Glucagon-Like Peptide 1 Receptor Agonists and the Eye

Forget Barbie and Oppenheimer; the true blockbuster of last summer was semaglutide. Raking in more than $16 billion, this drug, marketed as Ozempic (Novo Nordisk) and Wegovy (Novo Nordisk), became a household name and highly coveted commodity in the treatment of type 2 diabetes and for weight management, respectively. As optometrists, we must be mindful of any potential adverse effects our patients’ medications might have on their overall health and/or on their existing health conditions. Glucagon-like peptide 1 receptor agonists (GLP-1RAs) such as semaglutide are no different, and I’ll cover that a bit later. But first, here’s a brief overview of this class of drugs.

ALL ABOUT GLP-1

GLP-1 orchestrates activation of insulin release and inhibition of glucagon release. This endogenous hormone is discharged from the small intestine into the bloodstream post-food consumption. GLP-1 binds GLP-1Rs in the pancreas, triggering insulin release from beta cells.^1-3 GLP-1 also binds pancreatic alpha receptors, impeding glucagon synthesis. Glucagon stimulates glucose release into the bloodstream during fasting periods; reducing its levels aids in reducing blood glucose levels. Endogenous GLP-1 has a half-life of 2 minutes, as dipeptidyl peptidase enzymes rapidly inactivate incretin hormones. Consequently, GLP-1RAs extend the half-life of GLP-1 by mimicking its actions.^1,2 Given that GLP-1 is a large protein, analogs are primarily administered via subcutaneous injection, with the exception of oral semaglutide 7 mg or 14 mg (Rybelsus, Novo Nordisk).

Four GLP-1RAs are available on the market (Table). These incretin-based therapies are synthetic mimetics of GLP-1. These analogs emulate endogenous GLP-1 by activating GLP-1R, stimulating release of insulin. Elevated levels of GLP-1 with GLP-1RA prompt increased insulin secretion and decreased glucagon production. GLP-1RAs contribute to improved glycemic control by lowering glycated hemoglobin (HbA1c) and promoting weight loss without causing hypoglycemia, a notable advantage over sulfonylureas and meglitinides. GLP-1RAs vary in their efficacy in reducing HbA1c, magnitude of weight loss, duration of action, dosing frequency, and side effects.⁴

GLP-1RAs are FDA-approved for treating type 2 diabetes, which may be linked to potential GLP-1 impairment and slowed GLP-1 activation post-prandial.^5,6 Without the appropriate GLP-1 activation, insulin is not released promptly, and glucagon production releases glucose into the bloodstream, contributing to elevated blood glucose levels.

GLP-1RAs such as semaglutide and liraglutide (Saxenda, Novo Nordisk) are employed in weight loss regimens. Although the weight loss mechanism is not well-understood, GLP-1RAs curb hunger, leading to a reduction in food intake. Additionally, they slow gastric emptying from the stomach to the small intestine, promoting satiety more quickly and for longer.⁷ As practitioners, the slowed gastric emptying effect raises concern for co-administered drug absorption. However, one study found that drug exposure was not clinically significant, and no dosing adjustments were necessary for most oral medications.⁷ Special consideration should be given to medications that have a narrow therapeutic index and in individuals with kidney dysfunction. It’s worth noting that GLP-1RAs do not result in cytochrome-dependent or transporter-mediated drug-drug interactions.⁸

Gastrointestinal side effects are most common, particularly during medication initiation and with dose escalation. Nausea is most often reported by patients, and vomiting, diarrhea, abdominal pain, and/or constipation have also been documented.⁹ GLP-1RAs should not be prescribed in patients with a history of pancreatitis, a personal or family history of medullary thyroid cancer, or multiple endocrine neoplasia due to the observed development of thyroid tumors in animal studies.⁹ Reactions at the injection site have also been reported. A consideration in the optometric setting is transient, elevated IOP associated with vomiting, particularly in the pre- and postoperative period of ophthalmic surgery.

GLP-1RAS AND DIABETIC RETINOPATHY

The phenomenon of worsening diabetic retinopathy (DR), often termed rebound retinopathy, is a well-established, paradoxical retinal finding linked to improved blood glucose levels, typically observed 3 months to 3 years after intense glucose lowering.^10-14 The Diabetes Control and Complications Trial demonstrated a relationship between improved blood glucose control and increased risk of early worsening of DR, as well as between long-term risk reduction of DR with sustained blood glucose improvement.¹⁵

Two large, randomized control trials (RCTs) investigating liraglutide and semaglutide also suggested worsening retinopathy as an adverse effect of GLP-1RA use. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results study, a numerically higher incidence of complications associated with DR, such as panretinal photocoagulation, anti-VEGF injection, vitreous hemorrhage, and blindness, was observed, although results did not reach clinical significance.¹⁶ The RCT associated with semaglutide use displayed a statistically significant increased risk of DR complications.¹⁷ Conversely, findings from another population-based study suggested there was no overall increased risk of DR associated with GLP-1RA use, while a meta-analysis indicated albiglutide, a GLP-1RA no longer commercially available due to limited prescribing, was associated with an increased risk of early worsening (the four GLP-1RAs available did not exhibit a statistically significant association with DR).^18,19

Given the confounding information, there is no established DR screening protocol upon GLP-1RA initiation. Communication with primary care providers and endocrinologists regarding retinal health and the severity of any existing DR is imperative before initiating GLP-1RA use.²⁰ If DR is observed with GLP-1RA use, accelerated follow-up compared with typical monitoring should help rule out treatable retinopathy. The presence of severe nonproliferative DR or proliferative DR requires comanagement with retinology and further intervention, including intravitreal injection and/or laser photocoagulation consistent with the clinical standard of care.²¹

Although the long-term retinal effects of GLP-1RA in DR aren’t fully understood at this time, an ongoing trial is investigating the extended effect of semaglutide on DR after 5 years of treatment. The trial is set to conclude in the first quarter of 2027.²²

GLP-1RAS AND GLAUCOMA

GLP-1Rs are found in neurons and glial cells located throughout the central nervous system, as well as in ganglion cells of the retina and optic nerve.²³ Animal studies have demonstrated neuroprotective effects associated with GLP-1RA use in Alzheimer and Parkinson disease, stroke, and ocular hypertension.^11,24-26 A retrospective study of 1,961 individuals with newly initiated GLP-1RA therapy found a reduced risk of developing open-angle glaucoma.²⁶ Another study also found a statistically significant decrease in the development of glaucoma, with a duration-response pattern: Individuals using GLP-1RAs for 3 or more years had a higher risk reduction of 29%.²⁷ Contemporary glaucoma management targets only IOP. The association between GLP-1RA use and a decreased risk of glaucoma, along with its potential implication for other neurodegenerative diseases, offers a promising avenue for targeted treatment.

PROMISING POTENTIAL

GLP-1RAs offer a promising outlook as transformative therapies in glycemic control, weight management, neuroprotection, and cardiovascular and renal protection. With innovative drug delivery systems on the horizon, the potential of GLP-1RAs in optometry is only expected to rise.