Discussion
We found that the risk of hospitalization for HF was significantly higher in women than in men in our cohort of patients with type 2 diabetes and CAD. This result is consistent with that of a report by the Framingham Heart Study,9 which showed that the incidence of HF was significantly higher in women than in men aged >55 years among patients with diabetes and prior coronary or rheumatic heart disease. A more recent hospital-based cohort study in Italy, which included patients with diabetes without CAD, showed that women with diabetes of perimenopausal age had a higher risk of HF than men; however, there was no significant gender difference in the overall HF risk.15 In contrast to the Framingham study, our study showed that women aged <55 years had a higher risk of HF than men. This inconsistency among study results may be attributable to the extent to which patients with diabetes have comorbid CAD, the impact of modern medications, and the practice of PCI; however, there appears to be some consensus regarding the higher risk of HF in women with diabetes.16
A few possible explanations for the higher risk of HF in women than men are available. Although men still have higher rates of cardiovascular diseases (CVDs) than women, if they do not have CAD,17 it has been recognized that women with diabetes lose their relative protection against CVDs.1 18 Therefore, it is possible that higher risks of HF reflect higher risks of CAD progression in women with diabetes, based on the assumption that HF is the manifestation of ischemic heart diseases in patients with diabetes.7 Gender disparities in risk factor management may also contribute to gender differences in HF risk in patients with diabetes and CVDs. Gouni-Berthold et al19 showed that women with diabetes and CVDs have poorer control of important modifiable risk factors than men and receive less intensive lipid-lowering treatments. Similarly, Wexler et al20 reported that women with diabetes and CAD were less likely to be prescribed aspirin than men, or when treated for hypertension or hyperlipidemia women with diabetes and CAD were less likely to have blood pressures <130/80 mm Hg or LDL-c levels <100 mg/dL. Consistent with these reports, women in our registry also had significantly higher SBP, LDL-c, and HbA1c values at baseline. Concerning drugs for CVDs, statins were more prescribed and beta-blockers were less prescribed to women than men. In this study, patients were enrolled from a continuous CAG record and the number of women enrolled in this study was one-third of the number of men. This reflects real-world CAD practice, although it may also reflect gender disparity. Women may be more likely to miss the chance to undergo CAG at the appropriate time.21
If any of these explanations for the gender difference in HF risk are correct, a more intensive risk factor management strategy for women, equivalent to that for men, is recommended to improve HF outcomes. However, this may only be justified if there is no gender difference in the effects of risk factor management on CV outcomes. Therefore, we examined the interaction between gender and the risk factor management–outcome association.
Low-density lipoprotein cholesterol
A recent large-scale meta-analysis of randomized controlled trials of statins for primary and secondary prevention of HF events reported a modest (10%) reduction in first non-fatal HF hospitalizations with statin treatment.22 These results support LDL-c as a modest predictor of HF. However, gender-specific effects on HF risk have not been analyzed. In this study, we found a statistically significant interaction between gender and HF risk, as predicted from the stratified level of achieved LDL-c. We found a direct linear relationship between HF and LDL-c in men, but HF risk was not associated with LDL-c and was almost constant in women. This suggests that LDL-c could be a predictor of HF in men but not in women. Interestingly, this result is partially consistent with the Framingham Heart Study, which showed that total cholesterol is a weak predictor of HF in men but not in women, although not with statistically significant gender interaction.23 These results, although speculative, suggest that HF in women with diabetes may be more likely to result from diabetes itself rather than CAD progression, which is strongly associated with LDL-c. In fact, the history of diabetes in women was significantly longer than that in men; however, our sensitivity analysis using diabetes duration as an adjuster showed a similar HR.
Glycosylated hemoglobin A1c
We could rule out a gender difference in the association between HbA1c levels and HF risk. Poor glycemic control predicts macrovascular and microvascular complications in patients with type 2 diabetes.24 25 A previous cohort study by Iribarren et al,26 which enrolled nearly 50 000 patients, showed that poor glycemic control could also be associated with an increased risk of HF among patients with diabetes which is consistent with the results of the UK Prospective Diabetes Study.27 Unlike our result, these researchers found that the association was stronger in men than in women, with a significant gender interaction.
Systolic blood pressure
In our analysis of blood pressure, we found a significant interaction with respect to gender. While there was a nearly negative correlation between blood pressure and HF risk among men, women with the lowest SBP had an increased risk and those with an SBP >110 mm Hg had a constant risk, irrespective of SBP. These results, although somewhat presumptive, might be interpreted as follows: low blood pressure, whether achieved by strict blood pressure reduction or a decline in cardiac function without intervention, is associated with HF risk; this is linearly associated with an increased risk in men, but in women the association exists only if the SBP is <110 mm Hg.
Strengths and limitations
The strengths of this study were that, unlike analysis of an existing database, patient information was obtained directly from medical records. The large number of patients recruited from a high number of hospitals and the large number of hospitalizations due to HF may provide sufficient power to analyze the association between outcomes and variables. Conversely, a major limitation of our study may result from collecting data retrospectively. The non-rigorous assessment of risk factors, other variables, and outcomes are weaknesses inherent in any retrospective registry study. Particularly, similar to other studies, it is often difficult to accurately diagnose HF. To exclude patients presenting signs and symptoms similar to HF, such as pneumonia and chronic obstructive pulmonary disease, HF was diagnosed based on information available at admission, relevant to the Framingham criteria, and information available after hospitalization, such as improvements in symptoms and signs after specific treatments, including diuretics and nitrovasodilators, as recommended by the Atherosclerosis Risk in Communities study investigators28 and used in the A randomized trial of intensive versus standard blood-pressure control (SPRINT) study.29 We also performed sensitivity analysis after excluding patients with hemodialysis or severe renal dysfunction to exclude those whose renal dysfunction was likely to contribute to HF-like symptoms and signs.
Although the time period of our registry limits further discussion regarding the possible effects of gender on the development of HF with a preserved or reduced ejection fraction and newly developed antidiabetic drugs, such as sodium glucose cotransporter 2 inhibitors, for the prevention of HF in patients with diabetes, our continuous enrollment of patients may provide some evidence in the near future.
In conclusion, our registry-based cohort study indicated that Japanese women with type 2 diabetes and CAD had a higher risk of HF than men. Significant gender effects were found in the association between HF risk and risk factor management, particularly regarding LDL-c and SBP. This result suggests that a strategy for HF risk reduction specific to women should be established.