Does Baseline Hemoglobin A_1c Level Predict Diabetic Foot Ulcer Outcome or Wound Healing Time?

Abstract

Background: We sought to evaluate the relationship between baseline hemoglobin A_1c (HbA_1c) level and clinical outcomes, including foot ulcer outcome (resolved versus unresolved) and wound-healing time, in individuals with type 2 diabetes. Methods: A prospective observational study was conducted on 99 patients presenting with a diabetic foot ulceration. Patient and ulcer characteristics were recorded. Patients were followed up for a maximum of 1 year. Results: After 1 year of follow-up, 77% of ulcers healed and 23% did not heal. Although this study demonstrated that the baseline HbA_1c reading was not a significant predictor of foot ulcer outcome (P = .603, resolved versus amputated), on further statistical analyses, when HbA_1c was compared with the time taken for complete ulcer healing in the resolved group (n = 77), it proved to be significant (P = .009). Conclusions: These findings have important implications for clinical practice, especially in an outpatient setting. Improving glycemic control may improve ulcer outcomes. Prediction of outcome may be helpful for health-care professionals in individualizing and optimizing clinical assessment and management of patients. Identification of determinants of outcome could result in improved health outcomes, improved quality of life, and fewer diabetes-related foot complications. (J Am Podiatr Med Assoc 107(4): 272-279, 2017)

The incidence of diabetes is increasing worldwide, and an estimated 4% to 10% of people with type 2 diabetes develop foot ulceration.[1] This is of concern for both people with diabetes and health-care providers, with episodes of ulceration strongly associated with lower-extremity amputations, reduced quality of life, long periods of hospitalization, and substantial health-care costs.[2]

Diabetic foot ulcerations are a major complication of diabetes. They can take weeks or months to heal and can sometimes not heal at all.[3] Hemoglobin A_1c (HbA_1c) reflects glycemia over 2 to 3 months and is the gold standard measure used to monitor glycemia in patients living with diabetes; however, to date, studies have not shown a consistent association of HbA_1c with wound healing, although one would assume that elevated HbA_1c levels would be mostly associated with poor wound healing.[4]

Given the large number of diabetic foot complications, it is important to identify modifiable predictors that could determine foot ulcer outcome. Few studies have quantified predictors of ulcer outcomes, and these studies report confounding results. It also remains unclear in the literature whether HbA_1c is a good biomarker for foot ulcer outcomes in patients living with diabetic foot ulcerations.[4] This emphasizes the importance of ensuring continuous research to identify predictors of ulcer outcome. Understanding at-risk populations has advantages in many areas, including focusing efforts and healthcare costs, improving treatment compliance, defining patients who need more advanced therapies, and identifying new therapeutic targets.

This prompted us to conduct a study in a population with a high prevalence of diabetes to determine whether HbA_1c could be regarded as a potential biomarker for foot ulcer outcome and ulcer-healing time. Ten percent of the Maltese population has diabetes compared with 2% to 5% of the population in neighboring European countries. As expected, foot ulceration, and ulcer recurrence, is common in this specific population with diabetes.[5]

The aims of this study were to determine whether HbA_1c predicts foot ulcer outcome (resolved versus unresolved) in patients living with type 2 diabetes and to determine whether it predicted woundhealing time. We hypothesized that among other laboratory tests and clinical measurements, HbA_1c values would predict diabetic foot ulcer outcome or wound-healing time.

Methods

Patient Selection

Individuals were recruited from the diabetes podiatric medicine clinic of a local general hospital. An average of 5,000 people attend the clinic annually, with approximately 500 experiencing ulceration. A convenience cohort of the first 101 patients was enrolled for this investigation. This study was approved by the University of Malta research ethics committee, and all of the participants provided informed consent before data collection. All of the investigations were performed in accordance with the principles of the Declaration of Helsinki as revised in 2000. Individuals eligible for this study were Maltese, older than 18 years, and living with diabetes according to the World Health Organization diagnostic criteria.[6] Patients who presented for the first time with a new foot ulceration over a 1-year period at an outpatient hospital clinic were enrolled into this observational study. Patients were excluded if they presented with venous ulcers, had a history of foot ulceration or amputation, underwent revascularization procedures of the lower limb, or were either unable to participate in the study due to cognitive impairments or showed unwillingness to participate and follow the study protocol.

Methodological Rigor

To test the hypothesis, a prospective observational study was conducted following an a priori power analysis. The clinical tools used during this research were based on validated and previously published methods after a thorough review of the literature on international guidelines and recommendations.[7] A database was constructed to record all of the information.

Methods

One hundred and one patients were recruited in this prospective observational study and were followed up and treated until healing was achieved or up to a maximum of 12 months according to a standardized protocol, described herein, based on the International Consensus on the Diabetic Foot.[7] Two participants died during the study period, leaving 99 recruited patients. Assessment of the neurologic and vascular status, regular wound debridement, diagnosis and treatment of infection, dressing of ulcers, and off-loading were conducted.

The participants were asked to visit the diabetes foot clinic once every 4 weeks after recruitment and were followed up for a maximum of 12 months. The primary outcome measure was ulcer healing, which was defined as complete epithelialization without discharge and without amputation. Time to healing was calculated from the date of the first clinic visit to the date at which the foot ulcer was first confirmed as healed in the clinic. Those who had an ulcer-related amputation (major/minor) or who died during the study year were censored at the date of amputation or death. After informed consent was obtained, patients’ characteristics were gathered using a data collection sheet designed by the authors for gathering data from participants, including sex, age, type and duration of diabetes, and weight. In addition to the latter, details concerning date of diagnosis of diabetes, medication regimen for diabetes and other medications, renal function, heart failure, history of coronary artery bypass graft, hypertension, hypercholesterolemia, and neurologic disorders were recorded from patients’ history notes. Additional information, including vision, symptoms of peripheral arterial disease such as intermittent claudication and rest pain, and smoking habits, were recorded. Participants were also asked whether they are able to stand or walk without help. Foot disorders, type of shoe, and off-loading devices were also recorded. The type of wound dressing and the patients’ ability to change the dressing were noted. Participants’ present occupation was also recorded. Clinical measurements, including HbA_1c level, creatinine level, and estimated glomerular filtration rate, were measured every 4 months as part of the patients’ routine in the diabetes and endocrinology center. All of the patients underwent a standardized ulcer examination every 4 weeks up to 1 year using the Perfusion, Extent, Depth, Infection, and Sensation (PEDIS) classification system and score as the principal study tool.[8]

Ulcer Characteristics

To classify patients in this study, an examination of the foot following the PEDIS system was conducted, as recommended by the International Consensus on the Diabetic Foot.[8] Foot ulcerations were classified according to five categories: perfusion, extent, depth, infection, and sensation. The testing modalities and examination methods were performed by the same investigator (L.V.) to ensure uniformity. Testing was performed at the outpatient clinic. Room temperature was kept at 218 to 238C (688 to 758F) during the assessments to avoid vasoconstriction of digital arteries from the cold. The screening process involved review of the patient’s medical history and a lower-extremity physical examination. Individual assessments took approximately 45 minutes.

Peripheral Sensory Neuropathy. The 10-g Semmes-Weinstein monofilaments were used to identify peripheral sensory neuropathy. The fivepoint test was used. The plantar aspect of the hallux and the third digit together with the first, third, and fifth metatarsal heads were used for testing. With eyes closed, the patient related to the investigator when he or she could feel the monofilament. Participants with triphasic wave forms and normal ankle-brachial pressure indices (ABPIs) (0.9–1.2) who were unable to feel the 10-g monofilament on any of the five points were considered neuropathic.[7] Peripheral Arterial Disease. Peripheral arterial disease was assessed using the documentation of history of intermittent claudication, rest pain, and palpation of peripheral pulses. Palpation of pulses was conducted by an experienced clinician (L.V.). Dorsalis pedis and posterior tibial pulses were recorded. Cyanosis, cold feet, skin thinning, and hair anomalies were also recorded. Claudication was evaluated from information supplied by the patient regarding exercise-induced calf, thigh, and buttock pain.

Measurement of ABPI was performed using a portable handheld Doppler device and blood pressure cuffs. Apart from ABPI assessment, quantitative pedal wave form analysis was obtained from all of the recruited patients using continuous wave Doppler. The Doppler wave forms and the ABPI measurements were obtained using the Huntleigh Dopplex Assist vascular package (Huntleigh, Cardiff, England) as the principal study tool. The Huntleigh handheld continuous wave Doppler device with an 8-MHz probe, part of the Dopplex Assist vascular package, was used to measure the wave forms of the dorsalis pedis and posterior tibial arteries. The probe was held steadily on the anatomical artery location at an angle of 458 to 608 against the flow of arterial blood. Interpretation of arterial pressure wave form results was based on standards from the literature.[9] Wave forms were classified as triphasic, biphasic, monophasic discontinuous, and monophasic continuous. The triphasic wave forms were considered normal, whereas the biphasic and monophasic discontinuous and monophasic continuous wave forms were interpreted as abnormal and indicative of peripheral arterial disease. Measurements were performed after a 5-min rest in the supine position with the upper body as flat as possible. Participants were also asked to undo all tight clothing around the waist and the arm. The Huntleigh Dopplex Assist series was used to measure the resting ABPI. The series used for this study included an electric pump, which deflates the pressure cuffs, requiring the investigator to simply press a button. When measured, systolic blood pressures are automatically saved onto the system’s software, with the saved results then used to calculate the ABPI ratios by the system.

A blood pressure cuff was applied to the arm (to measure the brachial systolic pressure) and the ankle (to measure the dorsalis pedis and posterior tibial pressures) to determine the ankle pressure. The cuff was inflated to occlude the arterial pressure. Systolic pressure was obtained by listening and noting the pressure on the manometer, and the higher values of the brachial and the ankle pressures were used to calculate the ABPI. Values were interpreted according to the criteria proposed by the American Heart Association and the American Diabetes Association.[9] The ABPI calculations were interpreted to be 0.90 to 1.29 (normal). Lower-extremity vascular disease was defined as an ABPI less than 0.90 in either foot. An ABPI greater than or equal to 1.3 was considered significantly elevated and indicative of vascular calcification.

Extent of Ulcer. The extent was recorded using the acetate method, which involved tracing the circumference of the wound onto a two-layered, 1-mm² preprinted acetate tracing. The contact layer was discarded, and the area of the wound was calculated by counting each square that is more than half within the border of the wound as 1 mm2.10

Depth of Ulcer. Depth was measured by inserting a sterile probe into the deepest part of the wound, placing a sterile gloved forefinger at the level of the surrounding skin, and measuring the length of the probe in the wound against a paper ruler.

Infection. Infection was diagnosed in cases when two or more of the following signs were present: frank purulence, local warmth, erythema, lymphangitis, edema, pain, fever, and foul smell.

Ulcer site was documented and categorized as toe, first through fifth metatarsophalangeal joints, midfoot, or hindfoot. Other ulcer characteristics that were recorded include whether the ulcer base was wet, moist, or dry. The presence of slough, necrotic/eschar, granulating, or epithelializing tissue and the presence of biofilm were recorded. An attempt was also made to estimate the time in days that elapsed between ulcer onset and first attendance at the clinic.

Ulcers were also categorized according to their type. Participants whose ABPI was found to be less than 0.9 and whose peripheral sensation was poor were diagnosed as having a neuro-ischemic ulcer. The typical characteristics of a neuro-ischemic ulcer were a base of sparse, pale granulation tissue and a yellowish, closely adherent slough that were usually found on the margins of the foot, especially on the medial surface of the first metatarsophalangeal joint and over the lateral aspect of the fifth metatarsophalangeal joint.[11] Patients with an ABPI of 0.9 to 1.3 but presenting with poor peripheral sensation were diagnosed as having a neuropathic ulcer. The characteristics of a typical neuropathic ulcer were a punched out appearance; the presence of granulation tissue; a sloughy appearance; being surrounded by hyperkeratosis; and the presence of whitish, macerated, moist tissue.[11] Neuropathic ulcers were usually found on the plantar aspect of the foot under the metatarsal heads or the apices of digits and heels.[12] Patients whose ABPI was less than 0.9 but peripheral sensation was normal were diagnosed as having an ischemic ulcer.

If a patient happened to have multiple ulcers, the first, or the clinically most important (highest grades for area, depth, or arteriopathy at presentation [PEDIS classification]), was selected as the index lesion for the study. Ulcer area and depth, presence of infection, and state of the ulcer base were all recorded every 4 weeks for a maximum of 12 months.

Univariate analysis was performed using the x² test or one-way analysis of variance (ANOVA) for all potential predictor variables of wound healing, with values presented with the respective 95% confidence interval. Following this, all significant predictors found in the univariate analyses were entered simultaneously in a logistic regression analysis model. This model yielded a set of variables that can be regarded as independent predictors of foot ulcer outcome. One-way ANOVA was used to compare mean values for age, diabetes duration, and HbA_1c level between independent groups grouped by either patient characteristics or ulcer characteristics. These continuous variables were compared with foot ulcer outcome (resolved or amputated), time to healing (<4, 4–8, 8–12, or >12 weeks), and time to amputatation (<4, 4–8, or >8 weeks).

The null hypothesis specifies that mean values vary marginally between the groups and was accepted if P > .05. The alternative hypothesis specifies that mean values vary significantly between the groups and was accepted if P < .05.

Results

All of the data were recorded on a spreadsheet designed in Microsoft Excel (Microsoft Corp, Redmond, Washington) to group together the information required for interpretation of the results. Statistical analyses were performed using SPSS for Windows, Version 14.0 (SPSS Inc, Chicago, Illinois).

Patient Demographics and Ulcer Characteristics

Ninety-nine patients (69 men and 30 women) presenting with a new foot ulcer were recruited to this study. Six participants were living with type 1 diabetes and 93 with type 2 diabetes. The mean 6 SD age of the study group and duration of diabetes were 62.8 6 9.5 and 14.8 6 9.0 years, respectively. The mean HbA_1c level for the resolved group was 8.9% (74 mmol/mol) and for the amputated group was 9.2% (77 mmol/mol). Of the 99 ulcerations, 70.7% were neuropathic, 25.3% were neuro-ischemic, and 4.0% were ischemic. The ulcers presented with slough (59.6%), necrotic/eschar (6.1%), granulating (30.3%), and epithelializing (4.0%) tissue. Furthermore, 25.2% of the ulcers presented with biofilm, and 36.4% showed clinical evidence of infection at initial presentation.

Outcome

The primary outcome measure was ulcer healing. Those who had an amputation were classified as unhealed. At termination of the study, 77% of ulcers had healed/resolved completely and 23% resulted in lower-limb amputation over a maximum of 1 year. There were no participants with an unhealed ulcer who did not undergo amputation.

Patient Characteristics and Foot Ulcer Outcome: Univariate Analysis

Table 1. Patient Characteristics for the Resolved versus Amputated Groups (x²/One-Way ANOVA).

illustrates the univariate relationships between patient characteristics, including sex, age, weight, type of diabetes, duration of diabetes, diabetes treatment, HbA_1c level at baseline, medications, creatinine and estimated glomerular filtration rate at baseline, renal and visual impairment, ischemic heart disease, heart failure and coronary artery bypass graft, intermittent claudication and rest pain, hypertension, hypercholesterolemia, neurologic disorders, foot deformities, smoking history, current occupation, over-the-counter shoe type, off-loading devices, type and change of wound dressing, and foot ulcer outcome (resolved versus amputated). The results demonstrated no significant predictors of wound healing among the patient characteristics recorded.

However, on further statistical analysis using oneway ANOVA, which aimed to evaluate HbA_1c readings versus ulceration healing time, when this was compared with the time to ulcer healing in the resolved group (n = 76) it proved to be a significant biomarker (P = .009), with patients who healed in less than 4 weeks presenting with a baseline HbA_1c of 8.5% (69 mmol/mol) and those whose ulceration healed in more than 12 weeks presenting with an HbA_1c of 10.8% (95 mmol/mol) (

Table 2. HbA_1c versus Time to Heal in the Resolved Group at Time 0 (n = 77) (P = .009) (One-Way ANOVA).

Time to Healing (wk)	No. of Patients	Mean HbA1c (% [mmol/mol])	SD	SE	95% CI for the Mean
<4	41	8.5 (69)	1.939	0.307	7.88–9.13
4–8	16	9.5 (80)	2.306	0.577	8.32–10.78
8–12	12	8.1 (64)	2.110	0.609	6.72–9.40
>12	8	10.8 (95)	1.865	0.659	9.29–12.41

Abbreviations: ANOVA, analysis of variance; CI, confidence interval; HbA_1c, hemoglobin A_1c.

).

Discussion

This article focuses particularly on whether HbA_1c could be considered a potential biomarker for foot ulcer outcome because this blood test is widely used in all diabetes clinics as a routine test for glycemic control. This study demonstrated that the baseline HbA_1c reading was not a significant predictor of foot ulcer outcome (P = .603, resolved versus amputated); however, on further statistical analyses, when HbA_1c was compared with the time taken for complete ulcer healing in the healed group (n = 77), it proved to be significant (P = .009). The literature identifies many physiologic factors as contributors to poor wound healing in patients living with diabetes, including decreased or impaired keratinocyte and fibroblast migration and proliferation, cytokine and growth factor function, and angiogenic response and response to infection, among others[13]; however, these factors are all dependent on the levels of glucose in the blood.[14] Suboptimal HbA_1c levels may hold prognostic significance in patients presenting with diabetes ulcerations.

Findings from this prospective study are congruent with those in another retrospective study conducted by Christman et al[4] in which the authors concluded that individuals with a lower HbA_1c level had significantly faster healing rates (P = .027). The authors report that the association between HbA_1c and wound healing time is poorly reported in the literature. Furthermore, previous studies reported conflicting results or did not statistically analyze their data due to small sample sizes.[15,16] Christman et al[4] also advocate the need for prospective studies because in their study, diabetes duration, wound duration, and patient compliance were not evaluated as in the present prospective study. The results of our study make a useful contribution to this important and growing body of knowledge related to the relationship between baseline HbA_1c level and prediction of ulcer outcome and wound-healing time in a population of people living with type 2 diabetes. Given the growing numbers and burden of diabetic wounds, it is important to identify modifiable factors that could predict or aid healing.[4]

Diabetes care has benefited from the publication of large-scale randomized controlled trials in that there is now evidence that treating risk factors such as HbA_1c can reduce complications by up to 75%.[17,18] In 1993, the results of the Diabetes Control and Complications Trial[17] demonstrated that normalization of blood glucose levels in patients with type 1 diabetes reduces the risk of microvascular disease and neuropathy. The American Diabetes Association proclaimed that the Diabetes Control and Complications Trial results should be applicable to those living with type 2 diabetes given that the underlying causes of complications were similar for both types of diabetes. This recommendation, although intuitively sound, was not universally supported by the evidence available at the time. Five years later, the results of the 10-year, multi-arm UK Prospective Diabetes Study confirmed that intensive blood glucose control in patients living with type 2 diabetes did indeed reduce the incidence of diabetic complications, especially microvascular disease.[18]

Each 1% reduction in HbA_1c was associated with a 37% decrease in the relative risk of microvascular complications (95% confidence interval, 33%–41%; P < .0001) and a 21% decrease in the risk of any end point or death related to diabetes (95% confidence interval, 17%–24%; P < .0001).[18] Despite these important findings, ideal glycemic control is achieved in less than half of the patients living with type 2 diabetes,[19] and adherence to established evidence-based treatment guidelines aimed at controlling risk factors and use of preventive care services by providers and patients are low. This ultimately may result in patient outcomes that are less than optimal. Optimal HbA_1c levels are defined as those less than 7% (53 mmol/mol) and ideally less than 6.5% (48 mmol/mol), and levels higher than 7% indicate poorly controlled diabetes. Participants in this study had an HbA_1c level higher than recommended in both the resolved and unresolved groups at the start of the study.

Because HbA_1c has long been the most important way of measuring long-term metabolic control in this high-risk population, it is important that patients and caregivers set clinical treatment goals, including HbA_1c targets, because, as demonstrated in this study, HbA_1c proved to be a significant biomarker (P = .009), with patients whose ulcerations healed in less than 4 weeks presenting with a baseline HbA_1c level of 8.5% (69 mmol/mol) and those whose ulceration healed in more than 12 weeks presenting with an HbA_1c level of 10.8% (95 mmol/mol).

Furthermore, an association has also been found between higher levels of HbA_1c and peripheral arterial disease and other diabetes-related microvascular complications. Individuals with HbA_1c levels of 5.3% or greater should be targeted for aggressive risk factor reduction, which may reduce the burden of subclinical cardiovascular disease[20,21] and diabetic foot complications, including ulcerations and ultimate amputations.

Some limitations that are important to consider in the interpretation of these results include the sample size (N = 99) compared with other studies that have used larger samples; however, the sample size was small owing to the very strict inclusion and exclusion criteria used in this study in an attempt to control for all of the confounding variables known to affect wound healing. Note that this study recruited all of the patients who presented at the diabetes foot clinic over 1 year and who fulfilled the inclusion criteria; therefore, we can assume that study results are generalizable to this specific client group; however, because participants were recruited from patients attending a specialized diabetes foot clinic, the generalizability of these results may be limited. Furthermore, this article reports only the HbA_1c results taken at baseline because most of the sample’s ulcerations either healed or resulted in foot amputation after the first 4 months of the study. Antibiotic drugs were given according to the suggestion of the diabetologist when required, and no single treatment was used. This study also has an important strength. Data were collected prospectively compared with similar studies.[4] Duration of diabetes, wound duration, and patient compliance were also recorded compared with other retrospective studies.

Conclusions

The results of this study suggest that glycemia, as assessed by HbA_1c level, may be an important biomarker in predicting wound-healing time. These findings have important implications for clinical practice, especially in an outpatient setting. Prediction of outcome may be helpful for health-care professionals in individualizing and optimizing clinical assessment and management of patients. Identification of determinants of outcome could result in improved health outcomes, improved quality of life, and fewer diabetes-related foot complications.

Financial Disclosure

None reported.