Comparison of Efficacy of Suprachoroidal Triamcinolone Acetonide Alone or in Combination With Intravitreal Bevacizumab for Treatment of Diabetic Macular Edema: A Prospective Comparative Study

ABSTRACT

Background and Aims

This study was designed to evaluate the safety, efficacy, and durability of suprachoroidal triamcinolone acetonide, administered either alone or in combination with intravitreal bevacizumab (IVB), in the treatment of diabetic macular edema (DME).

Methods

This prospective comparative interventional study was conducted in the Ophthalmology Department at Mayo Hospital, Lahore, from May 2020 to March 2021. Sixty patients with DME were enrolled after obtaining informed consent. Baseline assessments included best‐corrected visual acuity (BCVA), intraocular pressure (IOP), a detailed fundus examination, and spectral‐domain optical coherence tomography (SD‐OCT) for measurement of central subfield thickness (CST). Participants were allocated into two groups. One group received a combination of 4 mg suprachoroidal triamcinolone acetonide and intravitreal bevacizumab, while the second group received 4 mg suprachoroidal triamcinolone acetonide alone. Patients were followed clinically and anatomically to assess treatment outcomes.

Results

Both groups demonstrated statistically significant reductions in CST from baseline (p < 0.05). However, patients receiving combination therapy showed a greater reduction in CST and superior improvement in visual acuity compared to those receiving triamcinolone alone. At 3 months, CST and IOP decreased in both groups, with greater reductions in the combination group. The between‐group differences were significant for both CST (p < 0.001) and IOP (p = 0.032). No major safety concerns or treatment‐related complications were observed during the study period.

Conclusion

Suprachoroidal administration of 4 mg triamcinolone acetonide combined with intravitreal bevacizumab is more effective than triamcinolone monotherapy in reducing central subfield thickness and improving visual acuity in patients with DME. The combination approach provides superior anatomical and functional outcomes, suggesting a synergistic therapeutic effect and representing a promising treatment strategy for DME.

1. Introduction

Diabetes mellitus is among the most widespread systemic metabolic disorders worldwide. Diabetic retinopathy (DR), a microvascular complication of diabetes, remains a common cause of visual impairment in the working‐age population. The global burden of DR is projected to rise substantially, increasing from approximately 103 million individuals in 2020 to 160.5 million by 2045. Diabetic macular edema (DME), a key vision‐threatening manifestation of DR, is characterized by accumulation of retinal fluid and progressive central visual loss during the course of the disease [1].

In both developed and developing nations, it is the primary cause of blindness in the working‐age group. One of the primary reasons for reduced vision in DR patients is DME [2]. DME is a prominent consequence of diabetes mellitus, posing a major global health concern. DME is defined as thickening of the retina caused by aberrant buildup of fluid at the macula [3].

High HbA1c levels, diabetes duration, excessive diuretic use, hypertension, obesity, hyperlipidemia, cardiovascular problems, and proteinuria are among the systemic risk factors for DME. There is no data supporting a complete definition of DME pathogenesis. However, the literature has attributed this multifaceted process to several interacting mechanisms, including hypercholesterolemia, accumulation of advanced glycation end products, oxidative stress, persistent hyperglycemia, and protein kinase C activation. DME is managed using laser therapy, anti‐VEGF therapies, intravitreal steroids, and pars plana vitrectomy [4].

DME has also been managed with intravitreal steroid injections (IVIs). Corticosteroids exert anti‐inflammatory, anti‐permeability, and angiostatic effects, which contribute to their therapeutic benefit. These effects are also associated with downregulation of VEGF expression. In addition, both a slow‐release biodegradable dexamethasone implant and a long‐acting non‐biodegradable fluocinolone acetonide implant is approved for DME treatment, potentially reducing treatment burden [2].

Patients with naïve or de novo DME typically require at least four consecutive intravitreal anti‐VEGF treatments at 4‐week intervals, which can be costly. Ziv‐Aflibercept, initially used in oncology situations (FDA approved since 2012), has discovered a new way to address ocular difficulties, particularly in areas where the ophthalmic form of aflibercept (Eylea) is still prohibitively expensive. Regeneron Pharmaceuticals' modification of Ziv‐Aflibercept, known as Zaltrap, has passed thorough testing to demonstrate its non‐toxicity as well as its efficacy and safety in treating DME [5].

This selective approach lessens systemic adverse effects while possibly boosting DME control effectiveness. By decreasing vascular leakage, inhibiting vascular endothelial growth factor, increasing retinal blood vessel vasoconstriction, and decreasing blood‐retinal barrier breakdown, intravitreal triamcinolone effectively treats DME. Although intravitreal triamcinolone injection is a great treatment for DME, it can also result in glaucoma and cataracts [6].

When compared with other therapeutic options, intravitreal combined therapy with bevacizumab (IVB) and triamcinolone acetonide (TA) has been reported as the most effective in reducing central macular thickness and improving best‐corrected visual acuity over a 3‐month follow‐up period. Over a longer follow‐up of 6 months, intravitreal dexamethasone (DEX) injection demonstrated superior efficacy in decreasing central macular edema and to improve best‐corrected visual acuity, particularly in patients with severe edema and reduced baseline visual acuity [7].

Currently, refractory diabetic macular edema represents the primary indication for TA, either as monotherapy or combined with laser treatment. Following a loading phase, suboptimal response is typically defined as an increase of ≤ 5 ETDRS letters in best‐corrected visual acuity (BCVA) or a reduction of ≤ 20% in central macular thickness (CMT), particularly in pseudophakic eyes [8].

Studies have looked at the pharmacologic properties of the suprachoroidal space to transfer pharmacological medicines, especially TA, to the eye. It was found that this procedure significantly increased the medicine concentration in the choroid and outer retina compared to typical intravitreal injections. It was also discovered that the reduced drug exposure to anterior segment structures caused by injecting suprachoroidal (TA) decreased the major steroidal side effects, including cataract and elevated intraocular pressure (IOP). Consequently, it appeared that this mode of administration simplified [9]. For macular edema resulting from vein occlusion, the Tanizite study found that the combination group (IV aflibercept and SCTA) had greater mean improvements from baseline BCVA, CMT, and the percentage of patients who did not require re‐treatments than the IV aflibercept monotherapy group [10].

2. Methodology

This prospective comparative interventional study was conducted at the ophthalmology department from May 2020 to March 2021. Visual acuity was taken on Snellen chart and best corrected was done and visual acuity was converted into log Mar Chart.

The patient's intraocular pressure was taken, then dilated with tropicamide, which was instilled 3 times every 10 min. Slit lamp with 90 D lens and fundus examination were performed to rule out diabetic retinopathy and DME, and thickness by Optical Coherence Tomography.

This study received approval from the ethical review board of the College of Ophthalmology and Allied Vision Sciences/King Edward Medical University Lahore (COAVS/341/2020) and followed the principles of the Declaration of Helsinki. Informed consent was obtained from all participants. Patients were prospectively enrolled and divided into two treatment groups, with 30 patients assigned to each group. The required sample size was calculated based on the expected difference in BCVA between the two treatment groups, using an effect estimate derived from a previously published study of suprachoroidal triamcinolone acetonide in diabetic macular edema [9]. Based on a two‐sided significance level of 5%, a statistical power of 80%, and equal allocation between the two treatment groups, the calculated sample size was 30 patients per group. Therefore, 60 patients were included in the present study, with 30 patients receiving suprachoroidal triamcinolone acetonide in combination with intravitreal bevacizumab and 30 patients receiving suprachoroidal triamcinolone acetonide alone.

Patients with DME underwent preoperative spectral‐domain optical coherence tomography (SD‐OCT), and central subfield thickness (CST) was measured. The study included type I and type II diabetic patients aged 25–75 years, both male and female, with intraocular pressure (IOP) below 25 mmHg, no prior laser therapy, intravitreal corticosteroid therapy, pars plana vitrectomy, or panretinal photocoagulation, and no previous history of glaucoma. Patients were excluded if they had received prior intravitreal or periocular steroid injections at any time, had a history of vitreoretinal surgery, had IOP greater than 25 mmHg, or had a history of penetrating ocular trauma. One group received suprachoroidal triamcinolone acetonide administered via microneedle under indirect ophthalmoscopic guidance with topical anesthesia. BCVA and CST were recorded at baseline, with follow‐up assessments conducted at 3 months post‐treatment. The investigators responsible for assessing BCVA and CST were masked to the treatment allocation. OCT measurements were performed by an assessor who was unaware of the treatment group, and BCVA was assessed independently without knowledge of treatment assignment.

Statistical analyses were conducted using IBM SPSS Statistics for Windows, version 25.0 (IBM Corp., Armonk, NY, USA) [11]. Continuous variables were expressed as means with standard deviations (SDs), whereas categorical variables were reported as frequencies and percentages. BCVA was converted to the logarithm of the minimum angle of resolution (logMAR) values, where applicable. CST and intraocular pressure (IOP) were also analyzed as continuous variables.

For within‐group comparisons of continuous variables measured at baseline and during follow‐up, the paired sample t‐test/McNemar–Bowker was utilized to assess changes from baseline. Statistical significance was defined as a two‐sided p value below 0.05. All tests were two‐sided unless otherwise specified. The analyses were conducted according to the predefined study objectives of comparing changes in visual acuity, CST, and IOP following treatment. No separate subgroup analyses were prespecified or performed. Results are reported with corresponding p values, with a value less than 0.05 considered statistically significant.

3. Results

Among the 30 participants in each treatment group, the mean age was 43.60 ± 16.59 years in the triamcinolone acetonide group and 47.74 ± 17.60 years in the combination therapy group (triamcinolone acetonide + intravitreal bevacizumab). A total of 40 patients (66.6%) were male, and 20 (33.3%) were female. The right eye was treated in 60.2% of cases, while the left eye was treated in 39.8%. CST and IOP were recorded both pre‐ and post‐treatment (see Table 1). No epiretinal membranes were observed in any of the cases. Elevated IOP (greater than 20 mmHg) was noted in 9 eyes (16.3%).

Table 1.

The comparison of pre‐ and post‐central subfield thickness (CST) and intraocular pressure (IP) examination after injection on suprachoroidal space on diabetic macular edema (DME) patients.

Findings		Patients treated with 4 mg triamcinolone acetonide + intravitreal bevacizumab	Patients treated with 4 mg triamcinolone acetonide alone	p value
Pair 1	Central subfield thickness (pre‐examination)	470.8 ± 70.3	468.5 ± 70.3	0.00
	Central subfield thickness (post‐examination)	267.6 ± 49.4	342.2 ± 63.7
Pair 2	Intraocular pressure (pre‐examination)	21.1 ± 1.5	21.8 ± 1.5	0.01
	Intraocular pressure (post‐examination)	15.4 ± 2.6	19.9 ± 3.0

Note: Data are presented as mean ± SD. The reported p values represent within‐group comparisons between pre‐treatment and post‐treatment measurements. A paired‐samples t‐test was used to assess changes in CST and IOP from baseline to post‐treatment, with p < 0.05 considered statistically significant.

The baseline best‐corrected visual acuity enhanced in conjugated treatment in 6/18 and 6/36 compared to those patients who underwent treatment with only suprachoroidal triamcinolone alone. The comparison of the standard visual acuity (VA) showed an increased percentage (63.6%) in post‐examination after 4 mg triamcinolone acetonide + intravitreal Bevacizumab treatment, compared to 9.4% found as normal visual acuity in patients treated with triamcinolone alone (Tables 2 and 3). At 3 months, CST and IOP decreased in both groups, with greater reductions in the combination group. The between‐group differences were significant for both CST (p < 0.001) and IOP (p = 0.032) (Table 4).

Table 2.

The comparison of pre and post‐visual acuity (VA) and best‐corrected visual acuity (BCVA) examination in DME patients treated with 4 mg triamcinolone acetonide + intravitreal bevacizumab.

Findings	Pre examination	Post examination	p value
Visual acuity	n (%)	n (%)
Normal	0	19 (63.3)	0.02*
Visual impairment	19 (63.3)	11 (36.7)	0.273
Severe visual impairment	11 (36.7)	0	0.001*
Best corrected visual acuity
6/6	0	2 (6.7)	0.001*
6/9	0	5 (16.7)	0.001*
6/12	0	6 (20.0)	0.003*
6/18	18 (60.0)	5 (16.7)	0.001*
6/24	2 (6.7)	9 (30.0)	0.068*
6/36	10 (33.3)	3 (10.0)	0.00*
6/60	0	0	0.00*

Note: Data are presented as frequency (percentage). The McNemar–Bowker test was used for the level of significance.

^* p < 0.05.

Table 3.

The comparison of pre‐ and post‐visual acuity (VA) and best‐corrected visual acuity (BCVA) examination in DME patients treated with 4 mg triamcinolone acetonide alone.

Findings	Pre examination	Post examination	p value
Visual acuity	n (%)	n (%)
Normal	0	3 (10.0)	0.00*
Visual impairment	19 (63.3)	27 (90.0)	0.14
Severe visual impairment	11 (36.7)	0	0.02*
Best corrected visual acuity
6/6	0	0	NA
6/9	0	1 (3.3)	0.001*
6/12	0	4 (13.3)	0.001*
6/18	10 (33.3)	7 (23.3)	0.15
6/24	20 (66.7)	8 (26.7)	0.011*
6/36	0	10 (33.3)	0.144
6/60	0	0	0.273

Note: Data are presented as frequency (percentage). McNemar–Bowker test was used for the level of significance.

^* p < 0.05.

Table 4.

Comparison of anatomical and functional outcomes at 3‐month follow‐up.

Outcome	4 mg TA + intravitreal bevacizumab (n = 30)	4 mg TA alone (n = 30)	Between‐group p value
Central subfield thickness (µm)	267.6 ± 49.4	342.2 ± 63.7	< 0.001*
Change in CST from baseline (µm)	−203.2 ± 58.6	−126.3 ± 61.4	< 0.001*
IOP (mmHg)	15.4 ± 2.6	19.9 ± 3.0	< 0.032*
Change in IOP from baseline (mmHg)	−5.7 ± 2.5	−1.9 ± 2.8	< 0.032*

Note: Data are presented as mean ± SD. Between‐group comparisons were performed using an independent‐samples t‐test. *p‐value < 0.05 was considered statistically significant.

4. Discussion

In this study, the most notable clinical improvement was observed in visual acuity, with both treatment groups demonstrating improvement following intervention. Our study population consisted of patients with treatment‐naïve diabetic macular edema based on the absence of previous laser therapy, intravitreal corticosteroid treatment, pars plana vitrectomy, or pan‐retinal photocoagulation. Therefore, the findings should be interpreted specifically within this treatment‐naïve population.

Previous studies have also reported beneficial outcomes with these treatment approaches. Anwar et al. reported efficacy rates of 29.5% in the intravitreal bevacizumab group and 37.5% in the triamcinolone acetonide group (p = 0.03), while safety was reported in 47.1% and 45.6% of patients, respectively (p = 0.746). These findings were derived from their study population and do not represent the present cohort [12].

Similarly, another study included 71 eyes from 59 patients with DME, divided into two groups of 34 and 37 patients. Both groups demonstrated significant improvements in thickness of macula and visual acuity, particularly at the 3‐month follow‐up, with suprachoroidal triamcinolone demonstrating a relatively stable response and fewer complications [6].

Cheng et al. reported that patients with severe macular edema and poor baseline visual acuity showed greater benefit from dexamethasone implants over a 6‐month period. They also reported improvements in BCVA and reductions in central macular thickness with intravitreal bevacizumab combined with triamcinolone acetonide over 3 months [7].

Marashi et al. reported findings from a separate cohort of 10 eyes from 6 patients treated with intravitreal ziv‐aflibercept combined with suprachoroidal triamcinolone acetonide. In that study, mean visual acuity improved, while central macular thickness decreased at 24 weeks [5].

Another study with 40 patients monitored for 3 months, 18 (45%) were male, and 22 (55%) were female. The pre‐injection CST was 612.89 ± 195.58 μm, with a mean logMAR BCVA of 0.90 ± 0.22. One month post‐injection, the CST dropped to 308.59 ± 56.75 μm, and at 3 months to 304.89 ± 54.29 μm. BCVA improved to 0.51 ± 0.30 and 0.36 ± 0.20 at 1 and 3 months. All changes in CST were statistically significant (p < 0.00001) [13].

Lin et al. conducted a 6‐month multicenter study comparing intravitreal aflibercept alone versus combined with a dexamethasone implant. They found that the combination therapy was not inferior to monotherapy and provided a longer treatment interval with better outcomes in pseudophakic patients [14].

Zakaria et al. evaluated the use of intravitreal versus suprachoroidal triamcinolone in a randomized controlled study involving 45 eyes. They concluded that the suprachoroidal route is as safe and effective as the intravitreal route, with potentially longer‐lasting improvements in CMT and BCVA [2].

Yousef et al. also confirmed the benefit of suprachoroidal triamcinolone in DME treatment [15]. In another study, the efficacy of suprachoroidal triamcinolone injected every 8 weeks versus 16 weeks was assessed. Eyes receiving 8‐week intervals showed a greater reduction in CMT from 456 to 309 μm by 6 weeks post‐injection, though it increased slightly to 384 μm by Week 8. A second injection reduced CMT to 330 μm, and BCVA improved from 20/125 to 20/40 in 16 weeks. In contrast, 58% of eyes required only one injection in 4 months, with BCVA improving from 20/80 to 20/50 [5].

During the 3‐month follow‐up, IVB + TA therapy yielded the most notable improvements in BCVA and central macular edema compared to other interventions. Over a 6‐month period, DEX injections were most effective in patients with severe macular edema [7].

In a comparative study, Group 2 (combination therapy) required fewer injections (2.47 ± 1.2) as compared to Group 1 (4.4 ± 1.5). Both groups showed significant improvements in CMT (p < 0.001) and BCVA (p < 0.001) at 12 months. Group 2 showed greater BCVA improvement at 6 and 12 months [16].

Another investigation included 12 eyes from 12 patients (50% male), with a median age of 58 years and a median diabetes duration of 13 years. Most participants (83.3%) were phakic. The median pre‐operative BCVA was 0.07, CMT was 544 μm, and IOP was 17 mmHg. At 12‐month follow‐up, BCVA improved to 0.15 (p = 0.02), CMT decreased to 404 μm (p = 0.4), and IOP was 19.5 mmHg (p = 1). 20% of the phakic patients developed nuclear sclerosis [17].

In another study, the change in BCVA from baseline to month 6 was not statistically significant between active and control groups. However, the active group showed greater CST reduction. Fewer treatments were needed in the active group, and no serious treatment‐related adverse effects were noted. Cataract formation and elevated IOP were observed but were not attributed to the intervention [18].

Over 12 months, combination therapy (aflibercept + triamcinolone) consistently outperformed monotherapy in reducing CMT (p < 0.05 across all time points). However, no significant differences in visual acuity were observed. These findings suggest that while combination therapy improves anatomical outcomes in persistent DME, it does not confer additional visual acuity benefits compared to anti‐VEGF monotherapy [19].

5. Conclusion

In this treatment‐naïve population with DME, a single 4 mg suprachoroidal triamcinolone acetonide injection combined with intravitreal bevacizumab was associated with greater reductions in CST and greater improvement in BCVA than suprachoroidal triamcinolone acetonide alone. However, because the study did not directly compare combination therapy with intravitreal anti‐VEGF monotherapy, these findings should not be interpreted as evidence that combination therapy is superior to standard anti‐VEGF treatment for treatment‐naïve DME [20, 21]. Further randomized comparative studies are warranted to determine the role of suprachoroidal corticosteroid therapy as an adjunct to anti‐VEGF treatment, particularly in patients with inadequate response to anti‐VEGF therapy.

Author Contributions

Muhammad Tahir Ghaffar: literature search and manuscript preparation. Asad Aslam Khan: manuscript review and final editing. Mohammad Hasan Bokhari: conceptualization, study design, data acquisition, statistical analysis, and manuscript review. Tahseen Mahmood Majhu: manuscript review. Faisal Anwar: data acquisition and manuscript review. Chaudhry Nasir Ahmed: final editing and manuscript review. Aalaa Saleh: manuscript review, scientific editing, correspondence, and supervision of publication process.

Funding

The authors have nothing to report.

Ethics Statement

The study was approved by the Ethical Review Committee of the College of Ophthalmology and Allied Vision Sciences, King Edward Medical University, Lahore, Pakistan (Approval No. COAVS/341/2020). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki.

Consent

Written and informed consent was obtained from all patients prior to enrollment.

Conflicts of Interest

The authors declare no conflicts of interest.

Transparency Statement

The corresponding author (Aalaa Saleh) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

Data Availability Statement

The data underlying the findings of this study are not publicly accessible due to privacy and confidentiality considerations. De‐identified data may be obtained from the corresponding author upon reasonable request, subject to relevant ethical and institutional requirements.