Kevin Kunzmann

If the COVID-19 pandemic has caused a lost year of healthcare for chronic disease patients, as so many clinicians describe in their practice, then it may take even more years to understand the total effect of such significant lapses in care between the beginning and the eventual end of the distance-driving health crisis.

And some chronic diseases are less forgiving than others; that lost year may make all the difference. In the case of millions of US patients with 

Consider that about one-third of all adults aged ≥40 years old with diabetes suffer from at least 1 symptom of diabetic retinopathy (DR), and that about 5% of all diabetic patients may suffer severe vision loss. Now consider that, per the Centers for Disease Control and Prevention (CDC) last year, 

more than 34 million Americans have diabetes

, and another 88 million have prediabetes.

Couple all that with context: new diabetes cases significantly decreased from 2008-2018 among adults, yet significantly increased among pediatric and adolescent persons. And new cases are notably greater among non-Hispanic blacks and people of Hispanic origin than that of non-Hispanic Asians and non-Hispanic whites—a trend which shows that greater US diabetes burden is falling on groups with lesser healthcare access and treatment retention across other chronic conditions.

The average diabetes patient—of which there are 1 for every 10 people in America—is getting younger, and more distant from clinicians, at a time when a global pandemic has already done unprecedented harm to in-person care rates and screenings.

Katherine Talcott, MD, of the Cleveland Clinic’s Cole Eye Institute, explained to 

 the multitude of ways in which COVID-19 has harmed the patients of her ophthalmology practice.

“A lot of our patients with diabetes who had been coming in have been lost to follow-up in the last year, and they have a lot worse macular edema or their diabetes is worse,” 

An epidemic of its own right, diabetes is worsening in the US, and its comorbid effects bleeds into other specialties of care. As covered in a series of research topics and presentations at the 

Association of Research in Vision and Ophthalmology (ARVO) 2021 Virtual Meeting

 last week, there is a trend heading toward a greater convergence between diabetic and related ophthalmic care.

But what is that current dynamic? And how will it change to improve the state of a patient’s diabetes, and associated visual wellbeing?

Research from the CDC, presented at ARVO 2021 by Elizabeth Lundeen, PhD, MPH, of the Division of Diabetes Translation, showed visually-impaired persons from a 2018 national health survey were 48% more likely to have diabetes than the general population.

The findings, which also illustrated significant ties between cardiovascular-associated risk factors including smoking and visual impairment, came as little surprise to Lundeen, who noted the “strong correlation” between cardiovascular, cardiometabolic, and visual health. Previous CDC research even depicted a similar relationship between stroke, cardiovascular events, and visual impairment.

“Cardiovascular health and vision health show a lot of the same risk factors, actually,” 

. “For example, a well-known risk factor for glaucoma would be (high) blood pressure—which is also a risk factor for cardiovascular disease. And age-related macular degeneration shares a lot of risk factors with cardiovascular disease.”

In fact, all 7 targeted risk factors for cardiovascular disease—even when controlled for patient demographics—were more likely to present in visually-impaired patients: smoking; physical activity; excessive alcohol intake; obesity; hypertension; high cholesterol; as well as diabetes.

The correlation is not always consistent; in fact, new ARVO research even suggested that currently available ophthalmic therapies may benefit regardless of comorbid diabetes or cardiovascular risk factors.

Talcott reported her team’s assessment of 

 which observed patients’ diabetic macular edema (DME) resolution and time to resolution when treated with intravitreal aflibercept, with consideration to baseline factors including HbA1c, hypertension, hyperlipidemia, smoking status, and more.

What they found was that ophthalmic status factors, including baseline central subfield thickness (CST) and best-corrected visual acuity (BCVA), were more influential in DME patient likelihood and time to disease clearance with aflibercept than cardiovascular risk factors were.

In fact, to Talcott’s surprise, diabetes severity at baseline did not affect treatment-based DME clearance at all—despite it being the disease which leads to DME development in the first place.

“I think it’s interesting,” she said. “Some of the preconceptions we have as clinicians as to how individual patients might do, don’t necessarily pan out when you conduct these large studies.”

The surprise of the findings speaks to the nature of collaborative care among ophthalmologists and prescribers managing the same patients with diabetes and vision impairment—a partnership in the US health system which clinicians themselves agree is subpar.

The connection between cardiovascular and cardiometabolic risk factors in visually impaired persons is not just correlative; it’s been proven causative enough that experts like Allen Ho, MD, considers such factors in the itinerary of diabetic retinopathy (DR) care.

, is significantly impacted by diet, exercise, smoking status, blood pressure, and A1c levels.

“You can be seeing well and just drop off a cliff the next day,” Ho, director of Retina Research at the Wills Eye Hospital said. “If you don’t know your A1c, that’s a risk factor for vision loss right there. It’s like driving with your eyes closed, is what I tell (patients.”

That’s reason enough for improved communication between providers with mutual interest in those risk factors—at least communication from a better mindset. Ho described the current ophthalmology-diabetes specialist connection as something mandated, and possible punitive: missing eye exam referrals for newly-diagnosed diabetics can result in penalties to physicians.

Unfortunately for clinicians like Talcott, collaborative care usually bookends a patient’s diabetes status: referral and monitoring at the beginning of their diagnosis, then reactive response when comorbid disease like DME or DR is in full effect.

“I think that we all tend to, unfortunately, focus on our problems and forget about other parts of the body,” she said. “But when we see patients who have disease that’s out of control, that usually means their diabetes is not well-controlled in other reasons as well.”

A promising connector, it could be suggested, may be the advancement which both specialties may be most interested in: drug classes which treat diabetes, DME, DR, all the same.

Not only are researchers beginning to interpret the absolute value of already-established drug classes like anti-VEGF injections, which Talcott’s team showed in the case of aflibercept benefits ophthalmic disease regardless of diabetes severity. They are also venturing into consideration of diabetic agents for the management of DME and DR.

Ashay D. Bhatwadekar, PhD, RPh, associate professor at the Eugene and Marilyn Glick Eye Institute, 

presented animal model findings at ARVO 2021

 indicating gluclose-lowering SGLT-2 inhibitor dapagliflozin—a dynamic add-on agent in cardiometabolic, cardiovascular, and renal outcome risk reduction—may provide anti-inflammatory and anti-angiogenic benefit to patients with DR.

The scientific rationale of Bhatwadekar’s work was based on the valuation of SGLT-2 in glucose rates among patients with diabetes, and believing that it correlates enough with DR pathology to consider dapagliflozin for treatment.

But the broader rationale of the research was simpler than that: dapagliflozin has shown benefit in numerous comorbid outcomes in patients with diabetes. Why not diabetic retinopathy?

“Considering its use into cardiovascular conditions, I think that kind of multi-regimented use you see makes sense that you look into seeing it in diabetic retinopathy,” he explained to 

The early-stage findings were hopeful enough for Bhatwadekar to discuss progression into human trials comparing outcomes, symptoms, and levels of DR among patients treated with and without dapagliflozin. But implementation of SGLT-2 inhibitors for the direct treatment of DR or DME—or even other glycemic control drug classes, including GLP-1 agonists—is a long time away still.

What may benefit experts most in bridging the gaps between diabetes and ophthalmology in the short term may be improved screening, mixed with referral and communication that’s more “carrot” than “stick,” as Ho put it.

“We tend to communicate in a way that, in an era of digital medicine, I think can improve,” Ho said. “Even detection of diabetic retinopathy, there are devices now involving artificial intelligence (AI) that keep patients from coming in to get their eyes dilated.”

Patient-centered detection and screening tools, which are currently available at most physician’s offices and pharmacies, may soon come to smartphones, Ho suggested. At-home AI-enabled detection may provide streamlined referrals and allocation of care.

Lundeen echoed Ho’s suggestions of improved screening integration in ophthalmology, with the addendum that it may be better managed by a host of stakeholders: general practitioners, endocrinologists, and cardiologists all worker to assure vision health monitoring is a universal touchpoint in routine care.

On the other end, ophthalmologists should be looking to integrate chronic disease prevention strategies into their routine practice.

“There are opportunities to better integrate healthcare—both general healthcare being more attentive to vision health, and vice versa,” she said.

Ho suggested that even patients could be more cognizant of the risk factors associated with diabetes, including chronic ophthalmic disease, before even being approached with the matter by a clinician. Improved awareness campaigns, led by notable affected figures, could help to educate the millions at risk, rather than the thousands dedicated to treating them.

Sometimes the elephant in the room goes unnoticed if it’s been there for too long. Diabetes is not always at the forefront of a treating ophthalmologist’s priority list, because the vision-related byproducts of diabetes already are. More than any comprehensive therapy, referral strategy, technology or campaign, the continued discussion and research of diabetes' total effect on a patient among experts should be what leads to better outcomes in ophthalmology.

“I think there’s a lot of overlap that we just don’t think about, and it’s part of the questions that we don’t think about asking,” Talcott said. “There’s definitely a lot more we could be doing to better communicate and understand how different organs are related in diabetes.”

Articles

Research at ARVO 2021 highlighted a gamut of interplaying diabetes and vision loss risk factors, and even treatments for both. But experts depict a referral and care process that lacks whole diabetes care.

Diabetic Vision Loss Care Lacks Specialty Collaborations

Association for Research in Vision and Ophthalmology (ARVO) 2021 Virtual Meeting

 this week showed investigative gene therapy AGTC-501 provided notable efficacy and safety mark benefit in patients with 

The six-moth findings, presented by author Paul Yang, MD, PhD, of the Casey Eye Institute at Oregon Health & Science University, lead to hope for even greater and more concrete outcomes as the agent is assessed through 5 years in the patients aged ≥6 years old with the rare vision loss disease.

In a DocTalk podcast interview conducted during ARVO 2021, Yang joined to discuss the newest phase 1/2 findings, as well as the properties of benefit being assessed in AGTC-501.

Yang also explained the reason for expansive gene therapy research in XLRP, the role of advocacy and awareness-building in gene therapy research for rare disease, and what he would define as the modern ocular gene therapy care team.

Six Month Findings from a Phase 1/2 Clinical Study of Subretinal Gene Therapy Drug AGTC-501 for X-Linked Retinitis Pigmentosa Show Clinically Meaningful Improvement in Macular Sensitivity

Podcasts

A podcast interview with study author Paul Yang, MD, PhD, on the current research and future implementation of the agent.

Gene Therapy AGTC-501 Hits Phase 1/2 Marks for Rare Pediatric Blindness

Association for Research in Vision and Ophthalmology (ARVO) 2021 Virtual Sessions

 this week showed baseline diabetes severity metrics were not associated with worse likelihood of 

 clearance among patients treated with anti-VEGF therapy aflibercept.

The outcomes, conducted and presented by experts from the Cleveland Clinic, helped correct preconceptions of what patient risk factors and demographic influence capability of DME clearance with the top-line drug class.

The findings also contributed to the annual meeting’s recurring topic of cardiometabolic disease influence on ophthalmic conditions including DME, a leading cause of blindness in the US.

In the second segment of an interview with 

during ARVO 2021, study author Katherin Talcott, MD, of the Cleveland Clinic’s Cole Eye Institute, discussed how the growing diabetes issue in the US will continue to affect visually-impaired patients—especially in this last year, due to COVID-19.

“I think the pandemic has been really hard for a lot of people in a lot of ways,” Talcott explained. “And a lot of our patients with diabetes who had been coming in have been lost to follow-up in the last year, and they have a lot worse macular edema or their diabetes is worse.”

Talcott advocated for more research including that presented at ARVO 2021 which sought projections of treatment response among diabetic patients, noting it’s a frequent practice by specialists to silo their practice from that of others, even when collaboration is opportune.

“I think that we all tend to, unfortunately, focus on our problem and forget about other parts of the body,” she said. “But when we see patients who have disease that’s out of control, that usually means their diabetes is not well-controlled in other reasons as well.”

She also highlighted her own team’s research into the prevalence of visual impairment in patients with diabetes who have suffered from limb loss, emphasizing the significant merging of patient needs.

Videos

The diabetes and ophthalmology overlap is significant and growing in the US. A Cleveland Clinic expert discusses crossover research and care.

Treating for Vision Loss in Diabetes

New animal model research presented at the 

 this week indicated cardiovascular, cardiometabolic, and renal outcome therapy dapagliflozin may possibly aid patients with 

The data, presented by Ashay D. Bhatwadekar, PhD, RPh, associate professor at the Eugene and Marilyn Glick Eye Institute, showedpositive effect on glycemic control and measures of potential anti-inflammatory and anti-angiogenic action in the dosed mouse models.

Dapagliflozin, an SGLT-2 inhibitor therapy indicated as an adjunct treatment for a litany of heart disease, diabetic, and kidney-related symptoms and events, was a clear selection for assessment by Bhatwadekar and colleagues.

 during ARVO 2021, he explained his team’s rationale—noting that no previous research has sought to interpret the dynamic SGLT-2 inhibitor drug class in the treatment of diabetic retinopathy.

“Since the majority of the glucose uptake is happening at the kidneys, about 90% from SGLT-2, I like the idea that this is the drug that this is the drug which is basically getting rid of the glucose rate,” Bhatwadekar said.

Additionally, he discussed the early study’s outcomes, and the pretext for progressed assessment into treating diabetic retinopathy symptoms with proven therapies including dapagliflozin.

“Considering its use into cardiovascular conditions, I think that kind of multi-regimented use you see makes sense that you look into seeing it in diabetic retinopathy,” he wrote.

Dapagliflozin treatment protects from diabetic retinopathy

A discussion with an investigator on how the SGLT-2 inhibitor may help affected patients.