Proliferative diabetic retinopathy (PDR) is a complication of long-standing and poorly controlled diabetes mellitus (DM). PDR is the most advanced stage of diabetic retinopathy (DR) and is heralded by the presence of ocular neovascularization. Alongside optimization of glycemic control and other systemic factors, standard treatment of high risk PDR involves application of laser burns to the peripheral retina with panretinal photocoagulation (PRP).1 PRP reduces the risk of vision loss and represents the current gold standard therapy for this condition. Unfortunately, neovascular activity persists such that one of three of eyes develops vitreous hemorrhages and one of six required vitrectomy despite the laser treatment in DRCR Protocol S .2 Furthermore, in 2-year outcomes of Protocol S, serial intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies demonstrated a potential role for the treatment of PDR, with lower rates of vitrectomy and lesser degrees of visual field loss compared with PRP, but the clinical utility in real-world settings still needs validation. Due to the risks of treatment of either modality, much interest exists in exploring less invasive, alternative therapies.
As mentioned above, the role of local therapy is under exploration. Data from clinical trials using serial anti-VEGF have demonstrated that these injections can reduce the severity of DR.3–5 This is an attractive approach to reduce the frequency of vision-threatening events including the development of PDR. At this time, the exact role of treatment with anti-VEGF for eyes that do not yet have proliferative disease is under investigation in DRCR Protocol W.
Beta-adrenergic signaling promotes angiogenesis and beta blockade inhibits VEGF. This is a well-established phenomenon in both oncology and vision research with varied pathophysiology but not for DR. For example, in the oxygen-induced retinopathy mouse model of retinopathy of prematurity, intraocular VEGF levels are reduced with beta-blockade.6,7 Additionally, beta-adrenergic inhibition regresses choroidal neovascular membrane formation and reduces VEGF expression in the laser-induced mouse model.8–11 Furthermore, clinical reports have demonstrated that oral propranolol induced clinical regression in patients with vascular tumors such as cutaneous capillary hemangiomas as well as both circumscribed and diffuse choroidal hemangiomas.12,13 Retrospective analysis of individuals taking oral beta-blockers with exudative macular degeneration demonstrated a reduced burden of anti-VEGF injections as compared with individuals not taking beta-blockers.14 Clinical research is actively examining this relationship in children with retinopathy of prematurity ( clinicaltrials.gov NCT01079715). A retrospective study suggested a reduced need for PRP in subjects taking beta-blockers with PDR, but overall, this relationship remains a largely unexplored therapeutic avenue.15 In this pilot study, we investigated the use of oral propranolol, a beta-adrenergic antagonist, to evaluate the effect of beta-blockade on retinal neovascularization in eyes with active PDR.
Patients and Methods
All patients provided signed informed consent prior to participation in the study. This study was approved by the University of Wisconsin – Madison Institutional Review Board, and the research adhered to the tenets of the declaration of Helsinki.
A total of 10 patients were prospectively recruited in the Department of Ophthalmology at the University of Wisconsin – Madison. For this pilot study, the sample size was limited by available funding. Subjects were eligible for enrollment if they were older than 18 years of age with PDR and no diabetic macular edema. To ethically determine the effect of oral propranolol on subjects with active neovascularization, two target populations were enrolled when investigators felt observation was a reasonable alternative to PRP or vitrectomy surgery. Group 1 included subjects with PDR but no high-risk characteristics, whereas Group 2 included subjects with PDR with persistent neovascularization despite prior “complete” PRP laser. Both eyes were included into this study if each independently met inclusion criteria. Contralateral eyes that did not meet study criteria were examined as exploratory analysis due to systemic exposure. Subjects were excluded if they were previously treated with anti-VEGF therapy or laser within 3 months of enrollment; if they were currently on a beta-blocker; had any contraindications to beta-blockers (eg, asthma, bradycardia, allergy); or if they were pregnant, allergic to fluorescein dye, or had other media opacity that would preclude adequate photography. All subjects were administered oral propranolol at 120 mg extended-release daily and monitored during a 12-week period with visits at 2 weeks, 4 weeks, 8 weeks, and 12 weeks.
Serial bilateral Early Treatment Diabetic Retinopathy Severity (ETDRS) seven-field stereoscopic fundus photography (TRC 50DX; Topcon Medical Systems, Oakland, NJ), fluorescein angiography (FA) (TRC 50DX, Topcon Medical Systems, Oakland, NJ), and spectral-domain optical coherence tomography (SD-OCT) (Cirrus; Carl Zeiss Meditec, Dublin, CA) were performed at baseline and at each of the follow-up visits. Color fundus photographs were graded by trained graders at the University of Wisconsin Fundus Photograph Reading Center according to standard protocols for ETDRS level and presence of high risk characteristics.16 Fluorescein angiograms were graded for extent of leakage in disc areas (DAs) and graded for nonperfusion. Central retinal thickness was documented from the SD-OCT.
Demographic data are summarized in the Table. All of the participants but one were between the ages of 40 years and 53 years without significant comorbidities. One participant was 83 years old and had significant medical comorbidities, including prior myocardial infarction and cerebrovascular accident, who happened to withdraw from the study due to malaise. Overall, the participant groups included both types of diabetes (seven Type 2, three Type 1), insulin-dependent and insulin-independent participants, and the presence and absence of hypertension. Twelve eyes of 10 participants were included for study group analysis. All participants had baseline pretreatment images. Post-treatment color fundus photographs were available for all visits in nine of 12 eyes, and SD-OCT in eight of 12 eyes. Pretreatment and week 12 post-treatment FA images were available in nine of 12 eyes.
Baseline Demographic Data of Study Participants
Color Fundus Photography
ETDRS grading results are summarized in Figure 1. At baseline, ETDRS level ranged between 61 to 75 (mild PDR to high-risk PDR). Five of the nine graded subjects developed a preretinal or vitreous hemorrhage and demonstrated a one-step worsening by week 12, and the other four demonstrated stability in the ETDRS scale. Of the five participants with worsened ETDRS severity, three were in Group 1 and two were in Group 2. In the eight non-study eyes, one worsened, five remained unchanged, and two demonstrated one-step improvements. Area of retinal neovascularization on color fundus photography was unable to be reliably determined due to variability in amount of vitreous hemorrhage that precluded adequate measurement.
Results of Early Treatment Diabetic Retinopathy Severity (ETDRS) grading of fundus photographs. (A) Each study eye over time by participant and group. (B) Each contralateral non-study eye over time. (C) Breakdown of percentage stable, worsening, or improving on one or more step of ETDRS severity.
SD-OCT central subfield thickness (CST) median at baseline was 301 μm, with interval stability in all eyes (308 μm). One eye increased by 106 μm and another was reduced by 85 μm. Results are summarized in Figure 2.
Average central subfield thickness on spectral-domain optical coherence tomography over time in study eyes.
Figure 3 summarizes results of area of leakage and capillary nonperfusion analysis from the FA. Median leakage within the ETDRS grid from FA images was 10.35 DAs (range: 0.5 DA to 1.88 DA). Leakage could not be assessed in two eyes due to spillover leakage from neovascular vessels. Of the remaining seven eyes with week 12 FA data, leakage remained stable in six eyes and increased in one eye. Overall, no significant improvement or worsening in FA leakage area was appreciated. Six eyes demonstrated capillary nonperfusion within the ETDRS grid, which remained stable in follow-up.
Analysis of fluorescein angiography, showing average area of leakage (A) and nonperfusion (B) over time.
This pilot study investigated the use of oral propranolol to treat PDR based upon biologic plausibility from prior indirect clinical evidence, as well as supportive evidence from prior basic science studies. Despite this, we were unable to determine an effect in a carefully selected clinic population. This study was designed to determine the potential effect of oral beta-blockade on retinal neovascularization in eyes with PDR, in a patient population in whom laser could ethically be deferred and before results of DRCR Protocol S had been published. Markers of neovascular activity, including area of retinal neovascularization and amount of fluorescein leakage, were chosen to represent VEGF activity whilst other measurements (ETDRS severity grading study and non-study eye; OCT CSF) were included to assess any secondary benefits of beta-blockade. Area of neovascularization proved to be challenging to assess on serial photographs due to vitreous hemorrhage that limited direct quantification in many eyes. Extent of leakage on FA was not reduced in this trial. The other metrics including DR severity level, SD-OCT CST, and capillary nonperfusion on FA did not demonstrate any effect from this dose of propranolol during a 12-week period.
This study has several limitations. The duration of treatment with propranolol necessary to observe the intended effect is uncertain, it is possible a longer duration of therapy would have demonstrated more robust effects. The number of subjects is low, and no control group exists for comparative purposes. Follow-up was sporadic, and imaging data were not fully captured in many eyes. Vitreous hemorrhage precluded excellent visualization and measurement of neovascularization. No reliable assessment of medication compliance was instituted. Propranolol dosing was not individualized, but instead chosen to maximize tolerance and compliance while minimizing the side effect profile. With these limitations and given the results, it seems unlikely that this dose of propranolol has a substantial benefit in this selected patient population.
Systemic targeting of VEGF-mediated retinal diseases may become an important tool to combat the associated visual impairment of DR. Beta adrenergic blockade is a compelling target based on strong scientific background, and further studies will be needed to best determine the clinical applications. Medical comorbidities may limit widespread application of systemic medications such as beta-blockers, and treatment should always be tailored to the individual under the auspices of primary care. In this study, propranolol was chosen as the beta-blocker due to its efficacy for hemangioma of infancy, lipophilicity, and bioavailability in cerebrospinal fluid. In mice, propranolol eye drops have shown equal bioavailability in the retina, compared to systemic propranolol delivery.16 It is possible that the anti-VEGF activity of propranolol is not substantial enough to have a clinical consequence. However, alternative beta-blockers, more selective beta blockade, higher doses, longer duration of treatment, or treatment at an earlier stage may have increased benefit and are worthwhile future directions for investigation.
- 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. 1981;88(7):583–600.
- Gross JG, Glassman AR, Writing Committee for the Diabetic Retinopathy Clinical Research Network et al. Panretinal photocoagulation vs intravitreous ranibizumab for proliferative diabetic retinopathy: A randomized clinical trial. JAMA. 2015;314(20):2137–2146. doi:10.1001/jama.2015.15217 [CrossRef]
- Bressler SB, Qin H, Melia M, Bressler NM, et al. Exploratory analysis of the effect of intravitreal ranibizumab or triamcinolone on worsening of diabetic retinopathy in a randomized clinical trial. JAMA Ophthalmol. 2013; 131(8):1033–1040. doi:10.1001/jamaophthalmol.2013.4154 [CrossRef]
- Ip MS, Domalpally A, Sun JK, Ehrlich JS. Long-term effects of therapy with ranibizumab on diabetic retinopathy severity and baseline risk factors for worsening retinopathy. Ophthalmology. 2015;122(2):367–374. doi:10.1016/j.ophtha.2014.08.048 [CrossRef]
- Ip MS, Domalpally A, Hopkins JJ, Wong P, Ehrlich JS. Long-term effects of ranibizumab on diabetic retinopathy severity and progression. Arch Ophthalmol. 2012;130(9):1145–1152. doi:10.1001/archophthalmol.2012.1043 [CrossRef]
- Ricci B, Ricci F, Maggiano N. Oxygen-induced retinopathy in the newborn rat: Morphological and immunohistological findings in animals treated with topical timolol maleate. Ophthalmologica. 2000;214(2):136–139. doi:10.1159/000027483 [CrossRef]
- Ristori C, Filippi L, Dal Monte M, et al. Role of the adrenergic system in a mouse model of oxygen-induced retinopathy: Antiangiogenic effects of beta-adrenoreceptor blockade. Invest Ophthalmol Vis Sci. 2011;52(1):155–170. doi:10.1167/iovs.10-5536 [CrossRef]
- Lavine JA, Sang Y, Wang S, Ip MS, Sheibani N. Attenuation of choroidal neovascularization by beta(2)-adrenoreceptor antagonism. JAMA Ophthalmol. 2013;131(3):376–382. doi:10.1001/jamaophthalmol.2013.1476 [CrossRef]
- Steinle JJ, Cappocia FC Jr., Jiang Y. Beta-adrenergic receptor regulation of growth factor protein levels in human choroidal endothelial cells. Growth Factors. 2008;26(6):325–330. doi:10.1080/08977190802442070 [CrossRef]
- Steinle JJ, Zamora DO, Rosenbaum JT, Granger HJ. Beta 3-adrenergic receptors mediate choroidal endothelial cell invasion, proliferation, and cell elongation. Exp Eye Res. 2005;80(1):83–91. doi:10.1016/j.exer.2004.08.015 [CrossRef]
- Lavine JA, Farnoodian M, Wang S, et al. β2-Adrenergic receptor antagonism attenuates CNV through inhibition of VEGF and IL-6 expression.Invest Ophthalmol Vis Sci. 2017;58(1):299–308. doi:10.1167/iovs.16-20204 [CrossRef]
- Leaute-Labreze C, Dumas de la Roque E, Hubiche T, Boralevi F, Thambo JB, Taïeb A. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358(24):2649–2651. doi:10.1056/NEJMc0708819 [CrossRef]
- Haider KM, Plager DA, Neely DE, Eikenberry J, Haggstrom A. Outpatient treatment of periocular infantile hemangiomas with oral propranolol. J AAPOS. 2010;14(3):251–256. doi:10.1016/j.jaapos.2010.05.002 [CrossRef]
- Montero JA, Ruiz-Moreno JM, Sanchis-Merino E, Perez-Martin S. Systemic beta-blockers may reduce the need for repeated intravitreal injections in patients with wet age-related macular degeneration treated by bevacizumab. Retina. 2013;33(3):508–512. doi:10.1097/IAE.0b013e3182695ba0 [CrossRef]
- Auyanet I, Rodríguez LJ, Esparza N, et al. [Does carvedilol minimize the requirements for laser photocoagulation in diabetic retinopathy?]. Nefrologia. 2010;30(4):473–474.
- No authors listed. Grading diabetic retinopathy from stereoscopic color fundus photographs – an extension of the modified Airlie House classification. ETDRS report number 10. Early Treatment Diabetic Retinopathy Study Research Group. Ophthalmology. 1991;98(5 Suppl):786–806. doi:10.1016/S0161-6420(13)38012-9 [CrossRef]
- Dal Monte M, Casini G, la Marca G, Isacchi B, Filippi L, Bagnoli P. Eye drop propranolol administration promotes the recovery of oxygen-induced retinopathy in mice. Exp Eye Res. 2013;111:27–35. doi:10.1016/j.exer.2013.03.013 [CrossRef]
Baseline Demographic Data of Study Participants
|ID #||Group OD||Group OS||Withdrew||Age||Sex||Ethnicity||DM Type||Hgb A1C||Baseline ETDRS Letter Score (OD/OS)||Final ETDRS Letter Score (OD/OS)||Lens||Insulin||HTN||Creatinine|
|2||Prior PRP||Non-high risk||40||F||White||2||7.8||86/71||67/74||Phakic||Y||N||0.64|
|3||Withdrew early in the study; data not analyzed.||Malaise||83||F||White||2||87/81||65/89||PCIOL||N||Y|
|5||Non-study||Prior PRP||Increased BUN/Cr||48||M||White||2||11.6||88/85||87/83||Phakic||Y||Y||0.98|