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Diabetic Patient Treatment Burdens & DMO

2 CPD in Australia | TBA in New Zealand | 3 May 2017

 

By Dr. Jagjit Singh Gilhotra

 

Diabetes and its effective management can present immense challenges to both the patient and clinician. Most diabetic patients live with at least one co-morbid condition, while over 60 per cent will be managing three or more co-morbidities – each with their own associated symptom and treatment burdens. Healthcare professionals can play a role in lessening patient treatment burdens by reviewing and simplifying treatment regimens where clinically possible.

Hyperglycaemia creates an inflammatory environment which plays a central role in the pathogenesis and progression of diabetes and its vascular complications – including diabetic retinopathy and diabetic macular oedema. The pathophysiology of these potentially serious diabetic complications is complex and treatment can present its own problems for the patient and the clinician.

There are currently three major treatment classes for diabetic macular oedema – laser photocoagulation, corticosteroids, and anti-VEGF agents. Current intravitreal anti-VEGF diabetic macular oedema treatments require an intensive four–weekly intravitreal injection regimen with associated frequent appointments and treatment related anxiety. Patients can sometimes cease because of injection fatigue (burden of treatment), especially in the working age group as treatments can interfere significantly with work. A recently approved intravitreal steroid implant treatment option can play a role in reducing treatment frequency and treatment burdens for diabetic patients that are pseudophakic or scheduled for a cataract.

The Treatment Burden for Chronic Patients

The concept of the ‘patient’ has substantially changed over the last 50 years or so. What it means to be a patient has shifted as our understanding of disease and treatments have advanced – both in terms of how the typical patient is characterised and the role the patient plays within the healthcare process. Historically, the main healthcare focus has been on infectious and acute diseases, which were often rapidly fatal due to the limited effectiveness of available treatments. The typical contemporary patient can now be described as one with not only a non-communicable disease, but increasingly, one with a chronic or long-term condition – such as diabetes.2

Diabetes is the fastest growing chronic condition in Australia affecting about one in 19 of the population.3,4 The prevalence of all types of diabetes (type 1, type 2 and gestational) is rising4 and consequently the diabetic patient is increasingly encountered by today’s healthcare providers, who have to deal with both its short-term and long-term complications. For the eye health professional, long-term diabetic complications such as diabetic retinopathy and diabetic macular oedema are of particular concern as they are among the leading causes of preventable vision loss.5,6 All types of diabetic eye disease (including cataracts and glaucoma) have the potential to cause severe vision loss and blindness.

It is estimated that about half of the Australian population now lives with at least one chronic condition,7 with one in five experiencing multiple chronic conditions.3 This rise of the ‘chronic’ patient has impacted on the nature of the therapeutic processes employed as these conditions are typically not ‘cured’, but instead are ‘managed’ over a life-time2 – and both patients and healthcare providers have to contend with the challenges of multimorbidity.8

Table 1. Diabetes related health complications15

 

Figure 1. Summary of inflammatory pathway for the pathogeneses of diabetic microvascular complications. Adapted from Nguyen et al. 201214

 

The predominantly passive ‘sick role’ assigned to the patient and the close doctor-patient relationship has also metamorphosed into a patient centric network of healthcare providers shaped by policy, both corporate and governmental.2 Patients are now seen as proactive partners involved in all aspects of their own treatment.2 For example, today’s diabetes patient may be expected, on a daily basis, to be employed in a variety of activities including:9

  • Understanding the details and implications of their health conditions (including diabetes, diabetes-related and non-diabetes related conditions) tests and treatments
  • Finding support, planning how to attend healthcare visits, as well as being engaged in recommended self-care activities (such as lifestyle changes and polypharmacy)
  • Attending healthcare visits and actualising self-monitoring aspects of their care (such as remote monitoring through patient-managed devices)
  • Monitoring and evaluating the value of the work they are participating in.

The Diabetic Patient’s Treatment Burden

Diabetes can impose substantial treatment burdens on the individual patient. In addition to having to cope with the condition itself, the diabetic patient is at a significantly higher risk of developing multiple diabetes-related health complications.10 Most diabetic patients will have at least one co-morbid chronic condition and two thirds will have at least three.11

Diabetes and hyperglycaemia create an inflammatory environment that plays an important role in the development and progression of diabetes and its vascular complications (see Table 1).12 Inflammatory processes are believed to be involved in the onset of type 1 diabetes through the destruction of pancreatic islets, and in type 2 diabetes inflammatory factors are thought to be linked to insulin resistance.13 Hyperglycaemia can create epigenetic changes that promote the persistent expression of inflammatory-related genes in certain tissues (such as retinal cells), which can then lead to the dysregulation of inflammation and eventually chronic inflammation.13 Hyperlipidaemia, with elevated levels of cholesterol and triglycerides, may also contribute to inflammation and diabetic retinopathy.14

When uncontrolled chronic hyperglycaemia occurs, cytokines infiltrate vascular tissues and can inhibit both their function and repair leading to the vascular complications of diabetes (Figure 1).14 Chronic hyperglycaemia mediates multiple cellular pathways, including protein kinase C activation, free radical production, polyol accumulation, and advanced glycation end-products (AGEs) generation.13 The upregulation of proinflammatory cytokines, chemokines, and adhesion molecules follows. Vascular permeability is affected and leukocyte infiltration occurs, leading to diabetic retinopathy and other diabetic complications.13 Achieving and maintaining good glycaemic control is, therefore, essential if the patient is to minimise inflammation and potential diabetic complications.

Modern comprehensive diabetes care with improved HbA1c monitoring along with tighter glycaemic control and the use of other medications (such as aspirin, hypertension and lipid-lowering medications have the potential to reduce cardiovascular disease and other complications.16 However, they can impose significant treatment burdens on the patient. Diabetes care today has become an inherently complex process with multiple medications (for glycaemic control, other diabetes-related complications and co-morbidities), alongside lifestyle changes (diet and exercise) plus routine regular blood glucose self-monitoring.17

The daily tasks that a diabetic patient has to undertake in order to follow their comprehensive diabetes care plan are considerable. It has been estimated that a diabetic patient requires more than two hours a day to carry out all the recommended diabetes self-care tasks.1 These estimated extra two hours a day are based on an experienced diabetic patient undertaking the tasks – not a newly diagnosed, elderly or physically impaired patient who may require considerably more time. If there are also co-morbid conditions to be managed, then the amount of time (and energy) available to the patient for diabetes self-care can be markedly reduced.1

In a study, one person who described the impact diabetes has on his life said, "Between myself and my wife, we spend an average of 28 hours a week, every week ... just doing diabetes management…”18

Complex treatment regimens can mean patients are faced with an increasing (and continual), treatment burden. In diabetic patients, this can lead to physiological distress and a state called ‘diabetic burnout’.17 When this occurs diabetic patients begin to ‘overlook’ their disease management activities and in some cases completely stop their treatments.17 The treatment tasks for diabetes, like other chronic diseases, are continual daily requirements, however the complications that these therapies are preventing, such as diabetic retinopathy and diabetic macular oedema, are perceived as distant, something that could possibly happen in the future. Consequently, the diabetic patient is continually weighing up the immediate treatment burden effect on their quality of life against possible future complications.

In order for clinicians to successfully support the diabetic patient, it is important to understand (and acknowledge) the perceived treatment burden they face. Education, particularly early in the disease, on the natural progression of diabetes and the potential for associated complications can be useful, as can education on the types of treatments that may be required at each stage of the disease.17 It is also helpful to reassure patients that they can successfully manage their condition and adapt to life with the various recommended treatments, emphasising that the symptom and complication burden of diabetes can be significantly reduced by starting therapeutic interventions early and applying them rigorously and consistently. For example, beneficial outcomes of various treatments can include:19

  • Improved blood glucose control reduces the risk of retinopathy, nephropathy and neuropathy
  • Lipid-lowering treatments can reduce 
  • the risk of coronary heart disease and renal disease
  • Control of blood pressure and glucose retards the progression of diabetic renal disease
  • Lowering blood pressure reduces the risk for stroke, heart failure and retinopathy.

It is important for the diabetic patient to appreciate the importance of good glycaemic control and the damage elevated glucose levels can cause. Even if the patient’s HbA1c levels are very high there is still a substantial benefit to be gained in lowering them to a moderate or intermediate level (8-9 per cent) as the relationship between HbA1c and relative risk of vascular complications is non-linear (Figure 2) and the disease will progress more radiply.20

Diabetic Macular Oedema and the Diabetic Patient

Diabetic retinopathy is the most commonly occurring form of diabetic eye disease. It is a common complication of both type 1 and type 2 diabetes, and if left untreated can lead to progressive vision loss and blindness. Approximately one in three people with diabetes will show signs of diabetic retinopathy and one third of these will have vision threatening diabetic retinopathy.5 Globally, diabetic retinopathy is now considered the leading cause of preventable vision loss among working-age populations.6

Diabetic retinopathy is considered an inflammatory disease that involves changes to retinal blood vessels causing them to bleed or leak fluid and distorting vision.21 The most clinically important risk factors for the development of diabetic retinopathy and resultant vision loss in diabetic patients include: the duration of diabetes, hyperglycaemia and hypertension.5 Vision loss from diabetic retinopathy is primarily related to two conditions that occur in the late-stages of diabetes: diabetic macular oedema and proliferative diabetic retinopathy.6

Figure 2: Diabetes Control and Complications Trial: Relative risks for microvascular complications (retinopathy, nephropathy and neuropathy) related to mean HbA1C level during follow up. Adapted from Skyler 199620

 

Diabetic Macular Oedema

Diabetic macular oedema is a major complication of diabetic retinopathy and can occur at any stage in its progression – although the risk of diabetic macular oedema occurring increases with the increasing severity of diabetic retinopathy.6 The condition is seen in about 7 per cent of patients diagnosed with diabetes,5 and it is now the most common cause of visual impairment in diabetic patients in developed countries.6

Diabetic macular oedema is characterised by the thickening and swelling of the central retina. Exudative fluid accumulates in the intraretinal layers of the macula due to the breakdown of the blood retinal barrier with vascular leakage from compromised capillaries and microaneurysms.21 Clinically significant macular oedema (a subset of diabetic macular oedema) occurs when macular thickening arises close to the fovea.6

The pathogenesis of diabetic macular oedema is complex and involves multiple factors. Chronic hyperglycaemia leads to thickening of vascular basement membranes, non-enzymatic glycosylation, free radical formation (oxidative stress) and pericyte death – leading to vascular dilation, increased capillary hydrostatic pressure and microaneurysm formation.

Systemic and local inflammatory processes are thought to contribute to both diabetic retinopathy and diabetic macular oedema,12 with the complex pathogenesis involving interactions between and overlapping inflammatory, vascular, and neuronal mechanisms.12,22

Vascular changes resulting from inflammation include:12

  • Dilation of blood capillaries to increase blood flow
  • Vascular structural changes resulting in the release of plasma proteins from the bloodstream
  • Leukocyte migration and accumulation at the injury site.

Neural changes resulting from inflammation include:12

  • Microglial activation – production of inflammatory factors by activated microglia accumulated in the subretinal space helps the progression of diabetic macular oedema pathology
  • Müller cell dysfunction – pro-inflammatory factors affect the cell’s ability to clear fluid from the inner retinal tissue and contributes to the development of macular oedema. Intracellular oedema impairs the Müller cell’s glutamate transport function and can lead to retinal excitotoxicity and chronic inflammation. Müller cells are involved in the stabilisation of the retinal structure and modulation of inflammatory and immune responses.

The key inflammatory mediators involved in the pathogenesis of diabetic macular oedema are proinflammatory cytokines and vascular endothelial growth factor (VEGF).6 Increased concentrations of pro-inflammatory cytokines, VEGF and other inflammatory mediators can lead to chronic inflammation in the diabetic retina resulting in leucocyte activation, leukostasis and blood retinal barrier dysfunction.6 These various inflammatory processes are thought to be involved in the structural and molecular alterations associated with diabetic macular oedema, play a central role in the alteration of the blood retinal barrier, and include:23

  • Increased expression of endothelial adhesion molecules
  • Adhesion of leukocytes to the vascular endothelium (leukostasis)
  • Release of inflammatory chemokines, cytokines, and vascular permeability factors
  • Tight junction dysfunction in endothelial cells
  • Infiltration of leukocytes into the retina (diapedesis).

Treatment of Diabetic Macular Oedema

Diabetic patients who are able to maintain good glycaemic control along with reduced hypertension and dyslipidaemia levels, from an early stage, may be able to prevent the development of retinopathy and diabetic macular oedema. Once diabetic macular oedema has developed, however, treatment is often required to reduce its progression and slow the rate of vision loss.

The treatment aims in diabetic macular oedema have progressively changed from that of ‘maintenance’ or only reducing the rate of visual loss, to that of the reversal of vision loss. There are currently three major treatment classes for diabetic macular oedema – laser photocoagulation, corticosteroids, and anti-vascular endothelial growth factor (anti-VEGF) agents:12

  • Laser photocoagulation: uses the heat from a laser to seal or destroy abnormal, leaking blood vessels in the retina.
  • Corticosteroids: can help regulate the local expression of proinflammatory and anti-inflammatory mediators. Steroid treatment has been associated with reductions in several inflammatory mediators such as TNF-α, IL-6, MCP-1, and VEGF.
  • Anti-VEGF agents: these agents inhibit the biologic activity of VEGF which plays a key role in vascular permeability and angiogenesis.

Macular laser photocoagulation has previously been the mainstay of diabetic macular oedema treatment, but more recently alternative treatment options are being used that may provide long-term improvement in visual acuity. These treatments include intravitreal corticosteroid therapies and intravitreal anti-VEGF agents.24

In Australia, there are currently three approved products for the treatment of diabetic patients that have visual impairment due to diabetic macular oedema:

  • One corticosteroid treatment administered by intravitreal implant (administered approximately every four to six months)

Dexamethasone (Ozurdex; Allergan) is a potent corticosteroid which suppresses inflammation by inhibiting multiple inflammatory cytokines (including VEGF) resulting in decreased oedema, fibrin deposition, capillary leakage and migration of the inflammatory cells.25

Ozurdex is PBS listed (Authority Required) for the treatment of adults with diabetic macular oedema who have already had cataract surgery or are scheduled to have cataract surgery, and are unsuitable for treatment with an anti-VEGF, or have had an insufficient response to an anti-VEGF or are contraindicated for an anti-VEGF. Ozurdex is required to be administered by an ophthalmologist.26

  • Two anti-vascular endothelial growth factors (anti-VEGFs) administered by four-weekly intravitreal injections.27

Aflibercept (Eylea; Bayer) is a recombinant fusion protein mimic of VEGFR-1 and VERGR-2 and the Fc region of a human immunoglobulin G1 (IgG1). It acts as a decoy receptor binding VEGF-A with higher affinity.27

Ranibizumab (Lucentis; Novartis) is humanised monoclonal antibody fragment that binds to VEGF-A with high affinity preventing it from binding to its receptors, VEGFR-1 and VEGFR-2.27

Eylea and Lucentis are PBS listed (Authority Required) for the treatment of adults with diabetic macular oedema and are required to be administered by an ophthalmologist.26

Diabetic Macular Oedema and Treatment Burdens

The type of therapy used to treat diabetic macular oedema can have a significant impact on the diabetic patient’s quality of life and overall treatment burden.

Patients’ quality of life can be severely affected by having to manage an intensive intravitreal injection regimen.28 A recent survey found that patients undergoing intensive intravitreal injection therapies spent about 20 hours every six months attending approximately 19 appointments with a number of different healthcare providers – this is in addition to other health related appointments for any co-morbid conditions they may have.28 On average, patients were found to spend a total of about four and a half hours per injection appointment (which also included nearly an hour and 20 minutes of travel time).28 Most patients required support from a carer for each injection session and during recovery, and the majority of working carers and patients needed to take time off work to attend these appointments.28

Intravitreal injection therapy can also cause high levels of anxiety in some patients. The survey showed that the majority (75 per cent) of diabetic macular oedema patients reported experiencing anxiety during their intravitreal injections, with over half feeling anxious for two or more days prior to their scheduled treatment.28

The most desired improvement to their intravitreal injection treatment regimen, requested by 42 per cent of patients, was to have fewer injections. Another 22 per cent of patients wished to have fewer appointments to achieve the same visual results.28

Current recommendations for approved anti-VEGFs intravitreal injection treatments is to initiate therapy with one injection per month, until maximum visual acuity is achieved or there are no signs of disease activity.29,30 In two key ranibizumab parallel clinical trials, diabetic macular oedema patients received an average of 20.9 (SD 6.2) and 21.9 (SD 5.8) injections (RISE and RIDE 0.5 mg ranibizumab dose arms respectively) over the two-year trial period.31,32 Patients in similar aflibercept clinical trials treated with four-weekly injections over a one-year period received, on average, 11.8 (SD 2.6) and 12.2 (SD 2.6) injections (VISTA and VIVID 2.0 mg arms respectively).33 When aflibercept was administered initially in four-weekly doses for five months and then subsequently every eight weeks, patients received an average of 8.4 (SD 1.3) and 8.7 (SD 1.2) injections (VISTADME and VIVIDDME 2 mg arms respectively) over the same one-year period.33

The current recommendation for dexamethasone intravitreal implant treatment of diabetic macular oedema is to treat approximately six-monthly, depending on when signs of disease activity reappear.25 In clinical trials of dexamethasone intravitreal implants, the majority of re-treatments were administered at five to seven month intervals after a prior treatment – with patients receiving an average of 4.1 (SD 2.0) 0.7 mg implants over three years.25,34

Take Home Message

It is important to understand that there can be a significant level of treatment burden imposed on a patient who has a chronic disease such as diabetes. This burden can reduce the patient’s ability to follow management plans, particularly where there are multiple co-morbidities involved. The healthcare professional can play a role in lessening patient treatment burdens by reviewing and simplifying treatment regimens where clinically possible. 

       

Dr. Jagjit Singh Gilhotra (Jolly) graduated from the University of Sydney Medical School in 1996 and trained in ophthalmology at Sydney Eye Hospital and Royal Victorian Eye and Ear Hospital from 2001 to 2004 before undertaking a fellowship training in medical and surgical retina. He is involved in research and training in medical retina and vitreo-retinal surgery at the South Australian Institute of Ophthalmology and the Royal Adelaide and Queen Elizabeth Hospitals. He has published papers in peer-reviewed journals and is a reviewer for ophthalmic journals. His main interests include macular degeneration, macular surgery, diabetic eye disease and uveitis.

Dr. Gilhotra is a Fellow of the Royal Australian and New Zealand College of Ophthalmologists, the Australian and New Zealand Society of Retinal Specialists, the American Society of Retinal Specialists, and the Oceanic Retina Association.

 

References
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Eylea is a registered trademark of the Bayer Group; Lucentis is a registered trade mark of Genentech Inc; Ozurdex is a registered trademark of Allergan Inc.
This article was commissioned by Allergan.

' Globally, diabetic retinopathy is now considered the leading cause of preventable vision loss among working-age populations '