Heart failure in type 2 diabetes: Current diagnostic methods unreliable in women
A MedUni Vienna study has investigated gender-specific differences in the diagnosis of systolic heart failure in patients with type 2 diabetes. The results, recently published in the journal Cardiovascular Diabetology, show that the current methods are less reliable in women than in men.
In view of the prevalence of heart disease, particularly in women with type 2 diabetes, it is recommended that gender aspects be taken into account in existing guidelines in order to ensure the best possible care for patients.
As part of the study, the scientific team led by gender medicine specialist Alexandra Kautzky-Willer from the Division of Endocrinology and Metabolism (Department of Medicine III), in collaboration with Martin Hülsmann and other colleagues from the Division of Cardiology (Department of Medicine II), analyzed data from 2,083 patients with type 2 diabetes (T2D) collected over a period of five years. Common methods and parameters for the diagnosis of systolic heart failure in T2D were analyzed, with a particular focus on gender-specific differences.
T2D patients are up to four times more likely to have heart failure than people without T2D, with women more than twice as likely to be affected as men. Despite the pathophysiological differences between men and women, which lead to different predispositions and courses of the disease, there are currently no gender-specific recommendations for the diagnosis of heart failure in patients with T2D.
If symptoms are noted, the current guidelines recommend further investigations for both sexes, such as determining the marker NT-proBNP in the blood and performing an echocardiogram (cardiac ultrasound). According to the NYHA classification, a categorization is made according to the severity of the symptoms, from which treatment strategies are derived.
Early diagnosis is crucial for prognosis
As the current study shows, this standardized approach does not meet the specific needs of female and male T2D patients. While higher NYHA grades (reduced exercise capacity) are associated with higher NT-proBNP values, more frequent heart failure diagnoses and a higher risk of death in men, this correlation was not found in women.
In contrast, the significance of NT-proBNP for heart failure was significantly higher in both sexes, but especially in women, than the clinical symptoms. Apparently, women often have no symptoms for a long time or do not report them, even though they already suffer from manifest heart failure.
"Our results suggest that reduced performance may not be suitable for screening heart failure in women with T2D," concludes first author Sarah Hofer-Zeni (Clinical Department of Endocrinology and Metabolism).
"NT-proBNP values, on the other hand, can be very sensitive and early markers of heart failure, especially in women. Diagnosing the heart disease as early as possible and adapting the treatment with new, very effective drugs is essential for the prognosis of patients with T2D," adds study leader Alexandra Kautzky-Willer.
According to the research team, the results of the analyses also support the need for heart failure screening in women with T2D that is based less on symptoms and more on biomarkers, and for gender-specific aspects to be taken into account in the guidelines.
From www.medscape.com
Sex differences in the diagnostic algorithm of screening for heart failure by symptoms and NT-proBNP in patients with type 2 diabetes
Cardiovascular Diabetology volume 23, Article number: 280 (2024)
Abstract
Objectives
This study aimed to assess the guideline recommended diagnostic tools NT-proBNP and NYHA classification, with a focus on sex-specific differences.
Background
Patients with Type 2 Diabetes (T2D) face a heart failure (HF) risk up to four times higher than those without T2D, particularly affecting women more than twice as much as men. Despite distinct pathophysiological differences between men and women, there are currently no sex-specific recommendations for the diagnostic algorithm of HF in diabetic patients.
Methods
A total of 2083 patients with T2D were enrolled, and the primary endpoint was heart failure during hospitalization within a 5-year timeframe. The secondary endpoint was all-cause death.
Results
In female patients, frequency of HF diagnosis prior to or during hospitalization and mortality did not differ significantly between NYHA II and III, in contrast to male patients. Additionally, there was no notable difference in mean NT-proBNP levels between NYHA stage II and III only in female patients. The multivariable regression analysis highlighted NYHA classification not to be a predictor of NT-proBNP levels in female but solely in male patients. On multivariable Cox regression NYHA score was also no significant risk factor for occurence of HF in female patients. Furthermore, there was no significant disparity in mortality between men with NT-proBNP levels between 125 and 400 pg/ml and those below 125 pg/ml, whereas in women mortality was significantly higher in the group with NT-proBNP levels between 125 and 400 pg/ml than below 125 pg/ml.
Conclusion
These findings suggest that NYHA classification may not be the most suitable tool for assessing the diagnosis of HF in female patients with T2D. Moreover, the need for consideration of a more symptom-independent screening for HF in female patients with T2D and re-evaluation of current guidelines especially regarding sex-specific aspects is highlighted.
From the article
Introduction
Type 2 Diabetes (T2D) is one of the most frequent chronic diseases worldwide with a prevalence rate of 11% [1, 2]. Uncontrolled hyperglycemia leads to an increased cardiovascular (CV) risk and mortality [3,4,5,6]. Furthermore, risk of heart failure (HF) in patients with T2D is up to 4 times higher than in patients without T2D [7,8,9,10,11]. Looking at sex differences, men are more often diagnosed with HF with reduced (HFrEF) ejection fraction while women more often feature HF with preserved ejection fraction (HFpEF). Pathophysiology of HFpEF is not clarified so far. Obesity and insulin resistance are hypothesized to play a critical role in the development of HFpEF, causing myocardial hypertrophy, collagen deposition and fibrosis [12, 13]. Independent of ejection fraction, T2D is associated with worse clinical status and increased CV mortality in HF patients [14].
The higher prevalence of HFpEF in women [15,16,17] may also be due to misclassification since women tend to have a higher LVEF compared to men [18,19,20,21]. Higher stroke volume of the heart might be explained by lower afterload due to estrogen-mediated stimulation of the production of nitric oxide, resulting in a lower total peripheral resistance [22, 23]. Despite a preserved systolic ejection fraction (EF), risk of HF and decompensation seems to be higher in female T2D patients compared to male T2D patients [16, 24,25,26,27]. Diabetes may represent a more crucial role in the pathophysiology of HF in women, since diabetes more than doubles the HF risk in women compared to men (5 times higher risk in women versus 2 times higher risk in men) [24], which highlights the importance of HF screening in patients with T2D.
ESC Guidelines state that “Plasma concentrations of NPs are recommended as initial diagnostic tests in patients with symptoms suggestive of HF to rule out the diagnosis” [28, p-3617]. More and more studies describe differences in symptoms and B-type natriuretic peptide (BNP) or N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels for diagnosing HF between men and women [29,30,31,32,33,34]. Especially pretest probability of symptoms depending on sex was never tested in a chronic setting. Therefore, the aim of this study is to analyze sex-specific differences in the diagnostic algorithm recommended by the guidelines.
Discussion
The aim of this study was to evaluate the diagnostic value of NT-proBNP and NYHA classification in terms of sex-specific differences. The findings from this study underscored several critical nuances in the relationship between NT-proBNP levels, NYHA classification, and their respective associations with future HF diagnosis (i.e. HF hospitalization) and showed that dyspnea estimated by NYHA classification might not be suitable at all for the evaluation of diagnosis of HF in female patients with T2D.
In this study population, frequency of HF diagnosis and mortality did not differ between NYHA II and III in female patients, whereas in males there was a significant stepwise risk elevation between all stages. Furthermore, on Cox regression analysis adjusted for age and cardiovascular diseases NYHA score > I was no significant risk factor for HF diagnosis in women with T2D. Sensitivity using NYHA score I compared to NT-proBNP cutoff of 125 pg/ml for HF diagnosis was significantly lower in both sexes (men: 64.9% vs. 89.2% p < 0.001; women: 57.4% vs. 97.1% p < 0.001). There was no significant difference in mean NT-proBNP levels between NYHA stage II and III in female patients, in contrast to male patients and in multivariable Cox regression analysis NYHA classification was a significant predictor of NT-proBNP level only in male patients. With rising NT-proBNP level, mortality in female patients of this study population aligned with male mortality. Women with a NT-proBNP level between 125 and 400 pg/ml had a higher mortality when compared to women with a NT-proBNP level below 125 pg/ml. However, there was no significant difference comparing men with a NT-proBNP level between 125 and 400 pg/ml and below 125 pg/ml in mortality.
These findings reveal a noteworthy sex difference in how NT-proBNP levels reflect symptomatic variations. While NT-proBNP levels in male patients significantly increased with higher NYHA scores, indicating a potential alignment with symptom severity, this trend was not observed in female patients. This discrepancy suggests that the relationship between NYHA classification and NT-proBNP levels may not be as consistent in female patients as in their male counterparts.
NYHA classification is commonly used for diagnosis and prognosis estimation of HF, but does not include sex-specific considerations. Current ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure, as well as diabetes-specific ESC Guidelines for the management of cardiovascular disease in patients with diabetes, recommend further evaluation such as measurement of NT-proBNP and echocardiography only in the presence of HF symptoms or signs [28, 37]. Furthermore, triage regarding the referral to an advanced HF centre of patients with advanced HF is recommended depending on the NYHA score [28]. Despite the widespread utilization of NYHA classification, our findings underscored its potential limitations, particularly when applied to women scoring higher NYHA classes. Unlike male patients, where higher NYHA stages correlated with increased frequency of HF diagnosis and mortality, NYHA stage did not exhibit a consistent association with adverse outcomes in female patients. This raises questions about the universality of NYHA classification as a prognostic tool in women with T2D and with and without HF. These observations appear inconsistent with other studies analyzing patient outcomes, disregarding their diabetes status [38, 39]. Notably, several studies have reported a more pronounced symptomatic profile in female HF patients compared to their male counterparts, despite similar survival rates [40,41,42], raising questions about the relationship between symptoms and prognosis in female patients.
Furthermore, diastolic dysfunction, especially elevated LV end-diastolic pressure, correlates with dyspnea [43, 44] and seems to be more predominant in female patients [45,46,47,48], offering a potential explanation for more pronounced and earlier onset of breathing disorders such as orthopnea, resulting in higher NYHA scores among women with HF.
In addition, depression prevalence in patients with T2D and HF is high, especially in women [42, 49,50,51], which might explain higher NYHA scoring in female patients of this study population without a worse HF prognosis or mortality, since fatigue or loss of energy seems to be more frequently reported by women than men with depressive disorders [52].
Using a NT-proBNP threshold level of ≥ 125 pg/ml as recommended by ESC, sensitivity for occurrence of HF during the 5-year observation period was higher in female than in male patients of this study population (97.1% vs. 89.2%). Compared to men, maximum YI assessing the diagnostic accuracy of NT-proBNP for HF was lower in women (190 pg/ml vs. 316 pg/ml). With rising NT-proBNP level, risk for HF was significantly higher in both men and women. All-cause mortality was significantly higher in male patients with a NT-proBNP level below 400 pg/ml compared to women with a similar NT-proBNP level. There was no sex-specific difference in the groups with NT-proBNP level ≥ 400 pg/ml. In general, women with or without HF have a survival advantage over men [53, 54]. Within our study population, this advantage was discernible in female patients with an NT-proBNP level below 400 pg/ml. As NT-proBNP levels rose, the mortality of women converged towards that of men. Cardiovascular disease is still undertreated in female patients [55], which could contribute to the increased mortality of women with a NT-proBNP level above 400 pg/ml. In agreement with other studies, significantly higher HbA1c and LDL levels in female patients of this study population might also point out an undertreatment for diabetes and cardiovascular diseases in women [56, 57].
Inconsistent with other studies, BMI did not correlate with NT-proBNP level in this study population [58, 59]. Higher BMI is associated with lower NT-proBNP levels and raises concerns about underestimated NT-proBNP levels in obese patients. These concerns were not substantiated in this study. A possible explanation for the missing correlation in this study population might be the high frequency of obesity of patients with T2D resulting in smaller BMI range in T2D populations.
Women with a NT-proBNP level between 125 and 400 pg/ml had a higher mortality when compared to women with a NT-proBNP level below 125 pg/ml. However, there was no significant difference comparing men with a NT-proBNP level between 125 and 400 pg/ml and below 125 pg/ml in mortality. Together this could indicate a stronger association of NT-proBNP level with mortality in female than in male patients and confirms the lower recommended NT-proBNP of 125 pg/ml, especially in women with T2D. Supporting our findings Rudolf et al. [60] found a stronger association between NT-proBNP level and mortality in women compared to men and Daubert et al. [61] demonstrated that an early NT-proBNP goal of ≤ 1000 pg/mL might have a greater prognostic value in female patients than in male patients. This contradicts with the findings of Cesaroni et al. [62] and Willeit et al. [63], who described a more pronounced association of logNT-proBNP with HF risk in male patients.
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