Maintenance semaglutide injections led to continued weight loss — STEP 4

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Sticking with weekly semaglutide injections resulted in continued weight loss for adults with overweight and obesity, according to the Semaglutide Treatment Effect in People with Obesity (STEP) 4 study.

MedPage Today reports Dr Domenica Rubino, of the Washington Centre for Weight Management and Research in Arlington, Virginia, and colleagues said that in this 68-week, randomised double-blind trial among adults with obesity but free of diabetes, mean weight loss for those on 2.4 mg semaglutide totalled 17.8 kg (39.2 lb), with 7.1 kg (15.6 lb) of that loss coming after participants had already been on the drug for 20 weeks.

Similar patterns were seen for other endpoints, according to the study's presentation at the Endocrine Society's virtual ENDO 2021 meeting .

The trial included 803 participants who all completed a 20-week run-in phase, in which they received the glucagon-like peptide 1 (GLP-1) receptor agonist semaglutide – starting with 16 initial weeks of dose escalation until they reached 4 weeks on the full maintenance dose of 2.4 mg per week – in conjunction with lifestyle intervention aimed around a 500-calorie-deficit diet and target of 150 minutes per week of physical activity.

All participants were 18 or older with at least one prior unsuccessful attempt to lose weight through diet. Participants had a body mass index (BMI) of 30 or higher, or a BMI of ≥27 plus at least one weight-related comorbidity including hypertension, dyslipidemia, obstructive sleep apnoea, or cardiovascular disease. None of the participants had type 2 diabetes at baseline.

During these initial 20 weeks, the total cohort experienced an average loss of 10.6% of baseline body weight.

Following this, 535 participants – who already achieved their target maintenance dose of 2.4 mg weekly – were randomised to continue on their 2.4-mg-per-week dose of semaglutide for an additional 48 weeks. They were compared with 268 participants who were switched to placebo.

Throughout the remaining 48 weeks of the trial, those who continued on semaglutide continued to shed the pounds, losing an additional average of 7.9% of body weight. On the other hand, those who were switched to placebo saw the weight loss benefits reverse, gaining back an average of 6.9% of body weight (difference -14.8%, 95% CI -16.0 to -13.5%, P<0.001).

Those who continued on treatment also saw a slew of other benefits, including a significant drop in 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 Short Form 36 Version 2 Health Survey, Acute Version (SF-36) physical functioning score (2.5 points, 95% CI 1.6-3.3).

As to be expected with a GLP-1 receptor agonist, about half of patients who continued on semaglutide experienced gastrointestinal adverse events versus about 26% of those on placebo. Most adverse events were mild to moderate, the most common of which included diarrhea, nausea, and constipation.

This is the fourth and final installment in the phase III STEP clinical programme, building upon three previous trials. The first trial – STEP 1 – found that patients with a BMI of 30 or higher without diabetes saw an average 14.9% loss of baseline body weight after 68 weeks of treatment.

As for the STEP 2 trial, semaglutide was also proven effective in overweight adults with type 2 diabetes, yielding an average 9.6% loss of baseline body weight after 68 weeks.

And the third installment in this clinical programme found that semaglutide plus intensive behavioural therapy helped adults with overweight or obesity lose an average of 16% of body weight.

MedPage Today reports that based on this clinical programme, Novo Nordisk filed for US Food and Drug Administration approval of the 2.4-mg weekly dose of semaglutide, seeking an indication for chronic weight management in December 2020.

Semaglutide is already available in a 0.5-mg and 1-mg injectable dose sold under the trade name Ozempic, which is indicated for type 2 diabetes and risk reduction of major cardiovascular events, including heart attack, stroke, and death, in adults with type 2 diabetes with known heart disease, which was first approved in December 2017.

And in September 2019, an oral form of semaglutide was approved in 7-mg and 14-mg tablets, sold under the trade name Rybelsus, likewise indicated for type 2 diabetes.

Novo Nordisk also holds approval for liraglutide, another GLP-1 receptor agonist, sold under the trade name Victoza (1.2 or 1.8 mg/day) indicated for type 2 diabetes.

Following this initial approval in 2010, liraglutide was later approved under the name Saxenda (3 mg/day) in 2014 for chronic weight management in adults with a BMI of 30 or higher, or a BMI of 27 or higher and at least one weight-related medical condition.

 

Study details
Effect of Continued Weekly Subcutaneous Semaglutide vs Placebo on Weight Loss Maintenance in Adults With Overweight or Obesity: The STEP 4 Randomized Clinical Trial

Domenica Rubino; Niclas Abrahamsson; Melanie Davies; Dan Hesse; Frank L Greenway; Camilla Jensen; Ildiko Lingvay; Ofri Mosenzon; Julio Rosenstock; Miguel A Rubio; Gottfried Rudofsky; Sayeh Tadayon; Thomas A Wadden; Dror Dicker; for the STEP 4 Investigators

Published in JAMA on 23 March 2021

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.

 

Full MedPage Today report (Restricted access)

JAMA study (Open access)

 

 

See also MedicalBrief archives:

STEP 2 trial: Semaglutide hope for patients with type 2 diabetes

 

Regulatory approval sought for ‘gamechanger’ obesity drug


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