Awareness of sex-specific differences in heart failure ‘critical’ for diagnosis, treatment

Key takeaways:

• One in four women will develop heart failure with a higher prevalence of preserved vs. reduced ejection fraction.
• Women present differently with heart failure and respond differently to certain treatments.

Women with heart failure with preserved ejection fraction have sex-specific differences in presentation, diagnosis and treatment responses, highlighting the importance of proper diagnoses and guideline-directed medical therapy initiation.

“Heart failure with preserved ejection fraction (HFpEF) is underdiagnosed, particularly in women. We don’t listen to women’s symptoms or take them as seriously and it can be challenging,” Erin D. Michos, MD, MHS, FAHA, FACC, FASE, FASPC, professor of medicine and director of Women’s Cardiovascular Health at Johns Hopkins School of Medicine, said during a presentation at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease.

Sex-specific differences in presentation, diagnosis

HFpEF incidence is rising relative to heart failure with reduced ejection fraction, Michos said, but HFpEF prevalence is higher among women. About 24% of women will develop heart failure with a higher prevalence of preserved ejection vs. reduced ejection fraction, according to Michos, whereas men have similar risk for heart failure with preserved or reduced ejection fraction. In addition, Michos noted, women have a steeper increase in HFpEF prevalence as they age compared with men.

Both obesity and diabetes have greater population attributable risk for HFpEF for women vs. men, Michos said. Approximately two-thirds of the population attributable risk is tied to hypertension and obesity while one-fourth is tied to diabetes and coronary heart disease.

In addition to traditional risk factors, preeclampsia and infertility are female-specific risk factors for incident HFpEF, Michos said.

In a pooled analysis published in Circulation: Heart Failure, researchers observed a higher likelihood of being older, having hypertension and obesity, having poorer quality of life and more evidence of congestion for women compared with men.

“[Women also] have sex-specific echo findings, more concentric remodeling and more impaired diastolic dysfunction,” Michos said. “When we talk about these measures for diastolic dysfunction, we don’t have sex-specific thresholds and maybe we should.”

Sex-specific treatment responses

Current treatments for HFpEF for women include angiotensin receptor-neprilysin inhibitors, mineralocorticoid receptor antagonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors and GLP-1 receptor agonists.

Results of the PARAGON-HF trial, published in Circulation, demonstrated that women treated with the angiotensin receptor-neprilysin inhibitor sacubitril/valsartan (Entresto, Novartis) had lower risk for heart failure hospitalization vs. men with similar adverse events.

For mineralocorticoid receptor antagonists, an analysis from TOPCAT found that women with HFpEF treated with spironolactone had lower all-cause mortality vs. men. In addition, in FINEARTS-HF, finerenone (Kerendia, Bayer) resulted in reduced worsening heart failure events similarly for both men and women with additional similar tolerability and quality of life improvements.

SGLT2 inhibitors were the first therapy to conclusively show benefit for people with HFpEF. The EMPEROR-Preserved study demonstrated that women treated with empagliflozin (Jardiance, Boehringer Ingelheim/Eli Lilly) had the lowest incident of heart failure events, but there was no sex interaction. Both men and women benefited equally from empagliflozin treatment with similar quality of life and psychologic variable improvements. Similar results were observed with treatment with dapagliflozin (Farxiga, AstraZeneca) in the DELIVER trial. A pooled analysis of all SGLT2 inhibitor data also showed that women benefited similarly across cardiometabolic indications, suggesting that this treatment should be considered for those at high CV risk, irrespective of sex.

“In women with HFpEF, obesity is more prevalent compared with men,” Michos said. “Individuals with the obesity phenotype have increased plasma volume, increased stress volume, more concentric remodeling, a higher prevalence of hypertension, more right ventricle dysfunction, more epicardial fat thickness and they are more diuretic resistant. With this obesity phenotype of HFpEF, they have more symptoms and poor quality of life, and we think obesity is playing a direct pathological role in the genesis and progression of HFpEF.”

In the STEP-HFpEF trials of semaglutide (Wegovy, Novo Nordisk), researchers observed a higher body weight reduction among women vs. men (mean difference, 9.6% vs. 7.2%; P = .006), but similar improvements in quality of life scores, suggesting that semaglutide may have a weight-independent effect on disease. These results were supported by a pooled analysis of SELECT, FLOW and STEP-HFpEF trials in which semaglutide reduced CV death or heart failure events by 31% overall with no sex interactions. Treatment with tirzepatide (Zepbound, Eli Lilly) in the SUMMIT trial also resulted in similar results with a 38% reduction in CV death or worsening heart failure with no sex interaction, Michos said.

“It’s critical and important to diagnose HFpEF and initiate guideline-directed medical therapy equitably across both sexes,” Michos said. “A lot of HFpEF is underdiagnosed, and with all these therapies we have now to help HFpEF, we really need to be diagnosing HFpEF better.”

References:

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