Long-acting insulin analogues and the risk of diabetic retinopathy in type 2 diabetes patients

Date of Approval: 
2020-09-01 00:00:00
Lay Summary: 
Type 2 diabetes is a disease characterized by high blood sugar levels. Although it is often treated only with medication taken by mouth, it sometimes requires treatment with insulin. There are two main types of insulin: human insulin and insulin analogues, which are bioengineered insulins that recently became available. One of the most commonly used human insulins is the intermediate acting Neutral Protamin Hagedorn insulin (NPH.) The long-acting analogues (which last about 24 hours) have a few advantages over older NPH, including once a day injections instead of twice a day, a lower risk of low blood sugar at night time, and less weight gain. Long-acting analogues also bind to a receptor implicated in diabetic retinopathy, an eye complication of diabetes. The available evidence regarding these drugs and the risk of diabetic retinopathy is inconsistent. Some studies comparing insulin analogues to NPH found that this eye complication worsens in patients taking insulin analogues more often compared to patients taking NPH. Other studies did not, but they were done before the introduction of insulin degludec, the newest analogue. No study has looked specifically at whether the long-acting analogues, including degludec, increase the risk of new diabetic retinopathy among patients with type 2 diabetes. Given the potential of diabetic retinopathy to cause blindness, it is important to assess this potential side effect. In this study, we will compare the number of patients with type 2 diabetes who develop diabetic retinopathy while using an insulin analogue to that of patients taking NPH insulin.
Technical Summary: 
Insulin analogues’ flat, long-acting profile and reduced hypoglycemia risk have made them popular choices as basal insulins for many patients with type 2 diabetes. Newer, longer acting and flatter insulins are being tested, and relatively recent additions to the market are the ultra-long-acting insulin analogues glargine 300U and degludec. Preclinical in vitro and in vivo studies have suggested that glargine increases the affinity of insulin-like growth factor 1 (IGF-1) receptors. Importantly, IGF-1 is implicated in the pathophysiology of diabetic retinopathy. Some registration studies inconsistently suggested that glargine might lead to greater progression of retinopathy compared to NPH insulin. In contrast, one randomized controlled trial found that glargine did not lead to increased progression of retinopathy than NPH over 5 years of follow-up. However, this non-inferiority trial examined glargine only, included some patients who did have non-proliferative retinopathy at baseline, and was not designed to determine if insulin glargine increased the risk of retinopathy progression or incidence. Given the morbidity associated with diabetic retinopathy and its adverse impact on quality of life, it is important to further assess this potential adverse drug reaction in a real-world setting. Our study will assess the risk of incident diabetic retinopathy with the use of long- and ultralong-acting insulin analogues versus with the use of NPH insulin among patients with type 2 diabetes using the United Kingdom’s (UK) Clinical Practice Research Datalink (CPRD). The primary endpoint will be incident diabetic retinopathy, defined by a new diagnosis for either non-proliferative or proliferative diabetic retinopathy. We will use Cox proportional hazards models to compare event rates with the use of insulin analogues to those with the use of NPH insulin. Secondary analyses will examine if the risks differ by molecule, duration of use, sex, age, or prior history of other microvascular or macrovascular complications.
Health Outcomes to be Measured: 
Incident diabetic retinopathy Incident non-proliferative diabetic retinopathy Incident proliferative diabetic retinopathy
Application Number: 

Samy Suissa - Chief Investigator - McGill University
Kristian Filion - Corresponding Applicant - McGill University
Christopher Filliter - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
pauline reynier - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Robert Platt - Collaborator - McGill University
Stephanie Larose - Collaborator - McGill University

HES Admitted Patient Care;ONS Death Registration Data