Semaglutide could be ‘practice changing’ for adults with diabetes, CKD
Click Here to Manage Email Alerts
The GLP-1 receptor agonist semaglutide may not only add another therapeutic option for chronic kidney disease, but it could also lead to changes in the way clinicians treat the condition.
Results from the FLOW trial, which assessed semaglutide (Ozempic, Novo Nordisk) in adults with type 2 diabetes and CKD, were first presented at the European Renal Association Congress and published in The New England Journal of Medicine in May. Adults assigned semaglutide had a lower risk for major kidney disease events and cardiovascular events compared with those assigned placebo.
Image: Richard E. Pratley, MD. Printed with permission.
The findings suggest semaglutide could become an important tool for clinicians treating both CKD and type 2 diabetes, according to Matthew Weir, MD, professor and chief of the division of nephrology at University of Maryland School of Medicine.
Weir said GLP-1s offer additional benefits that are not available with current CKD medications.
“[SGLT2 inhibitors] are very good, but they don’t lower glucose in people with an estimated glomerular filtration rate below 45 or 50 mL/min/1.73 m2,” Weir told Healio | Endocrine Today. “Finerenone is effective at reducing cardiorenal events, but it doesn’t treat diabetes. The long and short of it is the GLP-1 receptor agonists have looked so good for CV outcomes and ... we’re seeing data showing they reduce albuminuria. So why not see if they have impact on kidney and CV events?”
The data also suggest semaglutide could become the latest medication capable of slowing the progression of CKD. Multiple SGLT2 inhibitors have been approved to treat adults with CKD over the past 5 years, and in 2021, the nonsteroidal mineralocorticoid receptor antagonist finerenone (Kerendia, Bayer) was approved to lower risk for renal and CV complications for adults with type 2 diabetes and CKD.
“Over 20 years after [angiotensin-converting enzyme] inhibitor and [angiotensin receptor blocker] therapies were approved, we had no additional therapies approved to lower CKD risk,” Kevin M. Pantalone, DO, ECNU, FACE, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, director of diabetes initiatives and staff endocrinologist in the department of endocrinology at Cleveland Clinic, told Healio | Endocrine Today. “It is exciting to see a lot of options become available.”
Richard E. Pratley, MD, co-chair of the FLOW trial, the Samuel E. Crockett Chair in Diabetes Research, medical director of AdventHealth Diabetes Institute and a Healio | Endocrine Today Co-editor, described the FLOW findings as “practice changing.” Pratley said while the American Diabetes Association Standards of Care recommends SGLT2 inhibitors as the first-line treatment for most adults with type 2 diabetes and CKD, the FLOW trial may change that in the future.
“I think there is no doubt this will elevate GLP-1 receptor agonists in the treatment paradigm, perhaps even above SGLT2 inhibitors, because the benefit on mortality is substantial,” Pratley told Healio | Endocrine Today.
For semaglutide and other therapies to have an impact, however, screening for CKD is key. Multiple studies have found many adults with CKD or at risk for CKD do not have urinary albumin-to-creatine ratio (UACR), a key biomarker for CKD, measured on an annual basis.
“CKD is so prevalent in patients with hypertension and diabetes and those are major risk factors that show up in the cardiologist’s office,” Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC, professor of medicine and director of Women’s Cardiovascular Health at Johns Hopkins School of Medicine, told Healio | Endocrine Today. “I measure all of my patients’ eGFR but also UACR ratio because you won’t know who might benefit from these therapies until you actually identify CKD.”
FLOW findings
The FLOW trial enrolled 3,533 adults with type 2 diabetes and high-risk CKD on stable renin-angiotensin system (RAS) inhibitor therapy. Participants were randomly assigned 1:1 to once-weekly 1 mg semaglutide or placebo. A composite of major kidney disease events was the primary outcome of the trial and consisted of onset of kidney failure, a 50% or greater reduction in eGFR from baseline, or kidney or CV-related mortality.
At a median follow-up of 3.4 years, adults assigned semaglutide had lower risk for major kidney disease events compared with those assigned placebo (Graphic). The number of people needed to be treated over 3 years to prevent a major kidney disease event was 20. Risks for a kidney-specific primary outcome and CV death were also lower for the semaglutide group vs. placebo.
Beyond kidney outcomes, semaglutide was associated with lower risk for major CV events and all-cause mortality compared with placebo (Graphic). Over 3 years, 45 people needed to be treated to prevent one major CV event and 39 needed to be treated to prevent one death.
The FLOW trial is not the only to observe renal benefits with semaglutide. In a subanalysis of the SELECT trial, adults with overweight or obesity plus CVD but without diabetes had a 22% lower risk for a 5-component kidney composite endpoint if they received semaglutide 2.4 mg (Wegovy, Novo Nordisk) vs. placebo.
Michos said the risk reduction observed with major CV events in the FLOW trial was just as important as the primary outcome due to the high CV risk for people with CKD, especially as their kidney disease progresses.
“Semaglutide saves kidneys, saves hearts and saves lives,” Michos said. “This was really impressive that it, down the line of hierarchical outcome testing, consistently reduced [the risk] of everything.”
Weir agreed, saying the CV benefits in addition to the renal benefits are what makes semaglutide stand out from other CKD therapies.
“[The FLOW trial] places this therapy for me as choice No. 1 not only for glucose control, but also control of [cardiometabolic] risk,” Weir said.
Pillars for treating CKD
The FLOW trial could lead to changes in how CKD and cardiometabolic diseases as a whole are treated. Michos said she envisions CKD being treated with a “pillared approach,” similar to heart failure, with the four pillars of drug therapy consisting of RAS inhibitors, SGLT2 inhibitors, finerenone and semaglutide.
“When we think about these patients — the whole cardiorenal-metabolic spectrum — we are thinking about a holistic approach,” Michos said. “Patients aren’t just patients with diabetes, or patients with kidney disease or patients with heart failure. They may have all of these things and having agents that can help both the heart and kidney to [benefit] multiple pathways is really quite exciting.”
The 2024 ADA Standards of Care has several recommendations for CKD prevention and treatment. The standards recommend using angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for people with diabetes and hypertension, a UACR of 30 mg/g or higher or an eGFR of less than 60 mL/min/1.73 m2. SGLT2 inhibitors are recommended for adults with type 2 diabetes and CKD with an eGFR of 20 mL/min/1.73 m2 or higher. To lower CV risk in type 2 diabetes and CKD, the standards recommend an SGLT2 inhibitor, a nonsteroidal mineralocorticoid receptor antagonist such as finerenone or a GLP-1 receptor agonist.
For adults without type 2 diabetes, SGLT2 inhibitors are also the first-line therapy for most. The Kidney Disease Improving Global Outcomes 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease recommends adults with CKD and either an eGFR 20 mL/min/1.73 m2 or higher plus UACR of 200 mg/g or higher, or those with heart failure, receive SGLT2 inhibitor therapy.
Pratley said the best course of action for treating CKD may be to prescribe both an SGLT2 inhibitor and semaglutide so the drugs work synergistically to offer the greatest benefits. However, he said, some providers are hesitant to prescribe multiple drugs, though the use of multiple medications is used for some cardiometabolic conditions.
“If someone is admitted for myocardial infarction, they leave the hospital with four medicines, minimum,” Pratley said. “If someone is admitted for exacerbation of heart failure, they’re leaving the hospital with five medicines, all guideline-directed. We know that improves outcomes; that’s why the cardiologists do that. We need to move our thinking to getting people on these guideline-directed therapies that improve substantial outcomes like death at an early stage.”
Pantalone said first-line therapy may become individualized for each patient, with SGLT2 inhibitors being used for some people with CKD and semaglutide being prescribed to others.
“I still believe that SGLT2 inhibitors are going to be a very strong first-line options after ACE inhibitor and angiotensin receptor blocker therapy for most providers,” Pantalone said. “But certainly in patients who may have a greater level of obesity associated with their type 2 diabetes, perhaps initiating semaglutide before an SGLT2 inhibitor because of the weight benefit, the CV risk lowering, as well as the CKD benefit, may be appropriate.”
More screening needed
Providers are hopeful the FLOW trial may raise greater awareness of CKD screening, particularly the measurement of UACR. A study published in Diabetes Care in 2021 found the median testing rate for UACR among adults with type 2 diabetes receiving primary care across 24 U.S. health care organizations was 52.9%.
According to electronic health record data from Cleveland Clinic published in the Journal of Diabetes and Its Complications in 2023, urine protein assessments were completed for 7.6% of adults with CKD, 30.2% of those with CKD and type 2 diabetes and 20.1% of adults with type 2 diabetes in 2019.
“There is provider inertia where providers may not be thinking about it,” Pantalone said of factors contributing to low screening rates. “But I can also tell you that numerous times, you order blood and urine tests on patients with diabetes, they go get the blood test and they never provide the urine sample.”
Beyond screening, uptake of therapies to treat CKD has also been low. According to the study from Pantalone and colleagues, fewer than half of people with CKD were also being treated with an ACE inhibitor, ARB or SGLT2 inhibitor in 2019.
Some of the same factors contributing to low screening rates for CKD are also contributors to low therapy uptake, including treatment inertia, lack of knowledge about guidelines in practice, and concerns regarding insurance coverage and costs.
“In most recent years, within [Cleveland Clinic], we have seen much greater uptake of SGLT2 inhibitors as well as GLP-1 receptor agonists, specifically in people with CKD and CVD,” Pantalone said. “But there is still dramatic room for improvement. A lot of it has to do with provider concerns regarding prior authorization costs and potential coverage for their patients, and sometimes those perceived barriers lead to underprescribing.”
Pratley said incentivizing providers to screen for CKD may make it become as routine as checking a patient’s HbA1c. Additionally, Pratley said CKD screening should expand beyond people with diabetes.
“Clearly, everyone with diabetes should be screened once a year for eGFR and urine albumin-to-creatine ratio,” Pratley said. “Then it becomes more difficult. Hypertension is another risk factor for CKD, so an eGFR but probably also a urine albumin-to-creatine ratio [should be performed] in that population. Obesity is another risk factor for developing CKD. It’s much less common than it is with diabetes, but it has the same pathophysiology with endothelial dysfunction.”
Pratley said people with established CVD or heart failure are also very likely to have CKD and should be screened by cardiologists. Michos said some cardiologists did not screen for CKD prior to availability of SGLT2 inhibitors and finerenone, since many of their patients were using an ACE inhibitor or ARB already. However, the addition of more therapy options means cardiologists need to pay greater attention to UACR.
“We have to get on board with recognizing CKD,” Michos said. “It’s a sort of ‘silent killer’ that patients don’t even know they have. As a preventive cardiologist, we also want to prevent kidney disease earlier.”
On the horizon
Findings from trials assessing semaglutide revealed diseases of different organs are connected, according to Pratley. While the precise mechanisms of GLP-1s are still being studied, GLP-1s have been tied to reductions in inflammation, meaning they could also benefit diseases such as metabolic dysfunction-associated steatotic liver disease and cognitive impairment, Pratley said.
“In the past, we looked at diseases in silos. You have diabetes and the complication is kidney disease, or you have diabetes, and the complication is CVD,” Pratley told Healio | Endocrine Today. “But that’s not what’s happening biologically. Biologically, you’re having parallel processes in different organs that probably have some underlying pathophysiology in common. ... GLP-1s are working at a very fundamental level to alter this biology.”
Michos said renal benefits could be seen with other agents, such as tirzepatide (Mounjaro, Eli Lilly). Michos added that research is also needed to assess combination therapy for CKD and to determine optimal best medication sequencing.
“We need some guidance about whether to start them all at once. Or do you stagger? What is the order of onboarding and sequencing? We need more data about these combinations of therapies together,” Michos said.
Cost will also be a factor providers need to consider when prescribing a medication. Weir said while the FLOW data were very positive for semaglutide, the high price of the medication may be a barrier to access for some patients.
“GLP-1s are very expensive,” Weir said. “[The benefit] has to be tempered with the reality of being able to pay.”
If semaglutide receives a new indication from the FDA to treat CKD, Michos said, it could lead to a greater push from clinicians in multiple specialties to screen for the disease and identify it earlier.
“This is very much relevant for cardiologists, nephrologists, endocrinologists, primary care and family medicine,” Michos said. “This has exciting, broad implications for all of these [specialties].”
- References:
- American Diabetes Association Professional Practice Committee. Diabetes Care. 2023;doi:10.2337/dc24-S011.
- Colhoun HM, et al. Nat Med. 2024;doi:10.1038/s41591-024-03015-5.
- Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Int. 2024;doi:10.1016/j.kint.2023.10.018.
- Pantalone KM, et al. J Diabetes Complications. 2023;doi:10.1016/j.jdiacomp.2023.108418.
- Perkovic V, et al. N Engl J Med. 2024;doi:10.1056/NEJMoa2403347.
- Stempniewicz N, et al. Diabetes Care. 2021;doi:10.2337/dc20-2715.
- For more information:
- Erin D. Michos, MD, MHS, FACC, FAHA, FASE, FASPC, can be reached at edonnell@jhmi.edu; X (Twitter): @ErinMichos.
- Kevin M. Pantalone, DO, ECNU, FACE, can be reached at pantalk@ccf.org. LinkedIn: @KevinPantalone
- Richard E. Pratley, MD, can be reached at Richard.Pratley.MD@AdventHealth.com; X (Twitter): @RpratleyMD.
- Matthew Weir, MD, can be reached at mweir@som.umaryland.edu.
Collapse
Read more about
Click Here to Manage Email Alerts