For diabetes patients with hypertension, adding a mineralocorticoid receptor antagonist (MRA) to renin-angiotensin-aldosterone system (RAAS) inhibitor therapy can further reduce blood pressure and reduce urinary albumin excretion, according to a new review and meta-analysis. But combination therapy also mildly increases potassium levels.

“Serum potassium levels should be monitored to prevent hyperkalemia,” advised lead investigator Yokoyama Kazuhito, MD, DMSc, of Juntendo University Graduate School of Medicine in Tokyo, Japan, and colleagues in the Journal of Human Hypertension (2016;30:534-542).

The researchers reviewed 9 randomized controlled trials or prospective observational studies published though October 2014. The 486 type 1 or type 2 diabetes patients had persistent systolic blood pressure (BP) above 130 mm Hg even after RAAS inhibitor treatment. All studies used 25 to 50 mg daily of spironolactone for MRA therapy (none used eplerenone). Seven of the studies involved patients with albuminuria or proteinuria.

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Results showed that add-on MRA therapy reduced systolic BP by 9.4 mm Hg and diastolic BP by 3.8 mm Hg compared with placebo. Subgroup analysis yielded similar results, as did an analysis using systolic BP of above 140 mm Hg as a cutoff. In addition, the investigators observed consistent reduction of albuminuria or proteinuria, suggesting concomitant MRA possibly slows renal dysfunction.

To assess the risks of hyperkalemia, defined as serum potassium above 5.5 mEq, the investigators conducted a meta-analysis of 4 placebo-controlled studies of 233 patients. Hyperkalemia developed in 16 patients. MRA therapy slightly increased serum potassium by 0.4 mEq, a rate similar to that reported in patients with essential hypertension. Findings from other studies in this review corroborated increased hyperkalemia incidence with MRA therapy.

“Despite observing only a few cases with a marked increase in serum potassium, careful assessment of the patient’s background to identify any risk factors for hyperkalemia is necessary in clinical practice,” Dr Kazuhito and colleagues commented. “The risk/benefit balance of add-on MRA therapy should be considered on an individual basis.”

Some outstanding questions need to be addressed by future research, they added. For example, do inherited factors influence hyperkalemia development during MRA treatment? Does eplenerone produce different results than spironolactone? And, importantly, can MRA with RAAS inhibitors prevent cardiovascular events, kidney disease progression, or dialysis initiation?

Two of the study authors were employees of Pfizer Japan and another disclosed fees from various pharmaceutical companies.

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1.    1. Takahashi S, Katada J, Daida H, Kitamura F, and Yokoyama K. Effects of mineralocorticoid receptor antagonists in patients with hypertension and diabetes mellitus: a systematic review and meta-analysis. J Hum Hypertens. (2016) 30, 534–542. doi:10.1038/jhh.2015.119.