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Rubino D, Abrahamsson N, Davies M, et al. Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial. JAMA. 2021 Mar 23. pii: 2777886. doi: 10.1001/jama.2021.3224. (Original study)
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.

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.

Ratings
Discipline Area Score
Cardiology 6 / 7
Endocrine 6 / 7
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Special Interest - Obesity -- Physician 6 / 7
Rheumatology 5 / 7
Gastroenterology 5 / 7
Neurology 5 / 7
Respirology/Pulmonology Coming Soon...
Internal Medicine Coming Soon...
Comments from MORE raters

Cardiology rater

These are interesting and important data as few pharmacologic measures are effective at accomplishing weight loss. I am uncertain, however, how this research will translate into clinical cardiology practice.

Cardiology rater

Interesting parallel-study to the STEP 1 Study (NCT03548935) published online February 10, 2021 in the New England Journal of Medicine and funded by Novo Nordisk. This study offers additional insight to STEP 2 (obese with diabetes) and STEP 3 (intensive behavioral therapy).

Cardiology rater

This is a convincing study to support a new addition for treating the obesity epidemic.

Endocrine rater

A fairly good randomized double-blind control with weekly semaglutide, 2.4 mg, for weight loss with 900 participants over a 68-week period. The results showed that those with semaglutide had 7.9% weight loss vs 6.9% weight gain in the placebo group. Waist circumference, systolic blood pressure, and physical functioning score were better in the treatment group. GI side effects were twice as common in the treatment than the placebo group. Shows a good effect with higher-dose semaglutide for weight loss.

Endocrine rater

This supports what many of us have suspected: obesity is an ongoing chronic disease that requires ongoing pharmacologic therapy to control it, just as diabetes does.

Family Medicine (FM)/General Practice (GP) rater

This well-done study provides data on the effectiveness and safety of weekly subcutaneous semaglutide on obese non-diabetic patients after the original 20-week use of the medication. Obesity is an epidemic in our country, and clinicians struggle to find safe and efficacious adjuvant treatments for our patients. We should feel comfortable recommending semaglutide for weight loss on top of lifestyle modifications. High cost will likely be an issue, but we should not feel discouraged from using it.

Gastroenterology rater

I always cringe when I see "overweight" used as a noun.

Gastroenterology rater

Important study that reinforces the role of semaglutide in obesity and its metabolic complications including nonalcoholic fatty liver disease. Most gastroenterologist and hepatologists are probably unaware of this important study.

Internal Medicine rater

Obesity is a difficult problem to treat. The GLP-1 agonist semaglutide is shown to achieve greater weight loss than lifestyle interventions alone. This trial found that continuing semaglutide, 2.4 mg weekly, for an additional 48 weeks after the participants had lost 10.6% of body weight led to further weight loss, while those switched to placebo regained some of the weight they had lost.

Neurology rater

This is part of a large series of complementary randomized trials (STEP 1, STEP 2, etc) evaluating the efficacy and safety of the GLP-1 agonist semaglutide at higher dose (2.4 mg weekly vs usual 1.0 mg weekly dose for diabetes), in the setting of overweight/obesity in patients with and without diabetes. STEP trials 1 through 4 are all published (this is STEP 4), and show impressive reductions in weight with sustained use of semaglutide. STEP trials 5-8 are still underway or awaiting publication. The sponsor is also examining cardiovascular outcomes in the SELECT trial, which is currently recruiting. These results also complement earlier results from the SUSTAIN and PIONEER trials. The manufacturer is clearly pushing to expand their evidence-base and hopefully with it options to treat overweight/obesity in patients both with and without diabetes. I await the SELECT trial results with anticipation.

Respirology/Pulmonology rater

Long-term semaglutide resulted in continued weight loss and improved BP and lipids compared with 6 months of treatment. As the authors point out, the patients in the trial demonstrated tolerance to the drug's GI side-effects, so it may not be as effective in the general population. Nonetheless, this may be an effective tool in refractory obesity.

Rheumatology rater

I missed how many patients had diabetes mellitus and what kind of medications were taken. That makes the article difficult to interpret. The finding is interesting though, but I wonder why these data have been omitted.

Special Interest - Obesity -- Physician rater

Obesity is still a major public health problem in the USA and worldwide, so the effectiveness of a weekly injectable medicine, already approved for treatment of T2DM, is welcome news. It will be nice to know whether this treatment will also delay or reduce future development of diabetes in the cohort.

Special Interest - Obesity -- Physician rater

This study adds to the growing evidence supporting semaglutide for weight loss. It highlights the need for continued therapy through at least 68 weeks to maintain and add to the clinically significant (11 kg) weight loss acheived after 20 weeks of therapy. There were significant GI side effects, but they did not lead to discontinuation. Long-term follow-up is important to ensure that the weight loss translates into a reduction in clinical outcomes and that no unexpected rare harms arise.
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