SGLT2s Edge Out GLP-1s When It Comes to Retinopathy | ASRS 2024

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are associated with a lower risk of retinal complications more thanthe glucagon-like peptide-1 (GLP-1) drugs, but the GLP-1 are comparable to older classes of glucose-lowering drugs used to treat diabetes, according to research presented today at the American Society of Retina Specialty’s annual meeting, which is being held in Stockholm, Sweden.

Andrew Barkmeier, M.D.

“From my perspective, the fact that the GLP-1s did not cause an increased risk of [retinal] complications compared with the older medications is hugely reassuring,” said Andrew Barkmeier, M.D., an associate professor of ophthalmology at the Mayo Clinic, who presented the findings.

The two classes of older medications included in the study were the dipeptidyl peptidase-4 (DPP-4) inhibitors, a class that includes Januvia (sitagliptin) and Tradjenta (linagliptin), and the sulfonylureas, which include gliclazide, glipizide and glimepiride.

Barkmeier said it will take more research to sort out the difference between the SLGT2 inhibitors, a class that includes Invokana (canagliflozin), Farxiga (dapagliflozin) and Jardiance (empagliflozin) and the GLP-1s, which include Ozempic (semaglutide) and Victoza (liraglutide). For weight loss, semaglutide is sold under the brand name Wegovy and liraglutide as Saxenda.

In the findings he presented today the SGLT2 inhibitors were associated with a 27% lower risk of treatment for sight-threatening retinopathy compared with the GLP-1s. The study encompassed four years.

When asked why the SGLT2 inhibitors might be associated with less retinopathy, Barkmeier answered, “That’s the question.” He said the finding about advantage of the SGLT2 inhibitors was “hypothesis generating" rather than definitive.

Barkmeier noted that that preclinical findings for the classes of blood glucose-lowering drugs show that they may different direct effects on retinal tissue apart from their effects on blood sugar levels. Differing rates at which they lower blood sugar levels may also be a factor.

The superiority of the SGLT2 inhibitors in this area runs counters to the stream of recent research findings that has elevated the GLP-1s to almost-wonder drug status. Researchers have found suggestive associations between the GLP-1s and a lower risk of everything from kidney disease to many cancers to Alzheimer’s disease.

There have, though, been some notable exceptions to the GLP-1 winning streak. Researchers have found have an elevated risk of diabetic retinopathy during early treatment with GLP-1s, a finding that fits with a body of research linking sudden drops in blood sugar levels to diabetic retinopathy in the short run even though lower blood sugar levels are demonstrably beneficial for the eyes, and especially the retinas, over the long run.

In addition, findings reported in JAMA Ophthalmology earlier this month showed a possible connection between semaglutide and potentially sight-threatening optic nerve condition called nonarteritic anterior ischemic optic neuropathy (NAION).

Barkmeier said his study had been designed to detect diabetic retinopathy differences among the four classes of drugs included in the study but not NAION.

Barkmeier tapped into an Optum database to conduct his study that included people insured by commercial insurers, Medicare Advantage plans or by traditional Medicare. The people included in the study had type 2 diabetes with a moderate risk of cardiovascular disease but no history of advanced retinal complications from diabetes. Barkmeier used various statistical techniques to make his analysis resemble that of a clinical trial comparing the patients treated with the four different classes of medication. Altogether, the study population included 371,698 patients, of whom 42,265 were treated with GLP-1s; 53,476 with SGLT2 inhibitors; 78,444 with DPP-4 inhibitors; and 197,513 with sulfonylurea agents.

In addition to being associated with a lower risk of retinopathy compared to the GLP-1s, Barkmeier found that that SGLT2 inhibitors were 21% less likely to be associated with retinopathy compared with the DPP-4s and 29% less likely than the sulfonylureas agents.

The GLP-1s were associated with a similar risk of retinopathy as the DPP-4s and sulfonylureas, he reported.

Barkmeier said this study was motivated by concern that the studies that led to the approval of the new medications did not examine eye complications in depth.

“Our main question, with broad strokes, was, ‘Do these new medications that are powerful and have clear systemic benefits for heart and kidneys and obesity, are they causing retinal complications or problems?’” said Barkmeier. “Because their use is ramping up so quickly. And the studies that got them approved and got them ramped up for the systemic indications really do not look at retinopathy.”