Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin:
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《英国医生杂志》
1 Endocrinologie-Diabétologie-Nutrition, Groupe Hospitalier Bichat-Claude Bernard, Assistance Publique des H?pitaux de Paris, 46 rue Henri Huchard, 75877 Paris Cedex 18, France, 2 Service de Pharmacologie Clinique, Faculté de Médecine La?nnec, rue Guillaume Paradin, BP 8071, 69376 Lyon Cedex 08, 3 Département de Santé Publique, Informatique et Statistiques Médicales, 15 rue de l'Ecole de Médecine, 75270 Paris Cedex 06, 4 Schwabing General Hospital, Ludwig Maximilians University, D-80804 Munich, Germany, 5 Service de Diabétologie, H?pital Saint-Louis, Assistance Publique des H?pitaux de Paris, 1 avenue Claude Vellefaux, 75475 Paris Cedex 10
Correspondence to: Professor M Marre, Service d'Endocrinologie Diabétologie Nutrition, H?pital Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris Cedex 18, France michel.marre@bch.ap-hop-paris.fr
Abstract
People with type 2 diabetes develop severe cardiovascular and renal diseases prematurely, especially those with high urinary albumin excretion (microalbuminuria or proteinuria).1 2 The association of high urinary albumin excretion with poor cardiovascular prognosis in diabetes is well known.3 Inhibition of the renin-angiotensin system in patients with type 1 and type 2 diabetes reduces high urinary albumin excretion4-6 and improves renal outcome7 in addition to lowering blood pressure. A high dose (10 mg a day) of the angiotensin converting enzyme (ACE) inhibitor ramipril improved the cardiovascular prognosis of a broad range of patients at high cardiovascular risk, including people with type 2 diabetes.8-10
The contribution of the fall in blood pressure to these beneficial effects of ACE inhibitors is still debated.11 12 Low dose ramipril (1.25 mg a day), without measurable effect on blood pressure, reduced urinary albumin excretion in people with type 1 diabetes and microalbuminuria and left ventricular hypertrophy in hypertensive patients.13 14 The DIABHYCAR (non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril) study was established to test whether 1.25 mg ramipril daily would reduce cardiovascular and renal morbidity and mortality in normotensive or hypertensive patients with type 2 diabetes and microalbuminuria or proteinuria.15
Methods
Recruitment and follow up
From February 1995 to April 1998, 3973 investigators in the 16 participating countries screened 25 468 people with type 2 diabetes for high urinary albumin excretion: 19 520 did not meet this inclusion criterion—a proportion similar to that seen in other studies,16 and a further 1011 did not consent to participate. The remaining 4937 people—with type 2 diabetes and high urinary albumin excretion—were randomised. Twenty investigators (who had included 25 participants) were excluded from the study by the steering committee in September 1998 because they provided no data after randomisation and refused site visits. Among the remaining 4912 participants, 2443 were assigned to receive ramipril 1.25 mg a day and 2469 to receive placebo. Table 1 shows the characteristics of participants at entry.
Table 1 Baseline characteristics of the 4912 randomised participants, according to treatment group. Values are numbers (percentages) of patients unless stated otherwise
We report data collected up to 31 March 2001. The trial ended prematurely for 838 (17%) participants: 678 (14%) withdrew and refused to be followed up subsequently (344 (14%) taking ramipril and 334 (14%) taking placebo); and 160 (3.2%) were lost to follow up (62 (2.5%) taking ramipril and 98 (4.0%) taking placebo), and their primary end point status is unknown. These participants were censored at the time of discontinuation.
The median duration of follow up was 47 months (1st quarter 38 months, 3rd quarter 60 months). In all, 138 (2.8%) participants (70 (2.9%) assigned to take ramipril, 68 (2.8%) to take placebo) never started the study treatment. At one year, 2043 of the 2377 (85.9%) surviving participants in the ramipril group and 2111 of the 2415 (87.4%) surviving participants in the placebo group were still taking study drugs. At the end of the study, 1250/1209 (59.3%) surviving participants in the ramipril group and 1265/2145 (59.0%) surviving participants in the placebo group were still taking study drugs. In all, 4074 (82.9%) participants were followed to 31 March 2001, died, or presented with a non-fatal primary end point (fig 1).
Fig 1 Chart showing flow of participants through study. ACE=angiotensin converting enzyme inhibitor
Primary and secondary end points
Primary
There were 739 primary end point events (in 15.0% of the participants) during the study, 362 (14.8%, 37.8 per 1000 patient years) in the ramipril group and 377 (15.3%, 38.8 per 1000 patient years) in the placebo group (hazard ratio 1.03, 95% confidence interval 0.89 to 1.20, P = 0.65) (fig 2). We found no difference between the two groups for each of the components of the primary end point (table 2). There were 137 primary end point events among the 1065 (12.9%) normotensive participants taking ramipril and 137 (12.3%) among the 1112 normotensive participants taking placebo (relative risk 1.044, 95% confidence interval 0.837 to 1.303). There were 225 (16.3%) primary end point events among 1378 hypertensive participants taking ramipril and 240 (17.7%) among the 1357 hypertensive participants taking placebo (0.923; 0.782 to 1.09).
Fig 2 Incidence of the primary end point according to treatment group
Table 2 Incidence of primary end point (combined and in its separate components) and secondary end points, according to treatment group. Values are numbers (percentages) of participants in whom events occurred, unless stated otherwise
Secondary
We found no effect of the study treatment on the secondary end points (table 2).
Adverse events
More participants stopped taking ramipril than placebo because of coughing (3.3% v 0.9%). Two participants developed angio-oedema (one taking ramipril, related to treatment, and one taking placebo, not related to treatment). Table 3 shows the adverse events experienced by participants during the study.
Table 3 Numbers (percentages) of participants who experienced adverse events during study
Other analyses
More participants taking placebo than ramipril took angiotensin II receptor antagonists or ACE inhibitors other than ramipril during the study (543 (22.9%) v 477 (20.0%); log rank test P = 0.05).
At one year, compared with baseline values, systolic and diastolic blood pressure in those taking ramipril had fallen by 1.89 mm Hg and 1.34 mm Hg respectively, whereas in those taking placebo systolic blood pressure had risen by 0.22 mm Hg and diastolic pressure had fallen by 0.33 mm Hg (intergroup differences: systolic 2.12 (95% confidence interval 1.19 to 3.05); diastolic 1.01 (0.45 to 1.57)).
At two years, compared with baseline values, systolic and diastolic blood pressure had fallen by 2.52 mm Hg and 1.89 mm Hg respectively in those taking ramipril and by 0.09 mm Hg and 0.83 mm Hg respectively in those taking placebo (intergroup differences: systolic 2.43 (1.43 to 3.44); diastolic 1.06 (0.46 to 1.65)).
At final evaluation, compared with baseline values, systolic and diastolic blood pressure had fallen by 3.61 mm Hg and 2.37 mm Hg respectively in those taking ramipril and by 2.32 mm Hg and 1.98 mm Hg respectively in those taking placebo (intergroup differences: systolic 1.54 (0.34 to 2.75); diastolic 0.30 (-0.40 to 0.99)).
We found no differences between the two groups for blood glucose concentration and body weight (data not shown).
Between the first and the last examination, serum creatinine concentration increased comparably in the ramipril and placebo groups, by 8 μmol/l (standard deviation 37) and 9 μmol/l (SD 43) respectively. The urinary albumin excretion was measured in 1868 French participants (935 taking ramipril, 933 taking placebo) at the end of follow up. There was a trend towards more regression from proteinuria (urinary albumin excretion > 200 mg/l) and microalbuminuria (20-200 mg/l) to normal (urinary albumin excretion < 20 mg/l) or microalbuminuria among those taking ramipril than those taking placebo (27% v 23%; relative reduction in risk 14% (95% confidence intervals -4% to 28%), 2 test, 1 df, P < 0.07).
Discussion
Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984;310: 356-60.
Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrels TJ. Microalbuminuria predicts mortality in non insulin-dependent diabetics. Diabet Med 1984;1: 17-9.
Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia 1999;42: 263-85.
Marre M, Chatellier G, Leblanc H, Guyene TT, Menard J, Passa Ph. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ 1988;297: 1092-5.
Chan JCN, Cockram CS, Nicholls MG, Cheung CK, Swaminathan R. Comparison of enalapril and nifedipine in treating non-insulin-dependent diabetes associated with hypertension: one year analysis. BMJ 1992;305: 981-5.
Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Int Med 1996;156: 286-9.
Lewis EJ, Hunsiker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: 145-53.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355: 253-9.
Bosh J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, et al. Use of ramipril in preventing stroke: double blind randomised trial. BMJ 2002;324: 699-702.
Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358: 1305-15.
Sleight P, Yusuf S, Progue J, Tsuyuki R, Diaz R, Probstfield J, for the Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358: 2130-1.
Marre M, Hallab M, Billiard A, Le Jeune JJ, Bled F, Girault A, et al. Small doses of ramipril to reduce microalbuminuria in diabetic patients with incipient nephropathy independently of blood pressure changes. J Cardiovasc Pharmacol 1991;18: S165-8.
Lievre M, Gueret P, Gayet C, Roudaut R, Haugh MC, Delair S, et al. Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individual. HYCAR Study Group. Hypertension 1995;25: 92-7.
Lievre M, Marre M, Chatellier G, Plouin P, Reglier J, Richardson L, et al. The non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril (DIABHYCAR) study: design, organization, and patient recruitment. DIABHYCAR Study Group. Control Clin Trials 2000;21: 383-96.
Marre M, Lievre M, Vasmant D, Gallois Y, Hajadj S, Reglier JC, et al, on behalf of the DIABHYCAR Study Group. Determinants of elevated urinary albumin excretion in the 4937 type 2 diabetic subjects recruited for the DIABHYCAR study in Western Europe and north Africa. Diabetes Care 2000;23(suppl 2): B40-8.
The ATLANTIS Study Group. Low-dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension: results of a randomized controlled trial. Diabetes Care 2000;23: 1823-9.
Bojestig M, Karlberg B E, Lindstr?m T, Nystrom F H. Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patient with type 1 diabetes. Diabetes Care 2001;24: 919-24.
Trevisan R, Tiengo A. Effect of low-dose ramipril on microalbuminuria in normotensive or mild hypertensive non-insulin-dependent diabetic patients. North-East Italy Microalbuminuria Study Group. Am J Hypertens 1995;8: 876-83.
Chobanian AV, Hope S, Brecher P. Dissociation between the antiatherosclerotic effect of trandolapril and suppression of serum and aortic angiotensin-converting enzyme activity in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1995;25: 1306-10.
Lonn EM, Yusuf S, Dzavik V, Doris I, Yi Q, Smith S, et al, for the SECURE Investigators. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultra-sound changes in patients treated with Ramipril and vitamin E. Circulation 2001;103: 919-25.
Parving HH, Lehnert H, Br?chner-Mortensen J, Goms R, Andersen S, Arner P, for the Irbesartan in Patients Type 2 Diabetes And Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345: 870-8.
Maillard MP, Wurzner G, Nussberger J, Centeno C, Burnier M, Brunner HR. Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing. Clin Pharmacol Ther 2002;71: 68-76.(Michel Marre, professor1,)
Correspondence to: Professor M Marre, Service d'Endocrinologie Diabétologie Nutrition, H?pital Bichat-Claude Bernard, 46, rue Henri Huchard, 75877 Paris Cedex 18, France michel.marre@bch.ap-hop-paris.fr
Abstract
People with type 2 diabetes develop severe cardiovascular and renal diseases prematurely, especially those with high urinary albumin excretion (microalbuminuria or proteinuria).1 2 The association of high urinary albumin excretion with poor cardiovascular prognosis in diabetes is well known.3 Inhibition of the renin-angiotensin system in patients with type 1 and type 2 diabetes reduces high urinary albumin excretion4-6 and improves renal outcome7 in addition to lowering blood pressure. A high dose (10 mg a day) of the angiotensin converting enzyme (ACE) inhibitor ramipril improved the cardiovascular prognosis of a broad range of patients at high cardiovascular risk, including people with type 2 diabetes.8-10
The contribution of the fall in blood pressure to these beneficial effects of ACE inhibitors is still debated.11 12 Low dose ramipril (1.25 mg a day), without measurable effect on blood pressure, reduced urinary albumin excretion in people with type 1 diabetes and microalbuminuria and left ventricular hypertrophy in hypertensive patients.13 14 The DIABHYCAR (non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril) study was established to test whether 1.25 mg ramipril daily would reduce cardiovascular and renal morbidity and mortality in normotensive or hypertensive patients with type 2 diabetes and microalbuminuria or proteinuria.15
Methods
Recruitment and follow up
From February 1995 to April 1998, 3973 investigators in the 16 participating countries screened 25 468 people with type 2 diabetes for high urinary albumin excretion: 19 520 did not meet this inclusion criterion—a proportion similar to that seen in other studies,16 and a further 1011 did not consent to participate. The remaining 4937 people—with type 2 diabetes and high urinary albumin excretion—were randomised. Twenty investigators (who had included 25 participants) were excluded from the study by the steering committee in September 1998 because they provided no data after randomisation and refused site visits. Among the remaining 4912 participants, 2443 were assigned to receive ramipril 1.25 mg a day and 2469 to receive placebo. Table 1 shows the characteristics of participants at entry.
Table 1 Baseline characteristics of the 4912 randomised participants, according to treatment group. Values are numbers (percentages) of patients unless stated otherwise
We report data collected up to 31 March 2001. The trial ended prematurely for 838 (17%) participants: 678 (14%) withdrew and refused to be followed up subsequently (344 (14%) taking ramipril and 334 (14%) taking placebo); and 160 (3.2%) were lost to follow up (62 (2.5%) taking ramipril and 98 (4.0%) taking placebo), and their primary end point status is unknown. These participants were censored at the time of discontinuation.
The median duration of follow up was 47 months (1st quarter 38 months, 3rd quarter 60 months). In all, 138 (2.8%) participants (70 (2.9%) assigned to take ramipril, 68 (2.8%) to take placebo) never started the study treatment. At one year, 2043 of the 2377 (85.9%) surviving participants in the ramipril group and 2111 of the 2415 (87.4%) surviving participants in the placebo group were still taking study drugs. At the end of the study, 1250/1209 (59.3%) surviving participants in the ramipril group and 1265/2145 (59.0%) surviving participants in the placebo group were still taking study drugs. In all, 4074 (82.9%) participants were followed to 31 March 2001, died, or presented with a non-fatal primary end point (fig 1).
Fig 1 Chart showing flow of participants through study. ACE=angiotensin converting enzyme inhibitor
Primary and secondary end points
Primary
There were 739 primary end point events (in 15.0% of the participants) during the study, 362 (14.8%, 37.8 per 1000 patient years) in the ramipril group and 377 (15.3%, 38.8 per 1000 patient years) in the placebo group (hazard ratio 1.03, 95% confidence interval 0.89 to 1.20, P = 0.65) (fig 2). We found no difference between the two groups for each of the components of the primary end point (table 2). There were 137 primary end point events among the 1065 (12.9%) normotensive participants taking ramipril and 137 (12.3%) among the 1112 normotensive participants taking placebo (relative risk 1.044, 95% confidence interval 0.837 to 1.303). There were 225 (16.3%) primary end point events among 1378 hypertensive participants taking ramipril and 240 (17.7%) among the 1357 hypertensive participants taking placebo (0.923; 0.782 to 1.09).
Fig 2 Incidence of the primary end point according to treatment group
Table 2 Incidence of primary end point (combined and in its separate components) and secondary end points, according to treatment group. Values are numbers (percentages) of participants in whom events occurred, unless stated otherwise
Secondary
We found no effect of the study treatment on the secondary end points (table 2).
Adverse events
More participants stopped taking ramipril than placebo because of coughing (3.3% v 0.9%). Two participants developed angio-oedema (one taking ramipril, related to treatment, and one taking placebo, not related to treatment). Table 3 shows the adverse events experienced by participants during the study.
Table 3 Numbers (percentages) of participants who experienced adverse events during study
Other analyses
More participants taking placebo than ramipril took angiotensin II receptor antagonists or ACE inhibitors other than ramipril during the study (543 (22.9%) v 477 (20.0%); log rank test P = 0.05).
At one year, compared with baseline values, systolic and diastolic blood pressure in those taking ramipril had fallen by 1.89 mm Hg and 1.34 mm Hg respectively, whereas in those taking placebo systolic blood pressure had risen by 0.22 mm Hg and diastolic pressure had fallen by 0.33 mm Hg (intergroup differences: systolic 2.12 (95% confidence interval 1.19 to 3.05); diastolic 1.01 (0.45 to 1.57)).
At two years, compared with baseline values, systolic and diastolic blood pressure had fallen by 2.52 mm Hg and 1.89 mm Hg respectively in those taking ramipril and by 0.09 mm Hg and 0.83 mm Hg respectively in those taking placebo (intergroup differences: systolic 2.43 (1.43 to 3.44); diastolic 1.06 (0.46 to 1.65)).
At final evaluation, compared with baseline values, systolic and diastolic blood pressure had fallen by 3.61 mm Hg and 2.37 mm Hg respectively in those taking ramipril and by 2.32 mm Hg and 1.98 mm Hg respectively in those taking placebo (intergroup differences: systolic 1.54 (0.34 to 2.75); diastolic 0.30 (-0.40 to 0.99)).
We found no differences between the two groups for blood glucose concentration and body weight (data not shown).
Between the first and the last examination, serum creatinine concentration increased comparably in the ramipril and placebo groups, by 8 μmol/l (standard deviation 37) and 9 μmol/l (SD 43) respectively. The urinary albumin excretion was measured in 1868 French participants (935 taking ramipril, 933 taking placebo) at the end of follow up. There was a trend towards more regression from proteinuria (urinary albumin excretion > 200 mg/l) and microalbuminuria (20-200 mg/l) to normal (urinary albumin excretion < 20 mg/l) or microalbuminuria among those taking ramipril than those taking placebo (27% v 23%; relative reduction in risk 14% (95% confidence intervals -4% to 28%), 2 test, 1 df, P < 0.07).
Discussion
Mogensen CE. Microalbuminuria predicts clinical proteinuria and early mortality in maturity-onset diabetes. N Engl J Med 1984;310: 356-60.
Jarrett RJ, Viberti GC, Argyropoulos A, Hill RD, Mahmud U, Murrels TJ. Microalbuminuria predicts mortality in non insulin-dependent diabetics. Diabet Med 1984;1: 17-9.
Mogensen CE. Microalbuminuria, blood pressure and diabetic renal disease: origin and development of ideas. Diabetologia 1999;42: 263-85.
Marre M, Chatellier G, Leblanc H, Guyene TT, Menard J, Passa Ph. Prevention of diabetic nephropathy with enalapril in normotensive diabetics with microalbuminuria. BMJ 1988;297: 1092-5.
Chan JCN, Cockram CS, Nicholls MG, Cheung CK, Swaminathan R. Comparison of enalapril and nifedipine in treating non-insulin-dependent diabetes associated with hypertension: one year analysis. BMJ 1992;305: 981-5.
Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotensin-converting enzyme inhibition in non-insulin-dependent diabetes mellitus. A 7-year follow-up study. Arch Int Med 1996;156: 286-9.
Lewis EJ, Hunsiker LG, Bain RP, Rohde RD, for the Collaborative Study Group. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. N Engl J Med 1993;329: 1456-62.
Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med 2000;342: 145-53.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355: 253-9.
Bosh J, Yusuf S, Pogue J, Sleight P, Lonn E, Rangoonwala B, et al. Use of ramipril in preventing stroke: double blind randomised trial. BMJ 2002;324: 699-702.
Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358: 1305-15.
Sleight P, Yusuf S, Progue J, Tsuyuki R, Diaz R, Probstfield J, for the Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Blood pressure reduction and cardiovascular risk in HOPE study. Lancet 2001;358: 2130-1.
Marre M, Hallab M, Billiard A, Le Jeune JJ, Bled F, Girault A, et al. Small doses of ramipril to reduce microalbuminuria in diabetic patients with incipient nephropathy independently of blood pressure changes. J Cardiovasc Pharmacol 1991;18: S165-8.
Lievre M, Gueret P, Gayet C, Roudaut R, Haugh MC, Delair S, et al. Ramipril-induced regression of left ventricular hypertrophy in treated hypertensive individual. HYCAR Study Group. Hypertension 1995;25: 92-7.
Lievre M, Marre M, Chatellier G, Plouin P, Reglier J, Richardson L, et al. The non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular events, and ramipril (DIABHYCAR) study: design, organization, and patient recruitment. DIABHYCAR Study Group. Control Clin Trials 2000;21: 383-96.
Marre M, Lievre M, Vasmant D, Gallois Y, Hajadj S, Reglier JC, et al, on behalf of the DIABHYCAR Study Group. Determinants of elevated urinary albumin excretion in the 4937 type 2 diabetic subjects recruited for the DIABHYCAR study in Western Europe and north Africa. Diabetes Care 2000;23(suppl 2): B40-8.
The ATLANTIS Study Group. Low-dose ramipril reduces microalbuminuria in type 1 diabetic patients without hypertension: results of a randomized controlled trial. Diabetes Care 2000;23: 1823-9.
Bojestig M, Karlberg B E, Lindstr?m T, Nystrom F H. Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patient with type 1 diabetes. Diabetes Care 2001;24: 919-24.
Trevisan R, Tiengo A. Effect of low-dose ramipril on microalbuminuria in normotensive or mild hypertensive non-insulin-dependent diabetic patients. North-East Italy Microalbuminuria Study Group. Am J Hypertens 1995;8: 876-83.
Chobanian AV, Hope S, Brecher P. Dissociation between the antiatherosclerotic effect of trandolapril and suppression of serum and aortic angiotensin-converting enzyme activity in the Watanabe heritable hyperlipidemic rabbit. Hypertension 1995;25: 1306-10.
Lonn EM, Yusuf S, Dzavik V, Doris I, Yi Q, Smith S, et al, for the SECURE Investigators. Effects of ramipril and vitamin E on atherosclerosis: the study to evaluate carotid ultra-sound changes in patients treated with Ramipril and vitamin E. Circulation 2001;103: 919-25.
Parving HH, Lehnert H, Br?chner-Mortensen J, Goms R, Andersen S, Arner P, for the Irbesartan in Patients Type 2 Diabetes And Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001;345: 870-8.
Maillard MP, Wurzner G, Nussberger J, Centeno C, Burnier M, Brunner HR. Comparative angiotensin II receptor blockade in healthy volunteers: the importance of dosing. Clin Pharmacol Ther 2002;71: 68-76.(Michel Marre, professor1,)