What is the risk of diabetic retinopathy with semaglutide?

Comment by InpharmD Researcher

Semaglutide was associated with a significantly increase risk for diabetic retinopathy compared to placebo in the SUSTAIN-6 trial. This incident may possibly be linked to greater and more rapid reductions in HbA1c levels of patients with pronounced type-2 DM.

Background

The risk of diabetic retinopathy (DR) with the use of semaglutide was originally identified in the SUSTAIN-6 trial (table 1). In previous studies (i.e. SUSTAIN 1 to 5 and Japanese trials), patients with known retinopathy were excluded. Reports of DR were similar between semaglutide and comparators in previous studies with no serious incidents. This contrasts the SUSTAIN-6 trial which reported greater rates and serious incidents of DR complications in the semaglutide group versus placebo. Patients with pre-existing DR were associated with higher rates of DR complications versus placebo and the risk was further increased in those treated with insulin. Stratification of semaglutide-treated patients with pre-existing DR found the highest incidence of DR in those with > 1.5% HbA1c reduction by week 16, indicating that rapid and marked reductions of glycemic control may contribute to worsening DR. [1]

An abstract from a symposium presentation investigated the Food and Drug Administration (FDA) Adverse Event Reporting System and found higher rates of DR for semaglutide (16.4%) from all adverse ocular events compared to other GLP-1 agonists. [2]

An ongoing clinical trial (NCT03811561) sponsored by Novo Nordisk will assess the long-term effects of semaglutide on retinopathy compared to placebo in type-2 diabetic patients. The study is estimated to be completed in 2027 and is still in the recruitment phase. [3]

References:

[1] Vilsbøll T, Bain SC, Leiter LA, et al. Semaglutide, reduction in glycated haemoglobin and the risk of diabetic retinopathy. Diabetes Obes Metab. 2018;20(4):889-897. doi:10.1111/dom.13172
[2] Xiao G, Li A. Food and drug administration adverse event reports of diabetic retinopathy, macular edema and blurred vision associated with glp-1 receptor agonist use. Invest Ophthalmol Vis Sci. 2020;61(7):290-290.
[3] ClinicalTrials.gov. A Research Study to Look at How Semaglutide Compared to Placebo Affects Diabetic Eye Disease in People With Type 2 Diabetes (FOCUS). https://clinicaltrials.gov/ct2/show/NCT03811561. Updated July 15, 2021. Accessed July 24, 2021.
Literature Review

A search of the published medical literature revealed 1 study investigating the researchable question:

What is the evidence for semaglutide and diabetic retinopathy?

Level of evidence

B - One high-quality study or multiple studies with limitations  Read more→


Please see Table 1 for your response.

 

Semaglutide and Cardiovascular Outcomes in Patients with Type 2 Diabetes

Design

Randomized, double-blind, placebo-controlled, parallel-group trial

N=3297

Objective

To assess the noninferiority of semaglutide as compared with placebo in terms of cardiovascular safety in patients with type 2 diabetes.

Study Groups

Semaglutide 0.5 mg (n=826)

Semaglutide 1.0 mg (n=822)

Placebo 5 mg (n=824)

Placebo 10 mg (n=825)

Inclusion Criteria

Age > 50 years; Type 2 diabetes; glycated hemoglobin level > 7%; established cardiovascular disease, chronic heart failure (NYHA II or III), or chronic kidney disease (> stage 3)

Exclusion Criteria

Treated with an antihyperglycemic drug or treated with more than two oral antihyperglycemic agents with or without basal or premixed insulin, treated with DPP-4 inhibitor 30 days prior to screening, treated with GLP-1 receptor agonist or insulin aside from basal or premixed within 90 days before sceening, history of acute coronary or cerebrovascular events within 90 days before randomization, planned revascularization of coronary/carotid/peripheral artery, long-term dialysis

Methods

Patients were randomized (1:1:1:1) to receive either 0.5 mg or 1.0 mg of semaglutide Qweekly or matching placebos. Target HbA1c levels were < 7.0% but alos individualized per patient.

Duration

 109 weeks (104-week treatment and 5-week follow-up)

Outcome Measures

 Secondary: Occurence of retinopathy complications (defined as need for retinal photocoagulation or treatment with intravitreal agents or vitreous hemorrhage or diabetes-related blindness)

Baseline Characteristics

  

Semaglutide 0.5 mg (n=826)

Semaglutide 1.0 mg (n=822)

Placebo 5 mg (n=824)

 Placebo 10 mg (n=825) 

Age, years

 64.6 ± 7.3

64.7 ± 7.1

 64.8 ± 7.6 64.4 ± 7.5

Male

 495 (59.9%) 518 (63.0%) 482 (58.5%) 507 (61.5%)

Type 2 diabetes

Duration, years

Glycated hemoglobin

 

14.3 ± 8.2

8.7% ± 1.4%

 

14.1 ± 8.2

8.7% ± 1.5%

 

14.0 ± 8.5

8.7% ± 1.5%

 

13.2 ± 7.4

8.7% ± 1.5%

Results

 

 

  

Semaglutide (n=1648)

Placebo 5 mg (n=1649)

Occurence of diabetic retinopathy

Hazard ratio (95% confidence interval [CI])

50

1.76 (1.11 to 2.78)

29

 

Study Author Conclusions

 The reason for significant complications of diabetic retinopathy in the semaglutide group compared to placebo is unknown and has not been expounded upon by the authors.

InpharmD Researcher Critique

As incidence of diabetic retinopathy was a secondary outcome, it is unclear whether there is truly a greater risk of diabetic retinoapthy in patients taking semaglutide. A subsequent study that controlled for baseline variables specific to retinopathy is needed to sufficiently answer this question. This study was sponsored and designed by the manufacturers, Novo Nordisk.



References:

Marso SP, Bain SC, Consoli A, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375(19):1834-1844.