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

Abstract

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 m². 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.

Keywords: Cardiovascular disease; Chronic kidney disease; Diabetic kidney disease; GLP1-RA; Type 2 diabetes.

Fig. 1

Potential mechanisms by which glucagon-like peptide-1 receptor agonists (GLP1-RA) confer kidney and cardiovascular protection.

Fig. 2

AWARD 7 trial: Composite kidney outcome of ≥40% decline in estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD) with dulaglutide 0.75 or 1.5 mg/wk vs insulin glargine. Panel A: Proportion experiencing primary outcome by treatment group. Panel B: Time to first event for primary outcome by treatment group. Used with permission of American Society of Nephrology, from Clinical Outcomes by Albuminuria Status with Dulaglutide versus Insulin Glargine in Participants with Diabetes and CKD: AWARD-7 Exploratory Analysis, Kidney360, Tuttle KR, et al., 2, 2 © 2021; permission conveyed through Copyright Clearance Center, Inc.