Description of the condition
In 2011, 366 million people worldwide (8.3% of adults) were estimated to have diabetes mellitus (IDF 2012). It is expected that this figure will reach 552 million (10% of adults) by 2030 (IDF 2012). Diabetes mellitus is a metabolic disorder characterised by dysregulation in blood glucose levels. Type 1 diabetes (previously known as insulin-dependent, juvenile or childhood-onset) is characterized by deficient insulin production and requires daily administration of insulin (IDF 2012). The cause of type 1 diabetes is not known and it is not preventable with current knowledge (IDF 2012). Type 2 diabetes (formerly known as non-insulin-dependent or adult-onset) results from the body’s ineffective use of insulin. Ninety per cent of people with diabetes, worldwide, have type 2 diabetes (IDF 2012). One of the major complications of diabetes is foot ulceration (Boulton 2004). A diabetic foot ulcer has been defined as either a full-thickness wound below the ankle in patients with diabetes, irrespective of duration (Apelqvist 1999), or a lesion of the foot penetrating through the dermis (Schaper 2004). The prevalence of foot ulceration in people diagnosed with diabetes is 4% to 10%; the annual population incidence is 1% to 4%, and the lifetime incidence is as high as 25% (Singh 2005). In a recent multi-centre study, poor glycaemic control (blood glucose control) was evident in nearly half of the participants who had foot ulcers, with 49% having an HbA1c (glycaemic measure) level above 8.4% (Schaper 2012).
Foot ulceration is caused by the interplay of several factors, most notably diabetic peripheral neuropathy (DPN, i.e. loss of sensation to the foot), peripheral arterial disease (PAD, i.e. lack of blood-flow) and changes in foot structure (Clayton 2009; Shenoy 2012). These factors have been linked to chronic hyperglycaemia (high levels of glucose in the blood) and the altered metabolic state of diabetes (Ikem 2010; Ogbera 2008; Tesfaye 2012).The prevalence of DPN ranges from 16% to 66% in people with diabetes (Cook 2012). The prevalence rates for PAD are as high as 50% in patients with diabetic foot ulcers (Hinchliffe 2012). What is most notable, is that within one year of an ulcer healing, up to 60% of patients will develop another foot ulcer (Wu 2007), and often the end point is lower limb-amputation.
It is currently estimated that there is an amputation every 30 seconds, somewhere in the world, that is due to diabetes (Game 2012). The estimated likelihood of amputation is 10 to 30 times higher amongst people with diabetes compared to those without diabetes and 85% of all amputations in people with diabetes are preceded by a foot ulcer (Boulton 2004; Singh 2005). The five-year mortality rate after the onset of a foot ulcer ranges from 43% to 55%, and is up to 74% for patients with lower limb amputation (Robbins 2008).
Description of the intervention
Chronic hyperglycaemia appears to be one of the most important factors in the development of diabetic foot ulcers, and the potential of ulcers to heal (Christman 2011; Falanga 2005). Current guidelines recommend that treatment should involve a multidisciplinary team, as well as utilising several interventions (Table 1). This review is performed to clarify the effect of intensive glycaemic control on the healing of foot ulcers in people with diabetes.
|Guideline and management recommendations|
Level of evidence
(According to Oxford Centre for Evidence-based Medicine - Levels of Evidence (March 2009))
National Health and Medical Research Council (NHMRC): Prevention, identification and management of foot complications in diabetes mellitus 2011
Note: as per NHMRC levels of evidence
National Clearinghouse Guidelines 2011
HbA1c < 7%
National Clearinghouse guidelines 2012
(treatment of neuropathic wounds)
Assessment by a wound expert
National Health Service (NHS): Type 2 diabetes: prevention and management of foot problems 2004
National Health Service (NHS): 2011 National Institute for Health and Care Excellence (NICE) clinical guideline. Developed by the Centre for Clinical Practice at NICE: Diabetic foot problems: inpatient management of diabetic foot problems
2012 International Working Group on Diabetic Foot (IWGDF): Global guideline for type 2 diabetes
< 8 mmol/l
Australian Diabetes Foot Network: Management of diabetes related foot ulceration - a clinical update
American College of Foot and Ankle surgeons 2006 (revision): Diabetic foot disorders – a clinical practice guideline
Scottish Intercollegiate Guidelines Network (SIGN) Guidelines 2010
American Diabetes Association Standards of Medical Care in Diabetes 2012
Foot ulcers and wound care may require care by a podiatrist, orthopedic or vascular surgeon, or rehabilitation specialist experienced in the management of individuals with diabetes
As per position Statement for optimal Control
The management of diabetes includes glycaemic control (Table 2) (Daroux 2010; Geraldes 2010; Giacco 2010; Inzucchi 2012). A common list of glycaemic control medications used in diabetes management is shown in Table 3. Most guidelines have a glycaemic control target of 7% or lower for HbA1c (glycated haemoglobin) (Table 2). The revised guidelines of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend individualisation, with more stringent (6.5% or lower) or less stringent (8% or lower) HbA1c targets as appropriate for individuals (ADA 2012; Cheung 2009; Inzucchi 2012). There is a marked variation in the definition of intensive glycaemic control between guidelines and trials (Hemmingsen 2011a). For the purposes of this review we will include trials where an intervention has been performed with the aim of achieving improved glycaemic control in comparison to a conventional control group.
|Country||Guideline||Year||Hba1c targets in adults|
Level of Evidence
(According to Oxford Centre for Evidence-based Medicine - Levels of Evidence (March 2009))
|Australia||National Health and Medical Research Council/Diabetes Australia|
|≤ 7%||Grade A|
|Australian Paediatric Endocrine Group/ Australian Diabetes Society||2011||≤ 7%||Grade D|
National Institute for Health and Care Excellence (NICE)
- Managing type 1 DM diabetes in adults
- Blood glucose lowering therapy for type 2 DM
≤ 7.5% if increased arterial risk
≤ 6.5% Between 6.5% and 7.5%
Scottish Intercollegiate Guidelines Network (SIGN)
- Type 1 Diabetes
- Type 2 Diabetes
No set figure
|2012||< 7% or individualize to a goal of < 8%||Grade B|
American Diabetes Association
≤ 7% or individualise to a goal:
|American Association of Clinical Endocrinologists||2011||≤ 6.5%||Grade D|
|International Diabetes Federation (IDF)||International Diabetes Federation- Global Guideline for type 2 Diabetes||2012||< 7.0%||U/K|
Canadian Diabetes Association
≤ 6.5% (may be considered to lower risk of nephropathy further)
Grade C, Level 3
Grade A, Level 1A
|Europe||European Association for the Study of Diabetes (EASD) and American Diabetes Association (ADA)||2012|
< 7% or individualise to a goal of:
6-6.5% (patients with short disease, duration, long life expectancy, no significant CVD)
7.5–8.0% (history of severe hypoglycaemia, limited life expectancy, advanced complications, extensive comorbid conditions and those in
|New Zealand||New Zealand Group Guidelines||2003||≤ 7%||Grade D|
|Class/Drug||Expected decrease in HbA1c|
|ORAL ANTIDIABETIC THERAPY|
|Intermediate-acting||Isophane (protamine suspension)|
|Methods of insulin delivery|
Most of the current glycaemic targets for diabetes are based on several landmark trials that investigated the effects of intensive glycaemic control compared to conventional treatments (Table 2) (Cheung 2009; Hemmingsen 2011b; Macisaac 2011; Mazzone 2010). The findings from these studies also illustrate the benefits and risks associated with intensive glycaemic control. Therefore, when investigating intensive glycaemic control as a potential intervention for diabetic foot ulcers, it is important to take into account the present literature underpinning current glycaemic management.
Intensive glycaemic control implemented in the Diabetes Control and Complications Trial (DCCT) and United Kingdom Prospective Diabetes Study (UKPDS) led to a reduction in the progression and development of microvascular (small vessel) complications including DPN (Mattila 2010). The UKPDS demonstrated a 37% reduction in the risk of microvascular complications for each 1% decrease in HbA1c (95% confidence interval: 33% to 41%) (UKPDS 1998; Stratton 2000). Similarly, the ADVANCE trial found a 14% relative risk reduction for major microvascular events in the intensive control group when compared to the standard control group (9.4% versus 10.9%; hazard ratio (HR) 0.86; 95% CI: 0.77 to 0.97), although mainly in terms of reduced incidence of nephropathy (kidney disease) (ADVANCE 2007).
A recent Cochrane review concluded that intensive glucose control reduced the risk of amputation by 36% in type 2 diabetes (relative risk (RR) 0.64, 95% CI: 0.43 to 0.95; 6960 participants in eight trials) (Hemmingsen 2011b). In addition there was an 11% relative risk reduction (RR 0.89, 95% CI: 0.83 to 0.95; 25,760 participants in four trials) and a 1% to 2% absolute risk reduction in composite microvascular outcomes in favour of intensive glycaemic control for all included trials (Hemmingsen 2011b). A number of meta-analyses have demonstrated that the incidence of hypoglycaemia (low blood sugar) was increased during intensive glycaemic control, making this a significant adverse outcome (Hemmingsen 2011b; Ma 2009; Mattila 2010). It must be noted that the beneficial effects on microvascular complications from using intensive glycaemic control took more than five years to emerge, and the benefits were less pronounced for people with advanced type 2 diabetes compared to those with new-onset type 2 diabetes (Hemmingsen 2011b; Mattila 2010). Despite this, data on retinopathy (disease of the retina) suggest that people with the advanced stages of type 2 diabetes may also benefit from intensive glycaemic control (Hemmingsen 2011a). The effects of intensive glycaemic control in people with type 1 diabetes demonstrated in the DCCT were still evident after 14 years of follow-up (i.e. long after the intervention was completed), and this phenomenon has been termed 'glycaemic memory' (Giacco 2010). More recent data suggests that glycaemic memory also occurs in people with type 2 diabetes, where it is termed the 'legacy effect', whereby benefits of earlier interventions are evident later on in disease progression (Giacco 2010).
While intensive therapy, with the goal of achieving near normal HbA1c levels (7%), has altered the clinical course of nephropathy, neuropathy and retinopathy, the majority of studies have not examined the benefits of intensive therapy when implemented after the onset of late diabetes complications, such as diabetic foot ulcers (Nathan 2012).
How the intervention might work
Hyperglycaemia has been associated with delayed healing of foot ulcers (Burakowska 2006; Christman 2011; D'Souza 2009; Falanga 2005; Rafehi 2010). Therefore, interventions that target improvements in glycaemic control are of potential benefit. Delayed healing of foot ulcers appears to be the net result of both microvascular and macrovascular disease (Burakowska 2006; Dinh 2005). Well-orchestrated wound healing is essential for tissue replacement and restoration, and generally involves three main phases: acute inflammation, proliferation, and remodelling (Rafehi 2010). In contrast, diabetic foot ulcers do not follow the orderly process of wound healing and differ at a molecular level in terms of expression of growth factors, cytokines and proteins (Dinh 2005; Rafehi 2010). These processes are known to be affected by hyperglycaemia.
Several proposed pathogenic pathways exist to explain the adverse effects of hyperglycaemia (Geraldes 2010). These include: 1) activation of the polyol pathway; 2) non-enzymatic glycosylation and formation of advanced glycation end products (AGEs); 3) activation of the diacylglycerol- (DAG) protein kinase C pathway; and 4) overactivity of the hexosamine pathway (Brownlee 2004; Geraldes 2010; Giacco 2010; Gupta 2010). All four mechanisms have been linked to a single, unified preceding event, namely mitochondrial overproduction of reactive oxygen species (ROS) (Brownlee 2004). ROS are known to promote cellular dysfunction through damage to DNA synthesis, oxidation of lipids and amino acids and inactivation of key enzymes in metabolic function, which are implicated in the formation of diabetic foot ulcers. Hyperglycaemia also promotes endothelial dysfunction, vascular leakage and impaired angiogenesis (formation of new blood vessels) originating from the above mentioned pathways, and leads to activation of the inflammatory response via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) (D'Souza 2009; Giacco 2010). The incidence of infection is also increased in people with diabetes, and different immunological disturbances, such as deficiencies in polymorphonuclear leukocyte, monocyte and macrophage (types of white blood cell) function have been noted during hyperglycaemia (Delamaire 1997; Stegenga 2008). All these factors, which are a consequence of hyperglycaemia, may play a role in delayed healing of foot ulcers.
A recent observational study showed that HbA1c was an important clinical predictor of the rate of wound healing; with each 1% increase in HbA1c level associated with a decrease in the wound healing rate of 0.028 cm² per day (95% CI: 0.003 to 0.054) (Christman 2011). Despite this, the effects of short-term reduction in HbA1c did not appear to have any effect on endothelial function in patients with type 2 diabetes with a history of poor glycaemic control (Bagg 2001). Therefore, there remains a clear need to document benefits associated with improved glycaemic control in the diabetic foot ulcer population (Idris 2005). While chronic complications of diabetes such as DPN and PAD maybe difficult to reverse, it can be postulated that aspects of ulcer healing relating to immunological and connective tissue function may be more amenable to improvement if normoglycaemia (normal level of sugar in blood) is achieved (Jeffcoate 2004).
Why it is important to do this review
Foot ulcers continue to be a significant burden for patients with diabetes, their caregivers and the healthcare system (Schaper 2012). The outcome of a foot ulcer in people with diabetes should not only be viewed from a clinical perspective (e.g. healing and amputation), but also from a patient and socioeconomic perspective. Health-related quality of life (HRQoL) is significantly reduced in patients with diabetes, and further impaired by the presence of foot disease, whilst it is improved with foot ulcer healing (Hogg 2012). Healthcare costs associated with foot ulcers and amputations contribute significantly to the financial burden of diabetes (Jones 2007). In the United States in 2008, the total number of discharges attributed to diabetes-related amputations was 45,000. The average length of stay was 10.1 days and the in-hospital mortality rate was 1.29% (Cook 2012). The mean hospital charges were USD 56,216 per patient and the estimated aggregate cost for the year 2008 was USD 2,548,319,965 (Cook 2012).
Therefore, foot ulceration in people with diabetes has substantial socioeconomic, quality of life, and health care implications, and it is imperative that all efforts be made to prevent and treat the burden of foot ulceration in order to reduce amputation rates - as highlighted by the St Vincent Declaration in 1989 (Game 2012). Optimum healing of a foot ulcer requires a well-orchestrated integration of molecular and biological events including, cell migration, proliferation, extracellular matrix deposition and remodelling, which is hindered by the effects of hyperglycaemia (Falanga 2005; Rafehi 2010).
Advances in the treatment of diabetic foot ulcers are promising, however the intrinsic pathophysiological abnormalities of hyperglycaemia that lead to ulceration and delayed ulcer healing cannot be ignored (Falanga 2005). Recent changes to glycaemic targets and current emphasis on individualisation of glycaemic targets seems to open a new era in diabetes management. The review authors believe that this systematic review and meta-analysis will assess the effectiveness of intensive glycaemic control in the management of diabetic foot ulcers.