July/August 2023

Diabetic Retinopathy
By Mark D. Coggins, PharmD, BCGP, FASCP
Today’s Geriatric Medicine
Vol. 16 No. 4 P. 10

Early Detection Prevents Vision Loss

Diabetic retinopathy is a serious eye condition in which the retina—the delicate light-sensitive layer of tissue in the back of the eye—becomes damaged due to long-term diabetes. It’s the leading cause of vision loss and blindness in people with diabetes. The condition is progressive, and almost all persons with diabetes will experience some degree of retinopathy over several decades.1

The fear of worsening vision and possible vision loss is a major concern for most people with diabetes who may suffer increased distress and live with reduced function in daily life.2 Although it’s difficult to prevent retinopathy, routine eye exams, controlling risk factors such as blood sugar and blood pressure, and other interventions can help prevent vision loss.

How Diabetes Affects the Eyes
Diabetes mellitus is characterized by persistent high blood sugar levels (hyperglycemia) that, over time, damage organs, leading to macrovascular complications such as premature atherosclerosis, which in turn can result in strokes, peripheral vascular disease, myocardial infarctions, and microvascular complications such as nephropathy, neuropathy, and retinopathy.3 In diabetic retinopathy, persistent elevated blood sugar levels weaken and damage the tiny blood vessels that supply blood flow to the eye. The blockage of the blood vessels then results in reduced blood flow. To compensate, the eyes grow new blood vessels that tend to be fragile and fail to develop properly, causing them to bleed and leak easily. As a consequence, symptoms such as eye floaters, blurriness, black spots in vision, difficulty seeing colors, loss of central vision, and blindness can occur.

Risk Factors for Diabetic Retinopathy
Major risk factors for diabetic retinopathy include the duration of diabetes, poorly controlled blood sugar, high blood pressure, high cholesterol and lipids, obesity, renal disease, pregnancy, smoking, anemia, and being Black, Hispanic, or Native American.

Duration of Diabetes Mellitus
Anyone with diabetes, including type 1, type 2, and gestational diabetes, which occurs during pregnancy, are at risk of developing diabetes retinopathy. The time since diabetes diagnosis, independent of diabetic control, is the most important risk factor.4 The longer a person has diabetes, the higher the risk. The strong link between duration of diabetes and retinopathy is seen in the Wisconsin Epidemiologic Study of Diabetic Retinopathy. In this study, the prevalence of diabetic retinopathy varied from 28.8% in persons who had diabetes for less than five years to 77.8% in those who had diabetes for 15 or more years; the rate of proliferative diabetic retinopathy (PDR) varied from 2% in persons who had diabetes for less than five years to 15.5% in those who had the disease for 15 or more years.5

Pregnancy
Although pregnancy is outside the scope of practice of geriatricians, it’s among the risk factors. Women with diabetes who become pregnant and women who develop gestational diabetes are at higher risk of diabetic retinopathy. The American Diabetes Association recommends that women with preexisting type 1 or type 2 diabetes who are planning pregnancy or who have become pregnant should be counseled on the risk of development and/or progression of diabetic retinopathy.6 Eye examinations should occur before pregnancy and in the first trimester for patients with preexisting type 1 or type 2 diabetes, and then be monitored every trimester and for one year postpartum.

Poor Control of Diabetes
Poor control of blood glucose levels increases the risk of diabetes retinopathy and its progression. It’s well known that high blood glucose levels can damage the blood vessels, starving the retina of nutrients and oxygen, leading to retinopathy. Conversely, it’s been shown that early and continuous hyperglycemia control is beneficial for improving diabetic retinopathy.7 Furthermore, improved blood sugar control can reduce diabetic retinopathy risk, with studies having shown that for every 1% reduction in hemoglobin A1c (HbA1c), the risk of microvascular complications (mainly diabetic retinopathy) can be reduced by 37%.8

Episodes of low blood sugar (hypoglycemia) are a common occurrence with the use of insulin and many other diabetes medications. Researchers at Johns Hopkins Medicine found that low blood glucose levels in human and mouse retinal cells caused a cascade of molecular changes leading to blood vessel overgrowth and leaky blood vessels—a key culprit of vision loss in people with diabetic eye disease.9 The researchers noted that individuals with diabetic retinopathy may be particularly vulnerable to periods of low glucose, and keeping glucose levels stable should be an important part of diabetes management.

Cardiovascular Risk Factors
In addition to elevated HbA1c, other cardiovascular risk factors such as hypertension, dyslipidemia, hypercholesterolemia, smoking, and obesity are also risk factors for the development of diabetic retinopathy.

Hypertension
Increased blood pressure can cause thickened, narrowed, or torn blood vessels in the eyes. One study found that for every 10 mmHg increase in systolic blood pressure there was a 1.23 times increased risk of diabetic retinopathy and a 1.19 times increased risk of vision-threatening retinopathy.10

The effect of blood pressure control on preventing diabetic retinopathy or slowing its progression was evaluated in a Cochrane review.11 The researchers found modest support for lowering blood pressure to prevent diabetic retinopathy, regardless of diabetes type or baseline blood pressure level. However, there wasn’t sufficient evidence to support that lowering blood pressure kept diabetic retinopathy from worsening once it had developed or that it prevented advance stages of diabetic retinopathy that required laser or other treatment of affected eyes.

Hypercholesterolemia and Hyperlipidemia
Hard exudates that leak from abnormal retinal capillaries in more advanced retinopathy are largely made up of extracellular lipids. Elevated serum cholesterol and other lipids are linked to increased risk of diabetic retinopathy and higher rates of hard retinal exudates.12 Persons with cholesterol levels ≥ 240 mg/dL were found to be twice as likely to have hard retinal exudates than were those with cholesterol levels < 200 mg/dL. Similarly, a doubling of risk was seen in persons with LDL cholesterol ≥ 160 mg/dL compared with those with levels < 130 mg/dL. There also was a 1.84 times greater risk in those with very LDL cholesterol levels > 61 mg/dL compared with those with levels < 18 mg/dL.

Obesity
There’s a strong link between obesity and diabetes, and increased body mass index has been linked to an increased risk of diabetic retinopathy.13 In one study, those in the highest tertile of waist-to-hip ratio had 40 times the risk of developing diabetic retinopathy.14

Classifying Diabetic Retinopathy
Mild diabetic retinopathy is broadly classified into two categories: nonproliferative diabetic retinopathy (NPDR) and PDR, depending on symptoms. NPDR refers to early stages of the disease without neovascularization (abnormal blood vessel growth), while PDR refers to the presence of neovascularization in the retina. Diabetic retinopathy is further classified into four stages based on progression: mild NPDR, moderate NPDR, severe NPDR, and PDR.

NPDR
The first stage is mild NPDR, also called background retinopathy.15 At this stage, there are small areas of microaneurysms or balloonlike swellings in the tiny blood vessels of the retina. This may cause the vessels to leak small amounts of blood into the retina. Persons with mild NPDR may not experience vision problems. This stage can be easily detected during the dilated portion of an annual eye exam.16

Moderate NPDR
The second stage is moderate NPDR, also known as pre-PDR.15 During this stage, the tiny vessels that nourish the retina become weak and blocked, and their ability to carry blood to the eye is hampered.16 In moderate NPDR, a larger number of microaneurysms are present, along with dot hemorrhages, possibly some fluffy white patches known as cotton wool spots, and some lipid and protein deposits called hard exudates. Blood vessels in the eye may swell and become distorted, causing further obstruction of blood flow leading to physical damage to the retina. These changes can affect peripheral and central vision as well as color perception. At this stage, it’s common for people to also develop diabetic macular edema, characterized by swelling in the retina.

The treatment of moderate NPDR depends on the severity and location of the damage. The main goal of treatment is to prevent or slow the progression to more advanced stages of diabetic retinopathy.

Severe NPDR
At this stage, because a significant portion of the blood vessels has been damaged, the retina is so deprived of healthy blood flow that fluid leakage releases growth factors into it.16 These factors falsely instruct the retina to grow new abnormal blood vessels, which can eventually lead to the most severe stage of retinopathy.

PDR
The fourth stage is PDR, characterized by the presence of abnormal blood vessel growth that makes the eye prone to bleeding and other fluid leakage that threaten vision.16 Over time, scar tissue can also develop from the repeated swelling of the cells throughout the retina. This can lead to retinal detachment or a detached retina, which is when the retina pulls away from the underlying tissue of the eye. While usually painless, it should be treated immediately, usually with surgery. If left untreated, it can lead to a permanent loss of vision.

Routine Eye Exams
Early detection of retinal abnormalities, regular monitoring, and prompt treatment are essential in managing diabetic retinopathy.17 The American Diabetes Association recommends that people with type 1 diabetes have their first eye exam within the first five years of diagnosis. Because persons with type 2 diabetes may have gone years without their diabetes having been identified, there’s a greater chance that retinopathy may have already started. For people with type 2 diabetes, the American Diabetes Association recommends an eye exam shortly after receiving a diagnosis. For both type 1 and type 2 diabetics, a yearly eye exam may be appropriate after the first exam.

Common Tests and Procedures
Tests and procedures to identify and monitor the progression of diabetic retinopathy include the following:16

• Visual acuity test: An eye chart is used to measure how well a person sees at various distances.

• Pupil dilation: Drops are put into the eye to dilate the pupil, allowing the retina to be clearly seen.

• Ophthalmoscopy: An examination of the retina is made using an indirect ophthalmoscope with a special magnifying lens that provides a complete view of the retina.

• Sit lamp examination: This checks for any new blood vessels on the iris, indicating that some damage to the retina has stimulated new vessels to form in retina as well as on iris. These new blood vessels, if present, can also leak and increase pressure inside the eye.

• Optical coherence tomograph: This imaging produces cross sectional images of the retina.

• Fluorescein angiogram: An imaging technique that relies on the circulation of fluorescein dye in the body shows staining, leakage, or nonperfusion in the retina and identifies areas of damage.

Management and Treatment
Although there’s no cure, steps can be taken to reduce the risk of developing diabetic retinopathy and slow its progression. Keeping blood sugars in a healthy range, avoiding highs and lows, and managing other risk factors is the best way to lower the risk. Referral to endocrinologists and/or diabetes educators to improve diabetes management may be beneficial for some diabetics. Patients should be instructed to carefully follow their doctors’ instructions for insulin and other medications. Blood pressure should be managed, and control of serum cholesterol and lipids can lower complications from diabetic eye disease. Following a healthful diet, losing weight if obese, not smoking, and increasing physical exercise and health-style choices may also help reduce risk.

The choice of treatment largely will depend on the type and severity of the disease. Regardless of treatment selection, the goal is to slow or stop the progression.

Early Diabetic Retinopathy
For persons with mild or moderate NPDR, treatment may not be needed right away. Routine eye exams to monitor progression is essential to determine if treatment is appropriate. Maintaining good blood glucose control and reducing risk factors is essential to slowing the progression to more advanced stages.

Advanced Diabetic Retinopathy
In advanced diabetic retinopathy, the treatment will depend on the specific problems identified with the retina. Potential treatments include medications and laser/surgical procedures.

Medications
Injections into the eyes using endothelial growth factor inhibitors and corticosteroids may be used to treat advanced cases of diabetic retinopathy.

Antivascular Endothelial Growth Factor
Antivascular endothelial growth factor injections include three FDA-approved drugs: faricimab-svoa (Vabysmo), ranibizumab (Lucentis), and aflibercept (Eylea). A fourth drug, bevacizumab (Avastin), may also be injected into the vitreous of the eye to block vascular endothelial growth factor, a protein in the body that stimulates the growth of abnormal new blood vessels in the eye. This helps stop growth of new blood vessels and reduces the amount of fluid and swelling in the retina.

Corticosteroid Injections/Implants
Corticosteroids, including triamcinolone (Kenalog), dexamethasone (Ozurdex), and fluocinolone acetonide (Iluvien), may be used to decrease inflammation in the eye, which improves macular edema.

Laser and Surgical Treatments
Laser and surgical treatments may also be appropriate for patients with advanced retinopathy and may be used along with injectable medications.

Photocoagulation
Photocoagulation, also known as focal laser treatment, can stop or slow the leakage of blood and fluid in the eye. During the procedure, leaks from abnormal blood vessels are treated with laser burns. Photocoagulation treatment may reduce the likelihood of macular edema worsening.

Panretinal Photocoagulation
Panretinal photocoagulation, also known as scatter laser treatment, can shrink the abnormal blood vessels. During the procedure, the areas of the retina away from the macula are treated with scattered laser burns. The burns cause the abnormal new blood vessels to shrink and scar. Some loss of peripheral vision or night vision after the procedure is possible.

Vitrectomy
Vitrectomy is a surgical procedure performed in a surgery center or hospital using local or general anesthesia. It involves using a tiny incision in the eye to remove blood from the middle of the eye (vitreous) as well as scar tissue on the retina.

Health care professionals have an opportunity to help people with diabetes minimize progression and treat diabetic retinopathy by encouraging regular eye exams, blood sugar control, blood pressure control, and recommending appropriate treatment. By working together with their patients, they can help them maintain their vision and quality of life.

— Mark D. Coggins, PharmD, BCGP, FASCP, is vice president of pharmacy services and medication management for skilled nursing centers operated by Diversicare in nine states and is a past director on the board of the American Society of Consultant Pharmacists. He was nationally recognized by the Commission for Certification in Geriatric Pharmacy with the 2010 Excellence in Geriatric Pharmacy Practice Award.

References
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2. Simó-Servat O, Hernández C, Simó R. Diabetic retinopathy in the context of patients with diabetes. Ophthalmic Res. 2019;62(4):211-217.

3. Yuan T, Yang T, Chen H, et al. New insights into oxidative stress and inflammation during diabetes mellitus-accelerated atherosclerosis. Redox Biol. 2019;20:247-260.

4. Sultan M, Huang K, Starita C. Epidemiology, risk factors and management of paediatric diabetic retinopathy. Br J Ophthalmol. 2012;96(3):312-317.

5. Klein R. The epidemiology of diabetic retinopathy: findings from the Wisconsin Epidemiologic Study of Diabetic Retinopathy. Int Ophthalmol Clin. 1987;27(4):230-238.

6. Solomon SD, Chew E, Duh EJ, et al. Diabetic retinopathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(3):412-418.

7. Holman RR, Paul SK, Bethel AM, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. New Engl J Med. 2008;359(15):1577-1578.

8. White NH, Sun W, Cleary PA, 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. 2008;126(12):1707-1715.

9. Guo C, Deshpande M, Niu Y, et al. HIF-1α accumulation in response to transient hypoglycemia may worsen diabetic eye disease. Cell Rep. 2023;42(1):111976.  

10. Zheng Y, Lamoureux EL, Lavanya R, et al. Prevalence and risk factors of diabetic retinopathy in migrant Indians in an urbanized society in Asia: the Singapore Indian eye study. Ophthalmology. 2012;119(10):2119-2124.

11. Do DV, Wang X, Vedula SS, et al. Blood pressure control for diabetic retinopathy. Cochrane Database Syst Rev. 2015;1:CD006127.

12. Chew EY, Klein ML, Ferris FL 3rd, 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. 1996;114(9):1079-1084.

13. Porta M, Sjoelie AK, Chaturvedi N, et al. Risk factors for progression to proliferative diabetic retinopathy in the EURODIAB Prospective Complications Study. Diabetologia. 2001;44(12):2203-2209.

14. Dirani M, Xie J, Fenwick E, et al. Are obesity and anthropometry risk factors for diabetic retinopathy? The diabetes management project. Invest Ophthalmol Vis Sci. 2011;52(7):4416-4421.

15. Diabetic retinopathy — stages. NHS website. https://www.nhs.uk/conditions/diabetic-retinopathy/stages/. Updated December 16, 2021.

16. American Diabetes Association. Eye health: diabetic retinopathy. https://diabetes.org/sites/default/files/2022-04/FOD-Retinopathy.pdf

17. Eye health. American Diabetes Association website. https://diabetes.org/diabetes/eye-health