Short-term efficacy and safety of intravitreal brolucizumab in diabetic macular edema: A retrospective interventional study

Abstract

OBJECTIVES:

This study aims to evaluate the efficacy and safety of intravitreal brolucizumab (IVBr), a novel antivascular endothelial growth factor agent, in the treatment of diabetic macular edema (DME) by assessing both functional (visual) and structural (anatomical) improvements.

MATERIALS AND METHODS:

A retrospective, interventional study was conducted at the ophthalmology outpatient department of Sultan Qaboos University Hospital at University Medical City. A cohort of twenty patients (60 injections) with DME received three IVBr injections (6 mg/0.05 mL) over 18 weeks. This cohort consists of 10 male and 10 female patients, with a mean age of 57.1 years (range: 35–81; standard deviation [SD] 14.37). The best-corrected visual acuity (BCVA) was measured and recorded in equivalent logMAR. The subfoveal macular thickness (SFMT) was assessed with optical coherence tomography. Statistical analysis was carried out using paired t-test, and 95% confidence intervals were calculated to compare changes in outcomes, with a significance threshold set at P < 0.05.

RESULTS:

The BCVA improved significantly from a baseline mean of logMar 0.36 (SD 0.7) to 0.22 (SD 0.5) after the third injection (P < 0.002). SFMT decreased from a mean of 517.75 μm (SD 160.27) to 287.95 μm (SD 101.31), P < 0.001. One patient developed intraocular inflammation, and no other major complications were observed. However, 35% of patients (n = 7) experienced inadequate visual improvement, attributed to underlying factors such as macular ischemia, retinal layer disorganization, disruption of the ellipsoid zone, and residual macular edema.

CONCLUSION:

The study findings in this cohort demonstrated statistically significant improvement in BCVA and a substantial decrease in SFMT. However, more real-world studies are required to enhance the validation of this study’s findings.

Introduction

Diabetes mellitus (DM) is a chronic metabolic disease characterized by persistently elevated blood sugar levels. According to the 2021 International Diabetes Federation Diabetes Atlas, the global prevalence of diabetes is estimated to affect 537 million adults, with projections indicating an increase to 643 million by 2030.[1] The prevalence of DM in Oman is reported to be 11.8%.[1] Approximately 5.5% of diabetic patients develop diabetic macular edema (DME) at any stage, making it a leading cause of significant visual impairment.[2,3]

The pathogenesis of DME involves a combination of vascular endothelial growth factor (VEGF) and several other inflammatory mediators, including cytokines, tumor necrosis factor, and interleukins, which are upregulated in a hyperglycemic state. These mediators disrupt the integrity of the inner blood–retinal barrier, causing increased permeability in retinal capillaries, ultimately leading to the accumulation of fluid and DME.[4]

Currently, intravitreal anti-VEGF agents are considered as “gold standard” first-line therapy for DME, as they improve both visual function and macular structure.[5] However, these anti-VEGF injections are expensive, and DME tends to recur, requiring frequent treatments. These lead to a financial burden for patients, reimbursing agencies, and healthcare services, particularly in refractory cases that may necessitate a switch to alternative treatments.[6] A more efficacious agent with a longer duration of action could potentially reduce the number of injections and visits required.

Brolucizumab (Beovu, Novartis, Basel, Switzerland) is a next-generation anti-VEGF agent that was approved by the US Food and Drug Administration in 2022 for the treatment of DME. It is a humanized single-chain variable fragment antibody with a high affinity for VEGF, offering a higher concentration in the vitreous. Its low molecular weight (26 kDa) facilitates deep penetration into retinal tissues, and its prolonged duration of action effectively inhibits the disease process.[7,8] The rationale of this study is to share real-world data about intravitreal brolucizumab (IVBr) in the management of DME within our clinical settings.

Materials and Methods

This retrospective, interventional study was conducted at the ophthalmology outpatient department of Sultan Qaboos University Hospital at University Medical City. The approval was obtained from the Institutional Ethical Committee (SQU-EC/182/2024 MREC # 3368) and the study adhered to the tenets of the Declaration of Helsinki. The data were collected from electronic patients’ records and demographic data, as shown in Table 1. A total 20 adult patients with central involving DME (regardless of type 1 or type 2 diabetes) were included in the study. Patients with other maculopathies other than DME, such as age-related macular degeneration, macular edema secondary to uveitis, or retinal vasculitis, were excluded.

Table 1.

Patient’s demographic and baseline data and variables at a glance (Referenced in Materials and Methods)

Variables	Data, n (%)
Age (years)
Minimum	35
Maximum	81
Mean±SD	57.10±14.37
Gender
Male	10 (50)
Female	10 (50)
Diabetes type
Type 1	1 (5)
Type 2	19 (95)
Naïve	12 (60)
Nonnaïve	8 (40)
Laterality
Right eye	9 (45)
Left eye	11 (55)
BCVA baseline LogMar
Minimum	0.92
Maximum	0.10
Mean	0.40
SFMT baseline (μm)
Minimum	851
Maximum	304
Mean±SD	517.75±160.27

BCVA: Best-corrected visual acuity, SFMT: Sub-foveal macular thickness, SD: Standard deviation

Before initiating treatment, all participants underwent a comprehensive ophthalmological examination, including best-corrected visual acuity (BCVA) measured with a digital Snellen chart and recorded in decimals, which was later on converted to logMAR for analysis and comparison with published trials. In addition, intraocular pressure was measured; slit-lamp biomicroscopy, Zeiss spectral domain–optical coherence tomography (OCT) for central macular thickness measurement, and OCT-angiography was performed in selected cases to detect macular ischemia.

The patients received a series of three intravitreal injections of 6 mg/0.05 mL brolucizumab, administered at 6-week intervals, followed by a pro re nata regimen. The main outcome measures were BCVA and anatomical improvement in subfoveal macular thickness (SFMT). Safety outcomes were also monitored for adverse events. The data were analyzed using Statistical Package for Social Sciences (SPSS) version 27 (International Business Machines Corporation (IBM), Armonk, New York, USA) software. The continuous variables are described as mean ± SD, and categorical variables are expressed as percentages. Paired t-test and 95% confidence intervals were used to compare outcomes after each injection to baseline values, with a significance level set at P < 0.05.

In this study, visual acuity was measured using the traditional digital Snellen projector, which is routinely used in our clinical practice. However, conventional Snellen charts are not standardized for research purposes due to the irregular progression of letter sizes and the varying number of characters per line. To address this limitation, the measured values in decimals were converted to equivalent LogMar calculated by applying the standard conversion formula: Log (MAR) = log (1/V) = −log (Value).

Results

This study retrospectively analyzed data from 20 patients (60 Injections) diagnosed with central-involved DME. Among these, 12 patients (60%) were naïve, while the remaining 8 (40%) were nonnaïve who had received prior treatment. The cohort included an equal distribution of male and female patients (10 each), with a mean age of 57.1 years (range: 35–81 years). At baseline, the mean BCVA was recorded LogMAR value of 0.36 (SD 0.67).

Following course of three intravitreal anti-VEGF (brolucizumab 6 mg/0.05 mL) injections, BCVA improvement was noted after the first and third injections, whereas some reduction of vision was recorded after the second injection. The mean BCVA after the first injection (week 6) improved from baseline 0.36 to 0.23 (SD 0.28), however this change was statistically not significant (P = 0.245). By the second injection (week 12), BCVA mean LogMar 0.26 (SD 0.52) with P = 0.150. After the third injection (week 18), the mean BCVA statistically improved to 0.22 (SD 0.50). Figure 1 demonstrates the changes in BCVA from baseline to subsequent injections. Overall, the mean improvement in BCVA from baseline to the third injection was −0.16 (SD 0.20), equivalent to a 10-letter gain (P < 0.002). However, 35% of patients (n = 7) exhibited poor or inadequate visual improvement, attributed to various underlying factors such as residual macular edema, preexisting macular ischemia, retinal layer disorganization, and disruption of the ellipsoid zone.

Figure 1.

Mean best-corrected visual acuity (BCVA) outcome value (n = 20 subjects) compared to baseline. The yellow bar showing the mean baseline BCVA, and the blue bars reflect postinjection outcome (Referenced in Results). BCVA: Best-corrected visual acuity

Assessment of SFMT revealed a considerable reduction with subsequent treatment, as shown in Figure 2. The baseline SFMT was 517.75 μm (SD 160.27). There was severe pretreatment DME [Figure 3]. Macular edema significantly decreased with the course of injections. After the first injection, SFMT reduced to 386.90 μm (SD 161.81), reflecting a mean reduction of 128.85 μm (P < 0.001). By the second injection, SFMT further declined to 287.85 μm (SD 86.65), P < 0.001. Following the third injection, the final SFMT remained stable at 287.95 μm (SD 101.31), with a mean reduction of 227.80 μm (P < 0.001). Notably, a dry macula, as shown in Figure 4, was achieved in 65% of patients. Whereas 20% (n = 4) patients required additional treatment, and 15% (n = 3) patients with mild residual macular edema were kept under observation.

Figure 2.

Mean optical coherence tomography measurements across treatment time points (n = 20 subjects). Yellow bar showing the mean baseline subfoveal thickness and blue bars showing postinjection outcome (Referenced in Results). OCT: Optical coherence tomography

Figure 3.

Left eye macula optical coherence tomography of study patient showing diffuse diabetic macular edema with intraretinal fluid (Indicated with red arrow) and subretinal fluid (Indicated with yellow arrow). The thickness map (circle) showing massive edema. Pretreatment best-corrected visual acuity 0.50 (Referenced in results)

Figure 4.

Left eye macula optical coherence tomography of the same patient in Figure 3 showing remarkable resolution of sub-retinal fluid and intra-retinal fluid after three intravitreal brolucizumab injections. The thickness map (circle) showing normal sub-foveal thickness. Posttreatment best-corrected visual acuity was LogMar 0.00 (Referenced in Results)

Regarding adverse events, one patient developed intraocular inflammation (IOI) in the form of anterior uveitis, which was effectively managed with topical corticosteroids. No cases of vasculitis, retinal vascular occlusion, or any other major complications were observed.

Discussion

In our study, the results demonstrated a statistically significant improvement in BCVA in both naïve and nonnaïve DME patients. The BCVA outcomes are highly comparable to the results of two randomized, double-masked, multicenter phase III trials KESTREL and KITE, in which visual improvement was reported by 9.2 and 10.6 letters, respectively. These studies also concluded that brolucizumab was functionally noninferior to aflibercept.[7] In a prospective study from Germany, Rübsam et al. observed a statistically significant visual improvement (+0.12 LogMar, +6.4 letters, P = 0.03) in both naïve and nonnaïve DME cases.[8] Similarly, a double-masked randomized clinical trial by Singh et al. reported an improvement of 12.2 letters,[9] and Hashem Abu Serhan et al. also highlighted significant improvement in BCVA from baseline to final outcome in their meta-analysis.[10]

In this clinical study, a significant reduction in SFMT was observed after the first IVBr injection, with further resolution of macular edema noticed following the third injection.

Furthermore, Brown et al. reported a rapid reduction in macular thickness after the first injection in their phase III trial and achieved a central subfoveal thickness (CSFT) of <280 μm at week 32, with mean differences of −171.9 μm in the KESTREL study and −197 μm in the KITE study.[7] The variation in macular thickness improvements among studies could be due to differences in sample sizes, baseline CSFT, and the time points at which the analysis was performed. In our study, the mean difference in SFMT (−227.80 μm) was higher, correlating with the higher baseline mean SFMT of 517.75 μm. The Kingfisher study also reported a mean reduction of 237.8 μm in subfoveal thickness in the brolucizumab group, which is similar to our SFMT results.[9] In the meta-analysis by Abu Serhan et al., most studies of brolucizumab in DME also showed a significant reduction in macular edema.[10] In our study, overall dry macula was achieved in 65% of patients. Whereas the remaining 35% of patients required additional treatment and observation. Pastore MR et al. reported very similar results of dry macula in 64.3% of patients.[11]

The safety profile of brolucizumab, as reported in the literature, has shown some variability. In this study, no cases of vasculitis, retinal vascular occlusion, or any other major complications were observed. Only one patient developed moderate IOI, which was limited to anterior uveitis that completely resolved with topical corticosteroids. Some usual adverse effects, such as subconjunctival hemorrhage, mild eye pain, and transient conjunctival congestion, were observed; however, these side effects are similar to those associated with other intravitreal anti-VEGF injections. In the KESTREL trial, mild-to-moderate IOI occurred in 4.7% of patients receiving 3 mg brolucizumab and in 3.7% of those receiving 6 mg. A lower incidence of IOI (1.7%) was reported in the KITE trial.[7] Rübsam et al. in their study did not observe any major side effects with IVBr.[8] Singh et al. reported IOI in 4%, retinal vasculitis in 0.9%, and vascular occlusion 0.3% in brolucizumab-treated patients.[9] A meta-analysis highlighted that IOI is more commonly associated with the 3 mg dose of brolucizumab, particularly in cases of neovascular age-related macular degeneration.[10] Mishra et al. demonstrated a statistically insignificant difference in adverse effects in their comparative study of brolucizumab 6 mg with 3.6 mg.[12] Whereas, Chakraborty et al. did not report any ocular or systemic side effects of brolucizumab in DME patients.[13] KESTREL and KITE in phase III of 100-week studies observed similar adverse events with both brolucizumab and aflibercept anti-VEGFs.[14] Elhamaky has not reported brolucizumab-related ocular complications.[15]

This study specifically aims to evaluate short-term outcomes. Nevertheless, we realize that a short follow-up period limits the assessment of long-term efficacy and the detection of delayed adverse events. We also acknowledge that the small sample size of our study has limitations, affecting both statistical power and the generalizability of the findings. The analysis was performed separately for the three different time periods in comparison to the baseline by the paired t-test. Hence, Bonferroni correction was not applied.

Conclusion

This retrospective interventional study revealed favorable outcomes within a relatively short follow-up period. The study findings demonstrated statistically significant improvement in BCVA and a substantial decrease in SFMT. The overall outcomes of this study are consistent with findings from published literature. However, more real-world studies are required to enhance the validation of the present study findings, and further clinical trials may strengthen confidence among clinicians regarding the efficacy and safety of brolucizumab.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.