Background

In contrast to previous studies, recent data questioned the ability of renin–angiotensin–aldosterone system (RAAS) blockers to delay progression of diabetic nephropathy. This study evaluated the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in patients with diabetic nephropathy.

Methods

A systematic literature search of MEDLINE/PubMed and EMBASE databases was performed to identify randomized trials published up to June 2007 comparing the effects of ACEIs or ARBs with placebo and/or a regimen not including a RAAS blocker on the incidence of end-stage renal disease (ESRD), doubling of serum creatinine (DSC), or death from any cause in patients with diabetic nephropathy. Treatment effects were summarized as relative risks (RRs) using the Mantel–Haenszel fixed-effects model.

Results

Of the 1,028 originally identified studies, 24 fulfilled the inclusion criteria (20 using ACEIs and 4 using ARBs). Use of ACEIs was associated with a trend toward reduction of ESRD incidence (RR 0.70; 95% confidence interval (CI) 0.46–1.05) and use of ARBs with significant reduction of ESRD risk (RR 0.78; 95% CI 0.67–0.91). Both drug classes were associated with reduction in the risk of DSC (RR 0.71; 95% CI 0.56–0.91 for ACEIs and RR 0.79; 95% CI 0.68–0.91 for ARBs) but none affected all-cause mortality (RR 0.96; 95% CI 0.85–1.09 for ACEIs and RR 0.99; 95% CI 0.85–1.16 for ARBs).

Conclusion

Treatment of patients with diabetic nephropathy with a RAAS blocker reduces the risks of ESRD and DSC, but does not affect all-cause mortality. These findings are added to the evidence of a renoprotective role of RAAS blockers in such patients.

Methods

Selection criteria. We included randomized controlled trials of at least 1 year duration, conducted in adult patients with diabetic nephropathy in which the effect of an ACEI- or ARB-based regimen was compared with regimens not including these medications (placebo, placebo on top of background antihypertensive treatment, or antihypertensive treatment not including a RAAS blocker). Eligible studies had to be published as full-length articles in peer-reviewed English-language journals and should have assessed at least one of incidence of ESRD or death from any cause. Studies in patients with any type of diabetes and any stage of diabetic nephropathy were included.

Search strategy. A systematic literature search of MEDLINE/PubMed and EMBASE databases was performed to identify original articles on the effects of RAAS blockers in diabetic nephropathy published from 1977 (when ACEIs were approved for clinical trials in humans) to 30 June 2007. The search was limited to English-language articles in humans. Medical subject heading terms and search terms used were ACEIs, captopril, enalapril, cilazapril, enalaprilat, fosinopril, lisinopril, perindopril, ramipril, saralasin, angiotensin-receptor antagonists, ARBs, losartan, irbesartan, valsartan, olmesartan, candesartan, eprosartan, telmisartan combined with diabetes or diabetic nephropathy. Reference lists of identified articles, including previous meta-analyses and reviews on the field, were evaluated for additional relevant studies and information.

Data extraction and quality assessment. Each identified trial was assessed by the first two authors independently. They extracted data on the characteristics of the participants, interventions, comparisons, and outcomes (ESRD, DSC concentration, all-cause mortality). The methodological quality of eligible trials was assessed using standard criteria (allocation concealment, intention-to-treat analysis, percentage of loss to follow-up, blinding). Disagreements between the two authors were resolved by consensus.

Statistical analyses. Treatment effects were summarized as relative risks (RRs) and risk differences (RDs) with 95% confidence intervals (CIs), using the DerSimonian and Laird random-effects model or the Mantel–Haenszel fixed-effects model to pool the data, depending on the existence or not of heterogeneity of treatment effects across studies.¹⁵ To assess this heterogeneity, we used the Cochrane Q-test, along with I ² as a measure describing the percentage of the variability in effect estimates that is due to heterogeneity rather than sampling error (chance). The level of I ² was estimated using the formula I ² = ((Q - df)/Q) 100%, where Q is the ²-statistic and df are its degrees of freedom. A P value <0.10 in the Q-test and an I ² value >50% were considered as evidence of heterogeneity.¹⁵ The RRs of ESRD, DSC, and all-cause mortality were estimated by pooling the data of studies providing information for the respective outcome. The RD of ESRD was estimated from trials that have reported one or more patients reaching ESRD, in order to calculate the number-needed-to-treat to prevent one patient from developing ESRD. The possibility of publication bias (i.e., failure of small studies with negative results to be published in peer-reviewed journals) was examined with the funnel plot method (which involved plotting the RRs for each study on a logarithmic scale against their corresponding standard errors), the Begg's adjusted rank correlation test, and the Egger's regression asymmetry test.¹⁵ Analyses were performed using SPSS 13.0 (SPSS, Chicago, IL), Review Manager 4.2 for Windows (Wintertree Software, The Cochrane Collaboration, Oxford, England), and EasyMA 2001 (software for meta-analysis of clinical trials, Department of Clinical Pharmacology, Lyon, France).

Results

Study characteristics

A total of 1,028 studies were initially retrieved. Of those, 1,004 were excluded because of nonrandomized design, inclusion of nonadult populations, nondiabetic populations, mixed diabetic and nondiabetic populations, populations without diabetic nephropathy, no evaluation of renal outcomes, follow-up of <1 year, or duplicate publication. The search process led to the identification of 24 eligible randomized placebo- or active treatment-controlled studies that enrolled a total of 10,598 subjects.^14,16–38 Twenty of those (including 7,269 subjects)^14,16–34 compared an ACEI-based regimen with treatment not including ACEI, and four (including 3,329 subjects)^35,36,37,38 compared an ARB-based regimen with treatment not including ARB. The weighted mean follow-up of eligible studies was 41.62 months. The total number of subjects in the ACEI/ARB and the comparison groups included in the analysis were 5,430 and 5,168, respectively (Table 1). Testing for publication bias with the funnel plot method did not indicate systematic presence of bias favoring either the ACEI/ARB or the comparison groups. Similarly, neither Begg's test nor Egger's test were significant (P > 0.05), indicating absence of publication bias.

Table 1 - Included studies and patient characteristics.

Full table (117K)

Studies comparing ACEI-based regimens with non-ACEI regimens. Of the 20 trials^{14,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34} included in the ACEI subgroup of the meta-analysis, 13 enrolled patients with microalbuminuria,^{18,19,21,22,23,24,25,27,28,29,32,33,34} 5 patients with macroalbuminuria,^{16,17,26,30,31} and 2 mixed populations.^14,20 Eleven trials included patients with type 1 diabetes,^{16,18,19,20,22,25,27,28,31,33,34} six trials patients with type 2 diabetes,^{14,21,23,24,26,30} and three trials patients with either type 1 or type 2 diabetes.^17,29,32 In 10 trials^{17,19,20,23,24,26,29,30,32,34} subjects were hypertensive at baseline. In individual studies the number of ACEI-treated patients and controls ranged from 7 to 2,443 and from 4 to 2,469, respectively. The follow-up periods ranged from 12 to 60 months. The number of ACEI-treated and untreated patients included in the meta-analysis was 3,657 and 3,612, respectively. Only four trials with ACEIs reported at least one event of ESRD.^14,16,19,32

Studies comparing ARB-based regimens with non-ARB regimens. All four trials included in this subgroup enrolled hypertensive subjects with type 2 diabetes.^35,36,37,38 Two trials included patients with microalbuminuria,^35,36 and two patients with overt nephropathy.^37,38 The number of ARB-treated patients and controls in these trials ranged from 54 to 751 and from 24 to 762, respectively. The follow-up periods ranged from 13 to 40.8 months. The number of ARB-treated and untreated patients enrolled was 1,773 and 1,556, respectively. At least one event of ESRD was reported in two trials.^37,38

Effects of ACEIs and ARBs on renal outcomes

Across studies using ACEIs, there was no significant heterogeneity for ESRD (P = 0.62, I ² = 0%) or for DSC (P = 0.15, I ² = 37%). Of the 3,399 patients (1%) in the ACEI-treated groups, 36 developed ESRD compared with 52 of 3,374 (1.5%) in the control groups (RR 0.70; 95% CI, 0.46–1.05, P = 0.08) (Figure 1). DSC was noted in 103 of 3,386 patients (3%) in the ACEI-treated groups compared with 145 of 3,368 (4.3%) in the control groups (RR 0.71; 95% CI 0.56–0.91, P = 0.006) (Figure 2).

Figure 1.

Effect of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs)–based regimens compared to regimens without renin–angiotensin–aldosterone system (RAAS) inhibitors on the incidence of end-stage renal disease (ESRD).

Full figure and legend (20K)

Figure 2.

Effect of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs)–based regimens compared to regimens without renin–angiotensin–aldosterone system (RAAS) inhibitors on the incidence of doubling of serum creatinine concentration.

Full figure and legend (23K)

Similarly, with regard to studies with ARBs, the analysis presented no heterogeneity across combined studies for ESRD (P = 0.82, I ² = 0%) or DSC (P = 0.27, I ² = 18.2%). A total of 229 among 1,719 subjects (13.3%) in the ARB-treated groups developed ESRD compared with 295 of 1,532 subjects (19.2%) in the control groups (RR 0.78; 95% CI 0.67–0.91, P = 0.002) (Figure 1). DSC was observed in 260 of 1,719 (15%) ARB-treated subjects compared with 330 of 1,532 (21.5%) of subjects in control groups (RR 0.79; 95% CI 0.68–0.91, P = 0.001) (Figure 2).

In order to determine the number-needed-to-treat to prevent one patient from developing ESRD, we calculated the respective RD from trials reporting at least one patient reaching ESRD. Due to evidence of heterogeneity across studies using ACEIs (Figure 3), all these analyses were performed with the random-effects model. In the case of ACEI trials^14,16,19,32 the RD was not statistically significant (RD -0.003; 95% CI -0.0144 to 0.0085, P = 0.13), a result that can be attributed to the domination of these analysis by the Micro-HOPE study³² and the DIABHYCAR study¹⁴ which contributed 23.38 and 23.86%, respectively, to the weight of the summary estimate. With regard to ARBs, the RD of ESRD was significant in the RENAAL study³⁷ and this was the case for the total effect of ARBs when pooling RENAAL³⁷ and IDNT³⁸ (RD -0.0474, 95% CI -0.0773 to -0.0176, P = 0.0018) (Figure 3).

Figure 3.

Risk difference of angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs)–based treatment compared to regimens without renin–angiotensin–aldosterone system (RAAS) blockade on incidence of end-stage renal disease (ESRD).

Full figure and legend (34K)

The mean number-needed-to-treat to prevent one patient from developing ESRD was 333 for patients receiving ACEIs, a result that was not significant (P = 0.61), and the upper 95% confidence limit could not be estimated because the corresponding CI of the RD included zero. The respective number-needed-to-treat with an ARB was 21 (95% CI 12.94–56.82), which means that 21 patients with overt diabetic nephropathy needed to receive ARBs for 3 years (weighted mean follow-up) to prevent one patient from developing ESRD.

Effects of ACEIs and ARBs on all-cause mortality

Across studies using ACEIs or ARBs and reporting deaths from any cause, there was again no evidence for inter-study heterogeneity (Figure 4). In trials with ACEIs, a total of 438 among 3,657 (12.0%) subjects in the ACEI-treated groups died from any cause during follow-up compared with 465 of 3,612 (12.9%) subjects in the control groups (RR 0.96; 95% CI 0.85–1.09, P = 0.55). In trials with ARBs, a total of 248 among 1,773 (14.0%) subjects in the ARB-treated groups died from any cause compared with 249 of 1,556 (16.0%) subjects in the control groups (RR 0.99; 95% CI 0.85–1.16, P = 0.94).

Figure 4.

Effect of angiotensin-converting enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs)–based regimens compared to regimens without renin–angiotensin–aldosterone system (RAAS) inhibitors on all-cause mortality.

Full figure and legend (32K)

Discussion

The present meta-analysis demonstrated that inhibition of RAAS in patients with diabetic nephropathy with ACEIs or ARBs as a part of the treatment regimen is associated with reductions in the risk of ESRD and DSC concentration when compared with regimens that do not include RAAS blockers. Further, this study showed that use of an ACE or an ARB does not indicate a survival benefit as these agents did not decrease the risk of all-cause mortality.

Of note, in this study ARBs were found to significantly reduce the risk of ESRD and DSC by 22% and 21%, respectively, whereas ACEIs were associated with an insignificant (P = 0.08) reduction of 30% in the risk of ESRD and a significant reduction of 29% in the risk of DSC. These findings favoring ARBs over ACEIs should be viewed cautiously, given that point estimates of effect for both ESRD and DSC were lower for ACEIs compared with ARBs. This discordance can be partly attributed to the two pairs of studies dominating the reported effects of ACEIs (Micro-HOPE³² and DIABHYCAR¹⁴) and ARBs (RENAAL³⁷ and IDNT³⁸), which have important differences in design, primary outcomes, and studied populations; the ACEIs studies showed increased heterogeneity and lower renal event rates, allowing for wider CIs in the pooled estimate.

A previous meta-analysis in diabetic nephropathy by Strippoli et al.⁵ had similar findings; ARBs were associated with significant improvements in all renal outcomes, whereas ACEIs were associated with significantly reduced risk of progression from microalbuminuria to macroalbuminuria, and increased regression of microalbuminuria to normoalbuminuria, but only marginally significant reduction on the risk of ESRD or DSC. Strippoli et al.⁵ also observed no survival benefit with the use of ARBs, as in our study, but a significant reduction in all-cause mortality with ACEIs (RR 0.79; 95% CI, 0.63–0.99), which is slightly different from our relevant observation.

Studies included in the meta-analysis of Strippoli et al.⁵ had similar but no identical characteristics with those of our work, because that analysis included studies of shorter duration (>6 months), providing information on the effects of RAAS blockers on other renal outcomes beyond ESRD and DSC. The most important difference is the inclusion in our analysis of the DIABHYCAR study,¹⁴ which enrolled a large population with type 2 diabetes and elevated UAE (4,912 patients) to compare low-dose ramipril with placebo on top of usual treatment. The primary outcome was a combination of cardiovascular death, nonfatal myocardial infarction, stroke, heart failure leading to hospital admission, and ESRD.¹⁴ Inclusion of this trial in our analysis did not lead to different results from that of Strippoli et al.⁵ regarding the renal effects of ACEIs, as in the DIABHYCAR study, ramipril did not significantly affect renal outcomes and the number of renal events was relatively low.¹⁴ In contrast, the high number of death events and the absence of difference in all-cause mortality between ramipril and placebo groups in that study¹⁴ are rather responsible for the different findings of our analysis compared to Strippoli et al.⁵ on the ACEI effect on overall mortality. It should be noted, however, that the dose of ramipril used in the DIABHYCAR study (1.25 mg) is 1/8 of the dose used in other studies, i.e., the Micro-HOPE (10 mg). Thus, as in every meta-analysis, cautious interpretation of these differences on the basis of the characteristics of included studies is necessary to reach balanced conclusions.

A careful reader of data of the present analysis, and findings from the individual studies, would rather support that ACEIs and ARBs provide similar renoprotection. A regression analysis of treatment effects of these classes by Strippoli et al.⁵ using active treatment as the explanatory variable showed no difference between these classes for the risk of any outcome. These results are in accordance with the findings of relevant studies comparing directly an ACE and an ARB, i.e., a study from Lacourciere et al.³⁹ and the recently published DETAIL study⁴⁰ which showed that these classes provide similar renoprotection in patients with early diabetic nephropathy. In advanced diabetic nephropathy, it is difficult to conclude on the relative advantage of one class due to the absence of direct comparisons. However, current background and clinical evidence rather suggests that ACEIs and ARBs provide similar cardiovascular and renal protection and it is reasonable to be used interchangeably in clinical practice.⁴

A recent meta-analysis on the use of ACEIs and ARBs by Casas et al.⁹ has loudly challenged their renoprotective action. From studies only including patients with diabetes, in those comparing ACEIs and ARBs with placebo, RAAS blockers were associated with significant reductions of 21 and 22% in the risk of ESRD and DSC, whereas in those comparing RAAS blockers with active treatment, there was not any renal benefit of these agents. Further, in both cases, treatment with RAAS blockers was associated with lower BP levels and the authors suggested that the renoprotective effect of RAAS blockers in diabetic patients seem to derive from small placebo-controlled trials that do not provide adequate evidence on the existence of any true advantage above BP control.⁹ This meta-analysis met criticism for several methodological issues, i.e., substantial heterogeneity across included studies, domination of the results by the ALLHAT, ignorance of the issues of proteinuria and chronic kidney disease staging, equal attention to "soft" and "hard" renal endpoints, absence of patient-level data, and division of studies in those using placebo and those using "active treatment", although in all major placebo-controlled studies, placebo was added on standard therapy.^4,11,12,13 With regard to diabetic nephropathy, Casas et al. included data from diabetic patients of ALLHAT, which was not designed to examine the effects of antihypertensive agents on kidney disease^4,11,13 and, according to its own authors,⁸ presumably participants with decreased renal function were mostly patients with ischemic renal disease, for which an overwhelming renoprotective effect of ACEIs is not expected. Thus, Casas et al. aggregated patients with diabetic nephropathy and diabetic patients with hypertensive nephropathy,¹¹ and the magnitude of the ALLHAT may override an effect in patients with true diabetic nephropathy; therefore, the relevant findings should be interpreted with caution.

Recently, a population study from Canada¹⁰ suggested also that ACEIs do not decrease the long-term risk of ESRD in diabetes, but might actually increase it. This was a nested case–control analysis (ESRD cases vs. matched controls without ESRD) after forming a cohort of 6,102 diabetic patients treated with antihypertensive drugs in a Canadian Province between 1982 and 1986 that were followed up until 1997. In relation to thiazide diuretics, the adjusted rate ratio of ESRD for ACEIs was 2.5 (95% CI 1.3–4.7), and <1 for -blockers and calcium antagonists. This risk of ESRD with ACEIs was low during the first 3 years of follow-up, but increased considerably thereafter.¹⁰ However, this study suffered from major limitations, including its observational nature, the inherent indications bias (ACEIs may have been prescribed to patients with high renal risk), and the lack of information on doses, on major ESRD risk factors and ESRD cause.¹² Therefore, these results should be also interpreted with great caution.

Some limitations of our analysis should be acknowledged. Studies were retrieved from MEDLINE/PubMed and EMBASE databases and had to be published as full-length articles in peer-reviewed English-language journals. Thus, publication bias may have affected our estimates, with studies absent from these databases not included in the analysis, and patient-level data were unavailable. Further, the number of eligible studies was small and some of them may have been of suboptimal quality. However, these issues could not have influenced our findings considerably, as we used rather strict inclusion criteria, and examination with formal methods showed no evidence of publication bias. Further, well-designed larger studies dominated the results, as small studies included in the analysis (i.e., 11 studies with a sample size <50 subjects) had total weights between 0.83 and 2.85% in the various analyses and their removal produces minor changes in the final results for ACEIs and no change in the ARB results. Other potential limitations are the absence of a direct comparison between ACEIs and ARBs due to the sparseness of trials comparing directly the two agents and reporting incidence of ESRD and the heterogeneity of the included studies concerning the type of diabetes and the level of albuminuria.

In conclusion, the present analysis showed that treatment of patients with diabetic nephropathy with a RAAS blocker is associated with reductions in the risks of ESRD and DSC. The effect of ACEIs on ESRD, although slightly greater in magnitude than that of ARBs, was almost significant due to different design of large studies for each class included in the analysis. No apparent survival benefit was observed with either type of RAAS blockers in this study. These findings add to the existing evidence of a renoprotective role of RAAS blockers in patients with diabetic nephropathy and further support the current recommendations that ACEIs and ARBs should be used as first-line antihypertensive treatment in these patients.^3,6,7 Well-designed trials comparing head-to-head ACEIs and ARBs in patients with overt diabetic nephropathy are needed to elucidate potential differences between these classes on renal outcomes and all-cause mortality. Until then, based on existing evidence these two classes should be used interchangeably in diabetic nephropathy.

Disclosure:

The authors declared no conflict of interest.

References

1. Amos AF, McCarty DJ, Zimmet P. The rising global burden of diabetes and its complications: estimates and projections to the year 2010. Diabet Med 1997; 14(Suppl 5):S1–85.
2. Collins AJ, Kasiske B, Herzog C, Chavers B, Foley R, Gilbertson D, Grimm R, Liu J, Louis T, Manning W, McBean M, Murray A, St Peter W, Xue J, Fan Q, Guo H, Li Q, Li S, Qiu Y, Li S, Roberts T, Skeans M, Snyder J, Solid C, Wang C, Weinhandl E, Zhang R, Arko C, Chen SC, Dalleska F, Daniels F, Dunning S, Ebben J, Frazier E, Hanzlik C, Johnson R, Sheets D, Wang X, Forrest B, Berrini D, Constantini E, Everson S, Eggers P, Agodoa L. Excerpts from the United States Renal Data System 2006 Annual Data Report. Am J Kidney Dis 2007; 49:A6–A296. | Article | PubMed |
3. K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43:1–290. | Article | PubMed | ISI | ChemPort |
4. Sarafidis PA, Khosla N, Bakris GL. Antihypertensive therapy in the presence of proteinuria. Am J Kidney Dis 2007; 49:12–26. | Article | PubMed | ChemPort |
5. Strippoli GF, Craig M, Deeks JJ, Schena FP, Craig JC. Effects of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists on mortality and renal outcomes in diabetic nephropathy: systematic review. BMJ 2004; 329:828–838. | Article | PubMed | ChemPort |
6. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003; 289:2560–2572. | Article | PubMed | ISI | ChemPort |
7. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, Grassi G, Heagerty AM, Kjeldsen SE, Laurent S, Narkiewicz K, Ruilope L, Rynkiewicz A, Schmieder RE, Struijker Boudier HA, Zanchetti A, Vahanian A, Camm J, De Caterina R, Dean V, Dickstein K, Filippatos G, Funck-Brentano C, Hellemans I, Kristensen SD, McGregor K, Sechtem U, Silber S, Tendera M, Widimsky P, Zamorano JL, Kjeldsen SE, Erdine S, Narkiewicz K, Kiowski W, Agabiti-Rosei E, Ambrosioni E, Cifkova R, Dominiczak A, Fagard R, Heagerty AM, Laurent S, Lindholm LH, Mancia G, Manolis A, Nilsson PM, Redon J, Schmieder RE, Struijker-Boudier HA, Viigimaa M, Filippatos G, Adamopoulos S, Agabiti-Rosei E, Ambrosioni E, Bertomeu V, Clement D, Erdine S, Farsang C, Gaita D, Kiowski W, Lip G, Mallion JM, Manolis AJ, Nilsson PM, O'Brien E, Ponikowski P, Redon J, Ruschitzka F, Tamargo J, van Zwieten P, Viigimaa M, Waeber B, Williams B, Zamorano JL, The task force for the management of arterial hypertension of the European Society of Hypertension, The task force for the management of arterial hypertension of the European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007; 25:1105–1187. | Article | PubMed | ISI | ChemPort |
8. Rahman M, Pressel S, Davis BR, Nwachuku C, Wright JT Jr, Whelton PK, Barzilay J, Batuman V, Eckfeldt JH, Farber M, Henriquez M, Kopyt N, Louis GT, Saklayen M, Stanford C, Walworth C, Ward H, Wiegmann T. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005; 165:936–946. | Article | PubMed | ISI | ChemPort |
9. Casas JP, Chua W, Loukogeorgakis S, Vallance P, Smeeth L, Hingorani AD, MacAllister RJ. Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366:2026–2033. | Article | PubMed | ISI | ChemPort |
10. Suissa S, Hutchinson T, Brophy JM, Kezouh A. ACE-inhibitor use and the long-term risk of renal failure in diabetes. Kidney Int 2006; 69:913–919. | Article | PubMed | ISI | ChemPort |
11. Mann JF, McClellan WM, Kunz R, Ritz E. Progression of renal disease—can we forget about inhibition of the renin-angiotensin system? Nephrol Dial Transplant 2006; 21:2348–2351. | Article | PubMed | ChemPort |
12. Rossing P, Parving HH, de Zeeuw D. Renoprotection by blocking the RAAS in diabetic nephropathy—fact or fiction? Nephrol Dial Transplant 2006; 21:2354–2357. | Article | PubMed |
13. de Zeeuw D, Lewis EJ, Remuzzi G, Brenner BM, Cooper ME. Renoprotective effects of renin-angiotensin-system inhibitors. Lancet 2006; 367:899–900. | Article | PubMed | ISI |
14. Marre M, Lievre M, Chatellier G, Mann JF, Passa P, Ménard J; DIABHYCAR Study Investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with type 2 diabetes and raised excretion of urinary albumin: randomised, double blind, placebo controlled trial (the DIABHYCAR study). BMJ 2004; 328:495–502. | Article | PubMed | ChemPort |
15. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Intervention 4.2.6. The Cochrane Library, Issue 4. Wiley: Chichester, UK, 2006.
16. Parving HH, Hommel E, Damkjaer NM, Giese J. Effect of captopril on blood pressure and kidney function in normotensive insulin dependent diabetics with nephropathy. BMJ 1989; 299:533–536. | PubMed | ChemPort |
17. Bauer JH, Reams GP, Hewett J, Klachko D, Lau A, Messina C, Knaus V. A randomized, double-blind, placebo-controlled trial to evaluate the effect of enalapril in patients with clinical diabetic nephropathy. Am J Kidney Dis 1992; 20:443–457. | PubMed | ChemPort |
18. Chase HP, Garg SK, Harris S, Hoops S, Jackson WE, Holmes DL. Angiotensin-converting enzyme inhibitor treatment for young normotensive diabetic subjects: a two-year trial. Ann Ophthalmol 1993; 25:284–289. | PubMed | ChemPort |
19. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993; 329:1456–1462. | Article | PubMed | ISI | ChemPort |
20. Phillips PJ, Phillipou G, Bowen KM, Lowe J, Yue DK, Wischusen J, Pater G. Diabetic microalbuminuria and cilazapril. Am J Med 1993; 94:58S–60S. | PubMed | ChemPort |
21. Ravid M, Savin H, Jutrin I, Bental T, Katz B, Lishner M. Long-term stabilizing effect of angiotensin-converting enzyme inhibition on plasma creatinine and on proteinuria in normotensive type II diabetic patients. Ann Intern Med 1993; 118:577–581. | PubMed | ISI | ChemPort |
22. Bakris GL, Slataper R, Vicknair N, Sadler R. ACE inhibitor mediated reductions in renal size and microalbuminuria in normotensive, diabetic subjects. J Diabetes Complications 1994; 8:2–6. | Article | PubMed | ISI | ChemPort |
23. Capek M, Schnack C, Ludvik B, Kautzky-Willer A, Banyai M, Prager R. Effects of captopril treatment versus placebo on renal function in type 2 diabetic patients with microalbuminuria: a long-term study. Clin Investig 1994; 72:961–966. | Article | PubMed | ChemPort |
24. Sano T, Kawamura T, Matsumae H, Sasaki H, Nakayama M, Hara T, Matsuo S, Hotta N, Sakamoto N. Effects of long-term enalapril treatment on persistent micro-albuminuria in well-controlled hypertensive and normotensive NIDDM patients. Diabetes Care 1994; 17:420–424. | Article | PubMed | ISI | ChemPort |
25. Laffel LM, McGill JB, Gans DJ. The beneficial effect of angiotensin-converting enzyme inhibition with captopril on diabetic nephropathy in normotensive IDDM patients with microalbuminuria. North American Microalbuminuria Study Group. Am J Med 1995; 99:497–504. | Article | PubMed | ISI | ChemPort |
26. Maschio G, Alberti D, Janin G, Locatelli F, Mann JF, Motolese M, Ponticelli C, Ritz E, Zucchelli P. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334:939–945. | Article | PubMed | ISI | ChemPort |
27. Crepaldi G, Carta Q, Deferrari G, Mangili R, Navalesi R, Santeusanio F, Spalluto A, Vanasia A, Villa GM, Nosadini R. Effects of lisinopril and nifedipine on the progression to overt albuminuria in IDDM patients with incipient nephropathy and normal blood pressure. The Italian Microalbuminuria Study Group in IDDM. Diabetes Care 1998; 21:104–110. | Article | PubMed | ISI | ChemPort |
28. Garg SK, Chase HP, Jackson WE, Harris S, Carmain JA, Hansen MH, Riche CR, Icaza G, Marshall G. Renal and retinal changes after treatment with ramipril and pentoxifyline in subjects with IDDM. Ann Ophthalmol 1998; 30:33–37.
29. Nankervis A, Nicholls K, Kilmartin G, Allen P, Ratnaike S, Martin FI. Effects of perindopril on renal histomorphometry in diabetic subjects with microalbuminuria: a 3-year placebo-controlled biopsy study. Metabolism 1998; 47:12–15. | Article | PubMed | ChemPort |
30. Cordonnier DJ, Pinel N, Barro C, Maynard M, Zaoui P, Halimi S, Hurault de LB, Reznic Y, Simon D, Bilous RW. Expansion of cortical interstitium is limited by converting enzyme inhibition in type 2 diabetic patients with glomerulosclerosis. The Diabiopsies Group. J Am Soc Nephrol 1999; 10:1253–1263. | PubMed | ISI | ChemPort |
31. Mathiesen ER, Hommel E, Hansen HP, Smidt UM, Parving HH. Randomised controlled trial of long term efficacy of captopril on preservation of kidney function in normotensive patients with insulin dependent diabetes and microalbuminuria. BMJ 1999; 319:24–25. | PubMed | ChemPort |
32. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000; 355:253–259. | PubMed | ISI |
33. Bojestig M, Karlberg BE, Lindstrom T, Nystrom FH. Reduction of ACE activity is insufficient to decrease microalbuminuria in normotensive patients with type 1 diabetes. Diabetes Care 2001; 24:919–924. | Article | PubMed | ChemPort |
34. Katayama S, Kikkawa R, Isogai S, Sasaki N, Matsuura N, Tajima N, Urakami T, Uchigata Y, Ohashi Y. Effect of captopril or imidapril on the progression of diabetic nephropathy in Japanese with type 1 diabetes mellitus: a randomized controlled study (JAPAN-IDDM). Diabetes Res Clin Pract 2002; 55:113–121. | Article | PubMed | ChemPort |
35. Muirhead N, Feagan BF, Mahon J, Lewanczuk RZ, Rodger NW, Botteri F, Oddou-Stock P, Pecher E, Cheung R. The effects of valsartan and captopril on reducing microalbuminuria in patients with type 2 diabetes mellitus: A placebo-controlled trial. Curr Ther Res Clin Exp 1999; 60:650–660. | Article | ChemPort |
36. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345:870–878. | Article | PubMed | ISI | ChemPort |
37. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snapinn SM, Zhang Z, Shahinfar S. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 2001; 345:861–869. | Article | PubMed | ISI | ChemPort |
38. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde R, Raz I. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345:851–860. | Article | PubMed | ISI | ChemPort |
39. Lacourciere Y, Belanger A, Godin C, Halle JP, Ross S, Wright N, Marion J. Long-term comparison of losartan and enalapril on kidney function in hypertensive type 2 diabetics with early nephropathy. Kidney Int 2000; 58:762–769. | Article | PubMed | ISI | ChemPort |
40. Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med 2004; 351:1952–1961. | Article | PubMed | ISI | ChemPort |