Abstract
Diabetic retinopathy remains a leading cause of visual loss worldwide. Patients with diabetes mellitus commonly have multiple comorbidities treated with a wide variety of medications. Systemic medications that target glycemic control and coexisting conditions may have beneficial or deleterious effects on the onset or progression of diabetic retinopathy. In addition, data is accumulating to suggest that the use of systemic therapy primarily to address ocular complications of diabetic retinopathy may be a promising therapeutic approach. This article reviews our current understanding of the ocular-specific effects of systemic medications commonly used by patients with diabetes mellitus, including those directed at control of hyperglycemia, dyslipidemia, hypertension, cardiac disease, anemia, inflammation and cancer. Current clinical evidence is strongest for the use of angiotensin-converting enzyme inhibitors and angiotensin-2 receptor blockers in preventing the onset or slowing the progression of early diabetic retinopathy. To a more limited extent, evidence of a benefit of fibrates for diabetic macular edema exists. Numerous other agents hold considerable promise or potential risk. Thus, these compounds must undergo further rigorous study to determine the actual clinical efficacy and adverse effects before definitive therapeutic care recommendations can be offered.
Key Points
-
Individuals with diabetes mellitus are at risk of multiple systemic comorbidities, as well as numerous microvascular and macrovascular complications
-
An extensive and diverse array of medications, acting through multiple mechanisms, is available for managing the systemic comorbidities of diabetes mellitus
-
Systemic medications may have independent beneficial or deleterious effects on the onset or progression of diabetic retinopathy that are unrelated to the primary therapeutic intent
-
The ocular effects of systemic medications must be appreciated and considered when determining treatment regimens and suggesting ophthalmic follow-up
-
Accumulating data suggest that the use of systemic therapy to primarily address ocular complications of diabetic retinopathy could be a promising approach
-
As our understanding of the interactions between ocular status and systemic medications improves, close communication between all medical and eye-care providers will become increasingly important
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
[No authors listed] Standards of medical care in diabetes-—2010. Diabetes Care 33 (Suppl. 1) S11–S61 (2010).
Unwin, N., Gan, D. & Whiting, D. The IDF Diabetes Atlas: Providing evidence, raising awareness and promoting action. Diabetes Res. Clin. Pract. 87, 2–3 (2010).
Ioacara, S. et al. Improvements in life expectancy in type 1 diabetes patients in the last six decades. Diabetes Res. Clin. Pract. 86, 146–151 (2009).
Keenan, H. A. et al. Clinical factors associated with resistance to microvascular complications in diabetic patients of extreme disease duration: the 50-year medalist study. Diabetes Care 30, 1995–1997 (2007).
Bain, S. C. et al. Characteristics of type 1 diabetes of over 50 years duration (the Golden Years Cohort). Diabet. Med. 20, 808–811 (2003).
Centers for Disease Control and Prevention. National diabetes fact sheet: General information and national estimates on diabetes in the United States [online], (2007).
Luckie, R. et al. Fear of visual loss in patients with diabetes: results of the prevalence of diabetic eye disease in Tayside, Scotland (P-DETS) study. Diabet. Med. 24, 1086–1092 (2007).
Kempen, J. H. et al. The prevalence of diabetic retinopathy among adults in the United States. Arch. Ophthalmol. 122, 552–563 (2004).
Krolewski, A. S. et al. Predisposition to hypertension and susceptibility to renal disease in insulin-dependent diabetes mellitus. N. Engl. J. Med. 318, 140–145 (1988).
Agardh, C. D., Agardh, E. & Torffvit, O. The association between retinopathy, nephropathy, cardiovascular disease and long-term metabolic control in type 1 diabetes mellitus: a 5 year follow-up study of 442 adult patients in routine care. Diabetes Res. Clin. Pract. 35, 113–121 (1997).
Alexander, L. J., Cavallerano, J., Schwartz, G. L. & Zimmerman, B. R. Co-management of patients with hypertension or diabetes. Optom. Clin. 2, 131–142 (1992).
Marshall, G., Garg, S. K., Jackson, W. E., Holmes, D. L. & Chase, H. P. Factors influencing the onset and progression of diabetic retinopathy in subjects with insulin-dependent diabetes mellitus. Ophthalmology 100, 1133–1139 (1993).
Aiello, L. P., Cahill, M. T. & Wong, J. S. Systemic considerations in the management of diabetic retinopathy. Am. J. Ophthalmol. 132, 760–776 (2001).
Gabbay, K. H. The sorbitol pathway and the complications of diabetes. N. Engl. J. Med. 288, 831–836 (1973).
Brownlee, M., Vlassara, H. & Cerami, A. Nonenzymatic glycosylation and the pathogenesis of diabetic complications. Ann. Intern. Med. 101, 527–537 (1984).
Ways, D. K. & Sheetz, M. J. The role of protein kinase C in the development of the complications of diabetes. Vitam. Horm. 60, 149–193 (2000).
Baynes, J. W. & Thorpe, S. R. Role of oxidative stress in diabetic complications: a new perspective on an old paradigm. Diabetes 48, 1–9 (1999).
Kern, T. S. Contributions of inflammatory processes to the development of the early stages of diabetic retinopathy. Exp. Diabetes Res. 2007, 95103 (2007).
Grunwald, J. E. et al. Diabetic glycemic control and retinal blood flow. Diabetes 39, 602–607 (1990).
Aiello, L. P. et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N. Engl. J. Med. 331, 1480–1487 (1994).
Antonetti, D. A., Barber, A. J., Hollinger, L. A., Wolpert, E. B. & Gardner, T. W. Vascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors. J. Biol. Chem. 274, 23463–23467 (1999).
[No authors listed] Four risk factors for severe visual loss in diabetic retinopathy. The third report from the Diabetic Retinopathy Study. The Diabetic Retinopathy Study Research Group. Arch. Ophthalmol. 97, 654–655 (1979).
[No authors listed] Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch. Ophthalmol. 103, 1796–1806 (1985).
Turner, R. C. The U.K. Prospective Diabetes Study. A review. Diabetes Care 21 (Suppl. 3) C35–C38 (1998).
Keech, A. C. et al. Effect of fenofibrate on the need for laser treatment for diabetic retinopathy (FIELD study): a randomised controlled trial. Lancet 370, 1687–1697 (2007).
[No authors listed] Epidemiology of Diabetes Interventions and Complications (EDIC). Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort. Diabetes Care 22, 99–111 (1999).
[No authors listed] Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 837–853 (1998).
Sjølie, A. K. et al. Retinopathy and vision loss in insulin-dependent diabetes in Europe. The EURODIAB IDDM Complications Study. Ophthalmology 104, 252–260 (1997).
[No authors listed] Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317, 703–713 (1998).
White, N. H. et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch. Ophthalmol. 126, 1707–1715 (2008).
[No authors listed] Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA 287, 2563–2569 (2002).
[No authors listed] The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial. Arch. Ophthalmol. 113, 36–51 (1995).
Klein, R., Knudtson, M. D., Lee, K. E., Gangnon, R. & Klein, B. E. The Wisconsin Epidemiologic Study of Diabetic Retinopathy: XXII the twenty-five-year progression of retinopathy in persons with type 1 diabetes. Ophthalmology 115, 1859–1868 (2008).
Holman, R. R., Paul, S. K., Bethel, M. A., Matthews, D. R. & Neil, H. A. 10-year follow-up of intensive glucose control in type 2 diabetes. N. Engl. J. Med. 359, 1577–1589 (2008).
Anfossi, G., Russo, I., Doronzo, G. & Trovati, M. Relevance of the vascular effects of insulin in the rationale of its therapeutical use. Cardiovasc. Hematol. Disord. Drug Targets. 7, 228–249 (2007).
Lu, M. et al. Insulin-induced vascular endothelial growth factor expression in retina. Invest. Ophthalmol. Vis. Sci. 40, 3281–3286 (1999).
Poulaki, V. et al. Acute intensive insulin therapy exacerbates diabetic blood-retinal barrier breakdown via hypoxia-inducible factor-1alpha and VEGF. J. Clin. Invest. 109, 805–815 (2002).
Adamis, A. P. et al. Increased vascular endothelial growth factor levels in the vitreous of eyes with proliferative diabetic retinopathy. Am. J. Ophthalmol. 118, 445–450 (1994).
[No authors listed] Early worsening of diabetic retinopathy in the Diabetes Control and Complications Trial. Arch. Ophthalmol. 116, 874–886 (1998).
[No authors listed] Blood glucose control and the evolution of diabetic retinopathy and albuminuria. A preliminary multicenter trial. The Kroc Collaborative Study Group. N. Engl. J. Med. 311, 365–372 (1984).
Lauritzen, T., Frost-Larsen, K., Larsen, H. W. & Deckert, T. Effect of 1 year of near-normal blood glucose levels on retinopathy in insulin-dependent diabetics. Lancet 1, 200–204 (1983).
Funatsu, H., Yamashita, H., Ohashi, Y. & Ishigaki, T. Effect of rapid glycemic control on progression of diabetic retinopathy. Jpn. J. Ophthalmol. 36, 356–367 (1992).
Agardh, C. D., Eckert, B. & Agardh, E. Irreversible progression of severe retinopathy in young type I insulin-dependent diabetes mellitus patients after improved metabolic control. J. Diabetes Complications 6, 96–100 (1992).
Ernest, J. T., Goldstick, T. K. & Engerman, R. L. Hyperglycemia impairs retinal oxygen autoregulation in normal and diabetic dogs. Invest. Ophthalmol. Vis. Sci. 24, 985–989 (1983).
Grunwald, J. E. et al. Strict metabolic control and retinal blood flow in diabetes mellitus. Br. J. Ophthalmol. 78, 598–604 (1994).
Casati, S., Zoppini, G., Muggeo, M. & Marchini, G. Sustained regression of florid diabetic retinopathy in a patient with Donohue syndrome (leprechaunism). Eur. J. Ophthalmol. 20, 224–227 (2010).
Daneman, D. et al. Progressive retinopathy with improved control in diabetic dwarfism (Mauriac's syndrome). Diabetes Care 4, 360–365 (1981).
Rosenstock, J. et al. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 24, 631–636 (2001).
Stumvoll, M. & Häring, H. U. Glitazones: clinical effects and molecular mechanisms. Ann. Med. 34, 217–224 (2002).
Pershadsingh, H. A. & Moore, D. M. PPARgamma agonists: Potential as therapeutics for neovascular retinopathies. PPAR Res. 2008, 164273 (2008).
Shen, L. Q., Child, A., Weber, G. M., Folkman, J. & Aiello, L. P. Rosiglitazone and delayed onset of proliferative diabetic retinopathy. Arch. Ophthalmol. 126, 793–799 (2008).
Panigrahy, D. et al. PPARgamma ligands inhibit primary tumor growth and metastasis by inhibiting angiogenesis. J. Clin. Invest. 110, 923–932 (2002).
Nissen, S. E. & Wolski, K. Effect of rosiglitazone on the risk of myocardial infarction and death from cardiovascular causes. N. Engl. J. Med. 356, 2457–2471 (2007).
Home, P. D. et al. Rosiglitazone evaluated for cardiovascular outcomes--an interim analysis. N. Engl. J. Med. 357, 28–38 (2007).
Hollenberg, N. K. Considerations for management of fluid dynamic issues associated with thiazolidinediones. Am. J. Med. 115 (Suppl. 8A) 111S–115S (2003).
Ryan, E. H. Jr et al. Diabetic macular edema associated with glitazone use. Retina 26, 562–570 (2006).
Fong, D. S. & Contreras, R. Glitazone use associated with diabetic macular edema. Am. J. Ophthalmol. 147, 583–586 (2009).
Ambrosius, W. T. et al. Lack of association between thiazolidinediones and macular edema in type 2 diabetes: the ACCORD eye substudy. Arch. Ophthalmol. 128, 312–318 (2010).
Nathan, D. M. et al. Management of hyperglycemia in type 2 diabetes: A consensus algorithm for the initiation and adjustment of therapy: a consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 29, 1963–1972 (2006).
[No authors listed] Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet 352, 854–865 (1998).
Cusi, K., Consoli, A. & DeFronzo, R. A. Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J. Clin. Endocrinol. Metab. 81, 4059–4067 (1996).
Nagi, D. K. & Yudkin, J. S. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. A study of two ethnic groups. Diabetes Care 16, 621–629 (1993).
Xavier, D. O. et al. Metformin inhibits inflammatory angiogenesis in a murine sponge model. Biomed. Pharmacother. 64, 220–225 (2010).
Tan, B. K. et al. Metformin decreases angiogenesis via NF-kappaB and Erk1/2/Erk5 pathways by increasing the antiangiogenic thrombospondin-1. Cardiovasc. Res. 83, 566–574 (2009).
Joussen, A. M. et al. Suppression of Fas-FasL-induced endothelial cell apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-induced diabetes. FASEB J. 17, 76–78 (2003).
Chew, E. Y. et al. Association of elevated serum lipid levels with retinal hard exudate in diabetic retinopathy. Early Treatment Diabetic Retinopathy Study (ETDRS) Report 22. Arch. Ophthalmol. 114, 1079–1084 (1996).
Klein, B. E., Moss, S. E., Klein, R. & Surawicz, T. S. The Wisconsin Epidemiologic Study of Diabetic Retinopathy. XIII. Relationship of serum cholesterol to retinopathy and hard exudate. Ophthalmology 98, 1261–1265 (1991).
Lyons, T. J. et al. Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort. Invest. Ophthalmol. Vis. Sci. 45, 910–918 (2004).
Ansquer, J. C., Foucher, C., Aubonnet, P. & Le Malicot, K. Fibrates and microvascular complications in diabetes—insight from the FIELD study. Curr. Pharm. Des. 15, 537–552 (2009).
Panigrahy, D. et al. PPARalpha agonist fenofibrate suppresses tumor growth through direct and indirect angiogenesis inhibition. Proc. Natl Acad. Sci. USA 105, 985–990 (2008).
Bellosta, S., Ferri, N., Bernini, F., Paoletti, R. & Corsini, A. Non-lipid-related effects of statins. Ann. Med. 32, 164–176 (2000).
Danesh, F. R. & Kanwar, Y. S. Modulatory effects of HMG-CoA reductase inhibitors in diabetic microangiopathy. FASEB J. 18, 805–815 (2004).
Duncan, L. J. et al. A three-year trial of atromid therapy in exudative diabetic retinopathy. Diabetes 17, 458–467 (1968).
Cullen, J. F., Town, S. M. & Campbell, C. J. Double-blind trial of Atromid-S in exudative diabetic retinopathy. Trans. Ophthalmol. Soc. UK 94, 554–562 (1974).
Cullen, J. F., Ireland, J. T. & Oliver, M. F. A controlled trial of Atromid therapy in exudative diabetic retinopathy. Trans. Ophthalmol. Soc. UK 84, 281–295 (1964).
Freyberger, H., Schifferdecker, E. & Schatz, H. [Regression of hard exudates in diabetic background retinopathy in therapy with etofibrate antilipemic agent]. Med. Klin. (Munich) 89, 594–597, 633 (1994).
Emmerich, K. H. et al. [Efficacy and safety of etofibrate in patients with non-proliferative diabetic retinopathy]. Klin. Monbl. Augenheilkd. 226, 561–567 (2009).
Fioretto, P., Dodson, P. M., Ziegler, D. & Rosenson, R. S. Residual microvascular risk in diabetes: unmet needs and future directions. Nat. Rev. Endocrinol. 6, 19–25 (2010).
Gaede, P. et al. Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med. 348, 383–393 (2003).
Colhoun, H. M. et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 364, 685–696 (2004).
Chew, E. Y. et al. Rationale, design, and methods of the Action to Control Cardiovascular Risk in Diabetes Eye Study (ACCORD-EYE). Am. J. Cardiol. 99, 103i–111i (2007).
The ACCORD Study Group and ACCORD Eye Study Group. Effects of medical therapies on retinopathy progression in type 2 diabetes. N. Engl. J. Med. doi: 10.1056/NEJMoa1001288.
Wilkinson-Berka, J. L. Angiotensin and diabetic retinopathy. Int. J. Biochem. Cell Biol. 38, 752–765 (2006).
Wagner, J. et al. Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br. J. Ophthalmol. 80, 159–163 (1996).
Sarlos, S. et al. Retinal angiogenesis is mediated by an interaction between the angiotensin type 2 receptor, VEGF, and angiopoietin. Am. J. Pathol. 163, 879–887 (2003).
Klein, R. et al. Relationship of blood pressure to retinal vessel diameter in type 1 diabetes mellitus. Arch. Ophthalmol. 128, 198–205 (2010).
[No authors listed] Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ 317, 713–720 (1998).
[No authors listed] Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 317, 703–713 (1998).
Chaturvedi, N. et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB Controlled Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus. Lancet 351, 28–31 (1998).
Patel, A. et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet 370, 829–840 (2007).
Mauer, M. et al. Renal and retinal effects of enalapril and losartan in type 1 diabetes. N. Engl. J. Med. 361, 40–51 (2009).
Sjølie, A. K. et al. Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 372, 1385–1393 (2008).
Chaturvedi, N. et al. Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372, 1394–1402 (2008).
Colwell, J. A. et al. Platelet adhesion and aggregation in diabetes mellitus. Metabolism 28 (Suppl. 1) 394–400 (1979).
Boeri, D., Maiello, M. & Lorenzi, M. Increased prevalence of microthromboses in retinal capillaries of diabetic individuals. Diabetes 50, 1432–1439 (2001).
[No authors listed] Effects of aspirin treatment on diabetic retinopathy. ETDRS report number 8. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98, 757–765 (1991).
Chew, E. Y., Klein, M. L., Murphy, R. P., Remaley, N. A. & Ferris, F. L. III. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report no. 20. Arch. Ophthalmol. 113, 52–55 (1995).
[No authors listed] Effect of aspirin alone and aspirin plus dipyridamole in early diabetic retinopathy. A multicenter randomized controlled clinical trial. The DAMAD Study Group. Diabetes 38, 491–498 (1989).
Johnson, L. N., Stetson, S. W., Krohel, G. B., Cipollo, C. L. & Madsen, R. W. Aspirin use and the prevention of acute ischemic cranial nerve palsy. Am. J. Ophthalmol. 129, 367–371 (2000).
Chew, E. Y. et al. Aspirin effects on the development of cataracts in patients with diabetes mellitus. Early treatment diabetic retinopathy study report 16. Arch. Ophthalmol. 110, 339–342 (1992).
[No authors listed] Aspirin effects on mortality and morbidity in patients with diabetes mellitus. Early Treatment Diabetic Retinopathy Study report 14. ETDRS Investigators. JAMA 268, 1292–1300 (1992).
Joussen, A. M. et al. Nonsteroidal anti-inflammatory drugs prevent early diabetic retinopathy via TNF-alpha suppression. FASEB J. 16, 438–440 (2002).
Zheng, L., Howell, S. J., Hatala, D. A., Huang, K. & Kern, T. S. Salicylate-based anti-inflammatory drugs inhibit the early lesion of diabetic retinopathy. Diabetes 56, 337–345 (2007).
Sun, W., Gerhardinger, C., Dagher, Z., Hoehn, T. & Lorenzi, M. Aspirin at low-intermediate concentrations protects retinal vessels in experimental diabetic retinopathy through non-platelet-mediated effects. Diabetes 54, 3418–3426 (2005).
[No authors listed] Ticlopidine treatment reduces the progression of nonproliferative diabetic retinopathy. The TIMAD Study Group. Arch. Ophthalmol. 108, 1577–1583 (1990).
Superstein, R. et al. Prevalence of ocular hemorrhage in patients receiving warfarin therapy. Can. J. Ophthalmol. 35, 385–389 (2000).
Benzimra, J. D. et al. The Cataract National Dataset electronic multicentre audit of 55,567 operations: antiplatelet and anticoagulant medications. Eye (Lond.) 23, 10–16 (2009).
Jamula, E., Anderson, J. & Douketis, J. D. Safety of continuing warfarin therapy during cataract surgery: a systematic review and meta-analysis. Thromb. Res. 124, 292–299 (2009).
Fu, A. D. et al. Anticoagulation with warfarin in vitreoretinal surgery. Retina 27, 290–295 (2007).
Dayani, P. N. & Grand, M. G. Maintenance of warfarin anticoagulation for patients undergoing vitreoretinal surgery. Arch. Ophthalmol. 124, 1558–1565 (2006).
Dayani, P. N., Siddiqi, O. K. & Holekamp, N. M. Safety of intravitreal injections in patients receiving warfarin anticoagulation. Am. J. Ophthalmol. 144, 451–453 (2007).
Tilanus, M. A., Vaandrager, W., Cuypers, M. H., Verbeek, A. M. & Hoyng, C. B. Relationship between anticoagulant medication and massive intraocular hemorrhage in age-related macular degeneration. Graefes Arch. Clin. Exp. Ophthalmol. 238, 482–485 (2000).
[No authors listed] Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology 88, 583–600 (1981).
[No authors listed] Early photocoagulation for diabetic retinopathy. ETDRS report number 9. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology 98, 766–785 (1991).
Avery, R. L. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina 26, 352–354 (2006).
Yoshida, T. et al. Digoxin inhibits retinal ischemia-induced HIF-1α expression and ocular neovascularization. FASEB J. doi:10.1096/fj.09-145664.
Khan, M. I., Chesney, J. A., Laber, D. A. & Miller, D. M. Digitalis, a targeted therapy for cancer? Am. J. Med. Sci. 337, 355–359 (2009).
Prassas, I., Paliouras, M., Datti, A. & Diamandis, E. P. High-throughput screening identifies cardiac glycosides as potent inhibitors of human tissue kallikrein expression: implications for cancer therapies. Clin. Cancer Res. 14, 5778–5784 (2008).
Gao, B. B. et al. Extracellular carbonic anhydrase mediates hemorrhagic retinal and cerebral vascular permeability through prekallikrein activation. Nat. Med. 13, 181–188 (2007).
Phipps, J. A. et al. Plasma kallikrein mediates angiotensin II type 1 receptor-stimulated retinal vascular permeability. Hypertension 53, 175–181 (2009).
Schneider, L., Lumry, W., Vegh, A., Williams, A. H. & Schmalbach, T. Critical role of kallikrein in hereditary angioedema pathogenesis: a clinical trial of ecallantide, a novel kallikrein inhibitor. J. Allergy Clin. Immunol. 120, 416–422 (2007).
Jacques, M. L. Study to assess the safety and tolerability of a single administration of FOV2302 (ecallantide) in patients with macular edema associated with central retinal vein occlusion. ClinicalTrials.gov Identifier: NCT00969293. Clinical Trials.gov [online], (2010).
Aiello, L. P. Targeting intraocular neovascularization and edema—one drop at a time. N. Engl. J. Med. 359, 967–969 (2008).
Watanabe, D. et al. Erythropoietin as a retinal angiogenic factor in proliferative diabetic retinopathy. N. Engl. J. Med. 353, 782–792 (2005).
Tong, Z. et al. Promoter polymorphism of the erythropoietin gene in severe diabetic eye and kidney complications. Proc. Natl Acad. Sci. USA 105, 6998–7003 (2008).
Powell, E. D. & Field, R. A. Diabetic retinopathy and rheumatoid arthritis. Lancet 2, 17–18 (1964).
Goldfine, A. B. et al. Use of salsalate to target inflammation in the treatment of insulin resistance and type 2 diabetes. Clin. Transl. Sci. 1, 36–43 (2008).
Fleischman, A., Shoelson, S. E., Bernier, R. & Goldfine, A. B. Salsalate improves glycemia and inflammatory parameters in obese young adults. Diabetes Care 31, 289–294 (2008).
Chew, E. Y. et al. Preliminary assessment of celecoxib and microdiode pulse laser treatment of diabetic macular edema. Retina 30, 459–467 (2010).
Solomon, S. D. et al. Cardiovascular risk of celecoxib in 6 randomized placebo-controlled trials: the cross trial safety analysis. Circulation 117, 2104–2113 (2008).
Chew, E. et al. Randomized trial of peribulbar triamcinolone acetonide with and without focal photocoagulation for mild diabetic macular edema: a pilot study. Ophthalmology 114, 1190–1196 (2007).
Gillies, M. C. et al. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a double-masked, placebo-controlled, randomized clinical trial. Ophthalmology 113, 1533–1538 (2006).
Jonas, J. B., Kreissig, I., Sofker, A. & Degenring, R. F. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch. Ophthalmol. 121, 57–61 (2003).
Martidis, A. et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 109, 920–927 (2002).
[No authors listed] A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology 115, 1447–1449, 1449.e1–e10 (2008).
Beck, R. W. et al. Three-year follow-up of a randomized trial comparing focal/grid photocoagulation and intravitreal triamcinolone for diabetic macular edema. Arch. Ophthalmol. 127, 245–251 (2009).
Bressler, N. M. et al. Exploratory analysis of diabetic retinopathy progression through 3 years in a randomized clinical trial that compares intravitreal triamcinolone acetonide with focal/grid photocoagulation. Arch. Ophthalmol. 127, 1566–1571 (2009).
Silva, P. S., Sun, J. K. & Aiello, L. P. Role of steroids in the management of diabetic macular edema and proliferative diabetic retinopathy. Semin. Ophthalmol. 24, 93–99 (2009).
Genentech Inc., Avastin® (bevacizumab)—Full prescribing information [online], (2010).
Rosenfeld, P. J., Moshfeghi, A. A. & Puliafito, C. A. Optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration. Ophthalmic Surg. Lasers Imaging 36, 331–335 (2005).
Haritoglou, C. et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 26, 999–1005 (2006).
Arevalo, J. F. et al. Comparison of two doses of primary intravitreal bevacizumab (Avastin) for diffuse diabetic macular edema: results from the Pan-American Collaborative Retina Study Group (PACORES) at 12-month follow-up. Graefes Arch. Clin. Exp. Ophthalmol. 247, 735–743 (2009).
Chun, D. W., Heier, J. S., Topping, T. M., Duker, J. S. & Bankert, J. M. A pilot study of multiple intravitreal injections of ranibizumab in patients with center-involving clinically significant diabetic macular edema. Ophthalmology 113, 1706–1712 (2006).
Beck, R. W. & Glassman, A. R. Laser-Ranibizumab-Triamcinolone for proliferative diabetic retinopathy (LRTforDME+PRP). ClinicalTrials.gov Identifier: NCT00445003. Clinical Trials.gov [online], (2008).
Scott, I. U. et al. A phase II randomized clinical trial of intravitreal bevacizumab for diabetic macular edema. Ophthalmology 114, 1860–1867 (2007).
Diabetic Retinopathy Clinical Research Network et al. Randomized trial evaluating ranibizumab plus prompt or deferred laser or triamcinolone plus prompt laser for diabetic macular edema. Ophthalmology 117, 1064–1077 (2010).
Bakri, S. J. et al. Pharmacokinetics of intravitreal ranibizumab (Lucentis). Ophthalmology 114, 2179–2182 (2007).
Bakri, S. J., Snyder, M. R., Reid, J. M., Pulido, J. S. & Singh, R. J. Pharmacokinetics of intravitreal bevacizumab (Avastin). Ophthalmology 114, 855–859 (2007).
Moshfeghi, A. A. et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration: twenty-four-week results of an uncontrolled open-label clinical study. Ophthalmology 113, 2002–2012 (2006).
Mulcahy, M. F. & Benson, A. B. III. Bevacizumab in the treatment of colorectal cancer. Expert Opin. Biol. Ther. 5, 997–1005 (2005).
Ueta, T., Yanagi, Y., Tamaki, Y. & Yamaguchi, T. Cerebrovascular accidents in ranibizumab. Ophthalmology 116, 362 (2009).
Fung, A. E., Rosenfeld, P. J. & Reichel, E. The International Intravitreal Bevacizumab Safety Survey: using the internet to assess drug safety worldwide. Br. J. Ophthalmol. 90, 1344–1349 (2006).
Li, J. et al. Systemic administration of HMG-CoA reductase inhibitor protects the blood-retinal barrier and ameliorates retinal inflammation in type 2 diabetes. Exp. Eye Res. 89, 71–78 (2009).
Nauck, M., Karakiulakis, G., Perruchoud, A. P., Papakonstantinou, E. & Roth, M. Corticosteroids inhibit the expression of the vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur. J. Pharmacol. 341, 309–315 (1998).
Aiello, L. P. et al. Suppression of retinal neovascularization in vivo by inhibition of vascular endothelial growth factor (VEGF) using soluble VEGF-receptor chimeric proteins. Proc. Natl Acad. Sci. USA 92, 10457–10461 (1995).
Acknowledgements
Laurie Barclay, freelance writer and reviewer, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the MedscapeCME-accredited continuing medical education activity associated with this article.
Author information
Authors and Affiliations
Contributions
P. S. Silva, J. D. Cavallerano, J. K. Sun and L. P. Aiello researched the data for the article. P. S. Silva, J. D. Cavallerano, J. K. Sun, L. M. Aiello and L. P. Aiello provided a substantial contribution to discussions of the content. P. S. Silva, J. D. Cavallerano, J. K. Sun, L. M. Aiello and L. P. Aiello contributed equally to writing the article and to review and/or editing of the manuscript before submission.
Corresponding author
Ethics declarations
Competing interests
L. P. Aiello is a Data Monitoring Board Member for Genentech and a consultant for Eli Lilly, GlaxoSmithKline, Merck, Novartis and Pfizer. The other authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Silva, P., Cavallerano, J., Sun, J. et al. Effect of systemic medications on onset and progression of diabetic retinopathy. Nat Rev Endocrinol 6, 494–508 (2010). https://doi.org/10.1038/nrendo.2010.122
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrendo.2010.122
This article is cited by
-
Long Non-coding RNA SPAG5-AS1 Attenuates Diabetic Retinal Vascular Dysfunction by Inhibiting Human Retinal Microvascular Endothelial Cell Proliferation, Migration, and Tube Formation by Regulating the MicroRNA-1224-5p/IRS-1 Axis
Molecular Biotechnology (2023)
-
New anti-hyperglycaemic agents for type 2 diabetes and their effects on diabetic retinopathy
Eye (2019)
-
Retinopathie erfordert Teamarbeit
Info Diabetologie (2018)
-
Netzhautkomplikationen bei Diabetes
Der Diabetologe (2016)
-
Regression activity that is naturally present in vitreous becomes ineffective as patients develop proliferative diabetic retinopathy
Diabetologia (2013)