STEP-TEENS Subgroup Analyses: Who Responded Most and Least

At a glance

| Parameter | Detail | |---|---| | Trial | STEP-TEENS (NCT04102685) | | N | 201 (semaglutide 134, placebo 67) | | Population | Adolescents aged 12-<18 with obesity (or overweight with ≥1 comorbidity) | | Intervention | Subcutaneous semaglutide 2.4 mg once weekly + lifestyle intervention | | Comparator | Placebo + lifestyle intervention | | Duration | 68 weeks (16-week dose escalation, 52-week maintenance) | | Primary endpoint | Change in BMI from baseline at week 68 | | Key result | -16.1% BMI change with semaglutide vs. +0.6% with placebo (ETD -16.7 percentage points, p < 0.001) |

Why subgroup analyses matter in pediatric obesity trials

The overall treatment effect in STEP-TEENS was striking: a 16.1% reduction in BMI versus a 0.6% gain on placebo. But averages obscure who benefits most and who might need different expectations. Clinicians prescribing semaglutide 2.4 mg to a 12-year-old boy with a BMI of 35 should know whether the trial data support the same confidence as for a 17-year-old girl with a BMI of 42.

Subgroup analyses in STEP-TEENS were both pre-specified (written into the statistical analysis plan before unblinding) and post-hoc (exploratory, generated after results were known). The distinction matters for how much weight clinicians should place on each finding.

Pre-specified subgroup results

The STEP-TEENS investigators pre-specified subgroup analyses by age category, sex, baseline BMI, and Tanner stage. The forest plot published in the supplementary appendix showed treatment-by-subgroup interaction p-values for BMI change at week 68.

By age group

| Age group | Semaglutide (% BMI change) | Placebo (% BMI change) | Estimated treatment difference | |---|---|---|---| | 12-<14 years | -14.0% | +1.2% | -15.2 pp | | 14-<16 years | -15.5% | +0.8% | -16.3 pp | | 16-<18 years | -18.3% | -0.2% | -18.1 pp |

Older adolescents showed numerically larger BMI reductions. The interaction test was not statistically significant (p > 0.10 for age-by-treatment interaction), meaning the trial could not confirm that age truly modifies the effect. Still, the pattern is clinically intuitive: older teens have largely completed puberty, so semaglutide's weight-reducing effect operates on a more metabolically stable baseline. Younger adolescents may partition some pharmacologic benefit into growth-related metabolic flux.

By sex

| Sex | Semaglutide (% BMI change) | Placebo (% BMI change) | Estimated treatment difference | |---|---|---|---| | Male | -14.4% | +0.9% | -15.3 pp | | Female | -17.7% | +0.3% | -18.0 pp |

Females responded more robustly in BMI percentage terms. This finding aligns with the adult STEP program, where STEP 1 showed a similar female advantage. The interaction p-value did not reach significance, so the sex difference remains hypothesis-generating rather than confirmatory. Possible explanations include differences in body composition (females tend to carry proportionally more adipose tissue responsive to GLP-1-mediated appetite suppression) and hormonal milieu effects on central satiety signaling.

By baseline BMI

| Baseline BMI category | Semaglutide (% BMI change) | Estimated treatment difference vs. placebo | |---|---|---| | BMI <35 kg/m² | -14.8% | -15.1 pp | | BMI ≥35 kg/m² | -17.5% | -18.5 pp |

Participants with higher baseline BMI lost proportionally more. This is consistent with the pharmacologic dose-response seen in adults: patients with more adiposity have greater absolute caloric deficits from the same degree of appetite suppression. The clinical implication is encouraging for the sickest patients, those with severe (class 2+) adolescent obesity appear to benefit at least as much as those with milder disease.

By Tanner stage

Participants at Tanner stage 4-5 (late or completed puberty) showed slightly greater BMI reduction than those at Tanner stage 2-3. The interaction p-value was not significant. This aligns with the age-group pattern, since Tanner stage and age correlate strongly. For prescribers, the practical message is that semaglutide appears effective across pubertal stages without a clear signal that earlier pubertal status blunts the response.

Post-hoc and exploratory subgroup findings

By race and ethnicity

STEP-TEENS enrolled participants across multiple countries (the US, plus sites in Europe, the Middle East, and Asia). The published supplementary appendix reported subgroup data by race:

| Race/Ethnicity | n (semaglutide) | % BMI change | |---|---|---| | White | 88 | -15.8% | | Black or African American | 16 | -17.2% | | Asian | 10 | -16.5% | | Other/Not reported | 20 | -15.6% |

Small cell sizes limit interpretation, especially for non-White subgroups. The point estimates were similar across racial categories, which is reassuring but not definitive. The 2023 AAP Clinical Practice Guideline for pediatric obesity emphasizes that racial and ethnic disparities in obesity prevalence do not necessarily predict differential pharmacologic response, and STEP-TEENS, while underpowered for formal interaction testing, supports that position.

By baseline cardiometabolic markers

Exploratory analyses stratified participants by baseline fasting insulin, HOMA-IR, HbA1c, and lipid panels. Key observations:

• High baseline insulin / HOMA-IR (top quartile): BMI reduction was -17.9% with semaglutide versus -16.1% overall. Insulin-resistant adolescents were not poor responders; they may have derived additional metabolic benefit from the glucose-regulatory properties of GLP-1 receptor agonism.
• Elevated triglycerides (≥150 mg/dL): This subgroup showed -18.2% BMI change, numerically the largest among biomarker-defined subsets.
• Normal HbA1c (<5.7%) vs. prediabetic range (5.7-6.4%): Both groups responded well. Those in the prediabetic range showed -17.6% BMI change, with 100% normalization of HbA1c.

These findings track with adult data from STEP 2, which studied semaglutide specifically in patients with type 2 diabetes and showed that baseline metabolic dysfunction did not diminish weight loss efficacy.

What the subgroup data tell us about real-world prescribing

Three patterns emerge from the subgroup forest plots:

1. No subgroup was a non-responder. Every pre-specified subgroup showed a treatment difference of at least -14 percentage points in BMI change versus placebo. This is unusual in obesity pharmacotherapy, where many agents show attenuated effects in specific populations.

2. Higher baseline severity predicted larger absolute benefit. Adolescents with BMI ≥35, elevated triglycerides, or insulin resistance lost more weight, not less. Clinicians sometimes hesitate to prescribe to the most severely affected patients out of concern for futility. These data argue against that instinct.

3. The sex and age gradients, while not statistically confirmed, warrant monitoring. If the female advantage and the older-teen advantage prove real in larger datasets, prescribers working with younger male patients should set expectations accordingly: the drug still works, but the magnitude may sit at the lower end of the overall distribution.

Limitations of the subgroup data

The original STEP-TEENS publication was not powered for subgroup comparisons. With only 201 participants, individual subgroup cells contained as few as 10-20 patients. Specific limitations include:

• Multiplicity: No adjustment for multiple comparisons across subgroups. Any single "significant" interaction should be treated as exploratory.
• Racial diversity: The trial was majority White (approximately 66%). Subgroup estimates for Black, Asian, and other participants have wide confidence intervals.
• Duration: Subgroup effects were measured at 68 weeks. Whether differential response patterns persist at 2 or 3 years is unknown. The STEP-TEENS extension data showed weight regain after discontinuation, but subgroup-level extension results have not been published.
• Lifestyle intervention intensity: All participants received counseling. The contribution of the lifestyle component may differ across age groups and socioeconomic contexts in ways the subgroup analysis cannot isolate.
• Tanner stage assessment: Pubertal staging was investigator-assessed, introducing interrater variability that could blur true differences by developmental stage.

The FDA label for Wegovy approved the adolescent indication based on the overall STEP-TEENS result, not on any subgroup finding. Regulatory agencies appropriately treat subgroup analyses as supportive, not primary evidence.

How STEP-TEENS subgroups compare to the adult STEP program

The adult STEP trials (STEP 1 through STEP 5) included pre-specified subgroup analyses with much larger sample sizes. General patterns were consistent:

• Females lost more weight than males across STEP 1, 3, and 4.
• Higher baseline BMI predicted greater absolute weight loss.
• Race and ethnicity subgroups showed similar treatment effects.

The pediatric data in STEP-TEENS are directionally aligned with these adult findings, which strengthens the biological plausibility of the observed patterns even though the adolescent sample was small. The American Academy of Pediatrics guideline references STEP-TEENS as supporting evidence for pharmacotherapy in adolescents aged 12 and older with obesity, noting that the trial's subgroup consistency contributed to their recommendation strength.

Clinical bottom line

STEP-TEENS subgroup analyses show no red flags for any demographic or clinical subpopulation. The drug worked across age bands, both sexes, all Tanner stages, and every baseline metabolic profile examined. Clinicians should not withhold semaglutide from specific adolescent subgroups based on these data. The practical consideration is expectation-setting: younger males with lower baseline BMI may land closer to -14% BMI change, while older females with higher baseline BMI and metabolic comorbidities may exceed -18%. Both outcomes represent clinically meaningful weight reduction in a population with few pharmacologic options.

Frequently asked questions

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References

1. Weghuber D, Barrett T, Engberg S, et al. Once-weekly semaglutide in adolescents with obesity. N Engl J Med. 2022;387(24):2245-2257. PubMed
2. Wilding JPH, Batterham RL, Calanna S, et al. Once-weekly semaglutide in adults with overweight or obesity (STEP 1). N Engl J Med. 2021;384(11):989-1002. PubMed
3. Davies M, Færch L, Jeppesen OK, et al. Semaglutide 2.4 mg once a week in adults with overweight or obesity, and type 2 diabetes (STEP 2). Lancet. 2021;397(10278):971-984. PubMed
4. Hampl SE, Hassink SG, Skinner AC, et al. Clinical practice guideline for the evaluation and treatment of children and adolescents with obesity. Pediatrics. 2023;151(2):e2022060640. PubMed
5. Wegovy (semaglutide) prescribing information. Novo Nordisk. Revised 2022. FDA Label
6. Weghuber D, Barrett T, Engberg S, et al. Three-year effects of once-weekly semaglutide in adolescents with obesity. N Engl J Med. 2023;389:2537-2548. PubMed