Phase III FLOW Trial Results Establishes Semaglutide’s Role in Treating T2D and CKD

Phase III FLOW Trial Results Establishes Semaglutide’s Role in Treating T2D and CKD Posted By:
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The highly anticipated results of the FLOW (Evaluate Renal Function with Semaglutide Once Weekly) trial were published in the New England Journal of Medicine on May 24, 2024. This trial was a double-blind, placebo-controlled, parallel-group, randomized phase IIIb superiority trial conducted across multiple centers worldwide. It included 3534 participants with type 2 diabetes (T2D) and chronic kidney disease (CKD) at high risk for progression being treated with an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blockers (ARB). They were randomly assigned to receive either once-weekly semaglutide (1.0 mg) or placebo as adjunct therapy. Participants who were also taking a sodium-glucose cotransporter 2 (SGLT2) inhibitor and/or mineralocorticoid-receptor antagonist were not excluded. FLOW was an event-driven study with a predefined minimum number of renal events for the primary endpoint.

Definitions, Baseline Characteristics, and Outcomes
The mean age of participants was 67 years. Although the majority were White males, 30% were female, 24% were Asian, 16% were Hispanic or Latino/a, and 5% were Black. Further, high-risk CKD was defined as having an estimated glomerular filtration rate (eGFR) of 50-75 mL/min/1.73 m2 and urine albumin to creatinine ratio (UACR) of 301-4999 mg/g or an eGFR of 25-49 mL/min/1.73 m2 and UACR of 101-4999 mg/g. The mean eGFR was 47 mL/min/1.73 m2 and the median UACR was 568 mg/g at baseline, rendering 68% of participants at very high risk for progression of kidney disease, kidney failure, cardiovascular events, or death. 

The primary outcome was major kidney disease events comprised of kidney failure onset (initiation of dialysis or transplant) or persistent eGFR of less than 15 mL/min/1.73 m2 for 4 weeks or more, sustained reduction of eGFR from baseline by 50% or more, death from kidney disease, or death with cardiovascular cause. Secondary outcomes included the annual change rate in eGFR, time to initial occurrence of a major adverse cardiovascular event (MACE) (nonfatal stroke, nonfatal myocardial infarction, or cardiovascular-related death), or time to occurrence of death due to any cause. All endpoints were measured from study start (randomization) to end. 

As an event-driven trial, it was calculated that at least 854 primary-outcome events were needed to be powered appropriately to detect a 20% reduced relative risk in the semaglutide arm. However, the results from an interim analysis conducted in October 2023 met the prespecified criteria for stopping the trial early due to efficacy.

FLOW Trial Outcomes
The results demonstrated that semaglutide significantly reduced the risk of a primary outcome event by 24% compared with placebo (HR: 0.76; 95% CI: 0.66-0.88; P = .0003). Furthermore, semaglutide showed additional statistically significant benefit among all secondary endpoints vs placebo—slower decline in eGFR over time by 1.16 mL/min (P <.001), 18% lower risk for MACE (P = .029), and 20% lower risk for all-cause mortality (P = .01). 

The safety profile of semaglutide was consistent with previous trials, including the cardiovascular outcomes trial (CVOT), with the most common adverse events leading to discontinuation of semaglutide being gastrointestinal disorders, such as nausea, diarrhea, and vomiting.

Real-World Impact
It seems that the semaglutide molecule is the agent that keeps on giving. The CVOT for semaglutide (SUSTAIN-6) revealed a trend of positive effects on kidney disease but was not powered to show significance. That is why the results of FLOW are so critical. Hopefully other glucagon-like peptide-1 receptor agonists (GLP-1 RAs), as well as current and future GLP-1 RA combinations, will show similar benefits. 

I find the results of the FLOW trial very compelling. Semaglutide has clearly demonstrated significant renal protection, cardiovascular benefits, and weight loss—effectively addressing the 3 most common comorbidities and complications associated with T2D.  

The FLOW trial's findings may lead to updated clinical practice guidelines and potentially expand the indications for semaglutide so stay tuned! I hope that commercial and Medicare/Medicaid payers will thereby increase access to this disease-modifying medication. And I am looking forward to discussing these results with my colleagues and patients, as they provide new hope for improving outcomes in individuals with T2D and CKD. As healthcare professionals, it is our responsibility to stay informed about the latest research and treatment options to provide the best possible care to our patients.


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Filed under: Cardiometabolic , NPs & PAs

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