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.