Newer treatments for diabetes mellitus: A caveat with rapid glycaemic improvement and caution regarding changes in retinopathy screening guidelines within the UK NHS programme

dear editor,

Varughese and Jacob highlight the importance of monitoring for early worsening of diabetic retinopathy (DR) on initiation of GLP-1 receptor agonist (GLP-1RA) therapy and the ramifications for retinopathy screening. ¹ Pre-existent DR, high HbA1c at initiation, rapid and significant reduction in HbA1c can contribute to this risk.^2,3 Patients with significant DR and maculopathy generally have a personalised retinal management plan and frequent reviews in specialist clinics. This allows for close monitoring of any such deterioration. However, this pathological progression might be missed in diabetic patients with normal eyes or less severe grades of DR under the annual or biennial community-based Diabetes Eye screening (DES) programme in the UK (R0 – no DR, R1 – background DR, R2 – pre-proliferative DR and M0 – no maculopathy, M1 – maculopathy).

We undertook an observational analysis of patients who had completed 3 months of once weekly Semaglutide subcutaneous therapy, comparing their HbA1c and DR status before and at least 3 months after initiation of treatment. Of the n = 93 patients reviewed, n = 78 did not have maculopathy at initiation; n = 56 were normal and n = 22 had R1. Follow up DR screening done after a mean of 277 days showed progression of R0 to R1 in n = 9, unilateral R1 to bilateral R1 in n = 4 and progression from R1 to R2 in n = 1. One patient progressed from R2 to develop new maculopathy but did not require any additional treatment. The comparison between ‘progressors’ (n = 15) and ‘non-progressors’ (n = 63) showed that the mean HbA1c at initiation was significantly higher (89.5 ± 20.0 vs 72.9 ± 17.9 mmol/L, p < 0.0001) and mean reduction of HbA1c significantly greater (29.4 ± 21.6 vs 16.7 ± 12.3, p < 0.005) in the ‘progressors’; diabetes duration was comparable (13.4 vs 14.6 years). Though this is a retrospective observational study unadjusted for other confounders, the 19% incidence of DR within a year of initiation is higher than the documented 2–12% incidence in DR epidemiological studies. ⁴

The current positioning of GLP-1RA in the National Institute for Health and Care Excellence (NICE) guidelines as a later addition would mean that the duration of diabetes is likely to be longer in patients initiated on this class of medications, therefore increasing risk of DR progression. With GLP-1RA, there is no specific dose-response relationship or prediction of the magnitude of HbA1c reduction. In this context, as mentioned by Varughese and Jacob, the dual incretin mimetic, tirzepatide may trigger this phenomenon too, given its impact on HbA1c reduction and weight loss; it is pertinent to note that patients with DR were excluded from the tirzepatide trials (SURPASS).^1,5,6 The much-awaited outcome of the Long -term Effects of Semaglutide on Diabetic Retinopathy in subjects with Type 2 diabetes (FOCUS) study will provide useful information. ⁵ Thus, we reiterate the view that the risk of DR progression should be part of the counselling and consenting process when initiating potent anti-diabetic drugs. It is imperative that the diabetes team works closely with local ophthalmology services to ensure appropriate surveillance is arranged for patients with any DR, importantly for those with sight threatening DR. Patients who have no DR for two consecutive years currently have DES programme review biennially in the UK. With the introduction of newer GLP-1RA and dual incretin mimetics, reverting to annual screening should be considered as the standard of care within the recommendations of the DES in the UK.