Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy

Abstract

Aims: To evaluate diabetic retinopathy (DR) data from across the SUSTAIN clinical trial programme.

Materials and methods: The SUSTAIN clinical trial programme evaluated the efficacy and safety of semaglutide, a glucagon-like peptide-1 analogue, for the treatment of type 2 diabetes (T2D). In SUSTAIN 6, a 2-year, pre-approval cardiovascular outcomes trial, semaglutide was associated with a significant increase in the risk of DR complications (DRC) vs placebo. DR data from across the SUSTAIN trials were evaluated, and post hoc analyses of the SUSTAIN 6 data were conducted. These included subgroup analyses to identify at-risk patients and a mediation analysis with initial change in glycated haemoglobin (HbA1c; percentage-points at week 16) as a covariate, to examine the role of the magnitude of reduction in HbA1c as an intermediate factor affecting risk of DRC.

Results: There was no imbalance in DR adverse events across the SUSTAIN 1 to 5 and Japanese trials. The majority of the effect with semaglutide vs placebo in SUSTAIN 6 may be attributed to the magnitude and rapidity of HbA1c reduction during the first 16 weeks of treatment in patients who had pre-existing DR and poor glycaemic control at baseline, and who were treated with insulin.

Conclusions: Early worsening of DR is a known phenomenon associated with the rapidity and magnitude of improvement in glycaemic control with insulin; the DRC findings in SUSTAIN 6 are consistent with this. Guidance regarding the early worsening of DR is recommended with insulin. Similar recommendations may be appropriate for semaglutide.

Keywords: GLP-1 analogue; antidiabetic drug; diabetic retinopathy.

Figure 1

Kaplan–Meier plots showing time to first event adjudication committee (EAC)‐confirmed diabetic retinopathy complications (DRC) in SUSTAIN 6 by: baseline diabetic retinopathy (DR) status, yes (A), no (B); in patients with DR at baseline with insulin use prior to event, yes (C), no (D). The proportion of patients with events with “unknown” status of DR at baseline was 3 for semaglutide and 1 for placebo (hazard ratio [HR] 2.73; 95% confidence interval [CI] 0.28−26.26); the proportion of patients with events with “unknown” status of DR at baseline with insulin use “yes” was 1 for semaglutide and 1 for placebo (HR 1.29; 95% CI 0.07−22.15). The incidence rate per 100 patient‐years for DRC with semaglutide vs placebo by baseline DR status was 4.16 and 2.63 (with DR); 0.24 and 0.18 (without DR); and 1.33 and 0.49 (unknown/missing), respectively

Figure 2

Glycated haemoglobin (HbA1c) in SUSTAIN 6: Change in HbA1c over time and from baseline to week 104 in the overall population (A and B); change in HbA1c over time and from baseline to week 104 in subjects with diabetic retinopathy complications (DRC; C and D); Post hoc mediation analysis of the effect of change in HbA1c (%) at week 16 for time to first (external) event adjudication committee (EAC)‐confirmed DRC (E). Overall trial population, n = 3297; patients with DRC, n = 79. Values are estimated means (± SE) from a mixed model for repeated measurements analysis using “in‐trial” data from patients in the full analysis set. The table summarizes the results of a post hoc mediation analysis for time to first EAC‐confirmed DRC, together with the results of the prespecified analysis. The mediation analysis assesses the effect of change in HbA1c at week 16 on time to first DRC. This is analysed by an unstratified Cox proportional hazards model, which in addition to treatment (semaglutide, placebo) as a fixed factor also includes “change in HbA1c (% points) at week 16” as a covariate as well as confounding variables “HbA1c at baseline,” “retinopathy at baseline” (“yes,” “no,” “unknown/missing”) and “baseline duration of diabetes.” Variables were deemed to be confounding if they were significantly associated with both a change in HbA1c at week 16 and time to first retinopathy complications. This was analysed by use of separate univariate ANCOVAs and Cox proportional hazards models. Other considered confounders were “gender” and “body weight” at baseline. Missing values of HbA1c were imputed as predicted values from a mixed model for repeated measurements. “Proportion eliminated” is calculated as: (total effect of treatment − controlled direct effect of treatment)/(total effect of treatment −1); ie, the absolute risk reduction from the mediation analysis divided by the total excess risk. Panel A is from Marso SP, Bain SC, Consoli A. et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 375(19):1834–1844. Copyright © (2016) Massachusetts Medical Society. Reprinted with permission. CI, confidence interval; HR, hazard ratio

Figure 3

Incidence of diabetic retinopathy complications (DRC) in SUSTAIN 6 by baseline diabetic retinopathy (DR) and glycated haemoglobin (HbA1c) reduction: patients without baseline DR (A); patients with known pre‐existing DR (B). Values are observed incidence rates per 100 patient‐years of risk (PYR) with error bars representing 95% confidence intervals (CIs). A patient's risk time is defined as the time from randomization to first event or censoring