Vivian A Fonseca1, Matthew S Capehorn2, Satish K Garg3, Esteban Jódar Gimeno4, Oluf Hoejbjerg Hansen5, Anders Gaarsdal Holst5, Gurudutt Nayak5, Jochen Seufert6. 1. Tulane University Health Sciences Center, New Orleans, Louisiana, USA. 2. Rotherham Institute for Obesity, Clifton Medical Centre, Rotherham, UK. 3. University of Colorado Denver, Denver, Colorado, USA. 4. Hospital Universitario Quirón Salud Madrid, Universidad Europea de Madrid, Madrid, Spain. 5. Novo Nordisk A/S, Søborg, Denmark. 6. University of Freiburg Medical Center, Medical Faculty, University of Freiburg, Freiburg, Germany.
Abstract
CONTEXT: Semaglutide, a once-weekly glucagon-like peptide 1 (GLP-1) analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the SUSTAIN 1-3 clinical trials. OBJECTIVE: To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials. DESIGN: Post hoc analysis of the SUSTAIN 1-3 trials. SETTING: 311 sites in 30 countries. Patients or Other Participants: 2,432 subjects with T2D. INTERVENTIONS: Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg). MAIN OUTCOME MEASURE: To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW. RESULTS: Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7-4.3 kg; p<0.0001) and semaglutide 1.0 mg (4.5-6.1 kg; p<0.0001) vs comparators (1.0-1.9 kg). There were significantly greater reductions in IR with semaglutide 0.5 mg (27-36%) and semaglutide 1.0 mg (32-46%) vs comparators (17-28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70-80% and 34-94%, respectively, for semaglutide 0.5 mg and 1.0 mg vs comparator). CONCLUSIONS: Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1-3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.
CONTEXT: Semaglutide, a once-weekly glucagon-like peptide 1 (GLP-1) analog approved for use in patients with type 2 diabetes (T2D), demonstrated superior body weight (BW) reductions and decreased insulin resistance (IR) vs comparators across the SUSTAIN 1-3 clinical trials. OBJECTIVE: To investigate the relationship between IR and BW across the SUSTAIN 1-3 trials. DESIGN: Post hoc analysis of the SUSTAIN 1-3 trials. SETTING: 311 sites in 30 countries. Patients or Other Participants: 2,432 subjects with T2D. INTERVENTIONS: Semaglutide 0.5 or 1.0 mg, placebo or active comparator (sitagliptin 100 mg, exenatide extended release 2.0 mg). MAIN OUTCOME MEASURE: To assess the extent of the effect on IR that is mediated (indirect effect) and not mediated (direct effect) by the effect on BW. RESULTS: Across SUSTAIN 1-3, mean BW was significantly reduced with semaglutide 0.5 mg (3.7-4.3 kg; p<0.0001) and semaglutide 1.0 mg (4.5-6.1 kg; p<0.0001) vs comparators (1.0-1.9 kg). There were significantly greater reductions in IR with semaglutide 0.5 mg (27-36%) and semaglutide 1.0 mg (32-46%) vs comparators (17-28%). Greater reductions in BW were generally associated with greater decreases in IR. The effect on IR was primarily mediated by weight loss (70-80% and 34-94%, respectively, for semaglutide 0.5 mg and 1.0 mg vs comparator). CONCLUSIONS: Semaglutide consistently reduced BW and IR in subjects with T2D in SUSTAIN 1-3. In this analysis, IR improvement was positively associated with, and primarily mediated by, the effect of semaglutide on BW.
Authors: Ricardo J Samms; Michael E Christe; Kyla Al Collins; Valentina Pirro; Brian A Droz; Adrienne K Holland; Jessica L Friedrich; Samantha Wojnicki; Debra L Konkol; Richard Cosgrove; Ellen Ps Conceição Furber; Xiaoping Ruan; Libbey S O'Farrell; Annie M Long; Mridula Dogra; Jill A Willency; Yanzhu Lin; Liyun Ding; Christine C Cheng; Over Cabrera; Daniel A Briere; Jorge Alsina-Fernandez; Ruth E Gimeno; Julie S Moyers; Tamer Coskun; Matthew P Coghlan; Kyle W Sloop; William C Roell Journal: J Clin Invest Date: 2021-06-15 Impact factor: 14.808
Authors: Melissa K Thomas; Amir Nikooienejad; Ross Bray; Xuewei Cui; Jonathan Wilson; Kevin Duffin; Zvonko Milicevic; Axel Haupt; Deborah A Robins Journal: J Clin Endocrinol Metab Date: 2021-01-23 Impact factor: 5.958
Authors: Hussein N Yassine; Victoria Solomon; Angad Thakral; Nasim Sheikh-Bahaei; Helena C Chui; Meredith N Braskie; Lon S Schneider; Konrad Talbot Journal: Alzheimers Dement Date: 2021-10-14 Impact factor: 16.655