Go With the Flow

From the Chair

The FLOW study published recently in the New England Journal of Medicine by Vlado Perkovic and colleagues¹ provides the definitive fourth pillar in slowing kidney disease progression in patients with type 2 diabetes mellitus and kidney disease (diabetic kidney disease, or DKD; see Figure). This landmark study comes on the back of meta-analyses that point to the benefit of glucagon-like peptide 1 receptor agonists (GLP1-ra) in slowing kidney disease progression.² 

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FLOW recruited 3533 patients with moderately advanced DKD who were randomized to receive either subcutaneous semaglutide (1.0 mg/week) or placebo and followed for a median of 3.4 years. The primary outcome was major kidney disease events, a composite of the onset of kidney failure (dialysis, transplantation, or an estimated glomerular filtration rate [eGFR] <15 ml/min/1.73 m²), at least a 50% reduction in eGFR from baseline, or death from kidney-related or cardiovascular causes. Semaglutide treatment resulted in a 24% reduction in the primary outcome event of major kidney disease events (331 vs 410; hazard ratio, 0.76; 95% CI, 0.66-0.88; P=.0003). Likewise, the kidney-specific components and death from cardiovascular diseases also strongly favored semaglutide.  

 

Figure. Pillar Approach to Slowing the Progression of DKD 

The mechanism for why GLP1-ra are renoprotective has not been fully elucidated, but reducing oxidative stress and endothelial dysfunction seem the most likely explanations. The beneficial effect on slowing kidney disease progression is likely to extend to the whole class of GLP1-ra, including lixisenatide, liraglutide, exenatide, dulaglutide, and albiglutide.  

Semaglutide is available as both a subcutaneous (SC) and an oral medication. The data from SC administration were presented in FLOW. It is likely that the oral form of semaglutide will be similarly efficacious, but a trial may be needed to definitively prove this hypothesis. The benefits of oral versus SC administration include convenience, storage, and discomfort from injections with the SC route. 

The pillar approach to treating DKD has been championed by George Bakris, MD, who recently passed away³ and was a giant in the field.⁴ This approach is now widely recommended. Indeed, Dr. Bakris and a colleague, Sandra Naaman, MD, PhD, wrote, “Practice guidelines articulate that clinicians should start first by titrating to maximally tolerated [renin-angiotensin system] blockade before introducing these medications ([sodium-glucose transport inhibitors, nonsteroidal mineralocorticoid receptor antagonists, and GLP1-ra]) … endocrinologists, nephrologists, and cardiologists are strongly encouraged to use a pillared approach to DKD using the framework described, irrespective of the degree of kidney impairment, down to an eGFR of 25 mL/min/1.73 m².” 

The bottom line and rather tongue-in-cheek “go with the flow” in the title of this editorial really means that maximizing renoprotection is not now an uncertain exercise but rather one of using the pillar approach, and each of these pillars is based on high-quality, randomized, controlled trials. 

References 

1. Perkovic V, Tuttle KR, Rossing P, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. N Engl J Med. 2024. doi:10.1056/NEJMoa2403347 
2. Kristensen SL, Rørth R, Jhund PS, et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet Diabetes Endocrinol. 2019;7(10):776-785. doi:10.1016/S2213-8587(19)30249-9. Erratum for: Lancet Diabetes Endocrinol. 2020;8(3):e2. doi:10.1016/S2213-8587(20)30037-1 
3. McKeown LA. Hypertension expert George Bakris mourned by colleagues and friends. TCTMD. June 18, 2024. Accessed June 20, 2024. www.tctmd.com/news/hypertension-expert-george-bakris-mourned-colleagues-and-friends  
4. Naaman SC, Bakris GL. Diabetic nephropathy: update on pillars of therapy slowing progression. Diabetes Care. 2023;46(9):1574-1586. doi:10.2337/dci23-0030