Faselis C, Katsimardou A, Imprialos K, Deligkaris P, Kallistratos M, Dimitriadis K. Microvascular complications of type 2 diabetes mellitus. Curr Vasc Pharmacol. 2019 May 1. doi: 10.2174/1570161117666190502103733. [Epub ahead of print] PubMed PMID: 31057114.
Rangel ÉB, Rodrigues CO, de Sá JR. Micro- and Macrovascular Complications in Diabetes Mellitus: Preclinical and Clinical Studies. J Diabetes Res. 2019 Feb 17;2019:2161085. doi: 10.1155/2019/2161085. eCollection 2019. PubMed PMID: 30911551; PubMed Central PMCID: PMC6397960.
American Diabetes Association. Standards of Medical Care in Diabetes - 2019. Diabetes Care 2019;42(Suppl 1):S1-S193.
Araszkiewicz A, Bandurska-Stankiewicz E, Budzyński A, et al. 2019 Guidelines on the management of diabetic patients. A position of Diabetes Poland. Clinical Diabetology. 2019;8(1):1-95. doi: 10.5603/DK.2019.0001.
Davies MJ, D'Alessio DA, Fradkin J, et al. Management of Hyperglycemia in Type 2 Diabetes, 2018. A Consensus Report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018 Dec;41(12):2669-2701. doi: 10.2337/dci18-0033. Epub 2018 Oct 4. PubMed PMID: 30291106; PubMed Central PMCID: PMC6245208.
American Diabetes Association. Economic Costs of Diabetes in the U.S. in 2017. Diabetes Care. 2018 May;41(5):917-928. doi: 10.2337/dci18-0007. Epub 2018 Mar 22. PubMed PMID: 29567642; PubMed Central PMCID: PMC5911784.
Zhang P, Lu J, Jing Y, Tang S, Zhu D, Bi Y. Global epidemiology of diabetic foot ulceration: a systematic review and meta-analysis (†). Ann Med. 2017 Mar;49(2):106-116. doi: 10.1080/07853890.2016.1231932. Epub 2016 Nov 3. Review. PubMed PMID: 27585063.
Perkovic V, Agarwal R, Fioretto P, et al; Conference Participants. Management of patients with diabetes and CKD: conclusions from a "Kidney Disease: Improving Global Outcomes" (KDIGO) Controversies Conference. Kidney Int. 2016 Dec;90(6):1175-1183. doi: 10.1016/j.kint.2016.09.010. PubMed PMID: 27884312.
Lazzarini PA, Hurn SE, Fernando ME, et al. Prevalence of foot disease and risk factors in general inpatient populations: a systematic review and meta-analysis. BMJ Open. 2015 Nov 23;5(11):e008544. doi: 10.1136/bmjopen-2015-008544. Review. PubMed PMID: 26597864; PubMed Central PMCID: PMC4663442.
Lipsky BA, Berendt AR, Cornia PB, et al; Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012 Jun;54(12):e132-73. doi: 10.1093/cid/cis346. PubMed PMID: 22619242.
Bakker K, Apelqvist J, Schaper NC; International Working Group on Diabetic Foot Editorial Board. Practical guidelines on the management and prevention of the diabetic foot 2011. Diabetes Metab Res Rev. 2012 Feb;28 Suppl 1:225-31. doi: 10.1002/dmrr.2253. PubMed PMID: 22271742.
Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO Clinical Practice Guideline for Acute Kidney Injury. Kidney inter., Suppl. 2012; 2: 1–138.
Bril V, England J, Franklin GM, et al; American Academy of Neurology; American Association of Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011 May 17;76(20):1758-65. doi: 10.1212/WNL.0b013e3182166ebe. Epub 2011 Apr 11. Review. Erratum in: Neurology. 2011 Aug 9;77(6):603. Dosage error in article text. PubMed PMID: 21482920; PubMed Central PMCID: PMC3100130.
Giacco F, Brownlee M. Oxidative stress and diabetic complications. Circ Res. 2010 Oct 29;107(9):1058-70. doi: 10.1161/CIRCRESAHA.110.223545. Review. PubMed PMID: 21030723; PubMed Central PMCID: PMC2996922.
Tesfaye S, Boulton AJ, Dyck PJ, et al; Toronto Diabetic Neuropathy Expert Group. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010 Oct;33(10):2285-93. doi: 10.2337/dc10-1303. Review. Erratum in: Diabetes Care. 2010 Dec;33(12):2725. PubMed PMID: 20876709; PubMed Central PMCID: PMC2945176.
Mogensen CE, Christensen CK, Vittinghus E. The stages in diabetic renal disease. With emphasis on the stage of incipient diabetic nephropathy. Diabetes. 1983 May;32 Suppl 2:64-78. Review. PubMed PMID: 6400670.
Etiology, Pathogenesis, ClassificationTop
Diabetic retinopathy is present in most patients with diabetes mellitus (DM) (after 20 years from diagnosis in almost all patients with type 1 DM and in more than half of patients with type 2 DM). It is the most frequent cause of new cases of blindness and visual impairment among adults aged 20 to 74 years in developed countries and is a frequent cause of glaucoma, cataracts, and other disorders in the eye at early ages. The key factors in the pathogenesis and progression of diabetic retinopathy are DM duration, baseline retinopathy at the diagnosis of DM, chronic hyperglycemia, nephropathy, dyslipidemia, and hypertension.
Retinopathy usually progresses from mild nonproliferative abnormalities (microaneurysm formation and intraretinal hemorrhages) to retinal capillary nonperfusion, cotton wool spots, increased numbers of hemorrhages, venous abnormalities, and intraretinal microvascular abnormalities. Eventually this leads to increased vascular permeability, vascular occlusion, and neovascularization on the disc, retina, iris, and in the filtration angle, resulting in traction retinal detachments and neovascular glaucoma. All these changes can be accelerated by the presence of pregnancy and puberty.
The American Academy of Ophthalmology established the International Classification of Diabetic Retinopathy and Diabetic Macular Edema, which describes 5 clinical levels of diabetic retinopathy:
1) No apparent retinopathy and no abnormalities.
2) Mild nonproliferative diabetes retinopathy (NPDR) with microaneurysms only.
3) Moderate NPDR with microaneurysms and other abnormalities but less than severe NPDR.
4) Severe NPDR with any of the following: ≥20 intraretinal hemorrhages in each of the 4 retinal quadrants, definite venous beading in ≥2 retinal quadrants, prominent intraretinal microvascular abnormalities in ≥1 retinal quadrants, and no proliferative diabetic retinopathy (PDR).
5) PDR with ≥1 of the following: Retinal neovascularization, vitreous hemorrhage, or preretinal hemorrhage. Neovascular glaucoma can result from new vessels growing in the iris and anterior chamber angle structures.
Diabetic macular edema (DME) can be present with any level of diabetic retinopathy. It develops as a consequence of increased retinal vascular permeability that results in retinal thickening and lipid deposits (hard exudates). The DME classification is based on the ophthalmic findings (retinal thickening or hard exudates in the posterior pole):
1) Mild DME: Some retinal thickening or hard exudates in the posterior pole but distant from the center of the macula.
2) Moderate DME: Findings approaching but not involving the center of the macula.
3) Severe DME: Findings involving the center of the macula.
Clinically significant DME is considered, for example, when retinal edema or hard exudates are located at or within 500 microm of the center of the macula.
Vision loss due to diabetic retinopathy develops when the retinal neurons are damaged as a result of macular edema, capillary nonperfusion, retinal detachment, neovascularization, and/or in the preretinal or vitreous hemorrhage.
Diagnosis and Follow-UpTop
The first ophthalmologic examination should be performed within 5 years of establishing the diagnosis of type 1 DM and at the moment of diagnosis of type 2 DM. Perform follow-up examinations every 1 to 2 years in patients with no retinopathy, every 6 to 12 months in those with early stages of NPDR, every 3 months in patients with more advanced retinopathy, and within 3 to 4 months in patients with non–clinically significant DME. In women with preexisting DM who are planning pregnancy, eye examinations should take place before pregnancy or in the first trimester and then should be followed up every trimester and for 1 year postpartum, as dictated by the degree of retinopathy. Follow-up should be done every 1 to 3 months in case of severe NPDR or worse. No eye examinations are required during pregnancy in patients who develop gestational DM.
Eye examinations should be performed by an ophthalmologist or optometrist who is knowledgeable and experienced in diagnosing diabetic retinopathy. Examination must include visual acuity and color vision, dilated slit-lamp biomicroscopy with a hand-held lens, intraocular pressure, gonioscopy, pupillary assessment for optic nerve dysfunction, stereoscopic examination of the posterior pole, and examination of the peripheral retina and vitreous. Rarely specialized studies such as optical coherence tomography and fluorescein angiography of the fundus are indicated. These can be useful in patients with very early retinopathy (undetectable by ophthalmoscopy), macular edema, and NPDR, as well as for the assessment of the effects of laser therapy. Retinal photography with remote reading can be a useful screening tool in areas where qualified eye-care professionals are not available; however, it should not be a substitute for a comprehensive eye examination, at least initially.
Prevention and TreatmentTop
1. The goal of treatment in patients with no apparent retinopathy and mild and moderate NPDR is to optimize medical therapy. Early detection and optimal control of DM can reduce the risk or slow down the progression of diabetic retinopathy: a 10% reduction in glycated hemoglobin (HbA1c) reduces the risk of retinopathy progression by 43% in patients with type 1 DM, and every percentage-point decrease in HbA1c is associated with a 35% reduction in the risk of microvascular complications in patients with type 2 DM. Target levels of preprandial glucose are 4.4 to 7.2 mmol/L (80-130 mg/dL) and target levels of postprandial glucose are ≤10.0 mmol/L (180 mg/dL), with HbA1c ≤7.0% in the general population.
2. Effective treatment of hypertension and dyslipidemia is of key importance. Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are both effective treatments in diabetic retinopathy. The addition of fenofibrate has shown to slow down the progression of retinopathy in patients with dyslipidemia and preexisting diabetic retinopathy. The presence of retinopathy is not a contraindication to acetylsalicylic acid (ASA) therapy for prevention of cardiovascular disease.
3. The mainstay of treatment aimed at inhibiting the progression of vascular lesions is grid, focal, or panretinal laser photocoagulation therapy, which is used in patients with DME, advanced NPDR, and early proliferative retinopathy to reduce the risk of severe vision loss. Advanced proliferative retinopathy (vitreous hemorrhages, connective tissue proliferation) is an indication for vitrectomy.
4. In patients with severe central-involved DME, injections of intravitreal anti–vascular endothelial growth factor (anti-VEGF) preparations (bevacizumab, ranibizumab, and aflibercept) have replaced the need for laser photocoagulation, although the cost of treatment and need for frequent follow-up visits may limit their use.Evidence 1Weak recommendation (benefits likely outweigh downsides; but the balance is close or uncertain; an alternative course of action may be better for some patients). Note that a weak rather than strong recommendation is related to the moderate quality of evidence and high cost of the intervention. Moderate Quality of Evidence (moderate confidence that we know true effects of the intervention). Quality of Evidence lowered due to indirectness and no long-term follow-up. Virgili G, Parravano M, Menchini F, Evans JR. Anti-vascular endothelial growth factor for diabetic macular oedema. Cochrane Database Syst Rev. 2014 Oct 24;(10):CD007419. doi: 10.1002/14651858.CD007419.pub4. Review. Update in: Cochrane Database Syst Rev. 2017 Jun 22;6:CD007419. PubMed PMID: 25342124. Solomon SD, Chew E, Duh EJ, et al. Diabetic Retinopathy: A Position Statement by the American Diabetes Association. Diabetes Care. 2017 Mar;40(3):412-418. doi: 10.2337/dc16-2641. Review. Erratum in: Diabetes Care. 2017 Jun;40(6):809. Diabetes Care. 2017 Jul 13. PubMed PMID: 28223445; PubMed Central PMCID: PMC5402875. American Academy of Ophthalmology Retina/Vitreous Panel. Preferred Practice Pattern® Guidelines. Diabetic Retinopathy. San Francisco, CA: American Academy of Ophthalmology; 2017. https://www.aao.org/preferred-practice-pattern/diabetic-retinopathy-ppp-updated-2017. Updated December 2017. Accessed June 2019. Anti-VEGF preparations can also be used as an alternative or adjunct to laser photocoagulation in patients with PDR, as rapid regression of retinal neovascularization has been observed in several studies. Ranibizumab, a selective monoclonal antibody to VEGF, is the first-line agent in all patients with DME with central foveal involvement. Aflibercept is another agent indicated for the treatment of visual impairment due to DME, especially in patients with lower levels of acuity (20/50 or worse). The therapeutic regimen is based on near-monthly administrations during the first 12 months with fewer injections administered as needed in subsequent years as maintenance therapy.
5. Other treatments such as intravitreal glucocorticoids, topical nonsteroidal anti-inflammatory drugs, antioxidants, inflammatory molecule inhibitors, renin-angiotensin-aldosterone system blockers, and natural anti-inflammatory therapies can be considered, in a specialized settings, as adjunct therapies to reduce the rate of administration of anti-VEGF agents or in cases where anti-VEGF agents are contraindicated.