In T2DM with CKD, semaglutide reduced major kidney disease events at 3 y

In a manufacturer-funded trial of patients with type 2 diabetes (T2DM) and chronic kidney disease (CKD), semaglutide reduced the rate of a composite outcome of kidney failure, at least a 50% reduction in estimated glomerular filtration rate (eGFR), or death from kidney-related or cardiovascular causes. Rates of major cardiovascular events and death from any cause were also lower in patients randomized to subcutaneous semaglutide at a dose of 1 mg weekly compared to those getting a placebo.

The study was published by the New England Journal of Medicine on May 24. The following commentary by David Collister, MD, PhD, and Neesh Pannu, MD, SM, was published in the ACP Journal Club section of Annals of Internal Medicine on Sept. 3.

The FLOW trial by Perkovic and colleagues showed that weekly semaglutide reduced major kidney disease events and the annual rate of eGFR decline in adults with T2DM and CKD. Efficacy was consistent across subgroups including age, sex, race/ethnicity, body mass index, duration of T2DM, geography, eGFR values, [urinary albumin-to-creatinine ratio], history of cardiovascular events, and heart failure. The trial had 97% follow-up and excellent adherence.

FLOW solidifies glucagon-like peptide 1 (GLP-1) receptor agonists as a treatment for diabetic kidney disease (DKD) beyond their current indications for treatment of obesity and cardiovascular disease. However, questions remain.

First, FLOW was stopped early (after 570 of 854 planned primary events), so its treatment effect may be overestimated, and this is in the context of 26% of patients not completing treatment, mostly due to adverse events, such as gastrointestinal side effects. Approaches to mitigate side effects of GLP-1 receptor agonists and promote adherence are needed to reduce permanent discontinuation. Second, only 11% of patients had baseline eGFR <30 mL/min/1.73 m², so whether GLP-1 receptor agonists are safe and effective in patients with advanced CKD is unknown. Third, only 16% of patients were treated with sodium–glucose cotransporter-2 (SGLT2) inhibitors at baseline, and it is unclear whether there is effect modification between SGLT2 inhibitors and GLP-1 receptor agonists; there was no interaction, but the analysis was likely underpowered. Recent analyses by the SGLT-2 Inhibitor Meta-Analysis Cardio-Renal Trialists Consortium suggest that the beneficial cardiorenal effects of both medications across cardiovascular, heart failure, and kidney trials are independent. Fourth, the mechanism for the acute decline in eGFR within 12 weeks of initiation in the semaglutide group is unclear; hypotheses include changes in kidney blood flow, intraglomerular hemodynamics, and body composition.

The nephrology community now faces the challenge of implementing the results of the FLOW trial across international settings where the care of patients with DKD, social determinants of health, and medication coverage vary dramatically.