One of the sight threatening complication of long standing uncontrolled diabetes is diabetic macular edema (DME).¹ Various kind of therapies evolved for the management of DME with the passage of time and one of them was the intra-vitreal injection of anti-vascular endothelial growth factor (VEGF) drugs that achieved significant success. Different trials have explored the effectiveness of ranibizumab and bevacizumab on diabetic retinopathies, especially diabetic macular edema.²,³ Steroids are also utilized in the form of intra-vitreal injections for the management of DME.⁴ DME results from a complex array of various pathological pathways that ultimately culminates in angiogenesis and production of prostaglandin and other inflammatory and pro-inflammatory mediators which is the hallmark of diabetic maculopathy.⁵,⁶ Anti-VEGF agents such as ranibizumab and bevacizumab are used to block the production of VEGF, and steroid (triamcinolone) is used to inhibit the prostaglandin-induced inflammatory cascade. Non-steroidal anti-inflammatory drugs (NSAIDs) prevent the production of prostaglandins and leukotriene and has evolved as a new treatment modality in the management of DME.⁷,⁸

The inflammatory cascade leading to the development DME liberates arachidonic acid from the cell membrane phospholipids. Arachidonic acid is converted into prostaglandin (PG) and thromboxane (TXA2) by cyclooxygenases (COX1 and COX2) and into leukotriene with the help of 5-lipoxygenases. Prostaglandins are potent stimulators for angiogenesis. It was revealed in one study on cultured Müller cells that PG enhances the production of VEGFs. NSAIDs, are powerful COX inhibitors and hence potent anti-inflammatory agents, and has both anti-proliferative and anti-angiogenic effects.⁹ other possible explanation for the role of NSAIDs as anti-angiogenic agents is the inhibition of COX pathway, which blocks the production of PGE-1 and PGE-2. This inhibitory action of NSAIDs is responsible for suppression of angiogenesis in chronic inflammatory conditions.¹⁰,¹¹

Although steroids are considered to be potent anti-inflammatory agents by inhibiting two pathways at the same time (the cyclooxygenase and 5-lipoxygenase pathway), but NSAIDs have minimal deleterious effects than steroids. These adverse effects include raised intra-ocular pressure (IOP) and lens opacification. Diabetic patients are more prone to this complications.¹², ¹³

Also, intra-vitreal injection of steroids needs to be repeated quickly because of the short lived effects, which may increase the possibility of adverse effects.¹⁴,¹⁵ Another beneficial property of NSAID is tumor necrosis factor (TNF)-alpha inhibition, which may prevent early diabetic retinopathy progression.⁷ Topical use of NSAID is ineffective due to inadequate supply of drug to the vitreous because of the blood-aqueous barrier. Intra-vitreal injection of NSAIDs could possibly maximize the drug concentration in the vitreous, particularly in inflammatory conditions like DME and age-related macular degeneration (ARMD).¹⁶ Diclofenac sodium is a member of the NSAIDs family that inhibits both the cyclooxygenase and 5-lipoxygenase pathway, making it a powerful agent than steroid, with the added benefit of less serious adverse effects.¹⁷ Intravitreous injection of diclofenac sodium (IV-D) is efficacious in inflammatory retinal conditions such as macular edema due to occlusive retinopathies, ARMD, uveitis induced CME, and DME.¹⁸

Fifty eyes from 25 patients with bilateral DME were enrolled in this interventional case series study at an Eye Dept of Ayub Teaching Hospital Abbottabad from Sep 2019 to March 2020. All subjects who participated in the study signed an informed consent form before enrollment. Another written consent was acquired from the participants regarding the possible adverse reaction of intra-vitreal injections before the start of study. We excluded patients who underwent pan-retinal or focal/Grid laser photocoagulation, intra-ocular procedures or any sort of intra-ocular injections 6 months before study. All included eyes underwent a complete baseline ocular assessment including best-corrected visual acuity (BCVA), applanation tonometry, slit lamp examination, and retinal photographs. Measurement of central macular thickness (CMT) was done by using optical coherence tomography (OCT). Each eye of a patient was randomly allocated to one of two study groups: in the IV-D group, each eye received 500 µg/0.1 mL of diclofenac sodium (Inj. Voren®, Asian Continental, and Pak.) In the IV-B group, each eye received 1.25 mg/0.05 mL of bevacizumab (Avastin; Genentech Inc., Roche, Ltd., Basel, Switzerland). Complete ophthalmic assessments were conducted at 1st, 3rd and 6th month after injections along with OCT for measurement of central retinal thickness. The main outcome parameter was the change in best-corrected. CMT measurement changes as displayed in OCT prints were the secondary outcome measures. There wasn’t any serious side effect observed with injections throughout the study duration. Statistical analysis of data was done with SPSS version 20. Continuous and discrete variables were represented as Mean and standard deviation (SD), while the descriptive/qualitative variables were expressed as frequency and percentages. Within group analysis of variables were done by utilizing student t test and Wilcoxon signed rank test was used for comparing the variables with the baseline and within each treatment group. Mann-Whitney and paired sample t-test were used for comparing variables between groups. P value less than 0.05 was considered as statistically significant.

Fifty eyes of 25 patients (25 OD and 25 OS) with DME OU were analyzed. The mean age of the pts. was 58.4 yrs. (range 52 to 68 yrs.) 20 were male and 30 females. 14 pts. Had moderate non-proliferative diabetic retinopathy (NPDR) and 36 pts. had severe NPDR. At 1st, 3rd, and 6th month of follow-up, there was no significant difference between BCVA of both groups (p > 0.05) (Table-I).

Table- I: Log MAR BCVA at different phases in the study between the groups.

There was no significant difference between both groups (p = 0.512). After 1 month, the CMT decreased to 390.2 ± 110.3 µm in the IV-B group, and 402.4 ± 88.9 µm in the IV-D group. After 3rd months, the CMT was 361.8 ± 88.6 µm in the IV-B group and 392.8 ± 85.5 µm in the IV-D group. After 6th months, it was 352.4 ± 96.6 µm in the IV-B and 358.2 ± 85.4 µm in the IV-D group. Again the difference was not statistically significant between the groups (Table-I).

Table- II: Central Macular thickness on OCT at different phases in the study between the groups

At 6th month, the macular thickness difference to baseline was -58.0 ± 96.2 µm in the IV-B group and -68.3 ± 80.4 µm in the IV-D group. (p = 0.05 for the IV-B groups and p = 0.01 for the IV-D group). (Table- II). The IOP was measured in both groups at baseline and 07 days post injection. The IOP was lower in the IV-D group, from 16.4 mmHg to 14.4 mmHg (p = 0.030) (Table-III). The IOP was higher in the IV-B group, from 15.9 mmHg to 16.2 mmHg, however such difference didn’t achieve statistical significance (p=0.322).

Table- III: Intraocular Pressure (IOP) before and 01-week post injection between groups.

Intra-vitreal injections use is now common for quite some time in the management of diabetic retinopathy especially maculopathy i.e. DME as well as macular edema due to various etiologies. A number of studies have shown their better efficacy as compared to conventional treatment modalities.¹⁹ Various types of intra-vitreal agents are available than can halt the progressive diabetic retinopathy maculopathy. Underlying pathophysiologic mechanism of diabetic retinopathy is vital for appropriate selection of intra-vitreal agents to be used. Numerous studies have shown the beneficial effects of anti-VEGFs in the treatment of DME.²⁰ Another conceptual step in the management of diabetic retinopathy involves the use of steroids for inhibiting the inflammatory cascades involved in the progression of disease particularly DME.²¹–²⁷ Steroids blocks both cyclooxygenase and 5-lipoxygenase pathways but are associated with cataract formation and glaucoma.¹³,¹⁴ In this interventional case series trial, we opted for NSAIDs. One trial has shown the potency of Diclofenac-Na to inhibit the 5-lipoxygenases pathway. This property of Diclofenac-Na makes it identical to steroids to be used as an anti-inflammatory agent. In our study, we explored the intra-vitreal route of delivery for enhanced absorption of NSAIDs to retinal tissues. The intra-vitreal route basically increases the pharmacological efficacy of NSAIDs and prevents its degradation by various enzymes in different ocular tissues thus prolonging its half-life. Our study results have shown that both bevacizumab and Diclofenac-Na improved the visual acuity and reduced the CMT after intra-vitreal injection to a significant extent, but the difference between the two groups didn’t achieve statistical significance. Interestingly we observed lowering of IOP in the Diclofenac-Na group 01-week post injection, while there was a rise in IOP noted in the bevacizumab group, however this increase was not statistically significant. Our study had a follow-up of 6 months’ duration and the results have shown similarity to previous studies by Soheilian et al., who observed an improvement in visual acuity in DME as well as reduction in edema due to other etiologies.¹⁸, ³¹ Elbendary et al. findings also supported our study results by showing the efficacy of intra-vitreal Diclofenac-Na in visual improvement as well as reduction of macular thickness in patients with diabetic macular edema by comparing it with steroids. Reduction in IOP was also observed in Diclofenac-Na group.¹⁷ Due to widespread availability of Diclofenac-Na and its low price, it will be a paradigm shift in the management of diabetic patients with DME, as anti-VEGFs are costly which puts the patient in financial burden due to prolong treatment course resulting in non-compliance and unfortunately leading to debilitating visual impairment.

This study showed that intravitreal diclofenac (IV-D) by virtue of its anti-inflammatory properties showed improvement both in terms of visual acuity as well as reduction of the central macular thickness almost similar to bevacizumab but without any side effects of steroids.

Disclaimer:
Nothing to declare.

Acknowledgement:
The author thank the department medical staffs for their help and support. They keep patient record properly and managed the data carefully which helped in completing this research

Authors’ CONTRIBUTION:

¹Conceptualized the study and contributed in the data collection and aided in drafting of the article, ²Data collection, drafting of the article, ³Active Participation in active methodology.