Abstract
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.
Introduction
Obesity is a chronic, relapsing disease with a substantial burden on individuals, society, and the economy. Maintaining long-term weight loss is challenging because of metabolic adaptation and the difficulty of adhering to lifestyle interventions, with weight regain often following weight loss.
Sustained weight loss of 5% to 15% is advised to improve many conditions associated with overweight/obesity, with adjunctive pharmacotherapy recommended to help achieve this goal. However, approved antiobesity medications have only moderate efficacy (3%-8% body weight reduction beyond lifestyle intervention alone). Short-term treatment (3-6 months) fails to produce long-term health benefits, while several agents also have safety concerns. Well-tolerated new therapies that can produce substantial, sustained weight loss, when used long term, are therefore needed.
Subcutaneous semaglutide is a glucagon-like peptide 1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes at doses of 1.0 mg or less once weekly. Weight loss with semaglutide is believed to stem from improved appetite control, and consequent reduced energy intake, via effects in the hypothalamus and area postrema of the brain. Once-weekly subcutaneous semaglutide, 2.4 mg, is being investigated for the treatment of overweight/obesity in the global phase 3 Semaglutide Treatment Effect in People With Obesity (STEP) program. This dose, which is greater than what is currently approved for type 2 diabetes, was chosen based on a phase 2 clinical trial, in which greater weight loss was seen with once-daily semaglutide, 0.4 mg (equal to 2.8 mg/wk), vs current approved medical therapy. Proposed to be more clinically convenient, weekly administration was supported by a tolerability trial and pharmacokinetic modeling.
The STEP 4 withdrawal trial was conducted to compare the effect of continuing once-weekly treatment with subcutaneous semaglutide, 2.4 mg, vs switching to placebo (both with lifestyle intervention) on body weight in participants with overweight/obesity who reached a semaglutide treatment dosage of 2.4 mg once weekly during an initial 20-week run-in...
Discussion
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 vs participants who switched to placebo, who gained weight. Continued semaglutide also produced significantly better outcomes for waist circumference, systolic blood pressure, and SF-36 physical functioning scores vs placebo.
In those who continued semaglutide after randomization, weight loss achieved during the run-in period not only was sustained but continued, reaching a plateau at week 60 to week 68 and ultimately resulting in an estimated reduction of 17.4% over the entire trial. In contrast, participants who switched to placebo at week 20 gradually regained weight. The benefits of continuing semaglutide treatment for 68 weeks, rather than switching to placebo after 20 weeks, are consistent with findings from other withdrawal trials of antiobesity medications. These results emphasize the chronicity of obesity and the need for treatments that can maintain and maximize weight loss.
The significant and sustained weight loss demonstrated with continued semaglutide in this study was accompanied by sustained improvement in waist circumference, lipid profiles, and glucose metabolism, all of which are cardiometabolic risk factors. Sustained weight loss of a similar magnitude to that observed in this trial has been linked to improvements in obesity-related complications, such as type 2 diabetes, with treatment guidelines recommending sustained weight loss of 5% to 15% for people with these conditions. The sustained effects of semaglutide on body weight and cardiometabolic risk factors, as well as participants’ physical and mental functioning, indicate the potential for positive effects on such obesity-related complications.
The optimization and maintenance of weight loss are key goals of obesity management, but individuals can vary in their response to treatment; it is therefore of clinical interest to examine the proportions of people achieving clinically relevant weight loss to support applicability in nonresearch clinical settings. In the present study, 40% of participants who continued semaglutide lost an additional 10% of body weight during the randomized period, as shown by eFigure 2B in Supplement 1, supporting its use for long-term treatment of obesity. Furthermore, 64% of those who took semaglutide for 68 weeks lost at least 15% of their week 0 body weight, targets not achieved by currently approved pharmacotherapy. For example, with the GLP-1 receptor agonist liraglutide, at a 3.0-mg/d dosage, which is approved for weight management, weight losses of 10% or more and 15% or more were achieved by 33% and 14%, respectively, among people treated for 56 weeks. Furthermore, weight loss with liraglutide in clinical trials was of lesser magnitude and appeared to plateau earlier (at 20 weeks or 40 weeks) than with semaglutide in the present trial (at 60-68 weeks). Given the modest efficacy of currently approved pharmacotherapies, semaglutide may offer the potential to bridge the gap between behavioral and pharmacological options and bariatric surgery, which is currently considered the most effective and reliable intervention available for weight management. For example, 40% of participants in this trial who took semaglutide for 68 weeks lost 20% or more of their initial body weight, approaching the level of weight loss seen with sleeve gastrectomy.
Although a higher maintenance dosage of semaglutide (2.4 mg/wk) was used in this trial, the adverse event profile and tolerability were consistent with data from a phase 2 study in people with obesity and semaglutide trials in patients with type 2 diabetes using lower maintenance dosages (up to 1.0 mg/wk), as well as with that reported for other GLP-1 receptor agonists, with no new concerns. Typical of this class, transient, mild to moderate gastrointestinal tract disorders were the most frequently reported adverse events. More of these events occurred during the run-in period, when semaglutide was escalated to the target dose, compared with the randomized period, despite the randomized period being twice as long. 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. 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.
The withdrawal design was a strength of the study, as participants receiving the experimental treatment continued to do so only if they achieved a desired target, while also enabling study of the withdrawal effect in participants who switched to placebo. Additional strengths of the study include the large sample size, blinded design, and high rates of treatment regimen and trial completion. The high treatment and trial completion rates were likely a result of multiple factors, including a focus on participant retention, selection of a population who could tolerate semaglutide during run-in, and inclusion of participants who had previously attempted to lose weight and so were likely motivated to continue in the trial following weight loss in the run-in period...
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 41.9% 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.