Calanna, Salvatore

Kushner, Robert F

Wilding, John PH

Javor, Eugen

Lucijanic, Marko

Skelin, Marko

University of Liverpool Repository

Letter to NEJM re:  STEP 1 trial correspondenceJohn P.H. Wilding, D.M., Salvatore Calanna, MD Ph.D., and Robert F. Kushner, M.DWe would like to thank the editors for giving us the opportunity to respond to the correspondence relating to the STEP1 study1. Javor asks questions about hypoglycaemia; extensive clinical experience in type 2 diabetes with GLP1 RA and in obesity with liraglutide shows that severe hypoglycaemia is rare with these agents. In type 2 diabetes the majority of events occur in people taking concomitant sulfonylurea or insulin therapy which was not relevant for STEP 1 as no participants with diabetes were included in the trial. The suggestion of measuring fasting blood glucose during study visits is reasonable, but in the SCALE obesity and prediabetes trial2 most of the events reported were asymptomatic readings below 3.9mmol/l during fasting study visits, and there were no severe episodes of hypoglycaemia; similar results were seen in the phase 2 trial with semaglutide3, hence this was not considered essential for the safety of study participants during STEP 1. Koo and Lin ask about the efficacy in people with type 2 diabetes. This is indeed important and has been addressed in the separate STEP 2 study4. Their question about GLP1 RA as an adjunct to bariatric surgery is interesting. This group was excluded from the current trial, although a number of trials are addressing this question with liraglutide 3.0mg (e.g. NCT033414295 and NCT035343106). This is certainly an area that would be of interest for future research with semaglutide. ReferencesWilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity. N Engl J Med 2021;384:989-1002.Xavier Pi-Sunyer, Arne Astrup, Ken Fujioka et al. Liraglutide in Weight Management- A Double-blind Randomized Controlled Trial New England Journal of Medicine 2015 373:11-22.O'Neil PM, Birkenfeld AL, McGowan B, et al. Efficacy and safety of semaglutide compared with liraglutide and placebo for weight loss in patients with obesity: a randomised, double-blind, placebo and active controlled, dose-ranging, phase 2 trial. Lancet. 2018 Aug 25;392(10148):637-649. Davies M, Færch L, Jeppesen OK et al.  Semaglutide 24 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2): a randomised, double-blind, double-dummy, placebo-controlled, phase 3 trial. Lancet. 2021 Mar 13;397(10278):971-984Available at https://clinicaltrials.gov/ct2/show/NCT03341429Available at https://clinicaltrials.gov/ct2/show/NCT03534310

Once-Weekly Semaglutide in Adults with Overweight or Obesity REPLY

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