Obesity has become a global epidemic, with the World Health Organization estimating that nearly 1 billion people worldwide are affected by this condition. This chronic, relapsing disease is associated with numerous complications, including cardiovascular disease, type 2 diabetes, and certain types of cancer, leading to substantial morbidity, mortality, and healthcare costs.
While lifestyle interventions, such as diet and exercise, are the cornerstone of obesity management, they often result in limited weight loss that is difficult to maintain long-term. Pharmacological treatments, like semaglutide, offer a valuable adjunct to lifestyle modifications, providing a more effective means of achieving and sustaining clinically significant weight loss.
Understanding Semaglutide
Semaglutide is a glucagon-like peptide-1 receptor agonist (GLP-1RA) that mimics the effects of the naturally occurring hormone GLP-1. GLP-1RAs were first approved in the early 2000s, with semaglutide gaining FDA approval in 2017 for treating type 2 diabetes. Semaglutide promotes satiety, leading to a reduction in food intake and subsequent weight loss.
The Semaglutide Treatment Effect in People with obesity (STEP) clinical trial program comprehensively evaluated the efficacy of once-weekly subcutaneous semaglutide 2.4 mg in individuals with overweight or obesity. These trials addressed specific research questions and provided valuable insights into the drug's potential.
Semaglutide 2 mg: A Higher Dose for Enhanced Weight Loss
Recent research has explored the potential of higher doses of semaglutide for even greater weight loss benefits. A multicenter clinical trial led by a UT Southwestern Medical Center researcher investigated the effects of tripling the standard dose of semaglutide in patients with obesity.
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The STEP UP Diabetes Trial
The phase 3b STEP UP Diabetes trial tracked 512 adults with obesity and type 2 diabetes, dividing them into three groups:
- 307 participants took 7.2 mg of semaglutide weekly.
- 103 participants took 2.4 mg of semaglutide weekly.
- 102 participants took a placebo.
The patients were monitored by medical teams at 68 sites in eight countries across Europe, southern Africa, and North America, including UTSW, for 72 weeks.
The results mirrored those of earlier trials evaluating a 2.4 mg weekly dose of semaglutide in people with obesity and type 2 diabetes. Participants on the 2.4 mg dose lost significantly more body weight than those on the placebo, averaging 10.4% of their starting weight compared to 3.9%.
Notably, those taking the higher 7.2 mg dose experienced even greater weight loss, averaging 13.2%.
The STEP UP Obesity Trial
The STEP UP Obesity trial enrolled people living with obesity but without type 2 diabetes. Similar to the STEP UP Diabetes trial, the higher dose of semaglutide led to significant weight loss in this population as well.
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Safety and Tolerability
In both trials, the most common side effect was gastrointestinal symptoms, affecting approximately half of the patients on either semaglutide dose and about a quarter of patients on the placebo. These side effects typically occurred during the dose escalation phase in the first few weeks of the trial and tended to improve thereafter.
Dysesthesia, a condition that alters touch sensation, was the only side effect experienced by more patients on the higher semaglutide dose. About 20% of patients taking the 7.2 mg dose in both trials experienced this effect, compared to about 5% of those on the 2.4 mg dose.
The Broader STEP Program: Evidence for Semaglutide 2.4 mg
The STEP program provides a comprehensive evaluation of 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 without type 2 diabetes from baseline to week 68. Impressively, 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, which included 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.
These trials also 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. The safety profile of semaglutide 2.4 mg was consistent across trials, with primarily gastrointestinal adverse events reported.
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Key Findings from STEP Trials
- STEP 1: Semaglutide plus usual lifestyle intervention resulted in a mean weight loss of 14.9% compared to 2.4% with placebo.
- STEP 2: Among participants with type 2 diabetes, semaglutide 2.4 mg led to a weight reduction of 9.6% compared to 3.4% for placebo.
- STEP 3: Semaglutide combined with intensive behavioral therapy resulted in a mean weight loss of 16.0% compared to 5.7% with placebo.
- STEP 4: After a 20-week run-in period with semaglutide, participants who continued semaglutide maintained their weight loss, while those who switched to placebo experienced weight regain.
- STEP 5: Semaglutide resulted in a mean weight loss of 15.2% compared to 2.6% with placebo over 104 weeks.
- STEP 6: In an East Asian population, semaglutide 2.4 mg led to a mean weight loss of 13.2% compared to 2.1% with placebo.
- STEP 8: Semaglutide 2.4 mg resulted in greater weight loss than liraglutide 3.0 mg from baseline to week 68 (15.8% vs. 6.4%).
Safety and Tolerability in STEP Trials
The safety profile of once-weekly subcutaneous semaglutide 2.4 mg was broadly consistent across the STEP trials. Adverse events reported for semaglutide 2.4 mg were typical of the GLP-1RA class and primarily involved gastrointestinal events. Most events were transient and mild or moderate in severity. No new safety concerns arose from the STEP trials.
SELECT Trial: Semaglutide and Cardiovascular Outcomes
The SELECT (Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity) trial studied patients with established CVD and overweight or obesity but without diabetes. Semaglutide was associated with a 20% reduction in major adverse CV events.
A prespecified analysis of the SELECT trial investigated weight loss and changes in anthropometric indices in patients with established CVD and overweight or obesity without diabetes. The results showed that semaglutide produced clinically significant weight loss and improvements in anthropometric measurements versus placebo.
Key Findings from SELECT Analysis
- 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).
- Clinically meaningful weight loss occurred in both sexes and all races, body sizes, and regions.
- Semaglutide was associated with fewer serious adverse events.
Weight Loss and Anthropometric Outcomes in SELECT
The average percentage weight-loss trajectory with semaglutide continued to week 65 and was sustained for the study period through week 208 (−10.2% for the semaglutide group, −1.5% for the placebo group).
At week 104, weight loss of ≥5%, ≥10%, ≥15%, ≥20%, and ≥25% was achieved by 67.8%, 44.2%, 22.9%, 11.0%, and 4.9%, respectively, of those treated with semaglutide compared with 21.3%, 6.9%, 1.7%, 0.6%, and 0.1% of those receiving placebo.
At week 208, the average reduction in WC was −7.7 cm with semaglutide versus −1.3 cm with placebo. At week 104, 52.4% of patients treated with semaglutide achieved improvement in BMI category compared with 15.7% of those receiving placebo.
Weight Loss and Anthropometric Outcomes by Subgroups
Women had a greater difference in mean weight loss with semaglutide versus placebo compared to men. Patients from Asia and of Asian race experienced slightly lower mean weight loss. There was no difference in weight loss with semaglutide associated with ethnicity or glycemic status.
Practical Considerations for Semaglutide Use
The recommended starting dose of semaglutide is 0.25 mg injected subcutaneously once weekly. The dose is gradually increased every 4 weeks to 0.5 mg, 1 mg, and 1.7 mg, until the target maintenance dose of 2.4 mg is reached. This escalation schedule is designed to minimize gastrointestinal adverse events.
If a patient does not tolerate a dose during the escalation period, the subsequent escalation step can be delayed for a further 4 weeks. Patients should be counseled about the possibility of gastrointestinal side effects and advised that they are typically transient and mild-to-moderate in severity.
The Future of Obesity Pharmacotherapy
Semaglutide 2.4 mg has emerged as one of the most effective drugs currently approved for weight loss in adults with overweight or obesity. Ongoing trials with semaglutide and other investigational agents, such as tirzepatide, hold promise for even more effective and well-tolerated obesity treatments in the future.