TY - JOUR

T1 - Effect of continued weekly subcutaneous semaglutide vs placebo on weight loss maintenance in adults with overweight or obesity: The STEP 4 Randomized Clinical Trial

AU - Rubino, Domenica

AU - Abrahamsson, Niclas

AU - Davies, Melanie

AU - Hesse, Dan

AU - Greenway, Frank L

AU - Jensen, Camilla

AU - Lingvay, Ildiko

AU - Mosenzon, Ofri

AU - Rosenstock, Julio

AU - Rubio, Miguel A

AU - Rudofsky, Gottfried

AU - Tadayon, Sayeh

AU - Wadden, Thomas A

AU - Dicker, Dror

AU - Sjödin, Anders Mikael

AU - STEP 4 Investigators

N1 - CURIS 2021 NEXS 387

PY - 2021

Y1 - 2021

N2 - Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.Design, setting, and participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.Main outcomes and measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).Conclusions and relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

AB - Importance: The effect of continuing vs withdrawing treatment with semaglutide, a glucagon-like peptide 1 receptor agonist, on weight loss maintenance in people with overweight or obesity is unknown.Objective: To compare continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, with switch to placebo for weight maintenance (both with lifestyle intervention) in adults with overweight or obesity after a 20-week run-in with subcutaneous semaglutide titrated to 2.4 mg weekly.Design, setting, and participants: Randomized, double-blind, 68-week phase 3a withdrawal study conducted at 73 sites in 10 countries from June 2018 to March 2020 in adults with body mass index of at least 30 (or ≥27 with ≥1 weight-related comorbidity) and without diabetes.Interventions: A total of 902 participants received once-weekly subcutaneous semaglutide during run-in. After 20 weeks (16 weeks of dose escalation; 4 weeks of maintenance dose), 803 participants (89.0%) who reached the 2.4-mg/wk semaglutide maintenance dose were randomized (2:1) to 48 weeks of continued subcutaneous semaglutide (n = 535) or switched to placebo (n = 268), plus lifestyle intervention in both groups.Main outcomes and measures: The primary end point was percent change in body weight from week 20 to week 68; confirmatory secondary end points were changes in waist circumference, systolic blood pressure, and physical functioning (assessed using the Short Form 36 Version 2 Health Survey, Acute Version [SF-36]).Results: Among 803 study participants who completed the 20-week run-in period (with a mean weight loss of 10.6%) and were randomized (mean age, 46 [SD, 12] years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]), 787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment. With continued semaglutide, mean body weight change from week 20 to week 68 was -7.9% vs +6.9% with the switch to placebo (difference, -14.8 [95% CI, -16.0 to -13.5] percentage points; P < .001). Waist circumference (-9.7 cm [95% CI, -10.9 to -8.5 cm]), systolic blood pressure (-3.9 mm Hg [95% CI, -5.8 to -2.0 mm Hg]), and SF-36 physical functioning score (2.5 [95% CI, 1.6-3.3]) also improved with continued subcutaneous semaglutide vs placebo (all P < .001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide vs 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).Conclusions and relevance: Among adults with overweight or obesity who completed a 20-week run-in period with subcutaneous semaglutide, 2.4 mg once weekly, maintaining treatment with semaglutide compared with switching to placebo resulted in continued weight loss over the following 48 weeks.Trial Registration: ClinicalTrials.gov Identifier: NCT03548987.

KW - Adult

KW - Anti-Obesity Agents/pharmacology

KW - Blood Pressure/drug effects

KW - Double-Blind Method

KW - Female

KW - Glucagon-Like Peptide 1/agonists

KW - Glucagon-Like Peptides/adverse effects

KW - Humans

KW - Injections, Subcutaneous

KW - Male

KW - Middle Aged

KW - Obesity/drug therapy

KW - Overweight/drug therapy

KW - Waist Circumference/drug effects

KW - Weight Loss/drug effects

U2 - 10.1001/jama.2021.3224

DO - 10.1001/jama.2021.3224

M3 - Journal article

C2 - 33755728

VL - 325

SP - 1414

EP - 1425

JO - JAMA - Journal of the American Medical Association

JF - JAMA - Journal of the American Medical Association

SN - 0098-7484

IS - 14

ER -