The DIABESITY Working Group of the European Renal Association has flagged the paradigm shift in the management of cardio-renal-metabolic syndrome in recent years.

The group said the addition of SGLT2 inhibitors, GLP-1 RAs and nonsteroidal MRAs to standard renin–angiotensin–aldosterone system (RAAS) blockade has shown potential for cardio-renal protection in patients with obesity and/or metabolic syndrome and CKD.

However, they also noted the dire forecast for rates of obesity approaching 60% globally by 2050, health disparities which hinder early intervention, and a therapeutic inertia demonstrated by suboptimal uptake of novel therapies.

Writing in Nephrology Dialysis Transplantation [link here], they said translating therapeutic advances into routine clinical practice required a “…concerted effort in research, policy, and education.”

“Future studies should prioritise personalised, cost-effective, and equitable care models that harness both pharmacological and technological innovations.”

The Working Group identified a number of opportunities for ramping up the response to the challenges of obesity and metabolic syndrome in CKD and other nephropathies.

Lifestyle interventions

They noted the many dietary interventions which were well researched, including low-carbohydrate diets and intermittent fasting, which have a modest effect on weight loss and reduce metabolic and cardiovascular risks.

“Notably, certain dietary regimens—such as protein-restricted or plant-based diets—may confer additional renal benefits, potentially modifying the course of CKD. However, concerns persist regarding long-term safety, and most supporting evidence remains epidemiological in nature.”

They also said physical activity was an underutilised component of lifestyle therapy despite guidelines recommending ≥150 minutes of moderate-intensity physical activity per week.

“While exercise alone typically produces smaller weight reductions than dietary interventions, it plays a vital role in sustaining weight loss and improving overall metabolic health. Additionally, physical activity is safe in CKD patients and has been shown to enhance cardiovascular fitness and quality of life.”

Metabolic surgery

The group noted most RCTs of metabolic surgery in type 2 diabetes have focused on its effects on glycemic control rather than kidney outcomes.

Nevertheless, there was some evidence for greater albuminuria remission after surgery compared to medical therapy.

For example in the MOMS study [link here], gastric bypass was more effective in achieving remission of albuminuria and early-stage CKD than best medical treatment in patients with type 2 diabetes, microalbuminuria, and obesity.

“Future RCTs should enroll individuals with CKD stages G2–G3 and albuminuria, using direct GFR measurements and longer-term follow-up,” they said.

Sex differences

Another issue raised was the lack of sex-specific recommendations in obesity-related CKD.

They noted that women generally have higher rates of obesity than men but that men with obesity tend to have more rapid CKD progression and a greater risk of adverse outcomes including end-stage renal disease and mortality.

“Moreover, sex differences extend to the response to therapeutic interventions. For instance, weight loss strategies, pharmacologic treatments such as SGLT2 inhibitors or GLP-1 RAs, and bariatric surgery may have differing efficacy and safety profiles between men and women. These variations underscore the importance of incorporating sex as a biological variable in both clinical research and practice,” they said.

“Future research should prioritise sex-disaggregated analyses to inform personalised and equitable care strategies for this growing patient population.”

Pharmacotherapy

The Working Group said SGLT2 inhibitors, which may provide “renal and survival benefits regardless of BMI status”, are now considered foundational therapy alongside RAAS blockade in CKD management.

“Future research should explore optimal combinations with other renoprotective agents, such as finerenone, GLP-1 receptor agonists, and dual GLP-1/GIP receptor agonists, to further enhance kidney and cardiovascular outcomes in diverse patient populations.”

However the future lies in “Triple G agonists” – a novel and promising class of anti-obesity agents that simultaneously target GLP-1, GIP, and glucagon and offer a multifaceted approach to weight reduction and metabolic improvement.

“Beyond their primary indication for weight management, triple G agonists are showing emerging potential in kidney protection,” they said.

For example, a post hoc analysis of phase 2 data published in Kidney International Reports [link here] reported that retatrutide favourably influenced renal biomarkers, including reductions in albuminuria, in patients with obesity or T2D.

They said other novel therapies targeting inflammation, fibrosis and gut microbiota warrant exploration to mediate cardiovascular-kidney-metabolic syndrome risk.