Does Combination ACEi/ARB Therapy Benefit Patients With Proteinuria?

Q: I have a diabetic patient with microscopic proteinuria. I put her on an ACE inhibitor, but she still has the same albumin–creatinine ratio. My supervising physician suggested I add an ARB to her regimen, but I seem to remember reading that this does not work. Is that true? Or should I prescribe an ACE inhibitor/ARB combination?

This is a common question, but there is no consensus regarding the correct answer. The question should be: Are two drugs better than one when it comes to reducing proteinuria and progression to end-stage renal disease? Researchers have demonstrated a decrease in proteinuria in patients given combination ACE inhibitor/angiotension receptor blocker (ARB) therapy; however, the studies involved were found to have flaws, including small sample sizes and relatively short follow-up, once treatment was initiated.^1,2

A larger study, known as Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET),^3,4 is a multiyear study with more than 25,000 patients enrolled. ONTARGET (which excludes patients with heart failure) addresses the question of whether an ACE inhibitor in combination with an ARB, or either agent alone, is more effective in the reduction of proteinuria. In ONTARGET, combination therapy was associated with a decrease in proteinuria; however, the incidence of renal impairment was much higher.³

ONTARGET was the first trial to cast doubt on the belief that proteinuria is an accurate marker for progressive renal dysfunction. Combination treatment led to an advanced risk for increased serum creatinine and need for dialysis, despite the reduction in proteinuria. Further, combination therapy was more likely than either agent alone to cause adverse effects, including hypotension and hyperkalemia.^3,4

Finally, the study also demonstrated that ACE inhibitors are not superior to ARBs. Both drugs reduce proteinuria, and each one taken alone decreases progression to end-stage renal disease. Therefore, the conclusion is that either an ACE inhibitor or an ARB alone is more efficacious than the two drugs combined.

Tricia A. Howard, MHS, PA-C, South University PA Program, Tampa, FL

References

1. Misra S, Stevermer JJ. ACE inhibitors and ARBs: one or the other—not both—for high-risk patients. J Fam Pract. 2009;58:24-26.

2. Jennings DL, Kalus JS, Coleman CI, et al. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis. Diabet Med. 2007;24:486-493.

3. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553.

4. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.

Q: I have a diabetic patient with microscopic proteinuria. I put her on an ACE inhibitor, but she still has the same albumin–creatinine ratio. My supervising physician suggested I add an ARB to her regimen, but I seem to remember reading that this does not work. Is that true? Or should I prescribe an ACE inhibitor/ARB combination?

This is a common question, but there is no consensus regarding the correct answer. The question should be: Are two drugs better than one when it comes to reducing proteinuria and progression to end-stage renal disease? Researchers have demonstrated a decrease in proteinuria in patients given combination ACE inhibitor/angiotension receptor blocker (ARB) therapy; however, the studies involved were found to have flaws, including small sample sizes and relatively short follow-up, once treatment was initiated.^1,2

A larger study, known as Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET),^3,4 is a multiyear study with more than 25,000 patients enrolled. ONTARGET (which excludes patients with heart failure) addresses the question of whether an ACE inhibitor in combination with an ARB, or either agent alone, is more effective in the reduction of proteinuria. In ONTARGET, combination therapy was associated with a decrease in proteinuria; however, the incidence of renal impairment was much higher.³

ONTARGET was the first trial to cast doubt on the belief that proteinuria is an accurate marker for progressive renal dysfunction. Combination treatment led to an advanced risk for increased serum creatinine and need for dialysis, despite the reduction in proteinuria. Further, combination therapy was more likely than either agent alone to cause adverse effects, including hypotension and hyperkalemia.^3,4

Finally, the study also demonstrated that ACE inhibitors are not superior to ARBs. Both drugs reduce proteinuria, and each one taken alone decreases progression to end-stage renal disease. Therefore, the conclusion is that either an ACE inhibitor or an ARB alone is more efficacious than the two drugs combined.

Tricia A. Howard, MHS, PA-C, South University PA Program, Tampa, FL

References

1. Misra S, Stevermer JJ. ACE inhibitors and ARBs: one or the other—not both—for high-risk patients. J Fam Pract. 2009;58:24-26.

2. Jennings DL, Kalus JS, Coleman CI, et al. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis. Diabet Med. 2007;24:486-493.

3. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553.

4. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.

Q: I have a diabetic patient with microscopic proteinuria. I put her on an ACE inhibitor, but she still has the same albumin–creatinine ratio. My supervising physician suggested I add an ARB to her regimen, but I seem to remember reading that this does not work. Is that true? Or should I prescribe an ACE inhibitor/ARB combination?

This is a common question, but there is no consensus regarding the correct answer. The question should be: Are two drugs better than one when it comes to reducing proteinuria and progression to end-stage renal disease? Researchers have demonstrated a decrease in proteinuria in patients given combination ACE inhibitor/angiotension receptor blocker (ARB) therapy; however, the studies involved were found to have flaws, including small sample sizes and relatively short follow-up, once treatment was initiated.^1,2

A larger study, known as Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET),^3,4 is a multiyear study with more than 25,000 patients enrolled. ONTARGET (which excludes patients with heart failure) addresses the question of whether an ACE inhibitor in combination with an ARB, or either agent alone, is more effective in the reduction of proteinuria. In ONTARGET, combination therapy was associated with a decrease in proteinuria; however, the incidence of renal impairment was much higher.³

ONTARGET was the first trial to cast doubt on the belief that proteinuria is an accurate marker for progressive renal dysfunction. Combination treatment led to an advanced risk for increased serum creatinine and need for dialysis, despite the reduction in proteinuria. Further, combination therapy was more likely than either agent alone to cause adverse effects, including hypotension and hyperkalemia.^3,4

Finally, the study also demonstrated that ACE inhibitors are not superior to ARBs. Both drugs reduce proteinuria, and each one taken alone decreases progression to end-stage renal disease. Therefore, the conclusion is that either an ACE inhibitor or an ARB alone is more efficacious than the two drugs combined.

Tricia A. Howard, MHS, PA-C, South University PA Program, Tampa, FL

References

1. Misra S, Stevermer JJ. ACE inhibitors and ARBs: one or the other—not both—for high-risk patients. J Fam Pract. 2009;58:24-26.

2. Jennings DL, Kalus JS, Coleman CI, et al. Combination therapy with an ACE inhibitor and an angiotensin receptor blocker for diabetic nephropathy: a meta-analysis. Diabet Med. 2007;24:486-493.

3. Mann JF, Schmieder RE, McQueen M, et al; ONTARGET investigators. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet. 2008;372:547-553.

4. Yusuf S, Teo KK, Pogue J, et al; ONTARGET Investigators. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.