Doubling the Dose of Semaglutide for Weight Loss Approved

The new approval of Wegovy for weight loss is for a current medication, semaglutide, but more than doubling the standard dose for diabetes treatment.

The US Food and Drug Administration (FDA) recently approved Wegovy™, a 2.4 mg/week subcutaneous dose of the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide (Novo Nordisk) for weight loss. Specifically, this drug format and dosage are approved as an adjunct to a reduced-calorie diet and increased physical activity to treat adults who have obesity (body mass index [BMI] ≥ 30 kg/m2) or are overweight (BMI ≥ 27 kg/m2) with at least one weight-related comorbidity. The approval comes after the results of four 68-week trials of subcutaneous semaglutide 2.4 mg/week versus placebo, which looked at the effects of the 2.4mg dose in patients with overweight or obesity, with and without type 2 diabetes.  

STEP-2 examined the effect of the doubled semaglutide dose on patients who had type 2 diabetes as well as overweight/obesity. GLP-1 receptor agonists (GLP-1 RA) have previously shown efficacy in lowering HbA1c and decreasing body weight in this population. GLP-1 RA medications, which are injectable, are recommended as second-line treatment after metformin. From this class of medications, Victoza (liraglutide) treats patients with type 2 diabetes and overweight/obesity. These findings have brought scientists and new researchers to study other GLP-1 RA medications to see their effect on body weight or cardiovascular risk reduction. 

In this double-blind, randomized clinical trial, researchers evaluated the efficacy and safety of once-weekly subcutaneous semaglutide using 2.4mg, 1.0mg, and placebo for bodyweight management in adults with overweight, obesity, plus a diagnosis of type 2 diabetes. During this trial, 149 outpatient facilities participated in 12 countries around Europe, America, Middle East, South Africa, and Asia. Those who were 18 years or older, who reported at least one unsuccessful dietary effort to lose weight, with a Body Mass Index of at least 27 kg/m2, HbA1c of 7-10%, and who had been diagnosed with type 2 diabetes at least 180 days before the screening, were eligible to participate in the study. Those who participated were under diet and exercise or were treated with a stable dose of up to three oral antidiabetic drugs for at least three months before screening. The oral glucose-lowering agents used before screening were metformin, sulfonylureas, SGLT-2 inhibitors, or thiazolidinediones. 

The randomization was 1:1:1. Two injections once weekly were administered during the intervention process, either active drug plus placebo or placebo plus placebo. During the intervention process, patients received semaglutide 2.4mg, semaglutide 1.0mg, or placebo for 68 weeks in addition to lifestyle interventions, followed by seven weeks without treatment. For the groups where semaglutide was used, the starting dose was 0.25mg and titrated every four weeks until the target. Lifestyle modifications included diet (500 Kcal/day reduction) and physical activity (150 min/week), and they offered appropriate counseling every four weeks. Doses were decreased ~50% to avoid hypoglycemic episodes for those patients using sulfonylureas before the screening. For those patients with persistent hyperglycemia (FPG>15mmol/L), insulin was permitted. They assessed height, body weight, waist circumference, vitals, and HbA1c at baseline and during each follow-up, but they evaluated physical examination at baseline and week 68. 

As the primary endpoints, scientists looked at the change in body weight from baseline to week 68 and loss of at least 5% of baseline weight at week 68. For secondary endpoints, they looked at the proportion of patients achieving bodyweight reductions of at least 10% or 15% at week 68, changes from baseline to week 68 in waist circumference, the percentage change in body weight at week 68, and changes in HbA1c from baseline to week 68. These confirmatory secondary endpoints were measured only for semaglutide 2.4mg compared to placebo. The exploratory secondary endpoints included semaglutide 2.4mg versus 1.0mg and semaglutide 2.4mg versus placebo. During the study, 1200 participants provided a power of 94%, and the efficacy was assessed using intention-to-treat analysis. They measured the number of severe or blood-glucose confirmed symptomatic hypoglycemia episodes and side effects for safety parameters. 

During the study, 1,595 participants were screened between June 4 and November 14 of 2018, from which 1,210 were enrolled. Of these participants, 87% completed the treatment, and 96% completed the trial. The mean BMI was 35.7 kg/m2, the mean waist circumference was 114.6 cm, the mean duration of diabetes was eight years, and the mean body weight was 99.8 kg. During the treatment period, a mean weight change at week 68 was -9.6% with the semaglutide 2.4mg group versus -3.4% with placebo for a difference of -6.2 percentage points (95% CI: -7.3 to -5.2: p<0.0001). The difference reported for semaglutide 2.4mg versus 1.0mg was -2.7 percentage points (95% CI: -3.7 to -1.6; p<0.0001). During the trial period, the mean difference in weight for the participants under semaglutide 2.4mg was -10.6% versus -3.1% for placebo for a difference of -7.6 percentage points (95% CI: -8.6 to -6.6). The difference between the two doses of semaglutide was -3.1 percentage points (95% CI: -4.1 to -2.1). From the 388 participants under semaglutide 2.4mg, 68.8% had 5% reduction in baseline body weight at week 68 compared to 28.5% of 276 participants in the placebo group (OR:4.88; 95% CI: 3.58 to 6.64; p<0.0001). For semaglutide 1.0mg, 57.1% of 380 participants reported a bodyweight reduction of 5% (OR: 1.62; 95% CI: 1.21 to 2.18; p=0.0012). Improvement favored semaglutide 2.4mg in waist circumference, systolic blood pressure, lipid profile, and inflammatory markers. There was no actual difference in HbA1c between semaglutide 2.4mg and 1.0mg, but a significant difference of -1.2 percentage points was observed between semaglutide 2.4mg and placebo. Also, improvements in fasting plasma glucose were greater in both semaglutide groups compared to placebo. Patients under both semaglutide groups showed fewer antidiabetic medications than placebo (28.6%, 25.1%, and 7.1%). For safety measures, the most reported side effects were gastrointestinal disorders like nausea, vomiting, diarrhea, and constipation. An average of 5.6% of hypoglycemic events were reported in patients under semaglutide and 3.0% with placebo. 

This study showed relevant information for clinicians to apply in practice. The study included a large sample size, a randomized, double-blind trial, and a high treatment and trial completion rate. Some limitations presented in the study include the exclusion of patients using insulin. The safety profile reported is similar to other medications under GLP-1 RA Class. On the other hand, weight reduction in patients with type 2 diabetes is vital to reducing cardiovascular outcomes. Treatments to reduce cardiovascular events in patients with type 2 diabetes are needed. This class of medications has been shown in different studies to decrease these risks and support weight reduction. More studies should be made with patients with type 2 diabetes and a high risk of cardiovascular outcomes to evaluate the efficacy of semaglutide in this population. 

Practice Pearls: 

• Semaglutide 2.4mg as an adjunct to lifestyle modification showed a more significant bodyweight reduction from baseline of -9.6% in patients with overweight or obesity and who had type 2 diabetes. 
• Semaglutide 1.0mg is also indicated to reduce cardiovascular events in adult patients with type 2 diabetes. 
• Safety results of semaglutide 2.4mg were typical of the GLP-1 RA class. 

Davies, M., et al. Semaglutide 2.4mg Once a Week in Adults with Overweight or Obesity, and Type 2 Diabetes (STEP-2): A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Phase 3 Trial. Lancet (2021): 397:971-84.  

Laura Martínez López, PharmD. Candidate 2021, Lake Erie College of Osteopathic Medicine, College of Pharmacy