The combination of a sodium-glucose cotransporter-2 (SGLT2) inhibitor and a mineralocorticoid receptor antagonist (MRA) is potentially more effective for reducing risks of cardiovascular events than either drug alone, a new study concludes.

Hiromichi Wakui, MD, PhD, of Yokohama City University Graduate School of Medicine in Japan, and colleagues performed a systematic review and indirect network meta-analysis of 8 randomized controlled trials involving 36,186 patients. All patients had type 2 diabetes, more than 95% had chronic kidney disease (CKD), and 80% had a urine albumin to creatinine ratio (UACR) greater than 30 mg/g.

Of the full cohort, 841 were treated with a combination of an SGLT2 inhibitor and an MRA, 12,046 with an SGLT2 inhibitor alone, 6466 with an MRA alone, and 16,833 with placebo alone. Approximately 86% to 92% of patients also received background treatment with renin-angiotensin-system inhibitors.

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The primary outcome in each study was a composite of cardiovascular events, including at least 2 of the following: death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure.

Combination therapy significantly reduced the risk of the primary outcome by 24% compared with SGLT2 inhibitor monotherapy, 34% compared with MRA monotherapy, and 42% compared with placebo, Dr Wakui’s team reported in Diabetes Research & Clinical Practice.

MRA monotherapy vs placebo was significantly associated with a 2.1-fold increased risk of hyperkalemia, according to investigators. The combination of SLGT2 inhibitor and MRA significantly reduced the risk of hyperkalemia by 57% compared with MRA monotherapy. Serious adverse events occurred in comparable proportions of each group.

“The addition of SGLT-2 inhibitors to treatment with MRAs is likely to be recommended in the future because they may confer a greater therapeutic benefit and cause fewer [adverse events],” according to Dr Wakui’s team.

Among the study’s limitations, the investigators acknowledged that relatively few patients received combination therapy and not necessarily by random assignment. They noted that larger randomized trials that directly compare treatments are still needed to confirm results.


Tsukamoto S, Morita R, Yamada T, et al. Cardiovascular and kidney outcomes of combination therapy with sodium-glucose cotransporter-2 inhibitors and mineralocorticoid receptor antagonists in patients with type 2 diabetes and chronic kidney disease: A systematic review and network meta-analysis. Diabetes Res Clin Pract. 2022 Dec;194:110161. doi:10.1016/j.diabres.2022.110161