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Diabetes Mellitus: Epidemiology and Ocular Manifestations

2 CPD in Australia | 1CD + 0.4G in New Zealand | 30 May 2017

By Dr. V. Swetha Jeganathan and Clinical Associate Professor Nitin Verma AM

Diabetes Mellitus (DM) is a chronic disease associated with abnormally high levels of glucose in the blood. Besides being a significant cause of morbidity and mortality worldwide, diabetes is one of the leading causes of blindness and  visual impairment in the working age group. A person with diabetes has 25 times the risk of blindness compared to someone without the disease.

Commonly, diabetes mellitus is due to:

  1. Inadequate production of insulin (Type I or Insulin dependent diabetes T1DM) or;
  2. Inadequate sensitivity of cells to the action of insulin (non-insulin dependent or Type II diabetes (T2DM);
  3. Gestational diabetes.

 

Diabetes mellitus (DM) has serious complications with many parts of the body such as the eyes, kidneys, peripheral nerves and the circulatory system, affected by the condition. It may also result in premature death. Individuals with DM are often in their most productive years. No country, socioeconomic class or race is exempt from the ravages of the disease. Specifically:

  1. Diabetes mellitus is one of the fastest growing chronic debilitating metabolic diseases in the world. In one of two adults worldwide, diabetes is undiagnosed.1
  2. In Australia diabetes is the most common reason for commencing renal dialysis; for non-traumatic lower-limb amputation and one of the most common chronic diseases in children.2
  3. 12 per cent of the global health expenditure is spent on diabetes.1
  4. Deaths from diabetes (estimated at around 5 million/annum are more than from HIV /AIDS (1.5 million), Tuberculosis (1.5 million) and malaria (0.6 million).1
  5. Diabetic retinopathy (DR) is the leading cause of serious vision loss in workingage Australians, with a major impact on independence and quality of life.3
  6. Population-based studies show that between 30–50 per cent of Australians suffering from DM are not appropriately screened for retinopathy.4
  7. Eye health is often not a priority for people with diabetes because diabetic eye disease (DED) is often asymptomatic until its advanced stages.5
  8. Of those with known diabetes, it is estimated that between 22–50 per cent of non-Indigenous Australians and 48–80 per cent of Indigenous Australians do not have their eyes tested at the frequency recommended by the National Health and Medical Council (NHMRC).4
  9. Most diabetes-associated vision loss is preventable. Timely detection of DED and control of major diabetes risk factors are key to preventing vision loss.3
  10. Optometrists are in a unique position to increase patient awareness about DED, facilitate early detection with costeffective screening, and assist in disease management and treatment.6
  11. Promoting a healthy lifestyle, addressing risk factors and early treatment can significantly improve visual prognosis and reduce other micro and macrovascularcomplications.7,8
  12. Effective communication and collaboration with ophthalmologists improved patient care, decreased health care costs, and better disease outcomes.9

 

EPIDEMIOLOGY OF DIABETES MELLITUS

DM has reached epidemic proportions across the world. The prevalence and incidence of the disease continues to rise relentlessly. The International Diabetes Federation (IDF) statistics from 2015 and projections for 2040 are presented in Table 1. In 2015 one in 11 adults had diabetes; by 2040, this figure will be one in 10! Of those affected, 52 per cent are male, 65 per cent live in urban areas, 75 per cent are located in low and middleincome countries and 90 per cent have type II diabetes (T2DM). Every year five million deaths are attributable to diabetes. Increasing levels of obesity, sedentary lifestyles, and increased longevity have dramatically increased the prevalence of T2DM globally (see Figure 1).1

Table 1: A summary of diabetes worldwide: Persons affected and associated costs (US dollars), 2015 and 2040 estimates. Source: The IDF Diabetes Atlas 20151

 

In 2014–15 an estimated 1.2 million Australians (5 per cent) had diabetes, 86 per cent of them with T2DM.10 However these data, from self-reported cases, are likely to underestimate the true prevalence of the condition. Many people with T2DM are not aware that they have it until they develop complications, which may be many years after the onset of diabetes. Results from the AUsDiab2 study suggested that for each case of diabetes detected, one case remained undiagnosed. A similar result was reported by the 2011–12 Australian Health Survey where a combination of self reported data and fasting blood sugar levels identified that for every four diagnosed cases there would be one undiagnosed  case of diabetes and three others, with elevated fasting glucose putting them at high risk of developing the condition.10

Figure 1: Estimated age adjusted worldwide prevalence of diabetes. Source: IDF Diabetes Atlas 20151

 

As elsewhere in the world, the incidence and prevalence of T2DM in Australia increases with age (see Figure 2) and lower socioeconomic status.2,12 Other risk factors include: being overweight or obese; smoking, hypertension and having a fruit and vegetable intake and physical activity level lower than the NHMRC guidelines.7

Figure 2: Prevalence of diabetes in adult Australias, by age and sex, 2014-2015. Source: AIHW analysis of ABS Microdata:10 National Health Survey (NHS) 2014–15. Age-standardised to the 2001 Australian Standard Population.11

 

In contrast the incidence of T1DM, which is independent of the lifestyle factors associated with T2DM, remains. Between 2000 and 2013, 10 to 13 new cases of T1DM were diagnosed each year.12 The incidence was highest in children under 15  years (24 per 100,000 compared to eight per 100,000 in those 15 and over). In the same period the age-adjusted incidence rates for T1DM were lower in remote and very remote areas (seven cases per 100,000 per year) than in inner and  outer regional areas and major cities of Australia where rates were between 11 and 13 cases per 100,000 per year.13

Diabetes Mellitus in Indigenous Populations in Australia and New Zealand

Indigenous populations in Australia and New Zealand have a higher prevalence (three times) and an earlier onset of T2DM.14,15,16 The prevalence of T2DM is also higher in women than men, and is twice as common in remote communities than in urban areas14 (see Figure 3). In contrast the incidence (and prevalence) of T1DM is lower (seven per 100,000 compared to 10 per 100,000 per year between 2005 and 2013) than non-indigenous populations.13

Figure 3: Age standardised prevalence of diabetes by indigenous status and remoteness, 2011–13. Figures based on a combination of self reported information on diabetes diagnosis and medications use, HbA1c results. Source(s): Cardiovascular disease, diabetes and chronic kidney disease – Australian facts: Aboriginal and Torres Strait Islander people. 2012–13 Australian Aboriginal and Torres Strait Islander Health Survey and 2011–12 Australian Health Survey.14

 

The prevalence of undiagnosed versus diagnosed T2DM among Indigenous Australians has not been fully determined. In 2012–13 the Australian Aboriginal and Torres Strait Islander Survey (AATSIHS) used fasting and non-fasting blood glucose levels and self-reported data and reported that 11 per cent of those survey respondents had T2DM, of whom 1.5 per cent were not previously diagnosed. A further 4.7 per cent had elevated fasting glucose levels, suggesting a high risk of  developing T2DM.12,14 The survey also reported that indigenous adults had a higher prevalence of behavioral and biological modifiable risk factors associated with T2DM than the non-indigenous population.17,18 Using blood sugar measures in addition to self-reporting identified that in some age groups up to 29 per cent of Indigenous Australians with DM may be undiagnosed.19

DM is an underlying or associated cause for at least one in five of all deaths of Indigenous people and is a major contributing factor to the 10 to 20–year reduced life expectancy compared to the non-Indigenous population.14,19 Diabetes accounts for up to six times more visual loss in the Indigenous compared to non-Indigenous population and was the most commonly reported long term health condition in the 2012–13 AATHIS.19 Without appropriate medical management, one third would be expected to be legally blind within three years.

Diabetes Mellitus in Overseas Born Australians

Ethnic minorities living in industrialised countries face an increased risk of developing diabetes and those living in Australia are no different.11 Australian residents who speak languages other than English at home have a higher prevalence of self-reported diabetes (8.6 per cent) compared to those who speak only English (4.9 per cent).20 The age adjusted prevalence of diabetes, according to place of birth, is presented in Figure 4.

Figure 4: Diabetes age adjusted prevalence by population characteristics. Source: National Health Survey: First Results, 2014–1511 Includes Type 1 and Type 2 diabetes, and type unknown. Estimates include persons who reported they had diabetes but that it was not current at the time of interview. These persons were excluded from previous estimates of diabetes published in Australian Health Survey: First Results, 2011-12 (cat. no. 4364.0.55.001).

 

DIABETES MELLITUS IN PREGNANCY

In Australia approximately 5.3 per cent of all pregnancies are affected by diabetes. The majority are gestational diabetes mellitus (GDM) that resolve after the pregnancy. 1.5 per cent of cases diagnosed during pregnancy are T2DM or are GDM that persists post partum as T2DM. An increase in the prevalence of gestational T2DM over the last 10 years is a reflection of an earlier onset of T2DM in the community and women becoming pregnant later in life. The prevalence of pre-existing GDM in Aboriginal and Torres Strait Islander women is 1.6 per cent of pregnancies, 1.5 per cent being T2DM. This is ten times higher than non-indigenous Australian women but the highest rate of pre-existing diabetes in pregnancy occurs in Middle Eastern and North Africa women, with incidence rates of 3.1 per cent.21

AUSDRISK: THE AUSTRALIAN DIABETES RISK ASSESSMENT TOOL

Results from the five year follow up of AUSDIAB22 were used to develop a diabetes risk assessment tool to predict incident diabetes based on demographic, lifestyle and simple anthropometric information of Australian residents. The Australian diabetes risk assessment tool (AUSDRISK) has been validated and is now accessible by both patients and health professionals to assess an individual’s five-year risk of developing diabetes.23 It is available at: www.health.gov.au/preventionoftype2diabetes.

OCULAR INVOLVEMENT IN DIABETES MELLITUS

DM affects all parts of the eye and ocular adnexae.24 Generally all those with T1DM and more than 60 per cent of those with T2DM will develop diabetic eye disease at some time in their life. Some of the changes seen in diabetes mellitus include:

  1. Dry eyes, recurrent corneal erosion syndrome, hypoesthesia with risk of neurotrophic corneal ulcers
  2. Miosis, difficulty in dilating pupils
  3. Primary open angle glaucoma, neovascular glaucoma
  4. Cataracts, refractive error changes
  5. Diabetic retinopathy (DR), retinal vascular occlusions, vitreous hemorrhage
  6. Asteroid hyalosis
  7. Anterior ischemic optic neuropathy, diabetic papillopathy
  8. Cranial nerve palsies
  9. Orbital mucormycosis


The most important and common ocular complication in people suffering from DM is diabetic retinopathy (DR). It is characterised by the presence of: microaneurysms; hemorrhage; exudation; vascular abnormalities; ischemic changes; neovascularisation and oedema. In a patient with DM, one or more of these changes may be present at any one time.25 They may also be seen individually or collectively in other conditions affecting the retina in patients without DM.

DIABETIC RETINOPATHY

Epidemiology

The World Health Organization estimates that DR accounts for 37 million cases of blindness worldwide and that the global prevalence of DR will increase to 191 million by 2030.1

A pooled analysis of population-based studies published between 1980 and 2008 estimated the overall prevalence of any DR in 22,896 individuals with DM (T1DM or T2DM) to be 34.6 per cent.26 In studies where the diabetes type was reported, the estimated prevalence of DR in patients with T1DM was higher than in patients with T2DM. There is evidence that the incidence of DR in patients with T1DM is declining as a consequence of improved health care. However, the prevalence in T2DM patients continues to rise.8

In Australia, large population-based studies including the Blue Mountains Eye Study,27 The Melbourne Visual Impairment Project28 and AusDiab29 reported that between 22 and 35 per cent of individuals with self-reported diabetes may have DR and up to seven per cent may have sight threatening eye disease (Table 2).

The recent Australian National Health Survey (2015–16) collected data from a random selection of locations according to remoteness.33 The overall results were in alignment with previous studies34 but it was clear that DR, PDR, macular edema (ME) and vision threatening diabetic retinopathy (VTDR) were more common in the Indigenous population (39.4 per cent, 4.4 per cent, 3.8 per cent and 9.5 per cent) than the non-indigenous population (28.5 per cent, 1.5 per cent, 5.5 per cent and 4.5 per cent) respectively. Other than indigenous status, the strongest risk factors for both DR and VTDR were age, duration of diabetes and remoteness.35 Other risk factors for development of DR include poor glycemic control, hypertension and pregnancy. Associations with obesity, smoking, hyperlipidemia, nephropathy and insulin/hypoglycemic tablet use are not elucidated.

Pregnancy has been established as an independent risk factor for DR progression in women with pre-existing diabetes (T1DM or T2DM). DR progression generally occurs at the beginning of pregnancy, in the first and second trimesters. 

However, women with true GDM, where exposure to high blood sugars is a temporary condition, are not generally at risk of developing DR.21

Pathogenesis

Hyperglycemia has been associated with hematological, biochemical and paracrine alternations in the retina. Such changes trigger the release of chemical mediators with pro-angiogenic and vasopermeability properties8,36 and results in: thickening of the basement membrane; pericyte cell loss and the development of neovascularisation and/or macular edema. Local inflammation has also been identified as an important causal factor in the pathogenesis of diabetic macular edema (DME).36,37

Clinical Presentation

Diabetic retinopathy can be nonproliferative (NPDR) or proliferative(PDR) as determined by the presence (proliferative) or absence (non-proliferative) of abnormal new blood vessels (retinal neovascularisation).25
The first clinical sign of DR is the presence of a microaneurysm. As the disease progresses, intraretinal hemorrhages start to develop. These may be dot, blot (deep), or flame shaped (superficial) based on their location in the retina. Further progression is associated with retinal ischemia, cotton wool spots, tortuosity of the veins, venous beading and intraretinal microvascular abnormalities (IRMA).

Progressive ischemia often leads on to the development of neovascularisation and fibrovascular proliferation. These changes may be localised to the disc (new vessels at disc or NVD) or at the junction of the perfused and non-perfused retina (new vessels elsewhere or NVE). Left untreated these could result in vitreous hemorrhage and retinal detachment.

The International Clinical Diabetic Retinopathy Disease Severity Scale38,39 is based on the findings of the Wisconsin Epidemiologic Study of Diabetic Retinopathy and the Early Treatment of Diabetic Retinopathy Scale.

It has five levels:

1. No DR

2. Mild NPDR

  • One or more microaneurysm/s

3. Moderate NPDR

  • Microaneurysms
  • Retinal hemorrhages (dot, blot)
  • Hard exudates
  • Cotton wool spots
  • Venous beading
  • Arteriolar narrowing
  • Intraretinal microvascular abnormalities(IRMA)

4. Severe NPDR

The diagnosis of severe NPDR is based on the 4:2:1 rule. All of the above (in moderate NPDR) plus any one of the following: blot hemorrhages in four quadrants, venous beading in two quadrants or IRMA in one quadrant.

5. PDR

Early PDR:

  • NVD or within 1-disc diameter of the optic nerve head (DD) or elsewhere(NVE)
    High risk PDR:
  • NVD greater than ¼ DD
  • NVD less than ¼ DD with vitreoushemorrhage
  • NVE greater than ½ DD with vitreous hemorrhage

DIABETIC MACULAR EDEMA

Diabetic macular edema (DME) is the commonest cause of visual loss in diabetes. It is characterised by thickening of the macula secondary to the breakdown of the blood retinal barrier. Over expression of vascular endothelial growth factor (VEGF) has a major part to play in the pathogenesis of this condition.36

The meta-analysis of international studies by Yau et al26 suggested that of the 93 million people with DR globally 21 million have DME and 28 million have vision-threatening diabetic retinopathy and that over a period of three years, 24 per cent of eyes with DME will experience three lines of visual loss.

DME is categorised as follows:

Based on location:

  • Focal edema - well circumscribed retinal leakage associated with complete or incomplete rings of perifoveal hard exudates.
  • Diffuse edema – diffuse retinal thickening.
  • Ischemic macula

Or according to severity:

  • When the edema involves the centre (severe DME)
  • When the edema threatens the centre (moderate DME)
  • Is far from the centre (mild DME)

Clinically significant macular edema (CSME) includes any one of the following:

  • Retinal thickening at, or within, 500ηm of the centre of the macula
  • Hard exudates at or within 500 ηm of the centre of the macula associated with thickening of the adjacent retina
  • An area or areas of retinal thickening at least one-disc area in size, at least a part of which is within one-disc diameter of the centre of the macula.
  • A visual loss of two lines or more

Ocular Coherence Tomography (OCT) is a non-invasive, non-contact, transpupillary imaging modality which has greatly increased our understanding of DME and its management. Changes on OCT are seen in eyes of diabetic patients even before DR/DME develop.40

Ocular involvement in DM is often asymptomatic until development of macular edema; macular ischemia; significant retinal or vitreous hemorrhage;or retinal detachment.

Figure 5. Moderate, non-proliferative Diabetic retinopathy (fundus photo and fluorescein angiogram).

 

Figure 6. Diabetic retinopathy with proliferative changes (wide angle fundus photo).

 

Figure 7. Proliferative diabetic retinopathy with scattered vitreous hemorrhage (fundus photo).

 

Figure 8: Macular edema (fundus photo and OCT).

 

Figure 9: Macular ischemia (fluorescein angiogram).

 

DIABETIC EYE CARE PROGRAMS IN AUSTRALIA AND NEW ZEALAND

Despite the success of numerous pilot studies4 there is currently no universal DR screening program in Australia. Screening for diabetic eye disease is carried out mainly by optometrists and ophthalmologists. In some areas general practitioners are active in carrying out screening and recently a Medicare Benefit Schedule item number has been introduced for GPs to carry out fundus photography for this purpose. Teleophthalmology is a cost-effective, accurate, and reliable method for DR screening.4 Early detection and prompt treatment can significantly decrease the risk of severe vision loss. The Lions Outback Vision van (outbackvision.com.au/outbackvision-van), which conducts real-time tele ophthalmology programs in rural Western Australia, and the Indigenous Diabetes Eyes and Screening (IDEAS) van in Queensland (ideasvan.org) operate with a similar aim, to provide quality specialist eye care to Indigenous Australians in  
regional and remote communities. The prevalence of sight-threatening diabetic eye diseases, and any retinopathy, has been shown to be significantly lower in diabetic patients who undergo DR screening.4

However, screening does not replace regular eye examinations. The New Zealand National Diabetes Retinal Screening program, introduced in 2001, is administered by the District Health Boards who out-source the program to providers (diabetes centres, local hospital eye departments, ophthalmologists and optometrists). Patients are referred into the retinal screening service by their general practitioner. The National Diabetes Retinal Screening Grading System and referral guidelines were upgraded in 2016 and can be accessed at health.govt.nz/publication/diabetic-retinalscreening-grading-monitoring-andreferral-guidance.

A number of screening protocols have been published by different organisations around the world, including Optometry Australia.42 RANZCO recently introduced new guidelines in Australia and New Zealand,43 incorporating the 2008 National Health and Medical Research Council (NHMRC) Guidelines.44 The RANZCO version recommends that:

  • All patients with DM should undergo screening for DR at the time of diagnosis of diabetes and then every two years if no retinopathy is present.
  • Children with T1DM should begin screening for DR when they reach puberty.
  • Patients with DM who present opportunistically for optometric review should be screened for DR and the results of the screening examination communicated to their physician in the same way as a patient who is referred specifically for DR screening.
  • Patients already under the care of an ophthalmologist for management of diabetic eye disease do not require repeat screening, provided they are taking part in a regular programme of monitoring and treatment.
  • Pregnant women with a history of DM should be screened for the presence of DR in the first trimester of pregnancy, but women who develop GDM, but have no history of diabetes do not require screening for DR.

Annual screening for Diabetic Retinopathy should be undertaken routinely for the following groups of patients:

  • Those with diabetes of more than 15 years duration;
  • Those with poor glycemic control (HbA1c > 8 per cent or 64 mmol/mol);
  • Those with evidence of systemic disease e.g. those with:

– poorly controlled hypertension, blood lipids;
– other diabetic complications such as cardiac, cerebrovascular, or renal disease;
– foot ulcers (neuropathy, peripheral vascular disease).

  • Indigenous patients and patients with a non-English speaking background.

An overview of the current RANZCO guidelines is presented in Figure 11. The full guidelines are available at ranzco. edu/ophthalmology-and-eye-health/collaborative-care/referral-pathwayfor-diabetic-retinopathy. It is important to remember that these guidelines are recommendations and should be adapted to the individual circumstances of each patient. They are part of a living document and are evaluated on a continuous basis to further refine them. A national screening program for DR is urgently needed.

The University of Melbourne and the Centre for Eye Research Australia have recently developed a free self-directed online DR grading course for general practitioners and other health professionals.45 It provides an overview of the stages of DR and DME, using retinal photography, and an outline of the referral plan for each stage. A competency based examination is completed at the end of the course and, in order to achieve accreditation, a pass mark of greater than 75 per cent is required. See http://drgrading.iehu.unimelb.edu.au/cera/index.asp

 

Figure 10: Outreach eye care services in Western Australia and Queensland

 

CONCLUSIONS

Diabetes and its complications, including those in the eye, are increasing globally. Optometrists play a key role in screening for and monitoring diabetic retinopathy. They have the knowledge, skills and the diagnostic equipment required to perform ocular examination. Understanding the gravity of the situation in Australia and globally is important. Strict control of diabetes reduces the risk of diabetic retinopathy developing. Early diagnosis and prompt, effective, treatment can prevent visual loss. Better understanding of the disease and its treatment is useful in achieving this. Knowledge of current guidelines for screening and management of diabetic retinopathy will assist optometrists in their decision making process to effect a multidisciplinary, collaborative, approach to tackle this disease and achieve better visual outcomes for their patients.

Figure 11: RANZCO Referral pathway for DR 2016

 

     Dr V.Swetha E. Jeganathan is a post-doc clinical research fellow in e-health at the Kellogg Eye Center, Michigan Medicine, USA, and is Chair for Careers outside Academia for the University of Michigan Post-Doc Association. Graduating from Monash University in Australia, she attained first class honors for her MPhil in Ophthalmology, at the University of Melbourne in Australia, where she studied the retinal complications of diabetes under supervision of Professor Tien Wong at the Singapore Eye Research Institute and Centre for Eye Research Australia. Her additional qualifications include Master of Applied Management in Public Health (University of Newcastle, Australia), Graduate Certificate in International Health (Curtin University, Australia), Postgraduate Diploma in Cataract and Refractive Surgery (University of Ulster, UK), and Postgraduate Certificate in Academic Practice (University of Edinburgh, UK). She has more than 35 peer-reviewed publications, and has been awarded the Fellowship from the Higher Educators Academy in the UK for her educational contributions.  
     
  Clinical Associate Professor Nitin Verma AM studied medicine at CMC, Vellore, India, and has ophthalmology qualifications from India, Germany and Australia. He is a Director on the board of RANZCO, the RANZCO Eye Foundation and Macular Disease Foundation Australia. Dr. Verma is a Hospitaller of St John Ambulance Australia, and the Chair of the Research Committee and a member of the Medical Advisory Committee of Macular Disease Foundation Australia. He is a Member of the RANZCO Specialist International Medical Graduate Committee, President of the Tasmanian Medical Volunteers, Secretary of the Asia Pacific Academy of Ophthalmology Gateway Project, and a coordinator of the East Timor Eye Program which is run under the umbrella of the Royal Australian College of Surgeons. Dr. Verma’s many awards include the title of Member of the Order of Australia (2010) and the Order of Timor Leste.


References to this article are available at www.mivision.com.au/diabetes-mellitusepidemiology-&-manifestations

The authors thank Beverley Curry and Robert Cummins for their assistance in preparing this manuscript.

' Diabetes and its complications, including those in the eye, are increasing globally. Optometrists play a key role in screening for and monitoring diabetic retinopathy. '