29th June 2020, Dr Chee L Khoo
One in three patients with diabetes will develop diabetic foot ulcers (DFU). This typically occurs in the setting of peripheral artery disease, peripheral neuropathy and trauma. Foot ulcers invariably leads to lower extremity amputation (LEA) and both are associated with significant morbidity and mortality. We know that poor glycaemic control contributes to the development of DFU and LEA. We also have evidence that intensive glycaemic control can reduce the risk of both. What about intensive control AFTER the development of DFU and LEA? Does intensive glycaemic control assist in wound healing and reduce the progression from DFU to LEA in patients who already have DFU?
Glucose and DFU
DFU and retinopathy represent the two classic microvascular complications resulting from suboptimal glucose control. Tight glycaemic control has been demonstrated in many landmark studies (including DCCT, UKPDS) to reduce the incidence of the complications. Patients with diabetes on average lose 6-8 years of their life expectancy but 15-16 years of disease-free life. A 2017 meta-analysis by Kim et al., which evaluated a broad number of laboratory findings associated with LEA in DFU patients, found that higher HbA1c and fasting glucose were associated with higher amputation rate (1).
Patients with DFU and LEA would have to be one of those significant disabilities that will greatly affect our patients’ functional status. Once a patient has DFU and LEA, most physical activity and exercise recommendations goes out the window or needs to be heavily modified.
The diabetic foot – out of sight, out of mind
With the advent of EPC and care plans, most patients with diabetes have their foot care managed by the podiatrist. This part of the diabetes care can often be forgotten in primary care. Further once a patient developed DFU +/- LEA the foot care is managed by the high-risk foot service locally. They do a terrific job. There are often other specialists at the clinic including endocrinologist. However, they are usually seen every three to six months if they are stable. Glucose control is included in the total management but they are often only reviewed every three months. Once a patient has DFU +/- LEA, will further intensive glycaemic control help? Or is it all too late?
Studies on the effects of tight glycaemic control on wound healing is conflicting. The study by Musa et al. found that an HbA1c > 7% was associated with a significant reduction of wound healing (2). In another study by Bergellini et al., which reported HbA1c as a continuous independent variable, found that each 1 point increase in HbA1c was associated with a significantly increased odds of wound healing (OR 1.80; 95% CI, 1.20–2.80), after adjusting for serum creatinine and diabetes duration (3).
On the other hand, a study by Sanniec et al. found no significant association (4).
In a recent systematic review and meta-analysis of 60 observation studies, Lane et al explored the relationship between glycaemic control and wound healing and LEA in patients who already have DFU (5). They found that hyperglycaemia (higher HbA1c and higher fasting glucose) was associated with increased likelihood of LEA among subjects with DFUs.
For HbA1c, this association persisted in studies that compared subjects with an HbA1c ≥8% to those with an HbA1c < 8%, but not in studies that compared subjects with an HbA1c > 7–7.5% to those with an HbA1c ≤7–7.5%.
Considering that many patients with DFUs have advanced diabetes-related complications, an HbA1c target of 7% to 8% is likely appropriate for most of these patients and aligns with general practice guidelines. There does not appear to be compelling evidence supporting tight glycaemic control for the purpose of improving wound healing, though definitive evidence would require rigorously conducted cohort studies or RCTs with prospectively collected A1Cmeasurements and other confounding factors.
While our high-risk foot service team provides an efficient and excellent service in managing patients with high risk feet including patients who already have DFUs, the glycaemic control remains the domain of the general practitioner in primary care. It would be ideal to achieve optimal glycaemic control to minimise diabetic foot disease but often, by the time we see the patient, a lot of microvascular damage has been done and we have to manage the DFUs. It is still vital that we maintain optimal glycaemic control to facilitate wound healing and reduce the development of lower limb amputation.
References
- Kim JL, Shin JY, Roh SG, Chang SC, Lee NH. Predictive laboratory findings of lower extremity amputation in diabetic patients: meta-analysis. Int J Low Extrem Wounds 2017;16:260-8.
- Musa HG, Ahmed ME. Associated risk factors and management of chronic diabetic foot ulcers exceeding 6 months’ duration. Diabet Foot Ankle 2012;3.
- Bargellini I, Petruzzi P, Scatena A, Cioni R, Cicorelli A, Vignali C, et al. Primary infrainguinal subintimal angioplasty in diabetic patients. Cardiovasc Intervent Radiol 2008;31:713-22.
- Sanniec K, Nguyen T, van Asten S, Fontaine J, Lavery LA. Split-thickness skin grafts to the foot and ankle of diabetic patients. J Am Podiatr Med Assoc 2017;107:365-8.
- K.L. Lane,M.S. Abusamaan, B.F. Voss, et al., Glycemic control and diabetic foot ulcer outcomes: A systematic review and meta-analysis of observat…, Journal of Diabetes and Its Complications, https://doi.org/10.1016/j.jdiacomp.2020.107638