Oral semaglutide led to significant reductions in the risk for heart failure and major adverse cardiac events (MACEs) among patients with type 2 diabetes (T2D) with a history of heart failure, a secondary analysis of the SOUL trial showed.

People with T2D have a high prevalence of heart failure, particularly heart failure with preserved ejection fraction, and these data demonstrate “consistent effects of semaglutide on CV [cardiovascular] and heart failure outcomes independent of its formulation,” said first author Rodica Pop-Busui, MD, PhD, professor of medicine, Division Head of Endocrinology, Diabetes and Clinical Nutrition, and Director of the Harold Schnitzer Diabetes Health Center at Oregon Health & Science University, in Portland, Oregon.

This provides “additional information for clinicians when considering therapy choices and impact on heart failure outcomes in people with or without known heart failure,” she added.

As reported by Medscape Medical News, the phase 3b, double-blind SOUL trial, evaluating outcomes with oral semaglutide, showed benefits that are similar to those observed with injectable semaglutide, including a reduced risk for MACEs (a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) compared with placebo in patients with T2D, atherosclerotic cardiovascular disease (ASCVD) and/or chronic kidney disease (CKD).

However, the effect of the oral formulation on heart failure outcomes in people with a history of heart failure had not been established.

To investigate, the authors conducted a secondary analysis of the SOUL trial, which involved 9650 patients with T2D, ASCVD and/or CKD, enrolled at 444 centers in 33 countries between June 2019 and March 2021.

Participants were randomized to oral semaglutide, 3 mg, or a matched placebo once daily for 4 weeks, followed by 7 mg once daily for 4 weeks, and then to 14 mg once daily, in addition to the standard of care until the end of the trial.

The patients had a median age of 66 years, and 28.9% were women. Among them, 2229 (23.1%) had a history of heart failure, including 991 (10.3%) with preserved ejection fraction, 592 (6.1%) with reduced ejection fraction, and 646 (6.7%) with an unknown subtype.

Of these patients, 1105 were randomized to the oral semaglutide group and 1124 to the placebo group. The mean follow-up was 47.5 months.

Baseline characteristics between the treatment arms were well balanced, with those who had a history of heart failure having higher BMI, A1c, and diastolic blood pressure.

Those with heart failure at baseline receiving oral semaglutide had a lower risk for the composite heart failure outcome — consisting of time to first occurrence of heart failure, hospitalization, urgent heart failure visit, or CV death — than those receiving placebo (hazard ratio [HR], 0.78); in those without heart failure at baseline, the HR was 1.01 (P for interaction = .06).

Among those with heart failure with preserved ejection fraction, composite heart failure outcome events occurred in 8.1% of those receiving oral semaglutide vs 13.5% in the placebo group (HR, 0.59), however differences were not significant with reduced ejection fraction (23.0% and 22.6%, respectively; HR, 0.98).

There were no significant differences between those with and without heart failure at baseline in terms of risk reduction in MACEs with oral semaglutide (HR, 0.83 and HR, 0.86, respectively; P for interaction = .77).

“It is quite reassuring to see that oral semaglutide had similar benefits on cardiovascular outcomes as observed with the subcutaneous formulation, as some have raised some concerns regarding potential absorption or compliance issues with a daily oral intake,” said Pop-Busui.

In Combination With SGLT2 Inhibitors

Of note, the heart failure benefits were observed regardless of whether patients were receiving concomitant SGLT2 inhibitors, loop diuretics or mineralocorticoid receptor antagonists at baseline.

In addition, “the concomitant use of oral semaglutide and SGLT2 inhibitors was safe in this patient population,” Pop-Busui said.

The findings are notable as the use of SGLT2 inhibitors among patients with T2D can be considered to represent “a potential proxy for more severe CV disease, as clinical guidelines prioritize these and similar agents for individuals with established ASCVD, heart failure, and CKD,” the authors explained.

This highlights “the potential benefit for adding oral semaglutide to these therapies in people with T2D, atherosclerotic cardiovascular disease and/or CKD, and heart failure,” said Pop-Busui.

Notably, with 27% of patients in the study treated with SGLT2 inhibitors, the study “had the highest proportion of participants with SGLT2 inhibitor use compared with all prior GLP1-RA trials,” she added.

The rates of serious adverse events were similar between those with heart failure (53.8%) and placebo (57.1%). Among those with preserved ejection fraction, the incidence of serious adverse events was numerically lower in those randomized to oral semaglutide than in those to placebo (227 [46%] vs 261 [52.5%]).

“The safety of oral semaglutide in people with heart failure, including those with preserved ejection fraction, is clinically relevant, reassuring clinicians who provide daily care for such patients, who are often treated with multiple pharmaceutical therapies,” the study authors noted.

Results Boost Oral Semaglutide’s Cardiometabolic Role

In a recent systematic review, Thiago Gorayeb Rebelo, of the University of Ottawa, Ottawa, Ontario, Canada, and colleagues also showed consistent reductions in overall CV with oral semaglutide, “however, heart failure outcomes were not well characterized across early trials,” he told Medscape Medical News.

“The SOUL secondary analysis therefore provides valuable evidence suggesting that oral semaglutide may also reduce heart failure-related events, particularly among patients with established heart failure,” he said. “These findings strengthen the overall cardiometabolic role of oral semaglutide.”

Key notable results include the benefits across heart failure subtypes, particularly the stronger signal in individuals with preserved ejection fraction, Rebelo said.

“Therapeutic options for heart failure with preserved ejection fraction remain limited, so this signal is clinically important,” he explained.

“Additionally, the benefit appears more pronounced among patients with established heart failure rather than those without baseline disease,” he noted. “This aligns with broader CV outcomes suggesting that GLP-1 RAs may provide benefit in higher risk populations, although this remains an area that needs further investigation.”

Initial concerns surrounding the oral semaglutide formulation included whether cardiovascular benefits seen with the injectable formulation would carry over, Rebelo added.

“Because oral semaglutide relies on gastrointestinal absorption using a carrier molecule, there were questions regarding the pharmacokinetic variability and whether systemic exposure would be sufficient to reproduce the cardio benefits seen with injectable semaglutide,” he said.

“However, evidence has been very reassuring. Both the PIONEER clinical program and the pooled evidence from our meta-analysis demonstrated consistent reductions in composite cardiovascular outcomes with oral semaglutide,” Rebelo said.

“The SOUL trial further reinforces that the cardioprotective effects of semaglutide appear to be preserved regardless of the route of administration.”

The SOUL trial was funded by Novo Nordisk A/S. Pop-Busui reported receiving personal fees from Novo Nordisk during the conduct of the study, as well as grants from the National Institute of Diabetes and Digestive and Kidney Diseases, Breakthrough T1D, Bayer, and Novo Nordisk, and personal fees from Lexicon, Roche Diagnostic, and Vertex outside the submitted work. Rebelo had no disclosures to report.