Further data from the FLOW study were presented during the 2024 congress of the European Association for the Study of Diabetes (EASD) in Madrid. The FLOW study was originally presented in May at the European Renal Association’s 2024 congress in Stockholm. It was the first dedicated kidney outcomes trial to examine a GLP-1 receptor agonist.
The FLOW study demonstrated significant kidney, cardiovascular, and mortality benefits with semaglutide 1 mg once weekly in patients with type 2 diabetes and chronic kidney disease (CKD). This study has elevated semaglutide to a new pillar of care for the management of diabetic kidney disease (DKD) alongside RAAS inhibitors, SGLT2 inhibitors, and finerenone.
At first, whether the benefits of semaglutide were independent of baseline SGLT2 inhibitor use was uncertain. The data presented at the EASD congress, however, appeared to confirm the additive benefits of semaglutide, when combined with SGLT2 inhibitor use, in patients with DKD. The authors did acknowledge that study power was limited, given the low use of SGLT2 inhibitors at trial recruitment (no licensed SGLT2 inhibitor was available for CKD at that point), so small, clinically relevant interactions may not have been detected.
So, what are the implications of the FLOW study for primary care?
DKD is a common clinical challenge in primary care; a national diabetes audit in the United Kingdom suggested that over 40% of patients with type 2 diabetes had kidney disease. Moreover, DKD is the most common cause of kidney failure in adults starting renal replacement therapy in the United Kingdom.
Residual renal risk in patients with DKD persists despite optimal use of guideline-directed medical therapy (GDMT) with RAAS inhibitors, SGLT2 inhibitors, and finerenone, as demonstrated in the many landmark kidney outcomes trials over the past 25 years.
So, a new pillar of GDMT is welcome, but I am worried that this widened choice of therapies may worsen therapeutic inertia; baseline use of the newer DKD therapies (specifically SGLT2 inhibitors and finerenone) remains low.
In addition, during the EASD FLOW session, Katherine Tuttle, MD, executive director for research at Providence Inland Northwest Health Services in Spokane, Washington, presented data from the US CURE-CKD registry study showing that baseline ACE inhibitor/ARB use of about 70% dropped to 50% after just 90 days. Baseline use of SGLT2 inhibitors was only about 6% and dropped to 5% after 90 days.
I suspect that much of this reduction in prescribing of ACE inhibitors/ARBs will have been in response to an acute dip in estimated glomerular filtration rate (eGFR) or hyperkalemia, which has been a perennial challenge with RAAS inhibitor use in primary care. Ongoing education in primary care is required to manage hyperkalemia and reductions in eGFR after RAAS inhibitor initiation to prevent premature cessation of these foundational therapies.
On a positive note, there was no acute dip in eGFR after prescribing semaglutide in DKD. This observation will be reassuring for primary care and hopefully prevent unnecessary cessation of therapy.
Also reassuring was the lack of difference in diabetic retinopathy adverse events between the semaglutide and placebo groups. These events raised concerns about semaglutide following the SUSTAIN-6 CVOT study and have affected attitudes in primary care. But the rapidity and magnitude of improvement in glycemic control with semaglutide was believed to be the underlying issue, rather than semaglutide itself. A similar phenomenon has been observed with insulin. The ongoing FOCUS study is exploring the long-term effects of semaglutide on diabetic retinopathy in patients with type 2 diabetes. This study will hopefully provide a definite answer to this issue.
Another useful message from the FLOW study for primary care is the utility of semaglutide for glucose-lowering in the context of CKD. A1c was 0.81% lower in the semaglutide group compared with the placebo group in participants with eGFRs as low as 25 mL/min/1.73 m2. It is well established that SGLT2 inhibitors have negligible glucose-lowering effects once eGFR drops below 45 mL/min/1.73 m2. Indeed, my usual practice in CKD, if additional glucose-lowering is required once renal protection has been established with an SGLT2 inhibitor, was to add a GLP-1 receptor agonist. It is reassuring to have my clinical practice ratified by the FLOW study.
Semaglutide also helpfully provides an alternative therapeutic option for patients who do not tolerate SGLT2 inhibitors because of, for example, recurrent mycotic genital infections or polyuria, or for those in whom SGLT2 inhibitors are contraindicated, such as patients who have experienced an unprovoked episode of diabetic ketoacidosis. Many of these patients still require cardiovascular and kidney protection, so the FLOW study gives me a viable evidence-based alternative.
As a class, semaglutide and GLP-1 receptor agonists are, of course, not without side effects. Gastrointestinal side effects are the most common, and this finding was echoed in the FLOW study. Gastrointestinal disorders led to permanent treatment discontinuation in 4.5% of the semaglutide group compared with 1.1% of the placebo group. The overall safety profile of semaglutide was favorable, however.
Gastrointestinal side effects can be particularly concerning in the context of CKD because of the possibility of clinical dehydration and acute kidney injury with persistent vomiting or diarrhea. Patient education is particularly important when using GLP-1 receptor agonists in this group of individuals. Reassuringly, there was no imbalance in dehydration and acute kidney injury between trial arms in the FLOW study.
Notably, past studies have suggested that patients with CKD are more likely to experience gastrointestinal side effects with GLP-1 receptor agonists; in these patients, the usual mantra of GLP-1 receptor agonist prescribing is particularly important: Start low, go slow.
Finally, medication adherence is a challenge with multiple pillars of GDMT: These evidence-based disease-modifying therapies work only if our patients take them regularly. My senior partner had a lovely turn of phrase when reviewing patients with multiple long-term conditions; he would always start the consultation by asking individuals which medications they were not taking regularly.
Overall, the FLOW study confirms semaglutide’s position as a new therapeutic pillar for DKD. This treatment will help address the residual renal risk for patients with DKD despite optimal use of GDMT. However, education and support will be required in primary care to prevent worsening therapeutic inertia.
Kevin Fernando, general practitioner partner, North Berwick Health Centre, North Berwick, UK, has disclosed the following relevant financial relationships: Received speaker fees from: Amarin; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Dexcom; Daiichi Sankyo; Lilly; Menarini; Novartis; Novo Nordisk; Roche Diagnostics; Embecta; Roche Diabetes Care. Received honoraria for participation in advisory boards from: Amarin; Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Lilly; Menarini; Novartis; Roche Diabetes Care; Roche Diagnostics; Sanofi. Received funding for conference registration and subsistence from: Menarini; Daiichi Sankyo.
A version of this article first appeared on Medscape.com.