The main findings of the study is summarized in Fig. 1.
Clinical and echocardiographic features by DM
Among 4,180 patients with HF (mean 70.7 years), 1,431 (34.2%) had DM, with more prevalence in men than women (792 [35.7%] versus 639 [32.6%], p=0.036) (Additional file 1: Table S1). Baseline characteristics according to sex and DM are summarized in Table 1. In both men and women, diabetic patients had higher body mass index, and more prevalent hypertension and IHD compared to non-diabetic patients (Table 1). DM was also significantly associated with anemia, lower sodium level, and impaired renal function in both sex. Regarding the echocardiographic parameters, women had higher LV ejection fraction (LV-EF) and LV-GLS, smaller LV dimensions, and more frequent concentric LV hypertrophy (LVH) than men (Additional file 1: Table S1). When comparing echocardiography parameters according to sex and DM, diabetic men and women had higher E/e’ ratio and more concentric LVH compared to non-diabetic counterparts (Table 1).
Sex difference in the association of DM with clinical and echocardiographic features
DM severity assessed by HbA1c and presentation glucose levels was similar between men and women (Additional file 1: Table S1); however, clinical and echocardiographic features significantly differed when stratified by sex and DM. Compared to diabetic men, diabetic women were older and had lower values of hemoglobin and glomerular filtration rate, whereas diabetic men more often had IHD with elevated troponin I level (Table 1). DM was associated with more frequent LVH in women, but the difference was not identified among men. Diabetic women had the highest proportion of concentric LVH among the four groups (44.3% of LVH), as well as the highest E/e’ ratio (18.8 [IQR, 14.5-25.9]). Of note, diabetic women had significantly lower LV-EF than non-diabetic women (42.1% [IQR, 30.0%-57.0%] vs. 45.0% [IQR, 32.0%-58.0%], p=0.003), whereas no significant difference was observed between diabetic and non-diabetic men (34.0% [IQR, 25.0%-48.4%] vs. 34.7% [IQR, 25.0%-49.0%], p=0.554). In both sex, however, LV-GLS was significantly lower in diabetic patients than non-diabetics, with a more prominent difference in women (10.1% [IQR, 7.0%-14.1%] vs. 11.3% [IQR, 8.1%-15.4%], p<0.001 for women; 9.2% [IQR, 6.3%-12.6%] vs. 9.7% [IQR, 6.5%-13.8%], p=0.014 for men).
Mortality risk according to sex and DM
During a median of 31.7 months (IQR, 11.6–54.3 months), 1,765 deaths occurred. 5-year mortality according to sex and DM is shown (Fig. 2). Among the four groups, non-diabetic women had the lowest mortality during the early follow-up period, which was non-significantly lower than that of non-diabetic men. The difference in mortality rates between non-diabetic women and non-diabetic men gradually decreased and became similar at a longer follow-up of 5 years (37.0% versus 37.5%, p=0.773). The mortality rates between diabetic women and diabetic men were consistently similar throughout the entire follow-up.
Cox analysis showed that DM was significantly associated with increased unadjusted and adjusted risks of death in both sex (Table 2). The magnitude of HRs for mortality between DM and non-DM was greater in women than men, although not significant (adjusted HR=1.35 [95% CI: 1.15-1.59] versus 1.24 [1.07-1.44], p for interaction=0.669) (Table 2).
Sex-specific associations of presentation glucose level with mortality
The RCS curves showed the associations of presentation blood glucose level with 5-year mortality risk according to sex (Fig. 3A). Data on presentation glucose level was available in 4,125 (98.7%), consisting of 2,183 men and 1,942 women, and all these patients were included in the RCS analysis irrespective of DM status. The patterns of RCS curves differed by sex. At 5-year follow-up, the risk of mortality continually increased as glucose level rise in women, while the linear increase pattern was less pronounced in men, particularly if glucose level exceeds 200 mg/dL (Fig. 3A). Density plots showed that the distribution of patients according to glucose level was similar between sex.
Sex-specific associations of presentation glucose level with LV-GLS
The associations between presentation glucose level and LV-GLS in men and women are shown as the RCS curves with scatter plots (Fig. 3B). Overall, the gradual decrease in LV-GLS was observed with an increase in the glucose level, approximately until 200 mg/dL in both sex (Fig. 3B). When the glucose level exceeded 200 mg/dL, LV-GLS further declined approximately from 12% to 10% in a dose-dependent manner in women. In men, however, LV-GLS decreased to around 10% at the glucose level of 200 mg/dL and reached a plateau thereafter, resulting in the gradual convergence of the two curves (Fig. 3B).
Sex differences in regression paths between DM and mortality
The SEM diagrams with standardized path coefficients are presented for each sex in Fig. 4. This model included a direct path from DM to mortality, with two indirect paths from DM to mortality via IHD and LV-GLS as intermediate mediators, and it had an adequate statistical fit (Additional file 1: Table S2). The direct path from DM to mortality was significant in both men and women. Regarding the indirect paths, the path from DM to LV-GLS was significant in both sex, with a larger coefficient for women (coefficient=-0.10, p<0.001) than men (coefficient=-0.06, p=0.004). The path from DM to IHD was also significant in both sex, and the magnitude of coefficients was similar between men and women. Notably, the path from IHD to mortality was significant in men (coefficient=0.07, p=0.001), but not in women (coefficient=-0.003, p=0.890), while the path from LV-GLS to mortality was significant in both sex. Similar findings were observed in the sensitivity analysis using the presentation blood glucose level instead of DM (Additional file 1: Figure S1).
Table 3 summarizes the standardized coefficients of direct and indirect effects. In men, the indirect effect mediated through IHD was greater (DM–IHD–mortality path: coefficient=0.015, p=0.001) than that mediated through LV-GLS (DM–LV-GLS–mortality path: coefficient=0.008, p=0.009). In women, however, the indirect effect via IHD was markedly smaller than that in men, and not significant (DM–IHD–mortality path: coefficient=-0.001, p=0.890). The indirect effect mediated through LV-GLS was significant and more pronounced in women (DM–LV-GLS–mortality path: coefficient=0.015, p<0.001) compared to men.