Combining Semaglutide and Mineralocorticoids May Improve CKD

MADRID — The benefits of semaglutide treatment in reducing kidney disease, cardiovascular, and mortality risks in people with type 2 diabetes and chronic kidney disease (CKD) are observed regardless of whether patients are also being treated with mineralocorticoid receptor antagonists (MRAs), a subanalysis of the FLOW trial showed.

“Given the [separate] benefits of MRA, and particularly now with the drug finerenone, which we didn’t have when we started the FLOW trial, you could say we may consider using these agents in combination,” said first author Peter Rossing, MD, of the Steno Diabetes Center Copenhagen, Herlev, Denmark, in presenting the research at the European Association for the Study of Diabetes (EASD) 2024 Annual Meeting.

The overall findings from the landmark FLOW trial confirmed the potential of glucagon-like peptide 1 (GLP-1) receptor agonists vs placebo to prevent CKD progression, showing a 24% reduction in the primary composite kidney outcome of time to first kidney failure, persistent ≥ 50% estimated glomerular filtration rate (eGFR) reduction from baseline, or death due to kidney-related or cardiovascular causes, with the early observed success with semaglutide prompting the study to be stopped early.

With MRAs also shown separately to have important long-term cardiorenal benefits and known to have been used by some patients in the FLOW trial, the authors conducted the current prespecified analysis to determine semaglutide effects among those who were using MRAs at baseline (n = 257) and those who weren’t (n = 3276).

Despite the notably smaller MRA group size, participants’ baseline characteristics were similar, with an eGFR of 46 and 44 mL/min/1.73 m² and urine albumin-creatinine ratios of 536 and 569 mg/g in the MRA and non-MRA groups, respectively. Their median age was about 67 years, and about 29% were women.

Importantly, the nonsteroidal MRA finerenone, which has shown notable kidney benefits, was not used, as it was not available when the FLOW trial started.

With a median follow-up of 3.4 years, the primary composite kidney outcome was reduced by 49% among those treated with semaglutide who had MRA use vs placebo (hazard ratio [HR], 0.51), and the reduction was 21% in the non-MRA vs placebo group (HR, 0.79), for an interaction between the MRA and no-MRA groups that was not statistically significant (interaction P =.12).

“This suggests there is no difference in the effect of semaglutide on the primary outcome whether or not you are on an MRA,” Rossing told Medscape Medical News.

The specific kidney, cardiovascular disease, and heart failure outcomes, such as reduction in eGFR, all-cause mortality, MACE, nonfatal stroke, cardiovascular mortality, and heart failure events, generally showed no significant interactions between the MRA use at baseline and non-MRA groups.

Interactions were also not significant based on whether MRAs were used at baseline or introduced during the trial.

Likewise, there were no significant differences in safety profiles among semaglutide users in the MRA and non-MRA groups, and no unexpected adverse events were observed with the combination of semaglutide and MRAs.

A slight increase in hyperkalemia was observed in those receiving MRAs (22.8% vs 13.9% in the semaglutide-treated groups), but again, the difference was not significant.

“Although we had limited power to test effects in those on MRA, it seems there is no heterogeneity in the benefits of semaglutide for kidney, cardiovascular, and mortality outcomes,” Rossing said.

He added that the lack of patients on the MRA finerenone was a notable limitation.

“[Participants] were using MRAs in which the kidney protective effects are not known, and probably the MRAs were started for hypertension or heart failure,” Rossing explained. “In contrast, we know the nonsteroidal MRA finerenone shows kidney and heart benefits in a FLOW-like population.”

Specifically, finerenone was shown in the recent FIDELIO and FIGARO trials to provide benefits in cardiovascular disease and kidney outcomes in patients with CKD and type 2 diabetes, regardless of GLP-1 treatment at baseline or any time in the trial.

As in that trial, the new results suggested that the different mechanisms with the drugs provide benefits independent of each other, Rossing noted.

“I think these data would suggest these different drugs work by themselves, and whether or not they are combined, they seem to be to be additive,” he said.

Four Pillars — But When and How?

The collective research from FLOW and other trials has resulted in recommendations of a four-pillar approach for the treatment of CKD and diabetes, including renin-angiotensin system inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, finerenone, and semaglutide.

However, questions from the audience reflected uncertainty over the rationale of combining the drugs — particularly if the benefits appear the same with or without something like an MRA and, if they are used, which drugs to choose.

“I think you should choose them all,” Rossing said in response, underscoring the fact that 15% patients in the placebo group of the FLOW trial died during the study.

“These are very high-risk patients with a high mortality rate,” he said. “With heart failure or hypertension, we combine agents that have seemed to work to save lives, and we add them all into treatment of heart failure with reduced ejection fraction, and we don’t have all the trials that test all the combinations, but we do that,” he asserted.

“Maybe we need to develop algorithms for how you implement [combination therapy] and how to use biomarkers or other surrogates to find out who will need all the drugs, or if we can apply them stepwise and then see when we are at target and could stop adding more treatments.”

“But at the moment, we have four different classes or types of drugs that have reduced mortality, progression of kidney disease, and cardiovascular events, and I think we should use them in this disease.”

More Evidence Needed on Benefits of Combination

Andrea Giaccari, MD, who moderated the session, was among those suggesting the need for more evidence when it comes to combinations.

“Dr Rossing suggested that since the mechanisms of action are different, the renal protection provided should be additive, and therefore, they should be prescribed together,” Giaccari, who is chief and associate professor of medicine in the Endocrine and Metabolic Diseases Center, Fondazione Policlinico Universitario Agostino Gemelli, Catholic University of the Sacred Heart, in Rome, Italy, explained to Medscape Medical News.

“While this affirmation is understandable and could even be probable, there is no demonstration of the possible advantages of such combination,” he argued.

“Various subanalyses have found no statistical significance for the interaction between the combination of these drugs — but absence of interaction, mostly due to lack of statistical power, does not demonstrate that their combination is useful.”

Giaccari authored an editorial on the argument in response to the FIDELIO and FIGARO trials.

Giaccari said he looks forward to the results of the CONFIDENCE trial, evaluating the dual use of an SGLT2 inhibitor and finerenone in adults with CKD and type 2 diabetes (on which Rossing is a co-author).

In the meantime, regarding the questions of whether semaglutide works better in terms of kidney protection than other medicines or in combination, “we will probably never know,” Giaccari speculated.

“But the presence of CKD is not the main or the most common reason to prescribe semaglutide,” he added. “It is just a statistically significant and scientifically proven further reason to use it.”

The study was funded by Novo Nordisk. Rossing reported consulting and/or research relationships with Abbott, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Gilead, Novo Nordisk, and Sanofi. Giaccari is on the official guidelines board for type 2 diabetes therapy in Italy and reported receiving speaker’s fees from AstraZeneca, Lilly, Novo, and Sanofi and participating in Novo Italy Advisory Boards.