Doubling the Semaglutide Dose Improves Weight Loss

Lifestyle management and intervention alongside a once-weekly semaglutide dose of 2.4 mg (doubling the standard dose of 1.0) can lead to improved weight loss for patients with overweight or obesity.  

Obesity is a risk factor in many health conditions and can lead to hypertension, dyslipidemia, insulin resistance, type 2 diabetes (T2D), liver disease, and cardiovascular disease (CVD). It is a well-known health challenge globally. Experts have always recommended lifestyle changes like diet and exercise and adjunct pharmacologic approaches to help combat obesity. However, lifestyle interventions have not effectively sustained weight loss over a more extended period for most patients. Also, pharmacologic intervention is limited because of cost, safety concerns, and low efficacy. Semaglutide is a glucagon-like peptide-1 (GLP-1) analog approved for treating T2D in adults and reducing cardiovascular risk for a person with T2D. It was found to also induce weight loss in persons with T2D participating in a phase 3 trial. 

A recent study was conducted to evaluate the efficacy and safety of semaglutide at a dose of 2.4 mg weekly in people who have overweight or obesity, with or without weight-related complications. The study was a randomized, double-blind, placebo-controlled trial that spans over 16 countries in Asia, Europe, North America, and South America. Participants in the study include adults above 18 years who made unsuccessful dietary efforts to lose weight, with a BMI of 30 or greater, or a BMI of 27 or greater with conditions like hypertension, sleep apnea, dyslipidemia, or CVD. Patients with diabetes or glycated hemoglobin greater than or equal to 6.5%, history of pancreatitis, surgical treatment of obesity, and use of obesity medication, were excluded. A total of 1961 participants took part in the trial, with 94.3% completing the trial. The study’s primary endpoint was the percentage change in body weight from baseline at week 68, reducing the bodyweight of 5% or more from baseline to week 68. The secondary endpoint reduced body weight of 10% or more and 15% or more at week 68 and a change in waist circumference and systolic blood pressure. Statistical analysis accompanied by a two-sided 95% confidence interval and corresponding P values with significance defined as P<0.05. Two estimands, intention-to-treat analysis and the trial product estimand, were used to assess treatment efficacy. 

Study results showed that weight loss was observed within four weeks in the group treated with 2.4 mg semaglutide. This group’s estimated mean weight change was -14.9% compared with -2.4% in the placebo group. Change in body weight from baseline to week 68 was -15.3 kg in the semaglutide group compared with -2.6 kg in the placebo group (difference, -12.7 kg; 95% CI, -13.7 to -11.7). Other confirmatory secondary endpoints observed: semaglutide group showed more significant reductions from baseline than the placebo in waist circumference (-13.54 cm with semaglutide vs. -4.13 cm with placebo; difference, -9.42 cm; 95% CI, -10.30 to -8.53), BMI (-5.54 with semaglutide vs. -0.92 with placebo; difference, -4.61; 95% CI, -4.96 to -4.27), and systolic and diastolic blood pressure at 68th week. A comparable number of participants in both groups reported adverse events. Some of the adverse events reported include gastrointestinal disorders like nausea, diarrhea, vomiting, and constipation. This was observed more in the semaglutide group (74.2%) versus the placebo group (47.9%).   

This study showed that adults with obesity or overweight with one or more weight-related coexisting conditions and without diabetes had a mean weight reduction of 14.9% from baseline with semaglutide as an adjunct treatment to lifestyle management and intervention. This is far greater than the placebo group by 12.4%. This weight loss also resulted in significant improvements in cardiometabolic risk factors, including blood pressure, waist circumference, glycated hemoglobin levels, and lipid levels. Semaglutide also improved physical functioning and decrease from baseline c-reactive protein (a marker of inflammation). In the semaglutide group, up to 70% achieved a weight loss of at least 10%, while up to 50% achieved at least 15% weight loss. The study shows a substantial and clinically relevant mean weight reduction of 14.9%, with 86% of participants achieving weight loss of at least 5% at the minimum. 

Practice Pearls: 

• Patients with obesity or overweight achieved a sustained clinically relevant reduction in body weight with a once-weekly regimen of 2.4 mg of semaglutide (doubling the standard dose), in addition to lifestyle intervention. 
• Semaglutide has a more significant weight reduction in fat mass than lean body mass. 
• Semaglutide therapy leads to improvements in glycated hemoglobin levels. Patients with prediabetes on semaglutide had their glycated hemoglobin reverted to normoglycemia. 
• The FDA has not approved the dose of 2.4mg of semaglutide. 

Reference for “Doubling the Semaglutide Dose Improves Weight Loss”:
Wilding JPH, Batterham RL, Once-Weekly Semaglutide in Adults with Overweight or Obesity. New England Journal of Medicine. 2021; 

Emmanuel Obi, PharmD Candidate, Lake Erie College of Osteopathic Medicine (LECOM), School of Pharmacy, Bradenton, Florida