Kevin Fowler provides his perspective on the FLOW trial below
Introduction
On June 2019 I attended a National Kidney Foundation Workshop on SGLT2 inhibitors. One talk at that meeting simplified my understanding of Diabetic Kidney Disease (DKD), and still resonates with me. Dr. Meda Pavkov, MD, Centers for Disease Control and Prevention presented on the global burden of DKD. She emphasized that DKD was a medical condition associated with lower income communities. I have always wondered why there never was a strong patient voice for this community. I immediately saw the connection between lower income and absence of a strong patient voice. I saw this manifested when I travel to lower income or rural communities. Almost without exception, I always see a dialysis center. To this day, I wonder if these communities have similar access to nephrologists or preventive kidney care.
DKD develops in about 40% of diabetic patients. Globally, it is the leading cause of chronic kidney disease. In the United States it is the primary cause of kidney failure. Some of the risk factors for DKD include race/ethnicity. Black, Hispanic, and Native Americans are more susceptible to DKD. Systemic conditions such as hyperglycemia, hypertension, and obesity contribute to the progression of DKD. For DKD patients that progress to kidney failure, their kidney transplant outcomes are inferior to non-DKD kidney transplant recipients.
Until the CREDENCE trial was published in 2019, nephrologists and endocrinologists have been limited to ACEi/ARBs for renal protective treatments for DKD patients. The CREDENCE trial provided evidence of the renal protective benefits of SGLT2 inhibitors. This was followed by the FIDELIO-CKD trial that was published later in 2020. In this trial, finerenone reduced the risk of CKD progression in patients with CKD and type 2 diabetes. In May 2024 the much anticipated Evaluate Renal Function with Semaglutide Once Weekly (FLOW) was presented at the European Renal Association Meeting.
Trial Design
The FLOW trial was sponsored by Novo Nordisk and was a double-blind, randomized, placebo-controlled trial. The trial was designed to assess the efficacy and safety of subcutaneous semaglutide at a dose of 1.0mg once weekly for the prevention of kidney failure, substantial loss of kidney function, and death from kidney related or cardiovascular causes in patients with type 2 diabetes and chronic kidney disease (CKD). Almost 1800 patients were randomized to each arm. The trial was conducted in 28 countries at 387 trial sites
Adults with type 2 diabetes, HBA1C less than or equal to 10%, with CKD were eligible for enrollment. The average HBA1C for study subjects was 7.8. Over half of the DKD patients had diabetes for greater than 15 years. Almost 50% of the trial participants were either current or previous smokers. Patients with eGFRs from 25 to 75 were eligible for enrollment. Approximately 95% of study participants were on either an ACE inhibitor or an ARB. While participants could be on SGLT2 inhibitors, utilization was low, at around 15% at initiation. This is probably attributable to when the study was initiated in 2019.
The primary outcome of the trial was major kidney disease events. This was a composite of onset of kidney failure. Included in this composite was the initiation of long-term dialysis, reduction to eGFR to less than 15%, and 50% or greater reduction in eGFR from baseline, or death related to kidney or cardiovascular related events. In addition to the primary outcomes there were three secondary outcomes: eGFR slope, major cardiovascular events, and death from any cause.
Results
Primary-outcome occurred less frequently in the investigational arm. The interventional arm also had a lower risk of cardiovascular death. Positive results were also achieved in secondary outcomes. The mean annual GFR slope was -2.19 vs 3.36 in the placebo group. The risk of cardiovascular events was 18% lower in the investigational arm. Lastly, and most importantly, the risk of total mortality was 20% lower with semaglutide.
Serious adverse events were reported in fewer participants in the active arm compared to placebo. This was attributable to fewer participants in the intervention arm reporting serious infections, infestations, or cardiovascular events. Eye disorders were more common in the semaglutide group. Diabetic retinopathy was similar in both groups. Adverse events resulting in permanent study discontinuation were more common in the active arm due to gastrointestinal events.
Discussion
The trial results of the FLOW study are impressive when you consider the patient population studied. These were patients with long-term diabetes with co-morbid conditions. Over 60% of the trial participants were insulin dependent. Speaking from a US perspective there was a significant limitation of the study. Overall, only 4.5% of the study subjects were Black. Considering that African Americans have endured a greater burden of kidney failure, I was disappointed to see this low number. This observation in turn leads me to think about the important subject of access to innovative medications.
In the US, ACE inhibitors and ARB are widely accessible at a low out of pocket cost to the patient. In 2025 AstraZeneca loses patent protection to dapagliflozin. This provides the opportunity for generic manufacturers to enter the market for dapagliflozin to be multi-sourced and produce the medication at a lower cost to consumers. In theory, this should remove access barriers and establish a foundational approach to diabetic kidney disease. The combination of an ACEi/ARB in combination with dapagliflozin should be a cornerstone of kidney health for DKD and be widely accessible.
The question remains unanswered whether semaglutide will be accessible to African-American, Latino, and lower income communities. These communities stand to gain the most from innovation. It is unknown whether Novo Nordisk has a plan to ensure innovation benefits all members of society. It is a critically important question because innovation has the potential to address the economic costs and lost opportunities endured historically by the DKD community
Patient Voice Feature from Kevin Fowler