Addressing the Real-World Gaps in Diabetic Macular Edema Care: Rahul Khurana, MD

Persistent vision loss in diabetic macular edema (DME) is being driven not only by biological complexity but also by systemic failures in how care is delivered and who receives the most effective therapies, according to Rahul Khurana, MD, partner and president/CEO of Northern California Retina Vitreous Associates and volunteer clinical associate professor in ophthalmology at the University of California, San Francisco.

Despite more than a decade of anti–vascular endothelial growth factor (VEGF) therapy, real-world patients are receiving fewer than half the injections documented in clinical trials, and insurance step therapy mandates are steering the sickest patients toward less potent agents. Meanwhile, at least 8 distinct non-VEGF pathogenic pathways remain unaddressed by current monotherapy approaches.

In an interview with The American Journal of Managed Care^® (AJMC^®), Khurana explored the clinical blind spots perpetuating vision loss, the socioeconomic forces shaping drug selection, and the biological complexity driving research toward combination and next-generation therapies.

This interview has been lightly edited for clarity.

AJMC: Diabetic macular edema has been treated with anti-VEGF therapy for over a decade, yet vision loss remains a significant problem in this population. What are clinicians getting wrong about how the disease progresses and who's most at risk of losing ground?

Khurana: Despite over a decade of anti-VEGF therapy for diabetic macular edema, vision loss persists due to several interconnected clinical blind spots. These include, first, real-world undertreatment; second, failure to address non-VEGF drivers of disease; third, inadequate systemic risk factor management; and finally, underappreciation of structural biomarkers that may predict disease resistance.

AJMC: Anti-VEGF agents dominate the treatment landscape, but the biology of DME involves more than VEGF alone. Where do those gaps in understanding create the biggest challenges for clinicians today?

Khurana: I think the biggest challenge created by an incomplete understanding of DME biology is that there are at least 8 other distinct pathogenic pathways that contribute to diabetic macular edema,¹ most of which are not addressed by current anti-VEGF monotherapy. That's why we see persistent edema in nearly 30% to 60% of patients treated with anti-VEGF therapy,¹ and there is a growing recognition that DME is fundamentally a neurovascular—not purely vascular—disease. Targeting these other non-VEGF pathways, given that we've not yet achieved optimal results in treating diabetic macular edema, is what I think will get us the best outcomes.

AJMC: When you look at how anti-VEGF therapy is being used in community practices versus academic centers, where do you see the biggest divergence and what's driving it?

Khurana: The biggest divergence between community practice and academic centers in DME management centers on injection frequency, drug selection driven by cost and insurance constraints, and the compounding effect of socioeconomic barriers that disproportionately affect community-based patients.

In clinical trial protocols, people get more injections than that in the real world, and if you follow a protocol in a clinical trial, patients are getting 7 to 8 injections in the first year. In the real world, outside of a clinical trial, patients are only getting 3 to 4 treatments, representing a huge injection difference there. The other reason is insurance constraints, such as step therapy. Commercial insurance companies mandating step therapy has led to a disproportionate use of bevacizumab in community settings driven by insurance step therapy mandates and cost considerations. We are using more bevacizumab in the community.

The challenge is that many of our patients in the community are not the patients that were in the clinical trials—these are the patients who are sicker, are unfortunately poorer, and have more constrained insurance that limits insurance costs. Essentially, we're using less-effective medicines on our sicker patients, which is opposite of what you want. You'd want to use more potent drugs on the patients who need them the most, but instead the opposite is occurring, and as a result, it leads to a further mismatch. There was even a study from a database that showed that patients with an income of greater than $150,000 were 3.2 times more likely to receive either aflibercept or ranibizumab rather than bevacizumab. The socioeconomic factors really create a 2-tiered treatment landscape in managing our patients there, and so that also shows some of the differences that occur.²

AJMC: Clinical trials for anti-VEGF agents have shown strong outcomes under intensive treatment protocols, but real-world data always tells a different story. What accounts for that gap, and how significant is it in terms of patient outcomes?

Khurana: The efficacy-effectiveness gap in anti-VEGF therapy for DME is substantial and well-documented. Clinical trials consistently produce visual acuity gains of 10 to 13 letters at 1 year, while real-world data from studies examining more than 40,000 eyes have shown a mean gain of only 4 letters—roughly one-third of the trial benefit.³

This divergence is really driven by a convergence of undertreatment, patient attrition, population differences, and long-term visual decline that the trials were not really designed to capture. The magnitude of this gap is really seen between Protocol T,⁴ where patients were gaining nearly 10 to 13 letters, and real-world analyzes, where patients are only gaining 4 letters. I think this is a very significant problem and why we're not seeing the great clinical trial results in clinical practice, reflecting a combination of undertreatment; patient attrition, including loss to adherence; and also population differences between patients who were recruited for clinical trials and patients who we actually treat and long-term visual decline, because many of these trials were stopped at 1 to 2 years.

AJMC: Speaking of the patient population, how does the inclusion criteria for trials compare with the real patient population? Is the inclusion criteria too restrictive?

Khurana: They're very different. Clinical trial populations are very selective, and they exclude patients with recent anti-VEGF therapy, recent stroke, uncontrolled hypertension, or significant renal disease. In the real world, or in clinical practice, patients are often older, have more comorbidities, and present with more advanced disease. We're already taking a different patient population, and that leads to population differences that can play a role and may explain some of the differences that we see in clinical trials versus the real world.

The other factor we haven't yet addressed is treatment burden. In clinical trials, patients receive very intensive treatment regimens—in Protocol T, participants averaged nearly 8 to 10 treatments in the first year,⁴ while in real-world studies, patients are barely receiving 3 treatments. That undertreatment is probably the strongest driver of the gap between trial results and real-world outcomes.

AJMC: With ranibizumab, bevacizumab, aflibercept, and faricimab, clinicians now have several options in this class. How are most retina specialists making selection decisions, and where does clinical judgment most often override guideline guidance?

Khurana: Most retina specialists make anti-VEGF selection decisions based on a pragmatic integration of baseline visual acuity, insurance and cost constraints, anticipated treatment burden, and lens status, rather than following a single guideline algorithm.

The biggest driver is our insurance/cost constraints, with many commercial insurances mandating step therapy with bevacizumab, so there's not even a choice. We have strong data from Protocol T showing that patients who present with visual acuity of 20/50 or worse may do better with aflibercept. Even in Protocol AC, which evaluated initiating treatment with bevacizumab, nearly 70% of patients had to be converted to aflibercept.⁵

In practice, for patients presenting with worse visual acuity, we tend to favor more potent agents such as aflibercept or faricimab—though insurance constraints often dictate which agent we use. Finally, lens status can play a role in whether we consider corticosteroids, which are not anti-VEGF agents but may serve as a secondary treatment option.

References

1. Zhang J, Zhang J, Zhang C, et al. Diabetic macular edema: current understanding, molecular mechanisms and therapeutic implications. Cells. 2022;11(21):3362. doi:10.3390/cells11213362

2. Ko MY, Talebi R, Yu F, Tseng VL, Coleman AL, Hosseini H. Socioeconomic disparities in intravitreal injection use and anti-VEGF agent selection: aflibercept/ranibizumab versus bevacizumab. Clin Ther. 2025;47(8):559-565. doi:10.1016/j.clinthera.2025.04.010

3. Mehta H, Nguyen V, Barthelmes D, et al. Outcomes of over 40,000 eyes treated for diabetic macula edema in routine clinical practice: a systematic review and meta-analysis. Adv Ther. 2022;39(12):5376-5390. doi:10.1007/s12325-022-02326-8

4. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193-203. doi:10.1056/NEJMoa1414264

5. Grewal DS, Leung E, Busquets M, et al; for the ASRS Health Economics Committee. Bevacizumab first in DRCR Protocol AC vs real-world physician treatment choice for diabetic macular edema: two-year cost analysis. J Vitreoretin Dis. 2024;8(6):658-663. doi:10.1177/24741264241275283