Abstract
Aim
To explore changes in body weight and cardiometabolic risk factors after treatment withdrawal in the STEP 1 trial extension.
INTRODUCTION
Obesity is a highly prevalent, complex, chronic disease1-4 associated with cardiometabolic complications, including type 2 diabetes, hypertension, dyslipidaemia and cardiovascular disease.4-6 Obesity also leads to a wide range of other health problems, is associated with substantial socioeconomic burden and was estimated to cause 5 million deaths globally in 2019.2-4, 7
Weight loss activates compensatory biological changes that prevent the maintenance of long-term weight loss8, 9; weight regain is common.8, 10 In people with obesity, pharmacotherapy is indicated as an adjunct to lifestyle intervention for chronic weight management and can help with achieving and maintaining weight loss.2, 11, 12 Long-term obesity pharmacotherapy may be required for weight maintenance, as cessation of pharmacological treatment is frequently followed by weight regain, even with continued lifestyle intervention.13-15
The present observational study examined changes in body weight and cardiometabolic risk factors over 52 weeks following cessation of once-weekly subcutaneous (s.c.) semaglutide 2.4 mg (or placebo) and lifestyle intervention in participants who had completed 68 weeks of initial treatment in the randomized, placebo-controlled Semaglutide Treatment Effect in People with obesity (STEP) 1 trial.16 Semaglutide is a glucagon-like peptide-1 (GLP-1) analogue recently approved by the US Food and Drug Administration, Health Canada and the UK Medicines and Healthcare products Regulatory Agency for chronic weight management, as an adjunct to lifestyle intervention, at a once-weekly s.c. dose of 2.4 mg in adults with overweight (with ≥ 1 weight-related condition) or obesity.17-19 The efficacy and safety of semaglutide 2.4 mg for weight management have been investigated in the global phase III STEP programme.20 In the main phase of the STEP 1 trial, 68 weeks of treatment with semaglutide plus lifestyle intervention in adults with overweight/obesity produced clinically meaningful reductions in body weight, as well as improvements in cardiometabolic risk factors, and physical functioning.16
A prior trial (STEP 4) assessed the effects of semaglutide withdrawal, with participants initially receiving 20 weeks of semaglutide 2.4 mg treatment during a run-in period, followed by randomization to continued semaglutide treatment or withdrawal (switch to placebo) for an additional 48 weeks, with lifestyle intervention throughout.13 The present STEP 1 extension study complements STEP 4 by exploring post-treatment changes in body weight and cardiometabolic risk factors following a longer (68-week) initial treatment period with semaglutide or placebo, and in the absence of active lifestyle intervention support during the 1-year off-treatment follow-up period.
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...
DISCUSSION
In STEP 1, 68 weeks of treatment with once-weekly s.c. semaglutide 2.4 mg plus lifestyle intervention provided significant, clinically relevant reductions in body weight versus placebo among adults with overweight/obesity.16 After withdrawal of semaglutide and structured lifestyle intervention, participants regained a mean of two-thirds of their prior weight loss in the 1-year off-treatment extension phase; weight regain continued until the end of follow-up (week 120). However, some treatment effects were sustained and weight remained 5.6% below baseline in the semaglutide arm. Almost half of the participants in the semaglutide arm (48.2%) still had clinically meaningful weight loss of 5% or more from baseline at week 120, although this proportion represented a substantial fall from that originally achieved at the end of 68 weeks of treatment (86.4%).16 Subgroup analyses suggested that participants in the semaglutide arm with greater weight loss during the 68-week treatment period tended to have greater regain in body weight after semaglutide withdrawal, but ultimately retained greater weight loss at week 120 versus subgroups who lost less weight during the 68-week treatment period.
Weight regain has previously been observed following withdrawal of obesity pharmacotherapies, including orlistat and lorcaserin—and also semaglutide, as shown in STEP 4—despite continued lifestyle intervention.13-15 Taken together, these findings and those of the present study confirm the chronicity of obesity and highlight the importance of maintaining long-term pharmacological treatment for weight management in people with obesity.
In the STEP 1 extension, weight regain was comparatively rapid following semaglutide withdrawal compared with that seen in other obesity pharmacotherapy withdrawal trials, including after semaglutide withdrawal in STEP 4.13-15 This may well relate to participants who received semaglutide in STEP 1 having achieved greater weight loss prior to withdrawal than in other trials, and thus having greater potential for regain, driven by physiological and behavioural factors.22, 23 Accordingly, the steepest trajectory of weight regain after withdrawal was observed in participants who had lost 20% or more of baseline body weight during treatment. Furthermore, the absence of structured lifestyle intervention following semaglutide withdrawal contrasts with the continuation of lifestyle intervention in other withdrawal trials (including in STEP 4)13-15 and may also have contributed to the trajectory of weight regain.
Mean body weight data suggested a slowing of weight regain towards the end of the extension phase in participants withdrawn from semaglutide. By contrast, the STEP 4 study did not show a clear slowing of weight regain towards the end of its 48-week observation period following semaglutide withdrawal.14 However, interpretation of weight trajectory in STEP 4 is limited by the comparatively small magnitude of weight regain (owing to the shorter treatment duration and smaller initial weight loss in STEP 4 relative to STEP 1, and the continuation of lifestyle intervention).14 Whether the slowing in regain in the off-treatment STEP 1 extension represents a plateauing of mean body weight below baseline levels, or simply a slowing of weight regain as body weight approached baseline, cannot be determined without longer follow-up.
Subgroup analyses indicated no difference in weight loss based on age, but did suggest lesser mean weight loss in men relative to women in the semaglutide arm, both at the end of active treatment (at week 68) and at the end of the off-treatment extension phase (at week 120). Despite the small difference between men and women, weight losses during treatment were still substantial and clinically meaningful in both sexes. Subgroup analyses based on baseline BMI categories showed inconsistent trends in the semaglutide arm: weight loss during treatment (week 0 to week 68) showed no clear trend across increasing BMI categories, but over week 0 to week 120 showed a trend for greater weight loss in the subgroups of patients with higher versus lower baseline BMI categories, in part owing to a lesser weight regain in the 40 kg/m2 or higher subgroup than most others. However, the differences in weight loss between baseline BMI subgroups were comparatively small, and a meaningful effect of baseline BMI cannot be concluded based on the present data. Differences in weight loss in the semaglutide arm were also seen based on baseline glycaemic status, with lesser weight loss from baseline at week 68 and week 120 among those with prediabetes at baseline relative to those with normoglycaemia. This finding is consistent with the established difficulty of achieving weight loss among people with type 2 diabetes, and with the previous observation of smaller reductions in body weight with semaglutide 2.4 mg in patients with overweight/obesity and type 2 diabetes in the STEP 2 trial,24 relative to those seen during the main treatment period of STEP 1, which excluded patients with type 2 diabetes.16
We observed residual benefits in some cardiovascular risk factors at week 120 compared with baseline. Previously, a post hoc analysis of the Look AHEAD trial explored the effects of weight regain on cardiometabolic risk factors among people with overweight/obesity and type 2 diabetes who received intensive lifestyle intervention.25 In that analysis, large initial weight losses followed by partial or full regain by year 4 were associated with a sustained benefit on HbA1c at year 4 relative to that seen in participants with smaller or no initial weight loss.25 In the STEP 1 extension, the semaglutide arm maintained a small improvement from baseline in HbA1c, and also in other cardiometabolic risk factors (LDL, VLDL and HDL cholesterol, triglycerides and CRP) after 1 year off-treatment, despite partial weight regain. Although many participants who reverted from prediabetes to normoglycaemia during semaglutide treatment subsequently returned to prediabetes after withdrawal, the semaglutide arm maintained a relative improvement at week 120 compared with the placebo arm. Reversion from normoglycaemia to prediabetes after semaglutide withdrawal may relate to loss of the direct effects of GLP-1 receptor agonism on glycaemic levels. However, the present study does not allow definitive conclusions regarding mechanisms driving changes in glycaemic status. Overall, although a net beneficial effect on several cardiometabolic variables was maintained 1 year after semaglutide withdrawal, greater benefits were seen during the treatment period, supporting the need for continued treatment. The benefits remaining at 1 year post-withdrawal appear to be related to the magnitude of initial weight loss at week 68. A longer follow-up study is needed to determine if these remaining benefits would ultimately be lost or retained.
The strengths of the STEP 1 extension include the pragmatic trial design, with no active intervention and infrequent site contact. This more closely mimics a real-world setting and may aid understanding of real-world effects of semaglutide withdrawal. Additional strengths include the multinational setting and the high rates of trial completion. The key limitations of the extension were the relatively small sample size compared with the main STEP 1 trial population and the selection of sites based on those with the highest recruitment in the STEP 1 main phase, which could introduce an element of selection bias. However, participants were from a range of countries representative of those included in the main phase, and comparison of baseline characteristics among the ExAS and FAS indicated that the extension sample was representative. Weight losses with semaglutide versus placebo from week 0 to week 68 were slightly greater in the ExAS than in the FAS, as expected given that the ExAS only included participants who completed 68 weeks of treatment. Another limitation was the potential for obesity pharmacotherapy use during the extension. However, few participants used obesity pharmacotherapy so our findings were not confounded, as shown by the consistency of body weight changes in the overall ExAS and the subgroup of participants not using obesity pharmacotherapy. In addition, all analyses were exploratory and thus no formal tests of statistical significance were performed.
In conclusion, among adults with overweight/obesity, after a substantial reduction in body weight during 68 weeks of treatment with once-weekly s.c. semaglutide plus lifestyle intervention, subsequent treatment withdrawal led to most of the weight loss being regained within 1 year, and a similar change in some cardiometabolic variables back to baseline, reinforcing the need for continued treatment to maintain weight loss and cardiometabolic benefits...
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.
ACKNOWLEDGEMENTS
The authors thank the participants, investigators and site staff who were involved in the STEP 1 trial. The authors also thank Lauren McNally, MSci, of Axis, a division of Spirit Medical Communications Group Limited, for medical writing and editorial assistance (funded by Novo Nordisk A/S, Denmark).