Fig. 3

Exploring possible renal benefits with glucose-lowering drugs. CVOTs typically included renal endpoints among secondary outcomes. Effects on renal outcomes have been generally consistent between studies—showing a reduced risk for progression of renal impairment with SGLT2 inhibitors [28, 36, 37, 92, 95, 140], and a slowed progression of albuminuria with both SGLT2 inhibitors [28, 30, 36, 95] and GLP-1 RAs [31, 96, 97]. In addition to CVOTs, renal benefits of SGLT2 inhibitors have been shown in dedicated renal outcomes trials (CREDENCE and DAPA-CKD) [20, 36, 68, 72] (A). Dulaglutide showed a benefit for some renal impairment outcomes in an exploratory analysis of the REWIND CVOT [97]. Renal outcomes with DPP-4 inhibitors in CVOTs have typically been neutral, although linagliptin showed a modest benefit regarding reduced progression of albuminuria in CARMELINA, a CVOT notable for the prevalence of CKD among the population [14], and SAVOR-TIMI 53 showed a slower progression of albuminuria with saxagliptin compared with placebo [100]. Note that trials differed significantly in the measures used to assess renal function and albuminuria progression, and there was also a large variation in renal risk at baseline (for example, degree of renal impairment [20, 27, 31, 36, 63, 72, 96, 97, 125, 126, 140,141,142]), and therefore should not be directly compared [14] (B). While we await further results from dedicated renal studies, the consistency of effect size in slowing renal function decline has been sufficiently persuasive to lead to updated guidelines recommending SGLT2 inhibitors for patients with T2D in a CKD setting [40,41,42, 44, 102] (C). ADA, American Diabetes Association; CKD, chronic kidney disease; Cr, creatinine; CVD, cardiovascular disease; CVOT, cardiovascular outcomes trial; EASD, European Association for the Study of Diabetes; EDTA–ERA, European Dialysis and Transplant Association–European Renal Association; eGFR, estimated glomerular filtration rate; ESRD, end-stage renal disease; GLD, glucose lowering drug; GLP-1 RA, glucagon-like peptide-1 receptor agonist; Hb1Ac, haemoglobin A1c; KDIGO, Kidney Disease Improving Global Outcomes; RRT, renal-replacement therapy; RRR, relative risk reduction; SGLT2, sodium–glucose transporter 2; UACR, urinary albumin-to-creatinine ratio. *p < 0.05. ^†Exploratory analysis. ^‡Efpeglenatide is not a currently licensed treatment. ^§In AMPLITUDE-O, the composite renal outcome was incident macroalbuminuria (UACR > 300 mg/g or > 33.9 mg/mmol), ≥ 30% increase in UACR from baseline, sustained ≥ 40% decrease in eGFR for ≥ 30 days, renal-replacement therapy for ≥ 90 days, and sustained eGFR of < 15 mL/min/1.73 m² for ≥ 30 days). ^‖In AMPLITUDE-O, 31.6% of patients had eGFR < 60 mL/min/1.73 m², and proportions of patients with other eGFR levels were not reported; eGFR < 25 mL/min/1.73 m² was an exclusion criterion