What is the role of combined ACE inhibitor and ARB therapy in the treatment of diabetic nephropathy?

Updated: Oct 09, 2019
  • Author: Vecihi Batuman, MD, FASN; Chief Editor: Romesh Khardori, MD, PhD, FACP  more...
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The choice between an ARB and an ACE inhibitor is made more difficult by the results of the Microalbuminuria-Heart Outcomes Prevention Evaluation (MICRO-HOPE) Trial, in which ramipril reduced the risk for myocardial infarction, stroke, or cardiovascular death by 26% after 2 years. Perhaps the more interesting question is whether the combination of an ACE inhibitor and an ARB is more effective than either drug alone. One meta-analysis showed that ACEI + ARB reduced 24-hour proteinuria to a greater extent than ACEI alone. However, this benefit was associated with small effects on GFR, serum creatinine, potassium, and blood pressure. [38]

A study by Imai et al determined that combined treatment with ACE inhibitors and ARBs significantly decreased blood pressure, proteinuria, and rate of change of reciprocal serum creatinine; however, higher cardiovascular death was reported among the olmesartan-treated patients compared with placebo. Major adverse cardiovascular events and all–cause data were similar between the 2 groups. Hyperkalemia was more frequent in the olmesartan–treated group than in the placebo group. These findings confirm previous studies that combined therapy for patients with diabetic nephropathy may improve short-term biomarkers but is not associated with improvement in long-term hard endpoints. [39]

However, the recent Nephron-D trial, which evaluated the effect of adding losartan, an ARB, to the ACE inhibitor lisinopril on albumin-to-creatinine ratio in 1448 patients with type 2 diabetes was stopped early because of safety concerns. Combination therapy significantly increased the risk of hyperkalemia and acute kidney injury. [40] Thus, the combination should be avoided as a strategy to reduce proteinuria with the hope of slowing progression of diabetic nephropathy, and should be reserved for individual situations in which optimal control of blood pressure may require it. Until further studies shed additional light, for antiproteinuric effect, the addition of an aldosterone antagonist (ie, spironolactone) may be more effective.

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