Long-acting Insulin Analogues versus Neutral Protamine Hagedorn Insulin and the Risk of Severe Hypoglycemia Among Patients in Type 2 Diabetes in the United Kingdom

Background: Hypoglycemia is a well-recognized adverse effect of insulin treatment, and it is associated with serious consequences including hospitalization, coma, and death. Observational studies on the risk of hypoglycemia with the use of long-acting insulin analogues and NPH included important methodological limitations that limit the interpretability of their results.

Objectives: To compare the risk of severe hypoglycemia with long-acting insulin analogs versus Neutral Protamine Hagedorn (NPH) insulin among patients with type 2 diabetes in the United Kingdom (UK).

Methods: We used the UK Clinical Practice Research Datalink Aurum, linked with Hospital Episodes Statistics (HES) data and Office for National Statistics vital statistics data to conduct a retrospective cohort study of patients with type 2 diabetes initiating basal insulins between 2002 and 2018. Exposure was defined in a time-varying manner, where each person-month of follow-up was classified as either: 1) current use of long-acting insulin analogues (glargine, detemir, or degludec) or 2) current use of NPH insulin. Patients were censored upon insulin treatment combination or discontinuation. Our primary outcome was hospitalization for hypoglycemia. We used a marginal structural Cox proportional hazards model with time-varying inverse probability of treatment weights (IPTW) and inverse probability of censoring weights (IPCW) to estimate the hazard ratio (HR) and 95% confidence interval (CI) for the risk of hospitalization for hypoglycemia with current use of long-acting insulin analogues versus NPH insulin, overall and by insulin molecule.

Results: Our cohort (n = 57,336 patients) experienced 1,842 severe hypoglycemic events during a mean follow-up duration of 1.7 (standard deviation: 2.3) years (incidence rate: 19.6, 95% CI: 18.8, 20.6 per 1,000 person-years). After adjusting for potential confounders, long-acting insulin analogues were associated with a decreased risk of severe hypoglycemia compared to NPH (HR: 0.87, 95% CI: 0.79, 0.95). Secondary analyses by molecule revealed a reduced risk of severe hypoglycemia with glargine compared to NPH (HR: 0.83, 95% CI: 0.74, 0.94). The HRs were 0.93 (95% CI: 0.79, 1.11) for detemir and 1.22 (95% CI: 0.62, 2.37) for degludec. Results were consistent across sensitivity analyses.

Conclusions: Current use of long-acting insulin analogues is associated with a reduced risk of severe hypoglycemia compared to current use of NPH insulin among patients with type 2 diabetes.