Obesity, recognized as a chronic and relapsing disease, presents a significant global health challenge due to its association with numerous complications, increased morbidity and mortality, and a substantial burden on healthcare systems. While lifestyle interventions are often the first line of defense, they frequently yield limited and unsustainable weight loss. Pharmacological treatments, therefore, serve as a valuable adjunct in the management of obesity.
The STEP Program: Evaluating Semaglutide for Obesity Treatment
The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial program meticulously evaluated the efficacy of once-weekly subcutaneous semaglutide 2.4 mg, a glucagon-like peptide-1 (GLP-1) analog, in individuals with overweight or obesity. This review aims to comprehensively describe the study designs and clinical outcomes of the published trials within the STEP program, discuss the clinical implications of the data, explore the practical aspects of utilizing semaglutide 2.4 mg in individuals with obesity, and contextualize the STEP program within the current and future landscape of obesity pharmacotherapy.
Study Designs and Demographics
The STEP program was strategically designed to thoroughly investigate the efficacy of once-weekly subcutaneous semaglutide 2.4 mg in individuals with overweight or obesity, with each trial addressing a specific research question. All trials followed the same dose-escalation regimen. Participants treated with subcutaneous semaglutide 2.4 mg were initiated on a dose of 0.25 mg once weekly, and the dose was escalated every 4 weeks to 0.5 mg, 1.0 mg, and 1.7 mg until the target dose of 2.4 mg was reached at week 16. If participants were unable to tolerate the 2.4 mg dose because of adverse events (AEs), lower maintenance doses were permitted if the participant would otherwise discontinue trial treatment completely.
Across the STEP trials, the study populations exhibited some variations. For instance, STEP 2 had a lower proportion of female participants (51% vs. 74%-81% in the other trials), a greater mean age (55 years vs. 46-49 years), and a higher mean HbA1c (8.1% vs. Mean BMI was lower in STEP 2 than the other trials (35.7 kg/m2 vs. The STEP 6 trial population comprised mainly Japanese participants (90%) with the remainder from South Korea.
Key Findings from STEP Trials
The STEP program has consistently demonstrated the efficacy and tolerability of once-weekly subcutaneous semaglutide 2.4 mg in individuals with overweight or obesity. Across STEP 1, 3, 4, and 8, semaglutide 2.4 mg was associated with mean weight losses of 14.9%-17.4% in individuals with overweight or obesity without type 2 diabetes from baseline to week 68; 69%-79% of participants achieved ≥10% weight loss with semaglutide 2.4 mg (vs. 12%-27% with placebo), and 51%-64% achieved ≥15% weight loss (vs. 5%-13% with placebo). In STEP 5, mean weight loss was -15.2% with semaglutide 2.4 mg versus -2.6% with placebo from baseline to week 104. In STEP 2 (individuals with overweight or obesity, and type 2 diabetes), mean weight loss was -9.6% with semaglutide 2.4 mg versus -3.4% with placebo from baseline to week 68. All trials met their primary endpoints.
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- STEP 1: Mean weight loss with semaglutide plus usual lifestyle intervention was 14.9% (vs. 2.4% with placebo).
- STEP 3: Mean weight loss with semaglutide plus intensive behavioral therapy was 16.0% (vs. 5.7% with placebo).
- STEP 4: The mean decrease in body weight during the 20-week run-in period with semaglutide treatment was 10.6%.
- STEP 5: Mean weight loss from baseline to week 104 was 15.2% with semaglutide 2.4 mg versus 2.6% with placebo. Participants were more likely to probably lose ≥5%, ≥10%, ≥15% and ≥20% body weight with semaglutide versus placebo (77% vs. 34%, 62% vs. 13%, 52% vs. 7.0% and 36% vs.
- STEP 6: Mean weight loss from baseline to week 68 was 13.2% with semaglutide 2.4 mg, 9.6% with semaglutide 1.7 mg, and 2.1% with placebo.
- STEP 8: Mean weight loss was greater with semaglutide 2.4 mg than with liraglutide 3.0 mg from baseline to week 68 (15.8% vs. 6.4%).
Impact on Cardiometabolic Risk Factors and Quality of Life
Beyond weight loss, the STEP trials demonstrated improvements in cardiometabolic risk factors, including high blood pressure and atherogenic lipids, as well as benefits on physical function and quality of life with semaglutide 2.4 mg. Changes in glycemic status (shift from prediabetes to normoglycemia; tested while on treatment) were observed in STEP 1 and STEP 6. In STEP 2, the mean reduction in HbA1c from baseline to week 68 with semaglutide 2.4 mg was 1.6%, versus 1.5% with semaglutide 1.0 mg and 0.4% with placebo. More patients receiving semaglutide decreased use of concomitant glucose-lowering medications.
Safety and Tolerability
The safety profile of once-weekly subcutaneous semaglutide 2.4 mg was broadly consistent across the STEP trials. AEs reported for semaglutide 2.4 mg were typical of the GLP-1RA class in general and were primarily gastrointestinal (GI) events. Most events were transient and mild or moderate in severity. No new safety concerns arose from the STEP trials. There were no notable increases in the incidence of acute pancreatitis with semaglutide 2.4 mg. GI AEs generally led to more participants discontinuing treatment in the semaglutide 2.4 mg groups compared with placebo groups (0.8%-4.5% vs. In STEP 8, rates of AEs (which were mostly GI-related) were similar with semaglutide 2.4 mg and liraglutide 3.0 mg (95.2% vs. 96.1%). Of note, rates of discontinuation due to AEs were lower with semaglutide than with liraglutide (3.2% vs.
Weight Regain After Semaglutide Withdrawal
As obesity is a chronic and relapsing disease, weight regain after initial loss is common. This is reflected in the STEP 4 results, where the mean weight change after 48 weeks among participants who switched from semaglutide 2.4 mg to placebo was +6.9%, even though lifestyle intervention was continued (vs. Semaglutide 2.4 mg for 2 years resulted in substantial and sustained changes in body weight versus placebo in STEP 5 (-15.2% vs.
Real-World Evidence: Semaglutide in Clinical Practice
A retrospective cohort study, conducted at a referral center for weight management, retrospectively collected data on the use of semaglutide for adults with overweight or obesity between January 1, 2021, and March 15, 2022, with a follow-up of up to 6 months. The results of this cohort study suggest that weekly 1.7-mg and 2.4-mg doses of semaglutide were associated with weight loss similar to that seen in randomized clinical trials. The mean (SD) weight loss after 3 months was 6.7 (4.4) kg, equivalent to a mean (SD) weight loss of 5.9% (3.7%) (P < .001), and the mean (SD) weight loss after 6 months was 12.3 (6.6) kg, equivalent to a mean (SD) weight loss of 10.9% (5.8%) (P < .001 from baseline). Of the 102 patients who were followed up at 6 months, 89 (87.3%) achieved weight loss of 5% or more, 56 (54.9%) achieved weight loss of 10% or more, 24 (23.5%) achieved weight loss of 15% or more, and 8 (7.8%) achieved weight loss of 20% or more.
SELECT Trial: Semaglutide's Impact on Cardiovascular Outcomes and Weight Loss
The SELECT trial (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) studied patients with established CVD and overweight or obesity but without diabetes. In SELECT, semaglutide was associated with a 20% reduction in major adverse CV events (hazard ratio 0.80, 95% confidence interval (CI) 0.72 to 0.90; P < 0.001). In patients treated with semaglutide, weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with a mean reduction in weight (−10.2%), waist circumference (−7.7 cm) and waist-to-height ratio (−6.9%) versus placebo (−1.5%, −1.3 cm and −1.0%, respectively; P < 0.0001 for all comparisons versus placebo). Clinically meaningful weight loss occurred in both sexes and all races, body sizes and regions. Semaglutide was associated with fewer serious adverse events.
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Practical Considerations for Semaglutide Use
Figure 1 illustrates key considerations for the use of once-weekly subcutaneous semaglutide 2.4 mg in clinical practice. This escalation schedule is designed to minimize GI AEs, but if a patient does not tolerate a dose during the escalation period, the subsequent escalation step can be delayed for a further 4 weeks, after which it should be re-escalated to 2.4 mg. If needed, this re-escalation step can be postponed (e.g. There is limited evidence from trials and real-world studies on strategies for managing GI side effects of GLP-1RA treatment. Patients should be counselled about the possibility of GI side effects and advised that they are typically transient and mild-to-moderate in severity. For mild and short-term GI side effects, this should include providing advice on dietary modifications and recommending that patients increase their fibre and water intake for constipation and consider stool softeners. The lack of clinical trial data on switching between liraglutide 3.0 mg and semaglutide 2.4 mg in individuals with overweight or obesity precludes the development of formal evidence-based recommendations.
The Future of Obesity Pharmacotherapy
Taken together, the results from the STEP clinical trial program show semaglutide 2.4 mg to be the most effective drug currently approved for weight loss in adults with overweight or obesity. Tirzepatide has shown promising results on obesity with a side effect profile close to semaglutide. Figure 2 illustrates the future landscape of obesity pharmacotherapy.
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