Diabetic Retinopathy - Treatment

Aspirin - updated: 15 March 2008

Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy

Diabetes. 2007 Feb;56(2):337-45

Zheng L, Howell SJ, Hatala DA, Huang K, Kern TS.

It has been previously reported that aspirin inhibited the development of diabetic retinopathy in diabetic animals, raising the possibility that anti-inflammatory drugs may have beneficial effects on diabetic retinopathy. To further explore this, we compared effects of oral consumption of three different salicylate-based drugs (aspirin, sodium salicylate, and sulfasalazine) on the development of early stages of diabetic retinopathy in rats. These three drugs differ in their ability to inhibit cyclooxygenase but share an ability to inhibit nuclear factor-kappaB (NF-kappaB). Diabetes of 9-10 months duration significantly increased the number of TUNEL (transferase-mediated dUTP nick-end labeling)-positive capillary cells and acellular (degenerate) capillaries in the retinal vasculature, and all three salicylate-based drugs inhibited this cell death and formation of acellular capillaries without altering the severity of hyperglycemia. In short-term diabetes (2-4 months), all three salicylates inhibited the diabetes-induced loss of neuronal cells from the ganglion cell layer. Oral aspirin (as a representative of the salicylate family) inhibited diabetes-induced increase in NF-kappaB DNA-binding affinity in electrophoretic mobility shift assay and transcription factor array in nuclear extract isolated from whole retina. All three salicylates inhibited the diabetes-induced translocation of p50 (a subunit of NF-kappaB) into nuclei of retinal vascular endothelial cells of the isolated retinal vasculature, as well as of p50 and p65 into nuclei of cells in the ganglion cell layer and inner nuclear layer on whole-retinal sections. Sulfasalazine (also as a representative of the salicylates) inhibited the diabetes-induced upregulation of several inflammatory gene products, which are regulated by NF-kappaB, including vascular cell adhesion molecule, intracellular adhesion molecule-1, inducible nitric oxide synthase, and cyclooxygenase-2 in whole-retinal lysate. Salicylates, in doses administrated in our experiments, inhibited NF-kappaB and perhaps other transcription factors in the retina, were well tolerated, and offered new tools to investigate and inhibit the development of diabetic retinopathy.

Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects

Diabetes. 2005 Dec;54(12):3418-26

Sun W, Gerhardinger C, Dagher Z, Hoehn T, Lorenzi M.

The prevention of diabetic retinopathy requires drugs that leverage the benefits of glycemic control without adding the burden of side effects. Aspirin at dosages of 1-1.5 g/day has prevented manifestations of diabetic retinal microangiopathy in a clinical trial as well as in studies with dogs. Because lower and safer doses of aspirin could be used if its beneficial effects on retinopathy were due to antithrombotic effects, we compared the effects of a selective antiplatelet drug (clopidogrel) to those of aspirin in streptozotocin-induced diabetic rats. Clopidogrel did not prevent neuronal apoptosis, glial reactivity, capillary cell apoptosis, or acellular capillaries in the retina of diabetic rats. Aspirin, at doses yielding serum levels (<0.6 mmol/l) well below the anti-inflammatory range for humans, prevented apoptosis of capillary cells and the development of acellular capillaries but did not prevent neuroglial abnormalities. The aldose reductase inhibitor sorbinil, used as the benchmark for the effect of the other drugs, prevented all abnormalities. The diabetic rat retina showed increased expression of the transcription factor CCAAT/enhancer-binding protein-beta, one of the known targets of low-intermediate concentrations of aspirin. Thus we found a spectrum of drug efficacy on the prevention of experimental diabetic retinopathy, ranging from the absent effect of a selective antiplatelet drug to the prevention of all abnormalities by an aldose reductase inhibitor. Aspirin at low-intermediate concentrations selectively prevented microangiopathy. The minimal effective dose of aspirin should now be sought.

Publication Types:

• Review

Aspirin for diabetic retinopathy

BMJ 2003;327:1060-1061 (8 November), doi:10.1136/bmj.327.7423.1060

Editorial

The earliest clinically recognisable lesions in diabetic retinopathy are capillary occlusions, which can be shown on fluorescein angiograms, a standard investigation in patients with retinopathy. The response to capillary blockage is dilation of neighbouring ones, leading to breakdown of the blood-retina barrier and leakage. Later large vessels become affected, and the result is retinal ischaemia, which is responsible for the secretion of vasoactive cytokines, leading to formation of the sight threatening proliferative lesions.

Since capillary occlusion is a pivotal lesion, causes and cures for it have been sought for a long time. Aggregation of platelets is increased in diabetes, and this has been proposed as the underlying abnormality.1 An early paper by Pope et al showed platelet thrombi in retinal capillaries of diabetic patients.2 Furthermore, observational evidence showed that patients treated with acetyl salicylic acid had less retinopathy than expected in a general diabetic population.3 More recently in a detailed postmortem study on nine eyes Boeri et al found large thrombi more often in retinas from diabetic patients than in control retinas and double the number of vascular segments immunostaining for platelet glycoprotein IIIa.4 They suggested as a result of their findings that aspirin be considered as an intervention in early diabetic retinopathy. This work was supported by the finding of Kern and Engerman, who in diabetic dogs found that treatment with aspirin reduced the number of acellular capillaries and retinal haemorrhages after five years of diabetes.5

Publication Types:

• Editorial

Low-dose aspirin in patients with diabete melitus: risks and benefits regarding macro and microvascular complications

Arq Bras Endocrinol Metabol. 2007 Apr;51(3):457-65

Camargo EG, Gross JL, Weinert LS, Lavinsky J, Silveiro SP.

Aspirin is recommended as cardiovascular disease prevention in patients with diabetes mellitus. Due to the increased risk of bleeding and because of the hypothesis that there could be a worsening of microvascular complications related to aspirin, there has been observed an important underutilization of the drug. However, it is now known that aspirin is not associated with a deleterious effect on diabetic retinopathy and there is evidence indicating that it also does not affect renal function with usual doses (150 mg/d). On the other hand, higher doses may prove necessary, since recent data suggest that diabetic patients present the so called "aspirin resistance". The mechanisms of this resistance are not yet fully understood, being probably related to an abnormal intrinsic platelet activity. The employment of alternative antiplatelet strategies or the administration of higher aspirin doses (150-300 mg/d) should be better evaluated regarding effective cardiovascular disease prevention in diabetes as well as the possible effects on microvascular complications.

Preventive treatment of diabetic microangiopathy: blocking the pathogenic mechanisms

Diabete Metab. 1994;20(2 Pt 2):219-28

Guillausseau PJ.

The development of drugs in order to block metabolic pathway of glucose responsible for diabetic vascular dysfunction is in progress. Aldose reductase inhibitors prevent or reduce the different components of vascular dysfunction, cataract, neuropathy and nephropathy in animal models of diabetes. Promising results have been observed in diabetic patients concerning the prevention of neuropathy and of retinopathy. Larger scale studies with the second generation compounds are in progress. Glycation inhibitors, mainly aminoguanidine, have been shown to prevent or reduce vascular dysfunction and microvascular complications in animal models. Trials in diabetic patients with aminoguanidine are just beginning. Anti-oxidant therapy is also at its early stage of development (vitamin E, vitamin C, alpha lipoic acid). Antiplatelet agents (aspirin, ticlopidine) have been demonstrated to reduce the progression of non proliferative diabetic retinopathy. Angiotensin converting enzyme inhibitors are of particular interest in preventing diabetic glomerulopathy.

Publication Types:

• Review

Publication Types:

• Review