The FLOW Trial: Semaglutide for Kidney Disease Explained

What FLOW was testing

Semaglutide is a GLP-1 receptor agonist, and Ozempic is the once-weekly injection approved for type 2 diabetes; 1 mg weekly was the dose used in FLOW [2][1]. The trial asked a narrow question: in adults who already had type 2 diabetes and chronic kidney disease, does semaglutide 1 mg reduce major kidney events compared with placebo [1]?

The primary outcome was a composite of the onset of kidney failure (dialysis, transplant, or an eGFR below 15), a 50% or greater reduction in eGFR from baseline, or death from kidney or cardiovascular causes [1].

The result

A total of 3,533 adults were randomized, 1,767 to semaglutide and 1,766 to placebo, with a median follow-up of 3.4 years [1]. A first primary-outcome event occurred in 331 people on semaglutide and 410 on placebo: 18.7% versus 23.2%, hazard ratio 0.76 (95% CI 0.66 to 0.88) [1].

The confirmatory secondary outcomes pointed the same way [1]:

• Cardiovascular death: hazard ratio 0.71 [1].
• Major cardiovascular events: 12.0% versus 14.4%, hazard ratio 0.82 [1].
• Death from any cause: 12.8% versus 15.8%, hazard ratio 0.80 [1].

Serious adverse events were reported in 49.6% of the semaglutide group and 53.8% of the placebo group [1]. The Ozempic label notes that safety data collection in FLOW was limited to serious adverse events and selected predefined categories, and that no new serious or severe adverse reactions were identified in the trial [2].

Who was enrolled, and who was not

The entry criteria had two paths, and both required type 2 diabetes [1]:

• An eGFR of 50 to 75 with a urine albumin-to-creatinine ratio above 300 mg/g and below 5,000 mg/g, or
• An eGFR of 25 to under 50 with a urine albumin-to-creatinine ratio above 100 mg/g and below 5,000 mg/g.

That shape matters. People with heavy protein in the urine could enter with fairly preserved kidney function, and people with less protein could enter if their eGFR was lower, so FLOW was not a macroalbuminuria-only trial [1]. Both paths required an eGFR of at least 25, so adults with more advanced kidney failure were not studied, and people without diabetes were not enrolled at all [1].

Is semaglutide FDA-approved for kidney disease?

For Ozempic injection, yes. Its label lists three indications: improve glycemic control in adults with type 2 diabetes; reduce the risk of major cardiovascular events in adults with type 2 diabetes and established cardiovascular disease; and reduce the risk of sustained eGFR decline, end-stage kidney disease and cardiovascular death in adults with type 2 diabetes and chronic kidney disease [2]. For that kidney indication, the label directs increasing to 1 mg once weekly after at least 4 weeks on 0.5 mg [2].

The other semaglutide products are labeled differently. Wegovy injection covers cardiovascular risk reduction in adults with established cardiovascular disease and either obesity or overweight, weight reduction, and noncirrhotic MASH with moderate to advanced fibrosis; kidney outcomes are not among its labeled uses [3]. Rybelsus and Ozempic tablets are labeled for glycemic control and cardiovascular risk reduction in type 2 diabetes, not for kidney outcomes [4].

What the label says to watch for

• Acute kidney injury from volume depletion. The Ozempic label tells prescribers to monitor renal function in patients reporting reactions that could lead to volume depletion, especially during starting and dose increases [2].
• Kidney dosing. The Ozempic label recommends no dose adjustment for renal impairment [2]. Semaglutide is broken down by proteolytic cleavage and beta-oxidation rather than by CYP enzymes, and about 3% of a dose is excreted unchanged in urine [3].
• Severe gastrointestinal reactions. The label states that semaglutide is not recommended in patients with severe gastroparesis [2].
• Diabetic retinopathy. In a 2-year cardiovascular trial in type 2 diabetes, retinopathy complications occurred in 3.0% of patients on semaglutide versus 1.8% on placebo, and the label says patients with a history of diabetic retinopathy should be monitored [2].
• Other labeled warnings. Acute pancreatitis, acute gallbladder disease, hypoglycemia when combined with insulin or a sulfonylurea, serious hypersensitivity reactions, and pulmonary aspiration during general anesthesia or deep sedation [2].
• Boxed warning. Semaglutide caused thyroid C-cell tumors in rodents, human relevance is unknown, and it is contraindicated with a personal or family history of medullary thyroid carcinoma or MEN 2 [2].

How FLOW differs from STEP and SELECT

• STEP 1: 1,961 adults with obesity or overweight and no diabetes, semaglutide 2.4 mg weekly for 68 weeks, weight change -14.9% versus -2.4% [5].
• SELECT: 17,604 adults with established cardiovascular disease and a BMI of 27 or more, no diabetes, semaglutide 2.4 mg weekly, cardiovascular death, heart attack or stroke 6.5% versus 8.0%, hazard ratio 0.80 [6].
• FLOW: 3,533 adults with type 2 diabetes and chronic kidney disease, semaglutide 1 mg weekly, kidney composite as the primary outcome [1].

Different doses, different populations, different endpoints. A weight result from STEP or a cardiovascular result from SELECT does not describe what happened in FLOW.

What FLOW leaves open

• People without diabetes. FLOW enrolled people with both type 2 diabetes and chronic kidney disease. Its results do not establish the same benefit for people without type 2 diabetes [1].
• Advanced kidney failure. Both entry paths required an eGFR of at least 25, so people below that were not studied [1].
• SGLT2 inhibitors. The trial report states that benefit was not evident in the few patients who were taking an SGLT2 inhibitor at baseline [1].
• Mechanism. The precise mechanisms behind the kidney benefit of GLP-1 receptor agonists are not fully understood [8].