Empagliflozin May Slow Diabetic Retinopathy

TOPLINE:

Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, did not reduce the risk for incident nonproliferative diabetic retinopathy compared with dipeptidyl peptidase 4 (DPP-4) inhibitors in patients with type 2 diabetes, but the drug did reduce the risk for its progression by 22% in patients with existing retinopathy.

METHODOLOGY:

• Researchers conducted a new-user active-comparator cohort study using US insurance claims data between August 2014 and September 2019 to compare the risk for incident nonproliferative diabetic retinopathy and progression of diabetic retinopathy in patients with type 2 diabetes initiating empagliflozin or a DPP-4 inhibitor.
• They included 34,239 pairs of propensity score–matched patients with type 2 diabetes (52.4% men; mean age, 65.6 years) and no history of retinopathy.
• The 7831 pairs (52.5% men; mean age, 67 years) of patients with diabetes who were included in the diabetic retinopathy progression cohort were required to have a history of nonproliferative diabetic retinopathy.
• Outcome measures included incident nonproliferative diabetic retinopathy, defined by diagnostic codes, and progression of diabetic retinopathy, defined as a composite of treatment initiation or onset of vitreous hemorrhage or proliferative diabetic retinopathy.

TAKEAWAY:

• During a mean follow-up period of 8 months, the researchers observed no significant difference in the risk for incident nonproliferative diabetic retinopathy between the groups taking empagliflozin or a DPP-4 inhibitor (hazard ratio [HR], 1.04; 95% CI, 0.94-1.15).
• The initiation of empagliflozin was associated with a lower risk for progression of diabetic retinopathy compared with initiation of a DPP-4 inhibitor (HR, 0.78; 95% CI, 0.63-0.96).
• The findings remained consistent across multiple subgroups of sex, age, race, ethnicity, smoking status, baseline hypertension, hyperlipidemia, diabetic neuropathy and nephropathy, insulin use, and uncontrolled diabetes.

IN PRACTICE:

“Our study may be helpful when weighing the potential risks and benefits of various glucose-lowering therapies in patients with [type 2 diabetes] who are at high risk of developing DR [diabetic retinopathy] or among those with preexisting DR,” the authors of the study wrote.

In an editorial accompanying the journal article, Jonathan E. Shaw, MD, and Alicia J. Jenkins, MD, from the Baker Heart and Diabetes Institute, Melbourne, Australia, speculate that the apparent benefit of the SGLT2 inhibitor over the DPP-4 agent may be a byproduct of the latter drug’s relatively limited ability to reduce blood glucose.

“The weaker glucose-lowering effect of DPP-4 inhibitors may have meant that more people in this group were subsequently changed to what was likely a third- or fourth-line glucose-lowering drug. Insulin and glucagon-like peptide 1 receptor agonists are often used in this role, are the most potent glucose-lowering drugs, and have both (along with other therapies) been associated with the early worsening of DR [diabetic retinopathy] that can occur (3 months to 3 years) after rapid improvement in blood glucose control,” they wrote. “Thus, the apparent benefit of empagliflozin might have actually resulted from harms in the comparator arm. The relatively high baseline hemoglobin A1c(HbA1c) in this cohort, the short follow-up, and the fact that apparent benefits were only seen for DR progression and not for DR incidence are all consistent with this hypothesis.” 

The authors added: “Not all ophthalmologists are comfortable in prescribing systemic drugs such as fenofibrate and empagliflozin. As the evidence continues to grow for such agents, this will need to change, either by taking on this task directly or by developing communication and partnerships with primary care physicians and other physicians to ensure that appropriate prescribing and monitoring occur. Furthermore, in resource-limited settings, in which retinal laser equipment and intravitreal drugs and related skilled ocular clinicians may not be readily accessible or affordable, oral glucose-lowering and lipid modulating drugs may provide an affordable option to limit DR progression.” 

SOURCE:

This study was led by Helen Tesfaye, PharmD, MSc, of the Department of Medicine at Brigham and Women’s Hospital, Harvard Medical School, in Boston. It was published online on December 5, 2024, in JAMA Ophthalmology.

LIMITATIONS:

The presence of unmeasured or residual confounding could not be ruled out. Outcome misclassification may have occurred due to reliance on diagnosis codes for diabetic retinopathy in claims, and some progression events, including the shift from mild to moderate nonproliferative diabetic retinopathy, might not have been captured. The relatively short follow-up period of approximately 8 months may have affected the observation of potential differences between the treatment groups, particularly in terms of outcomes related to nonproliferative diabetic retinopathy.

DISCLOSURES:

This study was supported by a research grant from Boehringer Ingelheim to Brigham and Women’s Hospital. Some authors disclosed receiving grants, being employees, and owning stocks of various sources, including the funding agency.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.