New strategies to assess the risk of diabetes-related vision loss
A colleague recently told me that eye doctors should “stay within the lines” of traditional eye care because we barely have enough time as it is to do our jobs. My response was that today more than half of our adult patients have either diabetes or prediabetes, so our job now requires we go ”outside the lines” to avoid the leading cause of preventable blindness.
A colleague recently told me that eye doctors should “stay within the lines” of traditional eye care because we barely have enough time as it is to do our jobs. My response was that today more than half of our adult patients have either diabetes or prediabetes,1 so our job now requires we go ”outside the lines” to avoid the leading cause of preventable blindness.2
The incidence of severe vision loss caused by proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) appear to have declined significantly over the last 40 years due to improvements in blood glucose control, improved surveillance of diabetes patients, and widespread use of effective interventional therapies like photocoagulation and anti-VEGF injections.3
Nonetheless, diabetic retinopathy (DR) and DME remain hugely important causes of vision impairment and blindness and remain the leading causes of vision loss in Americans of working age.2
Previously from Dr. Chous: How diabetes is linked to gut bacteria
Increased prevalence of DR and DME is linked to increasing prevalence of diabetes and reduction in macrovascular mortality achieved with better treatment regimens. Ironically, improved longevity allows patients with diabetes to live long enough for development of vision-threatening complications.4
With recent estimates showing more than 12 percent of all U.S. adults having diabetes, it is becoming increasingly important to identify and remediate patients at highest risk for progression to clinical diagnosis of diabetes and all of its attendant complications, including vision loss.5
Additionally, identifying diabetes patients at highest risk for developing sight-threatening retinopathy (STR) and attempting earlier intervention will play an increasingly important role as we strive to improve public health outcomes and reduce medical expenditures.
Current algorithm
Landmark clinical trials inform the current algorithm for preventing diabetes and STR. The Diabetes Prevention Program (DPP) showed that walking 150 minutes per week lowered the risk of developing type 2 diabetes by 58 percent at 4 years and by 38 percent at 10 years in high-risk patients with prediabetes.6
The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) have shown that a majority of patients with diabetes will develop some degree of DR over time. This study informs recommendations about how often dilated retinal examinations should be performed and at what length of disease duration such exams should begin.7
In terms of preventing microvascular complications, The Diabetes Control and Complication Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) showed that tighter blood glucose (both studies) and blood pressure control (UKPDS) lowers the risk of DR and its progression.8
Related: Fasting regimens may be key in treating type 2 diabetes
As for preventing vision loss, the Diabetic Retinopathy Study (DRS) and Early Treatment Diabetic Retinopathy Study (ETDRS) showed that laser therapy significantly lowers the chance of severe vision loss from PDR and clinically significant DME (CSME), respectively.9
More recently, results from the Diabetic Retinopathy Clinical Research Network (DRCR.net) have shown that anti-VEGF therapy is superior to laser for ”center-involved” DME and equally effective as pan-retinal photocoagulation for PDR.10 Moreover, spectral domain optical coherence tomography (SD-OCT) has become the recognized standard for detecting DME and assessing response to therapy.11
Collectively, these studies have shaped the current care algorithm:
• Prevent diabetes by patient education to inspire behavioral change
• Achieve good metabolic control via patient education, behavioral change, and drug therapy once diabetes is diagnosed
• Monitor diagnosed patients routinely for the development of STR (and other complications)
• Treat patients with STR when it develops
More succinctly and towards preventing vision loss, the algorithm is: counsel, monitor, and wait to treat.
Related: Using OCT with your diabetes patients
This strategy has worked to reduce blindness and cardiovascular deaths from diabetes in the U.S. for a number of years (though rates of blindness increased 27 percent worldwide from 1990 to 2010)12 and would be “perfect” if it weren’t for a number of countervailing factors:
• Patient education is difficult, time-consuming, and often ineffective at motivating behavioral change that prevents diabetes and reduces the risk of eye disease13
• Achieving and maintaining good diabetes control is difficult even in the best of circumstances based on a number of factors (variable GI absorption of macronutrients and medications, variable onset of insulin action, hypoglycemia, and other environmental mediators of endocrine response)14
• A host of societal/environmental/market forces predispose our citizenry toward diabetes despite individually “good” behaviors and, despite declining incidence rates of diabetes in the U.S., prevalence continues to climb15
• Half of high-risk diabetes patients do not receive at least annual dilated eye exams as a function of “eye care ignorance” (by patients and providers) and other barriers to access16
Treatment of diabetes and STR is expensive and isn’t always effective. All of this begs the question: Can we do more?
Go outside the lines
We can start by targeting those at highest risk for developing diabetes with messages about prevention. Consider those with a positive family history of type 2 diabetes, overweight or obesity, sedentary lifestyle, people of color, high blood pressure, over age 40 years, with low fiber and plant food intake.17
Additional risk factors include history of gestational diabetes, use of statin therapy (especially simvistatin, atorvaststain, and rosuvistatin) or thiazide diuretics, and serum vitamin D deficiency.18-20 Agouridid, Elliott, McDonnell
Patients can be asked or surveyed about these risk factors as part of an eye examination and recommendations can be tailored to lower risk (see Table 1).
Regarding ocular findings that predict development of diabetes, we know that refractive shifts, dry eye, and staphylococcal lid disease are linked to chronic hyperglycemia as, of course, is any unexplained retinopathy.21
Related: Worldwide diabetes epidemic approaches half a billion
Additionally, long-term exposure to elevated glucose causes accelerated formation of indissoluble glyco-protein molecules in the crystalline lens called advanced glycation endproducts (AGEs), which can now be quantified easily in-office with ClearPath DS120 (Freedom Meditech) to gauge metabolic risk long before blood glucose testing establishes a diagnosis.22 Cahn
Recently, subclinical retinal microaneurysm formation as detected by multi-spectral imaging (MSI, Annidis RHA) has been strongly linked to insulin resistance and excess insulin production in adults without known diabetes, giving us a qualitative and quantitative tool for assessing the sentinel biological abnormalities underlying the development of type 2 diabetes (see Figure 1).23
Some of these abnormalities may also be seen via OCT angiography (OCTA). Laboratory assessment of insulin resistance and hyperinsulinemia are almost never done outside of research settings, so this represents a chance for ODs to get ahead of the curve and counsel our patients.
Low blood levels of the dietary carotenoids lutein and zeaxanthin that form the macular pigment are associated with increased risk of diabetic retinopathy, and low macular pigment optical density (MPOD) has been linked to type 2 diabetes.24,25 Macular pigment clearly plays a role in macular degeneration, which may progress more rapidly in patients with diabetes.25,26 MPOD is also something that can be easily measured in-office (QuantifEye MPS II, ZeaVision). MPOD improvements are likely after appropriate diet and especially supplement recommendations are made by optometrists and patient adherence is confirmed by follow-up testing.
Minimizing risk
Once a diabetes diagnosis has been established, our goal shifts from helping patients prevent diabetes to helping them minimize the risk of developing diabetic retinopathy in general and STR in particular.
We know that lower mean blood glucose as reflected by hemoglobin A1c (HbA1c) reduces DR incidence and progression, but it must be balanced against higher risks of tight control in some populations (preexisting cardiovascular disease, younger children, elderly, poor cognition, hypoglycemia unawareness, short life expectancy).27
Interestingly, mean HbA1c during the DCCT accounted for a mere 6 to 11 percent of variance in DR during the 10-year trial, suggesting that other aspects of blood glucose may confer greater risk (e.g., short-term spikes too brief to be captured by HbA1c but severe enough to initiate and sustain a biochemical cascade of retinal injury).28
It is helpful to counsel patients about individually appropriate blood glucose targets in coordination with the diabetes physician (see Table 2).
Many patients use insulin, including a significant number with type 2 diabetes, and I have learned through personal and professional experience to ask my patients about appropriate timing of insulin (prior to eating in the case of rapid-acting insulin like Novolog [lispro, NovoNordisk]) and the importance of rotating injection sites to minimize scarring (lipohypertrophy) that interferes with subcutaneous insulin absorption (see Figure 2).
Newer evidence suggests that certain, common oral medicines may significantly reduce the risk of DR progression, including blood pressure drugs that block the renin-angiotensin-aldosterone system (RAAS) as well as the triglyceride-lowering agent, fenofibrate.29,30 I would encourage every optometrist to discuss this with patients who have mild to moderate non-proliferative diabetic retinopathy (NPDR).
Related: Keeping up with the latest diabetic eye disease research
A number of studies have shown that diabetes affects visual function (contrast and visual field sensitivity, color discrimination) before the onset of DR, and that these measures worsen as DR progresses.31-34 Low contrast acuity charts and contrast sensitivity gratings are widely available, as are color vision instruments particularly suited to detecting acquired blue-yellow and red-green deficits commonly seen in patients with DR/DME (ColorDx, Konan Medical; Rabin Cone Contrast Test, Innova Systems).
ODs should consider routinely testing visual function in patients with diabetes and attempt remediation through improved metabolic control or nutritional supplementation.
Studies suggest that AREDS formula nutrients slowed progression of DR in human subjects,35 and my own research-the Diabetes Visual Function Supplement Study (DiVFuSS)-showed that a novel, multi-component nutritional supplement containing lutein, zeaxanthin, antioxidants, and select botanical extracts significantly improved visual function in patients with both type 1 and type 2 diabetes, both with and without DR, and without affecting HbA1c in a randomized, placebo-controlled clinical trial.36
The test formula also significantly reduced symptoms of diabetic neuropathy, LDL cholesterol, triglycerides, and the inflammatory serum marker, and high sensitivity C-reactive protein (hsCRP); in an animal model, the formula prevented DR (elevated VEGF, mitochondrial DNA damage, retinal pericyte death, and ERG abnormalities) without affecting blood glucose levels.37
Diabetes damages the retina long before we can see the vascular lesions of DR with conventional examination techniques. Earlier detection of subclinical DR has now become possible with the advent of advanced imaging modalities, including adaptive optics and more available (and affordable) options like multi-spectral imaging (Annidis RHA; see Figure 1) and OCT angiography (AngioVue, Optovue; AngioPlex, Zeiss) that utilizes motion contrast imaging with sequential OCT B-scans to construct a map of blood flow within the retina, choroid and optic nerve microvasculature.38,39
OCTA can show subclinical microaneurysm formation, abnormal capillary looping, and areas of reduced capillary density or non-perfusion that may precede development of ophthalmoscopically detectable lesions typically seen in early DR (see Figure 3). OCTA is quick and non-invasive. It may facilitate not only identification of higher-risk patients for more careful follow-up, but a new way to assess the efficacy of therapy to prevent DR progression.
We have more tools than ever to combat the diabetes epidemic and prevent blindness. If current trends hold, we’re going to be seeing an increasing number of patients with diabetes and at substantial risk for vision loss. By going outside the lines in our evaluation, management, and education, we can preserve and enhance eyesight and deliver the care a majority of our patients now require.
Related: Ocular manifestations of diabetes: Some clues for eyecare professionals
References:
1. Menke A, Casagrande S, Geiss L, Cowie CC. Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012. JAMA. 2015 Sep 8;314(10):1021-1029.
2. Centers for Disease Control and Prevention. Diabetic Retinopathy Fact Sheet. Available https://www.cdc.gov/visionhealth/pdf/factsheet.pdf. Accessed 5/16/17.
3. Wong TY, Mwamburi M, Klein R, Larsen M, Flynn H, Hernandez-Medina M, Ranganathan G, Wirostko B, Pleil A, Mitchell P. Rates of progression in diabetic retinopathy during different time periods: a systematic review and meta-analysis. Diabetes Care. 2009 Dec;32(12):2307-13.
4. Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye and Visi (Lond). 2015 Sep 30;2:17.
5. Menke A, Casagrande S, Geiss L, Cowie CC.Prevalence of and Trends in Diabetes Among Adults in the United States, 1988-2012. JAMA. 2015 Sep 8;314(10):1021-9.
6. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, Brown-Friday JO, Goldberg R, Venditti E, Nathan DM. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009 Nov 14;374(9702):1677-1686.
7. Ting DS, Cheung GC, Wong TY. Diabetic retinopathy: global prevalence, major risk factors, screening practices and public health challenges: a review. Clin Exp Ophthalmol. 2016 May;44(4):260-77.
8. Frank RN. Diabetic retinopathy and systemic factors. Middle East Afr J Ophthalmol. 2015 Apr-Jun;22(2):151-6.
9. Mohamed Q, Gillies MC, Wong TY. Management of diabetic retinopathy: a systematic review. JAMA. 2007 Aug 22;298(8):902-16.
10. Ajlan RS, Silva PS, Sun JK. Vascular Endothelial Growth Factor and Diabetic Retinal Disease. Semin Ophthalmol. 2016;31(1-2):40-8.
11. Virgili G, Menchini F, Murro V, Peluso E, Rosa F, Casazza G. Optical coherence tomography (OCT) for detection of macular oedema in patients with diabetic retinopathy. Cochrane Database Syst Rev. 2011 Jul 6;(7):CD008081.
12. Leasher JL, Bourne RR, Flaxman SR, Jonas JB, Keeffe J, Naidoo K, Pesudovs K, Price H, White RA, Wong TY, Resnikoff S, Taylor HR; Vision Loss Expert Group of the Global Burden of Disease Study. Global Estimates on the Number of People Blind or Visually Impaired by Diabetic Retinopathy: A Meta-analysis From 1990 to 2010. Diabetes Care. 2016 Sep;39(9):1643-9.
13. Nam S, Chesla C, Stotts NA, et al. Barriers to diabetes management: patient and provider factors. Diabetes Res Clin Pract. 2011 Jul;93(1):1-9.
14. Shao J, Zaro JL, Shen WC. Tissue barriers and novel approaches to achieve hepatoselectivity of subcutaneously-injected insulin therapeutics. Tissue Barriers. 2016 Mar 4;4(2):e1156804.
15. Chous AP. Worldwide diabetes epidemic approaches half a billion. Optometry Times. Available at: http://optometrytimes.modernmedicine.com/optometrytimes/news/worldwide-diabetes-epidemic-approaches-half-billion. Accessed 5/15/17.
16. Fisher MD, Rajput Y, Gu T, Singer JR, Marshall AR, Ryu S, Barron J, MacLean C. Evaluating Adherence to Dilated Eye Examination Recommendations Among Patients with Diabetes, Combined with Patient and Provider Perspectives. Am Health Drug Benefits. 2016 Oct;9(7):385-393.
17. Wu Y, Ding Y, Tanaka Y, Zhang W. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention. Int J Med Sci. 2014 Sep 6;11(11):1185-200.
18. Agouridis AP, Kostapanos MS, Elisaf MS. Statins and their increased risk of inducing diabetes. Expert Opin Drug Saf. 2015;14(12):1835-44.
19. Elliott WJ, Meyer PM. Incident diabetes in clinical trials of antihypertensive drugs: a network meta-analysis. Lancet. 2007 Jan 20;369(9557):201-7.
20. McDonnell SL, Baggerly LL, French CB, Heaney RP, Gorham ED, Holick MF, Scragg R, Garland CF. Incidence rate of type 2 diabetes is >50% lower in GrassrootsHealth cohort with median serum 25-hydroxyvitamin D of 41 ng/ml than in NHANES cohort with median of 22 ng/ml. J Steroid Biochem Mol Biol. 2016 Jan;155(Pt B):239-44.
21. Sayin N, Kara N, Pekel G. Ocular complications of diabetes mellitus. World J Diabetes. 2015 Feb 15;6(1):92-108.
22. Cahn F, Burd J, Ignotz K, Mishra S. Measurement of Lens Autofluorescence Can Distinguish Subjects With Diabetes From Those Without. J Diabetes Sci Technol. 2014 Jan;8(1):43-49.
23. Gelb KM, Richer SP, Zimmer CN, Sherman J, Gold JM. Retinal multispectral imaging of ‘sub-clinical’ capillary microaneurysms in non-diabetics correlates with insulin resistance. Diabesity. 2016 Jul;2(3):19-25.
24. Hu BJ, Hu YN, Lin S, Ma WJ, Li XR. Application of Lutein and Zeaxanthin in nonproliferative diabetic retinopathy. Int J Ophthalmol. 2011;4(3):303-306.
25. Scanlon G1, Connell P, Ratzlaff M, Foerg B, McCartney D, Murphy A, OüConnor K, Loughman J. Macular pigment optical density is lower in type 2 diabetes, compared with type 1 diabetes and normal controls. Retina. 2015 Sep;35(9):1808-16.
26. Lima VC, Rosen RB, Farah M. Macular pigment in retinal health and disease. Int J Retina Vitreous. 2016 Aug 15;2:19.
27. Chen X, Rong SS, Xu Q, Tang FY, Liu Y, Gu H, Tam PO, Chen LJ, Brelén ME, Pang CP, Zhao C. Diabetes mellitus and risk of age-related macular degeneration: a systematic review and meta-analysis. PLoS One. 2014 Sep 19;9(9):e108196.
28. American Diabetes Association. Standards of Medical Care in Diabetes-2016 Abridged for Primary Care Providers. Clin Diabetes. 2016 Jan; 34(1): 3–21.
29. Giacco F, Du X1, Carratú A, Gerfen GJ, D'Apolito M, Giardino I, Rasola A, Marin O, Divakaruni AS, Murphy AN, Shah MS, Brownlee M. GLP-1 Cleavage Product Reverses Persistent ROS Generation After Transient Hyperglycemia by Disrupting an ROS-Generating Feedback Loop. Diabetes. 2015 Sep;64(9):3273-3284.
30. Wang B, Wang F, Zhang Y, Zhao SH, Zhao WJ, Yan SL, Wang YG.
Effects of RAS inhibitors on diabetic retinopathy: a systematic review and meta-analysis. Lancet Diabetes Endocrinol. 2015 Apr;3(4):263-74.
31. Sharma N, Ooi JL, Ong J, Newman D. The use of fenofibrate in the management of patients with diabetic retinopathy: an evidence-based review. Aust Fam Physician. 2015 Jun;44(6):367-70.
32. Gualtieri M, Bandeira M, Hamer RD, Damico FM, Moura AL, Ventura DF. Contrast sensitivity mediated by inferred magno- and parvocellular pathways in type 2 diabetics with and without nonproliferative retinopathy. Invest Ophthalmol Vis Sci. 2011 Feb 28;52(2):1151-5.
33. Utku D, Atmaca LS. Farnsworth-Munsell 100-hue test for patients with diabetes mellitus. Ann Ophthalmol. 1992 Jun;24:205–8.
34. Pinilla I, Ferreras A, Idoipe M, Sanchez-Cano AI, Perez-Garcia D, Herrera LX, Pinilla MJ, Abecia E. Changes in frequency-doubling perimetry in patients with type I diabetes prior to retinopathy. Biomed Res Int. 2013;2013:341269.
35. Shrestha GS, Kaiti R. Visual functions and disability in diabetic retinopathy patients. J Optom. 2014 Jan-Mar;7(1):37-43.
36. Kowluru RA, Zhong Q. Beyond AREDS: Is There a Place for Antioxidant Therapy in the Prevention/Treatment of Eye Disease? Invest Ophthalmol Vis Sci. 2011 Nov 7;52(12):8665-71.
37. Chous AP, Richer SP, Gerson JD, Kowluru RA. The Diabetes Visual Function Supplement Study (DiVFuSS). Br J Ophthalmol. 2016 Feb;100(2):227-234.
38. Kowluru RA, Zhong Q, Santos JM, Thandampallayam M, Putt D, Gierhart DL. Beneficial effects of the nutritional supplements on the development of diabetic retinopathy. Nutr Metab (Lond). 2014 Jan 30;11(1):8.
39. Gao SS, Jia Y, Zhang M, Su JP, Liu G, Hwang TS, Bailey ST, Huang D. Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 2016 Jul 1;57(9):OCT27-36.
