In this prospective, five-participant, phase I/II pilot study, minocycline administered orally at a dose of 100 mg taken twice daily achieved a relatively high drug adherence rate (90 ± 9%, mean ± SD; range = 78%–99%) among participants during the study. The study drug was well tolerated, with minimal drug-related AEs or ocular complications. At month four, 5/5 participants did not meet criteria for disease worsening, and therefore did not require ancillary treatment for DME. As a result, all five participants were treated with minocycline only from baseline to month 6.
From baseline to month 6, mean visual acuity and mean central macular thickness and volume improved progressively with time in study and fellow eyes. While the improvements in visual acuity changes were modest overall (5.8 ± 5.4 in study eyes and 4.4 ± 3.5 in fellow eyes), all but one eye (9/10) demonstrated improvement in acuity; 1/10 eye remained stable at 85 letters (20/20); and 0/10 eyes demonstrated a decrease in visual acuity. One participant met the primary outcome measure of improvement in visual acuity by 15 letters (participant 4). The progressive improvements in visual acuity were generally concurrent with progressive decreases in macular edema as measured by CST and CMV, with some exceptions. The study eye in participant 4 demonstrated a consistent and durable improvement in visual acuity from baseline to month 6, even though improvements in macular edema measurements were more variable over follow-up. Of the eyes in the study, only one study eye (in participant 1) demonstrated a decrease in CST that exceeded 1 logOCT step. On FA, 9 out of 10 eyes demonstrated a decrease in the area of late leakage at month 6.
Taken together, these findings indicate a potential effect of the study drug in reducing abnormal vascular permeability, and thereby improving macular edema. Increased vascular permeability can be related to the presence of activated retinal microglia, which produce a host of inflammatory mediators, including TNF-α, interleukin-1β, intercellular adhesion molecule 1, cyclooxygenase, inducible nitric oxide synthase, and VEGF, which can induce retinal leukostasis and blood-retinal barrier breakdown.7
Although the initial stimulus for microglial activation is unclear, sustained microglial activation in the retina at sites of DR lesions can perpetuate chronic neuroinflammation and exacerbate DR-related pathological changes. In vitro, minocycline has been shown to inhibit the activation of microglia and effectively decrease the expression of inflammatory cytokines.23
In vivo, systemic minocycline in a rodent model of diabetes similarly repressed diabetes-induced upregulation of inflammatory mediators.13
As a result, the anatomical effects in terms of reduced edema and vascular leakage observed in the present study are likely a result of reduced microglial activation in the retina.
In addition to reducing vascular permeability and improving macular edema, microglia inhibition with minocycline may also act in other ways to improve visual acuity in DME. Activated microglia in the CNS can induce neuronal death24
and synapse degeneration25
; and in the diabetic retina, these effects may contribute to neurodegeneration, which may not be evident macroscopically on clinical examination.10,26
In animal models of retinal diseases including glaucoma,27
and photoreceptor degeneration,29,30
treatment with minocyline has resulted in a decrease in neuronal degeneration. Minocycline was also effective in reducing diabetes-induced upregulation of caspase-3, a mediator of apoptotic cell death in a rodent model of diabetic retinopathy.13
These studies highlight the involvement of microglial-mediated chronic neuroinflammation in neuronal and synaptic dysfunctions in DR, and suggest an additional mechanism by which minocycline may contribute toward the improvements in visual acuity observed in the current study.
Although the current pilot phase II study did not contain a control arm, study authors compared clinical outcomes with available data from control groups from other clinical studies of diabetic macular edema. Comparisons were made taking into account the use of rescue laser treatment in these control groups, and the time following enrollment that measurements were made. The safety and efficacy of ranibizumab in diabetic macular edema with center involvement (RESOLVE) study, a sham-controlled, double-masked study of eyes with DME,31
contained a sham-treatment control arm containing 49 eyes in which rescue laser was made available 3 months following enrollment. At the planned interim analysis of a subset of eyes at 6 months, mean OCT CST increased by 15% in the sham-treated group. Change in BCVA was not reported. At the 12-month primary outcome time point, the mean change in OCT CST was −48.4 ± 153.4 μm and the mean change in BCVA was −1.4 ± 14.2 letters. The phase III study of ranibizumab injection in subjects with clinically significant macular edema with center involvement secondary to diabetes mellitus (RISE) and the phase III study of ranibizumab injection in subjects with clinically significant macular edema with center involvement secondary to diabetes mellitus (RIDE) similarly included a sham-treatment control arm in which rescue laser was also available 3 months following enrollment. While the results of the RIDE and RISE studies have not been published, data was available from a presented abstract (Brown DM, et al. IOVS
2011;52: ARVO E-Abstract 6647), which reported that at 24 months, the control arm decreased in mean central foveal thickness by 133 μm, with 18% of participants improving by at least 3 lines of vision. Data from the ETDRS32
also demonstrated that the subset of study eyes that were comparable in disease severity (i.e., with mild to moderate nonproliferative diabetic retinopathy and macular edema at the center of the macula), in which focal/grid laser was deferred, experienced a vision decrease from baseline of −0.9 ± 7.3 letters.
While the current study included the possibility of providing rescue laser, no participant reached the laser-rescue criteria in the first 6 months of the study. As such, all participants were receiving minocycline treatment only. Although study authors observed modest improvements in visual acuity and OCT thickness at 6 months, these changes compared favorably with those from the control cohort in the RESOLVE study at the 6- and 12-month time points. Comparisons with the control groups in the RIDE and RISE studies are complicated by the longer duration (24 months) of follow-up, across which rescue laser was additionally made available. As a result, the data here is interpreted as potentially revealing a positive effect secondary to study drug as suggested by: (1) the favorable comparison with the control group at 6 months in the RESOLVE study; (2) the use of study drug without additional ancillary treatment; (3) the time-dependent improvement of functional and anatomical outcome measures over the first 6 months; (4) the simultaneous improvements in mean BCVA, macular thickness, and fluorescein leakage; and (5) the absence of systemic trends (i.e., HgbA1C, blood pressure) that would suggest alternative etiologies for improvements in outcome measures.
While effective, current therapies for DME—such as intravitreal anti-VEGF agents and steroids and focal laser—are limited by a high burden of treatment, ocular adverse effects, and unclear mechanisms of action.33
The therapeutic strategy of microglial inhibition may be a useful adjunct, as it broadly targets a central cellular mediator driving chronic neuroinflammation in DR Oral minocycline, with the advantages of high bioavailability, long history of use and known safety profile, and abundant preclinical data supporting its biological effects and its potential efficacy, is promising as a microglial-targeted therapy for DR and warrants further investigation.
In conclusion, the findings in this pilot proof-of-concept study indicate a potential effect of oral minocycline for the treatment of DME. Administered over 6 months, oral minocycline appeared to have potential efficacy in increasing visual acuity and reducing macular edema in a progressive time-dependent manner. These changes were associated with a decrease in vascular leakage as determined by fluorescein angiography and were not associated with concurrent changes in systemic factors such as glycemic index, blood pressure, or serum creatinine. The progressive improvement of outcomes measures with increasing duration of treatment was suggestive of a treatment effect that was secondary to the study drug. These findings encourage further investigation of the strategy of microglial inhibition with oral minocycline in the treatment of DME. These further studies may comprise of larger phase II trials in which minocycline or placebo may be assigned in combination with approved anti-VEGF therapies for DME, similar to pilot trials presently ongoing for the treatment of vein occlusions (NCT01468831 and NCT01468844). While current anti-VEGF therapies may strongly ameliorate VEGF-dependent pathological changes in the retina in diabetic retinopathy, they may not address the underlying etiology of VEGF dysregulation. Pharmacological strategies involving microglial inhibition hold promise in decreasing causative inflammatory changes and may constitute an ancillary treatment for reducing the chronicity of disease and the burden of treatment.