n a recently published study in Investigative Ophthalmology & Visual Science, researchers evaluated the risk of newly diagnosed retinal vein occlusion (RVO) in patients with type 2 diabetes (T2D) using sodium-glucose cotransporter-2 inhibitors (SGLT-2i) as opposed to dipeptidyl peptidase-4 inhibitors (DPP-4i).
Give me some background first.
SGLT-2i are glucose-lowering agents that have recently emerged as a treatment option for T2D patients. They work by increasing urinary glucose secretion by suppressing renal glucose reabsorption, which in turn leads to reduced blood glucose levels.
SGLT-2i include:
- Canagliflozin
- Dapagliflozin
- Empagliflozin
- Ertugliflozin
To start: Why investigate SGLT-2i?
SGLT-2i has been shown to reduce systemic levels of proinflammatory cytokines and improve endothelial function, which could mitigate the risk of RVO.
Plus: While a previous study found an increased risk of RVO regarding SGLT-2i use in participants with T2D, investigators noted that evidence was limited.
“Whether SGLT-2i use increases or decreases the risk of RVO in patients with T2D remains unclear”, they stated.
Which brings us to this study.
Indeed. Investigators performed a nationwide retrospective cohort study in which they used claims data obtained from the National Health Insurance Research Database of Taiwan.
They then applied a target trial emulation framework.
Details, please.
The study examined patients with T2D who met the following criteria:
- No prior diagnosis of RVO
- Newly commenced treatment with SGLT-2i or DPP-4i
- Administered between May 1, 2016 and December 31, 2020
Who was included in the study?
Participants were comprised of:
- 123,567 SGLT-2i patients
- 578,665 DPP-4i patients
- Aged 20+
How was the study conducted?
The researchers controlled for potential systematic differences in baseline characteristics between groups using stabilized inverse probability of treatment weighting (IPTW).
Outcomes of interest were defined as:
- Diagnosis of new-onset RVO
- Including central RVO
- Branch RVO
Hazard ratio (HR) for SGLT-2i compared to DPP-4i was estimated utilizing:
- A Cox regression model
Findings?
- Incidence of RVO was lower in patients newly receiving SGLT-2i (0.59 events per 1000 person-years) compared to those receiving DPP-4i (0.77 events per 1000 person-years)
- Over a mean follow-up of 1.61 years
- SGLT-2i users had a significantly lower risk of developing RVO compared to DPP-4i users
- HR = 0.76, 95% confidence interval (CI) = 0.59-0.98
Individual outcome analysis showed that:
- SGLT-2i use was significantly associated with a lower risk of branch RVO (HR = 0.71, 95% CI = 0.52-0.96)
- But not central RVO (HR = 0.84, 95% CI = 0.57-1.24)
Limitations?
Confounding by indication may have occurred due to the study being observational, the lack of granular data on clinical characteristics (i.e. smoking, lifestyle, physical activity), and bias related to unmeasured confounders.
The authors also noted that they based the ascertainment of RVO on ICD codes instead of direct assessment of participants.
What this means: Some participants with outcomes may not have been identified in the claims database since they did not seek medical assistance.
Go on …
Ertugliflozin use was not evaluated due to insufficient patient numbers and unavailability in Taiwan’s NHI program until 2019.
Lastly, a significantly lower risk of developing RVO was not seen in participants receiving SGLT-2i in the as-started design analysis.
Why this matters: Patients in real-world practice could discontinue or not adhere to SGLT-2i treatment, which may have led to misclassified cases in the cohort to bias the study results to null.
Expert opinion?
While the investigators were unaware of the exact processes that led to the better outcomes seen in the SGLT-2i group in their findings, they hypothesized that this could be due to the significant differences in the impact SGLT-2i and DPP-4i have on cardiometabolic markers.
They stated, “Prior network meta-analyses of clinical trials have illustrated that SGLT-2i demonstrate a superior reduction in systolic blood pressure (SBP) ranging from 2.3 to 5.8 mm Hg compared to DPP-4i.”
Take home.
The findings showed that RVO risk was lower in participants with T2D who were receiving SGLT-2 compared to T2D participants receiving DPP-4i, especially in patients younger than 65 or patients without concomitant hypertension (HTN) or hyperlipidemia.