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

Materials and Methods

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

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 β 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.

Discussion

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.