Glucagon-like peptide-1 receptor agonists in diabetic kidney disease: A review of their kidney and heart protection

Importance: Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality for patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). However, testing for albuminuria among patients with T2D is substantially underutilized in clinical practice; many patients with CKD go unrecognized. For patients with T2D at high cardiovascular risk, or with established CVD, the glucagon-like peptide-1 receptor agonists (GLP1-RA) have been shown to reduce ASCVD in cardiovascular outcome trials, while potential kidney outcomes are being explored. Observations: A recent meta-analysis found that GLP1-RA reduced 3-point major adverse cardiovascular events by 14% [HR, 0.86 (95% CI, 0.80-0.93)] in patients with T2D. The benefits of GLP1-RA to reduce ASCVD were at least as large among people with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2). GLP1-RA also conferred a 21% reduction in the composite kidney outcome [HR, 0.79 (0.73-0.87)]; however, this result was achieved largely through reduction in albuminuria. It remains uncertain whether GLP1-RA would confer similar favorable results for eGFR decline and/or progression to end-stage kidney disease. Postulated mechanisms by which GLP1-RA confer protection against CVD and CKD include blood pressure lowering, weight loss, improved glucose control, and decreasing oxidative stress. Ongoing studies in T2D and CKD include a kidney outcome trial with semaglutide (FLOW, NCT03819153) and a mechanism of action study (REMODEL, NCT04865770) examining semaglutide's effect on kidney inflammation and fibrosis. Ongoing cardiovascular outcome studies are examining an oral GLP1-RA (NCT03914326), GLP1-RA in patients without T2D (NCT03574597), and dual GIP/GLP1-RA agonists (NCT04255433); the secondary kidney outcomes of these trials will be informative. Conclusions and relevance: Despite their well-described ASCVD benefits and potential kidney protective mechanisms, GLP1-RA remain underutilized in clinical practice. This highlights the need for cardiovascular clinicians to influence and implement use of GLP1-RA in appropriate patients, including those with T2D and CKD at higher risk for ASCVD.