Background: We assessed the effect of once-weekly semaglutide and once-daily liraglutide on kidney outcomes in type 2 diabetes. Methods: Pooled (n=12 637) and by-trial data from SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes; n=3297) and LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; n=9340) were assessed for albuminuria change, annual slope of estimated glomerular filtration rate (eGFR) change, and time to persistent eGFR reduction (30%, 40%, 50%, and 57%) from baseline. Results: The median follow-up durations were 2.1 years for SUSTAIN 6 and 3.8 years for LEADER. In the pooled analysis, semaglutide/liraglutide lowered albuminuria from baseline to 2 years after randomization by 24% versus placebo (95% CI, 20%–27%; P <0.001). Significant reductions were also observed in by-trial data analyses ( P <0.001 for all), the largest being with semaglutide 1.0 mg (33% [95% CI, 24%–40%]; P <0.001) at 2 years. With semaglutide 1.0 mg and liraglutide, eGFR slope decline was significantly slowed by 0.87 and 0.26 mL/min/1.73 m ² /y ( P <0.0001 and P <0.001), respectively, versus placebo. Effects appeared larger in patients with baseline eGFR <60 versus ≥60 mL/min/1.73 m ² ( P _interaction =0.06 and 0.008 for semaglutide 1.0 mg and liraglutide, respectively). Semaglutide/liraglutide significantly lowered risk of persistent 40% and 50% eGFR reductions versus placebo (hazard ratio [HR], 0.86 [95% CI, 0.75–0.99]; P =0.039 and HR, 0.80 [95% CI, 0.66–0.97]; P =0.023, respectively). Similar, nonsignificant, directional results were observed for 30% and 57% eGFR reductions (HR, 0.92 [95% CI, 0.84–1.02]; P =0.10 and HR, 0.89 [95% CI, 0.69–1.13]; P =0.34). In patients with baseline eGFR 30 to <60 mL/min/1.73 m ² , the likelihood of persistent reduction for all thresholds was increased, ranging from HR 0.71 for 30% reduction (95% CI, 0.59–0.85; P =0.0003, P _interaction =0.017) to 0.54 for 57% reduction (95% CI, 0.36–0.81; P =0.003, P _interaction =0.035). Conclusions: In patients with type 2 diabetes, semaglutide/liraglutide offered kidney-protective effects, which appeared more pronounced in patients with preexisting chronic kidney disease.

Obesity is a serious chronic disease and an independent risk factor for the new onset and progression of chronic kidney disease (CKD). CKD prevalence is expected to increase, at least partly due to the continuous rise in the prevalence of obesity. The concept of obesity-related kidney disease (OKD) has been introduced to describe the still incompletely understood interplay between obesity, CKD, and other cardiometabolic conditions, including risk factors for OKD and cardiovascular disease, such as diabetes and hypertension. Current therapeutics target obesity and CKD individually. Non-pharmacological interventions play a major part, but the efficacy and clinical applicability of lifestyle changes and metabolic surgery remain debatable, because the strategies do not benefit everyone, and it remains questionable whether lifestyle changes can be sustained in the long term. Pharmacological interventions, such as sodium-glucose co-transporter 2 inhibitors and the non-steroidal mineralocorticoid receptor antagonist finerenone, provide kidney protection but have limited or no impact on body weight. Medicines based on glucagon-like peptide-1 (GLP-1) induce clinically relevant weight loss and may also offer kidney benefits. An urgent medical need remains for investigations to better understand the intertwined pathophysiologies in OKD, paving the way for the best possible therapeutic strategies in this increasingly prevalent disease complex.

Chronic kidney disease (CKD) affects around 10% of the global population and is most often caused by diabetes. Diabetes with CKD (diabetic kidney disease, DKD) is a progressive condition that may cause kidney failure and which contributes significantly to the excess morbidity and mortality in these patients. DKD is treated with direct disease-targeting therapies like blockers of the renin–angiotensin system, sodium–glucose cotransporter-2 (SGLT-2) inhibitors and non-steroidal mineralocorticoid receptor antagonists as well as indirect therapies impacting hyperglycaemia, dyslipidaemia, obesity and hypertension, which all together reduce disease progression. While no glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) are currently indicated to improve kidney outcomes, accumulating evidence from cardiovascular outcomes trials (CVOTs) corroborates a kidney-protective effect in people with T2D and CKD, and GLP-1 RAs are now mentioned in international treatment guidelines for type 2 diabetes (T2D) with CKD. GLP-1 RAs are indicated to improve glycaemia in people with T2D; certain GLP-1 RAs are also approved for weight management and to reduce cardiovascular risk in T2D. Ongoing pivotal trials are assessing additional indications, including T2D with CKD. In this article, we review and discuss kidney outcomes from a multitude of completed clinical trials as well as real-world evidence and ongoing clinical trials.