A 54-year-old woman with type 2 diabetes comes into your office. She has no evidence of diabetic nephropathy and needs medication for hypertension.
Is one class of antihypertensive agents superior to others for the prevention of diabetic nephropathy?
Angiotensin-converting enzyme (ACE) inhibitors are the only antihypertensive agents with proven effectiveness for the primary prevention of diabetic nephropathy (defined as an albumin excretion of less than 30 mg per day on three serial measurements) caused by type 1 or type 2 diabetes. However, ACE inhibitors have not been shown to decrease all-cause mortality in patients with diabetes. Based on limited data, ACE inhibitors have not been shown to reduce end-stage renal disease significantly when compared with placebo.1
The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, the American Diabetes Association, and the American Association of Clinical Endocrinologists each recommend aggressive treatment of hypertension in patients with diabetes.2–4 The recommendations include ACE inhibitors among various other classes of anti-hypertensive agents. Secondary prevention of kidney disease in patients with diabetes who have microalbuminuria is well established. However, none of these recommendation statements addresses the primary prevention of nephropathy using antihypertensive agents in patients who have normal kidney function with or without hypertension.
This Cochrane review1 included studies involving patients with type 1 and type 2 diabetes regardless of blood pressure. However, most trials involved patients with type 2 diabetes and hypertension. Study duration ranged from six to 72 months.
The review clearly identified ACE inhibitors as having the most substantial evidence for their usefulness in preventing diabetic nephropathy compared with placebo. It also demonstrated that, compared with calcium channel blockers, ACE inhibitors reduced progression to microalbuminuria but did not reduce all-cause mortality. The few data available do not show a significant reduction in end-stage renal disease with ACE inhibitor therapy. The number of patients with diabetes who need to be treated with an ACE inhibitor to prevent microalbuminuria in one patient is 25.
An additional question is whether patients with diabetes who are normotensive receive a marginal benefit from treatment with ACE inhibitors in preventing nephropathy. However, randomized controlled trials have not included a sufficient number of patients who are normotensive to provide an answer. Although some physicians prescribe ACE inhibitors to prevent nephropathy in patients with diabetes who are normotensive, there is no compelling evidence to support this.
Of primary importance is that, although a body of evidence addresses the intermediate outcome of microalbuminuria as a key point in the progression to end-stage renal disease, there is no evidence to prove that ACE inhibitors affect all-cause mortality. This may be because of the burden of cardiovascular disease, the most common cause of death among patients with diabetes. It is possible that all antihypertensive medications that are protective against cardiovascular mortality are equally effective in preventing morbidity and mortality in patients with diabetes, and that therapy with ACE inhibitors is no more effective than therapy with beta blockers (which have no known effect in preventing diabetic nephropathy) for the prevention of cardiovascular mortality in these patients. Another possibility is that preventing end-stage renal disease has no benefit for mortality because patients with diabetes may die at a similarly premature age from other causes. Considering that cardiovascular disease is the primary cause of mortality in patients with diabetes, other classes of antihypertensive agents that are effective in preventing coronary artery disease, such as beta blockers, diuretics, calcium channel blockers, and angiotensin-receptor blockers, also should be considered in this population.
Background. Twenty to 60 percent of patients with diabetes are affected by hypertension, and antihypertensive agents are used to treat this condition. These agents also are used to prevent the onset of kidney disease in patients with diabetes who are normotensive or hypertensive.
Objectives To evaluate the comparative effects of antihypertensive agents in patients with diabetes and normoalbuminuria.
Search Strategy. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, conference proceedings, and contact with investigators were used to identify relevant trials.
Selection Criteria. Randomized controlled trials comparing any antihypertensive agent with placebo or another agent in patients with diabetes who were hypertensive or normotensive and had no kidney disease (i.e., an albumin excretion rate less than 30 mg per day) were included.
Data Collection and Analysis. Two investigators independently extracted data on renal outcomes and other patient-relevant outcomes (e.g., all-cause mortality, serious cardiovascular events) and assessed quality of trials. Analysis was by a random-effects model and results were expressed as relative risk (RR) and 95% confidence interval (CI).
Primary Results. Sixteen trials (7,603 patients) were identified, six of angiotensin-converting enzyme (ACE) inhibitors versus placebo, six of ACE inhibitors versus calcium channel blockers, one of ACE inhibitors versus calcium channel blockers or combined ACE inhibitors and calcium channel blockers, and three of ACE inhibitors versus other agents. Compared with placebo, ACE inhibitors significantly reduced the development of microalbuminuria (six trials, 3,840 patients: RR 0.60; 95% CI, 0.43 to 0.84) but not doubling of creatinine (three trials, 2,683 patients: RR 0.81; 95% CI, 0.24 to 2.71) or all-cause mortality (four trials, 3,284 patients: RR 0.81; 95% CI, 0.64 to 1.03). Compared with calcium channel blockers, ACE inhibitors significantly reduced progression to microalbuminuria (four trials, 1,210 patients: RR 0.58; 95% CI, 0.40 to 0.84).
Reviewers’ Conclusions. A significant reduction in the risk of developing microalbuminuria in patients with diabetes and normoalbuminuria has been demonstrated for ACE inhibitors only. It appears that the effect of ACE inhibitors is independent of baseline blood pressure, renal function, and type of diabetes, but data are too sparse to be confident that these are not important effect modifiers, and an individual patient data meta-analysis is required.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).