Renal outcomes associated with glucose-lowering agents: Systematic review and meta-analysis of randomized outcome trials

Although the clinical questions of the recent glucose-lowering trials are principally oriented towards preventing macrovascular events, an updated review regarding renal outcome prevention is lacking. We assessed the impact of different antihyperglycemic classes on kidney damage progression. A systematic review and meta-analysis was performed by searching PubMed, Cochrane Collaboration Library, Medline, and previous overviews through June 2021 (any language) for earlier and contemporary glucose-lowering trials, including patients with, but not limited to, type 2 diabetes mellitus vs. placebo or less intense treatment. Incidences of kidney function worsening and macroalbuminuria development was extracted, and risk ratios and 95% confidence intervals (CI) under the random-effects model were calculated. The association between outcome reductions and glycohemoglobin (HBA1c) reductions was investigated through the meta-regression analyses. Among 27 eligible trials (n = 198,532 patients) an averaged HBA1c reduction of 0.6 +/- 0.3% was followed by a reduction of 17% (95% CI, 8-25%) in worsening of kidney function, and of 25% (95% CI, 19-32%) in macroalbuminuria. Analog of human glucagon-like peptide 1 (GLP1)-agonists, and sodium-glucose cotransporter (SGLT2)-inhibitors, considered separately, compared with placebo, were associated with a significant reduction of both renal outcomes, at variance with dipeptidyl peptidase 4 (DPP4)-inhibitors, where no outcome change was observed. Logarithmic risk ratios of macroalbuminuria were related to HBA1c reductions, in contrast to the worsening of kidney function related to systolic blood pressure reduction. Worsening of kidney function and macroalbuminuria development were reduced following glucose-lowering. GLP1 agonists and SGLPT2 inhibitors were associated with protection against both outcomes, while DPP4 inhibitors do not provide renal protection.