QUEBEC CITY — The Canadian Cardiovascular Society (CCS) has updated its guidelines on the management of heart failure (HF) with nonreduced ejection fraction (HFnrEF), highlighting the role that SGLT2 inhibitors and mineralocorticoid receptor antagonists play in this condition. The guidelines note that angiotensin receptor-neprilysin inhibitors and GLP-1 receptor agonists also have potential roles. Highlights of the new guidelines were presented at the Canadian Cardiovascular Congress (CCC) 2025. 

Sean Virani, MD, lead author of the new guidelines and president of the CCS, explained that the guidelines use the term “HFnrEF” to encompass HF with preserved ejection fraction (EF) and HF with mildly reduced EF, since both groups of patients respond similarly to treatment. “Part of the barrier to prescribing is confusion around nomenclature,” he told Medscape Medical News. “We wanted to make it as simple as possible for prescribers and patients to understand that there are largely two categories of patients in the HF space: those with reduced and those with nonreduced EF.”

SGLT2 Inhibitors

The document strongly recommends using SGLT2 inhibitors for patients with HFnrEF and left ventricular EF (LVEF) > 40% to reduce the risk for HF-related hospitalization. Data on SGLT2 inhibitors were presented by Natasha Aleksova, MD, a physician at Toronto General Hospital, Toronto. “SGLT2 inhibition decreases intravascular volume and blood pressure by reducing preload after afterload through osmotic diuresis and natriuresis,” she said. “It reverses remodeling, it is anti-inflammatory and antifibrotic, it reduces oxidative stress, and it improves endothelial function.”

The SGLT2 inhibitor-related recommendation was based on a meta-analysis of seven clinical trials that revealed that these medications resulted in about 11 fewer HF-related hospitalizations per 1000 patients. Compared with the standard of care, the addition of SGLT2 inhibitors also improved functional status without increasing the risk for adverse events.

Mineralocorticoid Receptor Antagonists

The guideline also strongly recommended the use of mineralocorticoid receptor antagonists (MRAs) for patients with HFnrEF and LVEF > 40% to reduce the risk for HF-related hospitalization. Kim Anderson, MD, assistant professor of cardiology at Dalhousie University in Halifax, observed that MRAs improve diastolic function. By blocking the binding of aldosterone to mineralocorticoid receptors, these drugs can interrupt endothelial dysfunction, myocardial fibrosis, and pathologic cardiac remodeling, she explained.

The recommendation was based on a meta-analysis of nine clinical trials that revealed a benefit of MRA for the prevention of HF-related hospitalization (hazard ratio [HR], 0.83), with no increase in withdrawal rate due to adverse events and an absence of increased mortality. Notably, the use of MRAs did not improve cardiovascular mortality. A lack of head-to-head clinical trials precluded any recommendation of steroidal over nonsteroidal MRAs. Anderson highlighted the importance of monitoring renal function and potassium levels in patients taking MRAs and of measuring serum creatinine and potassium within a week of initiation or dose change.

“Particularly in Canada, where we have barriers to access in terms of assessment of LV [Left venticular] function, people have oftentimes been delayed in treatment initiation because [they] don’t know what the EF is,” said Virani. The data now indicate that patients should be receiving SGLT2 inhibitors and MRAs regardless of their EF, he added. “It should give clinicians an opportunity to start disease-modifying therapy right up front while you’re waiting for those tests to come back.”

Angiotensin Receptor-Neprilysin Inhibitors

In a weak recommendation, the guideline suggested the use of an angiotensin receptor-neprilysin inhibitor (ARNI) in patients with symptomatic HFnrEF and LVEF > 40% who are at low risk for symptomatic hypotension to reduce the risk for HF-related hospitalization. Stephanie Poon, MD, associate professor of cardiology at Sunnybrook Health Sciences Centre in Toronto, pointed out that ARNIs have beneficial effects on cardiac remodeling and enhance cardiomyocyte survival.

“Clinical trials have shown that sacubitril-valsartan is more effective than enalapril at decreasing cardiovascular death, HF, hospitalizations, and symptom burden in patients with HF with preserved EF,” she said, “but as soon as we expand into the nonreduced EF range, there isn’t one large clinical trial that encompasses the entire LVEF spectrum greater than 40%. Much of the evidence that we have is from subgroup and post hoc analyses.”

In a meta-analysis of four clinical trials, ARNIs were associated with a small reduction in the risk for HF-related hospitalization compared with standard care (HR, 0.89). In subgroup analyses, better outcomes were observed in women, and efficacy was seen across all levels of LVEF, but the treatment effect was attenuated with increasing EF. Poon suggested using ARNIs with caution in patients with a systolic blood pressure < 100 mm Hg and exercising caution when using them in combination with other drugs that lower blood pressure. Renal function and electrolytes should be monitored in patients taking this class of drugs, she said.

GLP-1 Receptor Agonists

Another weak recommendation is the suggested use of evidence-based drugs with GLP-1 receptor agonist activity and with proven efficacy in patients with symptomatic HF, LVEF ≥ 45%, and BMI ≥ 30 to reduce the risk for HF-related hospitalization and improve quality of life. Michael McDonald, MD, professor of cardiology at the University of Toronto, noted a phenotypic relationship with overweight and obesity. “About 80% of patients with HFnrEF are obese, and about a third of our patients have diabetes. There are lots of pathophysiologic mechanisms and proposed mechanisms about why that is,” he said. GLP-1 receptor agonists have been associated with weight reduction and reduced risk for cardiovascular deaths, nonfatal myocardial infarction, and stroke in patients with obesity with or without diabetes.

In a meta-analysis (which did not include the SUMMIT data, because the results were not available at the time of the analysis), semaglutide was associated with 52 fewer HF-related hospitalizations per 1000 patients with HF and an LVEF ≥ 45% than standard care. It was not associated with a significant effect on overall or cardiovascular mortality.

Discussing the pros and cons of GLP-1 receptor agonists among patients who have obesity and HFnrEF is recommended, said McDonald. Patients taking these drugs may lose up to 10% of their muscle mass. Slow titration is important for optimizing tolerability.

Virani reported serving as the medical director of the HeartLife Foundation. Anderson reported receiving support from Alnylam, Abbott, Bayer, Bristol Myers Squibb, Pfizer, and Takeda. Poon reported receiving support from Abbott, Bayer, Boehringer Ingelheim, CSI, GSK, Novo Nordisk, and Servier. McDonald reported receiving support from Boehringer Ingelheim-Lilly, Novartis, and Abbott.