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For people with type 2 diabetes and chronic kidney disease (CKD), semaglutide (Ozempic) reduced the risk of major kidney events and death from cardiovascular causes, the phase III FLOW trial showed.

Added to usual care, the GLP-1 receptor agonist reduced the primary composite endpoint -- dialysis, kidney transplantation, an estimated glomerular filtration rate (eGFR) that falls at least 50% from baseline or to under 15 mL/min/1.73 m², or death from kidney-related or cardiovascular causes -- by 24% compared with placebo (HR 0.76, 95% CI 0.66-0.88).

The number needed to treat (NNT) for 3 years to prevent one such event was 20, reported Vlado Perkovic, MBBS, PhD, of the University of New South Wales in Sydney, and colleagues.

Results were similar and statistically significant for both the kidney outcomes and cardiovascular mortality independently as well, according to findings published in the in conjunction with a presentation at the European Renal Association meeting in Stockholm.

"These benefits reflect important clinical effects on kidney, cardiovascular, and survival outcomes among high-risk patients, particularly given the reassuring safety findings, and support a therapeutic role for semaglutide in this population," the researchers concluded.

The findings shore up in secondary and post hoc kidney outcomes in clinical trials of GLP-1 receptor agonists for cardiovascular outcomes and glycemic control and add to those proven for SGLT2 inhibitors in CKD trials.

"Because three other guideline-directed medical therapies have been shown to have benefits in patients with type 2 diabetes and chronic kidney disease (RAS inhibition, SGLT2 inhibition, and mineralocorticoid-receptor antagonism with finerenone [Kerendia]), clinicians and patients will need to consider the order and priority of use for semaglutide (and, once studied, other GLP-1 receptor agonists)," Perkovic's group noted.

The safety and efficacy seen in the trial also provide a rationale for combining semaglutide with the other proven therapies as initial therapeutic options in this patient population, they suggested. "Combination therapy is likely to be important in the future, and we found no clear heterogeneity of effect among patients receiving SGLT2 inhibitors at baseline as compared with those who were not, although the statistical power of this analysis was limited."

The international included 3,533 adults with type 2 diabetes and CKD, as defined by an eGFR of 50-75 mL/min/1.73 m² with a urinary albumin-to-creatinine ratio of 300-5,000 or an eGFR of 25 to <50 mL/min/1.73 m² with a urinary albumin-to-creatinine ratio of 100-5,000. They were randomized to receive subcutaneous semaglutide at a dose of 1.0 mg once weekly or placebo.

Participants averaged 66.6 years old, with 30.3% being women. Mean eGFR was 47.0 mL/min/1.73 m², and the median ratio of milligrams of urinary albumin to grams of creatinine was 567.6.

The trial was stopped early for efficacy after a median follow-up of 3.4 years.

For a composite of the kidney-specific components of the primary outcome, semaglutide held the advantage (HR 0.79, 95% CI 0.66-0.94). The same was true for death from cardiovascular causes (HR 0.71, 95% CI 0.56-0.89).

Hierarchical analysis of secondary outcomes also favored semaglutide, with 1.16 mL/min/1.73 m² less loss in eGFR per year (P<0.001), 18% less risk of major cardiovascular events (HR 0.82, 95% CI 0.68-0.98; NNT 45 over 3 years), and 20% lower all-cause mortality (HR 0.80, 95% CI 0.67-0.95; NNT 39).

Fewer serious adverse events occurred in the semaglutide group than in the placebo group (49.6% vs 53.8%), driven by fewer serious infections or infestations (17.9% vs 21.3%) or serious cardiovascular disorders (15.4% vs 18.1%). Serious eye disorder adverse events were more common with semaglutide (3.0% vs 1.7%).

A limitation of the trial included the "modest" proportion of patients on SGLT2 inhibitors and nonsteroidal mineralocorticoid receptor antagonists, which had not been approved for kidney protection at the time the trial started and thus limited the ability to assess the effects of combination therapy. Another was the limited proportion of non-white participants compared with the higher community prevalence among marginalized populations, especially Black persons, who accounted for just 4.5% of the trial population.

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