FLOW: Semaglutide Scores Big in Diabetic Patients With CKD

In patients with type 2 diabetes and chronic kidney disease (CKD), semaglutide drastically reduces the risk of major kidney disease events, MACE, and all-cause death while also slowing down loss of kidney function, according to full results of the FLOW trial.

FLOW was stopped early last year based on an interim analysis, with semaglutide manufacturer Novo Nordisk later announcing that the top-line results showed a 24% reduction in the risk of kidney disease-related events in trial participants randomized to 1.0 mg of semaglutide once a week compared with placebo patients.

The trial results were presented today at the European Renal Association (ERA) congress in Stockholm, Sweden, and simultaneously published in the New England Journal of Medicine.

“These benefits reflect important clinical effects on kidney, cardiovascular, and survival outcomes among high-risk patients, particularly given the reassuring safety findings, and support a therapeutic role for semaglutide in this population,” write the FLOW investigators led by Vlado Perkovic, MBBS, PhD (University of New South Wales, Sydney, Australia).

While semaglutide patients lost some weight, it was modest, with only about a 4-kg difference between intervention and placebo patients.

Commenting for TCTMD, Muthiah Vaduganathan, MD (Brigham and Women’s Hospital, Boston, MA), agreed with the FLOW investigators that the magnitude of benefit seen was unexplained by the degree of weight loss.

“I think that this substantiates the hypothesis that GLP-1 receptor agonists in this target population have effects on disease progression that go well beyond just weight loss,” he noted.

Calling the trial “exceptionally well conducted,” Vaduganathan said it cements semaglutide therapy as an additional pillar of care for those with type 2 diabetes and CKD.

“It now joins the foundational drug classes of renin-angiotensin-aldosterone-system inhibitors, the nonsteroidal mineralocorticoid receptor antagonist finerenone, and the SGLT2 inhibitors . . . as the fourth foundational pillar,” he added.

While the sequencing and integration of semaglutide into clinical practice in patients like those in FLOW is still an open question, Vaduganathan said in adjacent populations, including those with heart failure, clinicians have adopted the concept of early combination, rapid sequence implementation.

“I suspect that we will need ongoing evidence generation to formalize that concept in chronic kidney disease, predominantly because many people with chronic kidney disease have slower rates of disease progression than we've observed in very high-risk disease states like heart failure, where patients can be at early risk of acute disability or death,” he continued. “With a slower rate of disease progression, maybe we have a bit more time to understand the optimal sequencing.”

Also commenting for TCTMD, Darren McGuire, MD (UT Southwestern Medical Center, Dallas, TX), called FLOW a landmark trial and said the results are paradigm shifting.

“This will immediately impact guideline recommendations and change clinical practice,” he said in an email. “With the caveat, the medication will have to be accessible to patients (at least in the US) with 3rd party payor coverage, and the company will have to be able to produce adequate supply of the medication—the latter being the rate-limiting step across all injectable semaglutide indications/prescriptions.”

FLOW Results

For the trial, Perkovic and colleagues randomized 3,533 patients (mean age 66 years; 30% female; 4.5% Black) from 387 sites in 28 countries. All had diabetes plus high-risk CKD and were on an ACE inhibitor or ARB. Kidney disease was defined by an estimated glomerular filtration rate (eGFR) of 25 to 75 mL/min per 1.73 m² of body-surface area, and a urinary albumin-to-creatinine ratio of > 300 but < 5,000 if the eGFR was 50 mL/min per 1.73 m² of body-surface area or higher, or a urinary albumin-to-creatinine ratio of > 100 but < 5,000 if the eGFR was 25 to < 50 mL/min per 1.73 m² of body-surface area. Mean body mass index (BMI) was 32 kg/m².

Overall, 1,767 patients were randomized to semaglutide and 1,766 to placebo in an 8-week dose-escalation regimen that began with 0.25 mg per week for 4 weeks and maxed out at 1.0 mg per week throughout the remainder of the treatment period. The medication regimen was as-tolerated, with options for extending dose-escalation periods, pausing treatment, or continuing on a dose lower than 1.0 mg if patients experienced unacceptable side effects.

The primary outcome was major kidney disease events (a composite of onset of kidney failure, sustained 50% or greater reduction in eGFR from baseline, or death from kidney-related or CV causes).

This is really one of the first trials that has shown convincing mortality benefits with any therapy in a target population of CKD and type 2 diabetes. Muthiah Vaduganathan

At a median follow-up of 3.4 years, there were 410 primary outcome events in the placebo group compared with 331 in the semaglutide group (HR 0.76; 95% CI 0.66-0.88). The results were similar for the individual components of the primary outcome.

Additionally, the semaglutide group had a less steep mean annual slope of eGFR (indicating a slower decrease) compared with the placebo group (P < 0.001), a lower risk of MACE (HR 0.82; 95% CI 0.68-0.98), and lower risk of death from any cause (HR 0.80; 95% CI 0.67-0.95).

Semaglutide patients had more adverse events leading to permanent discontinuation of the study medication than did the placebo group, driven primarily by GI disorders. However, the overall incidence of serious adverse events was lower in the semaglutide group than in the placebo group (49.6% vs 53.8%), which the investigators say was due to fewer serious infections or serious CV disorders.

Compared with baseline, the semaglutide group lost an average of 5.5 kg during the study period, while the placebo group lost 1.45 kg.

Perkovic and colleagues say “it is possible that modest weight loss could slightly lower serum creatinine levels, but the almost identical effects on the cystatin C–based and creatinine-based eGFR indicate that this is unlikely to meaningfully influence the trial results.”

As for generalizability, the effects that were seen on kidney function “may not be generalizable to other populations, such as those at lower risk, and the trial was not powered to separately detect effects on kidney failure.”

To TCTMD, Vaduganathan said there have been some suggestions based on earlier data that kidney disease benefits seen in patients on GLP-1 drugs might be driven by more surrogate endpoints, like improvements in albuminuria.

“But in fact, in this trial, the investigators demonstrated across a number of clinically meaningful domains of kidney disease progression that this drug is quite effective,” he said. “It’s also very important to note that this is really one of the first trials that has shown convincing mortality benefits with any therapy in a target population of CKD and type 2 diabetes.”

Also important, as Perkovic and colleagues note, the FLOW population was predominantly white despite the fact that kidney disease disproportionately affects marginalized populations, particularly those who are Black or Indigenous, and therefore was not powered to detect differences within and between racial and ethnic subgroups.