OBJECTIVES: Guidelines for T2DM specify goals for biomarkers (e.g., A1c, SBP, LDL, weight), emphasize the avoidance of hypoglycemia, and acknowledge the critical role that individuals play in managing their disease. This study explored whether goal attainment was associated with HRQoL, using data from a previously reported 52 week study of canagliflozin 100 mg and 300 mg versus glimepiride with metformin and background diet and exercise. METHODS: This post-hoc analysis included subjects for whom baseline and post-baseline clinical and HRQoL data were available (n=1111/1450). HRQoL was measured using the Impact of Weight on Quality of Life – Lite (IWQOL-Lite) and Short Form 36 (SF-36) questionnaires. Distributions of subjects achieving/not achieving the following individual goals: A1c <7%, SBP < 130 mmHg, LDL-C < 100 mg/dL, no symptomatic hypoglycemia, and any weight loss were calculated for pooled canagliflozin arms and glimepiride. The least-square mean (LSM) change in IWQOL-Lite Total and SF-36 physical (PCS) and mental (MCS) composite scores were calculated by goal status, adjusting for baseline score, trial stratification factors, and treatment. RESULTS: The proportions of subjects meeting biomarker goals did not differ by treatment at baseline. At 52 weeks, the proportion meeting A1c, SBP, LDL, no symptomatic hypoglycemia, and weight goals were 61.5, 64.7, 40.3, 97.7, and 87.2, respectively for canagliflozin and 58.2, 53.3, 48.9, 73.0, and 28.1, respectively for glimepiride. LSM change in IWQOL-Lite by goal status was statistically different for weight loss (Δ = 2.1; 95% CI: 0.5, 3.7). LSM change in PCS did not differ by goal status. LSM change in MCS was statistically significant for symptomatic hypoglycemia (Δ = 2.7; 95% CI: 1.0, 4.3). CONCLUSIONS: These results show that the choice of glucose lowering agent can impact goal attainment and suggest that therapies offering weight loss and avoidance of symptomatic hypoglycemia can have a positive impact on HRQoL.