Table 1.

An overview of the limitations and drawbacks associated with the treatment strategies currently utilized for DR management.

Treatment	Pathway	Limitations and drawbacks
Glycemic control	Insulin signaling	Worsening of symptoms seen in patients over time Side effects can include headaches, weight gain, rashes, and inflammation at the site of injection [84] Metabolic memory phenomenon limits efficacy in poorly managed cases of DM [85]
Laser photocoagulation	Macular edema	Can result in scarring of the retina and apoptosis of retinal pigment epithelium and other retinal cell types, reducing visual acuity Choroidal neovascular membranes can develop if the laser scar affects the Bruch’s membrane [86]
Enalapril, losartan	RAAS	Significant renal and cardiovascular side effects seen in some patients, including hyperkalemia and worsening renal function [87]
Triamcinolone acetonide	Glucocorticoid signaling	Secondary ocular hypertension (40%), elevated intraocular pressure (2%), and nuclear cataracts (20%) are common side effects [88]
Ruboxistaurin	PKCβ signaling	Modest clinical benefits and only statistically significant improvements seen when combined with laser photocoagulation [89]
Fenofibrate	PPARɑ activator	Substantial side effect profile which includes stomach pain, nausea and vomiting, and muscle pain 20-h half-life necessitates daily-dosing regimen [90]
Bevacizumab, ranibizumab, aflibercept	VEGF signaling	High prevalence of nonresponders Resistance to therapy seen with repeated administration Repeated intravitreal injections has detrimental impact, including corneal scarring [91]

RAAS: Renin–angiotensin aldosterone system; PKC: protein kinase C; PPAR: Peroxisome proliferator activator protein; VEGF: vascular endothelial growth factor.