How Does Empagliflozin Stand in Terms of Diabetic Retinopathy Risk? We Have Answers Not Only from Controlled Studies but Also from Real Practice

GLP-1RA and Retinopathy? Study Results Vary 

The SUSTAIN-6 study demonstrated that the GLP-1RA semaglutide can reduce the risk of major CV events (3-point MACE = 3P-MACE), i.e., CV death, non-fatal myocardial infarction (MI), and non-fatal stroke (CVA) among type 2 diabetics compared to placebo, with a hazard ratio (HR) of 0.74 (95% confidence interval [CI] 0.58–0.95; p < 0.001).

However, the study also found that its use was associated with a 76% increase in the risk of diabetic retinopathy complications (bleeding, blindness, or conditions requiring intravitreal treatment or retinal photocoagulation) (1.49 vs. 0.86 events/100 patients; HR 1.76; 95% CI 1.11–2.78; p = 0.02). The cause is unknown, but it is assumed to be due to a rapid decrease in glucose levels.

In the LEADER study, another GLP-1RA, liraglutide, also reduced the risk of 3P-MACE (compared to placebo HR 0.87; 95% CI 0.78–0.97; p < 0.001), but the incidence of retinopathy events was similar to placebo (0.6 vs. 0.5 events/100 patient-years; HR 1.15; 95% CI 0.87–1.52; p = 0.33). 

Results of Empagliflozin Administration in Terms of Retinopathy Risk...

... Compared to Placebo in the EMPA-REG OUTCOME Study

Sodium-glucose cotransporter-2 inhibitors (SGLT2i, or gliflozins) have shown in studies with DM2 and CV disease patients the ability to reduce CV events. In the prospective randomized EMPA-REG OUTCOME study, treatment with empagliflozin led to a 14% reduction in the risk of 3P-MACE, particularly CV death, compared to placebo. In addition, empagliflozin showed a favorable effect on reducing the risk of the composite retinopathy endpoint, including time to first retinal photocoagulation, vitreous hemorrhage, intravitreal treatment administrations, and diabetes-related blindness. Compared to placebo, empagliflozin reduced the incidence of this composite endpoint by 28%.

At least 1 dose of the evaluated drug was received by 7020 patients, of whom 48% were on insulin, 32% had kidney disease (macroalbuminuria or an estimated glomerular filtration rate /eGFR/ <60 ml/min/1.73 m²), and 22% had retinopathy. The median follow-up time was 3.1 years. The composite retinopathy endpoint occurred in 1.6% (76) of patients treated with empagliflozin compared to 2.1% (48) in the placebo group (incidence 5.6 vs. 7.3 per 1000 patient-years; HR 0.78; 95% CI 0.54–1.12; p = 0.1732). The incidence of the composite retinopathy endpoint was higher in patients who had diabetic retinopathy at study entry: 13.6 with empagliflozin and 18.2 events/1000 patient-years with placebo (HR 0.73; 95% CI 0.44–1.20; p = 0.2187). Among those without retinopathy at study entry, the incidence of the composite endpoint was 3.6 versus 4.2/1000 patient-years (HR 0.84; 95% CI 0.50–1.42; p = 0.5214). 

... and Compared to DPP4i in Real Practice According to the EMPRISE Study 

The EMPRISE study evaluated diabetic retinopathy (DR) parameters in adults with DM2 who began using empagliflozin or dipeptidyl peptidase-4 inhibitors (DPP4i, or gliptins) in routine practice. This included two separate cohorts, with data sourced from Medicare-fee-for-service and two US commercial health insurance databases from 2014–2019. The first cohort evaluated the risk of developing non-proliferative DR (NPDR) in 34,262 patient pairs without a DR history, matched by propensity score, while the second cohort assessed DR progression in 7,839 patient pairs, also matched by propensity score, who had NPDR but no advanced DR at study entry.

After a median follow-up of 8 months, treatment with empagliflozin compared to DPP4i use was associated with a similar risk of developing NPDR (HR 1.05; 95% CI 0.95–1.16) and a significantly lower risk of DR progression (HR 0.77; 95% CI 0.62–0.95).

CDS Supports DR Screening in Diabetology Clinics

According to current data, prevention and treatment can reduce the risk of vision loss from diabetic retinopathy by >90%. The Czech Diabetes Society ČLS JEP (CDS) therefore emphasizes the importance of DR screening and collaboration between diabetologists, ophthalmologists, internists, and general practitioners. In DR screening, they supported the possibility of computer analysis of digital retinal images taken directly in diabetology clinics.

According to CDS, DR screening should be performed upon diabetes diagnosis, then at least annually, and also when starting insulin, initiating an intensified insulin regimen, insulin pump therapy, or dialysis, and during pregnancy. In its reasoning, the CDS board states that systems designed for DR screening by computer analysis of digital retinal images taken with a non-mydriatic camera are certified, have high sensitivity (typically >95%), and excellent agreement with an ophthalmologist. Moreover, machine learning technologies have significantly increased their accuracy. Such screening has been considered equivalent to DR screening by an ophthalmologist by the CDS.

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Sources:
1. Inzucchi S. E., Wanner C., Hehnke U. et al. Retinopathy outcomes with empagliflozin versus placebo in the EMPA-REG OUTCOME trial. Diabetes Care 2019; 42 (4): e53–e55, doi: 10.2337/dc18-1355.
2. Tesfaye H., Htoo P. T., Paik J. M. et al. Empagliflozin on the risk of retinopathy in patients with type 2 diabetes – results from the EMPRISE Study. Diabetes 2023; 72 (Suppl. 1): 269-OR, doi: 10.2337/db23-269-OR.
3. Prázný M., Šoupal J. Stanovisko České diabetologické společnosti ČLS JEP k vyšetření diabetické retinopatie pomocí počítačové analýzy digitálních snímků sítnice. ČDS, 1. 7. 2022. Accessible at: www.diab.cz/dokumenty/CDS_stanovisko_retinopatie.pdf