Use of Continuous Exposure Variables when Examining Dose-Dependent Pharmacological Effects - Application to the Association between Exposure to Higher Statin Doses and the Incidence of Diabetes

Background: Many observational studies have found an association between the exposure to statins and the increased risk of diabetes, mostly through the use of intent-to-treat (ITT) like exposure measure (EM). ITT like EM may not adequately reflect the mechanism of action by which statins could cause diabetes.

Objectives: To determine if continuous EMs can more accurately reflect the mechanism of action by which statins and incidence of diabetes would be associated than ITT like EM.

Methods: We obtained a cohort of 404,129 diabetes-free incident statin users from the Québec public drug insurance plan. Patients dispensed with a drug used in the treatment of diabetes or diagnosed with diabetes within 2-years follow-up were defined as cases. Controls were randomly matched to each case on the index date. Three EMs were tested. EM 1: exposure to a high versus low dose statin at baseline (ITT like); EM 2: cumulative standardized statin dose (cSSD) at the index date; and EM 3: cSSD in the 180 days prior to the index date. The optimal EM was selected based upon each model's Akaike's information criterion (AIC). Conditional logistic regressions were used to calculate conditional OR and model AIC.

Results: All three EMs identified an increased risk of diabetes among patients exposed to higher statin doses. Model AIC identified EM 3 as the best EM for this association.

Conclusions: Our results indicate that higher statin doses increase the risk of diabetes but favour a cumulative reversible diabetogenic effect of statins.