madman
Super Moderator
Once-Weekly Semaglutide in Adolescents with Obesity (2022)
Daniel Weghuber, M.D., Timothy Barrett, Ph.D., Margarita Barrientos-Pérez, M.D., Inge Gies, Ph.D., Dan Hesse, Ph.D., Ole K. Jeppesen, M.Sc., Aaron S. Kelly, Ph.D., Lucy D. Mastrandrea, M.D., Rasmus Sørrig, Ph.D., and Silva Arslanian, M.D., for the STEP TEENS Investigators*
BACKGROUND
A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but an assessment of the drug in adolescents has been lacking.
METHODS
In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary endpoint was the percentage change in BMI from baseline to week 68; the secondary confirmatory endpoint was a weight loss of at least 5% at week 68.
RESULTS
A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was −16.1% with semaglutide and 0.6% with placebo (estimated difference, −16.7 percentage points; 95% confidence interval [CI], −20.3 to −13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had a weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.
CONCLUSIONS
Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.)
Among children and adolescents with obesity (a chronic, progressive disease), other conditions such as dysglycemia, hypertension, dyslipidemia, nonalcoholic fatty liver disease, and obstructive sleep apnea may develop, alongside impairment in mental health and quality of life.1-3 It is predicted that more than 250 million children and adolescents will have obesity by 2030.4
For young people, obesity-management guidelines recommend multimodal lifestyle modification.5-9 However, resulting reductions in body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) are generally modest, and long-term weight maintenance is challenging and rarely achieved.7,10 Pharmacotherapy may be considered if lifestyle intervention alone is ineffective,5,9 but options are limited.9,11 The Food and Drug Administration has approved once-daily liraglutide (3.0 mg), orlistat (120 mg), and phentermine–topiramate (7.5 mg of phentermine with 46 mg of topiramate or 15 mg of phentermine with 92 mg of topiramate) for adolescents at least 12 years of age12-14; only liraglutide is approved by the European Medicines Agency.15
Semaglutide is a glucagon-like peptide-1 analog that induces weight loss by decreasing appetite, thereby improving control of eating and reducing energy intake.16 Among adults with overweight or obesity, once-weekly treatment with subcutaneous semaglutide at a dose of 2.4 mg plus lifestyle intervention elicited clinically meaningful weight loss and improvement with respect to cardiometabolic risk factors and participant-reported physical functioning.17 Semaglutide at a dose of 2.4 mg is approved for long-term weight management as an adjunct to a reduced-calorie diet and increased physical activity for adults with obesity or for adults with overweight who have weight-related coexisting conditions.18,19 The Semaglutide Treatment Effect in People with Obesity (STEP) TEENS trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide plus lifestyle intervention among adolescents with obesity.
Strengths of the trial include the double-blind, multinational design as well as the high percentages of participants in the semaglutide group who completed the trial (99%) and completed treatment (90%), which compare favorably with shorter trials involving adolescents with obesity that assessed liraglutide (79% trial completion and 81% treatment completion)29 and phentermine–topiramate (75% trial completion and 65% treatment completion; 70% of participants completed treatment with the 7.5-mg dose of phentermine and a 46-mg dose of topiramate and 61% completed treatment with the 15-mg dose of phentermine and a 92-mg dose of topiramate).32 As compared with other trials, the focus in this trial on participant retention by the sites and the sponsor, as well as aspects of the trial design, such as flexibility in dose escalation in order to limit unacceptable adverse effects, may have facilitated adherence. Furthermore, the inclusion of a 12-week lifestyle intervention run-in phase before randomization reflects clinical practice recommendations to implement lifestyle modifications for weight loss before initiating pharmacotherapy in adolescents.5,9 The inclusion of parents or guardians in the lifestyle intervention provided throughout the trial may also have contributed to the high completion rates since the inclusion of parents or guardians in lifestyle counseling is known to improve weight-loss outcomes among young people.35
This trial had certain limitations. A longer treatment period would have provided insight into the durability of the effect of semaglutide; in adults, the effect of semaglutide persists over 2 years of treatment.36 A longer follow-up period would have enabled the effect of treatment cessation to be monitored, considering the small BMI regain between weeks 68 and 75. Weight regain after treatment discontinuation has also been observed with liraglutide in adolescents29 and with semaglutide in adults.37,38 In addition, the enrolled trial population may limit the generalizability of the results, in light of the greater number of female than male participants, the relatively small proportions of some racial and ethnic groups, and the inclusion of only eight participants with type 2 diabetes and only one with overweight. Our sample may therefore not be fully representative of the adolescent population with obesity in all countries; for example, in the United States, the prevalence of obesity among male and female adolescents is generally equal and is greater among Hispanic and Black adolescents than among White adolescents.39 It is possible that adolescents of the racial and ethnic groups that were underrepresented in this trial may have different responses to semaglutide, and future studies should address this issue.
In adolescents with obesity, once-weekly treatment with subcutaneous semaglutide at a dose of 2.4 mg in addition to lifestyle intervention resulted in a substantial reduction in BMI as compared with lifestyle intervention alone.
Daniel Weghuber, M.D., Timothy Barrett, Ph.D., Margarita Barrientos-Pérez, M.D., Inge Gies, Ph.D., Dan Hesse, Ph.D., Ole K. Jeppesen, M.Sc., Aaron S. Kelly, Ph.D., Lucy D. Mastrandrea, M.D., Rasmus Sørrig, Ph.D., and Silva Arslanian, M.D., for the STEP TEENS Investigators*
BACKGROUND
A once-weekly, 2.4-mg dose of subcutaneous semaglutide, a glucagon-like peptide-1 receptor agonist, is used to treat obesity in adults, but an assessment of the drug in adolescents has been lacking.
METHODS
In this double-blind, parallel-group, randomized, placebo-controlled trial, we enrolled adolescents (12 to <18 years of age) with obesity (a body-mass index [BMI] in the 95th percentile or higher) or with overweight (a BMI in the 85th percentile or higher) and at least one weight-related coexisting condition. Participants were randomly assigned in a 2:1 ratio to receive once-weekly subcutaneous semaglutide (at a dose of 2.4 mg) or placebo for 68 weeks, plus lifestyle intervention. The primary endpoint was the percentage change in BMI from baseline to week 68; the secondary confirmatory endpoint was a weight loss of at least 5% at week 68.
RESULTS
A total of 201 participants underwent randomization, and 180 (90%) completed treatment. All but one of the participants had obesity. The mean change in BMI from baseline to week 68 was −16.1% with semaglutide and 0.6% with placebo (estimated difference, −16.7 percentage points; 95% confidence interval [CI], −20.3 to −13.2; P<0.001). At week 68, a total of 95 of 131 participants (73%) in the semaglutide group had a weight loss of 5% or more, as compared with 11 of 62 participants (18%) in the placebo group (estimated odds ratio, 14.0; 95% CI, 6.3 to 31.0; P<0.001). Reductions in body weight and improvement with respect to cardiometabolic risk factors (waist circumference and levels of glycated hemoglobin, lipids [except high-density lipoprotein cholesterol], and alanine aminotransferase) were greater with semaglutide than with placebo. The incidence of gastrointestinal adverse events was greater with semaglutide than with placebo (62% vs. 42%). Five participants (4%) in the semaglutide group and no participants in the placebo group had cholelithiasis. Serious adverse events were reported in 15 of 133 participants (11%) in the semaglutide group and in 6 of 67 participants (9%) in the placebo group.
CONCLUSIONS
Among adolescents with obesity, once-weekly treatment with a 2.4-mg dose of semaglutide plus lifestyle intervention resulted in a greater reduction in BMI than lifestyle intervention alone. (Funded by Novo Nordisk; STEP TEENS ClinicalTrials.gov number, NCT04102189.)
Among children and adolescents with obesity (a chronic, progressive disease), other conditions such as dysglycemia, hypertension, dyslipidemia, nonalcoholic fatty liver disease, and obstructive sleep apnea may develop, alongside impairment in mental health and quality of life.1-3 It is predicted that more than 250 million children and adolescents will have obesity by 2030.4
For young people, obesity-management guidelines recommend multimodal lifestyle modification.5-9 However, resulting reductions in body-mass index (BMI, the weight in kilograms divided by the square of the height in meters) are generally modest, and long-term weight maintenance is challenging and rarely achieved.7,10 Pharmacotherapy may be considered if lifestyle intervention alone is ineffective,5,9 but options are limited.9,11 The Food and Drug Administration has approved once-daily liraglutide (3.0 mg), orlistat (120 mg), and phentermine–topiramate (7.5 mg of phentermine with 46 mg of topiramate or 15 mg of phentermine with 92 mg of topiramate) for adolescents at least 12 years of age12-14; only liraglutide is approved by the European Medicines Agency.15
Semaglutide is a glucagon-like peptide-1 analog that induces weight loss by decreasing appetite, thereby improving control of eating and reducing energy intake.16 Among adults with overweight or obesity, once-weekly treatment with subcutaneous semaglutide at a dose of 2.4 mg plus lifestyle intervention elicited clinically meaningful weight loss and improvement with respect to cardiometabolic risk factors and participant-reported physical functioning.17 Semaglutide at a dose of 2.4 mg is approved for long-term weight management as an adjunct to a reduced-calorie diet and increased physical activity for adults with obesity or for adults with overweight who have weight-related coexisting conditions.18,19 The Semaglutide Treatment Effect in People with Obesity (STEP) TEENS trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide plus lifestyle intervention among adolescents with obesity.
Strengths of the trial include the double-blind, multinational design as well as the high percentages of participants in the semaglutide group who completed the trial (99%) and completed treatment (90%), which compare favorably with shorter trials involving adolescents with obesity that assessed liraglutide (79% trial completion and 81% treatment completion)29 and phentermine–topiramate (75% trial completion and 65% treatment completion; 70% of participants completed treatment with the 7.5-mg dose of phentermine and a 46-mg dose of topiramate and 61% completed treatment with the 15-mg dose of phentermine and a 92-mg dose of topiramate).32 As compared with other trials, the focus in this trial on participant retention by the sites and the sponsor, as well as aspects of the trial design, such as flexibility in dose escalation in order to limit unacceptable adverse effects, may have facilitated adherence. Furthermore, the inclusion of a 12-week lifestyle intervention run-in phase before randomization reflects clinical practice recommendations to implement lifestyle modifications for weight loss before initiating pharmacotherapy in adolescents.5,9 The inclusion of parents or guardians in the lifestyle intervention provided throughout the trial may also have contributed to the high completion rates since the inclusion of parents or guardians in lifestyle counseling is known to improve weight-loss outcomes among young people.35
This trial had certain limitations. A longer treatment period would have provided insight into the durability of the effect of semaglutide; in adults, the effect of semaglutide persists over 2 years of treatment.36 A longer follow-up period would have enabled the effect of treatment cessation to be monitored, considering the small BMI regain between weeks 68 and 75. Weight regain after treatment discontinuation has also been observed with liraglutide in adolescents29 and with semaglutide in adults.37,38 In addition, the enrolled trial population may limit the generalizability of the results, in light of the greater number of female than male participants, the relatively small proportions of some racial and ethnic groups, and the inclusion of only eight participants with type 2 diabetes and only one with overweight. Our sample may therefore not be fully representative of the adolescent population with obesity in all countries; for example, in the United States, the prevalence of obesity among male and female adolescents is generally equal and is greater among Hispanic and Black adolescents than among White adolescents.39 It is possible that adolescents of the racial and ethnic groups that were underrepresented in this trial may have different responses to semaglutide, and future studies should address this issue.
In adolescents with obesity, once-weekly treatment with subcutaneous semaglutide at a dose of 2.4 mg in addition to lifestyle intervention resulted in a substantial reduction in BMI as compared with lifestyle intervention alone.
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