STEP TEENS trial: Semaglutide in adolescents reduces weight and improves liver health
Two new secondary analyses of the STEP TEENS trial presented at this year's European Congress on Obesity have reported that almost half (45%) of the adolescents assigned to semaglutide managed to lose enough weight to drop below the clinical cut-off for obesity, and they experienced significant reductions in levels of liver enzymes that are an indicator of liver damage.
In the STEP TEENS randomised controlled trial adolescents with obesity received once-weekly subcutaneous semaglutide 2.4 mg or placebo, plus lifestyle intervention which comprised counselling in healthy nutrition and a goal of 60 minutes of moderate- to high-intensity physical activity per day. Achievement of an improvement in BMI category and attainment of normal weight or overweight BMI category by week 68 were analysed using logistic regression models. Participants were randomised 2:1 to once-weekly subcutaneous semaglutide 2.4 mg (n=134) or placebo (n=67) for 68 weeks.
The first study led by Dr Aaron S Kelly, co-director of the Center for Pediatric Obesity Medicine at the University of Minnesota, Minneapolis, and colleagues, examined the effect of semaglutide treatment on improvement in body mass index (BMI) categories. Adolescents aged 12 to under 18 years with BMI in the highest 5% were included in this analysis. The proportion of participants who achieved an improvement in BMI category from baseline to week 68 was assessed using on-treatment data.
BMI categories, based on Centers for Disease Control and Prevention BMI charts, were: normal weight (BMI ≥5th to <85th percentile); overweight (BMI ≥85th to <95th percentile); and obesity class I (OCI; BMI ≥95th percentile). Severe obesity class II (OCII) and class III (OCIII) are based on a percentage above the 95th percentile cutoff for obesity—OCII is defined as ≥20% above this cutoff and OCIII is defined as ≥40% above this cutoff.
Of 201 adolescents randomised, 62 (31%), 69 (34%) and 69 (34%) were in OCIII, OCII and OCI, respectively; only one participant (0.5%) had overweight and was excluded from this secondary analysis. At randomization, mean body weight was 107.5 kg and mean BMI was 37.0 kg/m2 (OCII).
At week 68, 74% of participants on semaglutide had an improvement of one or more BMI categories versus 19% on placebo. An improvement of ≥2 BMI categories occurred in 45% of participants treated with semaglutide versus 3% with placebo. Overall, treatment with semaglutide reduced the proportion of participants with the most severe degree of obesity (OCIII) from 37% to 14% after 68 weeks.
By week 68, a total of 45% participants in the semaglutide arm experienced a reduction in BMI below the clinical cutoff point for obesity (i.e., reached normal weight or overweight) versus 12% of participants in the placebo arm.
"Once-weekly semaglutide was associated with clinically meaningful improvements in BMI categories versus PBO across all BMI classes in adolescents with obesity. These results underscore the high degree of clinical effectiveness of semaglutide in adolescents with obesity," explained Kelly. "In a practical sense, we see that semaglutide reduced weight to a level below what is defined as clinical obesity in nearly 50% of the teens in our trial, which is historically unprecedented with treatments other than bariatric surgery."
The second sub-study of the STEP TEENS trial showws that adolescents using semaglutide experienced significant reductions in levels of liver enzymes that are an indicator of liver damage. The study was conducted by Dr Daniel Weghuber, Department of Pediatrics, Paracelsus Medical University, Salzburg, Austria, and D Rasmus Sørrig, Novo Nordisk A/S (the manufacturer of semaglutide), Søborg, Denmark, and colleagues.
This post-hoc analysis of the STEP TEENS trial examined the change in alanine aminotransferase enzyme (ALT) levels and presumed non-alcoholic fatty liver disease (NAFLD) in adolescents treated with semaglutide 2.4 mg vs. placebo.
At baseline, 38% had elevated ALT (42% in the semaglutide group and 30% in the placebo group) (corresponding to >25.8 U/L in males, >22.1 U/L in females); 34% were presumed to have NAFLD (37% of the semaglutide group and 27% in the placebo group) (defined as BMI in >85th percentile, fatty liver index [FLI, a surrogate index of fatty liver based on BMI, waist circumference, triglycerides and the liver enzyme gamma-glutamyl transferase] of 60 or above and elevated ALT).
The geometric mean ALT level at baseline was 23 U/L vs. 20 U/L in the semaglutide and placebo groups, respectively. The change from baseline in ALT with semaglutide was significantly greater vs. placebo (–18.1% vs. –1.1%). At week 68, mean ALT levels decreased from baseline levels in participants treated with semaglutide who achieved a weight loss of ≥10%, but not in those with <10% weight loss.
Estimated ALT changes in participants with presumed NAFLD were –15.5% vs. +10.6% with semaglutide vs. placebo group, respectively. Of participants with elevated baseline ALT levels, 53.8% vs. 33.3% had normal levels at week 68 with semaglutide vs. placebo, respectively.
Participants reporting liver-related adverse events, which were mostly non-serious, were higher in the semaglutide 2.4 mg group (7.5%) than with placebo (1.5%). The imbalance was mainly driven by events reported at the day of randomization (not exposure to semaglutide) and events in participants with pre-existing liver disorders.
"In the STEP TEENS trial, treatment with semaglutide 2.4 mg once weekly for 68 weeks was associated with a significant reduction of levels of the liver enzyme alanine aminotransferase compared with placebo,” conclude Weghuber. "Fatty liver disease is the most frequent liver disease in adolescents with no drug therapy currently available. The results of this work are encouraging and will inform studies specifically designed to test semaglutide in adolescents with NAFLD."