Combined therapy for diabetic macular edema.

Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients. Macular edema within 1 disk diameter of the fovea is present in 9% of the diabetic population. The management of DME is complex and often multiple treatment approaches are needed. This review demonstrates the benefits of intravitreal triamcinolone, bevacizumab and ranibizumab as adjunctive therapy to macular laser treatment in DME. The published results indicate that intravitreal injections of these agents may have a beneficial effect on macular thickness and visual acuity, independent of the type of macular edema that is present. Therefore, pharmacotherapy could complement focal/grid laser photocoagulation in the management of DME. For this review, we performed a literature search and summarized recent findings regarding combined therapy for DME.

INTRODUCTION

Diabetic macular edema (DME) is the main cause of visual impairment in diabetic patients.[12] Conventional treatment is based mainly on laser photocoagulation with the probable mechanism of rejuvenation of retinal pigment epithelium cells or improvement of outer retinal oxygenation.[34] The early treatment diabetic retinopathy study (ETDRS) showed that macular laser photocoagulation (MPC) was beneficial for eyes with clinically significant macular edema.[5] This effect was inferred because MPC reduced the risk of moderate visual acuity (VA) loss by 50%. In the ETDRS, approximately 17% of the treated eyes had a 3-line improvement in VA. For diffuse DME, the outcomes of MPC were even more limited. Lee and Olk[6] reported that modified grid MPC resulted in stabilized VA in 60.9% of eyes, decreased VA in 24.6% of eyes and increased VA in only 14.5% of eyes with diffuse DME. Therefore, alternative or adjunct treatments for DME, such as intravitreal triamcinolone acetonide (IVTA) and anti-vascular endothelial growth factor (VEGF) therapy, have been the focus of the most recent attention.

The pathogenesis of DME is multifactorial. It is predominantly due to a generalized breakdown of the inner blood-retinal barrier, leading to accumulation of fluid and plasma constituents, such as lipoproteins, within the intraretinal layers of macula.[78] Factors such as duration of diabetes, insulin dependence, glycosylated hemoglobin levels, proteinuria and hypertension have all been implicated in the development of DME.[9] VEGF has been identified as one of many growth factors that breakdown the blood-retinal barrier causing increased retinal permeability by affecting the endothelial tight junctions.[10] The normal human retina contains VEGF; however, the levels are significantly elevated in eyes with DME. Hypoxia and hyperglycemia are important contributing factors for increasing VEGF levels in eyes with DME.[1112] The pathogenesis of retinal vascular permeability has also been attributed to inflammation, particularly via leukostasis within the retinal capillaries. The attraction and adhesion of leukocytes to the vascular wall, in the setting of diabetes, may be due to an increased expression of leukocyte adhesion molecules such as retinal endothelial cell intercellular adhesion molecule-1 and CD18.[131415] Therefore, attenuation of the effects of VEGF and a reduction in inflammation may reduce macular edema associated with diabetes.

RATIONALE FOR COMBINATION TREATMENT OF DME

DME is a chronic disease with variable response and clinical manifestations during the whole life of the affected patients. Therefore, it does not appear reasonable that a single treatment may be enough for the entire course of the disease. A comprehensive approach should address the complex pathogenetic mechanism underlying DME and match with any specific manifestation of DME. The available treatments should also make the most of the beneficial effects of each existing approach, exploiting the opportunity of a combined and more effective therapy. In particular, it is well-known that laser treatment can lead to reduced oxygen consumption and induce a complex action on the retinal pigment epithelium.[1617] Anti-inflammatory drugs, especially corticosteroid drugs, can counteract the multifaceted inflammatory reactions correlated to diabetic retinopathy, whereas anti-VEGF drugs expressly aim at halting the effects of VEGF on retinal and vascular structures.

INTRAVITREAL TRIAMCINOLONE (IVT) AS COMBINED THERAPY

There are short and long-term clinical trials that have investigated the combined effects of IVT and laser on DME outcomes [Figures 1 and 2]. Tunc et al.[18] reported that eyes with diffuse DME undergoing laser treatment had better VA outcomes after 18 weeks of treatment was preceded by a posterior sub-Tenon's capsule injection of triamcinolone. Kang et al.[19] randomized 86 eyes with diffuse DME to receive either IVTA or IVTA followed by grid laser. They[19] found improvement in VA and central macular thickness in both groups after 3 weeks. However, after 6 months, these improvements were maintained in the combined group only, suggesting that laser treatment acted synergistically with IVTA resulting in an increased duration of effect attributable to IVTA.[19] Avitabile et al.[20] randomized 60 eyes with cystoid macular edema secondary to either diabetes or retinal occlusive disease to receive IVTA, laser photocoagulation, or both. Avitabile et al.[20] found that VA and macular thickness outcomes were consistently better in the two groups receiving triamcinolone for up to 9 months and there was no apparent difference between the laser plus triamcinolone and the triamcinolone alone groups. Avitabile et al.[20] suggested that triamcinolone may be superior to laser for cystoid macular edema. Lam et al.[21] performed a randomized controlled trial of 111 patients with DME randomized to grid laser photocoagulation, 4 mg IVTA, or 4 mg IVTA combined with sequential grid laser approximately 1 month later. They[21] showed that IVTA combined with laser produced a greater reduction in central macular thickness compared to laser alone. However, there was no significant difference in VA after 6 months.[21]

Figure 1

Patient with diffuse and focal diabetic macular edema in right eye. (a) color photos showing thick hard exudate and macular edema; (b) fluorescein angiography showing the corresponding leaking points; (c) optical coherence tomography showing subretinal and intraretinal fuid with corresponding macular topography that measure the macular thickhness

Figure 2

Same pateint after 4 mg/IVITA injection plus macular laser photocoagulation with 6 months follow-up: (a) Color photo showing dry macula with residual hard exudate; (b) fluorescein angiography showing absence of leaking points; (c) optical coherence tomography showing dry macula and marked reduction in central thickness in the corresponding macular topography

The diabetic retinopathy clinical research network (DRCRnet)[22] performed a randomized clinical trial of eyes with DME. in this study they found that in eyes receiving pan-retinal photocoagulation and concurrent focal/grid laser, that the addition of 1 IVT injection or 2 intravitreal ranibizumab injections in eyes receiving focal/grid laser for DME and pan retinal photocoagulation is associated with better VA and decreased macular edema by 14 weeks.

Recently, Gillies et al.[23] published a prospective, double-masked, randomized, placebo-controlled study of 84 eyes with DME. At 24 months, there was doubling of improvement in vision by 10 or more letters in 15 (36%) of 42 eyes treated with IVTA plus laser compared with 7 (17%) of 42 eyes treated with laser only in addition to his results he showed that in pseudophakic eyes that received IVTA did better than those that received laser alonein comparison with the recently published report by DRCRnet.[2425] that evaluated intravitreal injection of 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid The 1-year mean change (±standard deviation) in the VA letter score from baseline was significantly greater in the ranibizumab + prompt laser group and ranibizumab + deferred laser group, but not in the triamcinolone + prompt laser group compared with the sham + prompt laser group. Laser compared with focal/grid laser alone for treatment of DME. However in pseudophakic eyes at baseline, VA improvement in the triamcinolone + prompt laser group appeared comparable to that in the ranibizumab groups. 2 year VA outcomes were similar to 1-year outcomes.

The major limitation of using IVT as adjunctive therapy for DME is the short duration of action and the need for multiple injections that carry the risk of cataract and glaucoma.[22] The recent availability of implants with corticosteroid has allowed new approaches to treating DME with combined therapy.[26272829] Several intravitreal steroid-releasing implants have been designed in an attempt to provide long-term drug delivery to the macular region. These include nonbiodegradable and biodegradable implants with dexamethasone, fluocinolone acetonide and triamcinolone acetonide. The use of injectable, sustained-release steroid implants might be combined with grid laser treatment to achieve a beneficial long-term effect on DME.

In summary, IVTA used as adjunctive therapy to the macular laser in DME treatment showed. Better outcome compared with laser treatment alone and may consider it as optional treatment specially in diffuse type of DME and in pseudophakic patient’s.

INTRAVITREAL ANTI-VEGF INJECTION AS COMBINED THERAPY

Bevacizumab

Bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA, USA), a humanized monoclonal antibody, which encompasses all VEGF isoforms, was originally approved by the US Food and Drug Administration (FDA) for the treatment of colorectal cancer in 2004.[30] The off-label use of bevacizumab has been applied to many neovascular diseases of the eye, including DME.[3132] Although not currently approved by the FDA for intraocular use, the injection of 1.25-2.5 mg of bevacizumab into the vitreous cavity has been performed without significant intraocular toxicity.[3233] There is relative paucity of publications on the effect of IVB as adjunctive therapy for DME. Recently, Lee et al.[34] reported no significant differences between a bevacizumab injection only treatment group and a bevacizumab injection plus (MPC) combination treatment group with 6 months follow-up. However, bevacizumab plus (MPC) combination treatment could maintain VA and reduce the recurrence of macular edema.[34]

In summary and the benefit IVB used as adjunctive treatment to macular laser in the treatment of DME is uncertain larger studies are needed to prove its benefit.

Ranibizumab

Ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA, USA) is a recombinant humanized monoclonal antibody fragment with specificity for all isoforms of human VEGF-A and has been approved by FDA for intravitreal injection for treatment of retinal diseases. Ranibizumab has been evaluated as an adjunct to MPC well conducted prospective studies such as READ-2[3536] and RESTORE,[37] as well as two phase III trials performed by the DRCRnet.[2425]

Phase II Trial In the READ-2 study[35] indicated that two monthly injections of ranibizumab 0.5 mg followed by two bimonthly injections were more effective than laser monotherapy in improving functional outcomes in patients with visual impairment associated with DME. In terms of the primary endpoint, ranibizumab recipients had a mean increase in best corrected visual acuity (BCVA) of 7.24 ETDRS letters relative to baseline over the 6-month study period, whereas laser recipients had a mean decrease in BCVA of 0.43 letters (P > 0.0001). The mean increase in BCVA in patients treated with ranibizumab 0.5 mg plus laser (3.80 letters) did not differ significantly from that seen in patients treated with ranibizumab alone, nor did it differ significantly from the decrease in BCVA observed in patients treated with laser alone. According to the authors, the study appeared to lack the power to detect a significant difference (in the primary endpoint) between combination therapy and the individual monotherapies. Among patients with data available at 6 months, significantly more ranibizumab than laser recipients gained ± 10 letters (46% vs. 5%) and ± 15 letters (22% vs. 0%) of BCVA; significantly more patients treated with ranibizumab plus laser than with laser alone gained ± 10 letters (30% vs. 5%).[37] The reduction in mean central retinal thickness (CRT) from baseline to month 6 was 106.3 mm, 82.8 mm and 117.2 mm with ranibizumab alone, laser alone and ranibizumab plus laser, respectively. From months 6 through 24, most patients received ranibizumab monotherapy, irrespective of their initial treatment allocation; this resulted in a significant improvement in BCVA in patients previously treated with laser monotherapy. Among patients originally assigned to ranibizumab alone, laser alone and ranibizumab plus laser who remained in the study through 24 months, the mean improvement in BCVA was 7.4, 0.5 and 3.8 letters, respectively, at month 6, compared with 7.7, 5.1 and 6.8 letters, respectively, at month 24 and the proportion of patients who gained ± 15 letters was 21%, 0% and 6%, respectively, at month 6, compared with 24%, 18% and 26%, respectively, at month 24.[36] Among patients who remained in the study through 24 months, those originally assigned to ranibizumab alone and ranibizumab plus laser received a mean of 9.3 and 2.9 ranibizumab injections, respectively (out of a maximum possible number of 13 and 6, respectively); those originally assigned to laser alone received a mean of 4.4 ranibizumab injections (out of a maximum possible number of 9).[38]

Phase III Trials in the RESTORE study,[37] three monthly injections of ranibizumab 0.5 mg and then as needed either alone or combined with laser therapy was more effective than laser alone in improving functional and anatomical outcomes in patients with visual impairment associated with DME. However, no efficacy differences were detected between the ranibizumab alone and ranibizumab plus laser arms of this trial. Over the 12-month study period, the mean average gain in BCVA compared with baseline (primary endpoint) was significantly greater in patients treated with ranibizumab alone or with ranibizumab plus laser than in those treated with laser alone, with no significant difference between the ranibizumab-only and ranibizumab plus laser arms of the trial. A treatment effect of ranibizumab (alone or combined with laser) compared with laser alone was observed in all subgroups of patients with DME, including those with focal or diffuse DME and those with or without prior laser therapy. Secondary functional outcomes, including the mean gain in BCVA and the proportions of patients gaining ± 10 or ± 15 letters of BCVA or achieving < 20/40 vision (i.e., ETDRS letter score of < 73), were also improved significantly in patients receiving ranibizumab alone or ranibizumab plus laser compared with those receiving laser alone, with no significant differences between the ranibizumab only and ranibizumab plus laser arms. Ranibizumab alone or combined with laser therapy was associated with a rapid improvement in mean BCVA relative to laser alone; a treatment effect was seen at the first post-baseline assessment (month 1) and onward. The improvement in mean BCVA with ranibizumab alone or combined with laser therapy was continuous through month 3 and was thereafter sustained (at the month 3 level) through month 12. Furthermore, the improvements in BCVA were associated with gains in vision-related quality-of-life, as assessed using the NEI VFQ-25. At month 12, improvements in the NEI VFQ-25 composite score and quality of vision subscale scores in patients treated with ranibizumab alone or with ranibizumab plus laser were significantly (P > 0.05) greater than those in patients treated with laser alone. There was no statistically significant difference between the ranibizumab-only and ranibizumab plus laser arms (P < 0.05). The reduction in mean CRT from baseline to month 12 was significantly greater in patients treated with ranibizumab alone (−118.7 mm) or with ranibizumab plus laser (−128.3 mm) than in those treated with laser alone (−61.3 mm) (P > 0.0002, both comparisons). Similarly, the proportion of patients with resolution of leakage on fluorescein angiography at month 12 was higher in patients receiving ranibizumab alone (19.4%) or ranibizumab plus laser (13.7%) than in those receiving laser alone (2.2%).

Between months 3 and 11 (i.e., following the three monthly injections), patients in the ranibizumab-only and ranibizumab plus laser arms received a mean of 4.1 and 3.8 ranibizumab injections, respectively; those in the laser-only arm received a mean of 4.5 sham injections.[38]

DRCR.net-1 trial,[2425] outcomes indicated that four monthly injections of ranibizumab 0.5 mg and then as needed combined with prompt or deferred laser was more effective than prompt laser alone in improving both functional and anatomical outcomes in patients with visual impairment associated with DME. The efficacy of ranibizumab plus prompt laser appeared to be similar to that of ranibizumab plus deferred laser (statistical comparisons not reported).[38] With regard to the primary endpoint, the mean gain in BCVA from baseline to month 12 was significantly greater in patients receiving ranibizumab plus prompts or deferred laser (P > 0.05 conversely, substantial losses in BCVA were reported by fewer patients receiving ranibizumab plus prompt or deferred laser, compared with patients receiving prompt laser alone. The improvement in BCVA in patients receiving ranibizumab plus prompt or deferred laser was seen at the first post-baseline assessment (month 1) and onwards. Most of the improvement in BCVA occurred by month 3, with continued improvement through month 12 and stabilization thereafter. The reduction in mean CRT from baseline to month 12 was significantly greater in patients receiving ranibizumab plus prompt laser (−131 mm) or ranibizumab plus deferred laser (−137 mm), compared with patients receiving prompt laser alone (−102 mm) (P > 0.001).

The 24-month results from this trial were generally consistent with the 12-month results; patients in the ranibizumab plus prompt laser and ranibizumab plus deferred laser groups received a median of 11 and 13 ranibizumab injections, respectively.[25]

In the DRCR.net-2 trial,[22] two monthly injections of intravitreal ranibizumab 0.5 mg and one IVT injection, was more effective than sham as an adjunctive therapy in patients simultaneously receiving focal/grid laser (laser) therapy for DME and panretinal photocoagulation for DR. In terms of the primary endpoint, ranibizumab and triamcinolone recipients had mean increases in BCVA of 1 and 2 ETDRS letters, respectively, between baseline and week 14, whereas sham recipients had a mean decrease in BCVA of 4 letters (P > 0.001, both comparisons). These results reflected both a greater proportion of patients with a gain of ± 10 letters (19% and 22%) and a lower proportion of patients with a loss of ± 10 letters (9% and 10%) in the ranibizumab and triamcinolone arms, respectively, compared with the sham arm (8% and 23% for gain and loss of ± 10 letters, respectively) (P > 0.01). Results for the primary and secondary functional outcomes that were examined were consistent across all subgroups of patients with DME that were examined. Most of the improvement in BCVA in patients receiving ranibizumab or triamcinolone had occurred by the time of the first post-baseline assessment (week 4), with stabilization through week 14. The improvement in functional outcomes was accompanied by an improvement in CRT. The reduction in mean CRT from baseline to week 14 was significantly greater in ranibizumab (−39 mm) and triamcinolone (−92 mm) recipients than in sham recipients (−5 mm) (P > 0.007). The ocular side effects reported in the previous studies were conjunctival hemorrhage, increased intraocular pressure, eye pain, vitreous floaters, vitreous hemorrhage, ocular hyperemia, blurred vision, cataract, endophthalmitis and retinal detachment. The reported non-ocular adverse events related to systemic VEGF inhibition were arterial thromboembolic events, hypertension, myocardial infarction and stroke.[16] Conclusion of the previous studies showed that ranibizumab added to laser therapy for DME was more effective than laser alone when assessed over a 1-year period in two well-designed studies (RESTORE and DRCR.net-1).

Although ranibizumab plus laser appeared to be no more effective than ranibizumab alone (RESTORE), a follow-up period < 1 year may be required to assess the benefits (if any) of combination therapy versus ranibizumab monotherapy; patients are continuing to be followed in this trial.

CONCLUSIONS

The management of DME remains complex and often multiple treatment approaches are needed to resolve the persistence of fluid within the macular region. Combination treatment plays an important role in the complex management of DME. Further study is needed; including multicenter randomized clinical trials, to establish the best treatment algorithm for DME.