Weight regain and cardiometabolic effects after withdrawal of semaglutide: The STEP 1 trial extension

Abstract

Aim: To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension.

Materials and methods: STEP 1 (NCT03548935) randomized 1961 adults with a body mass index ≥ 30 kg/m² (or ≥ 27 kg/m² with ≥ 1 weight-related co-morbidity) without diabetes to 68 weeks of once-weekly subcutaneous semaglutide 2.4 mg (including 16 weeks of dose escalation) or placebo, as an adjunct to lifestyle intervention. At week 68, treatments (including lifestyle intervention) were discontinued. An off-treatment extension assessed for a further year a representative subset of participants who had completed 68 weeks of treatment. This subset comprised all eligible participants from any site in Canada, Germany and the UK, and sites in the United States and Japan with the highest main phase recruitment. All analyses in the extension were exploratory.

Results: Extension analyses included 327 participants. From week 0 to week 68, mean weight loss was 17.3% (SD: 9.3%) with semaglutide and 2.0% (SD: 6.1%) with placebo. Following treatment withdrawal, semaglutide and placebo participants regained 11.6 (SD: 7.7) and 1.9 (SD: 4.8) percentage points of lost weight, respectively, by week 120, resulting in net losses of 5.6% (SD: 8.9%) and 0.1% (SD: 5.8%), respectively, from week 0 to week 120. Cardiometabolic improvements seen from week 0 to week 68 with semaglutide reverted towards baseline at week 120 for most variables.

Conclusions: One year after withdrawal of once-weekly subcutaneous semaglutide 2.4 mg and lifestyle intervention, participants regained two-thirds of their prior weight loss, with similar changes in cardiometabolic variables. Findings confirm the chronicity of obesity and suggest ongoing treatment is required to maintain improvements in weight and health.

Keywords: GLP-1 analogue; antiobesity drug; clinical trial; obesity therapy; phase III study; weight control.

FIGURE 1

Change from baseline in body weight by week for A, All participants in the ExAS, B, Participants in the semaglutide arm, grouped by categorical weight loss from week 0 to week 68, C, Participants not using obesity pharmacotherapy during the extension^†, and D, Participants in the semaglutide arm for the full ExAS and the subgroup with prediabetes resolution at week 68 and subsequent reversion by week 120^‡. ^†Participants who did not use obesity pharmacotherapies (investigator‐assessed) during the extension phase. ^‡Participants who shifted from prediabetes at baseline to normoglycaemia at week 68 to prediabetes at week 120. Glycaemic category was determined from HbA1c assessments, as per American Diabetes Association HbA1c criteria. Normoglycaemia was defined by HbA1c < 5.7% (< 39 mmol/mol); prediabetes was defined by HbA1c 5.7%‐6.4% (39‐47 mmol/mol). Data are observed mean changes from baseline (± standard error) for the ExAS from the in‐trial period. The dashed vertical line at week 68 indicates the end of the main phase and start of the off‐treatment extension phase. Numbers shown in the lower panels are participants contributing to the mean. ExAS, extension analysis set

FIGURE 2

A, Systolic blood pressure, B, Diastolic blood pressure, C, C‐reactive protein, and D, HbA1c by week. Data are observed means (± standard error) for the extension analysis set from the in‐trial period; for C‐reactive protein, standard error was calculated on the logarithmic scale and back‐transformed to the linear scale. The dashed vertical line at week 68 indicates the end of the main phase and start of the off‐treatment extension phase. Numbers shown in the lower panels are participants contributing to the mean. CRP, C‐reactive protein

FIGURE 3

Change in glycaemic category from baseline (week 0) to weeks 68 and 120. Data are observed proportions (%) of participants for the extension analysis set from the in‐trial period. Proportions are based on participants with an observation at the visit. Glycaemic category was determined from HbA1c assessments, as per American Diabetes Association HbA1c criteria. Normoglycaemia was defined by HbA1c < 5.7% (< 39 mmol/mol); prediabetes was defined by HbA1c 5.7%‐6.4% (39‐47 mmol/mol); diabetes was defined by HbA1c ≥ 6.5% (≥ 48 mmol/mol)