麻豆传媒

Doubling the dose of semaglutide (Ozempic) might be a helpful option for people not achieving glycemic goals, according to the SUSTAIN FORTE study.

In the double-blind phase IIIb trial, adults on 2.0 mg of once-weekly injectable semaglutide had a 2.1% mean drop in baseline HbA1c over 40 weeks of treatment versus a 1.9% reduction in those on 1.0 mg of semaglutide (estimated treatment difference [ETD] -0.18%, 95% CI -0.31 to -0.04, P=0.0098 for treatment policy estimand), reported Juan Pablo Frías, MD, of the National Research Institute in Los Angeles, and colleagues.

The doubled dose of weekly semaglutide was also associated with greater weight loss, with an average 6.4 kg reduction over 40 weeks compared with 5.6 kg for those on the 1 mg weekly dose (ETD -0.77 kg, 95% CI -1.55 to 0.01, P=0.054 for treatment policy estimand), the group wrote in the study online in .

Although gastrointestinal adverse events were a bit more common with the bumped-up dose (34% vs 31% for 1.0 mg) -- common with the GLP-1 receptor agonist class -- there wasn't a significant difference in the rate of serious adverse events between the doses (4% vs 5% for 1.0 mg).

During the trial, three deaths occurred: two in the 2.0 mg semaglutide group and one in the 1.0 group. Both deaths in the 2.0 mg group were deemed unrelated to the study drug, but the death in the 1.0 mg group was considered "possibly related to the study product by the investigator and unlikely to be related to the study product by the sponsor," the researchers said.

"Semaglutide 2.0 mg offers a valuable treatment option for individuals with type 2 diabetes, in addition to already available 0.5 mg and 1.0 mg doses, and could be beneficial for those in need of treatment intensification while remaining on the existing therapy," the investigators wrote.

Semaglutide first gained FDA approval in 0.5 mg and 1.0 mg injectable dosing sold under the trade name Ozempic in December 2017 based on the results of the Semaglutide Unabated Sustainability In Treatment of Type 2 Diabetes (SUSTAIN) clinical trial program. This approval was for an indication of type 2 diabetes and risk reduction of major cardiovascular events including heart attack, stroke, and death in adults with type 2 diabetes with known heart disease.

Then in September 2019, an oral form of semaglutide was approved in 7 and 14 mg tablets, sold under the trade name Rybelsus, likewise indicated for type 2 diabetes.

Most recently this past June, a 2.4 mg injectable dose, sold under the name Wegovy, was approved for chronic weight management in adults with obesity -- body mass index (BMI) of 30 or greater -- or for adults with overweight (BMI of 27 or greater) with at least one weight-related condition, such as high blood pressure, type 2 diabetes, or high cholesterol, used in conjunction with a reduced calorie diet and an exercise regimen.

However, the author of a accompanying the study by Frías and colleagues, André Scheen, MD, PhD, of Liège University in Belgium, wasn't exactly convinced by this strategy.

"The add-on value of semaglutide 2.0 mg versus 1.0 mg once-weekly appears rather poor, when considering the incremental reductions in HbA1c and bodyweight," he wrote. "The changes were statistically significant but barely clinically relevant."

Instead of doubling the dose of the GLP-1 receptor agonist, Sheen suggested opting for another agent when faced with a patient struggling to control HbA1c.

"For instance a combination with a SGLT2 inhibitor, a dual therapy that also improves glucose control, reduces bodyweight, lowers blood pressure, and has the potential to improve both cardiovascular and renal outcomes," he recommended. "To this end, a pharmacoeconomical comparison using hard clinical outcomes between a higher dose of GLP-1 receptor agonist and such a dual therapy would be of major interest."

The 10-country SUSTAIN FORTE trial was conducted across 125 outpatient clinics and included adults with poorly controlled type 2 diabetes -- defined as an Hba1c of 8% to 10% -- treated with metformin. About half the 961 participants also received a sulfonylurea. The average age of participants was 58, mean baseline HbA1c was 8.9%, and average BMI was about 35.

Patients were started on a 0.25 mg dose of semaglutide for 4 weeks, followed by 4 weeks on a 0.5 mg dose; thereafter, the dose was titrated up to 1.0 mg for another 4 weeks. Starting at week 13, participants received another pen injection, containing either an additional 1.0 mg of semaglutide or placebo.

One study limitation, Sheen noted, was a lack of data on other surrogate endpoints, including blood pressure and lipids.

Based on the results of the study, sponsor in May 2021 for a label expansion to include the 2.0 mg dose indicated for type 2 diabetes. This was subsequent to the company receiving a from the FDA in March 2021 asking for additional information, including data relating to a proposed new manufacturing site. A decision is expected within 10 months.

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