OBJECTIVES: Few indirect comparisons have been performed examining health-related quality of life (HRQoL) data, owing in part to paucity of data collection.  As health care delivery becomes increasingly patient-centered, examining HRQoL outcomes with these methods will become important for decision making.  This analysis utilized indirect comparison methods to assess differences in Impact of Weight on Quality of Life – Lite (IWQoL-Lite) total score for canagliflozin (CANA), compared to exenatide QW (ExQW), sitagliptin (SITA), and pioglitazone (PIO), using trial data evaluating these agents as add-on to metformin. METHODS: Published results from the DURATION-2 trial of ExQW compared to PIO and SITA, and subject-level data from a trial comparing CANA to SITA (DIA3006), were available for analyses.  Disease characteristics and baseline IWQoL-Lite scores were similar, and both trials assessed change in IWQoL-Lite total score from baseline to Week 26.  Bayesian fixed-effect models with non-informative priors were used to estimate the difference in IWQoL-Lite total score for CANA (100 and 300 mg, pooled) versus ExQW, SITA, and PIO.  Analyses were also performed to test the robustness of these results, including those that adjusted for potential determinants of HRQoL. RESULTS: In the unadjusted analysis, the probability that CANA is better than ExQW, SITA, and PIO was 60.0% (median difference [95% CrI]: –0.43 [–2.84, 3.62]), 89.9% (1.02 [–0.55, 2.58]), and 99.5% (4.36 [1.06, 7.64]).  Restricted to DURATION-2 inclusion and exclusion criteria, the probabilities were 61.6%, 82.1%, and 98.9%, respectively.  Further adjustment for race and country differences yielded probabilities of 74.6% versus ExQW, 85.9% versus SITA, and 98.5% versus PIO. CONCLUSIONS: The adjusted analyses suggest that CANA is associated with at least similar IWQoL-Lite change scores compared to ExQW and greater improvements in IWQoL-Lite score compared to SITA and PIO.  These analyses illustrate that indirect comparisons of HRQoL data should explore potential determinants of HRQoL.