Comparison of Type 2 Diabetes Pharmacotherapy Regimens Using Targeted Learning
Conditions: Type 2 Diabetes Mellitus, Cardiovascular Diseases
Sponsor: Kaiser Permanente

 
 
Comparison of Type 2 diabetes Pharmacotherapy Regimens Using Targeted Learning 
 
NCT05073692 
11/10/2025 
 
 

Study Protocol 
Objectives 
This project aims to compare cardiovascular risks (3-point MACE) between four glucose-
lowering treatment regiments (SU, DPP4, GLP1, and SGLT2) in patients with type 2 
diabetes. 
Design 
This project is an observational retrospective cohort study using health care data from six 
health care systems. 
Methods 
All study aims are addressed by estimating causal eƯects conceptualized by the 
comparisons of time-to-event outcomes between exposure regimens in ideal Randomized 
Clinical Trials (RCTs), i.e., RCTs with perfect compliance and no loss to follow up.  
Statistical Analysis Plan 
 
How Data Were Analyzed 
Data were analyzed using R.  
 
What Statistical Methods Were Used 
We implemented Targeted Learning and Inverse Probability Weighting to estimate three 
classes of eƯect measures using longitudinal observational data: hazard ratios (HR), 
cumulative risk diƯerences (RD), and diƯerences between areas under the survival curves 
(also termed “restricted mean survival time”). Each of them were evaluated under both the 
intention-to-treat and per-protocol principles used in the analysis of RCT data.  
 
How Adjustments Were Made for Covariates 
All analyses were adjusted for 400 covariates using Super Learning for propensity score 
estimation, and LASSO for outcome regressions. 
 
Critical Assumption 
Analyses relied on the untestable no unmeasured confounding assumption. 
For additional details, see: 
Neugebauer R, An J, Dombrowski SK, et al. Glucose-Lowering Medication Classes and 
Cardiovascular Outcomes in Patients With Type 2 Diabetes. JAMA Netw Open. 
2025;8(10):e2536100. doi:10.1001/jamanetworkopen.2025.36100 

 
Informed Consent Form 
Not Applicable.