Research in context
Evidence before this study
We searched PubMed for reports published in English between Jan 1, 2010, and March 31, 2019, of double-blind, randomised, placebo-controlled trials that were designed and powered to test the effect of glucagon-like peptide-1 (GLP-1) receptor agonists on incident cardiovascular outcomes in people with type 2 diabetes and additional cardiac risk factors and that reported the effect of the intervention on renal outcomes. Search terms were “type 2 diabetes”, “GLP1-RA”, “glucagon-like peptide receptor 1 agonist”, “glucagon-like peptide receptor 1 analogue”, “lixisenatide”, “liraglutide”, “semaglutide”, “taspoglutide”, “albiglutide”, “dulaglutide”, “renal disease”, “renal function”, “renal”, “cardiovascular disease”, and “randomized controlled trial”. This search identified three cardiovascular outcomes trials that reported the effects of lixisenatide (ELIXA; n=6068), liraglutide (LEADER; n=9340), and semaglutide (SUSTAIN-6; n=3297) versus placebo on incident renal outcomes in middle-aged people (age ≥50 years) with type 2 diabetes. Mean glycated haemoglobin A1c (HbA1c) ranged from 7·7% to 8·7%, the proportion with an eGFR of 60 mL/min per 1·73 m2 or more ranged from 70% to 77%, and median follow-up durations ranged from 2·1 years to 3·8 years. The composite renal outcome for both the LEADER and SUSTAIN-6 trials (new macroalbuminuria, doubling of serum creatinine concentration and estimated glomerular filtration rate [eGFR] less than 45 mL/min per 1·73 m2, renal replacement therapy, or renal death) was reduced by the GLP-1 receptor agonist compared with placebo, with hazard ratios (HRs) of 0·78 (95% CI 0·67–0·92) and 0·64 (0·46–0·88), respectively. No composite renal outcome was prespecified for ELIXA. Reported renal outcomes in ELIXA were time to new macroalbuminuria (HR 0·81, 95% CI 0·66–0·99) and doubling of serum creatinine (HR 1·16, 0·74–1·83). All three trials suggested that the main renal effects of the GLP-1 receptor agonists were on progression of albuminuria, with modest effects on eGFR. These findings supported exploratory analyses of the effect on dulaglutide on renal outcomes in the REWIND trial.
Added value of this study
Participants in the REWIND trial had a mean baseline HbA1c of 7·3%, a mean baseline eGFR of 76·9 mL/min per 1·73 m2, and a 35·0% baseline prevalence of albuminuria, and were followed up for a median of 5·4 years. Dulaglutide reduced the prespecified composite renal outcome of new-onset macroalbuminuria, eGFR decline of 30% or more, or chronic renal replacement therapy, with the clearest effect on the macroalbuminuria component. Additional analyses suggested that the renal effects of dulaglutide could not be completely explained by its effect on glucose concentration or blood pressure.
Implications of all the available evidence
GLP-1 receptor agonists that have been shown to reduce cardiovascular outcomes also seem to have a salutary effect on renal outcomes and particularly albuminuria. Future large prospective trials of the effect of these drugs on prespecified renal outcomes should be done to more clearly characterise their effects on renal function in people with preserved and reduced baseline renal function.