Pharmacotherapy of Diabetic Retinopathy
Yoshihiro Yonekawa
Aziz A. Khanifar
Donald J. D’Amico
Paul R.V. Chan
Diabetes mellitus (DM) is a major cause of morbidity and mortality throughout the world. Over 170 million people are currently affected, and the prevalence is projected to more than double by 2030 (1). Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults in the United States, and annually blinds over 12,000 patients (2). Similar to diabetic nephropathy and neuropathy, DR is a microvascular complication of both type 1 and type 2 diabetes. After 20 years of diagnosis, nearly all patients with type 1 and approximately 60% with type 2 DM have some degree of DR (3,4). DR is broadly categorized into either nonproliferative (NPDR) or proliferative DR (PDR) (5), depending on the presence of retinal fibrovascular proliferation.
Historically, the mainstays of DR treatment are glucose, blood pressure, and cholesterol control, combined with photocoagulation and/or vitrectomy as necessary. However, recent advances in our understanding of the molecular mechanisms behind the pathogenesis of DR have catalyzed the development of pharmacologic therapies such as intravitreal corticosteroids and antivascular endothelial growth factor (VEGF) agents. Many other exciting pharmacological developments have taken place as well.
PATHOPHYSIOLOGY
Vascular basement membrane thickening, an early morphologic feature of DR (6), may cause both filtration defects and dysfunction of cell proliferation and differentiation (7,8). The loss of intramural capillary pericytes is another early histologic hallmark (9,10). Pericyte loss is thought to weaken the capillary wall, leading to microaneurysms, which are often the first clinically visible signs of DR.
Microaneurysms are hypercellular saccular outpouchings of the capillary wall (11), and an increase in their number is associated with progression of retinopathy (12,13). Microaneurysms cause disruption of the blood-retinal barrier, leading to capillary permeability, resulting in intraretinal and subretinal fluid accumulation. The fluid tends to collect in the macular area, causing diabetic macular edema (DME). Increased expression of VEGF in regions with relative hypoxia and inflammatory factors also play a role in the development of DME in addition to fibrovascular proliferative disease. Severity of retinopathy is directly correlated with the likelihood of developing DME and retinal neovascularization.
DME can be focal or diffuse, and the pathophysiology, clinical appearance, and treatment modalities are different. Hard exudates are common findings in DME that correlate with serum lipid levels (14, 15, 16 and 17). The Early Treatment Diabetic Retinopathy Study (ETDRS) defined clinically significant macular edema (CSME) as thickening of the retina within 500 μm of the center of the fovea, hard exudates within 500 μm of the fovea associated with thickening of the adjacent retina, or retinal thickening of at least one disc diameter in size, within one disc diameter of the foveal center (18).
Retinal capillary occlusion causes increasing ischemia, which can lead to the development of cotton-wool spots, retinal hemorrhages, venous beading, and intraretinal microvascular abnormalities (IRMA). Retinal ischemia upregulates signaling molecules such as VEGF that promote fibrovascular proliferation, leading to PDR, which can cause significant visual loss by vitreous hemorrhage and/or tractional or combined tractional-rhegmatogenous retinal detachment. Neovascularization of the iris (NVI) may also occur as a result of retinal ischemia.
METABOLIC CONTROL
Insulin and Hypoglycemic Agents
Pharmacologic primary and secondary interventions are essential in lowering the systemic risk factors for developing DR. Currently, the most effective method of preventing and slowing the progression of diabetic retinopathy is tight glycemic control. The Diabetes Control and Complications Trial (DCCT) (19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36) showed that in comparison to conventional insulin therapy, intensive glucose monitoring and aggressive insulin therapy to maintain strict glycemic control lowered the risk of developing DR in type 1 diabetics with no baseline retinopathy by 76% (95% confidence interval or CI, 62 to 85). Notably, intensive therapy lowered the risks of nephropathy and neuropathy as well. The DCCT cohort was followed by the Epidemiology of Diabetes Interventions and Complications (EDIC) study (20), which showed that former tight glucose control provided continued benefits after seven years.
The U.K. Prospective Diabetes Study (UKPDS) (21) demonstrated that in type 2 diabetics, intensive treatment with sulfonylureas (chlorpropamide, glibenclamide, or glipizide) or insulin had a protective relative risk of 0.79 (p = 0.015) for progression of DR, and 0.71 (p = 0.0031) for requiring retinal photocoagulation.
The American Diabetes Association currently recommends maintaining a hemoglobin A1c of <7.0%, preprandial capillary plasma glucose of 70 to 130 mg/dL, and peak postprandial capillary plasma glucose of <180 mg/dL for nonpregnant adult diabetics (22).The main concern of intensive glycemic control is hypoglycemic episodes, which were more common in the intensive treatment arms of both the DCCT and UKPDS.
ANTIHYPERTENSIVES
Hypertension is associated with the development and progression of DR. The UKPDS randomized 3867 type 2 diabetics to tight (aiming for <150/85), or milder blood pressure control (<180/105) with captopril or atenolol (23). The tight control group had a 34% (99% CI, 11 to 50) risk reduction of DR progression, and a 47% (99% CI, 7 to 70) risk reduction of visual acuity deterioration by three lines. Deaths related to diabetes and stroke were also reduced (24).
In 2008, the Diabetic Retinopathy Candesartan Trials (DIRECT) reported that although candesartan reduced the incidence of new DR by 18% (p = 0.051) in type 1 diabetics, there was no effect on DR progression for those with baseline retinopathy (25). However, the Renin-Angiotensin System
Study (RASS) published in July of 2009 indicated that enalapril and losartan reduced the odds of early DR progression in type 1 diabetics by 65% (p = 0.02) and 70% (p = 0.008), respectively (26). These effects appear to be independent of blood pressure changes (26,27).
Study (RASS) published in July of 2009 indicated that enalapril and losartan reduced the odds of early DR progression in type 1 diabetics by 65% (p = 0.02) and 70% (p = 0.008), respectively (26). These effects appear to be independent of blood pressure changes (26,27).
ANTILIPIDS
The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) (14) and the ETDRS (15) both found associations between serum lipid levels and retinal hard exudates. Lipid control may be beneficial in DR because visual acuity loss correlates with the degree of hard exudates, and permanent retinal damage can be caused by subretinal fibrosis (28).
Preliminary studies suggested the use of clofibrate to be beneficial (16,17). The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study (29) recently demonstrated that fenofibrate reduces the rate of first laser therapy for DR or DME, from 4.9% of patients on placebo to 3.4% of patients on fenofibrate (p = 0.0002), but without an overall effect on the progression of DR (30). Statins have also been shown to improve DME in preliminary studies (31, 32 and 33). Randomized clinical trials (RCTs) that are underway include the Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) (34), and the Action to Control Cardiovascular Risk in Diabetes Eye (ACCORD-EYE) studies (35).
ANTIPLATELETS
Platelet microthrombi have been identified in retinal capillaries of diabetics, and have been proposed to be a possible mechanism for the capillary occlusions resulting in retinal ischemia (36,37). The Dipyridamole Aspirin Microangiopathy of Diabetes (DAMAD) study randomized patients with mild DR to aspirin alone, aspirin combined with dipyridamole, or placebo. The treatment arms developed fewer microaneurysms on fluorescein angiograms, but there was little difference in visual acuity and ophthalmoscopy endpoints (38). Similarly, the Ticlopidine Microangiopathy of Diabetes study (TIMAD) showed that while ticlopidine slowed the formation of microaneurysms, there were no clinical benefits (39). The ETDRS concluded that aspirin therapy does not have clinical effects in DR (40), but there are no ocular contraindications (41) to taking aspirin for cardiovascular or other conditions (42).
The Steno-2 study examined the effects of multifactorial intensive therapy consisting of tight glucose control combined with renin-angiotensin system blockers, lipid-lowering drugs, and aspirin (43). There was a 43% risk reduction of DR progression (p = 0.01), and a 55% risk reduction in requiring laser treatment for PDR or DME (p = 0.02). However, multifactorial treatment of systemic risk factors was still insufficient to prevent DR progression in many patients. This highlights the importance of targeted therapies, discussed below, to be administered in conjunction with optimal metabolic control and current ophthalmic therapies.
ALTERATION OF BIOCHEMICAL PATHWAYS
Aldose Reductase
Several biochemical mechanisms have been proposed as links between hyperglycemia and diabetic microvascular complications (19,44). Aldose reductase is the first enzyme in the polyol pathway that catalyzes the nicotinamide adenine dinucleotide phosphate (NADPH) – dependent reduction of aldose sugars into sugar alcohols. Hyperglycemia activates the pathway and glucose becomes reduced to sorbitol, which is thought to cause osmotic stress. Aldose reductase’s NADPH-consuming reactions also may cause oxidative damage by decreasing the NADPH available for glutathione reductase (45).
Clinical trials of aldose reductase inhibitors (ARIs), however, have not been promising. Data from the Sorbinil Retinopathy Trial (SRT) (46), a Phase III RCT of 497 insulindependent diabetics, showed no significant difference in the progression of retinopathy between subjects randomized to sorbinil or placebo. Subsequent trials of other ARIs such as zenarestat, tolrestat, and lidorestat, were prematurely halted due to toxicities (47, 48 and 49).
NONENZYMATIC GLYCATION
Advanced glycation end-products (AGEs) are found in retinal vessels (50) and renal glomeruli of diabetic patients (51). Glycation of proteins alters their functions, causing them to bind to AGE receptors on endothelial cells and macrophages, which induces receptor mediated production of reactive oxygen species, proinflammatory and procoagulative molecules, growth factors, and transcription factors that cause pathologic gene expression (45). Studies suggest that AGE receptors also promote capillary wall hyperpermeability by inducing VEGF expression (52).
Aminoguanidine (Pimagedine) is a hydrazine derivative that binds AGE precursors to decrease AGE formation (53). The efficacy and safety of aminoguanidine against DR is currently controversial (54,55). Another anti-AGE drug, alagebrium chloride (ALT-711), is being investigated in diabetic macrovascular disease (56, 57 and 58).
Protein Kinase C
Protein Kinase C (PKC) is a family of serine-threonine kinases (59) that appear to mediate vascular contractility, hemodynamics, and cellular proliferation to modulate diabetic microvascular disease (60,61). Hyperglycemia induces the synthesis of diacylglycerol (DAG), which in turn activates PKC. The β isoform has been linked most strongly with diabetes. Animal models have demonstrated that PKC-β increases retinal vascular permeability and neovascularization (62, 63 and 64), most likely by involving VEGF (64,65).
Staurosporin (PKC412) is a nonselective PKC inhibitor that also inhibits VEGF receptors 1 and 2, the Platlet-derived Growth Factor (PDGF) receptor, and stem cell factor receptor.
In a Phase I/II RCT of 141 patients with DME, oral staurosporin decreased retinal thickening (p = 0.032) and slightly improved (4.36 letters; p = 0.007) visual acuity at 3 months (66), but further studies were abandoned due to gastrointestinal side effects and hepatotoxicity.
In a Phase I/II RCT of 141 patients with DME, oral staurosporin decreased retinal thickening (p = 0.032) and slightly improved (4.36 letters; p = 0.007) visual acuity at 3 months (66), but further studies were abandoned due to gastrointestinal side effects and hepatotoxicity.
Ruboxistaurin (RBX/LY333531) is a selective inhibitor of PKC-β (61). The PKC-β Inhibitor Diabetic Retinopathy Study (PKC-DRS) randomized 252 subjects with moderately severe to severe NPDR to placebo or RBX (67). Doubling of the visual angle was delayed with 32 mg/day of RBX (p = 0.012), but there was no difference in the progression of NPDR to PDR. In PKC-DRS 2 (68), the follow up Phase III study with 685 subjects and 36 to 42 months of follow-up, the relative risk reduction of moderate visual loss was 40% compared to placebo (p = 0.034). RBX reduced initial photocoagulation in eyes that had not received laser treatment before baseline (p = 0.008), and decreased the progression of DME to the center-involved stage (p = 0.003), but there was no difference in the composite end point of DR progression. Notably, unlike staurosporin, RBX had minimal side effects.
CORTICOSTEROIDS
Intravitreal Triamcinolone
Laser treatment is currently the first line therapy for DME, and can halve the risk for visual loss in eyes with focal DME (19
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