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Role of Blood Pressure Targets and Specific Antihypertensive Agents Used to Prevent Diabetic Nephropathy and Delay Its Progression

Giovanni F.M. Strippoli^*, Maria C. Craig^*, Francesco P. Schena and Jonathan C. Craig^*

^* National Health and Medical Research Council Centre for Clinical Research Excellence in Renal Medicine, Centre for Kidney Research, School of Public Health, University of Sydney, Sydney, Australia; and Department of Emergency and Organ Transplantation, Section of Nephrology, University of Bari, Bari, Italy

Address correspondence to: Dr. Giovanni F.M. Strippoli, NHMRC Centre for Clinical Research Excellence in Renal Medicine, University of Sydney, Australia. Phone/Fax: +39-080-5580776; gfmstrippoli{at}aliceposta.it

	Abstract

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This study evaluated the comparative effects of antihypertensive agents in patients with diabetes and normoalbuminuria and the evidence supporting equivalent use of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) in patients with diabetes and micro- or macroalbuminuria. A systematic review was conducted by searching for randomized controlled trials (RCT) of antihypertensive agent versus placebo or another agent in hypertensive or normotensive patients with diabetes and no nephropathy and RCT of ACEi or ARB in patients with diabetic nephropathy. Medline, Embase, the Cochrane Controlled Trials Register, conference proceedings, and contact with investigators were used to identify available evidence. Two investigators independently extracted data and assessed quality of trials. Sixteen RCT (7603 patients) of antihypertensive agents conducted in patients with diabetes and no nephropathy and 43 (7739 patients) of ACEi or ARB in patients with diabetic nephropathy were identified. A significant reduction in the risk for developing microalbuminuria in patients who had diabetes with no nephropathy was demonstrated for ACEi only (six trials, 3840 patients; relative risk [RR] 0.60; 95% confidence interval [CI] 0.43 to 0.84), and in patients with diabetic nephropathy, existing RCT have shown a survival benefit of ACEi (20 trials, 2383 patients; RR 0.79; 95% CI 0.63 to 0.99; P = 0.04) but not ARB (four trials, 3329 patients; RR 0.99; 95% CI 0.85 to 1.17). On the basis of available RCT evidence, ACEi are the only agents with proven renal benefit in patients who have diabetes with no nephropathy and the only agents with proven survival benefit in patients who have diabetes with nephropathy.

	Introduction

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Chronic kidney disease associated with diabetes is defined by the presence of microalbuminuria (20 to 200 µg/min) or macroalbuminuria (>300 µg/min) or proteinuria and occurs within 20 to 25 yr of the onset of type 1 or type 2 diabetes in a large proportion of patients, ranging from 25 to 40%. Approximately 30% of patients with diabetic nephropathy progress to ESRD (1,2). Nephropathy is a strong independent predictor of mortality in these patients, who already present a 10 to 40% death rate within 10 yr of the diagnosis, which may be doubled by the presence of nephropathy.

Several antihypertensive agents, including angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium antagonists, blockers, diuretics, and others, are used to prevent the onset of nephropathy in patients with diabetes. International guidelines indicate that any antihypertensive agent can be used equivalently in patients with diabetes provided a tight control of BP is achieved (3,4). These data seem to be based mainly on extrapolation from large trials that were conducted in the general hypertensive population, including a proportion of patients who had diabetes with uncertain baseline albuminuria, rather than in trials of patients who had diabetes without nephropathy only. When the patient with diabetes becomes albuminuric, international guidelines indicate that ACEi or ARB could be used equivalently to delay the progression of nephropathy (3,4). We reviewed all randomized controlled trials relating to use of antihypertensive agents for the primary prevention of microalbuminuria in patients with diabetes and normoalbuminuria (albuminuria <20 µg/min). We also assessed randomized trials in which ACEi or ARB were used for preventing the progression of diabetic nephropathy (albuminuria >20 µg/min) in patients with diabetes.

	Materials and Methods

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A broad literature search including Medline (1966 to September 2003), Embase (1988 to September 2003), the Cochrane Controlled trial Registry (2004 issue), reference lists, and contact with known investigators was performed to identify randomized trials of antihypertensive agents that were conducted in patients with diabetes and in patients with diabetic nephropathy (micro- or macroalbuminuria). The trials were analyzed without language restriction, and two authors independently extracted data on cardiovascular, renal, and safety outcomes (all-cause mortality, ESRD, doubling of serum creatinine, onset of microalbuminuria, progression from microalbuminuria to macroalbuminuria, regression from microalbuminuria to normoalbuminuria, cough, headache, hyperkalemia, and impotence). Whenever these were not reported, authors of the trials were contacted at least twice for the data. The quality of the trials was assessed using standard criteria (allocation concealment, intention-to-treat analysis, loss to follow-up, and blinding). Summary data for treatment effects were calculated with the relative risk (RR) measure and its 95% confidence intervals (CI) and pooled using the DerSimonian and Laird random-effects model. Analysis of heterogeneity of treatment effects between studies (which could be due to duration of follow-up, type of diabetes, type of antihypertensive agent, presence or absence of hypertension, stage of diabetic nephropathy, and quality of trials) was examined using the Cochran Q and I² statistics (5), subgroup analysis, random-effects meta-regression, and indirect comparisons. Analyses were undertaken in STATA version 8.0 and RevMan 4.2.

	Results

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Sixteen trials (26 publications, 8570 patients) that were conducted in patients who had diabetes with no nephropathy and 43 trials (59 publications, 7545 patients) that were conducted in patients who had diabetes with nephropathy were identified, respectively. The primary prevention trials that were conducted in patients with no nephropathy included seven randomized trials (n = 5225) of ACEi versus placebo, six (n = 1168) of ACEi versus calcium antagonists, and three (n = 2177) of ACEi versus blockers. Thirteen of these trials (n = 8317) were conducted in hypertensive patients, and 11 (n = 8228) were conducted in patients with type 2 diabetes. Additional antihypertensive co-interventions were administered in all but four trials to account for the potential confounding effect of BP.

The second group of trials relating to preventing the progression of diabetic nephropathy included 36 studies (n = 4008) of ACEi versus placebo, four (n = 3331) of ARB versus placebo, and three (n = 206) very small "head to head" trials of ACEi versus ARB. Of the trials that compared ACEi with placebo, 20 enrolled patients with type 1 diabetes, 11 enrolled patients with type 2 diabetes, and five enrolled mixed populations. Sixteen enrolled hypertensive patients, and in 18, antihypertensive co-interventions besides the randomized ones were given to equalize BP in both groups. Twenty-three trials enrolled patients with microalbuminuria, eight enrolled patients with macroalbuminuria, and five enrolled mixed populations.

The four trials that compared ARB with placebo all enrolled hypertensive patients with type 2 diabetes and used antihypertensive co-interventions. Two trials enrolled patients with microalbuminuria, and the other two trials enrolled patients with macroalbuminuria.

The three trials that compared ACEI with ARB directly all enrolled microalbuminuric patients with type 2 diabetes. Two trials enrolled hypertensive patients, and one trial enrolled normotensive participants. Antihypertensive co-interventions were given in two trials.

Primary Prevention of Diabetic Nephropathy Trials
Summary estimators of the effect of antihypertensive agents on cardiovascular, renal, and safety outcomes in available trials that were conducted in patients with diabetes and no nephropathy are reported in Table 1. Compared with other agents, ACEi were found to be associated with significant renal benefits.

	Discussion

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ACEi have been shown to reduce significantly the risk for onset of nephropathy, whereas similar data are not available with other agents in trials that have been conducted in normoalbuminuric patients with diabetes only. ACEi also are associated with a significant reduction in the risk for all-cause mortality in patients with diabetic nephropathy and significantly reduce the risk for progression of nephropathy and increase the rate of its regression. ARB are associated with a significant renal advantage with reduction in the risk for ESRD, doubling of creatinine, and progression of nephropathy and increase in the rates of regression of nephropathy. They have not yet been found to be associated with a reduction in the risk for all-cause mortality.

With respect to primary prevention of diabetic nephropathy, the large proportion of available trials are not conducted in patients with diabetes but enroll some patients with diabetes among many other categories. Few trials have been conducted in who had diabetes without hypertension, and there are no trial data on the renal effects of ARB in these populations. Nevertheless, available guidelines make recommendations that the BP target is more important than the type of antihypertensive agent in these patients. These indications derive from the many large-scale trials done in hypertensive patients (ALLHAT, CAPP, HOT, INSIGHT, NORDIL, SHEP, STOP-Hypertension2, Syst-EUR) and including significant proportions of patients with diabetes; unfortunately for clinicians and patients who want to know the comparative effects of these agents with kidney disease as an outcome, these trials are largely uninformative, because this outcome (onset of micro- or macroalbuminuria) is not reported. Data from available trials that were conducted exclusively in patients who had diabetes with no nephropathy suggest that ACEi could be the first-line agent suggested considering the additional renal benefits that they confer.

With respect to preventing the progression of nephropathy, several placebo-controlled trials of ACEi and ARB are available, but their findings are insufficient to consider these agents as equivalent for renal and mortality outcomes, contrary to what is indicated by most international guidelines. The major need to demonstrate the comparative efficacy of these agents would be a head-to-head comparative trial measuring patient-centered outcomes; unfortunately, this is not available. Three available head-to-head trials are small, of very short duration, and have not examined patient-centered end points. Available published trial data suggest that ACEi might be preferred in patients who have diabetes with diabetic nephropathy given the incremental renal benefits in the former and the proven survival advantage in the latter.

	Acknowledgments

 
This study was supported by the Cochrane Renal Group and the Australia/Europe Endeavour Scholarship, 2005.

	References

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1. Mogensen CE: Drug treatment for hypertensive patients in special situations: Diabetes and hypertension. Clin Exp Hypertens 21 : 895 –906, 1999[Medline]
2. Mogensen CE: Microalbuminuria in prediction and prevention of diabetic nephropathy in insulin-dependent diabetes mellitus patients. J Diabetes Complications 9 : 337 –349, 1995[CrossRef][Medline]
3. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, Roccella EJ; National Heart, Lung, and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National High Blood Pressure Education Program Coordinating Committee: Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: The JNC-7 report. JAMA 289 : 2560 –2572, 2003[Abstract/Free Full Text]
4. Arauz-Pacheo C, Parrott MA, Raskin P: Treatment of hypertension in adults with diabetes. Diabetes Care 26 : S80 –S82, 2003
5. Higgins JP, Thompson SG, Deeks JJ, Altaman DG: Measuring inconsistency in meta-analyses. BMJ 327 : 557 –560, 2003[Free Full Text]

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