A Novo Nordisk-designed trial, conducted at 68 international hospitals, specialist clinics, and medical centers with investigators from University of Texas Southwestern Medical Center and other institutions, reports greater reductions with once-weekly semaglutide 7.2 mg than placebo in bodyweight, waist circumference, and HbA1c over 72 weeks.

Obesity contributes to the development and progression of type 2 diabetes, raising risks for dyslipidemia, hypertension, and cardiovascular disease. GLP-1 receptors were designed to reduce blood sugar (HbA1c) and body weight in adults with type 2 diabetes.

Regulators in the U.S. and EU currently authorize a 2.4 mg once-weekly semaglutide dose (such as Wegovy) for weight management in adults with obesity or overweight with at least one complication.

In the study, titled “Once-weekly semaglutide 7.2 mg in adults with obesity and type 2 diabetes (STEP UP T2D): a randomised, controlled, phase 3b trial,” published in The Lancet Diabetes & Endocrinology, Novo Nordisk researchers designed a randomized, double-blind, controlled, three-arm, parallel-group trial to investigate the efficacy and safety of a 7.2 mg maintenance dose of once-weekly subcutaneous semaglutide in adults with obesity and type 2 diabetes.

Enrollment reached 512 adults at 68 hospitals, specialist clinics, and medical centers across Bulgaria, Canada, Hungary, Poland, Portugal, Slovakia, South Africa, and the U.S. The baseline profile included a mean age of 56 years, mean bodyweight 110.1 kg, mean BMI 38.6 kg/m², mean HbA1c 8.1%, and 51.8% female.

Randomization assigned participants 3:1:1 to a once-weekly dose of semaglutide at 7.2 mg or 2.4 mg, or to a placebo in a double-blind, three-arm, parallel-group design. Treatment ran 72 weeks with counseling targeting an approximately 500 kcal-per-day deficit and at least 150 minutes per week of physical activity. Dosing started at 0.25 mg weekly and escalated every four weeks to 2.4 mg by week 16, with the 7.2 mg arm advancing to the active dose at week 20.

Co-primary endpoints were percentage change in bodyweight and achievement of at least 5% bodyweight reduction versus placebo. Confirmatory secondary endpoints included 10%, 15%, and 20% weight-loss thresholds, waist circumference, and HbA1c.

Semaglutide reduced mean body weight by 13.2% with doses of 7.2 mg versus 10.4% with doses of 2.4 mg and 3.9% with placebo over 72 weeks. While the 7.2 mg group met the primary endpoints of a 5% change versus placebo, so did the already-approved 2.4 mg dosage under the exploratory conditions.

Waist circumference declined by a mean of 12.3 cm with 7.2 mg dosing versus 5.8 cm with placebo, and 10.7 cm with 2.4 mg dosing. The HbA1c decrease in the 7.2 versus 2.4 mg group was not statistically significant, and both were lower than placebo.

Gastrointestinal events occurred in 53.1% with 7.2 mg doses, 51.5% with 2.4 mg doses, and 25.5% with placebo, with serious adverse events in 9.1%, 8.7%, and 8.8%. Dysesthesia, an unpleasant or painful sensation, was more frequent with 7.2 mg doses at 18.9% versus 4.9% with 2.4 mg doses and 0% with placebo. Adverse events leading to dose reduction were higher in the 7.2 mg group (20.2%) versus the 2.4 mg group (13.6%) and placebo (2.0%). There was one death possibly related to the study drug at the 7.2 mg dose.

Exploratory analyses suggested greater mean bodyweight reduction in the 7.2 mg group versus the 2.4 mg group, an estimated treatment difference of −2.8% with a 95% CI −4.7 to −0.9. The study design does not include how much of the weight loss was from fat versus lean mass (muscle, organ and bone tissue.)

Authors conclude that semaglutide in a dose of 7.2 mg was superior to placebo for reducing bodyweight, waist circumference, and HbA1c in adults with obesity and type 2 diabetes. Safety and tolerability, within the limited scope of the trial, were similar to those of 2.4 mg group apart from a higher frequency of dysesthesia, higher necessity of dose reductions, and possibly death. Authors state that tripling the dose from 2.4 mg to 7.2 mg might provide additional clinical benefit in bodyweight reduction and suggest further exploration.

Obviously, any drug company-funded and designed study that suggests benefits from a tripling of the approved dosage of their product should be met with an equally increased dosage of skepticism.

An independent inquiry into the results could more rigorously compare the triple dose with the original dose and investigate safety and tolerability not comprehensively characterized in this study, specifically the ratio of weight lost from fat versus lean mass, as well as pancreatic events, liver-enzyme monitoring, arrhythmia surveillance, and retinopathy surveillance.

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