Diabetic retinopathy progression lower with empagliflozin vs DPP-4 inhibitor

In patients with type 2 diabetes (T2D), treatment with empagliflozin has a null effect on the risk of nonproliferative diabetic retinopathy (NPDR) compared with a DPP-4 inhibitor but may confer protection against DR progression, according to a study.

In propensity-score matched cohorts, the risk of incident NPDR over a mean follow-up of 8 months did not significantly differ between empagliflozin users and DPP-4 inhibitor users (hazard ratio [HR], 1.04, 95 percent confidence interval [CI], 0.94–1.15; rate difference [RD], 1.30 per 1,000 person-years, 95 percent CI, −1.83 to 4.44). [JAMA Ophthalmol 2024;doi:10.1001/jamaophthalmol.2024.5219]

However, the risk of DR progression was 22-percent lower for empagliflozin users than for DPP-4 inhibitor users (HR, 0.78, 95 percent CI, 0.63–0.96; RD, −9.44 per 1,000 person-years, 95 percent CI, −16.90 to −1.98).

Subgroup and sensitivity analyses yielded similar results.

The findings are consistent with the magnitude and direction of those of a post hoc analysis of the EMPA-REG OUTCOME trial. Compared with placebo, empagliflozin was associated with a 22-percent decrease in the risk of clinically significant DR in the overall population and with a 27-percent risk reduction in patients with DR at baseline. [Diabetes Care 2019;42:e53-e55]

The present study included 34,239 pairs of propensity-score matched adults in the NPDR cohort (mean age 65.6 years, 52.4 percent male) and 7,831 pairs in the DR progression cohort (mean age 67.0 years, 52.5 percent male).

A closer look

In an accompanying editorial, Drs Jonathan Shaw and Alicia Jenkins, both from the Baker Heart and Diabetes Institute, Diabetes and Population Health Research Laboratory in Melbourne, Victoria, Australia, noted that the short follow-up duration of 8 months limits the study’s ability to definitively conclude that SGLT2 inhibitors such as empagliflozin are more effective than DPP-4 inhibitors in terms of slowing DR progression due to their stronger glucose-lowering effect. [JAMA Ophthalmol 2024;doi:10.1001/jamaophthalmol.2024.5364]

A more plausible explanation might be that patients on DPP-4 inhibitors were more likely to be switched to more potent glucose-lowering drugs such as insulin or GLP-1 receptor agonists. These drugs, while effective, can sometimes lead to rapid blood sugar control, which has been associated with early worsening of DR, as Shaw and Jenkins explained. [Diabetes Obes Metab 2019;21:454-466]

“Thus, the apparent benefit of empagliflozin might have resulted from harms in the comparator arm. The relatively high baseline HbA_1c 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,” they said. “Unfortunately, data on postbaseline HbA_1c levels and therapy changes were not reported.”