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Dose Optimizing of Semaglutide for Type 2

Oct 23, 2021
Editor: Steve Freed, R.PH., CDE

Author: Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy

Additional benefits are observed with dose escalation of semaglutide to 2.0 mg for patients with type 2 diabetes. 

Glucagon-like peptide 1 (GLP-1) receptor agonists are an important therapeutic drug class for managing type 2 diabetes. GLP-1 receptor agonists proved to provide benefits in glycemic control, weight loss, and cardiorenal protection. The approved doses of semaglutide range from 0.25 mg to 1 mg once weekly; dose titration is dependent on the patient’s tolerance. However, data from previous trials showed that around 20% to 30% of patients on semaglutide 1.0 failed to reach the treatment target of HbA1c levels (less than 7.0%).  


The study in this discussion, SUSTAIN FORTE, is a 40-week, multination, randomized, active-controlled, parallel-group, double-blinded, phase 3B trial that aimed to evaluate the efficacy and safety of once-weekly semaglutide 2.0 mg in adults with inadequately controlled type 2 diabetes. The study included 961 adult participants that met the inclusion criteria of being diagnosed with type 2 diabetes for at least 180 days, HbA1c of 8.0 – 10.0% despite being on a stable dose of metformin therapy with or without a sulfonylurea for at least 90 days. Some exclusion criteria include eGFR < 30 ml/min per 1.73 m2, receiving other antidiabetic medications besides metformin and sulfonylurea (except short-term insulin for acute illness), uncontrolled/unstable diabetic retinopathy or maculopathy, chronic or acute pancreatitis, New York Heart Association class IV heart failure.  

Participants were randomly assigned in a 1:1 manner to receive either semaglutide 2.0 mg or semaglutide 1.0 mg subcutaneously once weekly. In the first 12 weeks, all patients followed the same dose escalation protocol to achieve the weekly dose of 1.0 mg. From week 13, participants in the semaglutide 2.0 mg group received an additional 1.0 mg pen, while participants in the semaglutide 1.0 group received a masked placebo pen.  

The primary outcome of the trial was the change from baseline at week 40 in HbA1c. The secondary outcomes were the change from baseline at week 40 in body weight, fasting plasma glucose, BMI, and weight circumference. The safety outcomes included the number and severity of treatment-emergent adverse events. ANCOVA was used to evaluate the continuous endpoints of the primary and secondary outcomes using the entire analysis population. Two estimate strategies, trial product estimand and treatment policy estimand, were used to evaluate the efficacy outcomes. The two different estimand strategies were used to explain the treatment effect in clinical scenarios. The trial product estimand reflects a patient’s scenario that matched the characteristics listed in the trial with good adherence. In contrast, the treatment policy estimand reflects the treatment effect at a population level.  

The baseline characteristics of this study were as follow: mean age of 58 ± 10, percentage of women of 41%, percentage of the white race of 88%, mean HbA1c of 8.9 ± 0.6%, mean fasting plasma glucose of 10.8 ± 2.8 mmol/L, the mean body weight of 99.3 ± 23.5 kg, mean BMI if 34.6 ± 7.0 kg/m2, percentage of current metformin of 100%, and percentage of current sulfonylurea of 53%.  

After 40 weeks of therapy, the mean change from baseline in HbA1c level was -2.2% for semaglutide 2.0 mg and -1.9% for semaglutide 1.0 mg when assessed using the trial product estimand (estimate treatment different [ETD] of -0.23%, 95% CI -0.36 to -0.11, p = 0.0003). When assessed with the treatment policy estimand, the mean changes from baseline in HbA1c level was -2.1% and -1.9% for semaglutide 2.0 mg and 1.0 mg (ETD of -0.18, 95% -0.31 to -0.04, p = 0.0098), respectively. Also, a greater proportion of participants in the semaglutide 2.0 group reached the HbA1c goal of less than 7.0% (p = 0.0010) and 6.5% (p < 0.001). In secondary outcomes, the ETD in reducing bodyweight was -0.93 kg (-6.9 vs -6.0, 95% CI -1.69 to -0.18), in fasting plasma glucose was -0.33 mmol/L (95% -0.61 to -0.04), in BMI was -0.30 kg/m2 (95% CI -0.57 to -0.04), and in waist circumference was -0.54 (95% CI -1.34 to 0.26). 

The most common adverse events were gastrointestinal symptoms of nausea, diarrhea, and vomiting. In addition, 57% and 52% of participants in the semaglutide 2.0 mg group and 1.0 mg group, respectively, experienced mild-to-moderate symptoms. The premature treatment discontinuation was low in both groups (4% and 5% in semaglutide 2.0 mg and 1.0 mg, respectively).  

The authors concluded that semaglutide 2.0 mg was superior to 1.0 in reducing HbA1c and in reducing body weight. Additionally, the high treatment completion rates upheld the vigor of the investigations due to the low discontinuation rate secondarily to adverse events. Due to more meaningful benefits in glycemic control and weight management, semaglutide 2.0 mg once weekly should be considered for approval for escalation of therapy for patients currently receiving semaglutide 1.0 mg.  

Practice Pearls: 

  • Semaglutide 2.0 mg weekly is superior to semaglutide 1.0 mg weekly in reducing HbA1c, with more significant proportions of participants reaching HbA1c targets of less than 7.0% and 6.5% or lower. 
  • Semaglutide 2.0 mg weekly also provides more weight loss with a similar safety profile. 
  • Patients who need treatment intensification while continuing their existing therapy will benefit from semaglutide 2.0 mg once weekly. 


Frías, Juan P et al. “Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomized, phase 3B trial.” The lancet. Diabetes & endocrinology vol. 9,9 (2021): 563-574.  

Capehorn, Matthew et al. “Once-Weekly Semaglutide Reduces HbA1c and Body Weight in Patients with Type 2 Diabetes Regardless of Background Common OAD: a Subgroup Analysis from SUSTAIN 2-4 and 10.” Diabetes therapy: research, treatment and education of diabetes and related disorders vol. 11,5 (2020): 1061-1075.  

Lingvay, Ildiko et al. “A 26-Week Randomized Controlled Trial of Semaglutide Once Daily Versus Liraglutide and Placebo in Patients With Type 2 Diabetes Suboptimally Controlled on Diet and Exercise With or Without Metformin.” Diabetes care vol. 41,9 (2018): 1926-1937.  


Ding Nguyen, PharmD Candidate, University of South Florida Taneja College of Pharmacy