Obese and overweight adults who continued treatment with subcutaneous semaglutide after a 20-week run-in period achieved continuous weight loss over the next 48 weeks, researchers found.
While sustained weight loss of between 5%-15% is recommended to improve several conditions associated with overweight/obesity, approved antiobesity medications are only moderately effective, Domenica Rubino, MD, of the Washington Center for Weight Management and Research in Arlington Virginia, and colleagues explained in JAMA. Subcutaneous semaglutide, a glucagon-like peptide 1 (GLP-1) receptor agonist that is currently approved to treat type 2 diabetes (T2D) at a dose of 1.0 mg or less once a week, has demonstrated some success in achieving greater weight loss versus standard obesity therapies when given once daily at a dose of 0.4 mg.
Based on this result, Rubino and colleagues conducted the phase III Semaglutide Treatment Effect in People with Obesity (STEP) 4 program — one in a series of five trials assessing high-dose semaglutide — to compare the efficacy of ongoing once-weekly treatment with subcutaneous semaglutide, 2.4 mg, versus placebo, both with lifestyle intervention, for weight loss among overweight/obese patients who were up-titrated to a 2.4 mg dose of semaglutide over the course of a 20-week run-in.
“In this multicenter, randomized clinical trial, adults with obesity/overweight who continued once-weekly treatment with subcutaneous semaglutide, 2.4 mg, had ongoing and persistent weight loss versus participants who switched to placebo, who gained weight,” Rubino and colleagues wrote. “Continued semaglutide also produced significantly better outcomes for waist circumference, systolic blood pressure, and SF-36 physical functioning scores versus placebo.”
The study authors stressed that, for those who remained on semaglutide, weight loss was not only sustained but continued, resulting in ultimate weight reduction of 17.4% across the entire trial — patients who switched to placebo instead gradually regained weight. “These results emphasize the chronicity of obesity and the need for treatments that can maintain and maximize weight loss,” they wrote.
These findings were presented March 23 at the virtual ENDO2021 meeting.
For this randomized, double-blind, 68-week phase III a withdrawal study, Rubino and colleagues recruited adults with a body mass index (BMI) of 30 or higher with at least one self-reported unsuccessful dietary effort to lose weight or a BMI of 27 or higher with at least one treated or untreated weight-related comorbidity, including hypertension, dyslipidemia, obstructive sleep apnea, cardiovascular disease — patients with T2D were excluded, as were those with hemoglobin A1c of 6.5% or greater and those with a self-reported change in body weight of more than 5 kg within 90 days of screening.
A total of 902 patients were started at a semaglutide dose of 0.25 mg a week, which was up-titrated every four weeks up to the maintenance dose of 2.4 mg once a week by week 16. Participants eligible for randomization at week 20 had to have reached the target 2.4 mg dose by week 16 and have continued taking that dose up to week 20, they added. Following the run-in period, 803 patients (mean age, 46 years; 634 [79%] women; mean body weight, 107.2 kg [SD, 22.7 kg]) were randomized 2:1 to either continue treatment or switch to placebo for 48 weeks with a seven-week follow-up.
Participants also received a lifestyle intervention from week 0-68, “including monthly counseling by qualified health care professionals, in person or by telephone,” the study authors added. “Participants were prescribed a reduced-calorie diet (500-kcal/d deficit relative to estimated energy expenditure calculated at week 0) and increased physical activity (150 min/wk), recorded daily by participants (using paper diaries, apps, or other tools) and reviewed during counseling visits.”
The primary endpoint was percent change in body weight from week 20-68; secondary endpoints included changes in waist circumference, systolic blood pressure, and physical functioning.
Of the 803 study participants who were randomized at week 20, “787 participants (98.0%) completed the trial and 741 (92.3%) completed treatment,” the study authors found. “With continued semaglutide, mean body weight change from week 20 to week 68 was −7.9% versus +6.9% with the switch to placebo (difference, −14.8 [95% CI, −16.0 to −13.5] percentage points; P<0.001). 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 versus placebo (all P<0.001). Gastrointestinal events were reported in 49.1% of participants who continued subcutaneous semaglutide versus 26.1% with placebo; similar proportions discontinued treatment because of adverse events with continued semaglutide (2.4%) and placebo (2.2%).”
A large number of trial participants experienced adverse events (AEs) over the course of the trial — 84.3% of patients reported AEs in the run-in period (2.3% serious AEs), with most (71.4%) experiencing gastrointestinal (GI) tract disorders. During the randomized period, 81.3% and 75.0% reported AEs in the semaglutide and placebo arms, respectively; serious AEs were reported by 7.7% and 5.6% in the semaglutide and placebo arms, respectively.
“Over the entire trial, few participants in either group discontinued treatment because of adverse events, with the majority of participants who continued semaglutide and completed treatment receiving the 2.4-mg dose at week 68,” the study authors wrote. “These results indicate that most participants tolerated the strict up-titration schedule in the trial, and those who continued treatment at the 2.4-mg/wk dose beyond 20 weeks were unlikely to experience significant tolerability challenges thereafter.”
Study limitations included inflexibility in the run-in period that limited assessment to participants who tolerated the dosing schedule, a lack of assessment of adherence to lifestyle interventions, and the withdrawal design, which may have resulted in selection bias.
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Patients who were overweight/obese who continued taking 2.4 mg semaglutide once a week following a 20 week run-in period saw sustained weight loss over the following 48 weeks compared to patients who switched to placebo.
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In addition to weight loss, continued semaglutide produced significantly better outcomes for waist circumference, systolic blood pressure, and SF-36 physical functioning scores versus placebo.
John McKenna, Associate Editor, BreakingMED™
This study was funded by Novo Nordisk A/S, Søborg, Denmark, and representatives for the company were involved in the trial design and conduct of the study.
Rubino reported being a clinical investigator for Boehringer Ingelheim and AstraZeneca and receiving speaker fees, consulting fees, and honoraria from Novo Nordisk and being a shareholder in Novo Nordisk. Study coauthors reported relationships with Novo Nordisk, Eli Lilly, Gilead Sciences, Janssen, Lexicon, Napp Pharmaceuticals, Takeda Pharmaceuticals, and others.
Cat ID: 795
Topic ID: 76,795,730,795,518,917
