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With observational data, standard regression analyses (e.g., Cox modeling) cannot account for time\u2010dependent confounders on causal pathways between exposures and outcome nor for time\u2010dependent selection bias that may arise from informative right censoring. Inverse probability weighting (IPW) estimation to fit marginal structural models (MSMs) has commonly been applied to properly adjust for these expected sources of bias in real\u2010world observational studies. We describe the application and performance of an alternate estimation approach in such a study. The approach is based on the recently proposed targeted learning methodology and consists in targeted minimum loss\u2010based estimation (TMLE) with super learning (SL) within a nonparametric MSM. The evaluation is based on the analysis of electronic health record data with both IPW estimation and TMLE to contrast cumulative risks under four more or less aggressive strategies for treatment intensification in adults with type 2 diabetes already on 2+ oral agents or basal insulin. Results from randomized experiments provide a surrogate gold standard to validate confounding and selection bias adjustment. Bootstrapping is used to validate analytic estimation of standard errors. This application does the following: (1) establishes the feasibility of TMLE in real\u2010world CER based on large healthcare databases; (2) provides evidence of proper confounding and selection bias adjustment with TMLE and SL; and (3) motivates their application for improving estimation efficiency. Claims are reinforced with a simulation study that also illustrates the double\u2010robustness property of TMLE. 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