STOCKHOLM — Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, has shown significant benefits in preventing major kidney disease, cardiovascular events, as well as mortality in patients with chronic kidney disease (CKD) and type 2 diabetes in the landmark FLOW trial.
“This is the first trial that’s specifically asked the question of whether this class of drugs — GLP-1 receptor agonists — protects the kidney and prevents major kidney outcomes, and the results clearly showed that that’s the case,” lead author Vlado Perkovic, MBBS, PhD, dean of medicine and health and scientia professor at UNSW Sydney, Australia, told Medscape Medical News.
Based on the results, “we anticipate that regulatory agencies and guidelines would incorporate this into the label for the drug and into all guidelines as the recommended care for people with diabetic kidney disease,” he said.
As reiterated by several speakers during the full session devoted to the groundbreaking study held on May 24 here at the 61st European Renal Association (ERA) Congress, the data suggest the addition of semaglutide as a fourth pillar to the guideline-recommended pillars of treatment for CKD and diabetes.
“The four pillars are now a renin-angiotensin-aldosterone system (RAAS) blocker, sodium-glucose cotransporter-2 (SGLT2) inhibitors, finerenone, and semaglutide,” said study co-author Katherine R. Tuttle, MD, who is a professor of medicine, Nephrology Division and Kidney Research Institute, at the University of Washington, Seattle, while presenting the findings.
The study was simultaneously published in the New England Journal of Medicine.
With a variety of kidney benefits of semaglutide shown in numerous clinical trials and regularly reported in clinical practice, the double-blind, international FLOW (Evaluate Renal Function With Semaglutide Once Weekly) trial was conducted to take on the issue with kidney measures in patients with CKD as a primary outcome.
The study, conducted in 28 countries, involved 3533 patients recruited between June 2019 and May 2021 who had CKD and type 2 diabetes. Patients were randomized to treatment with semaglutide 1.0 mg once weekly (n=1767) or placebo (n=1766), both in addition to standard care.
Patients were a mean age of about 66 years, about 30% were female, and about 66% were White.
Importantly, the study included high-risk patients, with 93% having high or very high-risk CKD, based on Kidney Disease: Improving Global Outcomes (KDIGO) criteria.
In addition, about 95% of patients were receiving a RAAS blocker, about 60% were receiving an angiotensin II receptor blocker (ARB), about 35% were receiving an angiotensin-converting enzyme (ACE) inhibitor, and as many as 80% were receiving lipid-lowering drugs.
About 15% were receiving an SGLT2 inhibitor, reflecting the time period when enrollment occurred (before increased use of the drugs).
A prespecified interim analysis clearly showed the efficacy of semaglutide, and therefore, the independent data and safety monitoring committee recommended the trial be stopped early.
With a median follow-up of 3.4 years, the results showed that patients treated with semaglutide had a 24% lower risk of a major kidney event, defined as a composite of kidney failure onset (dialysis, transplantation, or an estimated glomerular filtration rate [eGFR]
The results were similar for a composite of only the kidney-specific components of the primary outcome (HR, 0.79) and in terms of cardiovascular mortality (HR, 0.71).
In further analyses of all confirmatory secondary outcomes, the results continued to favor semaglutide, with the mean annual eGFR slope less steep (indicating a slower decrease) with semaglutide, by 1.16 mL per minute per 1.73 m2 (P <.001 in addition to the risk of major cardiovascular events which were lower with semaglutide p=".029).</p">
The risk of death from any cause was 20% lower with semaglutide versus placebo (HR, 0.80; P=.01).
“In looking at the components of the primary composite outcome, we see remarkable consistency across all the components, with no suggestion of a differential effect of any of those components,” Perkovic said during his presentation.
Serious adverse events were also lower in the semaglutide than placebo group (49.6% vs 53.8%).
The results are notable considering that patients with CKD often continue to experience declining kidney function and adverse outcomes despite the reduced cardiovascular risk provided by therapies, Perkovic noted.
“These findings offer great promise in reshaping treatment strategies for individuals at high risk of diabetes-related complications, offering a new avenue for kidney and cardiovascular protection,” he said during his talk.
Results “Reassuring”
Among the important aspects of the study was the high rate of patients receiving cardiovascular treatment, said current ERA President Christoph Wanner, MD, who provided an independent perspective during the session.
“The result that was achieved considering the high saturation of cardiovascular protection used is remarkable,” said Wanner, professor of medicine and head of the Division of Nephrology, University of Würzburg, Germany.
Furthermore, “I have never seen a kidney cohort where up to 80% of subjects [were treated with statins], so I’m happy to see that as well.”
Wanner said the primary endpoint results are “solid and give us the reassurance that we can use this treatment.”
Also providing comment for Medscape Medical News, Alberto Ortiz, MD, PhD, chief of nephrology and Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain, noted caveats, including the early termination of the trial and that few patients were taking an SGLT2 inhibitor.
“The number of participants on SGLT2 inhibitors was low and results were nonconclusive for this reason,” he said. Therefore, “this trial does not answer the question of whether semaglutide adds benefit for the primary endpoint for patients who are already on the standard of care, ie, SGLT2 inhibitors.”
The issue was also the first to be raised during the question and answer session, with one audience member asserting that regulatory authorities will argue that SGLT2 inhibitors should be the comparative treatment for GLP-1 receptor agonists.
Perkovic agreed that because of the trial’s timing, the proportion of patients taking an SGLT2 inhibitor was “relatively modest.” However, he added, “I think one of the assumptions is that we have to either choose SGLT2 inhibitors or GLP-1 receptor agonists, and I would challenge that.”
“I think the question is: What benefit do we get when we prescribe [the treatments] in combination? [Ongoing research] is looking at that issue of whether the effects are additive, and we believe they are,” he said.
Diabetes-Related Kidney Disease: The “Other Pandemic”
As many as 537 million people worldwide have type 2 diabetes. In addition, four out of 10 people with type 2 diabetes and three out of 10 people with type 1 diabetes will develop CKD, Tuttle said.
“Diabetes-related kidney disease is responsible for half of all CKD worldwide — it is the other pandemic,” she said.
She underscored further striking figures: only 7% to 20% of people with CKD are aware that they have the condition.
“Our challenge now is that low CKD awareness, detection, and access to care are major barriers to receiving kidney, heart, and lifesaving therapies,” Tuttle said.
“Effective strategies for therapeutic implementation are urgently needed to improve clinical outcomes in type 2 diabetes and CKD.”
Perkovic has disclosed consulting, advisory, or other relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, GSK, Jansen, Novo Nordisk, Novartis, Otsuka, Travere, Tricia Pharma, and UpToDate, and is the board director of George Clinical, St. Vincent’s Health Australia, Kidney Health Australia, and several independent medical research institutes. Tuttle has disclosed relationships with AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Novo Nordisk, ProKidney, and Travere.
The study was funded by Novo Nordisk.
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