Table 2.

List of oral hypoglycaemic agents, indications, mechanisms or action and relationship with diabetic retinopathy

Generic name	Administration and dosage	Mechanism of action	Indications, common adverse effects and contraindications	Relationship with diabetic retinopathy
Glucagon-like peptide 1 agonists (incretins) Exenatide (long and short acting) Lixisenatide Dulaglutide Liraglutide Semaglutide	Injection with or just before meals 5–10 mcg BD Once weekly or BD 10–20 mcg daily 0.75–1.5 mg once weekly 0.6–1.8 mg daily 0.5–1.0 mg weekly	- Stimulate pancreatic islet β-cell insulin production - Impair glucagon secretion - Slow gastric emptying and hence reduce glucose absorption, appetite and food intake	Indications: Adjunct to sulfonylurea or metformin (+/− sulfonylurea or basal insulin) in T2D Common adverse effects: GI side effects (nausea, vomiting, diarrhoea) CI: end stage renal disease or severe renal impairment; severe GI disease	Screening study • GLP-1 receptor agonist therapy associated with transient worsening of DR which improved with continued treatment [7, 8] Case reports • Complete regression of DME after injection with exenatide [5] • Dramatic deterioration in DR from background retinopathy to bilateral PDR and DME with reductions in HbA1c after exenatide treatment [6] Clinical trial • Rates of retinopathy complications (vitreous haemorrhage, blindness, or conditions requiring intravitreal treatment or photocoagulation) significantly higher in patients taking semaglutide (SUSTAIN 6) [9] Experimental research • Systemic administration of liraglutide prevents retinal neurodegeneration [17] • Exendin-4 (E4) shows neuroprotective effects in early experimental DR by maintaining BRB integrity [16] • Intravitreal administration of E4 analogue can protect the retina functionally and morphologically from diabetes [15]
DPP4 inhibitors (gliptins) Sitagliptin Vildagliptin Linagliptin Saxagliptin Alogliptin	Oral tablet with or without food 50 mg BD 50 mg BD 5 mg daily 5 mg daily 25 mg daily	Inhibition of DPP4 which is responsible for the breakdown of incretins (GLP-1 and GIP), thus enhancing their actions (see above)	Indications: For T2D monotherapy when metformin unsuitable; dual combination with metformin, sulfonylurea or thiazolidinedione; triple combination with metformin and sulfonylurea; add-on combination therapy with insulin (+/− metformin) Common: Hypoglycaemia if in combination therapy Reported URTI, GI upset, headache, skin irritation	Case reports • Retrospective chart review showed DPP4 inhibitors may reduce rates of DR progression [21] • However, use of gliptins <12 months may be associated with early worsening of DR [22] Experimental research • Sitagliptin may delay or prevent DR by preventing nitrosative (reactive nitrogen and oxygen species) stress, inflammation and apoptosis in retinal cells, and preventing increase in BRB permeability [18, 19] • Vildagliptin significantly inhibited increase in body weight and decreased average fasting glucose in rats, and inhibited inflammatory and thrombogenic reactions in the retinas of obese T2D rats [20] • Linagliptin has a neuroprotective effect on the microvasculature of the diabetic retina [67]
SGLT2 Inhibitors Dapagliflozin Empagliflozin Canagliflozin Ipragliflozin	Oral tablet with/without food 10mg daily 10–25 mg daily 100–300 mg daily 50 mg daily	Reversible, competitive inhibitor of sodium-glucose cotransporter-2 (SGLT2) that reduces renal glucose reabsorption, leading to urinary glucose excretion.	Indications: For T2D as monotherapy when metformin not tolerated; initial combination with metformin when diet, exercise and poor response to metformin expected; add-on combination with other AHG when diet/exercise/meds inadequate Common: UTI, genital infection, hypoglycaemia CI: Renal function eGFR <60 mL/min/1.73 m2	Case reports • Marked regression of DME after 16 weeks of ipragliflozin [26] Experimental research • Control of hyperglycaemia with ipragliflozin slows the progression of retinopathy in spontaneously diabetic Torii fatty rats [25]
Alpha-glucosidase inhibitors Acarbose	Oral tablet immediately before meals or chew with food 50 mg OD–200 mg TDS Average dose 100 mg TDS	Interferes with digestion of complex carbohydrates by alpha-glucosidase (intestinal enzyme) and slows rate of absorption of polysaccharides in proximal small intestine	Indication: adjunct to diet/exercise for T2D with inadequate control by diet/AHG agents Common adverse effects: Unsociable gastric side effects (flatulence, diarrhoea, abdominal discomfort and bloating) CI: severe renal impairment; malabsorption GI conditions; partial intestinal obstruction	Experimental research Acarbose Prevented basement membrane thickening in retinal capillaries [29] [68] • Prevented decrease in retinal blood flow rates after diabetes induction in rats and reduced increase in blood glucose levels [69] • Related to decreased diabetic cataract development through reduced aldose reductase activity and increased lenticular protein and glutathione levels [70]
Thiazolidinediones Pioglitazone	Once daily with/without food 15–45 mg daily	Peroxisome Proliferator Activator Receptor (PPAR-gamma) agonist: activate genes that regulate lipid and glucose metabolism, improves sensitivity to insulin in muscle and adipose, inhibits hepatic gluconeogenesis	Indication: T2D inadequately controlled by diet and exercise (+/− insulin or metformin and/or sulfonylurea) Common adverse effects: weight gain, fluid retention (ankle oedema), cardiac failure, bone fractures CI: cardiac failure; may be associated with adverse cardiovascular effects	Population-based studies and database reviews Positive effects Rosiglitazone use associated with a 59% relative risk reduction in progression to PDR over 3 years and lower rates of visual acuity loss [45] • TZD use associated with decreased mediators of endothelial dysfunction, reduced markers of inflammation and increased markers of angiogenic activity [47] • Inconclusive or no association with DME [48–51] Negative effects • TZD repeatedly associated with increased risk of DME [31, 40, 41, 43, 44] Case studies [39, 71–73] • TZD associated with increased frequency of reporting of MI and fractures [44] • Rosiglitazone use associated with increased rates of laser treatment and vitrectomy [46] Experimental research • Pioglitazone normalised insulin signalling, restored IGFBP-3 levels independent of TNF-alpha and elicited dilatation of retinal arterioles [32–34] • Rosiglitazone attenuated diabetes-induced apoptosis in retinal neurons [35]. • TZDs attenuated pathological microvessel formation and inhibited retinal leukostasis and retinal leakage [37, 38]
Sulfonylureas Gliclazide Glimepiride Glibenclamide Glipizide Tolbutamide	Oral tablet with meals 30–120 mg daily 1–4 mg daily 5–15 mg daily 5–15 mg daily 0.5–1.5 g daily	Insulin secretagogue: binds to sulfonylurea receptors in beta cells, leading to closing of KATP channels and insulin release	Indications: T2D not controlled by diet alone Common adverse effects: hypoglycaemia (caution with elderly patients); weight gain common CI: severe renal/hepatic insufficiency, treatment with miconazole	Population-based studies • Gliclazide seems to have additional properties compared with other sulfonylurea drugs in preventing deterioration of DR, and particularly in preventing progression to PDR [55] • No action of gliclazide on diabetic microangiopathy, independent of its hypoglycaemic action [56] • Gliclazide might be more effective than glibenclamide with respect to either improving diabetic retinopathy or preventing its progression [54]
Biguanides Metformin (immediate release or prolonged release)	Oral tablet with meals 500 mg–3 g daily	- Lowers fasting plasma insulin concentrations - Enhances insulin sensitivity - Inhibit hepatic glucose output - Action on AMP-kinase - Increased glucose uptake in peripheral tissues [74]	Indication: first line therapy for T2D especially for obese patients Common adverse effects: GI disturbances when starting therapy (diarrhoea, nausea, vomiting, abdominal pain, loss of appetite); taste disturbance Serious adverse effect: lactic acidosis CI: renal failure or conditions causing tissue hypoxia and increased lactate production, e.g., cardiac/hepatic failure, recent MI, PE, shock, pancreatitis, sepsis, alcoholism)	Case reports • Retrospective chart reviews suggest metformin may have protective effects on DR [58, 59]

AHG anti-hyperglycaemic, AHG anti-hyperglycaemic, BD twice daily, BRB blood retinal barrier, CI contraindications, DME diabetic macular oedema, DPP4 dipeptidyl peptidase 4, DR diabetic retinopathy, GI gastrointestinal, MI myocardial infarction, PDR proliferative diabetic retinopathy, PE pulmonary embolism, T2D type 2 diabetes, TDS three times daily, TNF-α tumour necrosis factor alpha, TZD thiazolidinediones, URTI upper respiratory tract infection, UTI urinary tract infection