OBJECTIVES:  With new classes of T2DM medications offering weight reduction in addition to better glycaemic control, HTA agencies expect fuller accounting of the impact of post-trial weight trajectory assumptions on cost-effectiveness.  Four alternative scenarios were examined using the example of the novel SGLT-2 inhibitor canagliflozin (CANA) in the UK treatment setting. METHODS:  The importance of alternative assumptions was illustrated using CANA 300mg versus glimepiride (GLIM; 1mg titrated to 6mg or 8mg) in dual therapy with metformin simulated over 40 years using the ECHO-T2DM model loaded with patient characteristics, treatment effects, and adverse event rates from the DIA3009 trial, in which CANA 300mg reduced body weight by –5.7% versus GLIM over 52 weeks. HbA1c was assumed to drift annually by 0.14% for CANA (similar to metformin in ADOPT), 0.24% for GLIM (as sulphonylurea in ADOPT), and 0.15% for rescue therapy with insulin (initiated when HbA1c >7.5%).  Upon treatment discontinuation, four alternative weight-trajectory assumptions were applied:  (A) weight change maintained permanently; (B) CANA weight reduction disappears fully at treatment discontinuation, GLIM weight-gain permanent; (C) GLIM weight-gain permanent, forced convergence of weight upon CANA discontinuation; (D) weight changes disappear fully at discontinuation for both treatments. A weight increase was applied when insulin was initiated and proportional weight changes were applied when insulin dose was titrated upwards. RESULTS:  CANA 300mg generated more QALYs at modest incremental cost, resulting in ICERs of £2,766 to £4,317 in the scenarios.  Maintaining the benefits permanently (A) generated the largest QALY gain (0.243); complete elimination of benefits at discontinuation (D) offered the smallest (0.198).  The proportions of incremental QALYs attributable to weight differences were 34.4%, 19.5%, 18.9% and 17.4% for Scenarios A to D, respectively.  CONCLUSIONS: CANA 300mg was cost-effective in each of four weight scenarios following discontinuation. Further work is required to define the most clinically plausible scenarios.