UAE measured 6 months after the treatment; UAE6)− (UAE measured before the therapy; UAE0). Correlation between DUAE and UAE0 were evaluated using Pearson’s analysis. P values B 0.05 were considered statistically significant. All calculations were made using commercially available programs (StatView-J 5.0, SAS Institute Inc., Cary, North Carolina).
181
Table 2 Values in 37 patients with type 2 diabetes before and after treatment with low-dose valsartan
Body mass index (kg/m2) HbA1c (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Serum creatinine (mg/dl) Creatinine clearance (ml/min) UAE (mg/min)
Before
After
P value
23.0 92.7
23.19 1.7
NS
7.2 90.8 137.6 9 15
7.2 9 1.0 136.4 9 14
NS NS
78.1 99.2
75.9 99.6
NS
0.8 90.3
0.8 9 0.5
NS
86.0 918
81.7 9 18
NS
86.8 9196
46.9 997
NS
Data presented as mean 9SD.
3. Results Baseline clinical characteristics of all patients are shown in Table 1. Of the 40 patients who entered the study, 37 (92.5%) completed it. Of
Table 1 Baseline clinical characteristics of study patients Number Sex (M/F) Age (years) Known diabetes duration (years) Body mass index (kg/m2) HbA1c (%) Treatment (%) (diet/oral hypoglycemic agent/insulin) Retinopathy (%) (nil/simple/proliferative) UAE rate (mg/min) Serum creatinine (mg/dl) Creatinine clearance (ml/min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Previous antihypertensive treatment (%) Duration of antihypertensive treatment (years) Number of the treatment with ACE inhibitor Beta-blocker Calcium antagonist Diuretics Alpha-blocker Data presented as mean 9SD.
40 (23/17) 59.7 9 9.4 12.3 9 7.9 23.49 2.7 7.24 9 0.9 14/40/46 44/17/39 82.239 187.7 0.89 0.4 94.59 27.6 137.4 9 15.1 77.99 9.3 52.5 5.09 0.7
these, 14 displayed diabetic nephropathy (UAE\ 20 mg/min). The three patients who discontinued the study were not in the nephropathy subgroup. Two patients withdrew complaining of giddiness, and one patient discontinued due to itching. No side effects were attributed to valsartan. Values before and after treatment with valsartan in the 37 patients who completed the study are shown in Table 2. No significant differences were observed between pre- and post-treatment in HbA1c, systolic and diastolic blood pressure, serum creatinine levels, or creatinine clearance. After 6 months of valsartan therapy, mean UAE had decreased from 86.89 196 to 46.9997 mg/ min. In the subgroup of patients with diabetic nephropathy, a statistically significant decrease in UAE (from 219.49 275 to 102.79 141 mg/min, PB 0.01) was observed (Fig. 1, Tables 2 and 3). Changes in UAE (DUAE) for valsartan correlated significantly with UAE at baseline (UAE0) (r= − 0.935, PB 0.0001) (Fig. 2).
6
4. Discussion
1 16 2 2
Our study demonstrated that low doses of the AT1 receptor antagonist valsartan significantly reduced UAE in type 2 diabetic patients with diabetic nephropathy; the dose used has been shown to exert no clinical effect on blood pres-
182
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
sure. To our knowledge, our study is the first to investigate the use of valsartan in type 2 diabetic patients with diabetic nephropathy. Several previous studies have documented that another AT1 receptor antagonist, losartan, demonstrates renoprotective effects in patients with types 1 [10] and 2 [5] diabetes with diabetic nephropathy, and in patients with non-diabetic kidney disease [11]. The renoprotective effects of irbesartan, another AT1 receptor antagonist, have recently been reported for patients with type 2 diabetes with incipient and long-term overt diabetic nephropathy [6,7]. As in our study, albuminuria was reduced and kidney function remained stable during the treatment period. However, in the irbesartan study, the effects could potentially be attributed to reductions in blood pressure brought about by irbesartan, although the au-
Table 3 Values in 14 diabetic patients with nephropathy (UAE\20 mg/min) before and after treatment with low-dose valsartan
Body mass index (kg/m2) HbA1c (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Serum creatinine (mg/dl) Creatinine clearance (ml/min) UAE (mg/min)
Before
After
P value
23.0 9 2.1
23.0 9 1.6
NS
7.1 90.6 145.0 9 10
6.9 9 0.8 143.4 913
NS NS
76.5 98
74.5 97
NS
1.0 90.4
1.1 90.7
NS
77.1 9 16
73.9 9 16
NS
219.4 9 275
102.7 9141
PB0.01
Data presented as mean 9SD.
thors argued that the benefit observed seemed to exceed the likely contribution of blood pressure changes alone.
Fig. 1. Effect of valsartan on UAE in 37 patients with type 2 diabetes and diabetic nephropathy.
Fig. 2. Correlations between DUAE and UAE0 were evaluated using Pearson’s analysis. DUAE was determined as follows: DUAE= (UAE measured 6 months after treatment; UAE6) − (UAE measured before the therapy; UAE0). r = −0.935, P B 0.0001.
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
Our study clearly indicated that even low-dose valsartan exerts renoprotective effects. A low dose of a drug is preferred for patients with diabetic nephropathy, as it is associated with fewer side effects and reduced expense. All patients in our study reported any side effect that was definitely attributed to valsartan administration, except for only two in whom giddiness may not have been attributed to valsartan because of no significant decrease in their blood pressure. Although our study did not reveal the mechanism by which low-dose valsartan reduced albuminuria without reducing blood pressure, several previous studies dealing with hypotensive drugs that do not interfere with the renin-angiotensin system (RAS) have clearly documented the significant impact of blood pressure on proteinuria, as reviewed by Parving [12]. Improvements in size-selectivity properties of the glomerular capillary membrane leading to reduction in proteinuria by losartan have been suggested in human [10] and animal studies [13]. This beneficial effect is probably due to a reduction in glomerular capillary hydraulic pressure. Glomerular angiotensin-converting enzyme immuno-staining was increased in patients with diabetic nephropathy in parallel with the progression of nephropathy [14]. As the RAS activity may be accelerated more in patients with severe diabetic nephropathy than in patients with incipient nephropathy, we interpreted that valsartan substantially reduced the UAE of macroproteinuric patients. In the present study, no differences in glycemic control were observed between pre- and post-treatment with valsartan. Therefore, metabolic factors are not considered to have played any role in conferring renoprotective effects. In conclusion, our data demonstrate that in type 2 diabetic patients with diabetic nephropathy, UAE is reduced with low-dose valsartan treatment for 6 months, with no concomitant reduction in blood pressure. Our study suggests that valsartan represents a valuable new drug in patients with type 2 diabetes. Long-term studies are required to examine whether the antiproteinuric effect of valsartan confers significant renoprotection.
183
References [1] C.E. Mogensen, Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes, N. Engl. J. Med. 310 (1984) 356 – 360. [2] A. Schmitz, M. Vaeth, Microalbuminuria: a major risk factor in noninsulin-dependent diabetes: a 10-year follow-up study of 503 patients, Diabetes 5 (1988) 126 – 134. [3] R.J. Jarret, C.C. Viberti, A. Argyropoulos, R.D. Hill, V. Mahmud, T.J. Murrels, Microalbuminuria predicts mortality in non-insulin-dependent diabetes, Diabet. Med. 1 (1984) 17 – 19. [4] S.M. Haffner, S. Lehto, T. Ronnemaa, K. Pyorala, M. Laakso, Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infection, N. Engl. J. Med. 339 (1998) 229 – 234. [5] B.M. Brenner, M.E. Cooper, D.D. Zeeuw, et al., Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, N. Engl. J. Med. 345 (2001) 862 – 869. [6] H.H. Parving, H. Lehnert, J. Brochner-Mortensen, R. Gomis, S. Andersen, P. Arner, The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes, N. Engl. J. Med. 345 (2001) 870 – 878. [7] E.J. Lewis, L.G. Hunsicker, W.R. Clarke, et al., Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes, N. Engl. J. Med. 345 (2001) 851 – 860. [8] G.A. Rose, Chest pain questionnaire, Milbank. Memorial. Fund. Quart. 43 (1965) 32. [9] B. Feldt-Rasmussen, B. Dinesen, M. Deckert, Enzyme immunoassay: an improved determination of urinary albumin in diabetics with incipient nephropathy, Scand. J. Clin. Lab. Invest. 45 (1985) 539 – 544. [10] S. Andersen, L. Tarnow, P. Rossing, B.V. Hansen, H.H. Parving, Renoprotective effects of angiotensin receptor blockade in type 1 diabetic patients with diabetic nephropathy, Kidney Int. 57 (2000) 601 – 606. [11] R.T. Gansevoort, D. De Zeeuw, P.E. De Jong, Is the antiproteinuric effect of ACE inhibition mediated by interference in the renin – angiotensin system?, Kidney Int. 45 (1994) 861 – 867. [12] H.H. Parving, Renoprotection in diabetes: genetic and non-genetic risk factors and treatment, Diabetologia 41 (1998) 745 – 759. [13] A. Remuzzi, N. Perico, C.S. Amuchastegui, et al., Short- and long-term effect of angiotensin receptor blockade in rats with experimental diabetes, J. Am. Soc. Nephrol. 4 (1993) 40 – 49. [14] S. Mizuiri, H. Yoshikawa, M. Tanegashima, et al., Renal ACE immunohistochemical localization in NIDDM patients with nephropathy, Am. J. Kidney Dis. 31 (1998) 301 – 307.
Renoprotective effects of low-dose valsartan in type 2 diabetic patients with diabetic nephropathy Katsunori Suzuki *, Satoshi Souda, Tomoo Ikarashi, Susumu Kaneko, Osamu Nakagawa, Yoshifusa Aizawa Department of Homeostatic Regulation and De6elopment, Di6ision of Endocrinology and Metabolism, Niigata Graduate School of Medical and Dental Sciences, 1 -754 Asahimachi, Niigata 951 -8510, Japan Received 4 January 2002; received in revised form 3 April 2002; accepted 16 April 2002
Abstract It is unknown whether the angiotensin receptor antagonist valsartan exerts a renoprotective effect on patients with type 2 diabetes and diabetic nephropathy independent of its hypotensive effects. Forty patients with type 2 diabetes participated in this study. All patients received valsartan 40 mg, a dose with no clinical effect on blood pressure levels. Blood pressure, urinary albumin excretion (UAE), and creatinine clearance were determined at baseline and at the end of the 6-month treatment period. Antihypertensive and/or antidiabetic drugs, including insulin, were permitted throughout the study. After 6 months of valsartan therapy, mean UAE decreased from 86.8 9196 to 46.9 9 97 mg/min (n=37). In addition, a significant decrease was observed in the UAE of the subgroup of patients displaying diabetic nephropathy (UAE\ 20 mg/min, n= 14), from 219.4 9 275 to 102.7 9 141 mg/min, (P B0.01). Changes in UAE for valsartan correlated significantly with UAE at baseline (r = −0.935, PB 0.0001). Serum creatinine levels and creatinine clearance remained stable before and after treatment with valsartan. No significant differences were observed between pre- and post-treatment body mass index, glycosylated hemoglogin, or systolic and diastolic blood pressure. In type 2 diabetic patients with diabetic nephropathy, 6 months of treatment with low dose valsartan, an angiotensin-II receptor antagonist, thus reduced UAE with no reduction in systemic blood pressure. The drug may be safely administered in this subset of type 2 diabetic patients. The long-term benefits in terms of risk reduction must still be evaluated in further trials. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Diabetic nephropathy; Valsartan; Type 2 diabetes
1. Introduction Diabetic nephropathy is the most serious complication of diabetes mellitus, and as both the * Corresponding author. Tel.: +81-25-227-2185; fax: + 8125-227-0774 E-mail address: [email protected] (K. Suzuki).
principal cause of end-stage renal failure and the strongest predictor of premature death and cardiovascular disease in patients with diabetes. Various studies have shown that increased urinary albumin excretion (UAE) is a valid predictor of clinical proteinuria and increased morbidity in patients with type 2 diabetes [1–4]. A new class of drugs that selectively inhibits the renin –an-
0168-8227/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 2 ) 0 0 0 9 8 - 0
180
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
giotensin –aldosterone system by specifically targeting the angiotensin type 1 (AT1) receptor has recently been developed for the treatment of hypertension. The Reduction of Endpoints in non-insulin-dependent diabetes mellitus (NIDDM) with the Angiotensin Antagonist Losartan (RENAAL) study demonstrated renal benefits of losartan, an AT1 receptor antagonist, in patients with type 2 diabetes and nephropathy [5]. At the same time, the renoprotective effects of another AT1 receptor antagonist, irbesartan, were reported in patients with type 2 diabetes displaying incipient and long-term overt diabetic nephropathy [6,7]. However, the renal protection conferred by both drugs may be partially attributable to the reduction in blood pressure occurring with these agents. To date, no studies have investigated the effects of valsartan, another AT1 receptor antagonist, in type 2 diabetic patients with diabetic nephropathy. The present study was therefore conducted to assess the effects of low-dose valsartan in patients with type 2 diabetes; the low dose of valsartan used in our study has no clinical effect on blood pressure.
2. Patients and methods
2.1. Subjects and design Patients with type 2 diabetes mellitus (according to World Health Organization criteria) were studied at Niigata University Hospital. Exclusion criteria comprised: type 2 diabetes for B 1 year; history of myocardial infarction; history of angina as defined by the Rose questionnaire [8]; abnormality of segmental wall motion in the left ventricle as seen on echocardiography; heart failure; uncontrolled hypertension (blood pressure \180/100 mmHg); significant aortic stenosis; known serious arrhythmia; left bundle branch block; previous coronary artery bypass surgery; atrial fibrillation; treatment with digoxin; severe chronic or acute illness; renal disease other than
diabetic nephropathy; or urinary tract infection. Antihypertensive and/or antidiabetic drugs, including insulin, were permitted during the study. In addition, patients were not required to follow a protein- or salt-restricted diet. All patients provided informed consent. All patients received valsartan 40 mg, a dose that has been shown to have no clinical effect on blood pressure levels. Blood pressure, UAE, and creatinine clearance were determined at baseline and at the end of the 6-month treatment period. UAE and creatinine clearance was determined from overnight urine samples that patients collected at home. Patients were instructed to empty their bladders before going to bed, and then during the night (or next morning), to void into a plastic container. The time at which urine was saved was noted. Overnight urine samples were collected once at baseline and at the end of the 6-month treatment period.
2.2. Clinical measurements Arterial blood pressure was measured in the sitting position after 10 min rest, using a standard sphygmomanometer with an appropriately sized cuff. Measurements were taken three times at each monthly office visit. Blood pressure at baseline and at the end of the 6-month treatment period was calculated as means of all measurements. Presence of diabetic retinopathy was determined by fundus photography after pupillary dilatation and graded as ‘nil’, ‘simple’, or ‘proliferative’.
2.3. Laboratory measurements Urinary albumin concentration was measured using an enzyme immunoassay [9]. Glycosylated hemoglobin (HbA1c) was measured by high performance liquid chromatography (Bio-Rad DIAMAT, Richmond, California) and averaged for the previous year. The normal upper limit at our clinics is 5.9%. Serum and urinary creatinine levels were measured by standard laboratory techniques (clearance was corrected to a body surface area of 1.73 m2).
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
2.4. Statistical analysis Values are presented as mean9standard deviation (SD). The significance of differences before and after treatment was evaluated using Wilcoxon signed-ranks test. DUAE was determined as follows: DUAE = (UAE measured 6 months after the treatment; UAE6)− (UAE measured before the therapy; UAE0). Correlation between DUAE and UAE0 were evaluated using Pearson’s analysis. P values B 0.05 were considered statistically significant. All calculations were made using commercially available programs (StatView-J 5.0, SAS Institute Inc., Cary, North Carolina).
181
Table 2 Values in 37 patients with type 2 diabetes before and after treatment with low-dose valsartan
Body mass index (kg/m2) HbA1c (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Serum creatinine (mg/dl) Creatinine clearance (ml/min) UAE (mg/min)
Before
After
P value
23.0 92.7
23.19 1.7
NS
7.2 90.8 137.6 9 15
7.2 9 1.0 136.4 9 14
NS NS
78.1 99.2
75.9 99.6
NS
0.8 90.3
0.8 9 0.5
NS
86.0 918
81.7 9 18
NS
86.8 9196
46.9 997
NS
Data presented as mean 9SD.
3. Results Baseline clinical characteristics of all patients are shown in Table 1. Of the 40 patients who entered the study, 37 (92.5%) completed it. Of
Table 1 Baseline clinical characteristics of study patients Number Sex (M/F) Age (years) Known diabetes duration (years) Body mass index (kg/m2) HbA1c (%) Treatment (%) (diet/oral hypoglycemic agent/insulin) Retinopathy (%) (nil/simple/proliferative) UAE rate (mg/min) Serum creatinine (mg/dl) Creatinine clearance (ml/min) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Previous antihypertensive treatment (%) Duration of antihypertensive treatment (years) Number of the treatment with ACE inhibitor Beta-blocker Calcium antagonist Diuretics Alpha-blocker Data presented as mean 9SD.
40 (23/17) 59.7 9 9.4 12.3 9 7.9 23.49 2.7 7.24 9 0.9 14/40/46 44/17/39 82.239 187.7 0.89 0.4 94.59 27.6 137.4 9 15.1 77.99 9.3 52.5 5.09 0.7
these, 14 displayed diabetic nephropathy (UAE\ 20 mg/min). The three patients who discontinued the study were not in the nephropathy subgroup. Two patients withdrew complaining of giddiness, and one patient discontinued due to itching. No side effects were attributed to valsartan. Values before and after treatment with valsartan in the 37 patients who completed the study are shown in Table 2. No significant differences were observed between pre- and post-treatment in HbA1c, systolic and diastolic blood pressure, serum creatinine levels, or creatinine clearance. After 6 months of valsartan therapy, mean UAE had decreased from 86.89 196 to 46.9997 mg/ min. In the subgroup of patients with diabetic nephropathy, a statistically significant decrease in UAE (from 219.49 275 to 102.79 141 mg/min, PB 0.01) was observed (Fig. 1, Tables 2 and 3). Changes in UAE (DUAE) for valsartan correlated significantly with UAE at baseline (UAE0) (r= − 0.935, PB 0.0001) (Fig. 2).
6
4. Discussion
1 16 2 2
Our study demonstrated that low doses of the AT1 receptor antagonist valsartan significantly reduced UAE in type 2 diabetic patients with diabetic nephropathy; the dose used has been shown to exert no clinical effect on blood pres-
182
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
sure. To our knowledge, our study is the first to investigate the use of valsartan in type 2 diabetic patients with diabetic nephropathy. Several previous studies have documented that another AT1 receptor antagonist, losartan, demonstrates renoprotective effects in patients with types 1 [10] and 2 [5] diabetes with diabetic nephropathy, and in patients with non-diabetic kidney disease [11]. The renoprotective effects of irbesartan, another AT1 receptor antagonist, have recently been reported for patients with type 2 diabetes with incipient and long-term overt diabetic nephropathy [6,7]. As in our study, albuminuria was reduced and kidney function remained stable during the treatment period. However, in the irbesartan study, the effects could potentially be attributed to reductions in blood pressure brought about by irbesartan, although the au-
Table 3 Values in 14 diabetic patients with nephropathy (UAE\20 mg/min) before and after treatment with low-dose valsartan
Body mass index (kg/m2) HbA1c (%) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Serum creatinine (mg/dl) Creatinine clearance (ml/min) UAE (mg/min)
Before
After
P value
23.0 9 2.1
23.0 9 1.6
NS
7.1 90.6 145.0 9 10
6.9 9 0.8 143.4 913
NS NS
76.5 98
74.5 97
NS
1.0 90.4
1.1 90.7
NS
77.1 9 16
73.9 9 16
NS
219.4 9 275
102.7 9141
PB0.01
Data presented as mean 9SD.
thors argued that the benefit observed seemed to exceed the likely contribution of blood pressure changes alone.
Fig. 1. Effect of valsartan on UAE in 37 patients with type 2 diabetes and diabetic nephropathy.
Fig. 2. Correlations between DUAE and UAE0 were evaluated using Pearson’s analysis. DUAE was determined as follows: DUAE= (UAE measured 6 months after treatment; UAE6) − (UAE measured before the therapy; UAE0). r = −0.935, P B 0.0001.
K. Suzuki et al. / Diabetes Research and Clinical Practice 57 (2002) 179–183
Our study clearly indicated that even low-dose valsartan exerts renoprotective effects. A low dose of a drug is preferred for patients with diabetic nephropathy, as it is associated with fewer side effects and reduced expense. All patients in our study reported any side effect that was definitely attributed to valsartan administration, except for only two in whom giddiness may not have been attributed to valsartan because of no significant decrease in their blood pressure. Although our study did not reveal the mechanism by which low-dose valsartan reduced albuminuria without reducing blood pressure, several previous studies dealing with hypotensive drugs that do not interfere with the renin-angiotensin system (RAS) have clearly documented the significant impact of blood pressure on proteinuria, as reviewed by Parving [12]. Improvements in size-selectivity properties of the glomerular capillary membrane leading to reduction in proteinuria by losartan have been suggested in human [10] and animal studies [13]. This beneficial effect is probably due to a reduction in glomerular capillary hydraulic pressure. Glomerular angiotensin-converting enzyme immuno-staining was increased in patients with diabetic nephropathy in parallel with the progression of nephropathy [14]. As the RAS activity may be accelerated more in patients with severe diabetic nephropathy than in patients with incipient nephropathy, we interpreted that valsartan substantially reduced the UAE of macroproteinuric patients. In the present study, no differences in glycemic control were observed between pre- and post-treatment with valsartan. Therefore, metabolic factors are not considered to have played any role in conferring renoprotective effects. In conclusion, our data demonstrate that in type 2 diabetic patients with diabetic nephropathy, UAE is reduced with low-dose valsartan treatment for 6 months, with no concomitant reduction in blood pressure. Our study suggests that valsartan represents a valuable new drug in patients with type 2 diabetes. Long-term studies are required to examine whether the antiproteinuric effect of valsartan confers significant renoprotection.
183
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