2.  Diabetic retinopathy is defined as a chronic, progressive, potentially sight-threatening disease of the retinal microvasculature. 1  Long-term hyperglycaemia and other conditions linked to diabetes mellitus such as hypertension can be the causative factors. 1  Among adults aged 20–74 years, it is the most frequent cause of new cases of blindness. 2  Within the first 20 years of developing diabetes, almost all patients with type 1 diabetes and >60% with type 2 diabetes develop this debilitating condition. 2 INTRODUCTION 1. Diabetic retinopathy guidelines. The Royal College of Opthalmologist. Available at: https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-301-FINAL-DR- GUIDELINESDEC-2012-updated-July-2013.pdf. As accessed on July 18, 2015 2. Fong DS, et al. Diabetic retinopathy. Diabetes Care. 2003 Jan;26 (Suppl1):S99–S102.https://www.rcophth.ac.uk/wp-content/uploads/2014/12/2013-SCI-301-FINAL-DR- GUIDELINESDEC-2012-updated-July-2013.pdf

3. Classification  Diabetic retinopathy is clinically classified in to nonproliferative and proliferative form. Non-proliferative diabetic retinopathy (NPDR)  In NPDR the lesions are within the retina and have microaneurysms, small dot and blot haemorrhages, splinter haemorrhages, intraretinal microvascular abnormalities (IRMA) and cotton wool spots.  NPDR is further divided into: Mild non-proliferative diabetic retinopathy: It is characterized by at least 1 microaneurysm; dot and blot or flame shaped hemorrhages in all 4 fundus quadrants. Viswanath K, et al. Diabetic retinopathy: clinical findings and management. Community Eye Health. 2003;16(46):21–4. DIABETIC RETINOPATHY: AN OVERVIEW

4. Moderate non-proliferative diabetic retinopathy: Intraretinal dot and blot haemorrhages of greater severity are seen in 1-3 quadrants. Cotton wool spots, venous calibre changes including venous beading, and intraretinal microvascular abnormalities are present but are mild in nature. Severe non-proliferative diabetic retinopathy: It should have at least one of the below mentioned abnormalities:  Severe haemorrhages and microaneurysms in all 4 quadrants of the fundus  Venous beading, which is more marked in at least 2 quadrants  Intraretinal microvascular abnormalities, which are more severe in at least 1 quadrant Viswanath K, et al. Diabetic retinopathy: clinical findings and management. Community Eye Health. 2003;16(46):21–4. DIABETIC RETINOPATHY: AN OVERVIEW

5. Very severe non-proliferative diabetic retinopathy: This type of diabetic neuropathy has 2 or more criteria of the severe non-proliferative diabetic retinopathy. Proliferative diabetic retinopathy (PDR)  PDR is characterised by capillary closure of the retina representing its microvascular pathology. This leads to hypoxia of the retinal tissue.  This hypoxia in turn causes release of vasoproliferative factors that potentiate newer blood vessel formation to provide better oxygenation of the retinal tissue.  These new vessels may grow on the retina [neovascularisation elsewhere (NVE)] or on the optic disc [neovascularisation of the disc (NVD)]. Viswanath K, et al. Diabetic retinopathy: clinical findings and management. Community Eye Health. 2003;16(46):21–4. DIABETIC RETINOPATHY: AN OVERVIEW

6. Prevalence  Individual studies in the past have shown a wide range of prevalence in people with both diagnosed or undiagnosed diabetes; it ranges from 17.6% in India to 33.2% in a large study in the US.  A study by Yau (2012), demonstrated an overall prevalence of 34.6% for any diabetic retinopathy; 6.96% for proliferative retinopathy; 6.81% for diabetic macular oedema and 10.2% for vision-threatening diabetic retinopathy (VTDR) (Figure 1).  When studies of age-standardised prevalence of any diabetic retinopathy by retinopathy risk factors was taken into account, it was seen that the prevalence of diabetic retinopathy varied across ethnic groups with a highest prevalence among African American and lowest among the Asians. Yau JW, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012 Mar;35:556–64. DIABETIC RETINOPATHY: AN OVERVIEW

7. Yau JW, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012 Mar;35:556–64. DIABETIC RETINOPATHY: AN OVERVIEW

8.  With increased duration of diabetes, the prevalence of diabetic retinopathy increased (21.1 vs. 76.3%, when comparing <10 with ≥20 years).  Patients with type 1 diabetes for ≥20 years had 2.7 times more chances of developing any diabetic retinopathy; 15 times, 5 times and 8.7 times more chances of developing PDR, diabetes macular oedema and VTDR. Yau JW, et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012 Mar;35:556–64. DIABETIC RETINOPATHY: AN OVERVIEW

9. Risk Factors  Diabetic retinopathy can result from several mechanisms. Around 21% patients with type 2 diabetes mellitus (T2DM) have retinopathy at the time of first diagnosis of diabetes, and most develop some degree of retinopathy over time. Central vision may be impaired by macular oedema or capillary nonperfusion.  The risk factors for diabetic retinopathy are enlisted below (Figure 2). Fong DS, et al. Diabetic retinopathy. Diabetes Care. 2003 Jan;26 (Suppl 1):S99–S102. DIABETIC RETINOPATHY: AN OVERVIEW

10. Symptoms  Diabetic retinopathy results due to the damage to the small blood vessels that supply blood to the retina. When they leak blood and other fluid, the retinal tissue swells which results in the clouding of vision.  In diabetic patients, longer incidences of hyperglycaemia can cause fluid accumulation in the eye lens which is responsible for focusing. As a result, the curvature of the lens changes ultimately causing a blurred vision.  This blurring of distance vision gets corrected when blood sugar returns to normal. Diabetic retinopathy. Available at: http://www.aoa.org/patients-and-public/eye-and-vision-problems/glossary-of-eye-and-vision-conditions/diabetic- retinopathy?sso=y. As accessed on July 18, 2015.http://www.aoa.org/patients-and-public/eye-and-vision-problems/glossary-of-eye-and-vision-conditions/diabetic- retinopathy?sso=y DIABETIC RETINOPATHY: AN OVERVIEW

11.  The early stages of diabetic retinopathy usually does not present with any visual symptoms. Some of the common symptoms are: o Seeing spots or floaters in the field of vision o Blurred vision o Having a dark or empty spot in the center of the vision o Difficulty seeing well at night Diabetic retinopathy. Available at: http://www.aoa.org/patients-and-public/eye-and-vision-problems/glossary-of-eye-and-vision-conditions/diabetic- retinopathy?sso=y. As accessed on July 18, 2015.http://www.aoa.org/patients-and-public/eye-and-vision-problems/glossary-of-eye-and-vision-conditions/diabetic- retinopathy?sso=y DIABETIC RETINOPATHY: AN OVERVIEW

12. Diagnosis  Until visual loss develops, diabetic neuropathy does not show any visual or ophthalmic symptoms. Therefore, early diagnosis is crucial for timely management of diabetic retinopathy. For achieving this, patients should be regularly checked for any sign or symptoms of vision loss (Table 1).  Of the various methods, the two most accepted techniques are dilated indirect ophthalmoscopy coupled with biomicroscopy and seven standard field stereoscopic 30 degree fundus photography.  Stereo fundus photography is more sensitive at detecting retinopathy than a clinical examination, but clinical examination ranks superior for diagnosing retinal thickening from macular oedema and for early neovascularisation. Fong DS, et al. Diabetic retinopathy. Diabetes Care. 2003 Jan;26 (Suppl 1):S99–S102. DIABETIC RETINOPATHY: AN OVERVIEW

13. Fong DS, et al. Diabetic retinopathy. Diabetes Care. 2003 Jan;26 (Suppl 1):S99–S102. DIABETIC RETINOPATHY: AN OVERVIEW

14. Management  Diabetes control: Among all modes of treatment, good glycaemic control can reduce the development and progression of diabetic retinopathy. 1 This emphasises the importance of good glycaemic control and also preventing prolonged hyperglycaemia in diabetic patients. 2  Laser photocoagulation: This procedure has made a significant change in the management of diabetic retinopathy. Macular photocoagulation is the photocoagulation of NPDR with clinically significant macular oedema while widespread photocoagulation for proliferative diabetic retinopathy is termed as pan-retinal photocoagulation. 2 1.Fong DS, et al. Diabetic retinopathy. Diabetes Care. 2003 Jan;26 (Suppl 1):S99–S102. 2.Viswanath K, et al. Diabetic retinopathy: clinical findings and management. Community Eye Health. 2003;16(46):21–4. DIABETIC RETINOPATHY: AN OVERVIEW

15.  Macular photocoagulation: Photocoagulation may be applied in a grid manner for diffuse leakage around the macula which may prevent leakage.  Pan-retinal photocoagulation: Photocoagulating the posterior 45°–60° of the retina along with graded burns, to lower the oxygen demand of the hypoxic retina in diabetic retinopathy, changes the hypoxic zones of the retina into anoxic zones. This reduces the release of vasoproliferative factors. Thus, pan-retinal photocoagulation prevents formation of new vessels and can result in the regression of already existing new vessels on the retina or optic disc. Viswanath K, et al. Diabetic retinopathy: clinical findings and management. Community Eye Health. 2003;16(46):21–4. DIABETIC RETINOPATHY: AN OVERVIEW

16.  Follow-up: Treated or untreated diabetic retinopathy, both need a timely follow-up. Patients with diabetic maculopathy must be reviewed every 3–4 months to check for any reductions in the macular oedema. Patients who receive panretinal photocoagulation must be followed every 3 months for any regression or closure of new vessels or formation of any new vessel.  Surgery: Surgical procedures are required for non-resolving vitreous haemorrhages and tractional retinal detachment. Vitreous haemorrhage usually requires a vitrectomy and is performed early in insulin dependent diabetics. In those with non-insulin dependent diabetics, it is conducted after 6 months if the haemorrhage does not clear. Viswanath K, et al. Diabetic retinopathy: clinical findings and management. Community Eye Health. 2003;16(46):21–4. DIABETIC RETINOPATHY: AN OVERVIEW

17.  The main function of vitamin D is to maintain mineral homeostasis and regulation of bone remodelling.  Apart from these, it imparts pleiotropic effects such as maintaining glucose homeostasis and pathogenesis of type 2 diabetes.  In the last few years, there has been an increased interest in the possible role of vitamin D as a causable factor for development of diabetic micro- and macroangiopathic complications including diabetic retinopathy.  Several studies have previously shown that vitamin D deficiency is highly prevalent in type 1 and type 2 diabetes.  Animal studies have demonstrated that vitamin D has preventive effect in the development of diabetes.  Literature search on vitamin D and diabetic retinopathy shows that only 31 studies are present of which only 7 demonstrate a possible association between vitamin D and presence of retinopathy. Alcubierre N, et al. Vitamin D Deficiency is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus. J Diabetes Res. 2015;2015:374178. RETINOPATHY AS A RESULT OF VITAMIN D DEFICIENCY

18. Vitamin D Insufficiency can Cause Microvascular Complications in Diabetics A study conducted by Usluogullari et al., determined the incidence of 25(OH)D deficiency in patients with type 2 diabetes and the association of 25(OH)D deficiency with microvascular complications. Results  Diabetic group showed significantly higher levels of HbA1c as compared to controls (p<0.001). However, serum 25(OH)D levels did not correlate with HbA1c levels.  25(OH)D concentrations were comparable in both the groups (p=0.302). However, the vitamin D concentrations were higher in women (21.89 ± 8.74 ng/mL) as compared to men (20.24 ± 8.53 ng/mL) (p=0.025). Usluogullari CA, et al. The relationship between microvascular complications and vitamin D deficiency in type 2 diabetes mellitus. BMC Endocr Disord. 2015;15(1):33. SCIENTIFIC EVIDENCES

19.  Microvascular complications were noted in both the groups. The mean 25(OH)D level in patients with microvascular complications was significantly lower as compared to patients without microvascular complications (19.1 ± 8.1 vs. 22.0 ± 8.7 ng/mL, p<0.001) (Table 2). Usluogullari CA, et al. The relationship between microvascular complications and vitamin D deficiency in type 2 diabetes mellitus. BMC Endocr Disord. 2015;15(1):33. SCIENTIFIC EVIDENCES

20.  Of the 311 diabetic patients, retinopathy was found in 73 patients (23.4%).  Diabetic patients with nephropathy showed low levels of serum 25(OH)D and the diabetic nephropathy was higher in patients without medication and who were treated with diet modifications only. Usluogullari CA, et al. The relationship between microvascular complications and vitamin D deficiency in type 2 diabetes mellitus. BMC Endocr Disord. 2015;15(1):33. SCIENTIFIC EVIDENCES Diabetic patients with microvascular complications showed lower levels of vitamin D.

21. Role of Vitamin D in Diabetic Retinopathy A study was conducted by Zoppini G et al., to observe possible association between circulating 25(OH)D levels and microvascular complications in patients with type 2 diabetes. Results  Hypovitaminosis D and vitamin D deficiency was observed in 75.4% and 36.6% patients, respectively.  The level of vitamin D was further decreased significantly with severity of either retinopathy or nephropathy or both.  Odds of vitamin D deficiency increased with the presence of microvascular complications (OR 0.758; 95% CI 0.607 to 0.947, p=0.015). Zoppini G, et al. Lower levels of 25-hydroxyvitamin D3 are associated with a higher prevalence of microvascular complications in patients with type 2 diabetes. BMJ Open Diabetes Res Care. 2015;3(1):e000058. SCIENTIFIC EVIDENCES Low level of circulating 25(OH)D were independently associated with microvascular complications in patients with type 2 diabetes.

22. Association of Vitamin D Deficiency and Diabetic Retinopathy With the lack of data on the association between vitamin D insufficiency and diabetic retinopathy, Alcubierre and colleagues sought to study this association. The study had dual objectives:  To analyse whether there lies an association between vitamin D and type 2 diabetic retinopathy in type 2 diabetes patients  To assess the link between levels of vitamin D and the frequency of the deficiency with the severity of retinopathy Alcubierre N, et al. Vitamin D Deficiency is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus. J Diabetes Res. 2015;2015:374178. SCIENTIFIC EVIDENCES

23. Results  Subjects with retinopathy has a higher frequency of having vitamin D deficiency, i.e., serum 25(OH)D below 20 ng/dL (p=0.07).  A significantly higher prevalence of retinopathy for 25(OH)D thresholds below 20 mg/mL was observed.  The associated relative risk for the above mentioned threshold was also higher. Alcubierre N, et al. Vitamin D Deficiency is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus. J Diabetes Res. 2015;2015:374178. SCIENTIFIC EVIDENCES

24. Conclusion  The study established the association between a higher frequency of vitamin D deficiency and lower concentrations of 25(OH)D with diabetic retinopathy in patients with type 2 diabetes.  The study also exhibited that poor vitamin D status is correlates with severity of retinopathy. Alcubierre N, et al. Vitamin D Deficiency is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus. J Diabetes Res. 2015;2015:374178. SCIENTIFIC EVIDENCES In type 2 diabetic patients, vitamin D deficiency is associated with the presence and severity of diabetic retinopathy.

25. Intensive Blood Glucose Control can Reduce Microvascular Complications The findings from The Diabetes Control and Complications Trial (DCCT) and Epidemiology of Diabetes Interventions and Complications (EDIC) study showed that maintaining blood glucose levels close to normal reduced the development and progression of retinopathy, neuropathy, and nephropathy in diabetes. DCCT study states  Intensive blood glucose control results in the risk reduction of – o Eye disease by 76% o Kidney disease by 50% o Nerve disease by 60% DCCT and EDIC: The Diabetes Control and Complications Trial and Follow-up Study. Available from: http://www.niddk.nih.gov/about-niddk/research- areas/diabetes/dcct-edicdiabetes-control-complications-trial-follow-up-study/Documents/DCCT-DIC_508.pdf. As accessed on July 15, 2015. SCIENTIFIC EVIDENCES

26. EDIC study states  Intensive blood glucose control results in risk reduction of – o Cardiovascular event by 42% o Nonfatal heart attack, stroke, or death from cardiovascular causes by 57% DCCT and EDIC: The Diabetes Control and Complications Trial and Follow-up Study. Available at: http://www.niddk.nih.gov/about-niddk/research- areas/diabetes/dcct-edicdiabetes-control-complications-trial-follow-up-study/Documents/DCCT-DIC_508.pdf. As accessed on July 15, 2015. SCIENTIFIC EVIDENCES

27. Role of Vitamin D in Diabetes Control A study by Bonadkaran et al., sought to assess the effects of calcitriol, the most active metabolite of vitamin D, on risk factors of cardiovascular disease such as HbA1c, lipid levels in type 2 diabetes patients with vitamin D deficiency. Results  Vitamin D insufficiency was observed in 36.13% patients.  After treatment with calcitriol, there was a reduction in the levels of fasting blood glucose and homeostasis model assessment-insulin resistance (HOMA-IR).  There was a significant reduction in the levels of HbA1c after calcitriol treatment (Table 3). Bonakdaran S, et al. Impact of oral 1,25-dihydroxy vitamin D (calcitriol) replacement therapy on coronary artery risk factors in type 2 diabetic patients. Endocr Metab Immune Disord Drug Targets. 2013;13(4):295–300. SCIENTIFIC EVIDENCES

28.  The supplementation with calcitriol also brought about reductions in levels of LDL (p=0.04) and total cholesterol (p=0.019), blood pressure, and albumin excretion rate. Also, the supplement was well-tolerated. Bonakdaran S, et al. Impact of oral 1,25-dihydroxy vitamin D (calcitriol) replacement therapy on coronary artery risk factors in type 2 diabetic patients. Endocr Metab Immune Disord Drug Targets. 2013;13(4):295–300. SCIENTIFIC EVIDENCES Deficiency of 25(OH)D levels <20 ng/mL (<50 nmol/L) has been associated with decreased beta-cell function and insulin sensitivity therefore supplement of vitamin D may improve glycaemic control in type 2 diabetes.

29. Role of Vitamin D in Improving Endothelial Dysfunction A Scottish study aimed to investigate whether a single dose of oral vitamin D can improve endothelial dysfunction in patients with type 2 diabetes. Results  Of the 87 subjects under study, 49% had 25(OH)D levels <50 nmol/L.  Those who received vitamin D supplementation had significant improvement in flow- mediated vasodilation (FMD) as compared to placebo (Figure 3).  Post hoc analysis of both the groups using HOMA score (which showed insulin sensitivity) significantly improved in patients with an increase of 11 nmol/L in 25(OH)D levels. Sugden JA, et al. Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25(3):320–5. SCIENTIFIC EVIDENCES

30. Sugden JA, et al. Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25(3):320–5. SCIENTIFIC EVIDENCES Supplementation with vitamin D improves endothelial function in type 2 diabetes patients. Vitamin D supplementation is economical, safe and easy form of medication to reduce risk of cardiovascular disease in diabetes patients.

31. Vitamin D and Glycaemic Control A prospective, non-blinded, non-randomized controlled trial was conducted to test the hypothesis that vitamin D supplementation can improve glycaemic control in type 1 DM patients who have vitamin D deficiency. Result  At 12 weeks there was significant difference in mean glycosylated haemoglobin level between the groups that achieved 25(OH)D levels of 51 nmol/L (p=0.02).  The level of difference of glycosylated haemoglobin from baseline to each tertile was significant. Aljabri KS, et al. Glycemic changes after vitamin D supplementation in patients with type 1 diabetes mellitus and vitamin D deficiency. Ann Saudi Med. 2010;30(6):454–8. SCIENTIFIC EVIDENCES

32.  In patients who achieved 25(OH)D levels of >51nmol/L, the correlation of baseline and follow-up was -1.0 (p=0.001).  At week 12, the mean SD of glycosylated haemoglobin in patients who had 25(OH)D levels of >75nmol/L was 7.3 as compared to 9.1 in those who had 25(OH)D levels of <75nmol/L. Aljabri KS, et al. Glycemic changes after vitamin D supplementation in patients with type 1 diabetes mellitus and vitamin D deficiency. Ann Saudi Med. 2010;30(6):454–8. SCIENTIFIC EVIDENCES The study supported the hypothesis that vitamin D supplementation can improve glucose control in type 1 diabetes patients. This effect was sustained for a period of 12 weeks.

33.  Diabetic retinopathy is defined as a chronic progressive, potentially sight-threatening disease of the retinal microvasculature.  With increased duration of diabetes, the prevalence of diabetic retinopathy increases. Until visual loss develops, diabetic neuropathy does not show any visual or ophthalmic symptoms.  In type 2 diabetes patients, vitamin D deficiency is associated with the presence and severity of diabetic retinopathy.  Studies have shown that vitamin D supplementation can improve glucose control in type 2 diabetes patients.  The findings from DCCT and EDIC study show that maintaining blood glucose levels close to normal reduce the development or progression of retinopathy, neuropathy, and nephropathy in diabetes. SUMMARY