Off-Label, On Point

In a recent newsletter, we discussed the increased off-label use of semaglutide for weight loss and asked whether ophthalmologists should be wary of this, given studies that demonstrated an increase in diabetic retinopathy associated with semaglutide use. Today, we hear from Blake Cooper – co-author on one of those studies, but also someone who has intimately witnessed the benefits of off-label Ozempic use.

As a retina physician who has been practicing for the past two decades – and the father of a child who has had diabetes for the past decade, I wanted to share my perspective and strong support of the off-label use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) for many indications, including weight loss. Moreover, I view the recent concerns regarding the worsening of retinopathy as an opportunity for eye care professionals to educate themselves on – and improve – the ocular, systemic, and mental health of their patients.

A little perspective
 

Approximately one in five of all prescriptions written in the US are for an off-label indication (1). For example, in ophthalmology this flexibility in prescribing FDA-approved medications has allowed the use of bevacizumab in patients with several ocular diseases, including the treatment of advanced stages of diabetes-related retinopathy (DR). The decision to prescribe off-label medications is done in the patient’s best interest. It is grounded on sound clinically-based evidence and based on experience of treating conditions where medications have not yet been formally tested.

GLP-1 RA is a modified form of the potent incretin hormone GLP-1, which is secreted by intestinal L-cells of the distal ileum during a meal. This naturally occurring hormone acts to enhance insulin and decrease glucagon production, slow gastric emptying, and act within the brain to increase satiety. GLP-1 RAs have not only emerged as powerful medications for type 2 diabetes mellitus (T2D) management and weight reduction, but have also been shown to provide strong cardiovascular and renal risk reduction.

When considering the recent use for weight loss of this class of medications, I believe it is important to remember that, despite medical professionals’ best efforts, rates of obesity and obesity-related chronic diseases continue to rise. Roughly one in three adults in the US is obese (2), a condition which increases early mortality and other comorbidities. The estimated annual medical cost of obesity in the US was nearly $173 billion in 2019 – and the medical costs for adults with obesity were $1,861 higher than medical costs for people of a healthy weight (3).

Weight and mental health
 

The practice of medicine is not only shaped by clinical trials, but also by our clinical experiences – both good and bad. Shortly after my daughter was diagnosed with type 1 diabetes mellitus (T1D) at 12, one of my dearest patients passed away from complications of heart failure. She was only 34 and had struggled with T1D since she was 14. Her battle had been with diabulimia. Eating disorders are more common in individuals with T1D than in the general population – likely related to the complex and constant requirements of diabetes management and the impact of living with a chronic medical condition on psychosocial functioning (4). In many ways, I failed my patient by focusing on her recurrent vitreous hemorrhages and traction retinal detachments that required multiple surgeries and periodic intravitreal injections to maintain reading and driving vision. I never once questioned why she was barely 100 pounds and always had double-digit A1Cs. Awareness of potential eating disorders and a lower threshold for referral to mental health professionals could be life-saving in a condition such as diabetes, where outcomes are so dependent on behavioral adherence.

Currently, the primary treatment for those with T1D combats insulin deficiency but neglects disease progression, alpha cell dysfunction, and cardiovascular and renal health. GLP-1 RAs have a unique mechanism of action in T1D, addressing alpha cell dysfunction and thereby suppressing inappropriate glucagon secretion. To this end, adding GLP-1 RAs to the treatment of diabetes, when indicated, can improve adherence with glycemic management by providing a reduction in the need for insulin, a strong cardiovascular and renal risk reduction, and help maintaining a healthy weight.

Ophthalmic opportunity and unmet needs
 

Despite clear evidence that near-normalization of blood glucose levels reduces the long-term risk of diabetic retinopathy, early worsening of DR is a well‐described phenomenon evident in patients with T1D and T2D, in those who have undergone bariatric surgery, and in pregnant women (5). Worsening of retinopathy does not appear to be agent‐specific as it has been described in patients receiving diverse treatments, including intensive insulin therapy, sulfonylureas, thiazolidinediones, and now GLP‐1 RAs. Though the mechanism leading to early worsening remains unclear, most evidence suggests an association with rapid improvement of hyperglycemia and the severity of pre‐existing diabetes-related retinopathy at baseline. Even with the potential for initial progression of retinopathy, intensive glycemic treatment reduces the risk for the onset and progression of DR over time, compared with conventional treatment.

Given that nearly one-third of patients with diabetes are unaware of their diabetes, and 10 percent have already developed DR (6), the eye care community is failing those with diabetes and needs to stress the importance of annual eye screenings. Early detection of diabetes and DR allows for the treatment of retinopathy when indicated. Anti-VEGF pharmacotherapy has become a first-line treatment for center-involved diabetic macular edema and proliferative diabetic retinopathy. What is potentially overlooked is that anti-VEGF medications can be used proactively to prevent vision-threatening complications of DR and can lead to a two-step disease regression on the Diabetic Retinopathy Severity Scale. Treatment of severe nonproliferative DR (NPDR) with intravitreal aflibercept injections in the PANORAMA clinical trial reduced the severity of retinopathy and showed an impressive 70–80 percent reduction in the rates of vision-threatening complications.

According to the American Diabetes Association guidelines, patients who have been newly diagnosed with T2D should have a comprehensive eye exam at the time of diagnosis (7). After the initial exam, subsequent eye exams should be conducted annually. As with any potent glucose-lowering agent, clinicians should consider retinopathy status at the time of treatment initiation and follow guidelines for monitoring patients with established retinopathy. In patients who have recently been initiated on a GLP-1 RA, especially those with a prior history of retinopathy, close monitoring for signs of new or worsening retinopathy should occur. Though DR has been identified as a potential adverse effect of GLP-1 RAs, there remains a positive benefit–risk profile when used accordingly with the FDA-approved prescribing information. Moreover, DR, when detected early, is treatable with anti-VEGF agents.

Real-world experiences and ongoing trials
 

GLP-1 RA cardiovascular outcome trials (CVOTs) provide long-term follow-up, allowing examination of retinopathy outcomes. It is also important to remember that none of the included CVOTs were designed or powered to assess retinopathy outcomes – nor were definitions of retinopathy in most of these trials standardized for these analyses. The ongoing FOCUS trial seeks to further investigate the long-term effects of semaglutide on DR in patients with T2D (8). This clinical trial will use validated and standard ophthalmic assessments to measure the presence of early treatment diabetic retinopathy level progression in 1500 patients with an A1C of 7–10 percent. The time frame of the trial will be five years and it is estimated to be completed in early 2027.

Until then, we can continue to use real-world data and experiences to guide our practice patterns. Last year, I presented at ARVO on the risk of DR progression in patients during one year of semaglutide use. We hypothesize that if worsening of DR occurs with semaglutide in patients with T2D, it is temporary and not associated with continued DR progression. This was a retrospective data analysis that identified 87 patients (36 female) for descriptive analysis. The group had an average age of 62.4 years (range of 38–84 years), and baseline level of DR ranging from 10 to 85; 11.5 percent of the group started with mild NPDR (level 10); 38.5 percent had moderate NPDR (level 35-43); 14.4 percent had severe NPDR (level 47-53); and 35.6 percent had proliferative DR (PDR) (level 61-85). The level of retinopathy progressed over one year in 5.7 percent of eyes, improved in 8 percent of eyes, and remained stable in 86.2 percent of eyes. The one-year visual acuity remained unchanged in 72.4 percent of patients, while 12.6 percent of patients lost greater than two lines of vision in at least one eye and 14.9 percent gained more than two lines of vision in at least one eye. CST remained unchanged in 44.2 percent, increased by at least 10 percent in one eye of 25.6 percent, and decreased by at least 10 percent in one eye of 30.2 percent of patients.

Semaglutide use was not associated with increased risk of progression of DR, visual loss, or an increased number of intravitreal injections over 12 months. If confirmed by prospective clinical trials, these findings would offer reassurance that the long-term use of semaglutide does not lead to the progression of DR and sight-threatening disease.