Role of alternative oral therapy for the management of wet age-related macular degeneration and proliferative diabetic retinopathy

Abstract

Proliferative diabetic retinopathy (PDR) affects approximately 6% of diabetic patients globally. The overall prevalence of diabetic retinopathy is around 22%. Wet age-related macular degeneration (ARMD), the sight-threatening type of ARMD, affects approximately 1.2%-1.3% of the general population and represents 15% of total ARMD cases. While intravitreal anti-vascular endothelial growth factor injections are still the mainstay therapy, there are a few challenges, such as frequent administration, cost burden, and compliance barriers that prompt the need for exploration into systemic oral alternative drugs like fenofibrate, candesartan, and vorolanib. These oral therapies have the advantage of being non-invasive and systemically accessible with few logistical burdens. This review highlights current evidence supporting the use of oral therapies in PDR and wet ARMD management, along with practical limitations and future prospects.

Key Words: Proliferative diabetic retinopathy; Wet age-related macular degeneration; Anti-angiogenesis; Oral therapy; Fenofibrate; Candesartan; Vorolanib; Diabetic macular edema; Systemic treatment; Retinal neovascularization

Core Tip: Anti-vascular endothelial growth factor injections are effective for proliferative diabetic retinopathy (PDR) and wet age-related macular degeneration (ARMD), but patient compliance and healthcare strain limit their utility. This review explores the role of oral drugs such as fenofibrate, candesartan, and vorolanib in the management of PDR and wet ARMD. These agents offer ease of administration and may serve as adjuncts or substitutes for injection-averse patients. Further multicenter randomized controlled trials are warranted to confirm long-term safety and efficacy.

INTRODUCTION

Age-related macular degeneration (ARMD) and diabetic retinopathy are leading causes of visual impairment globally. Treatments for advanced forms, such as wet ARMD and proliferative diabetic retinopathy (PDR), have been revolutionized by anti-vascular endothelial growth factor (VEGF) intravitreal injections, namely bevacizumab, ranibizumab, aflibercept, and faricimab[1,2] with or without the previous standard laser photocoagulation[3,4]. However, the high frequency of injections places significant economic and psychological burdens on patients and healthcare systems alike[5]. Barriers to adherence include patient discomfort, financial costs, travel logistics, and anxiety related to repeated ocular procedures[6].

In this context, oral therapies are being investigated as adjunctive or alternative treatments due to their non-invasive nature and potential for systemic effects. Repurposed agents like fenofibrate and candesartan, along with new agents like vorolanib, demonstrate anti-angiogenic and anti-inflammatory properties that may benefit retinal conditions. This mini-review synthesizes existing literature and clinical trial data to evaluate the practicality of these systemic options.

METHODOLOGY

We conducted a comprehensive search of PubMed/MEDLINE, Embase, Cochrane Library, and ClinicalTrials.gov from January 2000 to June 2024. Keywords included “oral therapy”, “oral treatment”, “fenofibrate”, “candesartan”, "vorolanib”, “diabetic macular edema”, “anti-angiogenesis“, “retinal neovascularization”, “proliferative diabetic retinopathy“, and “wet age-related macular degeneration“. Two independent authors screened abstracts and full texts, resolving discrepancies through consensus with the third author. This review included randomized controlled trials, prospective cohort studies, retrospective cohort studies, and case-control studies. We excluded case reports, non-peer-reviewed articles, and case series with sample sizes < 20.

REVIEW OF EXISTING ORAL DRUGS

Fenofibrate

Fenofibrate, a derivative of fibric acid with hypolipidemic properties, acts as an agonist for the PPARα.

Mechanisms of action: The mechanisms through which fenofibrate mitigates the progression of diabetic retinopathy appear to be multifaceted, extending beyond its capacity to lower serum lipid levels. Several hypotheses have been put forth regarding its action. Fenofibrate is recognized for its ability to elevate the levels of circulating apolipoprotein A-I. Recent studies have identified this apolipoprotein as an independent protective factor in the prevention of diabetic retinopathy[7]. Furthermore, fenofibrate plays a role in regulating intraretinal lipid metabolism, thereby reducing lipid deposition and lipotoxicity[8]. In addition, various non-lipid mechanisms have been identified to elucidate fenofibrate’s effects on diabetic retinopathy. These mechanisms include anti-apoptotic properties, antioxidant activity, anti-inflammatory actions, anti-angiogenic effects, and protective roles concerning the maintenance of the integrity of the blood-retinal barrier. Several non-lipid mechanisms have been identified that elucidate the action of fenofibrate in the context of diabetic retinopathy. These mechanisms encompass anti-apoptotic, antioxidant, anti-inflammatory, and anti-angiogenic activities, along with protective effects that counteract the breakdown of the blood-retinal barrier[9].

Pharmacokinetics: Fenofibrate exhibits a bioavailability of approximately 60%, with peak plasma concentrations occurring within 4 to 8 hours post-administration. Achieving steady-state levels requires approximately 5 days. This medication demonstrates a high protein-binding capacity of 99% and undergoes hydrolysis to form fenofibrate acid, which subsequently conjugates with glucuronic acid. The terminal half-life of fenofibrate is between 20 and 23 hours, with approximately 60% of the drug excreted via urine and 25% through feces[10,11] (Table 1).

Table 1 Molecular structure of fenofibrate, candesartan, and vorolanib.

Name of oral drug	Molecular structure
Fenofibrate	C20H21CIO4, with a molecular weight of 360.8 g/mol
Candesartan	C24H20N6O3, with a molecular weight of 440.46 g/mol
Vorolanib	C23H26FN5O3, with a molecular weight of 439.49 g/mol

Administration: Fenofibrate is administered orally on a once-daily basis, and it can be taken with or without food. It is crucial to ensure that the capsules are swallowed whole. Given that different formulations are not bioequivalent, any switch between them should be approached with caution.

Contraindications: Fenofibrate needs to be avoided in patients with liver disease[12], severe renal impairment, gallbladder disease, or hypersensitivity to fenofibrate. It is a pregnancy category C medicine. The impact of the drug on milk production as well as its effects on breastfed infants remains undetermined[13]. Fenofibrate is primarily indicated for diabetic retinopathy in patients with controlled diabetes. However, caution is required when there are concurrent risk factors for myopathy (e.g., statin use, hypothyroidism). Moreover, the use of fibrates may increase the risk of gallstone formation[12]. Thus, patient selection is essential to maximize the benefits of oral fenofibrates for PDR while minimizing side effects. It is essential to evaluate patients for the presence of rhabdomyolysis or vitamin D deficiency should any muscle-related symptoms manifest. In the event of an overdose, the provision of supportive care is paramount; while gastric lavage may be contemplated, it is important to note that hemodialysis is ineffective due to the high protein-binding characteristics of the substance involved[13,14].

Clinical evidence: Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study: The FIELD study was a randomized clinical trial involving 9795 participants aged 50 to 75 years diagnosed with type 2 diabetes mellitus. The subjects were randomly assigned to two groups: One group received fenofibrate 200 mg per day (n = 4895), while the other group was administered a matching placebo (n = 4900). The findings reported by Keech et al[16] indicated that laser treatment was required more frequently among participants exhibiting poorer glycemic or blood pressure control compared to those with optimal control, as well as among individuals with a higher burden of clinical microvascular complications. The need for laser treatment was found to be independent of plasma lipid levels. The necessity for initial laser treatment in all cases of retinopathy was significantly lower in the fenofibrate cohort compared to the placebo cohort. Specifically, 164 patients (3.4%) in the fenofibrate group required treatment, in contrast to 238 patients (4.9%) in the placebo group. The hazard ratio (HR) was calculated at 0.69, with a 95% confidence interval (95%CI) of 0.56-0.84 (P = 0.0002). This translates to an absolute risk reduction of 1.5% with a range of 0.7% to 2.3%. In the ophthalmology sub-study, the primary endpoint of a 2-step progression in retinopathy grade revealed no significant difference between the two groups overall, with 46 patients on fenofibrate (9.6%) compared to 57 patients on placebo (12.3%; P = 0.19). Within the subset of patients without pre-existing retinopathy, the results were similarly non-significant, showing 43 patients (11.4%) on fenofibrate vs 43 patients (11.7%) on placebo (P = 0.87). Conversely, among patients with preexisting retinopathy, a significantly lower number of individuals on fenofibrate exhibited a 2-step progression compared to those on placebo, with three patients (3.1%) vs fourteen patients (14.6%; P = 0.004). An exploratory composite endpoint, encompassing a two-step progression of retinopathy grade, macular edema, or the necessity for laser treatment interventions, exhibited a statistically significant reduction in the fenofibrate group in comparison to the placebo group. This finding is supported by an HR of 0.66 (95%CI: 0.47–0.94; P = 0.022). Although fenofibrate reduced the need for laser treatment in patients with existing diabetic retinopathy, it did not significantly prevent the onset of retinopathy in patients without baseline disease. This underscores its role as a disease-modifying agent primarily for individuals with preexisting microvascular changes[15,16].

Action to Control Cardiovascular Risk in Diabetes (ACCORD)-Eye study: The ACCORD trial consisted of three randomized comparisons that evaluated the impact of intensive management of blood glucose and blood pressure. Additionally, the trial examined the efficacy of combining fenofibrate with statin therapy in comparison to statin monotherapy for the management of dyslipidemia. This trial specifically targeted the incidence of cardiovascular events in patients with type 2 diabetes who also presented with established cardiovascular disease and/or additional cardiovascular risk factors[17]. The ACCORD-Eye study was a substudy involving 2856 patients, designed to evaluate the impact of various treatment strategies on the progression of diabetic retinopathy, as well as the necessity for retinal laser interventions or vitrectomy surgery[18]. The 1593 patients were enrolled in the lipid control component of the ACCORD-Eye study. After four years, fenofibrate combined with statins significantly reduced the progression of diabetic retinopathy compared to statins alone. However, there was no difference in moderate vision loss, suggesting a structural rather than visual benefit. These outcomes indicate that fenofibrate’s benefits are more pronounced in delaying structural progression rather than improving vision directly[18].

The anti-fibrotic effects of fenofibrate have been documented within both renal and cardiovascular systems. A study demonstrated that fenofibrate effectively reduced the expression of fibrotic factors in the kidneys of models representing both type 1 and type 2 diabetes[18]. Additionally, Zhang et al[19] reported that fenofibrate inhibited fibrosis and inflammation in the hearts of rats induced with streptozotocin to model diabetes. Furthermore, Paw et al[20] reported that fenofibrate effectively diminishes the transition of fibroblasts to myofibroblasts and reduces subepithelial fibrosis in patients with asthma. Research has indicated that the TGF-β-Smad2/3 signaling pathway and the Wnt signaling pathway are the predominant pathways involved in the formation and progression of tissue fibrosis[21,22]. Tosi et al[23] investigated the role of TGF-β-Smad2/3 signaling in the development of subretinal fibrosis associated with neovascular ARMD (nAMD). In their study on very low-density lipoprotein knockout (Vldlr-/-) mice, Chen et al[24] discovered that subretinal fibrosis was present in the retina of an animal model of nAMD. The researchers found that fenofibrate effectively inhibited subretinal fibrosis by suppressing the TGF-β-Smad2/3 signaling pathway and Wnt signaling, thereby inhibiting the activation of Müller cells and reducing the expression of connective tissue growth factor[24].

Huang et al[25] conducted a study utilizing murine models, which demonstrated that nanoemulsion-based fenofibrate eye drops significantly reduced the adherence of leukocytes to the retinal vasculature and diminished the overexpression of several inflammatory factors within the retinas of very low-density lipoprotein receptor knockout (Vldlr-/-) mice, a model exhibiting ARMD phenotypes, as well as in streptozotocin-induced diabetic rats. Furthermore, the administration of fenofibrate eye drops resulted in a decrease in retinal vascular leakage within these models. Additionally, the treatment alleviated laser-induced choroidal neovascularization. It is important to highlight that the administration of fenofibrate eye drop treatment did not result in any observed ocular toxicities[25].

Candesartan

Candesartan is classified as an angiotensin II (Ang-II) type 1 receptor blocker and is primarily utilized in the management of hypertension and heart failure. Recent years have seen an increased interest in the ocular renin-angiotensin system (RAS), particularly following the discovery of RAS components within ocular tissues. The examination of the ocular RAS was notably initiated by Igic et al[26], who conducted a study that detected angiotensin-converting enzyme (ACE) activity in retinal homogenates.

Mechanism of action: The circulatory RAS commences with the enzyme renin, which cleaves angiotensinogen to yield the decapeptide angiotensin I. The peptide undergoes conversion to the octapeptide Ang-II through the action of the ACE. Ang-II exerts various biological effects through the activation of Ang-II type I receptors (AT1R) and Ang-II type 2 receptors (AT2R)[27]. The majority of Ang-II's well-documented biological effects, including vasoconstriction, electrolyte homeostasis, fibrosis, inflammation, and cellular proliferation, primarily occur through AT1R activation. Conversely, AT2R similarly influences processes such as cell growth, apoptosis, and angiogenesis in specific tissues[28-30].

The existence and functional significance of RAS components, including prorenin, renin, ACE, angiotensinogen, Ang-II, (pro)renin receptor [(P)RR], and AT1R, have been well established in various species, including those affecting ocular systems[28-32]. AT1R is predominantly expressed in retinal cells, such as Müller cells, retinal pigment epithelium, blood vessels, and ganglion cells, and plays a critical role in the pathogenesis of serious ocular disorders, including diabetic retinopathy, ARMD, and glaucoma. Candesartan, an AT1R antagonist, selectively promotes vasodilation, diminishes inflammation, and reduces fibrosis.

ACE inhibitors confer protective effects against diabetic retinopathy and wet ARMD by mitigating the overexpression of VEGF in the retina. Additionally, Ang-II type 1 receptor blockers exhibit protective qualities in diabetic retinopathy by alleviating inflammatory responses and oxidative stress within the ocular environment[33]. (P)RR blockers have been shown to negate the angiogenic actions of extracellular signal-regulated kinase (ERK) signaling molecules[34,35]. Furthermore, ACE2 has been identified as a protective factor against retinal ganglion cell death (Table 1).

Clinical evidence: The DIRECT-prevent 1 and protect 1 trials, focusing on the effects of candesartan in patients with type 1 diabetes, did not demonstrate a beneficial impact on the progression of diabetic retinopathy[36]. The DIRECT-protect 2 trial involved a total of 1905 participants aged between 37 and 75 years, who were randomly assigned to receive either candesartan (n = 951) or a placebo (n = 954). Within the study, 161 participants (17%) in the candesartan group experienced a progression of retinopathy by three steps or more on the Early Treatment Diabetic Retinopathy Study scale, compared to 182 participants (19%) in the placebo group[37]. The 34% increased regression rate was observed in patients with type 2 diabetes and mild-to-moderate retinopathy. There is currently no clinical evidence supporting its efficacy in wet ARMD, and its utility in that population remains hypothetical based on preclinical mechanisms involving VEGF modulation and oxidative stress reduction. Numerous studies have indicated that Ang-II enhances the expression of various cytokines, including IL-6, IL-1, and TNF-α, as well as chemokines such as MCP-1 and leukocyte adhesion molecules (specifically P, E, and L selectins; integrins α1 and β2; VCAM; and ICAM)[38,39]. Moreover, within the spectrum of RAS blockers, Candesartan is recognized for its highest affinity to the AT-1 receptor. This class of medication is widely employed to manage arterial hypertension and has been demonstrated to reduce soluble ICAM-1 Levels in hypercholesterolemic patients[40].

Safety and tolerability: Common adverse effects associated with oral candesartan include dizziness and hyperkalemia. Therefore, it is essential to conduct regular monitoring of renal function and electrolyte levels throughout the course of treatment.

Furthermore, the available data concerning its efficacy in wet ARMD is limited. Therefore, further robust clinical trials are necessary to substantiate its protective effects on the retina.

Vorolanib (X-82)

Vorolanib is an oral tyrosine kinase inhibitor that inhibits VEGFR, PDGFR, and c-Kit. By blocking VEGFR and PDGFR, vorolanib interferes directly with neovascular signaling pathways crucial to both PDR and wet ARMD[41]. Vorolanib demonstrated significant antiangiogenic properties in human umbilical vein endothelial cells activated by recombinant human VEGF (rHuVEGF165). Furthermore, it notably inhibited retinal neovascularization and reduced the avascular area in the retina of mice subjected to oxygen-induced retinopathy[41] (Table 1).

Clinical evidence: In a phase 1/2 study, patients with neovascular AMD treated with oral vorolanib (25-100 mg) experienced visual gains of 5.4 to 13 Letters over 180 days[42]. Importantly, the dropout rate was low, and adverse events were mild, with the most common being fatigue and gastrointestinal discomfort. No serious drug-related adverse events were reported. This indicates a favorable safety profile, though larger randomized trials are needed to confirm long-term safety and optimal dosing.

PRACTICAL APPLICATIONS AND FUTURE RESEARCH

Fenofibrate’s advantages are most relevant for patients with diabetic retinopathy and comorbid dyslipidemia, and in settings where intravitreal injection access is limited. Also, candesartan and vorolanib should not be considered first-line or standalone treatments for wet ARMD, and robust clinical data are still lacking. While anti-VEGF injections remain the gold standard, these oral therapies may be especially advantageous in populations where injectable therapy is limited by cost, access, or patient reluctance, particularly in low-resource or rural settings.

Multicenter randomized controlled trials are required to analyze long-term safety, optimal dosing regimens, and comparative efficacy against current gold standards. Future trials should incorporate strict inclusion criteria, baseline lab assessments, and regular monitoring (e.g., electrolytes, liver enzymes) to mitigate serious side effects like hyperkalemia or gallstone formation.

CONCLUSION

Although anti-VEGF injections remain the gold standard for PDR and wet ARMD management, systemic therapies offer unique benefits like compliance improvement and systemic disease modification. In patients without preexisting retinopathy, fenofibrate has been shown to reduce the progression of diabetic retinopathy. Although careful monitoring is required due to the risk of hyperkalemia, candesartan offers modest regression benefits in diabetic retinopathy. In wet ARMD, vorolanib, a novel tyrosine kinase inhibitor, has shown promising early results with good visual outcomes and tolerability. Despite these encouraging results, human trials are still limited, and long-term data are lacking. To determine the complete clinical utility of these oral agents, large-scale, multicenter RCTs with clear endpoints and safety monitoring are necessary in the future.