OBJECTIVES To investigate HbA1c-reduction by baseline BMI in patients treated with canagliflozin or sitagliptin, using clinical trial and electronic medical record (EMR) data. METHODS Patient-level data from two randomised controlled trials (RCTs) were used to explore HbA1c-reduction from baseline after 52 weeks treatment with canagliflozin (100/300mg) or sitagliptin (100mg) by baseline BMI.  Ordinary least squares (OLS) regression was performed with HbA1c, BMI, eGFR and demographics as covariates, in patients with metformin (MET) or metformin+glimepiride (MET+SU) background therapy. EMR-data (UK General Practitioner data from CPRD) on HbA1c over time in patients treated with sitagliptin were analysed by background therapy using repeated measures analysis, with baseline BMI, HbA1c and demographics as covariates. RESULTS In both RCTs sitagliptin showed a decreasing HbA1c-reduction by increasing baseline BMI, while efficacy of canagliflozin was independent of BMI. The estimated HbA1c-reduction (%) from baseline for sitagliptin in patients with baseline BMI of 25 vs. 40 varied between -0.87 to -0.58 (MET; Δ=0.29,p=0.01) and -0.87 to -0.54 (MET+SU;Δ=0.33,p=0.0014), while a non-significant increase in HbA1c-reduction was observed in high BMI-patients in all canagliflozin-arms (Δ between -0.04 and -0.07).  EMR-data showed similar decreasing effectiveness of sitagliptin in high BMI-patients. Estimated HbA1c-reduction (month 10; baseline HbA1c 9%) was significantly less (MET: Δ=0.30, MET+SU: Δ=0.35, p<0.0001) in patients with BMI 40 vs. 25. No data for canagliflozin were yet available. Lower efficacy of sitagliptin in obese patients has been previously reported in the literature. CONCLUSIONS RCT and EMR-data consistently show that the relative efficacy of anti-diabetic treatments may depend on baseline BMI. Reduced efficacy of sitagliptin and DPP-4 inhibitors in general in obese patients may be explained by a higher degree of insulin-resistance.  Efficacy of canagliflozin is independent of BMI, due to its insulin-independent mechanism of action. Patients' BMI should be taken into account to select effective therapeutic options for patients with T2DM.