medwireNews: People with type 2 diabetes taking a weekly semaglutide dose of 2.0 mg experience significantly greater reductions in glycated hemoglobin (HbA1c) and bodyweight than those taking the standard 1.0 mg dose, show phase 3 trial results.
Moreover, the two doses of the glucagon-like peptide (GLP)-1 receptor agonist had “a similar safety profile,” reported Juan Frias (National Research Institute, Los Angeles, California, USA) at the virtual ADA 81st Scientific Sessions.
Frias explained that around 20–30% of people taking the currently approved 0.5 mg and 1.0 mg weekly doses of semaglutide in the previous SUSTAIN trials did not achieve HbA1c levels below 7% (53 mmol/mol), and the SUSTAIN FORTE investigators hypothesized that treatment with the higher 2.0 mg/week dose would result in “more patients achieving treatment targets.”
To test this theory, 961 adults with type 2 diabetes and average baseline HbA1c levels of 8.9% (74 mmol/mol) were randomly assigned to receive once-weekly subcutaneous semaglutide at a maintenance dose of 1.0 mg or 2.0 mg for 28 weeks, following a 12-week dose-escalation period in which all participants started on a dose of 0.25 mg/week, doubling every 4 weeks until the maintenance dose was reached. All participants were receiving a stable dose of metformin, while approximately 53% were also on sulfonylureas.
Juan Pablo Frías discusses whether the findings of SUSTAIN-FORTE will justify an increase in the approved maximum dose of semaglutide for people with type 2 diabetes (3:31).
In the trial product estimand analysis – reflecting the effect of taking the drug as intended – average HbA1c levels decreased by 2.2 percentage points from baseline to week 40 in the semaglutide 2.0 mg arm, and by 1.9 percentage points in the 1.0 mg arm, a significant difference. Participants treated with the 2.0 mg versus the 1.0 mg dose were also significantly more likely to achieve HbA1c levels below 7.0% at week 40, with rates of 67.6% versus 57.5%.
Similarly, in the treatment policy estimand analysis, reflecting the effect of having the drug prescribed, the average HbA1c reduction was significantly greater with the 2.0 mg than the 1.0 mg dose, at mean reductions of 2.1 and 1.9 percentage points, respectively.
Frias said that there was a “very similar pattern” of results for the confirmatory secondary endpoint of weight loss. In the trial product estimand analysis, participants in the 2.0 mg group experienced a significantly greater decrease in bodyweight than those in the 1.0 mg group, at 6.9 versus 6.0 kg, from a baseline average of 99.3 kg. The corresponding decreases in the treatment policy estimand analysis were 6.4 kg and 5.6 kg.
In all, 56.8% and 52.3% of participants in the 2.0 and 1.0 mg groups, respectively, experienced adverse events (AEs), while a corresponding 4.4% and 5.2% experienced serious AEs. Rates of gastrointestinal AEs were higher in the 2.0 mg arm (34.0 vs 30.8%), which “in large part was driven by increased incidence of reduced appetite” with the higher dose, said Frias.
Reduced appetite was reported in 6.1% of participants given the 2.0 mg dose compared with 3.8% of those in the 1.0 mg arm; the corresponding rates of nausea, diarrhea, and vomiting were 14.4% versus 14.6%, 9.4% versus 8.8%, and 7.7% versus 6.7%.
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