Ophthalmic Surgery, Lasers and Imaging Retina

Clinical Science 

An International Comparison of Baseline Characteristics of Patients Undergoing Initiation of Anti-VEGF Therapy for DME

Felipe F. Conti, MD; Arturo Alezzandrini, MD; Chandruganesh Rasendran, BSE; Chinmay Nakhwa, MD; Diogo Neves, MD; Fabiana S. Queiroga, MD; Jay Chhablani, MD; Jorge Rocha, MD; Ramon P. Martins, MD; Jose Romero, MD; Lihteh Wu, MD; Michael Han, BA; Ram Kailash Gurjar, OD; Siraj Haq, BA; Suhwan Lee, MD; Sundaram Natarajan, MD; Waseem H. Ansari, MD; Young Hee Yoon, MD; Rishi P. Singh, MD; for the Global Diabetic Macular Edema Study Group

Abstract

BACKGROUND AND OBJECTIVE:

Diabetic macular edema (DME) is a leading cause of vision loss worldwide. The object of this study is to compare global differences of baseline characteristics of patients undergoing initiation of anti-vascular endothelial growth factor (VEGF) therapy for DME.

PATIENTS AND METHODS:

This multicenter, cross-sectional study included diabetic patients with foveal-involving retinal edema secondary to DME as documented by fundus exam and optical coherence tomography who were undergoing initiation of intravitreal anti-VEGF drugs. Variables were collected to find possible risk factors and to create an epidemiological profile of DME patients undergoing initiation of anti-VEGF agents.

RESULTS:

Nine hundred two patients were selected. Mean age was 62.4 (±11) years, 49.7% were Caucasians, 57.6% were male, and 96% had type two diabetes with an average disease duration of 181.7 months ± 113 months. Of the patients included, 74.7% suffered from hypertension, 26.6% from cardiovascular disease, 12.1% from cerebrovascular disease, 12.8% from peripheral vascular disease, and 12.8% from renal insufficiency. Best-corrected visual acuity (BCVA) was 65 (±20) Early Treatment Diabetic Retinopathy Study letters, central subfield thickness was 364 (±162) μm, cube volume 11.1 ± 3.1 mm3, cube average thickness 328.8 μm ± 61 μm, and 63.9% had nonproliferative diabetic retinopathy. Comparison between U.S. versus international patients, and patients with BCVA 70 letters or less versus more than 70 letters were performed, significant differences were acknowledged, and risk factors were recognized.

CONCLUSION:

There were key differences in the epidemiologic profile between patients presenting with DME in the U.S. and internationally.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:e300–e310.]

Abstract

BACKGROUND AND OBJECTIVE:

Diabetic macular edema (DME) is a leading cause of vision loss worldwide. The object of this study is to compare global differences of baseline characteristics of patients undergoing initiation of anti-vascular endothelial growth factor (VEGF) therapy for DME.

PATIENTS AND METHODS:

This multicenter, cross-sectional study included diabetic patients with foveal-involving retinal edema secondary to DME as documented by fundus exam and optical coherence tomography who were undergoing initiation of intravitreal anti-VEGF drugs. Variables were collected to find possible risk factors and to create an epidemiological profile of DME patients undergoing initiation of anti-VEGF agents.

RESULTS:

Nine hundred two patients were selected. Mean age was 62.4 (±11) years, 49.7% were Caucasians, 57.6% were male, and 96% had type two diabetes with an average disease duration of 181.7 months ± 113 months. Of the patients included, 74.7% suffered from hypertension, 26.6% from cardiovascular disease, 12.1% from cerebrovascular disease, 12.8% from peripheral vascular disease, and 12.8% from renal insufficiency. Best-corrected visual acuity (BCVA) was 65 (±20) Early Treatment Diabetic Retinopathy Study letters, central subfield thickness was 364 (±162) μm, cube volume 11.1 ± 3.1 mm3, cube average thickness 328.8 μm ± 61 μm, and 63.9% had nonproliferative diabetic retinopathy. Comparison between U.S. versus international patients, and patients with BCVA 70 letters or less versus more than 70 letters were performed, significant differences were acknowledged, and risk factors were recognized.

CONCLUSION:

There were key differences in the epidemiologic profile between patients presenting with DME in the U.S. and internationally.

[Ophthalmic Surg Lasers Imaging Retina. 2019;50:e300–e310.]

Introduction

Diabetes mellitus is a leading cause of vision loss in developed countries. The World Health Organization Global Report estimates that 422 million adults were living with diabetes in 2014, reflecting a global prevalence (age-standardized) of approximately 8.5%. Diabetic retinopathy (DR) alone caused 2% of moderate or severe visual impairment worldwide and 2.6% of blindness in 2010.1 Diabetic macular edema (DME) is a common complication during the progression of DR, which can occur in approximately 7% of individuals with the disease.2 There are approximately 21 million individuals worldwide with DME, and this number is rising due to the increasing prevalence of diabetes in emerging nations.3

Phase 3 studies have validated anti-vascular endothelial growth factor (VEGF) treatment results in improved visual outcomes in DME patients.4 Protocol T by the Diabetic Retinopathy Clinical Research Network (DRCR.net) evaluated the efficacy and safety of intravitreous aflibercept (Eylea; Regeneron, Tarrytown, NY), bevacizumab (Avastin; Genentech, South San Francisco, CA), and ranibizumab (Lucentis; Genentech, South San Francisco, CA) in DME treatment. After 1-year follow-up, it was revealed that outcomes might vary based on presenting baseline visual acuity (VA). Aflibercept resulted in greater VA improvements in patients with 20/50 and worse vision, whereas there was no difference between drugs in the outcomes of patients whose VA was 20/40 or better.5

These results show that baseline characteristics are important for determining the appropriate treatment for DME patients. However, little is known about baseline characteristics of patients presenting with DME. Report No. 7 from the Early Treatment Diabetic Retinopathy Study (ETDRS) group described baseline characteristics of patients enrolled in the pivotal DME study, with about half of the patients being between 50 and 70 years of age with a duration of diabetes between 10 and 19 years.6 However, this manuscript was published more than 20 years ago, and the advances in patient-care technology, diagnostic methods, definitions for initiating treatment, and therapeutics have certainly changed the characteristics of diabetic patients.

Herein, the goal of this study is to comprehensively assess baseline ocular and systemic characteristics of DME patients initiating anti-VEGF treatment in routine clinical practice on a global scale.

Patients and Methods

Data Collection

This multicenter study was performed at Cole Eye Institute, Cleveland; University of Buenos Aires, Buenos Aires, Argentina; IBOL-Brazilian Institute of Ophthalmology, Rio de Janeiro, Brazil; iRetina Eye Institute, Salvador, Brazil; Macula Vitreous and Retina Associates of Costa Rica, San José, Costa Rica; National Ophthalmology Unit, Guatemala City, Guatemala; Aditya Jyot Eye Hospital, Mumbai, India; Smt. Kanuri Santhamma Retina Vitreous Centre, Hyderabad, India; and Asan Medical Center, Seoul, Korea, after receiving approval from each local investigational review board. All study-related procedures were performed in accordance with good clinical practice (International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use E6), applicable U.S. Food and Drug Administration regulations, and in accordance with the Health Insurance Portability and Accountability Act. A retrospective chart review was performed to identify patients who were anti-VEGF treatment-naïve and diagnosed with DME from April 2012 to December 2017.

Study Participants

Patients were enrolled if they presented with Type 1 or 2 diabetes determined by current or historical use of insulin or oral hypoglycemic, or a documented HbA1C greater than 6.5% at the time of the encounter. Patients were aged 18 years or older and all presented with foveal-involving clinically significant diabetic macular edema (CSME) secondary to DR as documented by fundus exam and OCT, and initiation of edema treatment with intravitreal anti-VEGF therapy based on investigator discretion as documented in the medical record. The ETDRS introduced the term “CSME.” CSME was defined upon slit-lamp biomicroscopy as “(1) thickening of the retina at or within 500 μm of the center of the macula; (2) hard exudate at or within 500 μm of the center of the macula associated with thickening of adjacent retina; or (3) a zone of retinal thickening 1 disc area or larger, any part of which is within 1 disc diameter of the center of the macula.”7 Exclusion criteria included any early disease that may confuse the diagnosis of DME, including choroidal neovascularization, age-related macular degeneration, polypoidal choroidal vasculopathy, angioid streaks, choroidal rupture, ocular histoplasmosis syndrome, pathologic myopia (spherical equivalent of –6 diopters or more negative, or axial length of 25 mm or more), macular edema following retinal vein occlusion, and any history of intraocular surgery within 3 months of encounter. Patients with macular hole, lamellar hole, or vitreomacular traction syndrome were excluded. Presence of epiretinal membranes were not considered exclusion criteria.

Study Variables

Study variables obtained from the medical records included demographics such as age, gender, race, systemic and ocular comorbidities, type and duration of diabetes, medications, history of previous treatments or surgeries for ocular and systemic complications, systolic/diastolic blood pressures and relevant lab values, when available, including HbA1c, creatinine, blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, cholesterol levels (total, LDL, HDL, triglycerides), urine protein, and urine microalbumin within 3 months of initiation of anti-VEGF treatment. Ophthalmic data such as best-corrected VA (BCVA), lens status, OCT measurements, and fluorescein angiography (FA) results were also collected. Duration of DME before entry into the study after diabetes onset was not analyzed because establishing DME duration before a patient's first encounter with a clinician is difficult to estimate.

Statistical Methods

Categorical variables were described using frequencies and percentages, whereas continuous variables were described using means and standard deviations, medians and quartiles, and/or ranges. Relationships between categorical variables and ETDRS groups were assessed using Pearson Chi-square tests, Fisher's exact tests, or Kruskal-Wallis tests (for ordered variables), whereas relationships between continuous variables and ETDRS group were assessed using t-tests (for normally distributed variables) or Kruskal-Wallis tests (for non-normally distributed variables). Analyses were performed using SAS Software (version 9.4; Cary, NC).

Results

Nine hundred two patients were selected, of whom 638 were from the U.S and 264 were from other international sites. The mean BCVA for the whole cohort was 65 (±20) ETDRS letters (± 20/50), whereas the mean BCVA in the international cohort was 60 (±25) ETDRS letters (± 20/63), and in the U.S. cohort was 65 (±18) ETDRS letters (± 20/50; P < .001). Mean central subfield thickness (CST) for the entire cohort was 364 (±162) μm, whereas in the international cohort it was 365 (±243) μm, and in the U.S. cohort it was 363 (±141) μm (P = .97). Other ocular characteristics are shown in Table 1.

Ocular Characteristics From DME Patients Under Initiation of Anti-VEGF Therapy

Table 1:

Ocular Characteristics From DME Patients Under Initiation of Anti-VEGF Therapy

The average age of the whole cohort was 62.4 (±11) years-old, whereas in the international cohort was 60.8 (±10) years old and in the U.S. cohort was 63.1 (±11) years old (P = .006). The overall cohort consisted of 57.6% male patients, whereas the international cohort was 68.9% male, and the U.S. cohort was 53% male (P < .001). Other systemic characteristics are shown in Table 2.

Systemic Characteristics From DME Patients Under Initiation of Anti-VEGF Therapy

Table 2:

Systemic Characteristics From DME Patients Under Initiation of Anti-VEGF Therapy

When looking at comorbidities in the overall cohort, 74.7% suffered from hypertension (international 65.2% vs. U.S. 78.4%; P < .01), cardiovascular disease was seen in 26.6% (international 26.6% vs. U.S. 18.8%; P = .03), cerebrovascular disease was observed in 12.1% (international 4.2% vs. U.S. 14.9%; P < .01), peripheral vascular disease was observed in 12.8% (international 2.3% vs. U.S. 16.5%; P < .01), and renal insufficiency was seen in 12.8% (international 6.9% vs. U.S. 22.6%; P < .01).

Intravitreal drug chosen for DME management initiation was also recorded. In the overall cohort, 80.1% initiated treatment with bevacizumab. In the international cohort, 44.3% started treatment with bevacizumab, whereas 94.8% in the U.S. used the bevacizumab to begin therapy. Other medications used are shown in Table 3.

Medications From DME Patients Under Initiation of Anti-VEGF Therapy

Table 3:

Medications From DME Patients Under Initiation of Anti-VEGF Therapy

Recent treatment trials have confirmed anti-VEGF efficacy on DME treatment. However, 1-year results from Protocol T showed that baseline characteristics might be associated with visual outcomes. Therefore, the study patients were divided into the equivalent two cohorts by their VA (>70 ETDRS letters vs. ≤ 70 ETDRS letters) as done in the above trial to assess differences between cohorts (Tables 4 and 5). Patients with ETDRS 70 or less were non-white (P = .023), older (P = .006), and had higher Creatinine (P = .010) and BUN levels (P = .048). They were also less likely to use biguanides (P = .009) compared to those with ETDRS greater than 70. OCT measurements were also significantly different. CST (P < .001), cube average thickness (CAT; P < .001), and cube volume (CV; P = .009) were higher in the ETDRS 70 or less group. Patients with BCVA 70 ETDRS or less were also more likely to have subretinal fluid (SRF) and epiretinal membranes on OCT (P < .001 for both variables). Patients with ETDRS 70 or less were more likely to have proliferative diabetic retinopathy (PDR; P = .006), history of panretinal photocoagulation (PRP; P = .002), and intraocular surgery (P = .039) compared to those with ETDRS greater than 70.

Summaries and Comparisons by Site are Shown Below for Patients With ETDRS ≤ 70Summaries and Comparisons by Site are Shown Below for Patients With ETDRS ≤ 70

Table 4:

Summaries and Comparisons by Site are Shown Below for Patients With ETDRS ≤ 70

Summaries and Comparisons by Site for Patients With ETDRS > 70

Table 5:

Summaries and Comparisons by Site for Patients With ETDRS > 70

Discussion

DME is one of the most common causes of visual loss in developed countries and baseline characteristics may play an essential role concerning treatment choice. However, few studies have reported on these findings. ETDRS report number 7 summarized baseline characteristics of the patients enlisted in its pivotal study of laser photocoagulation.6 Nevertheless, clinical trials have strict inclusion/exclusion criteria and patients enrolled might not mimic real-world practice. Additionally, the report included only patients within the United States besides having been published more than 20 years ago. This study uses more recent data from patients found in routine clinical practice and assesses characteristics of patients on a global scale.

This study reports that patients under initiation of anti-VEGF treatment for DME are, on average, 60 years old; over 90% suffer from type two diabetes, with an average disease duration of 181.7 months, and have HgbA1c levels of 8.1%. When U.S. and international cohorts were compared, many ocular characteristics presented differently. BCVA was significantly worse in the international cohort (65 ± 18 vs. 60 ± 20; P < .001). This finding may be explained by the higher rates of SRF on OCT (45.6% vs. 21.5%; P < .001) and diffuse leakage on FA (57.1% vs. 41.7%; P = .003). Alasil et al., in a cross-sectional study of 67 eyes, investigated the relationship between retinal morphology in OCT and VA in DME patients.8 It was reported that variables such CST, SRF volume, and photoreceptor outer segment thickness seemed to be an important predictors of function and VA. Additionally, many publications have reported that diffuse DME is a prognostic factor for worse VA.9–14 The greater rate of positive intraocular surgeries history (60.2% vs. 31.3%; P < .001) may also relate to eyes with unrecorded comorbidities that possibly affected VA.

History of laser treatment between cohorts was also significantly different. The international cohort showed a higher rate of focal laser treatment history (17.1% vs. 1.7%; P < .001) and PRP (39% vs.15.5%; P < .001). Even though anti-VEGF has shown to deliver superior outcomes then focal laser on many DME comparison trials,15,16 the former gold standard has its advantages over intravitreal therapy especially with regard to follow-up and cost of care. Most DME patients need multiple interventions to reach edema stability, whereas focal laser has much lower retreatment rates.17 Additionally, laser treatment shows lower cost than anti-VEGF. Stein et al. compared the cost-effectiveness of various interventions for newly diagnosed DME patients.18 Their analysis of a hypothetical cohort included costs of eye care provider visits, ancillary testing (OCT and FA), costs of each intervention, and costs of treating side effects caused by the interventions. It was showed that laser monotherapy can be up to three-times less costly than anti-VEGF therapy. Differences regarding PRP rates might be explained by the recent reports of anti-VEGF use to treat PDR. DRCR Protocol S and the CLARITY study, two similar noninferiority randomized clinical trials, reported that intravitreal anti-VEGF was non inferior to PRP for PDR treatment.19,20 Therefore, more retinal specialist in North America might be opting to start non-damaging treatments in lieu of destructive laser therapies especially when presented with PDR in the setting of DME.

There are also differences in systemic characteristics between the two groups. Albeit diastolic blood pressure, LDL, and HDL were statistically different (P < .05); measurements of both groups were within normal range. Systolic blood pressure (142.8 vs. 138.2; P = .001), blood creatinine (1.6 vs.1.2; P = .003), and BUN (26.7 vs. 19.5; P = .003) were significantly different and above normal range in the U.S. cohort. The two cohorts also showed significant differences in medical history. The North American cohort presented higher rates of hypertension history (78.4% vs. 65.2%; P < .001), cardiovascular disease (29.3% vs.18.8%; P = .003), cerebrovascular disease (14.9% vs. 4.2%; P < .001), peripheral vascular disease (16.5% vs. 2.3%; P < .001), and renal insufficiency (22.6% vs. 6.9%; P < .001). These findings may not represent real differences but issues in accessing comprehensive and quality health services instead. Wallace et al., in a multicenter, cross-sectional study of 6,141 patients, reported the health care access inequity in Latin American cities.21 Likewise, Akeroyd et al., in a meta-analysis of 17 studies, reported similar issues in health care access in South Asian nations.22 Finally, Younger et al., reported the struggling in health care financing and delivery services in India.23

This study also found major differences in the types of medications taken by patients for their diabetes. This may be largely due to the differences in approaches utilized by physicians in the treatment of diabetes.24 Insulin usage was higher for domestic patients (67.4% vs. 45.5%; P < .001), whereas alpha-glucosidase inhibitors (6.4% vs. 0%; P < .001) and purely diet-controlled diabetes (28.8% vs. 5.0%; P < .001) were higher in international patients. The United States is known for using insulin more exclusively, whereas diet is more suggested as a treatment in other nations.25,26 Alpha-glucosidase inhibitors are frequently used internationally, especially in South Asian countries.27 However, usage of these inhibitors is limited in the United States mostly due to its high rates of side effects.28 The choice of anti-VEGF for treatment initiation was also significantly different between the two cohorts. Although bevacizumab was the most frequent drug chosen to start DME treatment in both groups, the international cohort showed higher rates of aflibercept (7.6% vs. 3.0%; P < .001) and ranibizumab use (28.6% vs. 1.7%; P < .001). This finding might show the impact of DRCR Protocol T 2-year results, which showed that eyes with BCVA of 20/50 or worse had less vision improvement with bevacizumab compared to ranibizumab and aflibercept for retinal specialists worldwide.29

When the cohorts were separated by presenting VA (ETDRS < 70 vs. ETDRS ≥ 70), 46% of patients were allocated in the worse VA group, similar to the 49% of Protocol T baseline VA of 20/50 or worse. Significant differences were noticed between VA groups: CST (390 μm vs. 342 μm; P < .001), CV (11.4 mm3 vs. 10.8 mm3; P = .009), and CAT (341.6 μm vs. 314.3 μm; P < .001) were significantly higher in the ETDRS ≥ 70 group. The association of abnormal retinal findings and low VA in DME patients is in accordance with current reports.8,30,31 The history of intraocular surgery was higher in the worse VA group (42.7% vs. 35.9%; P = .04) possibly relate to eyes with unrecorded comorbidities that perhaps affected VA.

PDR (40% vs. 31%; P = .006) and history of PRP (26.1% vs. 17.6%; P = .002), were higher in the ETDRS less than 70 group. Macular ischemia is closely related to poor VA.32 Since PDR patients experience worse ischemic insults then non-PDR, it is reasonable to find most of these patients in the worse VA group.33 The use of biguanides was higher in the best VA group (47.8% vs. 38.9%; P = .009).This drug class may inhibit development of diabetic retinopathy and a result prevent the decrease of VA by decreasing VEGF receptor 2 binding to VEGF-A and inhibiting VEGF-A protein translation using microRNA.34,35 Blood creatinine (1.6 vs. 1.3; P = .010) and BUN levels (27.4 vs. 24.4; P = .048) were significantly higher in the worse VA group. Chronic kidney disease can lead to elevated creatinine and BUN and may also be correlated with worsening DR. Park et al., in a cross-sectional study of 15,409 individuals, reported the strong association between chronic kidney disease, especially in the presence of proteinuria, and clinically significant DME.36 These findings represent significant risk factors for VA improvement and should be taken into consideration when assessing and treating DME.

Strengths of this study include its multicentric nature and a large number of patients with comprehensive data. Additionally, it has less rigorous inclusion criteria compared to randomized clinical trials, exhibiting real-world interpretation. The data reviewed were collected during the last few years, which presents a more modern viewpoint into patients with DME than previous, older studies. Weaknesses include the retrospective nature of the research; the uneven distribution of patients between the two geographic cohorts; the absence of patients from Europe, Oceania, Middle East, and Africa; and the lack of detailed information on surgical/clinical history.

In conclusion, results from this study show that there are significant ocular, systemic, and medication differences between patients presenting with DME in the United States and internationally and between patients with distinct presenting VA. The United States cohort presents with DME as slightly older (63.1 ± 11 years) than the international cohort (60.8 ± 10 years) and having better VA (65 ± 18 ETDRS vs. 60 ± 25 ETDRS, respectively). Bevacizumab was more commonly used as the initial form of anti-VEGF treatment in the United States versus internationally (94.8% vs 44.3%, respectively). Lastly, patients with worse vision tended to more commonly be non-white, older, have higher Creatinine and BUN levels (P = .048), and were less likely to use biguanides. These discrepancies might represent significant risk factors that should be taken into consideration when evaluating and treating DME patients. Furthermore, future prospective studies are needed to assess DME risk factors and prognostic factor for VA improvement in DR patients under initiation of anti-VEGF treatment.

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Ocular Characteristics From DME Patients Under Initiation of Anti-VEGF Therapy

OverallInternationalU.S.

NNNP Value

ETDRS89765 ± 2025960 ± 2063865 ± 18< .001

CST (μm)889364 ± 162251365 ± 243638363.5 ± 141.97

Cube Volume (mm3)77511.1 ± 3.11378.4 ± 5.463811.7 ± 1.9< .001

Cube Average Thickness (μm)718328.8 ± 6180350.5 ± 100638326.1 ± 54< .001

+ Subretinal Fluid on OCT90228.3%26445.6%63821.5%< .001c

+ Tractional Macular Edema on OCT90215.1%26420.6%63817.2%.26

+ ERM on OCT90218.2%26420.6%63817.2%.25

+ Hard Exudates on OCT90247.5%26439.7%63850.5%.004

+ Cystoid Leakage on FA90249.3%26433%63841.7%< .001c

+ Diffuse Leakage on FA90250.5%26457.1%63841.7%.003

+ Capillary Ischemia on FA90236.3%26433.2%63840.5%.14

+ History of Glaucoma8967.9%2617.9%6357.9%.13

+ History of Dry AMD9021.7%2582.7%6361.3%.12

Lens Status902264638.025
  Aphakic.011%0.0%0.16%
  Phakic67.3%61.0%69.9%
  Pseudophakic32.6%39.0%29.9%

Type of DR901263638.37
  NPDR63.9%66.2%63%
  PDR36.1%33.8%37%

+ History of Focal Laser8896.1%25117.1%6381.7%< .001

+ History of PRP89622.3%25839%63815.5%< .001

+ History of Intraocular Surgery90239.8%26460.2%63831.3%< .001

Systemic Characteristics From DME Patients Under Initiation of Anti-VEGF Therapy

OverallInternationalU.S.

NNNP Value

Male Sex90257.6%26468.9%63853%< .001

Age90262.4 ± 1126460.8 ± 1063863.1 ± 11.006

Race864226638< .001
  Asian14.4%52.7%0.78%
  Black23.7%4.0%30.7%
  Hispanic2.9%11.1%0%
  Indian3.4%12.8%0%
  Other6.0%0.88%7.8%
  White49.7%18.6%60.7%

Type 2 Diabetes90196%26397%63895.6%< .001

Duration of Diabetes (Months)626181.7 ± 113156191.4 ± 126530177.5 ± 107.12

Systolic Blood Pressure (mm Hg)902141.7 ± 23156138.2 ± 24470142.8 ± 22.001

Diastolic Blood Pressure (mm Hg)62577.5 ± 1215681.2 ± 1146976.3 ± 11.8.001

HgbA1c (%)4988.1 ± 1.91008.1 ± 1.93988.1 ± 1.8.82

Creatinine (mg/dL)5321.5 ± 1.3561.2 ± 0.724191.6 ± 1.4.003

BUN (mg/dL)46625.9 ± 165119.5 ± 1541526.7 ± 16.003
EGFR (mL/min/1.73m2)26646.5 ± 231283.5 ± 3723541.6 ± 15< .001a

Triglycerides (mg/dL)381140.5 ± 8867143.0 ± 63314140.0 ± 93.80

Total Cholesterol (mg/dL)392171.9 ± 4776174.1 ± 51316171.3 ± 46.48

LDL-c (mg/dL)393100.2 ± 44.473117.1 ± 61.732096.3 ± 38.5< .001

HDL-c (mg/dL)38746.6 ± 16.17341.2 ± 11.031447.8 ± 16.9.001

Urine Protein (g/gL)36837.6 ± 2037651.1 ± 132936125.7 ± 73.8< .001

+ Hypertension history87274.7%24765.2%62578.4%< .001

+ Cardiovascular disease84326.6%21818.8%62529.3%.003

+ Cerebral disease84212.1%2164.2%62614.9%< .001

+ Peripheral vascular disease84212.8%2162.3%62616.5%< .001

+ Renal insufficiency84218.5%2186.9%62422.6%< .001

Medications From DME Patients Under Initiation of Anti-VEGF Therapy

OverallInternationalU.S.P Value

NNN

Intravitreal Injections During Visit900262638< .001
  Aflibercept4.3%7.6%3.0%
  Bevacizumab80.1%44.3%94.8%
  Ranibizumab9.6%28.6%1.7%
  Steroids1.9%6.1%0.16%
  Unknown4.1%13.4%0.31%

Insulin85861.8%22045.5%63867.4%< .001

Biguanides85143.4%21344.1%63843.1%.79

Sulfonylureas84631.8%20828.8%63832.8%.29

Metiglinides2155.1%2105.2%50%.99

D-Phenylalanine Derivatives8400.83%2020.50%6380.94%.54

Thiazolodinediones8353.5%1972.0%6383.9%.21

DPP-4 Inhibitors84412.1%20613.1%63811.8%.21

Alpha-Glucosidade Inhibitors8421.5%2046.4%6380.0%< .001

Bile Acid Sequestrants8400.48%2020.99%6380.31%%.25

Diet Controlled Diabetes29222.3%21228.8%805.0%< .001

Summaries and Comparisons by Site are Shown Below for Patients With ETDRS ≤ 70

Overall (N = 485)International (N = 159)U.S. (N = 326)P Value+P Value*

BCVA ≤ 70 ETDRS lettersBCVA ≤ 70 ETDRS lettersBCVA ≤ 70 ETDRS letters

NNN

Male Sex485286 (59.0)159111 (69.8)326175 (53.7)< .001c.42c

Age (Years)48163.4 ± 11.515561.7 ± 9.832664.2 ± 12.1.026a.006a

Race457131326< .001c.023 c
  Asian58 (12.7)57 (43.5)1 (0.31)
  Black109 (23.9)6 (4.6)103 (31.6)
  Hispanic20 (4.4)20 (15.3)0 (0.0)
  Indian20 (4.4)20 (15.3)0 (0.0)
  Other31 (6.8)1 (0.76)30 (9.2)
  White219 (47.9)27 (20.6)192 (58.9)

Type 2 Diabetes484467 (96.5)158155 (98.1)326312 (95.7).18c.40 c

Duration of Diabetes (Months)407186.8 ± 117.0141199.9 ± 125.1266179.8 ± 112.0.099a.20a

HgbA1c (%)2578.2 ± 1.8548.4 ± 2.02038.1 ± 1.8.30a.14a

Creatinine (mg/dL)2741.6 ± 1.5561.3 ± 0.942181.7 ± 1.6.089a.010a

BUN (mg/dL)24327.4 ± 17.52723.6 ± 19.821627.9 ± 17.2.23a.048a

+ Biguanides use452176 (38.9)12653 (42.1)326123 (37.7).40c.009c

+ Hypertension history465354 (76.1)14693 (63.7)319261 (81.8)< .001c.27c

+ Cardiovascular disease446122 (27.4)12722 (17.3)319100 (31.3).003c.59c

+ Cerebral disease44456 (12.6)1252 (1.6)31954 (16.9)< .001c.68c

+ Peripheral vascular disease44356 (12.6)1244 (3.2)31952 (16.3)< .001c.82c

+ Renal insufficiency44692 (20.6)12710 (7.9)31982 (25.7)< .001c.11c
Ocular Characteristics
CST (µm)482390.0 [323.0,509.0]156410.0 [320.5,588.0]326383.5 [323.0,486.0].081b< .001b

Cube Volume (mm3)42111.4 ± 3.6958.8 ± 5.632612.2 ± 2.2.081b.009a

Cube Average Thickness (µm)381341.6±71.555360.0 ± 112.2326338.5 ± 61.9.039a< .001a

Type of DR485159326.13c.006c

NPDR291 (60.0)103 (64.8)188 (57.7)

PDR194 (40.0)56 (35.2)138 (42.3)

+Tractional Macular Edema on OCT48570 (14.7)15024 (16.0)32646 (14.1).59c.66c

+ ERM on OCT485107 (22.4)15042 (27.8)32665 (19.9).055c< .001c

+ Subretinal Fluid on OCT485168 (35.1)15085 (55.6)32683 (25.5)< .001c< .001c

+ History of Focal Laser47834 (7.1)15229 (19.1)3265 (1.5)< .001c.12c

+ History of PRP482126 (26.1)15664 (41.0)32662 (19.0)< .001c.002c

+ History of Intraocular Surgery485207 (42.7)15959 (37.1)326219 (67.2)<.001c.039c

Summaries and Comparisons by Site for Patients With ETDRS > 70

Overall (N = 412)International (N = 100)U.S. (N = 312)P Value

BCVA > 70 ETDRS LettersBCVA > 70 ETDRS LettersBCVA > 70 ETDRS Letters

NNN

Male sex412232 (56.3)10069 (69.0)312163 (52.2).003c

Age (Years)9859.2 ± 10.231261.9 ± 11.0.031a

Race40391312< .001c
  Asian63 (15.6)59 (64.8)4 (1.3)
  Black96 (23.8)3 (3.3)93 (29.8)
  Hispanic5 (1.2)5 (5.5)0 (0.0)
  Indian9 (2.2)9 (9.9)0 (0.0)
  Other21 (5.2)1 (1.1)20 (6.4)
  White209 (51.9)14 (15.4)195 (62.5)

Type 2 Diabetes412393 (95.4)10095 (95.0)312298 (95.5).83c

Duration of Diabetes (months)352176.2 ± 109.588179.6 ± 127.4264175.1 ± 103.0.74a

HgbA1c (%)2398.0 ± 1.9447.8 ± 1.91958.0 ± 1.9.53a

Creatinine (mg/dL)2551.3 ± 0.97541.02 ± 0.332011.4 ± 1.06.006a

BUN (mg/dL)22224.4 ± 15.42315.2 ± 7.219925.5 ± 15.7.002a

+ Biguanides use395189 (47.8)8337 (44.6)312152 (48.7).50c

+ Hypertension history402293 (72.9)9664 (66.7)306229 (74.8).12c

+ Cardiovascular disease393101 (25.7)8718 (20.7)30683 (27.1).23c

+ Cerebral disease39446 (11.7)877 (8.0)30739 (12.7).23c
disease
+ Peripheral vascular disease39552 (13.2)881 (1.1)30751 (16.6)< .001c

+ Renal insufficiency39264 (16.3)875 (5.7)30559 (19.3).002c

Ocular Characteristics
CST (µm)405342.0 [291.0, 407.0]93311.0 [253.0, 403.0]312350.0 [300.0, 408.0]< .001b

Cube Volume (mm3)35210.8 ± 2.4407.4 ± 4.731211.3 ± 1.5< .001a

Cube Average Thick-ness (µm)335314.3 ± 43.123329.4 ± 67.7312313.2 ± 40.7.082a

Type of DR41199312.84c

NPDR283 (68.9)69 (69.7)214 (68.6)

PDR128 (31.1)30 (30.3)98 (31.4)

+Tractional Macular Edema on OCT41264 (15.8)948 (8.5)31256 (17.9).028c

+ERM on OCT41253 (13.1)948 (8.5)31245 (14.4).14c

+ Subretinal Fluid on OCT41282 (20.2)9428 (29.8)31254 (17.3).008c

+ History of Focal Laser40819 (4.7)9613 (13.5)3126 (1.9)< .001c

+ History of PRP41072 (17.6)9835 (35.7)31237 (11.9)< .001c

+ History of Intraocular Surgery412148 (35.9)10045 (45.0)312219 (70.2)< .001c
Authors

From Cole Eye Institute, Cleveland Clinic Foundation, Cleveland (FFC, FSQ, WHA, RPS); Center for Ophthalmic Bioinformatics, Cole Eye Institute, Cleveland Clinic, Cleveland (FFC, RPS); Federal University of São Paulo, São Paulo, Brazil (FFC); University of Buenos Aires, Buenos Aires, Argentina (AA); Case Western Reserve University School of Medicine, Cleveland (CR, MH, SH, RPS); Aditya Jyot Eye Hospital, Mumbai, India (CN, SN); IBOL - Brazilian Institute of Ophthalmology, Rio de Janeiro, Brazil (DN); Smt. Kanuri Santhamma Retina Vitreous Centre, Hyderabad, India (JC, RKG); iRetina Eye Institute, Salvador, Brazil (JR); Clihon- Feira de Santana Eye Hospital, Feira de Santana, Brazil (RPM); National Ophthalmology Unit, Guatemala City, Guatemala (JR); Macula Vitreous and Retina Associates of Costa Rica, San José, Costa Rica (LW); and Asan Medical Center, Seoul, Korea (SL).

Supported in part by an unrestricted research grant by RegeneronPharmaceuticals.

Dr. Wu has received personal fees from Bayer, Novartis, and Quantel Medical outside the submitted work. Dr. Yoon has received grants from Allergan and Bayer as well as personal fees from Allergan, Alcon, Bayer, and Boehringer Ingelheim outside the submitted work. Dr. Singh has received grants and personal fees from Regeneron Pharmaceuticals during the conduct of the study, as well as grants and personal fees from Genentech/Roche and Alcon/Novartis; grants from Apellis; and personal fees from Optos, Zeiss, and Biogen outside the submitted work. The remaining authors report no relevant financial disclosures.

Dr. Singh did not participate in the editorial review of this manuscript.

The authors note that all personnel involved in the study provided permission to be acknowledged.

Address correspondence to Rishi P. Singh, MD, Cole Eye Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Mail Code i-32, Cleveland, OH 44195; email: singhr@ccf.org.

Received: September 27, 2018
Accepted: June 10, 2019

10.3928/23258160-20191031-18

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