Mortality among patients with diabetic foot ulcers and its relationship with Wagner classification and glucose regulation

INTRODUCTION

Diabetes mellitus (DM) affects people across all age groups and progresses, requiring chronic and constant care.¹ The prevalence of this disease is increasing.²

The WHO defines diabetic foot syndrome as a complex condition characterized by infection, ulceration, and profound tissue degradation in the lower limbs, often occurring alongside neuropathic disorders, varying degrees of peripheral vascular disease, and/or metabolic complexities in people living with diabetes. It is estimated that around a quarter of people with diabetes will develop a diabetic foot ulcer.³

Studies conducted on people living with DM have reported that the risk of death from all causes is higher in people with diabetic foot ulcers.⁴ Cohort studies show that diabetic foot ulcer is a significant independent predictor of mortality, even after adjusting for recognized cardiovascular disease (CVD) and other comorbid conditions.^5,6

We calculated the mortality rate among individuals diagnosed with diabetic foot who sought consultation at our hospital’s diabetes outpatient clinic and to assess the relationship between the Wagner class of the patients, haemoglobin A1c (HbA1c) levels, and mortality.

METHODS

We did a retrospective study among people diagnosed with type 2 DM who sought consultation at the Training and Research Hospital Diabetes Polyclinic from April 2019 to June 2022. The study was approved by the institution’s ethics committee vide decision number 2022/182 dated 03.10.2022.

The Wagner classification at the time of presentation to the outpatient clinic, along with laboratory data collected within the designated timeframe, including HbA1c levels, glucose, triglyceride, creatinine, aspartate aminotransferase (AST), alanine aminotransferase (ALT), total cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and uric acid levels, were retrieved from the hospital’s data management system and the medical records of individuals with diabetic foot. Data on patient deaths was also retrieved from these sources.

Individuals under 18 years of age, those diagnosed with type 1 or other types of diabetes, individuals lacking a diabetic foot ulcer, or those with undetermined Wagner class in their diabetic feet, as well as those with missing measurements for HbA1c, glucose, ALT, AST, creatinine, LDL, HDL, total cholesterol, triglyceride, and uric acid values, were excluded from the study.

Data were compared for patients who died between April 2019 and June 2022 and those who were alive.

Continuous variables, including age, duration of diabetes, and laboratory measurements, underwent graphical assessment and the Shapiro-Wilks test to evaluate normal distribution. Variables that did not conform to a normal distribution were presented using median (interquartile range [IQR]).

Independent sample t-test was used for parameters exhibiting normal distribution, while the Mann–Whitney U test was utilized for those that did not exhibit normal distribution. Logistic regression analysis was utilized to assess the independent effects of variables on mortality. The results were assessed in terms of odds ratio and 95% CI. Spearman’s non-parametric correlation coefficient was used in the correlation analysis between continuous variables.

Statistical analyses and computations were done using IBM SPSS Statistics 21.0 (IBM Corp., Released 2012, IBM SPSS Statistics for Windows, Version 21.0, Armonk, NY: IBM Corp.) and MS-Excel 2007 software.

RESULTS

Of the 216 individuals with diabetic foot admitted to the diabetes outpatient clinic during the study period, 3 were diagnosed with type 1 DM, 13 had not been evaluated for the Wagner stage, and 30 had deficiencies in their laboratory data. These individuals were excluded from the study and the analysis was done with the remaining 170 patients.

The mean (SD) age of the individuals was 61.34 (10.61) years, and the mean (SD) duration of diabetes was 13.41 (8.11) years. 47 (27.6%) subjects were women and 50 subjects (29.4%) died during the study period (Table 1).

Statistically significant differences were found in triglyceride, glucose, AST, uric acid, and creatinine values between the alive and deceased people (Table 2).

A negative weakly significant correlation was observed between age and HbA1c, triglycerides, and glucose (rho= –0.302; p<0.001, rho=–0.295; p<0.001, rho=–0.307; p<0.001, respectively). A weak positive correlation was observed between age and HDL (rho=0.175; p=0.022), as well as between age and creatinine (rho=0.275; p<0.001).

Among survivors, a weak negative correlation was evident between age and HbA1c, triglyceride, and glucose values (rho=–0.288; p=0.001, rho=–0.295; p=0.001, rho=–0.327; p<0.001, respectively). Additionally, a weak, positive correlation was found between age and HDL (rho=0.239; p=0.009).

Conversely, no significant correlations were found between age and HbA1c, LDL, HDL, total cholesterol, triglyceride, glucose, AST, ALT, uric acid, and creatinine among those who died (p>0.05).

Multivariate logistic regression analysis showed that elevation in AST levels increased the risk of mortality by 1.05 times, whereas a high creatinine value increased it by 4.855 times. As glucose increased, the mortality risk decreased by 0.7% (1–0.993). The explanatory capacity of the models assessed using the Nagelkerke R² value was 0.3 (Table 3).

DISCUSSION

Diabetic foot ulcer is a recognized predictor of high mortality among people with diabetes.^7,8 The mean age of patients diagnosed with diabetic foot syndrome in our study was 61.3 years, and the mortality rate in 3 years was 29.4%.

Moulik et al. studied 185 poeple and found, the 5-year mortality rate was 44%.⁹ Morbach et al. studied patient’s with a mean age of 68.8 years, mean duration of diabetes of 15.7 years and found a 3-year mortality rate of 33.1%.⁷ Brennan et al. included 66 323 patients admitted between 2006 and 2010 and followed until 2012 or death, with a mean age of 69 years, and a 2-year mortality rate of 31%.¹⁰ The fact that mortality rates in these studies differed from our study may be related to the difference in the duration of diabetes, the mean age, and the fact that mortality was calculated for different durations.

A decade-long observational study in Norway identified male gender as a significant factor affecting mortality in 155 patients with diabetic foot ulcers.¹¹ However, despite more men being included, gender did not significantly affect mortality in our study. Although why diabetic foot ulcers are more common in men is unclear, it has been suggested that men being taller than women increases the risk of developing neuropathy and that women of reproductive age have better endothelial function. However, when neuropathy or other risk factors are present, the risk of diabetic foot in women has been found to be the same as in men.¹² Jeyaraman et al. also showed that gender does not affect mortality, even the number of male patients was higher.¹³

In our study, the duration of diabetes differed significantly between the two groups. Amadou et al. examined the 5-year mortality of patients with diabetic foot ulcers between 2009 and 2010. The average duration of diabetes among the included patients was 16 years and was positively associated with mortality.¹⁴ Longer duration of diabetes increases microvascular complications and affects mortality.¹⁵

Wagner classification was not predictive of mortality in our study. This is similar to the study by Jeyaraman et al.¹³ and Rubio et al.¹⁶ However, similar to our study, these studies did not determine the duration of the ulcer and initiation of treatment and this may affect outcomes.

We found the median HbA1c level to be higher among survivors than among the deceased, although the association was not statistically significant. Additionally, a significant negative correlation was identified between age and HbA1c. Despite the lower HbA1c values observed in elderly individuals, it can be inferred that the mortality rate is higher in this age group.

Winkley et al. also reported that low HbA1c was associated with increased mortality.¹⁷ Jeyaraman et al. found similar results.¹³ The increased risk of hypoglycaemia in individuals with tighter glycaemic control may explain the high mortality in these individuals at high cardiovascular risk.¹⁸ Chronic kidney disease is more common in individuals with diabetic foot¹⁹ and the resulting decrease in insulin clearance and increase in plasma insulin levels may also explain these findings.²⁰

Cardiovascular factors account for approximately half of all deaths in patients with diabetic foot.^7,8 Huang et al. reported a correlation between elevated uric acid levels and mortality among 172 patients with diabetic foot.²¹ Dayan et al. reported uric acid as an independent risk factor for cardiovascular incidents.²² It appears logical that since cardiovascular events are the predominant cause of mortality in individuals with diabetic foot, uric acid is an independent risk factor for such events.

Serum creatinine levels affect both the prevalence and severity of coronary artery disease (CAD).^23,24 We found that creatinine is an independent risk factor for mortality, increasing the risk by 4.8 times. Given that CAD is one of the principal causes of death among individuals with diabetic foot, the elevated median creatinine levels observed in the deceased group in our study might suggest that the cause of death could be attributed to CAD or renal impairment.

In our study, the median triglyceride value of the survivors was significantly higher than the deceased group. Similarly, the median HbA1c of the survivors was higher than in the deceased group. Özdoðan et al., reported that total cholesterol, triglyceride, and LDL levels are higher in patients with high HbA1c values.²⁵ Similarly, Khan et al., in a study of 1011 patients with type 2 DM, reported that patients with HbA1c >7.5 had higher triglyceride levels.²⁶

Chronic mild elevation of transaminases is frequently observed in patients with type 2 DM.²⁷ In our study, the AST values of the patients were within normal limits. However, when the alive and deceased groups were compared, the AST values of the patients in the deceased group were significantly higher.

Conclusion

We found the mortality rate among patients with diabetic foot to be 29.4%. Neither HbA1c levels nor the Wagner class were associated with mortality. AST, glucose, and creatinine values were predictors of mortality and close monitoring of these parameters is recommended.