There are a number of fundamental physiological differences between females and males. In terms of body composition, women generally have a higher body fat percentage than men [25]. This affects the volume of distribution (Vd) of lipophilic drugs, defined as the total amount of drug in the body/blood plasma concentration of drug. Lipophilic drugs tend to have a greater Vd in women, potentially leading to prolonged action and altered pharmacokinetics (PKs). Moreover, men typically have a higher lean body mass compared to women. Lean body mass is a crucial determinant of the Vd of hydrophilic drugs. Drugs that are hydrophilic will have a higher Vd in men, affecting the drug concentrations in the plasma and tissue. In addition, men have a higher total body water percentage than women, which can influence the PK of hydrophilic drugs as they tend to have a larger Vd in individuals with higher body water content [25].

Differences in drug metabolism also lead to differences in PKs and pharmacodynamics (PDs). There are sex-specific differences in the activities of liver enzymes responsible for drug metabolism. For example, cytochrome P450 (CYP) enzymes exhibit sex-dependent variation. Women generally have lower activity of CYP1A2 and higher activity of CYP3A4 compared to men, impacting the metabolism of drugs processed by these enzymes [26]. Differences in renal clearance and gastrointestinal enzyme activity also influence drug absorption and excretion. Finally, hormonal fluctuations, particularly in women, can significantly impact drug metabolism. Estrogen and progesterone levels, which vary with the menstrual cycle, pregnancy, and menopause, can alter enzyme activity and drug metabolism pathways [27].

Understanding these sex-specific differences is very important for the effective treatment of HF. For example, dosing regimens for drugs such as beta-blockers, ACE inhibitors, and diuretics may require adjustment based on the sex of the patient to optimize therapeutic outcomes and minimize adverse effects. Precision medicine approaches taking these physiological differences into consideration will lead to more personalized and effective management of HF.

The “four pillar-therapy” is well established in HFrEF, and titrating these therapies within 4 weeks is related to better prognosis [4,28]. However, an examination of the baseline characteristics of landmark HFrEF studies starting from the 1990s revealed notable sex-related disparities (Fig. 3). The proportion of male participants was 70–80%, with female participants accounting for only 20–30% of patients, with a significant portion having an ischemic etiology. Although subgroup analyses in all studies have shown significant therapeutic effects in women, allowing guidelines to be applied regardless of sex, it is essential to take these sex disparities into consideration when treating individual patients. Accounting for the PK and PD of each medication based on sex is crucial to maximize patient safety and treatment efficacy. Therefore, it is important to take the sex-specific effects of each medication and their PK/PD characteristics into consideration in individual cases.

Captopril is better absorbed in female patients when administered on an empty stomach. In addition, adverse drug reactions, including cough, taste disturbance, skin rash, increased serum levels of creatinine, and gastrointestinal upset, are more frequently observed in females than in males [29].

The original analyses of angiotensin-converting enzyme inhibitors (ACEI) in HF studies that began in the 1980s did not include sex differences. Subsequent subgroup analyses showed statistically significant differences in overall mortality and hospitalization for HF in men but not in women [30]. In a meta-analysis, the pooled random effects estimates for mortality from the six studies (CONSENSUS, SAVE, SMILE, SOLVED-Prevention, SOLVD-Treatment, and TRACE) with RR data yielded values of 0.82 (95% confidence interval [CI] 0.74–0.90) for men and 0.92 (95% CI 0.81–1.04) for women [31]. That study did not find evidence that women with asymptomatic LV dysfunction may not have reduced mortality when treated with ACEI [31].

There were no SRDs in the PKs of candesartan, irbesartan, or valsartan after normalization of the dose for body weight. Angiotensin II receptor blockers (ARBs) have better efficacy and adherence profiles than ACEIs in women with HFrEF but not in men [32]. Female patients may have lower risks of death and hospitalization for HF at half the guideline-recommended doses compared to males [33].

There were no SRDs in the PK of angiotensin receptor-neprilysin inhibitors (ARNIs) [34]. The PARADIGM-HF trial showed superiority of ARNI compared to enalapril in reducing the primary end points, mortality, and hospitalization for HF [35]. In subgroup analyses, similar prognostic benefit was found for the primary end point in both men and women. However, with regard to cardiovascular death, ARNI showed a significant benefit in men but not in women.

The large-scale HFpEF trial PARAGON-HF showed significant benefits of ARNIs in women on subgroup analysis (women 0.73 [95% CI 0.59–0.90] vs. men 1.03 [0.84–1.25 p = 0.017], although it failed to meet the primary end point of composite first and recurrent hospitalization for HF and death from cardiovascular causes in the total population. Women comprised 52% of the study population in PARAGON-HF, and were older, had higher rates of obesity, reduced frequency of coronary artery disease, higher baseline LVEF, worse symptoms of HF, lower estimated glomerular filtration rate (eGFR), and lower NT-proBNP levels compared to men. Overall, women had higher rates of hospitalization for HF and lower rates of cardiovascular death compared to men [36]. The authors suggested that women may have a more favorable response to neprilysin inhibition than men because the normal LVEF range is higher in women than in men, reflecting sex-related differences in cardiac remodeling in response to factors including blood pressure and age, and there are also known sex differences in NP biology where any reduction in cGMP-protein kinase G signaling attributable to a relative NP deficiency may be exacerbated in post-menopausal women by loss of alternative estrogen-dependent stimulation of this pathway through eNOS activation and nitric oxide generation. Consequently, by augmenting NPs, sacubitril-valsartan may be of greater benefit in women than in men, if women have deficient cGMP–protein kinase G signaling [36].

In terms of adverse events, the differences between sacubitril-valsartan and valsartan were similar in women and men. There were too few cases of angioedema for meaningful subgroup analysis according to sex [36].

Beta blockers (BBs) are among the oldest drugs included in the four pillars of HF therapy following ACEIs/ARBs and their effects have been examined in many clinical studies. However, the proportions of women included in these clinical studies were about 20–30% (Fig. 3A).

At present, there are no sex-specific dosage guidelines for administration of BBs. However, among the drugs included in the four pillars, caution is required for BBs because systemic exposure is greater in women than in men at the same dosage. Women were reported to show higher plasma levels of metoprolol and propranolol due to slower Cl and lower Vd (hydrophilic drugs), resulting in a greater reduction in exercise heart rate and systolic blood pressure than in men [37]. Moreover, hormones such as estrogens and progesterone can inhibit the cardiac expression of β₁-adrenoceptors, thereby reducing β-adrenergic-mediated stimulation [37]. In addition, women typically have greater nerve activity, higher cardiac noradrenaline spillover, and increased β₂-adrenoreceptor sensitivity [38].

The clinical impact of the PK/PD differences in BB depending on sex was examined in the BIOSTAT-CHF study. The lowest rates of death or hospitalization for HFrEF were observed at 100% of the target BB dose in male patients, while female participants showed approximately 30% lower risk at only 50% of the target dose [33]. However, analyses of pooled data from the CIBIS-II, MERIT-HF, and COPERNICUS trials showed that the overall mortality benefit was similar regardless of sex [39].

The two well-established drugs spironolactone and eplerenone and the new drug finerenone are all mineralocorticoid receptor antagonists (MRAs) that block the final stage of the rennin–angiotensin–aldosterone system (RAAS). No sex-related differences in the PKs of MRAs have been reported [40]. The Randomized Aldactone Evaluation Study (RALES) and the Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) trial showed marked reductions in the primary end point [41,42]. However, treatment with spironolactone did not show a reduction in the incidence of the time-to-first composite of cardiovascular death, aborted cardiac arrest, or hospitalization for HF in patients with LVEF ≥ 45% in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial. There were no sex-related differences in clinical outcomes in these trials.

Finerenone is a nonsteroidal MRA used for the treatment of HF, which is characterized by its high selectivity for mineralocorticoid receptors (MRs) and reduced risk of hyperkalemia [43]. In 2021, the Food and Drug Administration (FDA) granted approval for the use of finerenone for the treatment of adult patients with chronic kidney disease (stages 3 and 4) associated with type 2 diabetes, based on the results of large phase III clinical trials, such as FIDE-LIO-DKD, FIGARO-DKD, and FIDELITY [44,45]. In a post hoc analysis of cardiovascular and kidney outcomes by age and sex, finerenone was shown to improve cardiovascular and kidney composite outcomes with no significant differences between subgroups according to sex, although the rate of hospitalization for HF was higher in males [46]. The results of the FINEARTS-HF trial were announced at the European Cardiology Society Congress 2024 and published concurrently in The New England Journal of Medicine (NEJM) [47]. Patients with symptomatic HF and LVEF ≥ 40% were randomized in a 1:1 manner to receive finerenone at a maximum dose of 40 mg daily (20 mg if eGFR < 60 mL/min/1.73 m², n = 3,003) or placebo (n = 2,998, female 45%). The primary outcome, a composite of worsening HF events (first or recurrent unplanned hospitalization for HF or urgent visit) and cardiovascular death, for finerenone vs. placebo was 14.9 vs. 17.7 events per 100 patient-years, respectively. Subgroup analysis showed a significant decrease in the primary end point in females vs. males. However, the authors commented that the confidence intervals in subgroup analysis were not adjusted for multiplicity [47]. Therefore, further studies of the sex differences in the effects of the new MRA finerenone are warranted.

Sodium glucose transporter inhibitors (SGLT2i) have been included in the current HF guidelines because they show marked hospitalization for HF and cardiovascular mortality risk reduction despite being used in addition to the previously mentioned essential HF medications.

These medications are effective across all categories of HF, regardless of LVEF, and exhibit clinical advantages in both men and women [48–51]. However, a recent meta-analysis of pooled data from four major randomized controlled trials on SGTIs suggested higher rates of primary composite outcomes in women compared to men [52]. There is evidence of sex differences in terms of side effects. The incidences of mycotic infections of the urinary and genital tract were higher in women, while acute renal failure and limb ischemia were more frequent in male patients receiving SGTIs [40].

The soluble guanylyl cyclase stimulator (sGC) vericiguat is included in “quintuple therapy” and is expected to play a role in the treatment of WHF. The sex of patients was not a significant covariate in population PK analysis of patients with HFrEF. Rather, lower body weight seemed to be associated with an increase in drug exposure [53]. The only large-scale randomized controlled trial performed to date, VICTORIA, showed no significant sex-related differences in the efficacy or safety profile of vericiguat in patients with LVEF < 45% [54]. Recently reported real-world data from Germany showed that women started on vericiguat were older than men (76 ± 13 yr vs. 72 ± 12 yr, respectively). There were no sex- or age-specific differences in the starting dose of vericiguat or uptitration time. However, women reached the maximum dose of 10 mg less often compared to men (34% vs. 37%, respectively). The discontinuation rate tended to be higher in women than in men, but the confidence intervals overlapped and the difference diminished toward the end of the observation period. Nevertheless, the median time until discontinuation was shorter in women than in men (29 days vs. 42 days, respectively) [55]. These results suggest that women had poor adherence to the drug due to side effects or other reasons.

The sex-related differences in principal HF drugs are summarized in Table 1.

Digoxin is no longer a principal drug used to treat HF and the continuously decreasing prescription rate reached 10% in the mid-2010s [56]. Sex-specific analysis was not performed in the pivotal trials of digoxin (DIG, PROVED, RADIANCE) in patients with HFrEF. Therefore, data on sex-related differences in the use and effects of digoxin are mainly based on post hoc analyses. The trials of digoxin were underpowered to test for the interaction of sex, and there has been debate on selection bias, such as the higher rate of prescription in older adult women with more comorbidities [57]. A retrospective analysis of the DIG trial including 4,944 women demonstrated significant linear relations between serum drug concentration and all-cause mortality in women and men [58]. At low serum concentrations of drug (0.5–0.9 ng/mL) a reduction in all-cause mortality was observed in men but not in women compared to placebo. The combined end point of all-cause mortality or first hospital stay due to worsening HF, or first hospital stay due to worsening HF alone, and hospital stay for worsening HF was significantly reduced in both sexes. Therefore, the currently recommended serum concentration of digoxin is 0.5–0.9 ng/mL in general [59]. However, caution is needed considering the reduced Vd and lower clearance in women, so slightly lower plasma levels are recommended in women than in men (< 0.8 ng/mL) [60].

An implantable cardioverter-defibrillator is recommended as primary prevention in patients with LVEF < 35% despite guideline-directed medical therapy and secondary prevention in various situations [4]. Implantable cardioverter-defibrillator implantation rates for primary prevention of sudden cardiac death are lower in women.

On the other hand, cardiac resynchronization therapy (CRT) is recommended for symptomatic patients with HF in sinus rhythm with QRS duration ≥ 150 ms and left bundle branch block (LBBB) QRS morphology and LVEF ≤ 35% despite optimal medical therapy to improve symptoms and reduce morbidity and mortality rates. Female patients generally have LBBB with nonischemic etiology and dyssynchrony at higher rates and have better responses to CRT than male patients. Smaller body size and cardiac dimensions have been suggested as possible reasons for the sex-related disparities in response to CRT [61].

The most common forms of cardiogenic shock (CS) are acute myocardial infarction (AMI)-CS and HF-CS [62]. A recent report presented the results of a Cardiogenic Shock Working Group (CSWG) analysis of 5,083 patients with AMI-CS and HF-CS (30% women, n = 1,522; 70% men, n = 3,560) [63]. More women presented with de novo HF-CS compared to men (26.2% vs. 19.3%, respectively; p < 0.001). Women with HF-CS had decreased survival at discharge (69.9% vs. 74.4%; p = 0.009) and greater severity of CS compared to men. Women with HF-CS were less likely to receive HT or OHT (6.5% vs. 10.3%; p < 0.001) or left ventricular assist device (LVAD) implantation (7.8% vs. 10%; p = 0.01). Regardless of CS etiology, women had higher rates of vascular complications (8.8% vs. 5.7%; p < 0.001), bleeding (7.1% vs. 5.2%; p = 0.01), and limb ischemia (6.8% vs. 4.5%; p = 0.001) than men [63]. These results were similar to previous studies indicating that women are more likely to die, are less likely to be referred to tertiary care shock centers, have lower rates of early revascularization, and have higher adjusted in-hospital mortality rates compared to men in AMI-CS [64–66]. Anatomical differences, such as small vessel sizes, could influence the incidence of limb ischemia, as women have smaller iliofemoral arteries than men, even when matched for body mass index and peripheral artery disease. Therefore, securing vascular access should always be kept in mind in preparation for emergency temporary mechanical circulatory support (MCS) when managing female patients with CS.

Socioeconomic factors are thought to result in differences in the rates of MCS, HTx, and LVAD implantation. Analysis of AMI-CS and ADHF data using National Inpatient Sample (NIS) showed that women were more likely to be older, non-Caucasian, insured by Medicare, and to have a higher burden of comorbidities, including hypertension and cerebrovascular disease, than men [67]. Women were less likely to receive a peripheral ventricular assist device or pulmonary arterial catheter. Consistent with previous studies, women requiring peripheral MCS had a higher in-hospital mortality rate than men.

There are still no Korean data on sex differences in incidence and management of CS, and further research is warranted.