The global prevalence of diabetes mellitus (DM) has reached concerning levels, putting immense pressure on public health systems worldwide [1]. The chronic nature of the disease and its tendency to cause various complications present significant challenges to both individuals and healthcare providers [1]. The impact of DM goes beyond just metabolic issues, often leading to a range of serious microvascular and macrovascular complications that significantly reduce patients' quality of life [2].

One of the most serious complications of DM is the development of diabetic foot ulcers (DFUs). These minor wounds, often caused by small injuries or infections, can quickly become complex and difficult to heal [3]. The impaired ability to heal in DM, combined with the possibility of nerve damage and poor blood circulation, creates a high risk for infection, tissue death, and, eventually, amputation. The burden of DFUs is not just physical; it also causes significant emotional and financial stress for patients and their families [4].

The strong connection between DFUs and mortality has been well documented in the literature. Studies consistently show a much higher risk of early death among individuals with DFUs compared to those without it, with a 2.5 hazard ratio [5,6]. This increased risk of death highlights the broader impact of DFUs, indicating its role as a sign of a more severe decline in overall health. The complex relationship between DFUs and other diabetes-related complications, such as heart disease and kidney problems, further complicates the situation and adds to the increased risk of death reaching up to 50% at 5 years, a higher risk than that of many cancers [7].

Several factors have been identified to contribute to the higher mortality seen in patients with DFUs. Older age, the presence of poor blood circulation, chronic kidney disease, and poor blood sugar control have all been recognized as independent predictors of mortality. Additionally, the severity and extent of the DFU, along with the presence of infection, further increases the risk. Understanding how these risk factors interact is essential for developing effective strategies to reduce mortality in this vulnerable population [8].

This study aims to explore the complex relationship between inflammatory markers and early and late mortality in diabetic patients with DFUs. While previous research has looked at the importance of various clinical and demographic factors, the role of inflammatory markers in predicting long-term mortality has not been as thoroughly investigated. By examining a broad range of inflammatory markers, we hope to identify potential biomarkers that could serve as early warning signs of a worsening condition, allowing for timely interventions and better patient outcomes. The main goal of this study is to determine the risk factors for mortality over a 3-year follow-up period, with a particular focus on the predictive value of inflammatory markers.

During the study period, we enrolled 90 patients; for the final analysis, after applying the inclusion and exclusion criteria, 74 patients remained (as shown in Figure 1).

The total number of deaths recorded in the study was 21 out of 74, 28% of total number of patients analyzed.

Comparing the survivors with the total death group, we found several significant differences in inflammatory markers and some laboratory blood tests (Table 1).

Female sex was a risk factor for death.

When comparing the patients who died before 90 days after surgery with the patients who died later, we found more significant differences in the inflammatory markers’ values (Table 2).

DFUs are a severe complication in patients with diabetes, often leading to significant morbidity and mortality. The mortality rate among individuals with DFUs is notably high, with studies indicating that the death rate can reach alarming levels within a few years of diagnosis [7]. In our study, we observed that the death rate was 28% at three years for diabetic individuals with infected foot ulcers. This statistic underscores the grave prognosis associated with DFUs, reflecting a broader trend seen in the literature.

The five-year mortality rate associated with diabetic foot complications is comparable to that of some of the most aggressive forms of cancer [7]. For instance, the five-year mortality rate for patients with DFUs has been reported to range from 30% to 68%, depending on various factors such as the presence of additional comorbidities, the severity of the ulceration, and whether the patient underwent an amputation [9]. Specifically, major amputations are associated with a five-year mortality rate that can exceed 50%, illustrating the severe impact of this condition [7].

Several factors contribute to the high mortality rate observed in patients with DFUs. First, DFUs are often indicative of advanced systemic disease, including peripheral neuropathy and peripheral arterial disease, both of which are associated with increased cardiovascular mortality [10].

In our study, female sex was identified as a significant risk factor for mortality among patients with DFUs. More than half of the women included in our cohort died within the study period, highlighting the severe impact of DFUs on female patients. The mortality rate among women with DFUs was lower than in men, but still significant, with around 16.1% of women dying during the follow-up period versus 24.5% men [11]. Another study suggested a slightly higher mortality rate for women compared to men in certain contexts, emphasizing the variability in outcomes based on the population and healthcare setting [12].

In our cohort, the mortality rate for women exceeded 50%, underscoring the heightened vulnerability of female patients in our study compared to those in other studies. This discrepancy might be due to differences in comorbidities, access to care, or severity of the disease at presentation.

In our study, we found that 20 out of 21 deaths occurred in patients who had a history of diabetes mellitus for longer than five years. This finding suggests a strong correlation between the duration of diabetes and the risk of mortality in patients with DFUs.

Comparing this to other studies, a similar trend is observed. For instance, in one study, the median duration of diabetes among patients who died was around seven years, with the majority of deaths occurring in patients who had diabetes for several years before the onset of DFUs [13]. This aligns with our observation that prolonged exposure to the complications of diabetes, such as vascular and neuropathic damage, significantly increases the risk of mortality.

Another study reported that the duration of diabetes was a critical factor in determining the outcomes for patients with DFUs. Patients with a longer history of diabetes were more likely to experience severe complications and had higher mortality rates [14]. These findings reinforce the importance of early intervention and aggressive management of diabetes to prevent the progression to severe complications like DFUs, which are closely linked to higher mortality, especially in those with a longer history of the disease.

In our study, we found a significant association between apolipoprotein E (ApoE) levels and mortality in patients with diabetic foot ulcers (DFUs). ApoE plays a crucial role in lipid metabolism by mediating the clearance of lipoprotein remnants from the bloodstream, which is essential in maintaining lipid homeostasis. Variations in ApoE can lead to dyslipidemia, contributing to the development and progression of atherosclerosis, a major risk factor for neuropathy and cardiovascular complications in diabetic patients [15].

In patients with DFUs, impaired lipid metabolism due to ApoE dysfunction can exacerbate peripheral neuropathy by increasing oxidative stress and inflammation, further compromising blood flow to the extremities and hindering wound healing [16]. This pathological process likely contributes to the higher mortality observed in our study, as patients with altered ApoE function are more prone to severe vascular complications. Thus, monitoring ApoE levels could be useful in managing and predicting outcomes in diabetic patients with DFUs.

In our study, we observed a significant correlation between elevated levels of pentraxin 3 (PTX3) and increased mortality in patients with diabetic foot ulcers (DFUs). PTX3 is an acute-phase protein involved in the body’s immune response and plays a critical role in inflammation and vascular health [17]. Elevated PTX3 levels are indicative of systemic inflammation, which is a common complication in diabetic patients, particularly those with DFUs. In the context of DFUs, high PTX3 levels may reflect ongoing vascular inflammation and endothelial dysfunction, which can exacerbate peripheral artery disease and impair wound healing [17]. The persistent inflammatory state associated with elevated PTX3 can lead to more severe infections and slower recovery, increasing the risk of sepsis and other life-threatening complications. PTX3 serves not only as a biomarker of inflammation but also as a potential predictor of poor outcomes [18].

In our study, we observed that patients with infected diabetic foot ulcers (DFUs) who had elevated procalcitonin (PCT) levels were more likely to experience early mortality, specifically within the first 90 days after surgery. Procalcitonin is a biomarker that rises significantly in response to bacterial infections and systemic inflammation, making it a useful indicator of the severity of infection.

Higher PCT levels suggest a more aggressive infection and a heightened systemic inflammatory response, which can lead to rapid deterioration in patients with DFUs. The early deaths observed in those with elevated PCT may be due to the overwhelming infection and ensuing sepsis, which can cause multi-organ failure and death if not swiftly managed. The elevated PCT levels in these patients likely reflect the severity of their condition, indicating that the infection was more extensive and harder to control, leading to poor outcomes despite surgical intervention [19].

In our study, impaired renal function emerged as a significant risk factor for mortality in patients with diabetic foot ulcers (DFUs), with differences between survivors and overall deaths, but also between early and later deaths. Patients with compromised renal function are more vulnerable to complications due to the kidneys' reduced ability to filter waste and manage electrolyte balance, which exacerbates the systemic effects of diabetes. Renal impairment also contributes to poor wound healing and increased susceptibility to infections, both of which are critical in the context of DFUs [20,21].

The significance of renal dysfunction in both early and later deaths suggests that kidney health plays a crucial role throughout the disease course. Early deaths may result from acute complications like sepsis, while later deaths could be linked to chronic issues such as cardiovascular disease, both of which are exacerbated by renal insufficiency.

The prognosis for patients with DFUs remains poor despite advances in medical and surgical care. The recurrent nature of foot ulcers, with a high likelihood of re-ulceration even after successful initial healing, places patients in a continuous state of risk. This ongoing risk, coupled with the underlying diabetes and associated comorbidities, means that patients with DFUs face a substantially shortened life expectancy compared to the general population or even diabetics without foot complications.

Our study has several limitations that must be acknowledged. As a single-center study, the findings may not be generalizable to broader populations or different healthcare settings. The sample size was relatively small, limiting the statistical power of our analyses. Additionally, the study's observational design introduces potential biases, such as selection bias. Recall bias could also affect the accuracy of patient-reported data. Furthermore, the reliance on retrospective data from medical records might have led to incomplete or inaccurate information, affecting the validity of our conclusions.

This study highlights the significant impact of inflammatory markers, apolipoprotein E levels, and renal function on the mortality of patients with diabetic foot ulcers. Despite advances in treatment, the prognosis for patients with diabetic foot ulcers remains poor, underscoring the importance of early detection and aggressive management of risk factors to improve outcomes and reduce mortality in this vulnerable population.