The quest for a safe and effective weight loss treatment has been a long-standing endeavor. The Food and Drug Administration (FDA) has approved semaglutide, an injectable drug initially used for diabetes, for chronic weight management in overweight or obese adults. This marks the first such approval since Saxenda in 2014. Obesity is a heterogenous, chronic, and complex condition that requires lifelong treatment.
What is Semaglutide?
Semaglutide belongs to the class of medications known as glucagon-like peptide-1 receptor agonists (GLP-1 RAs). It functions by mimicking the GLP-1 hormone, which is released in the gut in response to eating. GLP-1 prompts the body to produce more insulin, thus reducing blood sugar levels. For over 15 years, healthcare providers have used semaglutide to treat type 2 diabetes. In higher amounts, GLP-1 interacts with the brain to suppress appetite and create a feeling of fullness.
Semaglutide Injections for Weight Loss
Semaglutide is approved for weight loss under the brand name Wegovy. The typical dosage for weight loss is 2.4 milligrams, administered weekly via subcutaneous self-injections. Due to growing interest, healthcare professionals prescribe other semaglutide brands, like Ozempic and Rybelsus, off-label for weight management.
Efficacy of Semaglutide for Weight Loss in Non-Diabetics
Semaglutide is highly effective for weight loss, performing on a new level compared to other anti-obesity medications.
An early study involving 2,000 obese adults compared those using semaglutide with diet and exercise to those who only made lifestyle changes. After 68 weeks, half of the semaglutide users lost 15% of their body weight, and nearly a third lost 20%. In contrast, those who only changed their lifestyle lost approximately 2.4% of their weight. Additional studies have shown similar results, but participants tended to regain the weight after stopping semaglutide.
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A study of 17,604 adults with preexisting cardiovascular disease, overweight or obesity, without diabetes, showed a 20% reduction in major adverse cardiovascular events. Weight loss continued over 65 weeks and was sustained for up to 4 years. At 208 weeks, semaglutide was associated with 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).
Semaglutide and Lifestyle Changes
Changes to diet and exercise are still fundamental to obesity management. Anti-obesity medications are another tool, depending on the person’s clinical history. Lifestyle interventions were consistent with STEP 1, including 150 minutes per week of moderate-intensity exercise spread over 3 to 5 sessions per week; and 30 individual visits with a registered dietitian.
Side Effects of Semaglutide Injections
The side effects of semaglutide are generally mild, especially when compared to the complications of being overweight or obese. Common side effects include dizziness, fatigue, gastrointestinal issues (diarrhea, constipation, gassiness), headache, and stomach issues (nausea, vomiting, pain, or bloat). Gastrointestinal issues are most common when starting semaglutide. These side effects can be reduced by starting with a lower dose and gradually increasing it.
Who Should (and Should Not) Take Semaglutide?
The FDA recommends Wegovy for weight loss for individuals who:
- Have a body mass index (BMI) of 27kg/m2 or greater with at least one weight-related condition, such as high blood pressure, type 2 diabetes, or high cholesterol.
- Have a BMI of 30kg/m2 or greater.
Semaglutide should be avoided by individuals with:
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- A history of medullary thyroid cancer
- A history of gallbladder disease
- A history of pancreatitis
- Multiple endocrine neoplasia syndrome type 2 (MEN2)
Consulting a primary care physician (PCP) is the first step when considering semaglutide for weight loss.
Semaglutide Efficacy Without Diet: A Detailed Analysis of Clinical Trials
To assess the long-term efficacy of semaglutide for weight loss among individuals without type 2 diabetes, researchers from McGill University in Canada conducted a comprehensive analysis of relevant trials up to June 2023. Their investigation focused on data derived from the Semaglutide Treatment Effect in People with Obesity (STEP) study.
Study Selection and Population
The analysis included a total of four randomized controlled trials from the STEP study. The pooled study population consisted of 3087 individuals, with 1991 randomly assigned to receive once-weekly semaglutide and 1096 assigned to a placebo.
Key Findings
The results of the analysis revealed significant differences in weight loss outcomes between the semaglutide and placebo groups. A greater proportion of semaglutide recipients achieved substantial weight loss compared to those receiving the placebo. Specifically, 85.8% of semaglutide recipients experienced weight loss of 5% or more, while 33.4% achieved weight loss of 20% or more. In contrast, only 34.7% and 2.2% of placebo recipients achieved 5% or more and 20% or more weight loss, respectively.
Adverse Events
The analysis also assessed the risk of adverse events associated with semaglutide treatment. The findings indicated that the risk for adverse events was not significantly higher among semaglutide recipients compared to the placebo group (RR, 1.02; 95% CI, 0.97-1.08). However, semaglutide recipients were more likely to report gastrointestinal disorders (RR, 1.47; 95% CI, 1.28-1.68), such as nausea, vomiting, constipation, and diarrhea.
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SELECT Trial: Weight Loss Efficacy Over 4 Years
Data from the SELECT trial provided an opportunity to evaluate the weight loss efficacy of semaglutide compared with placebo over 208 weeks. The trial population was geographically and racially diverse and received standard-of-care recommendations for secondary CVD prevention.
Study Population
The SELECT study enrolled 17,604 patients from 41 countries between October 2018 and March 2021. The mean age of participants was 61.6 years, with a mean BMI of 33.3 kg m−2.
Weight and Anthropometric Outcomes
The average percentage weight-loss trajectories with semaglutide and placebo over 4 years showed that weight loss continued to week 65 in the semaglutide group and was sustained through week 208 (−10.2% for the semaglutide group, −1.5% for the placebo group; treatment difference −8.7%; 95% CI −9.42 to −7.88; P < 0.0001).
At week 208, mean weight loss in the semaglutide group analyzed as first on-treatment was −11.7% compared with −1.5% for the placebo group (treatment difference −10.2%; 95% CI −11.0 to −9.42; P < 0.0001).
Categorical Weight Loss
At week 104, 67.8%, 44.2%, 22.9%, 11.0% and 4.9% of those treated with semaglutide achieved weight loss of ≥5%, ≥10%, ≥15%, ≥20% and ≥25%, respectively, compared with 21.3%, 6.9%, 1.7%, 0.6% and 0.1% of those receiving placebo.
Change in Waist Circumference (WC)
At week 208, average reduction in WC was −7.7 cm with semaglutide versus −1.3 cm with placebo, with a treatment difference of −6.4 cm (95% CI −7.18 to −5.61; P < 0.0001).
Waist-to-Height Ratio
At week 208, the group randomized to semaglutide had a relative reduction of 6.9% in WHtR compared with 1.0% in placebo (treatment difference −5.87% points; 95% CI −6.56 to −5.17; P < 0.0001).
BMI Category Change
At week 104, 52.4% of patients treated with semaglutide achieved improvement in BMI category compared with 15.7% of those receiving placebo. In the semaglutide group, 12.0% of patients achieved a BMI <25 kg m−2, compared with 1.2% for placebo. The proportion of patients with obesity (BMI ≥30 kg m−2) fell from 71.0% to 43.3% in the semaglutide group versus 71.9% to 67.9% in the placebo group.
Weight and Anthropometric Outcomes by Subgroups
Women had a greater difference in mean weight loss with semaglutide versus placebo (−11.1% versus −7.5% in men; P < 0.0001). There was a linear relationship between age category and degree of mean weight loss, with younger age being associated with progressively greater mean weight loss.
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, glycemic status, or renal function.
Potential to Improve Adherence
Once-weekly therapy has the potential to improve adherence over daily therapy.
Considerations for Use
The gastrointestinal side effects of semaglutide 2.4 mg may limit its usability in some patients.
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