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 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. While their ability to maintain blood sugar control has been compared extensively between NPH and the long-acting analogues, evidence is lacking or inconsistent on these drugs and the risk of eye, nerve, and kidney complications of diabetes. To our knowledge, there are no studies comparing the risk of nerve and kidney complications between NPH and insulin analogues. A few studies have investigated eye complications and found that they worsen in patients taking insulin analogues more often compared to patients taking NPH. Other studies did not, and they were all done before the introduction of insulin degludec, the newest analogue.
Given the morbidity and mortality associated with diabetic complications, it is important to assess these important outcomes. In this study, we will compare the number of patients with type 2 diabetes who develop these complications while using an insulin analogue to that of patients taking NPH insulin.
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.
While their ability to maintain glycemic control has been compared between NPH and the long-acting analogues, evidence is lacking on comparative risk of microvascular complications (retinopathy, nephropathy, and neuropathy). Some registration studies and RCTs have reported inconsistent results with respect to the impact of glargine and progression of retinopathy compared to NPH, and there are no studies comparing the risk of neuropathy and nephropathy complications between NPH and insulin analogues.
Given the morbidity associated with diabetic microvascular complications and its adverse impact on quality of life, it is important to further assess these important outcomes in a real-world setting. Our study will assess the risk of incident diabetic retinopathy, nephropathy, and neuropathy (as individual endpoints) with the use of long- and ultra long-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 endpoints will be incident diabetic retinopathy, incident non-traumatic minor or major lower limb amputation, and albuminuria. 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.
Retinopathy:
Primary:
Incident diabetic retinopathy
Secondary:
Incident non-proliferative diabetic retinopathy
Incident proliferative diabetic retinopathy
Neuropathy:
Primary
Incident non-traumatic minor or major lower limb amputation
Secondary:
Incident non-traumatic minor lower limb amputation
Incident non-traumatic major lower limb amputation
Re-Amputation of lower limb
Nephropathy:
Primary
Nephropathy
Secondary:
Incident chronic kidney disease
End stage renal disease (ESRD)
Samy Suissa - Chief Investigator - Sir Mortimer B Davis Jewish General Hospital
Kristian Filion - Corresponding Applicant - McGill University
Christopher Filliter - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Julia Brillinger - Collaborator - McGill University
Oriana Hoi Yun Yu - Collaborator - Sir Mortimer B Davis Jewish General Hospital
pauline reynier - Collaborator - Sir Mortimer B Davis Jewish General Hospital
Rachelle El Haber - Collaborator - McGill University
Robert Platt - Collaborator - McGill University
Shahrzad Salmasi - Collaborator - IQVIA Canada
Stephanie Larose - Collaborator - McGill University
WANG-CHOI TANG - Collaborator - McGill University
Wanning Wang - Collaborator - McGill University
Shahrzad Salmasi - Collaborator - McGill University
HES Admitted Patient Care;ONS Death Registration Data