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STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.
“These data are important because they are the first data to suggest a kidney benefit of semaglutide in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.
“This is a population at high risk of chronic kidney disease with an increased need for kidney protection,” she said.
The late-breaking study was presented this week at the 61st European Renal Association (ERA) Congress 2024 and simultaneously published in Nature Medicine.
SELECT Trial Patients Without Diabetes
The findings are from a secondary analysis of the randomized SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.
For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.
With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making FLOW trial, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.
Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.
The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.
With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; P = .02).
A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m2 (P < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m2 (P < .001).
Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary albumin-to-creatinine ratio (UACR) compared with placebo (–10.7%; P < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.
Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).
There were no reports of acute kidney injury associated with semaglutide, regardless of baseline eGFR.
“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.
Benefits the Result of Weight Loss or Something Else?
Considering the beneficial effects of semaglutide on weight loss, underscored in an analysis also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.
But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.
“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.
“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”
Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.
And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.
Studies of weight loss through bariatric surgery have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.
In terms of whether the benefits may extend to tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from another secondary analysis also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.
Primary Prevention of CKD?
Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m2 or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease.
Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.
“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m2 and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.
“This suggests a potential role in primary prevention of CKD in this population,” he said.
To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”
SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.
A version of this article first appeared on Medscape.com.
STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.
“These data are important because they are the first data to suggest a kidney benefit of semaglutide in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.
“This is a population at high risk of chronic kidney disease with an increased need for kidney protection,” she said.
The late-breaking study was presented this week at the 61st European Renal Association (ERA) Congress 2024 and simultaneously published in Nature Medicine.
SELECT Trial Patients Without Diabetes
The findings are from a secondary analysis of the randomized SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.
For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.
With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making FLOW trial, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.
Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.
The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.
With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; P = .02).
A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m2 (P < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m2 (P < .001).
Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary albumin-to-creatinine ratio (UACR) compared with placebo (–10.7%; P < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.
Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).
There were no reports of acute kidney injury associated with semaglutide, regardless of baseline eGFR.
“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.
Benefits the Result of Weight Loss or Something Else?
Considering the beneficial effects of semaglutide on weight loss, underscored in an analysis also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.
But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.
“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.
“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”
Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.
And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.
Studies of weight loss through bariatric surgery have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.
In terms of whether the benefits may extend to tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from another secondary analysis also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.
Primary Prevention of CKD?
Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m2 or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease.
Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.
“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m2 and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.
“This suggests a potential role in primary prevention of CKD in this population,” he said.
To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”
SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.
A version of this article first appeared on Medscape.com.
STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.
“These data are important because they are the first data to suggest a kidney benefit of semaglutide in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.
“This is a population at high risk of chronic kidney disease with an increased need for kidney protection,” she said.
The late-breaking study was presented this week at the 61st European Renal Association (ERA) Congress 2024 and simultaneously published in Nature Medicine.
SELECT Trial Patients Without Diabetes
The findings are from a secondary analysis of the randomized SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients With Overweight or Obesity) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.
For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.
With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making FLOW trial, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.
Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.
The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m2; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.
With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; P = .02).
A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m2 (P < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m2 (P < .001).
Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary albumin-to-creatinine ratio (UACR) compared with placebo (–10.7%; P < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.
Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).
There were no reports of acute kidney injury associated with semaglutide, regardless of baseline eGFR.
“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.
Benefits the Result of Weight Loss or Something Else?
Considering the beneficial effects of semaglutide on weight loss, underscored in an analysis also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.
But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.
“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.
“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”
Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.
And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.
Studies of weight loss through bariatric surgery have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.
In terms of whether the benefits may extend to tirzepatide, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from another secondary analysis also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.
Primary Prevention of CKD?
Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m2 or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease.
Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the Hypertension Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.
“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m2 and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.
“This suggests a potential role in primary prevention of CKD in this population,” he said.
To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”
SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.
A version of this article first appeared on Medscape.com.
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This material may not be published, broadcast, copied, or otherwise reproduced or distributed without the prior written permission of Frontline Medical Communications Inc.</copyrightNotice> </rightsInfo> </provider> <abstract/> <metaDescription>STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to </metaDescription> <articlePDF/> <teaserImage/> <teaser>The kidney benefits observed in patients who are at high risk of kidney disease but do not yet have diabetes or chronic kidney disease is encouraging.</teaser> <title>Semaglutide Kidney Benefits Extend to Those Without Diabetes</title> <deck/> <disclaimer/> <AuthorList/> <articleURL/> <doi/> <pubMedID/> <publishXMLStatus/> <publishXMLVersion>1</publishXMLVersion> <useEISSN>0</useEISSN> <urgency/> <pubPubdateYear/> <pubPubdateMonth/> <pubPubdateDay/> <pubVolume/> <pubNumber/> <wireChannels/> <primaryCMSID/> <CMSIDs/> <keywords/> <seeAlsos/> <publications_g> <publicationData> <publicationCode>fp</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>endo</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> <publicationData> <publicationCode>im</publicationCode> <pubIssueName/> <pubArticleType/> <pubTopics/> <pubCategories/> <pubSections/> </publicationData> </publications_g> <publications> <term>15</term> <term>34</term> <term canonical="true">21</term> </publications> <sections> <term>53</term> <term canonical="true">39313</term> </sections> <topics> <term>205</term> <term>261</term> <term canonical="true">255</term> </topics> <links/> </header> <itemSet> <newsItem> <itemMeta> <itemRole>Main</itemRole> <itemClass>text</itemClass> <title>Semaglutide Kidney Benefits Extend to Those Without Diabetes</title> <deck/> </itemMeta> <itemContent> <p>STOCKHOLM — Improvements in kidney function outcomes observed with glucagon-like peptide-1 (GLP-1) receptor agonists in patients with type 2 diabetes extend to patients who are overweight or obese but don›t yet have type 2 diabetes, new research shows.</p> <p>“These data are important because they are the first data to suggest a kidney benefit of <a href="https://reference.medscape.com/drug/ozempic-rybelsus-wegovy-semaglutide-1000174">semaglutide</a> in this patient population in the absence of diabetes,” lead author Helen M. Colhoun, MD, of the Institute of Genetics and Cancer, University of Edinburgh, Scotland, United Kingdom, told this news organization.<br/><br/>“This is a population at high risk of <a href="https://emedicine.medscape.com/article/238798-overview">chronic kidney disease</a> with an increased need for kidney protection,” she said.<br/><br/>The late-breaking study was presented this week at the <a href="https://www.medscape.com/viewcollection/37507">61st European Renal Association (ERA) Congress 2024</a> and <a href="https://www.nature.com/articles/s41591-024-03015-5">simultaneously published</a> in <em>Nature Medicine</em>.<br/><br/></p> <h2>SELECT Trial Patients Without Diabetes</h2> <p>The findings are from a secondary analysis of the randomized <a href="https://www.nejm.org/doi/10.1056/NEJMoa2307563">SELECT</a> (Semaglutide Effects on Heart Disease and <a href="https://emedicine.medscape.com/article/1916852-overview">Stroke</a> in Patients With Overweight or <a href="https://emedicine.medscape.com/article/123702-overview">Obesity</a>) trial, which evaluated cardiovascular outcomes of semaglutide treatment among 17,604 adults with preexisting cardiovascular disease who were overweight or obese — but did not have diabetes.</p> <p>For its primary endpoint, the trial showed semaglutide was associated with a 20% reduction in major adverse cardiovascular events compared with placebo.<br/><br/>With obesity also associated with a significantly increased risk of chronic kidney disease — and the headline-making <a href="http://www.nejm.org/doi/full/10.1056/NEJMoa2403347">FLOW trial</a>, also presented at the congress, showing key benefits of semaglutide in improving kidney function in people with CKD and type 2 diabetes the secondary analysis of SELECT was conducted to investigate whether those kidney benefits extended to people without type 2 diabetes.<br/><br/>Patients were randomized 1:1 to once-weekly subcutaneous semaglutide at a dose of 2.4 mg or placebo. Baseline patient characteristics were well-balanced, including kidney function and albuminuria status.<br/><br/>The primary endpoint for the analysis was a nephropathy composite of time from randomization to the first occurrence of death from kidney causes; initiation of chronic kidney replacement therapy; onset of persistent estimated glomerular filtration rate (eGFR) < 15 mL/min/1.73 m<sup>2</sup>; persistent ≥ 50% reduction in eGFR compared with baseline; or onset of persistent macroalbuminuria.<br/><br/>With a median follow-up of 182 weeks, the results showed that the semaglutide group was significantly less likely to develop the primary composite endpoint compared with the placebo group (1.8% vs 2.2%; hazard ratio [HR], 0.78; <em>P</em> = .02).<br/><br/>A significantly reduced decline in eGFR in the semaglutide group was observed at a prespecified 104-week time point, with a treatment effect of 0.75 mL/min/1.73 m<sup>2</sup> (<em>P</em> < .001), and the effect was more pronounced among participants with baseline eGFR < 60 mL/min/1.73 m<sup>2</sup> (<em>P</em> < .001). <br/><br/>Furthermore, those in the semaglutide group had a significantly lower proportionate increase in urinary <a href="https://emedicine.medscape.com/article/2054430-overview">albumin</a>-to-<a href="https://emedicine.medscape.com/article/2054342-overview">creatinine</a> ratio (UACR) compared with placebo (–10.7%; <em>P</em> < .001) at the prespecified 104 weeks, with a net treatment benefit of –27.2% and –31.4% among those with randomization to UACR 30 to < 300 mg/g and 2300 mg/g, respectively.<br/><br/>Improvements varied according to baseline UACR status and were more pronounced among those with macroalbuminuria, at –8.1% for those with normoalbuminuria (n = 14,848), –27% for microalbuminuria (n = 1968), and –31% for macroalbuminuria (n = 325).<br/><br/>There were no reports of <a href="https://emedicine.medscape.com/article/243492-overview">acute kidney injury</a> associated with semaglutide, regardless of baseline eGFR. <br/><br/>“We were hopeful that there would be similar benefits as those observed in the diabetes studies, but there are differences in kidney disease among those with and without type 2 diabetes, so we weren’t sure,” Dr. Colhoun told this news organization.<br/><br/></p> <h2>Benefits the Result of Weight Loss or Something Else?</h2> <p>Considering the beneficial effects of semaglutide on weight loss, underscored in <a href="https://www.nature.com/articles/s41591-024-02996-7">an analysis</a> also published this month that showed a mean 10.2% reduction in weight sustained for up to 4 years, a key question is whether the kidney benefits are a direct result of weight loss — or the drug mechanism or something else.</p> <p>But Dr. Colhoun said the role of weight loss in terms of the kidney benefits is still uncertain, particularly considering the various other factors, including cardiometabolic improvements, which could also have an effect.<br/><br/>“It’s a very difficult question to answer,” she said. “We did do a mediation exploratory analysis suggesting a substantial part of the effect might be due to the weight change, but it’s difficult to demonstrate that because you have weight change going on in the placebo arm as well, but for different reasons,” she said.<br/><br/>“So, I would say the data suggest there is some component of this that is attributable to weight, but we certainly can’t attribute all of the [effects] to weight change.”<br/><br/>Small studies involving animals have shown a direct effect of semaglutide on kidney hemodynamics “but they’re small and not definitive,” Dr. Colhoun added.<br/><br/>And although weight loss achieved through other measures such as lifestyle changes show a small benefit on eGFR, “interestingly, those studies showed no effect at all on albuminuria, whereas we see a really substantial effect on albuminuria with semaglutide,” Dr. Colhoun said.<br/><br/>Studies of weight loss through <a href="https://emedicine.medscape.com/article/197081-overview">bariatric surgery</a> have shown kidney benefits; however, those were in the context of type 2 diabetes, unlike the current analysis.<br/><br/>In terms of whether the benefits may extend to <a href="https://reference.medscape.com/drug/mounjaro-tirzepatide-4000264">tirzepatide</a>, the dual glucose-dependent insulinotropic polypeptide (GIP)/GLP-1 receptor agonist, increasingly used in weight loss, results from <a href="https://www.thelancet.com/journals/landia/article/PIIS2213-8587(22)00243-1/abstract">another secondary analysis</a> also show encouraging kidney benefits in people with type 2 diabetes, and there is ongoing research in patients with type 2 diabetes and those with obesity without diabetes, Dr. Colhoun noted.<br/><br/></p> <h2>Primary Prevention of CKD?</h2> <p>Limitations of the current analysis include that only about a fifth of participants in SELECT had an eGFR < 60 mL/min/1.73 m<sup>2</sup> or UACR ≥ 30 mg/g at baseline, suggesting a relatively low proportion of participants with kidney disease. </p> <p>Importantly, however, the kidney benefits observed in patients who are at such high risk of kidney disease but do not yet have diabetes or CKD, is encouraging, said Alberto Ortiz, MD, PhD, commenting on the study. Dr. Ortiz is chief of nephrology and the <a href="https://emedicine.medscape.com/article/241381-overview">Hypertension</a> Renal Unit, Health Research Institute of the Jiménez Díaz Foundation, Madrid, Spain.<br/><br/>“It is especially significant that protection was observed in participants with an eGFR > 60 mL/min/1.73 m<sup>2</sup> and across UACR categories, ie, including people without CKD at baseline, in whom it appeared to decrease the incidence of de novo CKD,” Dr. Ortiz told this news organization.<br/><br/>“This suggests a potential role in primary prevention of CKD in this population,” he said.<br/><br/>To further investigate this, he said, “It would have been extremely interesting to assess whether there is a potential role for primary prevention of CKD in people without baseline CKD by assessing subgroup results for the no-CKD, low-risk KDIGO [Kidney Disease: Improving Global Outcomes] category [of patients].”<br/><br/>SELECT was funded by Novo Nordisk. Dr. Colhoun has reported consulting, research, and/or other relationships with Novo Nordisk, Bayer, Sanofi, Roche, and IQVIA. Dr. Ortiz has reported being a member of the European Renal Association council and Madrid Society of Nephrology (SOMANE), which developed a document in 2022 on the treatment of diabetic kidney disease sponsored by Novo Nordisk. He also reported collaborating with companies developing drugs for kidney disease.<span class="end"/></p> <p> <em>A version of this article first appeared on <span class="Hyperlink"><a href="https://www.medscape.com/viewarticle/semaglutide-kidney-benefits-extend-those-without-diabetes-2024a10009wg">Medscape.com</a></span>.</em> </p> </itemContent> </newsItem> <newsItem> <itemMeta> <itemRole>teaser</itemRole> <itemClass>text</itemClass> <title/> <deck/> </itemMeta> <itemContent> </itemContent> </newsItem> </itemSet></root>
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