Effects of sodium‐glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists, and their combination on albuminuria in diabetic patients

Abstract

Aims Diabetes mellitus (DM) is the leading cause of chronic kidney disease. Albuminuria is associated with an increased risk of cardiovascular mortality. Sodium‐glucose cotransporter 2 inhibitors (SGLT2‐Is) and mineralocorticoid receptor antagonists (MRAs) protect against albuminuria; however, their combined effects on albuminuria are unclear. We performed a network meta‐analysis to investigate the effects of SGLT2‐Is, MRAs and their combination on albuminuria in type 2 DM. Methods We systematically searched PubMed, Medline, EMBASE and the Cochrane Library from inception up to 20 November 2022. We selected randomized control and crossover trials that compared MRAs, SGLT2‐Is, MRAs + SGLT2‐Is, or a placebo in patients with type 2 DM with a urinary albumin‐creatinine ratio (UACR) ≥30 mg/g creatinine. The primary outcome was the change in the UACR. Results This meta‐analysis analysed 17 studies with 34 412 patients. The use of combination treatment with SGLT2‐Is and MRAs was associated with lower albuminuria compared with the use of SGLT2‐Is, MRAs, or the placebo alone [mean difference (95% CI): −34.19 (−27.30; −41.08), −32.25 (−24.53; −39.97) and −65.22 (−57.97; −72.47), respectively]. Treatment with SGLT2‐Is or MRAs alone caused a significant reduction in UACR compared with the placebo [mean difference (95% CI): −31.03 (−28.35; −33.72) and −32.97 (−29.68; −36.27), respectively]. The effects of MRAs on the UACR are comparable with those of SGLT2‐Is. Sensitivity analyses showed similar results. Conclusion Combination therapy with SGLT2‐Is and MRAs was associated with lower albuminuria in patients with type 2 DM compared with monotherapy with SGLT2‐Is or MRAs alone.

Comparative efficacy of sodium‐glucose co‐transporter‐2 inhibitors, glucagon‐like peptide‐1 receptor agonists and non‐steroidal mineralocorticoid receptor antagonists in chronic kidney disease and type 2 diabetes: A systematic review and network meta‐analysis

“…A real‐world evidence study and subgroup analyses from a trial have shown that combinations of SGLT‐2is and GLP‐1RAs, as well as finerenone and SGLT‐2is or GLP‐1RAs, may be efficacious in reducing CV events, although sample sizes of these groups were small 4,55 . A recent network meta‐analysis also indicated that the combination of SGLT‐2is and nsMRAs was associated with significantly lower albuminuria than each of the drugs alone among patients with T2D and a UACR of 30 mg/g or higher 56 . However, even if these combinations have promising results, high costs may be a barrier to their use in clinical practice.…”

“…4,55 A recent network meta-analysis also indicated that the combination of SGLT-2is and nsMRAs was associated with significantly lower albuminuria than each of the drugs alone among patients with T2D and a UACR of 30 mg/g or higher. 56 However, even if these combinations have promising results, high costs may be a barrier to their use in clinical practice.…”

Studying and learning

“…In a metaanalysis of 17 studies of effect on albuminuria of an SGLT2i, a mineralocorticoid antagonist (MRA), both, or neither, including 34 412 patients with urine albumin/creatinine ratio (UACR) >30 mL/min/1.73 m 2 , combination treatment reduced UACR 65%, whereas SGLT2i and MRA alone reduced UACR 34% and 32%, respectively. Compared with placebo, SGLT2i, MRA, and the combination reduced systolic blood pressure 3, 3, and 9 mm Hg, respectively 16 . A somewhat different conclusion was reached in a randomized crossover trial of 63 persons with diabetes (26 type 1 and 37 type 2) and microalbuminuria (mean UACR 115) treated over sequential 4 week periods with 4‐week washouts.…”

Mineralocorticoid Receptor Antagonists for Preventing Chronic Kidney Disease Progression: Current Evidence and Future Challenges

“…In a metaanalysis that included the studies of non-steroidal MR antagonists, the hazard ratio for the composite kidney outcomes (a 40% or 57% reduction in eGFR, renal death, and kidney failure) was 0.83 (95% confidence interval, 0.75-0.91) in the treatment group (based on six studies with finerenone) [177]. A network meta-analysis of 17 studies examining preand post-treatment UACR changes in diabetic patients with UACR > 30 mg/gCr with MR antagonists, SGLT2is, or their combination showed that the combined use of MR antagonists and SGLT2is is associated with low levels of albuminuria compared with MR antagonists, SGLT2is, or placebo alone [178]. In a single-center observational study of 3195 CKD patients with an eGFR of 10-60 mL/min/1.73 m 2 , the rate of initiation of renal replacement therapy was significantly lower in patients treated with MR antagonists than in those treated without MR antagonists [179], with a hazard ratio of 0.72, which also suggests that the use of MR antagonists is associated with improved kidney outcome.…”