FLOW Trial: Semaglutide (Ozempic) Shows Kidney Protection in Type 2 Diabetes

What Did the FLOW Trial Show About Semaglutide and Kidney Disease?

The FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial was a landmark Phase 3, randomized, double-blind, placebo-controlled trial that enrolled 3,533 participants with type 2 diabetes and chronic kidney disease (CKD) across 28 countries. Participants had an estimated glomerular filtration rate (eGFR) of 50-75 mL/min/1.73m2 with a urine albumin-to-creatinine ratio (UACR) of 300-5,000 mg/g, or an eGFR of 25-50 with a UACR of 100-5,000 mg/g. All participants received standard of care, including maximally tolerated doses of renin-angiotensin system (RAS) inhibitors.

The primary composite outcome included onset of kidney failure (dialysis, transplantation, or eGFR below 15), a sustained 50% or greater reduction in eGFR, or death from kidney-related or cardiovascular causes. Semaglutide reduced this composite outcome by 24% (hazard ratio 0.76; 95% CI, 0.66-0.88; P = 0.0003). The trial was stopped early for efficacy after a median follow-up of 3.4 years, a strong indication of the robustness of the benefit observed.

Notably, semaglutide also slowed the annual rate of eGFR decline. The mean annual eGFR slope was -2.19 mL/min/1.73m2 per year in the semaglutide group compared to -3.36 in the placebo group, a difference of 1.16 mL/min/1.73m2 per year. This preservation of kidney function translates to potentially years of delayed dialysis for individual patients, representing a meaningful quality-of-life and economic benefit given that the annual cost of hemodialysis in the United States exceeds $90,000 per patient.

How Does Semaglutide Compare to Other Kidney-Protective Medications?

Before the FLOW trial, the kidney-protective armamentarium for patients with type 2 diabetes and CKD consisted primarily of RAS inhibitors (ACE inhibitors and ARBs), SGLT2 inhibitors, and the nonsteroidal mineralocorticoid receptor antagonist finerenone. The DAPA-CKD trial showed dapagliflozin reduced the primary kidney composite outcome by 39%, while the EMPA-KIDNEY trial demonstrated empagliflozin reduced kidney disease progression by 28%. Finerenone, in the FIDELIO-DKD and FIGARO-DKD trials, reduced the composite kidney outcome by 18% and 23%, respectively.

Semaglutide's 24% reduction in the primary kidney outcome positions it comparably to these established therapies, but its mechanism of action differs substantially. While SGLT2 inhibitors work primarily through tubuloglomerular feedback to reduce intraglomerular pressure and finerenone blocks the mineralocorticoid receptor to reduce inflammation and fibrosis, semaglutide appears to exert renoprotective effects through multiple pathways. These include reductions in body weight (mean 4.7 kg in FLOW), blood pressure, HbA1c, and systemic inflammation, as well as potential direct effects on tubular cells mediated through GLP-1 receptors expressed in the kidney.

The cardiovascular benefits observed in FLOW were equally impressive. Semaglutide reduced cardiovascular death by 29% (HR 0.71; 95% CI, 0.56-0.89) and all-cause mortality by 20% (HR 0.80; 95% CI, 0.67-0.95). These findings are consistent with the cardiovascular benefits demonstrated in the SELECT and SUSTAIN-6 trials and suggest that semaglutide provides comprehensive cardiorenal protection in this high-risk population. Current clinical practice guidelines are expected to recommend a combination approach using RAS inhibitors, SGLT2 inhibitors, finerenone, and GLP-1 receptor agonists for maximal kidney and cardiovascular protection.

Who Should Consider Semaglutide for Kidney Protection?

The FLOW trial enrolled a well-defined population that can guide clinical decision-making. Eligible patients had type 2 diabetes with chronic kidney disease characterized by an eGFR between 25 and 75 mL/min/1.73m2 with elevated urinary albumin excretion. The mean age of participants was 66.6 years, mean diabetes duration was 17.4 years, and mean HbA1c was 7.8%. Approximately 70% of participants were also taking SGLT2 inhibitors, suggesting that semaglutide provides additional benefit on top of established kidney-protective therapies.

The safety profile of semaglutide in the FLOW trial was consistent with its known profile in other indications. Gastrointestinal events (nausea, vomiting, diarrhea) were the most common adverse effects, occurring in approximately 40% of semaglutide-treated patients compared to 24% in the placebo group. However, the rate of treatment discontinuation due to adverse events was modest (13.2% vs. 11.9%), and there were no new safety signals in this CKD population. Importantly, the initial hemodynamic dip in eGFR observed with semaglutide (similar to that seen with SGLT2 inhibitors) was reversible and did not signal kidney harm.

For clinicians, the FLOW trial results suggest that semaglutide should be discussed with patients who have type 2 diabetes and CKD, particularly those at high risk for kidney disease progression despite treatment with RAS inhibitors and SGLT2 inhibitors. The potential to delay dialysis by preserving kidney function represents a transformative benefit, as dialysis significantly impacts quality of life and carries substantial morbidity. Ongoing research is evaluating whether GLP-1 receptor agonists may benefit patients with CKD without diabetes, which could further expand the clinical utility of this drug class.