Year : 2018 | Volume
: 9 | Issue : 3 | Page : 73--77
Systemic Factors Affecting Diabetic Retinopathy
Brijendra Kumar Srivastava, B Ramya, V Prathiba, V Mohan
Dr. Mohan's Diabetes Specialties Centre, Madras Diabetes Research Foundation, Chennai, Tamil Nadu, India
Dr. Brijendra Kumar Srivastava
Dr. Mohan's Diabetes Specialities Centre, No. 6, Conran Smith Road, Gopalapuram, Chennai - 600 086, Tamil Nadu
Diabetic retinopathy (DR) is one of the leading causes of preventable blindness in the world. Apart from local pathophysiological changes happening at the level of retina, various systemic factors also play a role in pathogenesis and progression of DR. In this article, we will discuss systemic factors affecting DR such as hyperglycaemia, hypertension, hyperlipidaemia, nephropathy, pregnancy, anaemia and cardiovascular disease, with their association to progression of DR.
|How to cite this article:|
Srivastava BK, Ramya B, Prathiba V, Mohan V. Systemic Factors Affecting Diabetic Retinopathy.J Diabetol 2018;9:73-77
|How to cite this URL:|
Srivastava BK, Ramya B, Prathiba V, Mohan V. Systemic Factors Affecting Diabetic Retinopathy. J Diabetol [serial online] 2018 [cited 2020 Feb 23 ];9:73-77
Available from: http://www.journalofdiabetology.org/text.asp?2018/9/3/73/239564
Diabetic retinopathy (DR) is one of the leading causes of preventable blindness in the world. Amongst the non-communicable diseases, diabetes mellitus is fast becoming a global epidemic, resulting in huge public health burden. Based on 2015 International Diabetes Federation report, India has 69.2 million people with diabetes, which can increase to 123.5 million by 2040. Diabetes mellitus can cause microvascular (retinopathy, neuropathy and nephropathy) and macrovascular (cardiovascular disease [CVD], peripheral arterial disease and cerebrovascular disease) complications. In the Chennai Urban Rural Epidemiology Study (CURES), the overall prevalence of DR was 17.6%, with 20.8% of the known diabetic patients and 5.1% of patients with newly detected diabetes having DR. The prevalence of DR in the Aditya Jyot Diabetic Retinopathy in Urban Mumbai Slums Study was 15.37%. A recent study from Sankara Nethralaya, Chennai, has also shown the prevalence of DR amongst urban diabetic patients (aged >40 years) to be 18%.
The two sight-threatening stages of DR are proliferative diabetic retinopathy (PDR) and diabetic macular oedema (DME). In the CURES, higher glycated haemoglobin (HbA1c), long duration of diabetes, male gender, microalbuminuria and insulin therapy were found to be risk factors of DR. The other associated risk factors are anaemia, lipid abnormalities, systemic hypertension, pregnancy, nephropathy and CVD. In a recent meta-analysis done in type 1 diabetes across different studies and populations, hyperglycaemia was found to be the most consistent risk factor for DR.
Structural and functional alterations occur in both microvascular and neuroglial components of the retina and number of factors are associated with causation and progression of DR. In this review article, we describe the systemic factors affecting DR.
The Diabetes Control and Complications Trial (DCCT) has shown that, in type 1 diabetes mellitus, intensive glycaemic therapy reduced the risk for DR by 76% (95% CI: 62% to 85%) and its progression by 54% (95% CI: 39% to 66%)., In the United Kingdom, Prospective Diabetes Study (UKPDS) which looked at the effect of improved blood glucose on macro- and microvascular complications in type 2 diabetes, the risk of retinopathy was found to reduce by 31% for 1% decrease in HbA1c. In the DCCT, long-term benefits of intensive insulin treatment greatly outweighed the risks of early worsening. Diabetic patients with long duration of diabetes and advanced stage of retinopathy at baseline were more likely to have early worsening of DR.
Glycaemic control from onset of diabetes mellitus is the key to prevent DR and thus its long-term blinding complications. In CURES, for every 2% elevation of HbA1c, the risk for DR increased by factor of 1.7 (95% CI: 1.545–1.980; P < 0.0001) and for every 5-year increase in the duration of diabetes, the risk for DR increased 1.89-fold (95% CI: 1.679–2.135; P < 0.0001). The Action to Control Cardiovascular Risk in Diabetes Follow-On Eye Study found that progression of DR was seen in only 5.8% of intensive glycaemic treatment compared to 12.7% with standard treatment group (P < 0.0001). The Collaborators on Trials of Lowering Glucose group showed that, in more intensive glucose control arm when compared to the less intensive treatment arm, there was significant 13% relative risk reduction of eye events (a composite of requirement for retinal photocoagulation therapy or vitrectomy, development of PDR or progression of DR) (P = 0·04). During hyperglycaemia, major mediators of coagulation-fibrinolytic system such as fibrinogen, antithrombin-III, plasminogen activator inhibitor-1 and von Willebrand factor get altered. Inhibiting the pathways by which these altered mediators get involved in the pathophysiology of DR can serve as potential targets for the development of an adjuvant novel alternative therapy. It is the glycaemic control rather than drugs to achieve it matters for prevalence and progression of DR.
Hypertension in the diabetic individual markedly increases the risk and accelerates the course of cardiac disease, peripheral vascular disease, stroke, retinopathy and nephropathy. Possible mechanisms of hypertension affecting DR are both haemodynamic (impaired autoregulation and hyperperfusion) and vascular endothelial growth factor (VEGF) induced. Hypertension has been found to upregulate VEGF expression in retinal endothelial cells and ocular fluids.
In the UKPDS, patients assigned to tight control (<150/85 mmHg) had a 34% reduction in progression of retinopathy and 47% reduced risk of deterioration in visual acuity of three lines in association with a 10/5 mmHg reduction in blood pressure (BP). Beneficial effect in DR prevention for up to 4–5 years on BP control has been observed. In otherwise quiescent PDR, uncontrolled hypertension has been found to be risk factor for vitreous haemorrhage. In patients with DR and nephropathy, tight control of BP (<130/80 mmHg) delays the progression of retinopathy and nephropathy in addition to reducing cardiovascular morbidity and mortality. The level of BP control is debatable, but nearer to the normal BP levels have a better chance of preventing the onset and progression of DR. The lowering of BP to a normal range is more important than the type of antihypertensive medication used.
Diabetic nephropathy, characterised by persistent proteinuria of >500 mg/day, is a serious diabetic complication. Many studies have shown association between diabetic nephropathy and DR., In the Japan Diabetes Complications Study, the presence of microalbuminuria and DR was associated with the fastest glomerular filtration rate decline. In another study, DR was found to be risk factor for rapid progression of diabetic nephropathy. The effects of renal transplantation on DR have been studied. Stabilisation of DR was observed at the final follow-up after renal transplantation done for end-stage renal disease due to diabetic nephropathy.
Increased microalbumin levels in the urine (macroalbuminuria: albumin levels of >500 mg of creatinine in urine) are associated with greater prevalence of DR (60.5% vs. 31.0% vs. 14.1%, P < 0.001) in comparison to microalbuminuria (albumin levels of 30–300 mg of serum creatinine in urine) or normal albumin levels in the urine. There was also increased risk of progression of non-PDR to PDR (hazard ratio [HR] = 2.26, 95% CI [CI] = 1.68–3.03) in diabetic patients with nephropathy. It is thus important to assess blood urea, serum creatinine and presence of microalbuminuria in all diabetic patients.
Significant association has been found between retinal hard exudates, total cholesterol and low-density lipoprotein (LDL) levels. In CURES, even after adjusting for HbA1c, serum triglycerides maintained a significant association with DR and LDL cholesterol with DME. Total-to-high density lipoprotein cholesterol ratio and LDL cholesterol were found to be independent risk factors for both clinically significant macular oedema and retinal hard exudates.
Serum apolipoprotein (apo) levels are being evaluated as future biomarkers of DR. Apo-B (P < 0.001) and apo-B-to-apo-AI ratio (P < 0.001) have found to be associated with increasing DR severity levels. Another study has shown one-step progression of DR for every 10 mg/dL increase in serum total cholesterol (odds ratio [OR]: 15.65).
The Fenofibrate Intervention and Event Lowering in Diabetes study was done to assess the effect of long-term lipid-lowering therapy with fenofibrate on DR. There was reduced requirement for laser treatment in the fenofibrate group compared to the placebo group (HR: 0.69, 95% CI: 0.56–0.84; P = 0.0002; absolute risk reduction 1.5% [0.7–2.3]). On long-term follow-up for 5 years, fenofibrate group had demonstrated less likely progression of preexisting DR and also DME development. In another study, statin use significantly lowered the risk of DME (OR: 0.33, P = 0.032). The presence of hypertriglyceridaemia 6 months before development of DME was found to be associated with central retinal thickness (OR: 1.52, P = 0.005).
In type 2 diabetes, the prevalence of anaemia was found to be 12.3%. Anaemia is an important risk factor for DR and its progression. Chronic hyperglycaemia results in anaemia by causing erythropoietin unresponsiveness. Haemoglobin level is not only an independent baseline risk factor for DR but also it factitiously reduces the HbA1c levels, resulting in masking of hyperglycaemia. In the Sankara Nethralaya-Diabetic Retinopathy Epidemiology and Molecular Genetics Study, incident DR and DME were found to be associated with the presence of anaemia (OR 1.96 and 10.14, respectively). In diabetic patients with anaemia (haemoglobin <12 g/dl), a higher risk of DR (OR = 2.0, 95% CI 1.2–3.3) was observed when compared with those with normal levels of haemoglobin.(≥12 g/dl).
The ETDRS showed that lower haematocrit was an also important risk factor for high-risk PDR. Anaemia has been found to be an important risk factor for progression of PDR in spite of prompt laser photocoagulation (P < 0.001). The level of haemoglobin should be thus evaluated periodically in diabetic patients and anaemia treated if present.
Women with diabetes and childbearing potential should be educated about the need for glycaemic control before pregnancy and should participate in effective family planning. Preconception retinal evaluation is necessary for early detection of DR and management of PDR and DME. During the first trimester, an eye examination should be performed with repeat and follow-up visits scheduled depending on the severity of retinopathy. More frequent ophthalmic examination is recommended in pregnant women with long duration of diabetes and who have DR before pregnancy.
Pregnancy increases the short-term risk of DR progression. The risk factors in pregnancy for progression are longer duration of diabetes, poor glycaemic control, greater severity of retinopathy at conception, presence of hypertension and pregnancy itself. Lower haemoglobin has also been found to be important risk factor for DR during pregnancy (P < 0.01). Laser photocoagulation should be done in sight-threatening DR and there is no contraindication in pregnancy. Gestational diabetes mellitus does not pose a major risk of DR due to short-term exposure of retina to hyperglycaemic milieu. The DCCT also showed that pregnancy induced a transient increase in the risk of retinopathy.
Many studies have shown a significant association between CVD and DR. In the CURES study, coronary artery disease was found to be significantly higher in the DR group compared to no DR group (11.3% vs. 6.7%; P = 0.007). Patients with type 2 diabetes mellitus with DME or PDR were more likely to have incident CVD (incidence rate ratio, 1.39; 95% CI, 1.16–1.67) and fatal CVD (incidence rate ratio, 2.33; 95% CI, 1.49–3.67) compared with those without DME or PDR. Macrovascular plaque vulnerability and acute coronary syndrome were found to be significantly greater in DR than in non-DR patients. (P = 0.002 and P = 0.004, respectively). Greater estimated insulin sensitivity at baseline predicted lower odds of developing DR (OR: 0.79, 0.64–0.97), PDR (OR: 0.76, 0.57–0.99) and also reduced odds of coronary artery calcium progression (OR: 0.71, 0.60–0.85). In the Singapore Epidemiology of Eye Disease study, aspirin use has not been significantly associated with the presence of DR. It was, however, co-present with more severe form of DR and indicator of diabetic complications (CVD and chronic kidney disease).
DR is a multifactorial retinal disorder. Keeping blood sugar levels (HbA1c of <7%), BP levels (<140/90 mmHg) and lipid levels (Total cholesterol <200 mg/dl, LDL cholesterol <100 mg/dl and triglycerides <150 mg/dl) under control would be beneficial., DR can be asymptomatic and hence lifelong periodic annual retinal examination is important for early detection and prompt treatment of this blinding disease. Many people with diabetes mellitus are unaware that diabetes can affect the retina and cause blindness. They only undergo refraction and miss the important fundus examination. Hence, all physicians should motivate their patients to have periodic retinal evaluation and undergo laser treatment when required. It is also their responsibility to explain the importance of glycaemic control from onset of diagnosis as DR can be silent. Screening facilities for DR should be available for all people with diabetes to increase compliance and prompt management when required. Collaborative efforts between diabetologists, ophthalmologists and dieticians are the need of the hour to help improve quality of life and reduce public health burden due to diabetic-related complications.
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